Bio

Bio


Clinical Focus: Cardiovascular Medicine: Atrial Fibrillation; Chronic CAD; ACS;

Research Focus:

My primary research interest is the design and conduct of multicenter clinical trials and analyses of important clinical cardiac issues using large patient databases. My research focuses on novel anticoagulation agents for the treatment of acute coronary syndromes and atrial fibrillation, the study of agents targeted to protect the myocardium during reperfusion therapy for acute myocardial infarction, and the evaluation of cardiovascular safety of diabetic therapies. I am also interested in the methodology of clinical trials. Current research activities include standardization of the definition of myocardial infarction used in clinical trials, the adjudication of suspected clinical endpoint events by Clinical Event Committees (CEC), and the efficient operational conduct of large multinational clinical trials.

Administrative Focus: Vice Chair of Clinical Research in the Department of Medicine and Member of the Stanford IRB

Professional Training:

1985 Stanford University, BS Chemistry
1989 University of Washington, MD
1993 University of Arizona, Internship/Residency/Chief Residency
1996 Duke University, Fellowship in Cardiology
1996 Duke University, Faculty in Cardiology
2013 Stanford University, Vice Chair of Clinical Research, Department of Medicine

Clinical Focus


  • Cardiovascular Disease

Academic Appointments


Administrative Appointments


  • Vice Chair of Clinical Research, Department of Medicine (2013 - Present)
  • Member, Stanford Diabetes Research Center (2017 - Present)

Boards, Advisory Committees, Professional Organizations


  • Editorial Board Member, Current Cardiology Reviews (2004 - Present)
  • Associate Editor, American Heart Journal (2005 - Present)
  • Editorial Board Member, Current Cardiology Reports (2012 - Present)
  • Editorial Board Member, Cardiology & Therapy Journal (2012 - Present)

Professional Education


  • Fellowship: Duke University (1996) NC
  • Residency: University of Arizona Internal Medicine Residency (1993) AZ
  • Medical Education: University of Washington Medical Center (1989) WA
  • Board Certification: American Board of Internal Medicine, Cardiovascular Disease (1997)

Research & Scholarship

Clinical Trials


  • Project Baseline Health Study Recruiting

    This study is the first initiative of Project Baseline, a broader effort designed to develop a well-defined reference, or "baseline," of good health as well as a rich data platform that may be used to better understand the transition from health to disease and identify additional risk factors for disease. Project Baseline endeavors to test and develop new tools and technologies to collect, organize, and activate health information.

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  • Vorapaxar Study for Maturation of AV Fistulae for Hemodialysis Access Recruiting

    The Objectives of this study are: 1. To determine if vorapaxar safely improves arteriovenous (AV) fistula functional maturation when administered during the maturation process compared with placebo. 2. To determine if vorapaxar safely improves AV fistula patency, allowing for secondary procedures to aid in fistula maturation compared with placebo. 3. To determine if vorapaxar safely facilitates successful cannulation of AV fistulas for hemodialysis compared with placebo. This is a randomized placebo-controlled double-blind pilot trial. Study procedures will be conducted at Stanford University Medical Center, and standard-of-care (SOC) procedures will be conducted at Stanford and it's affiliated hospitals (Veteran's Affairs Palo Alto Health Care System and the Stanford Vascular Surgery Clinic at Valley Medical Center). The investigators expect to enroll 128 patients. Patients will be assigned to treatment groups with a 1:1 randomization in blocks of 4 at the conclusion of the AV fistula creation. Patients will be stratified based on fistula location (lower arm versus upper arm).

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Projects


Teaching

Stanford Advisees


Publications

All Publications


  • Effects of Canagliflozin on Cardiovascular, Renal, and Safety Outcomes in Participants With Type 2 Diabetes and Chronic Kidney Disease According to History of Heart Failure: Results From the CREDENCE Trial. American heart journal Sarraju, A., Li, J., Cannon, C. P., Chang, T. I., Agarwal, R., Bakris, G., Charytan, D. M., de Zeeuw, D., Greene, T., Heerspink, H. J., Levin, A., Neal, B., Pollock, C., Wheeler, D. C., Yavin, Y., Zhang, H., Zinman, B., Perkovic, V., Jardine, M., Mahaffey, K. W. 2020

    Abstract

    We aimed to assess the efficacy and safety of canagliflozin in patients with type 2 diabetes and nephropathy according to prior history of heart failure in the Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation (CREDENCE) trial. We found that participants with a prior history of heart failure at baseline (15%) were more likely to be older, female, white, have a history of atherosclerotic cardiovascular disease, and use diuretics and beta blockers (all P<0.001), and that, compared with placebo, canagliflozin safely reduced renal and cardiovascular events with consistent effects in patients with and without a prior history of heart failure (all efficacy P interaction >0.150). These results support the efficacy and safety of canagliflozin in patients with type 2 diabetes and nephropathy regardless of prior history of heart failure.

    View details for DOI 10.1016/j.ahj.2020.12.008

    View details for PubMedID 33358942

  • Insights from CREDENCE trial indicate an acute drop in estimated glomerular filtration rate during treatment with canagliflozin with implications for clinical practice. Kidney international Oshima, M., Jardine, M. J., Agarwal, R., Bakris, G., Cannon, C. P., Charytan, D. M., de Zeeuw, D., Edwards, R., Greene, T., Levin, A., Lim, S. K., Mahaffey, K. W., Neal, B., Pollock, C., Rosenthal, N., Wheeler, D. C., Zhang, H., Zinman, B., Perkovic, V., Heerspink, H. J. 2020

    Abstract

    Canagliflozin slows the progression of chronic kidney disease in patients with type 2 diabetes and induces a reversible acute drop in estimated glomerular filtration rate (eGFR), believed to be a hemodynamic effect. Predictors of the initial drop and its association with long-term eGFR trajectories and safety outcomes are unknown. To assess this, we performed a post-hoc analysis of 4289 participants in the CREDENCE trial with type 2 diabetes and chronic kidney disease equally split into treatment and placebo groups who had eGFR measured at both baseline and week three. The eGFR was categorized at week three as greater than a 10% decline; between 0 and 10% decline; and no decline. Long-term eGFR trajectories and safety outcomes were estimated in each category of acute eGFR change by linear mixed effects models and Cox regression after adjustment for baseline characteristics and medications use. Significantly more participants in the canagliflozin (45%) compared to the placebo (21%) group experienced an acute drop in eGFR over 10%. An over 30% drop occurred infrequently (4% of participants with canagliflozin and 2% with placebo). The odds ratio for a drop in eGFR over 10% with canagliflozin compared to placebo was significant at 3.03 (95% confidence interval 2.65, 3.47). Following the initial drop in eGFR, multivariable adjusted long-term eGFR trajectories, as well as overall and kidney safety profiles, in those treated with canagliflozin were similar across eGFR decline categories. Thus, although acute drops in eGFR over 10% occurred in nearly half of all participants following initiation of canagliflozin, the clinical benefit of canagliflozin was observed regardless. Additionally, safety outcomes were similar among subgroups of acute eGFR drop.

    View details for DOI 10.1016/j.kint.2020.10.042

    View details for PubMedID 33316282

  • Cause of Death Among Patients With Peripheral Artery Disease: Insights From the EUCLID Trial. Circulation. Cardiovascular quality and outcomes Kochar, A., Mulder, H., Rockhold, F. W., Baumgartner, I., Berger, J. S., Blomster, J. I., Fowkes, F. G., Katona, B. G., Lopes, R. D., Al-Khalidi, H. R., Mahaffey, K. W., Norgren, L., Hiatt, W. R., Patel, M. R., Jones, W. S. 2020: CIRCOUTCOMES120006550

    Abstract

    BACKGROUND: Peripheral artery disease is common and associated with high mortality. There are limited data detailing causes of death among patients with peripheral artery disease.METHODS: EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) was a randomized clinical trial that assigned patients with peripheral artery disease to clopidogrel or ticagrelor. We describe the causes of death in EUCLID using mortality end points adjudicated through a clinical events classification process. The association between baseline factors and cardiovascular death was evaluated by Cox proportional hazards modeling. The competing risk of noncardiovascular death was assessed by the cumulative incidence function for cardiovascular death and the Fine and Gray method to ascertain the association between baseline characteristics and cardiovascular mortality.RESULTS: A total of 1263 out of 13 885 (9.1%) patients died (median follow-up: 30 months). There were 706 patients (55.9%) with a cardiovascular cause of death and 522 (41.3%) with a noncardiovascular cause of death. The most common cause of cardiovascular death was sudden cardiac death (20.1%); while myocardial infarction (5.2%) and ischemic stroke (3.2%) were uncommon. The most common causes of noncardiovascular death were malignancies (17.9%) and infections (11.9%). The factor most associated with a higher risk of cardiovascular death was age per 5 year increase (HR, 1.26 [95% CI, 1.20-1.32]). Female sex was associated with a lower risk of cardiovascular death (HR, 0.68 [95% CI, 0.56-0.82]). To evaluate the effect of noncardiovascular death as a competing risk, we superimposed the cumulative incidence function curve with the Kaplan-Meier curve. These curves closely approximated each other. After accounting for the competing risk of noncardiovascular death, the magnitude and direction of the factors associated with cardiovascular death were minimally changed.CONCLUSIONS: Among patients with symptomatic peripheral artery disease, noncardiovascular causes of death reflected a high proportion (40%) of deaths. Accounting for noncardiovascular deaths as a competing risk, there was not a significant change in the risk estimation for cardiovascular death.REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01732822.

    View details for DOI 10.1161/CIRCOUTCOMES.120.006550

    View details for PubMedID 33176462

  • Effects of canagliflozin on anaemia in patients with type 2 diabetes and chronic kidney disease: a post-hoc analysis from the CREDENCE trial. The lancet. Diabetes & endocrinology Oshima, M., Neuen, B. L., Jardine, M. J., Bakris, G., Edwards, R., Levin, A., Mahaffey, K. W., Neal, B., Pollock, C., Rosenthal, N., Wada, T., Wheeler, D. C., Perkovic, V., Heerspink, H. J. 2020; 8 (11): 903–14

    Abstract

    BACKGROUND: Sodium-glucose co-transporter 2 inhibitors might enhance erythropoiesis and increase red blood cell mass. We assessed the long-term effects of canagliflozin on anaemia-related outcomes.METHODS: In a post-hoc analysis of the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial, we included patients with type 2 diabetes and chronic kidney disease who were randomly assigned to treatment with canagliflozin or placebo at 690 sites in 34 countries. We assessed the effects of canagliflozin versus matched placebo on haemoglobin and haematocrit using linear mixed-effects models. The primary outcome of this post-hoc analysis was a composite outcome of investigator-reported anaemia or treatment for anaemia, which was assessed using Kaplan-Meier analysis and Cox regression models. All analyses were done by intention to treat.FINDINGS: Between March 24, 2014, and May 5, 2017, 4401 participants were randomly assigned to receive canagliflozin (100 mg; n=2202) or placebo (n=2199). At baseline, mean haemoglobin concentration was 132·0 g/L (SD 17·7), 1599 (36%) of 4401 participants had anaemia (defined as haemoglobin <130 g/L in men or <120 g/L in women), and 33 (<1%) of 4401 participants used erythropoiesis-stimulating agents. During a median follow-up period of 2·6 years (IQR 2·1-3·1), mean haemoglobin concentration was 7·1 g/L (95% CI 6·4-7·8) higher and haematocrit was 2·4% (2·2-2·6) higher in the canagliflozin group than the placebo group. Overall, 573 of 4401 participants had either an investigator-reported anaemia event or initiation of treatment for anaemia: 358 (8%) of 4401 participants reported anaemia events, 343 (8%) initiated iron preparations, 141 (3%) initiated erythropoiesis-stimulating agents, and 114 (2%) received blood transfusion. The risk of the composite outcome of anaemia events or initiation of treatment for anaemia was lower in the canagliflozin group than the placebo group (hazard ratio 0·65, 95% CI 0·55-0·77; p<0·0001). Compared with the placebo group, participants in the canagliflozin group also had lower risks of anaemia events alone (0·58, 0·47-0·72; p<0·0001), initiation of iron preparations (0·64, 0·52-0·80; p<0·0001), and need for erythropoiesis-stimulating agents (0·65, 0·46-0·91; p=0·012).INTERPRETATION: These data suggest that canagliflozin reduces the risk of anaemia-associated outcomes, including the need for erythropoiesis-stimulating agents, among patients with type 2 diabetes and chronic kidney disease.FUNDING: Janssen Research and Development.

    View details for DOI 10.1016/S2213-8587(20)30300-4

    View details for PubMedID 33065060

  • International consensus definitions of clinical trial outcomes for kidney failure: 2020. Kidney international Levin, A., Agarwal, R., Herrington, W. G., Heerspink, H. L., Mann, J. F., Shahinfar, S., Tuttle, K. R., Donner, J., Jha, V., Nangaku, M., de Zeeuw, D., Jardine, M. J., Mahaffey, K. W., Thompson, A. M., Beaucage, M., Chong, K., Roberts, G. V., Sunwold, D., Vorster, H., Warren, M., Damster, S., Malik, C., Perkovic, V., participant authors of the International Society of Nephrologys 1st International Consensus Meeting on Defining Kidney Failure in Clinical Trials, Anand, S., Argent, N., Babak, E., Banerjee, D., Barratt, J., Bello, A. K., Bernardo, A. A., Blais, J., Canovatchel, W., Caskey, F. J., Coresh, J., de Boer, I. H., Eckardt, K., Evans, R. D., Feldman, H. I., Fogo, A. B., Gudmundsdottir, H., Hamano, T., Harris, D. C., Hauske, S. J., Haynes, R., Herzog, C. A., Hiemstra, T., Idorn, T., Inker, L., Ishida, J. H., Johnson, D. W., Jones-Burton, C., Joseph, A., Koitka-Weber, A., Kretzler, M., Lawatscheck, R., Liew, A., Moist, L., Naicker, S., Nakashima, R., Patel, U., Filho, R. P., Rose, J. B., Rosenberg, N. L., Sinsakul, M., Smoyer, W. E., Sola, L., Sood, A. R., Stengel, B., Taal, M. W., Tanaka, M., Tonelli, M., Tong, A., Toto, R., Trask, M., Ulasi, I. I., Wanner, C., Wheeler, D. C., Wolthers, B. O., Wright, H. M., Yamada, Y., Zakharova, E. 2020; 98 (4): 849–59

    Abstract

    Kidney failure is an important outcome for patients, clinicians, researchers, healthcare systems, payers, and regulators. However, no harmonized international consensus definitions of kidney failure and key surrogates of progression to kidney failure exist specifically for clinical trials. The International Society of Nephrology convened an international multi-stakeholder meeting to develop consensus on this topic. A core group, experienced in design, conduct, and outcome adjudication of clinical trials, developed a database of 64 randomized trials and the 163 included definitions relevant to kidney failure. Using an iterative process, a set of proposed consensus definitions were developed and subsequently vetted by the larger multi-stakeholder group of 83 participants representing 18 different countries. The consensus of the meeting participants was that clinical trial kidney failure outcomes should be comprised of a composite that includes receipt of a kidney transplant, initiation of maintenance dialysis, and death from kidney failure; it may also include outcomes based solely on laboratory measurements of glomerular filtration rate: a sustained low glomerular filtration rate and a sustained percent decline in glomerular filtration rate. Discussion included important considerations, such as (i) recognition of existing nomenclature for kidney failure; (ii) applicability across resource settings; (iii) ease of understanding for all stakeholders; and (iv) avoidance of inappropriate complexity so that the definitions can be used across ranges of populations and trial methodologies. The final definitions reflect the consensus for use in clinical trials.

    View details for DOI 10.1016/j.kint.2020.07.013

    View details for PubMedID 32998816

  • Early Change in Albuminuria with Canagliflozin Predicts Kidney and Cardiovascular Outcomes: A PostHoc Analysis from the CREDENCE Trial. Journal of the American Society of Nephrology : JASN Oshima, M., Neuen, B. L., Li, J., Perkovic, V., Charytan, D. M., de Zeeuw, D., Edwards, R., Greene, T., Levin, A., Mahaffey, K. W., De Nicola, L., Pollock, C., Rosenthal, N., Wheeler, D. C., Jardine, M. J., Heerspink, H. J. 2020

    Abstract

    BACKGROUND: The association between early changes in albuminuria and kidney and cardiovascular events is primarily based on trials of renin-angiotensin system blockade. It is unclear whether this association occurs with sodium-glucose cotransporter 2 inhibition.METHODS: The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial enrolled 4401 patients with type 2 diabetes and CKD (urinary albumin-creatinine ratio [UACR] >300 mg/g). This post hoc analysis assessed canagliflozin's effect on albuminuria and how early change in albuminuria (baseline to week 26) is associated with the primary kidney outcome (ESKD, doubling of serum creatinine, or kidney death), major adverse cardiovascular events, and hospitalization for heart failure or cardiovascular death.RESULTS: Complete data for early change in albuminuria and other covariates were available for 3836 (87.2%) participants in the CREDENCE trial. Compared with placebo, canagliflozin lowered UACR by 31% (95% confidence interval [95% CI], 27% to 36%) at week 26, and significantly increased the likelihood of achieving a 30% reduction in UACR (odds ratio, 2.69; 95% CI, 2.35 to 3.07). Each 30% decrease in UACR over the first 26 weeks was independently associated with a lower hazard for the primary kidney outcome (hazard ratio [HR], 0.71; 95% CI, 0.67 to 0.76; P<0.001), major adverse cardiovascular events (HR, 0.92; 95% CI, 0.88 to 0.96; P<0.001), and hospitalization for heart failure or cardiovascular death (HR, 0.86; 95% CI, 0.81 to 0.90; P<0.001). Residual albuminuria levels at week 26 remained a strong independent risk factor for kidney and cardiovascular events, overall and in each treatment arm.CONCLUSIONS: In people with type 2 diabetes and CKD, use of canagliflozin results in early, sustained reductions in albuminuria, which were independently associated with long-term kidney and cardiovascular outcomes.

    View details for DOI 10.1681/ASN.2020050723

    View details for PubMedID 32998938

  • An exploration of the heterogeneity in effects of SGLT2 inhibition on cardiovascular and all-cause mortality in the EMPA-REG OUTCOME, CANVAS Program, DECLARE-TIMI 58, and CREDENCE trials. International journal of cardiology Yu, J., Zhou, Z., Mahaffey, K. W., Matthews, D. R., Neuen, B. L., Heerspink, H. J., Jardine, M., Li, J., Perkovic, V., Neal, B., Arnott, C. 2020

    Abstract

    BACKGROUND: Large-scale outcome trials of sodium glucose co-transporter 2 (SGLT2) inhibitors in patients with type 2 diabetes have identified consistent effects on major adverse cardiovascular events, heart failure, and progression of kidney disease. However, the magnitude of effects on cardiovascular and all-cause death appeared to vary between some of the studies.METHODS: We explored the impact of differences in trial methodologies, participant characteristics, types of deaths, follow-up duration, effects on intermediate markers of risk, and drug selectivity for SGLT2 on the magnitude of the protective effect against fatal events achieved in the 4 trials.RESULTS: The trial populations differed substantively in the proportions with baseline atherosclerotic cardiovascular disease history (99.2% in EMPA-REG OUTCOME to 40.6% in DECLARE-TIMI 58), and macroalbuminuria (88.0% in CREDENCE to 7.6% in the CANVAS Program). Meta-regression analyses identified no clear effect of these (both P > 0.09) or other participant characteristics on mortality benefits (all P > 0.55). Other differences between the trials (duration, selectivity of the SGLT2 inhibitor, or effects on intermediate markers of risk) also did not explain the heterogeneity in effects on mortality observed (all P > 0.30).CONCLUSION: No clear explanation for the statistical evidence of heterogeneity in effects of SGLT2 inhibition on fatal outcomes between the trials could be identified. While the analyses had limited statistical power, these results raise the possibility that the observed variations in treatment effects on fatal outcomes between trials may be at least partly due to chance.

    View details for DOI 10.1016/j.ijcard.2020.09.050

    View details for PubMedID 32979427

  • 2020 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants A Report of the American College of Cardiology Solution Set Oversight Committee JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Tomaselli, G. F., Mahaffey, K. W., Cuker, A., Dobesh, P. P., Doherty, J. U., Eikelboom, J. W., Florido, R., Gluckman, T. J., Hucker, W. J., Mehran, R., Messe, S. R., Perino, A. C., Rodriguez, F., Sarode, R., Siegal, D. M., Wiggins, B. S., Report Amer Coll Cardiology Soluti, Solution Set Oversight Comm 2020; 76 (5): 594–622

    View details for DOI 10.1016/j.jacc.2020.04.053

    View details for Web of Science ID 000557886000001

    View details for PubMedID 32680646

  • Different eGFR Decline Thresholds and Renal Effects of Canagliflozin: Data from the CANVAS Program. Journal of the American Society of Nephrology : JASN Oshima, M., Neal, B., Toyama, T., Ohkuma, T., Li, Q., de Zeeuw, D., Heerspink, H. J., Mahaffey, K. W., Fulcher, G., Canovatchel, W., Matthews, D. R., Perkovic, V. 2020

    Abstract

    BACKGROUND: Traditionally, clinical trials evaluating effects of a new therapy with creatinine-based renal end points use doubling of serum creatinine (equivalent to a 57% eGFR reduction), requiring large sample sizes.METHODS: To assess whether eGFR declines <57% could detect canagliflozin's effects on renal outcomes, we conducted a post hoc study comparing effects of canagliflozin versus placebo on composite renal outcomes using sustained 57%, 50%, 40%, or 30% eGFR reductions in conjunction with ESKD and renal death. Because canagliflozin causes an acute reversible hemodynamic decline in eGFR, we made estimates using all eGFR values as well as estimates that excluded early measures of eGFR influenced by the acute hemodynamic effect.RESULTS: Among the 10,142 participants, 93 (0.9%), 161 (1.6%), 352 (3.5%), and 800 (7.9%) participants recorded renal outcomes on the basis of 57%, 50%, 40%, or 30% eGFR reduction, respectively, during a mean follow-up of 188 weeks. Compared with a 57% eGFR reduction (risk ratio [RR], 0.51; 95% confidence interval [95% CI], 0.34 to 0.77), the effect sizes were progressively attenuated when using 50% (RR, 0.61; 95% CI, 0.45 to 0.83), 40% (RR, 0.70; 95% CI, 0.57 to 0.86), or 30% (RR, 0.81; 95% CI, 0.71 to 0.93) eGFR reductions. In analyses that controlled for the acute hemodynamic fall in eGFR, effect sizes were comparable, regardless of whether a 57%, 50%, 40%, or 30% eGFR reduction was used. Estimated sample sizes for studies on the basis of lesser eGFR reductions were much reduced by controlling for this early hemodynamic effect.CONCLUSIONS: Declines in eGFR <57% may provide robust estimates of canagliflozin's effects on renal outcomes if the analysis controls for the drug's acute hemodynamic effect.CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: CANagliflozin cardioVascular Assessment Study (CANVAS), NCT01032629 and CANVAS-R, NCT01989754.

    View details for DOI 10.1681/ASN.2019121312

    View details for PubMedID 32694216

  • Effects of canagliflozin on initiation of insulin and other antihyperglycaemic agents in the CANVAS Program. Diabetes, obesity & metabolism Matthews, D. R., Wysham, C., Davies, M., Slee, A., Alba, M., Lee, M., Perkovic, V., Mahaffey, K. W., Neal, B. 2020

    Abstract

    This study compared initiation of insulin and other AHAs with canagliflozin versus placebo for participants with type 2 diabetes and a history/high risk of cardiovascular disease in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program. After 1 year fewer participants treated with canagliflozin versus placebo initiated any AHA (7% vs 16%), insulin (3% vs 9%;) or any non-insulin AHA (5% vs 12%; p<0.001 for all); overall AHA initiation rates increased over time but were consistently lower with canagliflozin compared with placebo. During the study, the likelihood of initiating insulin was 2.7 times lower for participants treated with canagliflozin compared with placebo (hazard ratio, 0.37; 95% CI: 0.31,0.43; p<0.001). The time difference between 10% of patients in the canagliflozin and placebo groups being initiated on insulin from the beginning of the trial was about two years. Time to initiation of other AHAs, including metformin, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists and sulphonylureas, was also delayed for canagliflozin versus placebo (p<0.001 for each). Compared with placebo, canagliflozin delayed the need for initiation of other AHAs and delayed time to insulin therapy, an outcome that is important to many people with diabetes. Trial registration: ClinicalTrials.gov identifiers NCT01032629, NCT01989754. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1111/dom.14143

    View details for PubMedID 32691499

  • A Call for a New Paradigm for Diabetes Care in the Era of Sodium-Glucose Cotransporter2 Inhibitors (SGLT2i). Cardiology and therapy Kim, S. H., Chang, T. I., Mahaffey, K. W. 2020

    Abstract

    In 2013, canagliflozin was the first sodium-glucose cotransporter2 inhibitor (SGLT2i) approved by the US Food and Drug Administration for the treatment of type2 diabetes (T2DM). Today, there are four SGLT2i approved for T2DM, and some SGLT2i have been approved for indications beyond glucose control. For example, SGLT2i reduce major adverse clinical events (MACE) including nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death (canagliflozin); cardiovascular death (empagliflozin, dapagliflozin); diabetic kidney disease progression (canagliflozin); and heart failure hospitalization (canagliflozin, dapagliflozin). However, despite the potential benefits of SGLT2i in reducing adverse clinical events, providers underprescribe SGLT2i for eligible patients. Thus, we propose the CKD-PCP framework which allows multiple providers to utilize the benefits of SGLT2i. CKD-PCP has dual meaning: it applies to providers who most often care for patients with T2DM (Cardiologists, Kidney specialists, Diabetologists, and Primary Care Physicians) and it refers to the benefits of SGLT2i (treatment of Cardiovascular disease, Kidney disease, Diabetes, and reduction of blood Pressure, Calories, and Plasma volume). This article is based on previously conducted studies and the authors disclosetheir roles in relevant trialsin the Acknowledgements.

    View details for DOI 10.1007/s40119-020-00190-7

    View details for PubMedID 32661684

  • Effect of Temporary Interruption of Warfarin Due to an Intervention on Downstream Time in Therapeutic Range in Patients With Atrial Fibrillation (from ORBIT AF). The American journal of cardiology Madhavan, M., Holmes, D. N., Piccini, J. P., Freeman, J. V., Fonarow, G. C., Hylek, E. M., Kowey, P. R., Mahaffey, K. W., Pieper, K., Peterson, E. D., Chan, P. S., Allen, L. A., Singer, D. E., Naccarelli, G. V., Reiffel, J. A., Steinberg, B. A., Gersh, B. J., ORBIT AF Investigators 2020

    Abstract

    The aim of this study was to quantify time in therapeutic range (TTR) before and after a temporary interruption of warfarin due to an intervention in the Outcomes Registry for Better Informed Treatment of atrial fibrillation (AF). AF patients on warfarin who had a temporary interruption followed by resumption were identified. A nonparametric method for estimating survival functions for interval censored data was used to examine the first therapeutic International Normalized Ratio (INR) after interruption. TTR was compared using Wilcoxon signed rank test. Cox proportional hazards model was used to investigate the association between TTR in the first 3 months after interruption and subsequent outcomes at 3 to 9 months. Of 9,749 AF patients, 71% were on warfarin. Over a median (IQR) follow-up of 2.6 (1.8 to 3.1) y, 33% of patients had a total of 3,022 temporary interruptions. The first therapeutic INR was recorded within 1 week in 35.0% (95% confidence interval 32.6% to 37.4%), 2 weeks in 54.6% (52.2% to 57.0%), 30 days in 70.0% (67.9% to 72.1%) and 90 days in 91.3% (90.0% to 92.5%) of patients. Compared with pre-interruption, TTR 3 months after interruption was significantly lower (61.1% [36.6% to 85.0%] vs 67.6% [50.0% to 81.3%], p <0.0001). A 10 unit increment in the TTR in the first 3 months after interruption was associated with a lower risk of major bleeding [Hazard ratio 0.91 (0.85 to 0.97), p = 0.005]. This association was noted in patients who received bridging anticoagulation, but not in those who did not. In conclusion, temporary interruption of warfarin is common, and nearly half of these patients had subtherapeutic INR after 2 weeks. Lower TTR in the first 3 months after interruption was associated with higher incidence of major bleeding in patients who received bridging anticoagulation.

    View details for DOI 10.1016/j.amjcard.2020.07.006

    View details for PubMedID 32826041

  • Patterns of oral anticoagulation use with cardioversion in clinical practice. Heart (British Cardiac Society) Geurink, K., Holmes, D., Ezekowitz, M. D., Pieper, K., Fonarow, G., Kowey, P. R., Reiffel, J. A., Singer, D. E., Freeman, J., Gersh, B. J., Mahaffey, K. W., Hylek, E. M., Naccarelli, G., Piccini, J. P., Peterson, E. D., Pokorney, S. D. 2020

    Abstract

    BACKGROUND: Cardioversion is common among patients with atrial fibrillation (AF). We hypothesised that novel oral anticoagulants (NOAC) used in clinical practice resulted in similar rates of stroke compared with vitamin K antagonists (VKA) for cardioversion.METHODS: Using the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II, patients with AF who had a cardioversion, follow-up data and an AF diagnosis within 6 months of enrolment were identified retrospectively. Clinical outcomes were compared for patients receiving a NOAC or VKA for 1year following cardioversion.RESULTS: Among 13004 patients with AF, 2260 (17%) underwent cardioversion. 1613 met the inclusion criteria for this analysis. At the time of cardioversion, 283 (17.5%) were receiving a VKA and 1330 (82.5%) a NOAC. A transoesophageal echocardiogram (TOE) was performed in 403 (25%) cardioversions. The incidence of stroke/transient ischaemic attack (TIA) at 30 days was the same for patients having (3.04 per 100 patient-years) or not having (3.04 per 100 patient-years) a TOE (p=0.99). There were no differences in the incidence of death (HR 1.19, 95%CI 0.62 to 2.28, p=0.61), cardiovascular hospitalisation (HR 1.02, 95%CI 0.76 to 1.35, p=0.91), stroke/TIA (HR 1.18, 95%CI 0.30 to 4.74, p=0.81) or bleeding-related hospitalisation (HR 1.29, 95%CI 0.66 to 2.52, p=0.45) at 1year for patients treated with either a NOAC or VKA.CONCLUSIONS: Cardioversion was a low-risk procedure for patients treated with NOAC, and there were statistically similar rates of stroke/TIA 30 days after cardioversion as for patients treated with VKA. There were no statically significant differences in death, stroke/TIA or major bleeding at 1year among patients treated with NOAC compared with VKA after cardioversion.

    View details for DOI 10.1136/heartjnl-2019-316315

    View details for PubMedID 32591363

  • The Project Baseline Health Study: a step towards a broader mission to map human health NPJ DIGITAL MEDICINE Arges, K., Assimes, T., Bajaj, V., Balu, S., Bashir, M. R., Beskow, L., Blanco, R., Califf, R., Campbell, P., Carin, L., Christian, V., Cousins, S., Das, M., Dockery, M., Douglas, P. S., Dunham, A., Eckstrand, J., Fleischmann, D., Ford, E., Fraulo, E., French, J., Gambhir, S. S., Ginsburg, G. S., Green, R. C., Haddad, F., Hernandez, A., Hernandez, J., Huang, E. S., Jaffe, G., King, D., Koweek, L. H., Langlotz, C., Liao, Y. J., Mahaffey, K. W., Marcom, K., Marks, W. J., Maron, D., McCabe, R., McCall, S., McCue, R., Mega, J., Miller, D., Muhlbaier, L. H., Munshi, R., Newby, L., Pak-Harvey, E., Patrick-Lake, B., Pencina, M., Peterson, E. D., Rodriguez, F., Shore, S., Shah, S., Shipes, S., Sledge, G., Spielman, S., Spitler, R., Schaack, T., Swamy, G., Willemink, M. J., Wong, C. A. 2020; 3 (1): 84

    Abstract

    The Project Baseline Health Study (PBHS) was launched to map human health through a comprehensive understanding of both the health of an individual and how it relates to the broader population. The study will contribute to the creation of a biomedical information system that accounts for the highly complex interplay of biological, behavioral, environmental, and social systems. The PBHS is a prospective, multicenter, longitudinal cohort study that aims to enroll thousands of participants with diverse backgrounds who are representative of the entire health spectrum. Enrolled participants will be evaluated serially using clinical, molecular, imaging, sensor, self-reported, behavioral, psychological, environmental, and other health-related measurements. An initial deeply phenotyped cohort will inform the development of a large, expanded virtual cohort. The PBHS will contribute to precision health and medicine by integrating state of the art testing, longitudinal monitoring and participant engagement, and by contributing to the development of an improved platform for data sharing and analysis.

    View details for DOI 10.1038/s41746-020-0290-y

    View details for Web of Science ID 000538242900001

    View details for PubMedID 32550652

    View details for PubMedCentralID PMC7275087

  • CANAGLIFLOZIN AND RISK OF GENITAL INFECTIONS AND URINARY TRACT INFECTIONS IN PEOPLE WITH DIABETES MELLITUS AND KIDNEY DISEASE- A POST-HOC ANALYSIS OF THE CREDENCE TRIAL Kang, A., Neuen, B., Heerspink, H., Di Tanna, G., Neal, B., Zhang, H., Hockham, C., Agarwal, R., Bakris, G., Charytan, D. M., De Zeeuw, D., Greene, T., Levin, A., Pollock, C., Wheeler, D., Zinman, B., Mahaffey, K. W., Perkovic, V., Jardine, M. OXFORD UNIV PRESS. 2020: 1336
  • EFFECTS OF CANAGLIFLOZIN ON MAJOR ADVERSE CARDIOVASCULAR OUTCOMES IN PATIENTS WITH DIFFERENT BASELINE LEVELS OF TYPE 2 DIABETES MELLITUS DISEASE SEVERITY: RESULTS FROM THE CANVAS PROGRAM Young, T., Li, J., Kang, A., Heerspink, H., Hockham, C., Arnott, C., Neuen, B., Zoungas, S., Mahaffey, K. W., Perkovic, V., De Zeeuw, D., Fulcher, G., Neal, B., Jardine, M. OXFORD UNIV PRESS. 2020: 1351
  • CANAGLIFLOZIN AND RISK OF SKIN AND SOFT TISSUE INFECTIONS IN PEOPLE WITH DIABETES MELLITUS AND KIDNEY DISEASE - A POST-HOC ANALYSIS OF THE CREDENCE TRIAL Kang, A., Smyth, B., Neuen, B., Heerspink, H., Di Tanna, G., Neal, B., Zhang, H., Hockham, C., Agarwal, R., Bakris, G., Charytan, D. M., De Zeeuw, D., Greene, T., Levin, A., Pollock, C., Wheeler, D., Zinman, B., Mahaffey, K. W., Perkovic, V., Jardine, M. OXFORD UNIV PRESS. 2020: 1342
  • Outpatient Inhaled Nitric Oxide in a Patient with Vasoreactive IPAH and COVID-19 Infection. American journal of respiratory and critical care medicine Zamanian, R. T., Pollack, C. V., Gentile, M. A., Rashid, M., Fox, J. C., Mahaffey, K. W., de Jesus Perez, V. 2020

    View details for DOI 10.1164/rccm.202004-0937LE

    View details for PubMedID 32369396

  • Preventing Atrial Fibrillation With Treatments for Diabetes Mellitus. Circulation Granger, C. B., Mahaffey, K. W. 2020; 141 (15): 1235–37

    View details for DOI 10.1161/CIRCULATIONAHA.120.045864

    View details for PubMedID 32282249

  • Methods for safety and endpoint ascertainment: identification of adverse events through scrutiny of negatively adjudicated events. Trials Fanaroff, A. C., Haque, G., Thomas, B., Stone, A. E., Perkins, L. M., Wilson, M., Jones, W. S., Melloni, C., Mahaffey, K. W., Alexander, K. P., Lopes, R. D. 2020; 21 (1): 323

    Abstract

    BACKGROUND: The primary goal of phase 2 and 3 clinical trials is to evaluate the safety and effectiveness of therapeutic interventions, and efficient and reproducible ascertainment of important clinical events, either as clinical outcome events (COEs) or adverse events (AEs), is critical. Clinical outcomes require consistency and clinical judgment, so these events are often adjudicated centrally by clinical events classification (CEC) physician reviewers using standardized definitions. In contrast, AEs are reported by sites to the trial coordinating center based on common reporting criteria set by regulatory authorities and trial sponsors. These different requirements have led to the development of separate tracks for COE and AE review.MAIN BODY: Potential COEs that fail to meet standardized definitions for CEC adjudication - i.e. negatively adjudicated events (NAE) - may meet criteria for AEs. Trial oversight practices require the sponsor to process AEs regardless of how the AEs are submitted; therefore, review of NAEs may be necessary to ensure that important AEs do not go unreported. The Duke Clinical Research Institute (DCRI) developed and implemented a process for scrutinizing NAEs to detect potential missed serious AEs. Initial experience with this process across two trials suggests that approximately 0.2% of NAEs are serious unexpected AEs that were not otherwise reported and another 1.5% are serious expected AEs.CONCLUSIONS: Given their infrequent concealment of serious AEs in two large trials assessing cardiovascular outcomes, routine scrutiny of NAEs to identify AEs is not recommended at this time, though it may be useful in some trials and should be carefully considered by the trial team. Closer integration of data across safety surveillance and endpoint adjudication systems may enable scrutiny of NAEs when indicated while limiting complexity associated with this process.

    View details for DOI 10.1186/s13063-020-04254-w

    View details for PubMedID 32272961

  • Cangrelor in clinical use. Future cardiology Feng, K. Y., Mahaffey, K. W. 2020

    Abstract

    Inadequate antiplatelet effects can result in substantial morbidity and mortality in patients with acute coronary syndrome and percutaneous coronary intervention (PCI). Cangrelor is a rapid onset and potent intravenous P2Y12 inhibitor that has been shown in large randomized controlled trials to reduce periprocedural complications for PCI compared with clopidogrel, the most commonly used P2Y12 inhibitor. Cangrelor should be considered in the setting of PCI to reduce the risk of periprocedural complications such as myocardial infarction, repeat coronary revascularization and stent thrombosis in patients not yet treated with another P2Y12 inhibitor or glycoprotein IIb/IIIa inhibitor. In this review, the importance of adequate P2Y12 inhibition, cangrelor's pharmacology and clinical profiles, and future directions for the cangrelor are discussed.

    View details for DOI 10.2217/fca-2019-0095

    View details for PubMedID 32067479

  • Risk of major cardiovascular and neurologic events with obstructive sleep apnea among patients with atrial fibrillation. American heart journal Dalgaard, F., North, R., Pieper, K., Fonarow, G. C., Kowey, P. R., Gersh, B. J., Mahaffey, K. W., Pokorney, S., Steinberg, B. A., Naccarrelli, G., Allen, L. A., Reiffel, J. A., Ezekowitz, M., Singer, D. E., Chan, P. S., Peterson, E. D., Piccini, J. P. 2020; 223: 65–71

    Abstract

    BACKGROUND: Obstructive sleep apnea (OSA) is a known risk factor for atrial fibrillation (AF). However, it remains unclear whether OSA is independently associated with worse cardiovascular and neurological outcomes in patients with AF.METHODS: We used the ORBIT-AF I and ORBIT-AF II to conduct a retrospective cohort study of 22,760 patients with AF with and without OSA. Adjusted multivariable Cox proportional hazards models was used to determine whether OSA was associated with increased risk for major adverse cardiac and neurologic events (MACNEs) (cardiovascular death, myocardial infarction, stroke/transient ischemic attack/non-central nervous system embolism (stroke/SE), and new-onset heart failure], combined and individually.RESULTS: A total of 4,045 (17.8%) patients had OSA at baseline. Median follow-up time was 1.5 (interquartile range: 1-2.2) years, and 1,895 patients experienced a MACNE. OSA patients were younger (median [interquartile range] 68 [61-75] years vs 74 [66-81] years), were more likely male (70.7% vs 55.3%), and had increased body mass index (median 34.6 kg/m2 [29.8-40.2] vs 28.7 kg/m2 [25.2-33.0]). Those with OSA had a higher prevalence of concomitant comorbidities such as diabetes, chronic obstructive pulmonary disease, and heart failure. OSA patients had higher use of antithrombotic therapy. After adjustment, the presence of OSA was significantly associated with MACNE (hazard ratio: 1.16 [95% CI: 1.03-1.31], P = .011). OSA was also an independent risk factor for stroke/SE beyond the CHA2DS2-VASc risk factors (HR: 1.38 [95% CI 1.12-1.70], P = .003) but not cardiovascular death, myocardial infarction, new-onset heart failure, or major bleeding.CONCLUSIONS: Among patients with AF, OSA is an independent risk factor for MACNE and, more specifically, stroke/SE.

    View details for DOI 10.1016/j.ahj.2020.01.001

    View details for PubMedID 32179257

  • Mediators of the effects of canagliflozin on kidney protection in patients with type 2 diabetes. Kidney international Li, J. n., Neal, B. n., Perkovic, V. n., de Zeeuw, D. n., Neuen, B. L., Arnott, C. n., Simpson, R. n., Oh, R. n., Mahaffey, K. W., Heerspink, H. J. 2020

    Abstract

    Canagliflozin reduced kidney disease progression in participants with type 2 diabetes in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program that explored potential mediators of the effects of canagliflozin on kidney outcomes. The percent mediating effect of 18 biomarkers indicative of disease was determined by comparing the hazard ratios for the effect of randomized treatment from an unadjusted model and from a model adjusting for the average post-randomization level of each biomarker. Multivariable analyses assessed the joint effects of biomarkers that mediated most strongly in univariable analyses. The kidney outcome was defined as a composite of 40% estimated glomerular filtration rate decline, end-stage kidney disease, or death due to kidney disease. Nine biomarkers (systolic blood pressure [8.9% of effect explained], urinary albumin:creatinine ratio [UACR; 23.9%], gamma glutamyltransferase [4.1%], hematocrit [51.1%], hemoglobin [41.3%], serum albumin [19.5%], erythrocytes [56.7%], serum urate [35.4%], and urine pH [7.5%]) individually mediated the effect of canagliflozin on the kidney outcome. In a parsimonious multivariable model, erythrocyte concentration, serum urate, and systolic blood pressure maximized cumulative mediation (115%). Mediating effects of UACR, but not other mediators, were highly dependent upon the baseline level of UACR: UACR mediated 42% and 7% of the effect in those with baseline UACR 30 mg/g or more and under 30 mg/g, respectively. The identified mediators support existing hypothesized mechanisms for the prevention of kidney outcomes with sodium glucose co-transporter 2 inhibitors. Thus, the disparity in mediating effects across baseline UACR subgroups suggests that the mechanism for kidney protection with canagliflozin may vary across patient subgroups.

    View details for DOI 10.1016/j.kint.2020.04.051

    View details for PubMedID 32470492

  • Association of Disease Progression With Cardiovascular and Limb Outcomes in Patients With Peripheral Artery Disease: Insights From the EUCLID Trial. Circulation. Cardiovascular interventions Rymer, J. A., Mulder, H. n., Narcisse, D. I., Rockhold, F. n., Hiatt, W. R., Fowkes, F. G., Baumgartner, I. n., Berger, J. S., Katona, B. G., Mahaffey, K. n., Norgren, L. n., Blomster, J. I., Jones, W. S., Patel, M. R. 2020: CIRCINTERVENTIONS120009326

    Abstract

    Patients with peripheral artery disease have a high risk of future cardiovascular disease events and mortality. Little is known about the changes in symptom classification over time in patients with peripheral artery disease and the association of changes in symptom classification with subsequent cardiovascular disease events.In this analysis of the EUCLID trial (Examining Use of Ticagrelor in Peripheral Artery Disease), we examined the changes in Rutherford classification (RC) of patients over 12 months. We examined the baseline characteristics of patients by change in symptom classification at 12 months (improved=decreased RC, no change, or worsened=increased RC), and the association between changes in symptom classification (RC) at 12 months and subsequent cardiovascular disease events.Among 12 759 patients, 3240 (25%) were classified as improved by RC at 12 months, 8132 (64%) as no change, and 1387 (11%) as worsened. At 12 months, many patients who were asymptomatic or had mild/moderate claudication at enrollment had no change in symptom classification over 12 months (73.7% and 70.9%). Patients who worsened over 12 months were more likely to have comorbidities (diabetes mellitus and prior myocardial infarction) and more events (myocardial infarction, amputation, and major bleeding) by 12 months postrandomization, all P<0.001. Worsened symptom classification over 12 months was associated with increased risk of all-cause death (adjusted hazard ratio, 1.29 [95% CI, 1.03-1.62]), major amputation (adjusted hazard ratio, 4.12 [95% CI, 2.46-6.88]), and a composite of cardiovascular death, myocardial infarction, or stroke (adjusted hazard ratio, 1.30 [95% CI, 1.05-1.62]), all P<0.05 after 12 months postrandomization.Patients with comorbidities and prior history of cardiovascular disease events at baseline and within the first 12 months of the trial were more likely to have worsened symptom classification at 12 months. Worsening symptom classification over 12 months was associated subsequently with an increased risk of all-cause death, amputation, and a composite of cardiovascular death, myocardial infarction, or stroke.

    View details for DOI 10.1161/CIRCINTERVENTIONS.120.009326

    View details for PubMedID 33040584

  • SGLT2 inhibitors with and without metformin: a meta-analysis of cardiovascular, kidney and mortality outcomes. Diabetes, obesity & metabolism Neuen, B. L., Arnott, C. n., Perkovic, V. n., Figtree, G. n., de Zeeuw, D. n., Fulcher, G. n., Jun, M. n., Jardine, M. J., Zoungas, S. n., Pollock, C. n., Mahaffey, K. W., Neal, B. n., Heerspink, H. J. 2020

    Abstract

    Almost all clinical practice guidelines recommend that SGLT2 inhibitors are used as second-line pharmacotherapy in people with type 2 diabetes and chronic kidney disease or heart failure if they do not achieve sufficient glucose control with metformin. We sought to assess whether the effects of SGLT2 inhibitors on cardiovascular, kidney and mortality outcomes are consistent with and without concomitant metformin use.We conducted a meta-analysis of event-driven, randomized, placebo-controlled SGLT2 inhibitor trials that reported cardiovascular, kidney or mortality outcomes by baseline metformin use. Treatment effects reported as hazards ratios (HR) and 95% confidence intervals (CI) were pooled using random effects meta-analysis. The main outcomes in this analysis were (1) major adverse cardiovascular events (MACE) and (2) hospitalized heart failure (HHF) or cardiovascular death.We included six trials of four SGLT2 inhibitors that enrolled 51,743 participants. Baseline metformin use varied from 21% in DAPA-HF to 82% in DECLARE-TIMI 58. SGLT2 inhibitors reduced the risk of MACE, with and without concomitant metformin use (HR 0.93, 95% CI 0.87-1.00 and HR 0.82, 95% CI 0.71-0.86 respectively; P-heterogeneity=0.14). There were also clear and separate reductions in HHF or cardiovascular death with SGLT2 inhibitors irrespective of metformin use (HR 0.79, 95% CI 0.73-0.86 and HR 0.74, 95% CI 0.63-0.87 respectively; P-heterogeneity=0.48), as well as for major kidney outcomes and all-cause mortality (all P-heterogeneity>0.40).Treatment with SGLT2 inhibitors results in clear and consistent reductions in cardiovascular, kidney and mortality outcomes regardless of whether patients are receiving or not receiving metformin. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1111/dom.14226

    View details for PubMedID 33043620

  • Factors Associated with Large Improvements in Health-Related Quality of Life in Patients with Atrial Fibrillation: Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). Circulation. Arrhythmia and electrophysiology Steinberg, B. A., Holmes, D. N., Pieper, K. n., Allen, L. A., Chan, P. S., Ezekowitz, M. D., Freeman, J. V., Fonarow, G. C., Gersh, B. J., Hylek, E. M., Kowey, P. R., Mahaffey, K. W., Naccarelli, G. n., Reiffel, J. n., Singer, D. E., Peterson, E. D., Piccini, J. P. 2020

    Abstract

    Background - Atrial fibrillation (AF) adversely impacts health-related quality of life (hrQoL). While some patients demonstrate improvements in hrQoL, the factors associated with large improvements in hrQoL are not well described. Methods - We assessed factors associated with a 1-year increase in AFEQT of 1 standard deviation (≥18 points; 3x clinically important difference), among outpatients in the ORBIT-AF I registry. Results - Overall, 28% (181/636) of patients had such a hrQoL improvement. Compared with patients not showing large hrQoL improvement, they were of similar age (median 73 vs. 74, p=0.3), equally likely to be female (44% vs. 48%, p=0.3), but more likely to have newly-diagnosed AF at baseline (18% vs. 8%; p=0.0004), prior antiarrhythmic drug use (52% vs. 40%, 0.005), baseline antiarrhythmic drug use (34.8% vs, 26.8%, p=0.045), and more likely to undergo AF-related procedures during follow-up (AF ablation: 6.6% vs. 2.0%, p=0.003; cardioversion:12.2% vs. 5.9% p=0.008). In multivariable analysis, a history of alcohol abuse (adjusted OR 2.41, p=0.01) and increased baseline diastolic BP (adjusted OR 1.23 per 10-point increase and >65 mm Hg, p=0.04) were associated with large improvements in hrQoL at 1 year, whereas patients with prior stroke/TIA, COPD, and PAD were less likely to improve (p<0.05 for each). Conclusions - In this national registry of AF patients, potentially treatable AF risk factors are associated with large hrQoL improvement, whereas less reversible conditions appeared negatively associated with hrQoL improvement. Understanding which patients are most likely to have large hrQoL improvement may facilitate targeting interventions for high-value care that optimizes patient reported outcomes in AF. Clinical Trial Registration - clinicaltrials.gov.; Unique Identifier: NCT01165710.

    View details for DOI 10.1161/CIRCEP.119.007775

    View details for PubMedID 32298144

  • Cost-Effectiveness of Alirocumab in Patients With Acute Coronary Syndromes: The ODYSSEY OUTCOMES Trial. Journal of the American College of Cardiology Bhatt, D. L., Briggs, A. H., Reed, S. D., Annemans, L. n., Szarek, M. n., Bittner, V. A., Diaz, R. n., Goodman, S. G., Harrington, R. A., Higuchi, K. n., Joulain, F. n., Jukema, J. W., Li, Q. H., Mahaffey, K. W., Sanchez, R. J., Roe, M. T., Lopes, R. D., White, H. D., Zeiher, A. M., Schwartz, G. G., Gabriel Steg, P. n. 2020; 75 (18): 2297–2308

    Abstract

    Cholesterol reduction with proprotein convertase subtilisin-kexin type 9 inhibitors reduces ischemic events; however, the cost-effectiveness in statin-treated patients with recent acute coronary syndrome remains uncertain.This study sought to determine whether further cholesterol reduction with alirocumab would be cost-effective in patients with a recent acute coronary syndrome on optimal statin therapy.A cost-effectiveness model leveraging patient-level data from ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was developed to estimate costs and outcomes over a lifetime horizon. Patients (n = 18,924) had a recent acute coronary syndrome and were on high-intensity or maximum-tolerated statin therapy, with a baseline low-density lipoprotein cholesterol (LDL-C) level ≥70 mg/dl, non-high-density lipoprotein cholesterol ≥100 mg/dl, or apolipoprotein B ≥80 mg/l. Alirocumab 75 mg or placebo was administered subcutaneously every 2 weeks. Alirocumab was blindly titrated to 150 mg if LDL-C remained ≥50 mg/dl or switched to placebo if 2 consecutive LDL-C levels were <15 mg/dl. Incremental cost per quality-adjusted life-year (QALY) was determined with the addition of alirocumab versus placebo and, based on clinical efficacy findings from the trial, was stratified by baseline LDL-C levels ≥100 mg/dl and <100 mg/dl.Across the overall population recruited to the ODYSSEY OUTCOMES trial, using an annual treatment cost of US$5,850, the mean overall incremental cost-effectiveness ratio was US$92,200 per QALY (base case). The cost was US$41,800 per QALY in patients with baseline LDL-C ≥100 mg/dl, whereas in those with LDL-C <100 mg/dl the cost per QALY was US$299,400. Among patients with LDL-C ≥100 mg/dl, incremental cost-effectiveness ratios remained below US$100,000 per QALY across a wide variety of sensitivity analyses.In patients with a recent acute coronary syndrome on optimal statin therapy, alirocumab improves cardiovascular outcomes at costs considered intermediate value, with good value in patients with baseline LDL-C ≥100 mg/dl but less economic value with LDL-C <100 mg/dl. (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab [ODYSSEY OUTCOMES]; NCT01663402).

    View details for DOI 10.1016/j.jacc.2020.03.029

    View details for PubMedID 32381160

  • Discontinuation rates of warfarin versus direct acting oral anticoagulants in US clinical practice: Results from Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II (ORBIT-AF II). American heart journal Jackson, L. R., Kim, S. n., Blanco, R. n., Thomas, L. n., Ansell, J. n., Fonarow, G. C., Gersh, B. J., Go, A. S., Kowey, P. R., Mahaffey, K. W., Hylek, E. M., Peterson, E. D., Piccini, J. P. 2020; 226: 85–93

    Abstract

    While oral anticoagulation is a cornerstone of stroke prevention therapy in atrial fibrillation (AF), few studies have evaluated comparative discontinuation rates in clinical practice. The objective of this study is to evaluate discontinuation rates among patients on warfarin and direct oral anticoagulants (DOACs) in clinical practice.The ORBIT-AF II Registry enrolled 10,005 total AF patients with a CHA2DS2VASc score of ≥2 on warfarin or DOACs from 235 clinical practices across the US from February 13, 2013 and July 12, 2017. Descriptive statistics and multivariable Cox regression modeling were used to describe baseline characteristics and predictors of discontinuation. Unadjusted and adjusted discontinuation rates and 95% confidence intervals (CI) were calculated using Cox proportional hazards models and propensity score adjustment, respectively.At baseline, 16.4% (N = 1642/10,005) were treated with warfarin, 83.6% (N = 8363/10,005) with DOACs and 1498/10,005 patients (15.0%) discontinued therapy [warfarin = 236/1642 (14.4%) vs DOACs = 1262/8363 (15.1%)]. At 6 and 12 months respectively, among 7049 patients with a new diagnosis of AF within 6 months, adjusted discontinuation rates for warfarin versus DOACs were as follows: [6 months: 7.9%, 95%CI (6.8%-9.0%) vs 9.6% (8.4%-10.7%), P = .16]; [12 months: 12.7% (11.0%-14.3%) vs 15.3% (13.6%-16.9%), P = .02)]. Patients who discontinued therapy with warfarin or DOACs had higher risk of adverse clinical outcomes including: all-cause mortality and cardiovascular death (CV) than those who continued treatment.In a community based AF cohort, adjusted rates of discontinuation at 12-months were higher in DOAC-treated versus VKA-treated patients. Discontinuation of oral anticoagulation was associated with increased absolute risk of all-cause mortality and CV death.URL:https://clinicaltrials.gov. Unique Identifier: NCT01701817.

    View details for DOI 10.1016/j.ahj.2020.04.016

    View details for PubMedID 32526533

  • Sex-Specific Risks of Major Cardiovascular and Limb Events in Patients With Symptomatic Peripheral Artery Disease. Journal of the American College of Cardiology Haine, A. n., Kavanagh, S. n., Berger, J. S., Hess, C. N., Norgren, L. n., Fowkes, F. G., Katona, B. G., Mahaffey, K. W., Blomster, J. I., Patel, M. R., Jones, W. S., Rockhold, F. W., Hiatt, W. R., Baumgartner, I. n. 2020; 75 (6): 608–17

    Abstract

    Patients with peripheral artery disease (PAD) have a higher risk of major adverse cardiovascular events (MACE) compared with those without PAD.The aim of this post hoc analysis was to evaluate sex-specific differences in MACE and limb events in the EUCLID (Examining Use of Ticagrelor in PAD) trial.Cox proportional hazards models were used to compare time-to-event outcomes stratified by sex. Covariates were introduced after adjusted model selection.EUCLID enrolled 13,885 patients with PAD (28% women [n = 3,888]). PAD severity and medical treatment were comparable between sexes, whereas prior lower extremity revascularization was reported less frequently in women (54.8% vs. 57.3%; p = 0.006). Women were older (mean ± SD age: 67.8 ± 8.9 vs. 66.1 ± 8.2 years; p < 0.001) and more likely to have diabetes mellitus (p = 0.004), hypertension, hyperlipidemia, and chronic kidney disease (all p < 0.001). Over a mean follow-up of 30 months, women had a lower risk of MACE (9.5% vs. 11.2%; adjusted hazard ratio: 0.77; 95% confidence interval: 0.68 to 0.88; p < 0.001) and all-cause-mortality (7.6% vs. 9.7%; adjusted hazard ratio: 0.61; 95% confidence interval: 0.53 to 0.71; p < 0.001). In contrast, risk for major adverse limb events (2.6% vs. 3.0%) and hospitalization for acute limb ischemia (1.6% vs. 1.7%) were not different by sex.Although women with PAD are at lower risk for MACE and all-cause mortality, risk for limb events was similar between sexes over a mean follow-up of 30 months. Understanding sex-specific differences and dissociation between baseline cardiovascular risk and subsequent cardiovascular events requires further investigation. (A Study Comparing Cardiovascular Effects of Ticagrelor and Clopidogrel in Patients With Peripheral Artery Disease [EUCLID]; NCT01732822).

    View details for DOI 10.1016/j.jacc.2019.11.057

    View details for PubMedID 32057375

  • Effects of Canagliflozin on Amino-Terminal Pro-B-Type Natriuretic Peptide: Implications for Cardiovascular Risk Reduction. Journal of the American College of Cardiology Januzzi, J. L., Xu, J. n., Li, J. n., Shaw, W. n., Oh, R. n., Pfeifer, M. n., Butler, J. n., Sattar, N. n., Mahaffey, K. W., Neal, B. n., Hansen, M. K. 2020; 76 (18): 2076–85

    Abstract

    Canagliflozin reduces cardiovascular events including hospitalization for heart failure (HHF) in patients with type 2 diabetes and cardiovascular risk. Elevated amino-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations are associated with HF diagnosis and predict cardiovascular risk.The purpose of this study was to measure NT-proBNP in CANVAS (Canagliflozin Cardiovascular Assessment Study) participants.Associations between baseline NT-proBNP and cardiovascular, renal, and mortality outcomes and intervention-associated changes were determined.Of the 4,330 participants in the CANVAS trial, NT-proBNP was measured in 3,587, 2,918, and 995 participants at baseline, 1 year, and 6 years, respectively. The median baseline NT-proBNP concentration was 91 pg/ml, and 39.3% had NT-proBNP ≥125 pg/ml. NT-proBNP was higher in those with investigator-reported HF (13% of participants at baseline) versus those without (187 pg/ml vs. 81 pg/ml), with substantial overlap between groups. By 1 year, NT-proBNP increased with placebo, whereas canagliflozin reduced NT-proBNP by 11% (geometric mean ratio for canagliflozin vs. placebo = 0.89 [95% confidence interval (CI): 0.84 to 0.94]; p < 0.001). Lower NT-proBNP with canagliflozin was also observed at 6 years (p = 0.004). In adjusted models, baseline NT-proBNP ≥125 pg/ml was prognostic for incident HHF (hazard ratio [HR]: 5.40; 95% CI: 2.67 to 10.9), HHF/cardiovascular death (HR: 3.52; 95% CI: 2.38 to 5.20), and all-cause death (HR: 2.53; 95% CI: 1.78 to 3.61). Mediation analyses suggested that 10.4% of the effects of canagliflozin on HHF were reflected in NT-proBNP lowering.A substantial percentage of patients in the CANVAS trial had elevated NT-proBNP values. Canagliflozin reduced NT-proBNP concentrations versus placebo; however, reduction in NT-proBNP explained only a small proportion of the benefit of canagliflozin on HF events. (CANVAS [CANagliflozin cardioVascular Assessment Study]; NCT01032629).

    View details for DOI 10.1016/j.jacc.2020.09.004

    View details for PubMedID 33121714

  • Incidence and Factors Associated With Major Amputation in Patients With Peripheral Artery Disease: Insights From the EUCLID Trial. Circulation. Cardiovascular quality and outcomes Long, C. A., Mulder, H. n., Fowkes, F. G., Baumgartner, I. n., Berger, J. S., Katona, B. G., Mahaffey, K. W., Norgren, L. n., Blomster, J. I., Rockhold, F. W., Hiatt, W. R., Patel, M. R., Jones, W. S., Nehler, M. R. 2020: CIRCOUTCOMES119006399

    Abstract

    Background Peripheral artery disease (PAD) is associated with increased risk of mortality, cardiovascular morbidity, and major amputation. Data on major amputation from a large randomized trial that included a substantial cohort of patients without critical limb ischemia (CLI) have not been described. The objective was to describe the incidence and types of amputations in the EUCLID trial (Examining Use of Ticagrelor in Peripheral Artery Disease) population, subcategorize amputations in the CLI versus no CLI cohorts, and describe the events surrounding major amputation. Methods and Results Postrandomization major amputation was analyzed in the EUCLID trial. Patients were stratified by baseline CLI status. The occurrence of major amputation was ascertained and defined as the highest level. Perioperative events surrounding major amputation were obtained including acute limb ischemia, revascularization, and all-cause mortality. All variables were assessed for significance in univariable and multivariable models. The rate of major amputation during the course of the trial was 1.6% overall, 8.4% in the CLI at baseline group, and 1.2% in the no CLI at baseline group. The annualized rate of major amputation was 0.6% in PAD overall, 3.9% in the CLI at baseline group, and 0.5% in the no CLI at baseline group. Several factors were associated with increased risk of major amputation, including history of amputation, the presence of diabetes mellitus, baseline Rutherford category 4 to 6, and an ankle-brachial index <0.8. Factors associated with a lower risk for major amputation included prior statin use. The 30-day mortality rate after major amputation was 6.5% overall, 5.6% in the CLI at baseline group, and 6.8% in the no CLI at baseline group. The annual mortality rate following major amputation was 22.8% in the CLI at baseline group and 16.0% in the no CLI at baseline group. Conclusions The risk factors for major amputation in EUCLID patients are similar to previous large registries' reports except for diabetes mellitus in patients with CLI. The mortality following major amputation is lower in the Examining Use of Ticagrelor in Peripheral Artery Disease trial compared with registry data. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01732822.

    View details for DOI 10.1161/CIRCOUTCOMES.119.006399

    View details for PubMedID 32615798

  • Effects of Canagliflozin in Patients with Baseline eGFR <30 ml/min per 1.73 m2: Subgroup Analysis of the Randomized CREDENCE Trial. Clinical journal of the American Society of Nephrology : CJASN Bakris, G. n., Oshima, M. n., Mahaffey, K. W., Agarwal, R. n., Cannon, C. P., Capuano, G. n., Charytan, D. M., de Zeeuw, D. n., Edwards, R. n., Greene, T. n., Heerspink, H. J., Levin, A. n., Neal, B. n., Oh, R. n., Pollock, C. n., Rosenthal, N. n., Wheeler, D. C., Zhang, H. n., Zinman, B. n., Jardine, M. J., Perkovic, V. n. 2020

    Abstract

    The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial demonstrated that the sodium glucose cotransporter 2 (SGLT2) inhibitor canagliflozin reduced the risk of kidney failure and cardiovascular events in participants with type 2 diabetes mellitus and CKD. Little is known about the use of SGLT2 inhibitors in patients with eGFR <30 ml/min per 1.73 m2. The participants in the CREDENCE study had type 2 diabetes mellitus, a urinary albumin-creatinine ratio >300-5000 mg/g, and an eGFR of 30 to <90 ml/min per 1.73 m2 at screening. This post hoc analysis evaluated participants with eGFR <30 ml/min per 1.73 m2 at randomization.Effects of eGFR slope through week 130 were analyzed using a piecewise, linear, mixed-effects model. Efficacy was analyzed in the intention-to-treat population, on the basis of Cox proportional hazard models, and safety was analyzed in the on-treatment population. At randomization (an average of 29 days after screening), 174 of 4401 (4%) participants had an eGFR <30 ml/min per 1.73 m2 (mean [SD] eGFR, 26 [3] ml/min per 1.73 m2).From weeks 3 to 130, there was a 66% difference in the mean rate of eGFR decline with canagliflozin versus placebo (mean slopes, -1.30 versus -3.83 ml/min per 1.73 m2 per year; difference, -2.54 ml/min per 1.73 m2 per year; 95% confidence interval [CI], 0.90 to 4.17). Effects of canagliflozin on kidney, cardiovascular, and mortality outcomes were consistent for those with eGFR <30 and ≥30 ml/min per 1.73 m2 (all P interaction >0.20). The estimate for kidney failure in participants with eGFR <30 ml/min per 1.73 m2 (hazard ratio, 0.67; 95% CI, 0.35 to 1.27) was similar to those with eGFR ≥30 ml/min per 1.73 m2 (hazard ratio, 0.70; 95% CI, 0.54 to 0.91; P interaction=0.80). There was no imbalance in the rate of kidney-related adverse events or AKI associated with canagliflozin between participants with eGFR <30 and ≥30 ml/min per 1.73 m2 (all P interaction >0.12).This post hoc analysis suggests canagliflozin slowed progression of kidney disease, without increasing AKI, even in participants with eGFR <30 ml/min per 1.73 m2.

    View details for DOI 10.2215/CJN.10140620

    View details for PubMedID 33214158

  • Relative and Absolute Risk Reductions in Cardiovascular and Kidney Outcomes With Canagliflozin Across KDIGO Risk Categories: Findings From the CANVAS Program. American journal of kidney diseases : the official journal of the National Kidney Foundation Neuen, B. L., Ohkuma, T. n., Neal, B. n., Matthews, D. R., de Zeeuw, D. n., Mahaffey, K. W., Fulcher, G. n., Blais, J. n., Li MBiostat, Q. n., Jardine, M. J., Perkovic, V. n., Wheeler, D. C. 2020

    Abstract

    Canagliflozin reduces the risk of cardiovascular and kidney outcomes in type 2 diabetes. This study aimed to assess the relative and absolute effects of canagliflozin on clinical outcomes across different Kidney Disease: Improving Global Outcomes (KDIGO) risk categories based on estimated glomerular filtration rate (eGFR) and urinary albumin:creatinine ratio (UACR.Post-hoc analysis of the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program.& Participants: The CANVAS Program randomized 10,142 participants with type 2 diabetes at high cardiovascular risk and an eGFR of ≥30 mL/min/1.73 m2 to canagliflozin or placebo.Canagliflozin or matching placebo.The primary outcome was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death, with a set of other cardiovascular and kidney pre-specified outcomes.Of 10,142 participants, 10,031 (98.9%) had available baseline eGFR and UACR data. The proportions of participants in low-, moderate-, high-, and very high-risk categories were 58.6%, 25.8%, 10.6%, and 5.0%, respectively. The relative effect of canagliflozin on the primary outcome (HR 0.86, 95% CI 0.75-0.97) was consistent across KDIGO risk categories (P-trend=0.21), with similar results for other cardiovascular and kidney outcomes. Absolute reductions in the primary outcome were greater within higher KDIGO risk categories (P-trend=0.03) with a similar pattern of effect for the composite of cardiovascular death or hospitalization for heart failure (P-trend=0.06) and for chronic eGFR slope (P-trend=0.04).Predominantly a low kidney risk population, relatively few participants in higher KDIGO risk categories, and exclusion of individuals with eGFR <30 mL/min/1.73 m2.While the relative effects of canagliflozin are similar across KDIGO risk categories, absolute risk reductions are likely greater for individuals at higher KDIGO risk. The KDIGO classification system may be able to identify individuals who might derive greater benefits for end-organ protection from treatment with canagliflozin.

    View details for DOI 10.1053/j.ajkd.2020.06.018

    View details for PubMedID 32971190

  • Diabetes and heart failure post-acute myocardial infarction: Important associations and need for evidence-based interventions. European journal of preventive cardiology Parizo, J. n., Mahaffey, K. W. 2020: 2047487320904232

    View details for DOI 10.1177/2047487320904232

    View details for PubMedID 32090588

  • Post-Discharge Bleeding and Mortality Following Acute Coronary Syndromes With or Without PCI. Journal of the American College of Cardiology Marquis-Gravel, G. n., Dalgaard, F. n., Jones, A. D., Lokhnygina, Y. n., James, S. K., Harrington, R. A., Wallentin, L. n., Steg, P. G., Lopes, R. D., Storey, R. F., Goodman, S. G., Mahaffey, K. W., Tricoci, P. n., White, H. D., Armstrong, P. W., Ohman, E. M., Alexander, J. H., Roe, M. T. 2020; 76 (2): 162–71

    Abstract

    The long-term prognostic impact of post-discharge bleeding in the unique population of patients with acute coronary syndrome (ACS) treated without percutaneous coronary intervention (PCI) remains unexplored.The aim of this study was to assess the association between post-discharge bleeding and subsequent mortality after ACS according to index strategy (PCI or no PCI) and to contrast with the association between post-discharge myocardial infarction (MI) and subsequent mortality.In a harmonized dataset of 4 multicenter randomized trials (APPRAISE-2 [Apixaban for Prevention of Acute Ischemic Events-2], PLATO [Study of Platelet Inhibition and Patient Outcomes], TRACER [Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome], and TRILOGY ACS [Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes]), the association between post-discharge noncoronary artery bypass graft-related GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) moderate, severe, or life-threatening bleeding (landmark 7 days post-ACS) and subsequent all-cause mortality was evaluated in a time-updated Cox proportional hazards analysis. Interaction with index treatment strategy was assessed. Results were contrasted with risk for mortality following post-discharge MI.Among 45,011 participants, 1,133 experienced post-discharge bleeding events (2.6 per 100 patient-years), and 2,149 died during follow-up. The risk for mortality was significantly higher <30 days (adjusted hazard ratio: 15.7; 95% confidence interval: 12.3 to 20.0) and 30 days to 12 months (adjusted hazard ratio: 2.7; 95% confidence interval: 2.1 to 3.4) after bleeding, and this association was consistent in participants treated with or without PCI for their index ACS (p for interaction = 0.240). The time-related association between post-discharge bleeding and mortality was similar to the association between MI and subsequent mortality in participants treated with and without PCI (p for interaction = 0.696).Post-discharge bleeding after ACS is associated with a similar increase in subsequent all-cause mortality in participants treated with or without PCI and has an equivalent prognostic impact as post-discharge MI.

    View details for DOI 10.1016/j.jacc.2020.05.031

    View details for PubMedID 32646565

  • Sodium-Glucose Cotransporter 2 Inhibition for the Prevention of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis. Journal of the American Heart Association Arnott, C. n., Li, Q. n., Kang, A. n., Neuen, B. L., Bompoint, S. n., Lam, C. S., Rodgers, A. n., Mahaffey, K. W., Cannon, C. P., Perkovic, V. n., Jardine, M. J., Neal, B. n. 2020; 9 (3): e014908

    Abstract

    Background Several trials have demonstrated protective effects from inhibition of sodium-glucose cotransporter 2 among patients with type 2 diabetes mellitus. There is uncertainty about the consistency of the cardiovascular benefits achieved across patient subsets. Methods and Results We included 4 large-scale trials of sodium-glucose cotransporter 2 inhibition compared with placebo in patients with diabetes mellitus that reported effects on cardiovascular outcomes overall and for participant subgroups defined at baseline by cardiovascular disease, reduced kidney function, and heart failure. Fixed effects models with inverse variance weighting were used to estimate summary hazard ratios and 95% CIs. There were 38 723 patients from 4 trials, with a mean 2.9 years of follow-up. Of the patients, 22 870 (59%) had cardiovascular disease, 7754 (20%) had reduced kidney function, and 4543 (12%) had heart failure. There were 3828 major adverse cardiac events. There was overall benefit for major adverse cardiac events (0.88; 95% CI, 0.82-0.94; P<0.001) and no evidence that the effects of sodium-glucose cotransporter 2 inhibition varied across patient subgroups, defined by the presence of cardiovascular disease or heart failure at baseline (all P interaction >0.252; I2<25%). All patient subgroups benefited with respect to hospitalization for heart failure (all P interaction>0.302; I2<10%), cardiovascular death (all P interaction>0.167; I2<50%), and death from any cause (all P interaction>0.354; I2=0%). The only difference in effects across subgroups was for stroke, with protection observed among those with reduced kidney function but not those with preserved kidney function (P interaction=0.020; I2=81%). Conclusions Sodium-glucose cotransporter 2 inhibitors protect against cardiovascular disease and death in diverse subsets of patients with type 2 diabetes mellitus regardless of cardiovascular disease history.

    View details for DOI 10.1161/JAHA.119.014908

    View details for PubMedID 31992158

  • Apixaban versus Warfarin for Stroke Prevention in Patients With End Stage Renal Disease on Hemodialysis and Atrial Fibrillation: Results of a Randomized Clinical Trial Assessing Safety Pokorney, S. D., Chertow, G. M., Al-Khalidi, H., Gallup, D., Dignacco, P., Mussina, K., Bansal, N., Gadegbeku, C. A., Garcia, D., Jones-Burton, C., Lopes, R. D., Mahaffey, K. W., Middleton, J., Mills, D., Rymer, J. A., Thadhani, R., Thomas, K. L., Winkelmayer, W. C., Granger, C. B. LIPPINCOTT WILLIAMS & WILKINS. 2019: E988–E989
  • Amino-Terminal Pro-B Type Natriuretic Peptide in the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program Januzzi, J. L., Xu, J., Shaw, W., Oh, R., Ranadive, G., Butler, J., Sattar, N., Mahaffey, K., Neal, B., Hansen, M. K. LIPPINCOTT WILLIAMS & WILKINS. 2019: E996
  • Apple Watch App Identifies Clinically Important Arrhythmias Other Than Atrial Fibrillation: Results From the Apple Heart Study Perez, M. V., Mahaffey, K., Hedlin, H., Rumsfeld, J. S., Garcia, A., Ferris, T., Balasubramanian, V., Russo, A. M., Rajmane, A., Cheung, L., Hung, G., Lee, J., Kowey, P. R., Talati, N., Nag, D., Gummidipundi, S., Beatty, A. L., Hills, M. T., Desai, S., Granger, C. B., Desai, M., Turakhia, M. LIPPINCOTT WILLIAMS & WILKINS. 2019: E988
  • The effects of canagliflozin on gout in type 2 diabetes: a post-hoc analysis of the CANVAS Program LANCET RHEUMATOLOGY Li, J., Badve, S., Zhou, Z., Rodgers, A., Day, R., Oh, R., Lee, M., Perkovic, V., de Zeeuw, D., Mahaffey, K. W., Futcher, G., Matthews, D. R., Neal, B. 2019; 1 (4): E220–E228
  • Outcomes and Anticoagulation Use After Catheter Ablation for Atrial Fibrillation. Circulation. Arrhythmia and electrophysiology Freeman, J. V., Shrader, P., Pieper, K. S., Allen, L. A., Chan, P. S., Fonarow, G. C., Gersh, B. J., Kowey, P. R., Mahaffey, K. W., Naccarelli, G., Reiffel, J. A., Singer, D. E., Go, A. S., Hylek, E. M., Steinberg, B. A., Peterson, E. D., Piccini, J. P. 2019; 12 (12): e007612

    Abstract

    BACKGROUND: Studies evaluating the effects of atrial fibrillation (AF) catheter ablation versus antiarrhythmic therapy on outcomes have shown mixed results. In addition, guidelines recommend continuing oral anticoagulation (OAC) after ablation for those at risk of stroke, but real-world data are lacking.METHODS: We evaluated outcomes including death, myocardial infarction, stroke or systemic embolism, intracranial bleeding, major bleeding, and hospitalization in patients undergoing AF ablation compared with a propensity score matched cohort of patients treated with anti-arrhythmic medications only in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation registries. Cox proportional hazards regression was performed to evaluate the association between AF ablation and outcomes. We then evaluated patterns of treatment with OAC among AF ablation patients.RESULTS: Among 21595 patients, 1190 (6%) underwent de novo AF ablation. Our propensity score-matched cohort included 1087 patients who underwent AF ablation matched 1:1 with 1087 patients treated with antiarrhythmic medications only. There were no significant differences in the risk of all-cause and cardiovascular death, and most other major adverse cardiovascular and neurological events. AF catheter ablation was associated with an increased risk of all-cause hospitalization during follow-up (hazard ratio, 1.24 [95% CI, 1.05-1.46]), particularly in the first 3 months (the standard blanking period) after the procedure. Among those who underwent AF ablation with a CHA2DS2 VASc score ≥2 for men and ≥3 for women, 23% had OAC discontinued after ablation. Among those who discontinued OAC, the median time to discontinuation was 6.2 months.CONCLUSIONS: In this large US national registry, we found no difference in adjusted rates of cardiovascular or all-cause death between patients treated with AF catheter ablation and antiarrhythmic medications only. Notably, discontinuation of OAC after ablation remains relatively common despite guideline recommendations for continued stroke prevention therapy in patients at risk of stroke.

    View details for DOI 10.1161/CIRCEP.119.007612

    View details for PubMedID 31830822

  • A double-blind, randomized, placebo-controlled pilot trial to evaluate safety and efficacy of vorapaxar on arteriovenous fistula maturation. The journal of vascular access Olivier, C. B., Sundaram, V., Chertow, G. M., Shashidhar, S., McDonnell, L. K., Ding, V. Y., Desai, M., Mahaffey, K. W., Mell, M. 2019: 1129729819887269

    Abstract

    BACKGROUND: Protease-activated receptor-1 antagonism by vorapaxar could facilitate arteriovenous fistula maturation but may increase bleeding risk.OBJECTIVE: The primary objective of the Vorapaxar Study for Maturation of arteriovenous fistula for Hemodialysis Access (VorapAccess) was to determine if vorapaxar improves arteriovenous fistula functional maturation in patients with end-stage renal disease.METHODS: VorapAccess was a randomized, placebo-controlled, double-blind pilot trial comparing 2.5mg vorapaxar per day with placebo for twelve weeks starting on day two after arteriovenous fistula creation. The primary outcome was time to functional maturation defined as successful cannulation for six hemodialysis sessions within three weeks. The planned sample size was 50 participants. The study was terminated early after withdrawal of planned financial support. Given the small number of randomized patients, we performed descriptive analyses without inference testing.RESULTS: A total of 13 participants were randomly allocated study drug (six vorapaxar and seven placebo). The median age was 56years and seven participants (54%) were female. The median (minimum-maximum) days to functional maturation were 169 (77-287)days in the vorapaxar group and 145 (48-198)days in the placebo group. Six of the 13 (46%) participants had arteriovenous fistula functional maturation within 180days; two of six (33%) in the vorapaxar group and four of seven (57%) in the placebo group. There was one bleeding event in the placebo group.CONCLUSION: Fewer than half of participants had functional maturation within 180days after surgery, suggesting a major need for agents or strategies that enhance arteriovenous fistula maturation.

    View details for DOI 10.1177/1129729819887269

    View details for PubMedID 31774037

  • Evaluating the Effects of Canagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Chronic Kidney Disease According to Baseline HbA1c, Including Those with HbA1c <7%: Results From the CREDENCE Trial. Circulation Cannon, C. P., Perkovic, V., Agarwal, R., Baldassarre, J., Bakris, G., Charytan, D. M., de Zeeuw, D., Edwards, R., Greene, T., Heerspink, H. J., Jardine, M. J., Levin, A., Li, J., Neal, B., Pollock, C., Wheeler, D. C., Zhang, H., Zinman, B., Mahaffey, K. W. 2019

    Abstract

    Traditional management of diabetes mellitus has focused on glycemic control, beginning with lifestyle changes, followed by metformin, and then other classes of antiglycemic agents.1 Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce cardiovascular (CV) events, including CV death, myocardial infarction (MI) and heart failure, and slow progression of renal dysfunction, including prevention of end-stage kidney disease (ESKD).2-3 Because initial clinical trials included mostly patients with baseline HbA1c >7%, current guidelines have recommended this class as add-on therapy for patients whose HbA1c is not at goal, typically ≥7%.1 We hypothesized that there would be similar benefits on CV and renal endpoints regardless of baseline HbA1c, including those with HbA1c <7%.

    View details for DOI 10.1161/CIRCULATIONAHA.119.044359

    View details for PubMedID 31707795

  • Guideline-directed therapies for comorbidities and clinical outcomes among individuals with atrial fibrillation. American heart journal Loring, Z., Shrader, P., Allen, L. A., Blanco, R., Chan, P. S., Ezekowitz, M. D., Fonarow, G. C., Freeman, J. V., Gersh, B. J., Mahaffey, K. W., Naccarelli, G. V., Pieper, K., Reiffel, J. A., Singer, D. E., Steinberg, B. A., Thomas, L. E., Peterson, E. D., Piccini, J. P. 2019; 219: 21–30

    Abstract

    BACKGROUND: Comorbidities are common in patients with atrial fibrillation (AF) and affect prognosis, yet are often undertreated. However, contemporary rates of use of guideline-directed therapies (GDT) for non-AF comorbidities and their association with outcomes are not well described.METHODS: We used the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF) to test the association between GDT for non-AF comorbidities and major adverse cardiac or neurovascular events (MACNE; cardiovascular death, myocardial infarction, stroke/thromboembolism, or new-onset heart failure), all-cause mortality, new-onset heart failure, and AF progression. Adjustment was performed using Cox proportional hazards models and logistic regression.RESULTS: Only 6,782 (33%) of the 20,434 patients eligible for 1 or more GDT for non-AF comorbidities received all indicated therapies. Use of all comorbidity-specific GDT was highest for patients with hyperlipidemia (75.6%) and lowest for those with diabetes mellitus (43.1%). Use of "all eligible" GDT was associated with a nonsignificant trend toward lower rates of MACNE (HR 0.90 [0.79-1.02]) and all-cause mortality (HR 0.90 [0.80-1.01]). Use of GDT for heart failure was associated with a lower risk of all-cause mortality (HR 0.77 [0.67-0.89]), and treatment of obstructive sleep apnea was associated with a lower risk of AF progression (OR 0.75 [0.62-0.90]).CONCLUSIONS: In AF patients, there is underuse of GDT for non-AF comorbidities. The association between GDT use and outcomes was strongest in heart failure and obstructive sleep apnea patients where use of GDT was associated with lower mortality and less AF progression.

    View details for DOI 10.1016/j.ahj.2019.10.008

    View details for PubMedID 31710841

  • Mediators of the Effects of Canagliflozin on HeartFailure in Patients With Type 2 Diabetes. JACC. Heart failure Li, J., Woodward, M., Perkovic, V., Figtree, G. A., Heerspink, H. J., Mahaffey, K. W., de Zeeuw, D., Vercruysse, F., Shaw, W., Matthews, D. R., Neal, B. 2019

    Abstract

    OBJECTIVES: The purpose of this study was to explore potential mediators of the effects of canagliflozin on heart failure in the CANVAS Program (CANagliflozin cardioVascular Assessment Study; NCT01032629 and CANagliflozin cardioVascular Assessment Study-Renal; NCT01989754).BACKGROUND: Canagliflozin reduced the risk of heart failure among patients with type 2 diabetes in the CANVAS Program. The mechanism of protection is uncertain.METHODS: The percentages of mediating effects of 19 biomarkers were determined by comparing the hazard ratios for the effect of randomized treatment from an unadjusted model and from a model adjusting for the biomarker of interest. Multivariable analyses were used to assess the joint effects of biomarkers that mediated most strongly in univariable analyses.RESULTS: Early changes after randomization in levels of 3 biomarkers (urinary albumin:creatinine ratio, serum bicarbonate, and serum urate) were identified as mediating the effect of canagliflozin on heart failure. Average post-randomization levels of 14 biomarkers (systolic blood pressure, low-density lipoprotein and high-density lipoprotein cholesterol,total cholesterol, urinary albumin:creatinine ratio, weight, body mass index, gamma glutamyltransferase, hematocrit, hemoglobin concentration, serum albumin, erythrocyte concentration, serum bicarbonate, and serum urate) were identified as significant mediators. Individually, the 3 biomarkers with the largest mediating effect were erythrocyte concentration (45%), hemoglobin concentration (43%), and serum urate (40%). In a parsimonious multivariable model, erythrocyte concentration, serum urate, and urinary albumin:creatinine ratio were the 3 biomarkers that maximized cumulative mediation (102%).CONCLUSIONS: A diverse set of potential mediators of the effect of canagliflozin on heart failure were identified. Some mediating effects were anticipated, whereas others were not. The mediators that were identified support existing and novel hypothesized mechanisms for the prevention of heart failure with sodium glucose cotransporter 2 inhibitors.

    View details for DOI 10.1016/j.jchf.2019.08.004

    View details for PubMedID 31676303

  • Patterns of amiodarone use and outcomes in clinical practice for atrial fibrillation. American heart journal Pokorney, S. D., Holmes, D. N., Shrader, P., Thomas, L., Fonarow, G. C., Mahaffey, K. W., Gersh, B. J., Kowey, P. R., Naccarelli, G. V., Freeman, J. V., Singer, D. E., Washam, J. B., Peterson, E. D., Piccini, J. P., Reiffel, J. A. 2019; 220: 145–54

    Abstract

    BACKGROUND: Amiodarone is the most effective antiarrhythmic drug (AAD) for atrial fibrillation (AF), but it has a high incidence of adverse effects.METHODS: Using the ORBIT AF registry, patients with AF on amiodarone at enrollment, prescribed amiodarone during follow-up, or never on amiodarone were analyzed for the proportion treated with a guideline-based indication for amiodarone, the variability in amiodarone use across sites, and the outcomes (mortality, hospitalization, and stroke) among patients treated with amiodarone. Hierarchical logistic regression modeling with site-specific random intercepts compared rates of amiodarone use across 170 sites. A logistic regression model for propensity to receive amiodarone created a propensity-matched cohort. Cox proportional hazards modeling, stratified by matched pairs evaluated the association between amiodarone and outcomes.RESULTS: Among 6,987 AF patients, 867 (12%) were on amiodarone at baseline and 451 (6%) started on incident amiodarone during the 3-year follow-up. Use of amiodarone varied among sites from 3% in the lowest tertile to 21% in the highest (p<0.0001). Among those treated, 32% had documented contraindications to other AADs or had failed another AAD in the past. Mortality, cardiovascular hospitalization, and stroke were similar among matched patients on and not on amiodarone at baseline, while incident amiodarone use in matched patients was associated with higher all-cause mortality (adjusted HR 2.06, 95% CI 1.35-3.16).CONCLUSIONS: Use of amiodarone among AF patients in community practice is highly variable. More than 2 out of 3 patients treated with amiodarone appeared to be eligible for a different AAD.

    View details for DOI 10.1016/j.ahj.2019.09.017

    View details for PubMedID 31812756

  • The Association of Health-Related Quality-of-Life Scores With Cardiovascular and Limb Outcomes in Patients With Symptomatic Peripheral Artery Disease: Insights From the EUCLID Trial Rymer, J., Mulder, H., Smolderen, K., Hiatt, W., Conte, M., Berger, J., Katona, B., Norgren, L., Mahaffey, K., Rockhold, F., Fowkes, F., Jones, S., Patel, M. ELSEVIER SCIENCE INC. 2019: B547
  • Open versus Endovascular Repair of Abdominal Aortic Aneurysm REPLY NEW ENGLAND JOURNAL OF MEDICINE Jardine, M. J., Mahaffey, K. W., Perkovic, V. 2019; 381 (11): 1089–90
  • Alirocumab in Patients With Polyvascular Disease and Recent Acute Coronary Syndrome ODYSSEY OUTCOMES Trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Jukema, J., Szarek, M., Zijlstra, L. E., de Silva, H., Bhatt, D. L., Bittner, V. A., Diaz, R., Edelberg, J. M., Goodman, S. G., Hanotin, C., Harrington, R. A., Karpov, Y., Moryusef, A., Pordy, R., Prieto, J. C., Roe, M. T., White, H. D., Zeiher, A. M., Schwartz, G. G., Steg, P., ODYSSEY OUTCOMES Comm Investigator 2019; 74 (9): 1167–76
  • Risk Categorization Using New American College of Cardiology/American Heart Association Guidelines for Cholesterol Management and Its Relation to Alirocumab Treatment Following Acute Coronary Syndromes. Circulation Roe, M. T., Li, Q. H., Bhatt, D. L., Bittner, V. A., Diaz, R., Goodman, S. G., Harrington, R. A., Jukema, J. W., Lopez-Jaramillo, P., Lopes, R. D., Louie, M. J., Moriarty, P. M., Szarek, M., Vogel, R., White, H. D., Zeiher, A. M., Baccara-Dinet, M. T., Steg, P. G., Schwartz, G. G., ODYSSEY OUTCOMES Investigators 2019

    View details for DOI 10.1161/CIRCULATIONAHA.119.042551

    View details for PubMedID 31475572

  • Cardiovascular Risk Factors and Secondary Events Among Acute and Chronic Stable Myocardial Infarction Patients: Findings from a Managed Care Database. Cardiology and therapy Bash, L. D., White, K., Patel, M. D., Liu, J., Mavros, P., Mahaffey, K. W. 2019

    Abstract

    INTRODUCTION: Long-term risk for recurrent cardiovascular events among myocardial infarction (MI) patients in the acute versus chronic stable phase is not well characterized. This study was conducted to evaluate risk factors associated with all-cause mortality and cardiovascular (CVD) morbidity and to determine the transition period from the acute to chronic stable phase of disease.METHODS: Administrative claims data from a managed care database (2007-2012) were linked to the Social Security Death Index. Kaplan-Meier curves were generated over a 3-year period. The association between risk factors and clinical endpoints was assessed using Cox proportional hazard models. Poisson models estimated the 'transition time' from acute to chronic phase of disease.RESULTS: On average, recurrent cardiovascular event rates were higher among acute MI patients in comparison to the chronic MI patients during the first 3months of follow-up. Over the 3-year follow-up period, survival curves became parallel and for some outcomes (i.e., acute myocardial infarction and bleeding events), were not statistically significantly different between the two groups. In both the acute and chronic MI cohorts, diabetes, heart failure, and renal disease were consistently statistically significant and positively associated with greater risk of death and ischemic events. PAD was consistently associated with increased risk among the chronic cohort and composite endpoints among the acute patients.CONCLUSIONS: Greater understanding of differences in the CVD risk profiles and the transition from acute to chronic stable phase may help identify high-risk patients and inform clinical risk stratification and long-term disease management in MI patients.FUNDING: Merck & Co., Inc., Kenilworth, NJ, USA.

    View details for DOI 10.1007/s40119-019-00147-5

    View details for PubMedID 31432429

  • Canagliflozin and fracture risk in individuals with type 2 diabetes: results from the CANVAS Program. Diabetologia Zhou, Z., Jardine, M., Perkovic, V., Matthews, D. R., Mahaffey, K. W., de Zeeuw, D., Fulcher, G., Desai, M., Oh, R., Simpson, R., Watts, N. B., Neal, B. 2019

    Abstract

    AIMS/HYPOTHESIS: An increased risk of fracture with canagliflozin vs placebo was reported from the CANagliflozin cardioVascular Assessment Study (CANVAS) Program, with heterogeneity of findings identified between the two trials that comprise the CANVAS Program, CANVAS and CANVAS-R. The objective of these analyses was to identify reasons for the possibly different effects on fracture observed between CANVAS and CANVAS-R.METHODS: This study was an analysis of two highly similar trials, CANVAS and CANVAS-R, conducted in 10,142 individuals with type 2 diabetes and history or high risk of cardiovascular disease who received canagliflozin (pooled 100/300mg once daily) or placebo. Outcomes assessed in this analysis were effects on adjudicated fractures overall and by type, location, association with a fall, dose and follow-up time.RESULTS: A total of 496 participants recorded ≥1 fracture event during follow-up (15.40 vs 11.93 per 1000 patient-years with canagliflozin vs placebo; HR 1.26 [95% CI 1.04, 1.52]). There was significant heterogeneity in the effects on fracture (p=0.005) between CANVAS (n=4330: HR 1.55 [95% CI 1.21, 1.97]) and CANVAS-R (n=5812: HR 0.86 [95% CI 0.62, 1.19]). The between-study heterogeneity in fracture risk was not clearly explained by differences in baseline characteristics, interactions of randomised treatment with participant characteristics, dose effects, duration of follow-up, metabolic effects, adverse events related to falls or adverse events possibly causing falls.CONCLUSIONS/INTERPRETATION: There was no evidence to explain clearly the fracture risk observed in the CANVAS Program or the heterogeneity in fracture risk between the two studies. The recently reported null result for fracture in the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial suggests that the observed association in CANVAS is likely to be a chance finding, although an unidentified fall-related mechanism remains a possibility.TRIAL REGISTRATION: ClinicalTrials.gov NCT01032629, NCT01989754.

    View details for DOI 10.1007/s00125-019-4955-5

    View details for PubMedID 31399845

  • Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups: Results from the Randomized CREDENCE Trial. Circulation Mahaffey, K. W., Jardine, M. J., Bompoint, S., Cannon, C. P., Neal, B., Heerspink, H. J., Charytan, D. M., Edwards, R., Agarwal, R., Bakris, G., Bull, S., Capuano, G., de Zeeuw, D., Greene, T., Levin, A., Pollock, C., Sun, T., Wheeler, D. C., Yavin, Y., Zhang, H., Zinman, B., Rosenthal, N., Brenner, B. M., Perkovic, V., CREDENCE study investigators 2019

    Abstract

    BACKGROUND: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without prior cardiovascular disease (primary prevention).METHODS: In CREDENCE, 4401 participants with type 2 diabetes and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care.RESULTS: Primary prevention participants (N=2181; 49.6%) were younger (61 vs 65 years), more often female (37% vs 31%), and had shorter diabetes duration (15 vs 16 years) compared to secondary prevention participants (N=2220; 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80; 95% confidence interval [CI] 0.67-0.95; P=0.01), with consistent reductions in both the primary (HR, 0.68; 95% CI, 0.49-0.94) and secondary (HR, 0.85; 95% CI, 0.69-1.06) prevention groups (P-interaction 0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78; 95% CI, 0.61-1.00), nonfatal myocardial infarction (HR, 0.81; 95% CI, 0.59-1.10), and nonfatal stroke (HR, 0.80; 95% CI, 0.56-1.15). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P-interaction >0.5 for each outcome).CONCLUSIONS: Canagliflozin significantly reduced major cardiovascular events, as well as kidney failure, in patients with type 2 diabetes and chronic kidney disease, including in participants who did not have prior cardiovascular disease.CLINICAL TRIAL REGISTRATION: URL: https://ClinicalTrials.gov Unique identifier: NCT02065791.

    View details for DOI 10.1161/CIRCULATIONAHA.119.042007

    View details for PubMedID 31291786

  • Association Between Warfarin Control Metrics and Atrial Fibrillation Outcomes in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation. JAMA cardiology Pokorney, S. D., Holmes, D. N., Thomas, L., Fonarow, G. C., Kowey, P. R., Reiffel, J. A., Singer, D. E., Freeman, J. V., Gersh, B. J., Mahaffey, K. W., Hylek, E. M., Naccarelli, G. V., Ezekowitz, M. D., Piccini, J. P., Peterson, E. D., Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Investigators 2019

    Abstract

    Importance: Bleeding and thrombotic events (eg, stroke and systemic embolism) are common in patients with atrial fibrillation (AF) taking warfarin sodium despite a well-established therapeutic range.Objective: To evaluate whether history of therapeutic warfarin control in patients with AF is independently associated with subsequent bleeding or thrombotic events.Design, Setting, and Participants: In this multicenter cohort study of 176 primary care, cardiology, and electrophysiology clinics in the United States, data were obtained during 51 830 visits among 10 137 patients with AF in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Registry; 5545 patients treated with warfarin were included in the bleeding analysis, and 5635 patients were included in the thrombotic event analysis. Patient follow-up was performed from June 29, 2010, to November 30, 2014. Data analysis was performed from August 4, 2016, to February 15, 2019.Exposures: Multiple measures of warfarin control within the preceding 6 months were analyzed: time in therapeutic range of 2.0 to 3.0, most recent international normalized ratio (INR), percentage of time that a patient had interpolated INR values less than 2.0 or greater than 3.0, INR variance, INR range, and percentage of INR values in therapeutic range.Main Outcomes and Measures: Association of INR measures, alone or in combination, with clinical factors and risk for thrombotic events and bleeding during the subsequent 6 months was assessed post hoc using logistic regression models.Results: A total of 5545 patients (mean [SD] age, 74.5 [9.8] years; 3184 [57.4%] male) with AF were included in the major bleeding analysis and 5635 patients (mean [SD] age, 74.5 [9.8] years; 3236 [57.4%] male) in the thrombotic event analysis. During a median follow-up of 1.5 years (interquartile range, 1.0-2.5 years), there were 339 major bleeds (6.1%) and 51 strokes (0.9%). Multiple metrics of warfarin control were individually associated with subsequent bleeding. After adjustment for clinical bleeding risk, 3 measures-time in therapeutic range (per 1-SD increase ≤55: adjusted odds ratio [aOR], 1.16; 95% CI, 1.02-1.32), variation in INR values (aOR, 1.32; 95% CI, 1.19-1.47), and maximum INR (aOR, 1.20; 95% CI, 1.10-1.31)-remained associated with bleeding risk. Adding INR variance to a clinical risk model slightly increased the C statistic from 0.68 to 0.69 and had a net reclassification improvement index of 0.028 (95% CI, -0.029 to 0.067). No INR measures were associated with subsequent stroke risk.Conclusions and Relevance: Three metrics of prior warfarin control were associated with bleeding risk but only marginally more so than traditional clinical factors. This study did not identify any measures of INR control that were significantly associated with stroke risk.

    View details for DOI 10.1001/jamacardio.2019.1960

    View details for PubMedID 31268487

  • Effects of alirocumab on cardiovascular and metabolic outcomes after acute coronary syndrome in patients with or without diabetes: a prespecified analysis of the ODYSSEY OUTCOMES randomised controlled trial. The lancet. Diabetes & endocrinology Ray, K. K., Colhoun, H. M., Szarek, M., Baccara-Dinet, M., Bhatt, D. L., Bittner, V. A., Budaj, A. J., Diaz, R., Goodman, S. G., Hanotin, C., Harrington, R. A., Jukema, J. W., Loizeau, V., Lopes, R. D., Moryusef, A., Murin, J., Pordy, R., Ristic, A. D., Roe, M. T., Tunon, J., White, H. D., Zeiher, A. M., Schwartz, G. G., Steg, P. G., ODYSSEY OUTCOMES Committees and Investigators, Schwartz, G. G., Steg, P. G., Bhatt, D. L., Bittner, V. A., Diaz, R., Goodman, S. G., Harrington, R. A., Jukema, J. W., Szarek, M., White, H. D., Zeiher, A. M., Tricoci, P., Roe, M. T., Mahaffey, K. W., Edelberg, J. M., Hanotin, C., Lecorps, G., Moryusef, A., Pordy, R., Sasiela, W. J., Tamby, J., Aylward, P. E., Drexel, H., Sinnaeve, P., Dilic, M., Lopes, R. D., Gotcheva, N. N., Prieto, J., Yong, H., Lopez-Jaramillo, P., Pecin, I., Reiner, Z., Ostadal, P., Viigimaa, M., Nieminen, M. S., Chumburidze, V., Marx, N., Danchin, N., Liberopoulos, E., Montenegro Valdovinos, P. C., Tse, H., Kiss, R. G., Xavier, D., Zahger, D., Valgimigli, M., Kimura, T., Kim, H. S., Kim, S., Erglis, A., Laucevicius, A., Kedev, S., Yusoff, K., Ramos Lopez, G. A., Alings, M., Halvorsen, S., Correa Flores, R. M., Budaj, A., Morais, J., Dorobantu, M., Karpov, Y., Ristic, A. D., Chua, T., Murin, J., Fras, Z., Dalby, A. J., Tunon, J., de Silva, H. A., Hagstrom, E., Landmesser, U., Chiang, C., Sritara, P., Guneri, S., Parkhomenko, A., Ray, K. K., Moriarty, P. M., Vogel, R., Chaitman, B., Kelsey, S. F., Olsson, A. G., Rouleau, J., Simoons, M. L., Alexander, K., Meloni, C., Rosenson, R., Sijbrands, E. J., Tricoci, P., Alexander, J. H., Armaganijan, L., Bagai, A., Bahit, M. C., Brennan, J. M., Clifton, S., DeVore, A. D., Deloatch, S., Dickey, S., Dombrowski, K., Ducrocq, G., Eapen, Z., Endsley, P., Eppinger, A., Harrison, R. W., Hess, C. N., Hlatky, M. A., Jordan, J. D., Knowles, J. W., Kolls, B. J., Kong, D. F., Leonardi, S., Lillis, L., Maron, D. J., Marcus, J., Mathews, R., Mehta, R. H., Mentz, R. J., Moreira, H. G., Patel, C. B., Bernardez-Pereira, S., Perkins, L., Povsic, T. J., Puymirat, E., Schuyler Jones, W., Shah, B. R., Sherwood, M. W., Stringfellow, K., Sujjavanich, D., Toma, M., Trotter, C., Van Diepen, S., Wilson, M. D., Yan, A. T., Schiavi, L. B., Garrido, M., Alvarisqueta, A. F., Sassone, S. A., Bordonava, A. P., Alves De Lima, A. E., Schmidberg, J. M., Duronto, E. A., Caruso, O. C., Novaretto, L. P., Hominal, M. A., Montana, O. R., Caccavo, A., Gomez Vilamajo, O. A., Lorenzatti, A. J., Cartasegna, L. R., Paterlini, G. A., Mackinnon, I. J., Caime, G. D., Amuchastegui, M., Salomone, O., Codutti, O. R., Jure, H. O., Bono, J. O., Hrabar, A. D., Vallejos, J. A., Ahuad Guerrero, R. A., Novoa, F., Patocchi, C. A., Zaidman, C. J., Giuliano, M. E., Dran, R. D., Vico, M. L., Carnero, G. S., Guzman, P. N., Medrano Allende, J. C., Garcia Brasca, D. F., Bustamante Labarta, M. H., Nani, S., Blumberg, E. D., Colombo, H. R., Liberman, A., Fuentealba, V., Luciardi, H. L., Waisman, G. D., Berli, M. A., Garcia Duran, R. O., Cestari, H. G., Luquez, H. A., Giordano, J. A., Saavedra, S. S., Zapata, G., Costamagna, O., Llois, S., Waites, J. H., Collins, N., Soward, A., Hii, C. L., Shaw, J., Arstall, M. A., Horowitz, J., Ninio, D., Rogers, J. F., Colquhoun, D., Oqueli Flores, R. E., Roberts-Thomson, P., Raffel, O., Lehman, S. J., Aroney, C., Coverdale, S. G., Garrahy, P. J., Starmer, G., Sader, M., Carroll, P. A., Dick, R., Zweiker, R., Hoppe, U., Huber, K., Berger, R., Delle-Karth, G., Frey, B., Weidinger, F., Faes, D., Hermans, K., Pirenne, B., Leone, A., Hoffer, E., Vrolix, M. C., De Wolf, L., Wollaert, B., Castadot, M., Dujardin, K., Beauloye, C., Vervoort, G., Striekwold, H., Convens, C., Roosen, J., Barbato, E., Claeys, M., Cools, F., Terzic, I., Barakovic, F., Midzic, Z., Pojskic, B., Fazlibegovic, E., Kulic, M., Durak-Nalbantic, A., Vulic, D., Muslibegovic, A., Goronja, B., Reis, G., Sousa, L., Nicolau, J. C., Giorgeto, F. E., Silva, R. P., Nigro Maia, L., Rech, R., Rossi, P. R., Cerqueira, M. J., Duda, N., Kalil, R., Kormann, A., Abrantes, J. A., Pimentel Filho, P., Soggia, A. P., de Santos, M. O., Neuenschwander, F., Bodanese, L. C., Michalaros, Y. L., Eliaschewitz, F. G., Vidotti, M. H., Leaes, P. E., Botelho, R. V., Kaiser, S., Manenti, E. R., Precoma, D. B., Moura Jorge, J. C., de B Silva, P. G., Silveira, J. A., Saporito, W., Marin-Neto, J. A., Feitosa, G. S., Ritt, L. E., de Souza, J. A., Costa, F., Souza, W. K., Reis, H. J., Machado, L., Ayoub, J. C., Todorov, G. V., Nikolov, F. P., Velcheva, E. S., Tzekova, M. L., Benov, H. O., Petranov, S. L., Tumbev, H. S., Shehova-Yankova, N. S., Markov, D. T., Raev, D. H., Mollov, M. N., Kichukov, K. N., Ilieva-Pandeva, K. A., Ivanova, R., Gospodinov, M., Mincheva, V. M., Lazov, P. V., Dimov, B. I., Senaratne, M., Stone, J., Kornder, J., Pearce, S., Dion, D., Savard, D., Pesant, Y., Pandey, A., Robinson, S., Gosselin, G., Vizel, S., Hoag, G., Bourgeois, R., Morisset, A., Sabbah, E., Sussex, B., Kouz, S., MacDonald, P., Diaz, A., Michaud, N., Fell, D., Leung, R., Vuurmans, T., Lai, C., Nigro, F., Davies, R., Nogareda, G., Vijayaraghavan, R., Ducas, J., Lepage, S., Mehta, S., Cha, J., Dupuis, R., Fong, P., Lutchmedial, S., Rodes-Cabau, J., Fadlallah, H., Cleveland, D., Huynh, T., Bata, I., Hameed, A., Pincetti, C., Potthoff, S., Prieto, J. C., Acevedo, M., Aguirre, A., Vejar, M., Yanez, M., Araneda, G., Fernandez, M., Perez, L., Varleta, P., Florenzano, F., Huidobro, L., Raffo, C. A., Olivares, C., Nahuelpan, L., Montecinos, H., Chen, J., Dong, Y., Huang, W., Wang, J., Huang, S., Yao, Z., Li, X., Cui, L., Lin, W., Sun, Y., Wang, J., Li, J., Zhang, X., Zhu, H., Chen, D., Huang, L., Dong, S., Su, G., Xu, B., Su, X., Cheng, X., Lin, J., Zong, W., Li, H., Feng, Y., Xu, D., Yang, X., Ke, Y., Lin, X., Zhang, Z., Zheng, Z., Luo, Z., Chen, Y., Ding, C., Zhong, Y., Zheng, Y., Li, X., Peng, D., Zhao, S., Li, Y., Liu, X., Wei, M., Liu, S., Yu, Y., Qu, B., Jiang, W., Zhou, Y., Zhao, X., Yuan, Z., Guo, Y., Xu, X., Shi, X., Ge, J., Fu, G., Bai, F., Fang, W., Shou, X., Yang, X., Wang, J., Xiang, M., Sun, Y., Lu, Q., Zhang, R., Zhu, J., Xu, Y., Fan, Z., Li, T., Wu, C., Jaramillo, N., Sanchez Vallejo, G., Luna Botia, D. C., Botero Lopez, R., Molina De Salazar, D. I., Cadena Bonfanti, A. J., Cotes Aroca, C., Diego Higuera, J., Blanquicett, M., Barrera Silva, S. I., Garcia Lozada, H. J., Coronel Arroyo, J. A., Accini Mendoza, J. L., Fernandez Ruiz, R. L., Quintero Ossa, A. M., Manzur Jatin, F. G., Sotomayor Herazo, A., Castellanos Parada, J., Suarez Arambula, R., Urina Triana, M. A., Fernandez Trujillo, A. M., Strozzi, M., Car, S., Jeric, M., Milicic, D., Bencic, M. L., Pintaric, H., Prvulovic, D., Sikic, J., Persic, V., Mileta, D., Stambuk, K., Babic, Z., Tomulic, V., Lukenda, J., Mejic-Krstulovic, S., Starcevic, B., Spinar, J., Horak, D., Velicka, Z., Stasek, J., Alan, D., Machova, V., Linhart, A., Novotny, V., Kaucak, V., Rokyta, R., Naplava, R., Coufal, Z., Adamkova, V., Podpera, I., Zizka, J., Motovska, Z., Marusincova, I., Svab, P., Heinc, P., Kuchar, J., Povolny, P., Matuska, J., Poulsen, S. H., Raungaard, B., Clemmensen, P., Bang, L. E., May, O., Bottcher, M., Hove, J. D., Frost, L., Gislason, G., Larsen, J., Betton Johansen, P., Hald, F., Johansen, P., Jeppesen, J., Nielsen, T., Kristensen, K. S., Walichiewicz, P. M., Lomholdt, J. D., Klausen, I. C., Nielsen, P. K., Davidsen, F., Videbaek, L., Soots, M., Vahula, V., Hedman, A., Soopold, U., Martsin, K., Jurgenson, T., Kristjan, A., Helsinki, J. K., Vikman, S., Huikuri, H., Airaksinen, J., Coste, P., Ferrari, E., Morel, O., Montalescot, G., Machecourt, J., Barone-Rochette, G., Mansourati, J., Cottin, Y., Leclercq, F., Belhassane, A., Delarche, N., Boccara, F., Paganelli, F., Clerc, J., Schiele, F., Aboyans, V., Probst, V., Berland, J., Lefevre, T., Citron, B., Khintibidze, I., Shaburishvili, T., Pagava, Z., Ghlonti, R., Lominadze, Z., Khabeishvili, G., Hemetsberger, R., Edward, K., Rauch-Krohnert, U., Stratmann, M., Appel, K., Schmidt, E., Omran, H., Stellbrink, C., Dorsel, T., Lianopoulos, E., Vohringer, H. F., Marx, R., Zirlik, A., Schellenberg, D., Heitzer, T., Laufs, U., Werner, C., Marx, N., Gielen, S., Nuding, S., Winkelmann, B., Behrens, S., Sydow, K., Karakas, M., Simonis, G., Muenzel, T., Werner, N., Leggewie, S., Bocker, D., Braun-Dullaeus, R., Toursarkissian, N., Jeserich, M., WeiSSbrodt, M., Schaeufele, T., Weil, J., Voller, H., Waltenberger, J., Natour, M., Schmitt, S., Muller-Wieland, D., Steiner, S., Heidenreich, L., Offers, E., Gremmler, U., Killat, H., Rieker, W., Patsilinakos, S., Kartalis, A., Manolis, A., Sionis, D., Chachalis, G., Skoumas, I., Athyros, V., Vardas, P., Parthenakis, F., Alexopoulos, D., Hahalis, G., Lekakis, J., Hatzitolios, A., Fausto Ovando, S. R., Arango Benecke, J. L., Rodriguez De Leon, E. R., Yan, B. P., Siu, D. C., Turi, T., Merkely, B., Ungi, I., Lupkovics, G., Nagy, L., Katona, A., Edes, I., Muller, G., Horvath, I., Kapin, T., Szigeti, Z., Falukozy, J., Kumbla, M., Sandhu, M., Annam, S., Proddutur, N. R., Regella, R., Premchand, R. 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K., Bhansali, P., Borse, R., Rahul, P., Das, S., Kumar, V., Abdullakutty, J., Saathe, S., Palimkar, P., Sathe, S., Atar, S., Shechter, M., Mosseri, M., Arbel, Y., Ehud, C., Ofer, H., Lotan, C., Rosenschein, U., Katz, A., Henkin, Y., Francis, A., Klutstein, M., Nikolsky, E., Zukermann, R., Turgeman, Y., Halabi, M., Marmor, A., Kornowski, R., Jonas, M., Amir, O., Hasin, Y., Rozenman, Y., Fuchs, S., Zvi, V., Hussein, O., Gavish, D., Vered, Z., Caraco, Y., Elias, M., Tov, N., Wolfovitz, E., Lishner, M., Elias, N., Piovaccari, G., De Pellegrin, A., Garbelotto, R., Guardigli, G., Marco, V., Licciardello, G., Auguadro, C., Scalise, F., Cuccia, C., Salvioni, A., Musumeci, G., Senni, M., Calabro, P., Novo, S., Faggiano, P., Metra, M., De Cesare, N. 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D., Alsweiler, C., Luyten, A., Butters, J., Griffith, L., Shaw, M., Grunberg, L., Islam, S., Bregeault, M., Bougon, N., Faustino, D., Fontecave, S., Murphy, J., Verrier, M., Agnetti, V., Andersen, D., Badreddine, E., Bekkouche, M., Bouancheau, C., Brigui, I., Brocklehurst, M., Cianciarulo, J., Devaul, D., Domokos, S., Gache, C., Gobillot, C., Guillou, S., Healy, J., Heath, M., Jaiwal, G., Javierre, C., Labeirie, J., Monier, M., Morales, U., Mrabti, A., Mthombeni, B., Okan, B., Smith, L., Sheller, J., Sopena, S., Pellan, V., Benbernou, F., Bengrait, N., Lamoureux, M., Kralova, K., Scemama, M., Bejuit, R., Coulange, A., Berthou, C., Repincay, J., Lorenzato, C., Etienne, A., Gouet, V., Lecorps, G., Loizeau, V., Normand, M., Ourliac, A., Rondel, C., Adamo, A., Beltran, P., Barraud, P., Dubois-Gache, H., Halle, B., Metwally, L., Mourgues, M., Sotty, M., Vincendet, M., Cotruta, R., Chengyue, Z., Fournie-Lloret, D., Morrello, C., Perthuis, A., Picault, P., Zobouyan, I., Colhoun, H. M., Dempsey, M. A., McClanahan, M. A. 2019

    Abstract

    BACKGROUND: After acute coronary syndrome, diabetes conveys an excess risk of ischaemic cardiovascular events. A reduction in mean LDL cholesterol to 1·4-1·8 mmol/L with ezetimibe or statins reduces cardiovascular events in patients with an acute coronary syndrome and diabetes. However, the efficacy and safety of further reduction in LDL cholesterol with an inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) after acute coronary syndrome is unknown. We aimed to explore this issue in a prespecified analysis of the ODYSSEY OUTCOMES trial of the PCSK9 inhibitor alirocumab, assessing its effects on cardiovascular outcomes by baseline glycaemic status, while also assessing its effects on glycaemic measures including risk of new-onset diabetes.METHODS: ODYSSEY OUTCOMES was a randomised, double-blind, placebo-controlled trial, done at 1315 sites in 57 countries, that compared alirocumab with placebo in patients who had been admitted to hospital with an acute coronary syndrome (myocardial infarction or unstable angina) 1-12 months before randomisation and who had raised concentrations of atherogenic lipoproteins despite use of high-intensity statins. Patients were randomly assigned (1:1) to receive alirocumab or placebo every 2 weeks; randomisation was stratified by country and was done centrally with an interactive voice-response or web-response system. Alirocumab was titrated to target LDL cholesterol concentrations of 0·65-1·30 mmol/L. In this prespecified analysis, we investigated the effect of alirocumab on cardiovascular events by glycaemic status at baseline (diabetes, prediabetes, or normoglycaemia)-defined on the basis of patient history, review of medical records, or baseline HbA1c or fasting serum glucose-and risk of new-onset diabetes among those without diabetes at baseline. The primary endpoint was a composite of death from coronary heart disease, non-fatal myocardial infarction, fatal or non-fatal ischaemic stroke, or unstable angina requiring hospital admission. ODYSSEY OUTCOMES is registered with ClinicalTrials.gov, number NCT01663402.FINDINGS: At study baseline, 5444 patients (28·8%) had diabetes, 8246 (43·6%) had prediabetes, and 5234 (27·7%) had normoglycaemia. There were no significant differences across glycaemic categories in median LDL cholesterol at baseline (2·20-2·28 mmol/L), after 4 months' treatment with alirocumab (0·80 mmol/L), or after 4 months' treatment with placebo (2·25-2·28 mmol/L). In the placebo group, the incidence of the primary endpoint over a median of 2·8 years was greater in patients with diabetes (16·4%) than in those with prediabetes (9·2%) or normoglycaemia (8·5%); hazard ratio (HR) for diabetes versus normoglycaemia 2·09 (95% CI 1·78-2·46, p<0·0001) and for diabetes versus prediabetes 1·90 (1·65-2·17, p<0·0001). Alirocumab resulted in similar relative reductions in the incidence of the primary endpoint in each glycaemic category, but a greater absolute reduction in the incidence of the primary endpoint in patients with diabetes (2·3%, 95% CI 0·4 to 4·2) than in those with prediabetes (1·2%, 0·0 to 2·4) or normoglycaemia (1·2%, -0·3 to 2·7; absolute risk reduction pinteraction=0·0019). Among patients without diabetes at baseline, 676 (10·1%) developed diabetes in the placebo group, compared with 648 (9·6%) in the alirocumab group; alirocumab did not increase the risk of new-onset diabetes (HR 1·00, 95% CI 0·89-1·11). HRs were 0·97 (95% CI 0·87-1·09) for patients with prediabetes and 1·30 (95% CI 0·93-1·81) for those with normoglycaemia (pinteraction=0·11).INTERPRETATION: After a recent acute coronary syndrome, alirocumab treatment targeting an LDL cholesterol concentration of 0·65-1·30 mmol/L produced about twice the absolute reduction in cardiovascular events among patients with diabetes as in those without diabetes. Alirocumab treatment did not increase the risk of new-onset diabetes.FUNDING: Sanofi and Regeneron Pharmaceuticals.

    View details for DOI 10.1016/S2213-8587(19)30158-5

    View details for PubMedID 31272931

  • Acute Limb Ischemia in Peripheral Artery Disease: Insights from EUCLID. Circulation Hess, C. N., Huang, Z., Patel, M. R., Baumgartner, I., Berger, J. S., Blomster, J. I., Fowkes, F. G., Held, P., Jones, W. S., Katona, B., Mahaffey, K. W., Norgren, L., Rockhold, F. W., Hiatt, W. R. 2019

    Abstract

    BACKGROUND: Acute limb ischemia (ALI) is an important clinical event and an emerging cardiovascular clinical trial outcome. Risk factors for and outcomes after ALI have not been fully evaluated.METHODS: EUCLID randomized patients with peripheral artery disease (PAD) to ticagrelor versus clopidogrel. Enrollment criteria included an ankle-brachial index (ABI) ≤0.80 or prior lower extremity revascularization. Patients were grouped according to the primary outcome, post-randomization ALI hospitalization. Baseline factors associated with ALI were identified using Cox proportional hazards modeling. Models with ALI hospitalization as a time-dependent covariate were developed for secondary outcomes of major adverse cardiovascular events (MACE: myocardial infarction, cardiovascular death, ischemic stroke), all-cause mortality, and major amputation.RESULTS: Among 13,885 patients, 1.7% (n=232) had 293 ALI hospitalizations (0.8 per 100 patient-years). Patients with versus without ALI were younger and more often had prior peripheral revascularization and lower baseline ABI. Treatment during ALI hospitalization included endovascular revascularization (39.2%, n=115), surgical bypass (24.6%, n=72), and major amputation (13.0%, n=38). After multivariable adjustment, any prior peripheral revascularization (HR 4.7, 95% CI 3.3-6.8, p<0.01), baseline atrial fibrillation (HR 1.8, 95% CI 1.1-3.2, p=0.03), and baseline ABI ≤0.60 (HR 1.3 per 0.10 decrease, 95% CI 1.1-1.5, p<0.01) were associated with higher ALI risk. Older age (HR 0.8 per 10-year increase, 95% CI 0.7-1.0, p=0.02) and baseline statin use (HR 0.7, 95% CI 0.5-0.9, p<0.01) were associated with lower risk for ALI. There was no relationship between randomized treatment to ticagrelor or clopidogrel and ALI. Among patients with prior revascularization, surgical versus endovascular procedures performed more than 6 months prior were associated with ALI (adjusted HR 2.63, 95% CI 1.75-3.96). In the overall population, ALI hospitalization was associated with subsequent MACE (adjusted HR 1.4, 95% CI 1.0-2.1, p=0.04), all-cause mortality (adjusted HR 3.3, 95% CI 2.4-4.6, p<0.01), and major amputation (adjusted HR 34.2, 95% CI 9.7-20.8, p<0.01).CONCLUSIONS: Prior peripheral revascularization, baseline atrial fibrillation, and lower ABI identify PAD patients at heightened risk for ALI, an event associated with subsequent cardiovascular and limb-related morbidity and mortality.CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov Unique Identifier: NCT01732822.

    View details for DOI 10.1161/CIRCULATIONAHA.119.039773

    View details for PubMedID 31238713

  • Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy NEW ENGLAND JOURNAL OF MEDICINE Perkovic, V., Jardine, M. J., Neal, B., Bompoint, S., Heerspink, H. L., Charytan, D. M., Edwards, R., Agarwal, R., Bakris, G., Bull, S., Cannon, C. P., Capuano, G., Chu, P., De Zeeuw, D., Greene, T., Levin, A., Pollock, C., Wheeler, D. C., Yavin, Y., Zhang, H., Zinman, B., Meininger, G., Brenner, B. M., Mahaffey, K. W., CREDENCE Trial Investigators 2019; 380 (24): 2295–2306
  • EGFR LOSS WITH GLUCAGON-LIKE PEPTIDE-1 (GLP-1) ANALOGUE TREATMENT: DATA FROM SUSTAIN 6 AND LEADER Perkovic, V., Bain, S., Bakris, G., Buse, J., Gondolf, T., Idorn, T., Lausvig, N., Mahaffey, K., Marso, S., Nauck, M., Pratley, R., Rossing, P., Zinman, B., Mann, J. OXFORD UNIV PRESS. 2019
  • Stroke in Patients With Peripheral Artery Disease: Insights From the EUCLID Study STROKE Kolls, B. J., Sapp, S., Rockhold, F. W., Jordan, J., Dombrowski, K. E., Fowkes, F. R., Mahaffey, K. W., Berger, J. S., Katona, B. G., Blomster, J. I., Norgren, L., Abramson, B. L., Leiva-Pons, J. L., Carlos Prieto, J., Sokurenko, G., Hiatt, W. R., Jones, W., Patel, M. R. 2019; 50 (6): 1356–63
  • Effects of canagliflozin on amputation risk in type 2 diabetes: the CANVAS Program DIABETOLOGIA Matthews, D. R., Li, Q., Perkovic, V., Mahaffey, K. W., de Zeeuw, D., Fulcher, G., Desai, M., Hiatt, W. R., Nehler, M., Fabbrini, E., Kavalam, M., Lee, M., Neal, B. 2019; 62 (6): 926–38
  • Characteristics of Digital Health Studies Registered in ClinicalTrials.gov JAMA INTERNAL MEDICINE Chen, C. E., Harrington, R. A., Desai, S. A., Mahaffey, K. W., Turakhia, M. P. 2019; 179 (6): 838–40
  • DIFFERENT EGFR THRESHOLDS AND THE RENAL EFFECTS OF CANAGLIFLOZIN: DATA FROM THE CANVAS PROGRAM Oshima, M., Ohkuma, T., Neal, B., Li, Q., De Zeeuw, D., Mahaffey, K. W., Fulcher, G., Canovatchel, W., Matthews, D. R., Perkovic, V. OXFORD UNIV PRESS. 2019: 206
  • EFFECTS OF SEMAGLUTIDE AND LIRAGLUTIDE ON URINARY ALBUMIN-TO-CREATININE RATIO (UACR) - A POOLED ANALYSIS OF SUSTAIN 6 AND LEADER Perkovic, V., Bain, S., Bakris, G., Buse, J., Idorn, T., Mahaffey, K., Marso, S., Nauck, M., Pratley, R., Rasmussen, S., Rossing, P., Tornoe, K., Zinman, B., Mann, J. OXFORD UNIV PRESS. 2019: 205–U715
  • EFFECTS OF THE GLUCAGON-LIKE PEPTIDE-1 (GLP-1) ANALOGUES SEMAGLUTIDE AND LIRAGLUTIDE ON RENAL OUTCOMES - A POOLED ANALYSIS OF THE SUSTAIN 6 AND LEADER TRIALS Perkovic, V., Bain, S., Bakris, G., Buse, J., Idorn, T., Mahaffey, K., Marso, S., Nauck, M., Pratley, R., Rasmussen, S., Rossing, P., Tornoe, K., Zinman, B., Mann, J. OXFORD UNIV PRESS. 2019: 338
  • Stroke in Patients With Peripheral Artery Disease. Stroke Kolls, B. J., Sapp, S., Rockhold, F. W., Jordan, J. D., Dombrowski, K. E., Fowkes, F. G., Mahaffey, K. W., Berger, J. S., Katona, B. G., Blomster, J. I., Norgren, L., Abramson, B. L., Leiva-Pons, J. L., Prieto, J. C., Sokurenko, G., Hiatt, W. R., Jones, W. S., Patel, M. R. 2019: STROKEAHA118023534

    Abstract

    Background and Purpose- Predictors of stroke and transient ischemic attack (TIA) in patients with peripheral artery disease (PAD) are poorly understood. The primary aims of this analysis were to (1) determine the incidence of ischemic/hemorrhagic stroke and TIA in patients with symptomatic PAD, (2) identify predictors of stroke in patients with PAD, and (3) compare the rate of stroke in ticagrelor- and clopidogrel-treated patients. Methods- EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) randomized 13 885 patients with symptomatic PAD to receive monotherapy with ticagrelor or clopidogrel for the prevention of major adverse cardiovascular events (cardiovascular death, myocardial infarction, or ischemic stroke). Ischemic/hemorrhagic stroke and TIA were adjudicated and measured as incidence rates postrandomization and cumulative incidence (per patient-years). Post hoc multivariable competing risk hazards analyses were performed using baseline characteristics to determine factors associated with all-cause stroke in patients with PAD. Results- A total of 458 cerebrovascular events in 424 patients (317 ischemic strokes, 39 hemorrhagic strokes, and 102 TIAs) occurred over a median follow-up of 30 months, for a cumulative incidence of 0.87, 0.11, and 0.27 per 100 patient-years, respectively. Age, prior stroke, prior atrial fibrillation/flutter, diabetes mellitus, geographic region, ankle-brachial index <0.60, prior amputation, and systolic blood pressure were independent baseline factors associated with the occurrence of all-cause stroke. After adjustment for baseline factors, the rates of ischemic stroke and all-cause stroke remained lower in patients treated with ticagrelor as compared with those receiving clopidogrel. There was no significant difference in the incidence of hemorrhagic stroke or TIA between the 2 treatment groups. Conclusions- In patients with symptomatic PAD, ischemic stroke and TIA occur frequently over time. Comorbidities such as age, prior stroke, prior atrial fibrillation/flutter, diabetes mellitus, higher blood pressure, prior amputation, lower ankle-brachial index, and geographic region were each independently associated with the occurrence of all-cause stroke. Use of ticagrelor, as compared with clopidogrel, was associated with a lower adjusted rate of ischemic and all-cause stroke. Further study is needed to optimize medical management and risk reduction of all-cause stroke in patients with PAD. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT01732822.

    View details for PubMedID 31092165

  • Blood Pressure Control and Cardiovascular Outcomes in Patients With Atrial Fibrillation (From the ORBIT-AF Registry) AMERICAN JOURNAL OF CARDIOLOGY Vemulapalli, S., Inohara, T., Kim, S., Thomas, L., Piccini, J. P., Patel, M. R., Chang, P., Fonarow, G. C., Ezekowitz, M. D., Hylek, E., Go, A. S., Kowey, P. R., Mahaffey, K. W., Gersh, B. J., Peterson, E. D. 2019; 123 (10): 1628–36
  • Association of frailty and cognitive impairment with benefits of oral anticoagulation in patients with atrial fibrillation AMERICAN HEART JOURNAL Madhavan, M., Holmes, D. N., Piccini, J. P., Ansell, J. E., Fonarow, G. C., Hylek, E. M., Kowey, P. R., Mahaffey, K. W., Thomas, L., Peterson, E. D., Chan, P., Allen, L. A., Gersh, B. J., ORBIT AF Investigators 2019; 211: 77–89
  • Treatment of atrial fibrillation with concomitant coronary or peripheral artery disease: Results from the outcomes registry for better informed treatment of atrial fibrillation II. American heart journal Inohara, T., Shrader, P., Pieper, K., Blanco, R. G., Allen, L. A., Fonarow, G. C., Gersh, B. J., Go, A. S., Ezekowitz, M. D., Kowey, P. R., Reiffel, J. A., Naccarelli, G. V., Chan, P. S., Mahaffey, K. W., Singer, D. E., Freeman, J. V., Steinberg, B. A., Peterson, E. D., Piccini, J. P., ORBIT AF Patients and Investigators 2019; 213: 81–90

    Abstract

    BACKGROUND: Treatment patterns and outcomes of individuals with vascular disease who have new-onset atrial fibrillation (AF) are not well characterized.METHODS: Among patients with new-onset AF, we analyzed treatment and outcomes in those with or without vascular disease in the ORBIT-AF II registry. Vascular disease was defined as coronary disease with or without myocardial infarction (MI) or revascularization, or peripheral artery disease. The primary outcomes included major adverse cardiovascular or neurological events (MACNE) and major bleeding. Cox proportional hazard models were used to adjust the difference in patient characteristics.RESULTS: Overall 1920 of 6203 (31.0%) of new-onset AF had vascular disease. In patients with vascular disease, 62.2% of those were treated with direct oral anticoagulants (DOACs) and 23.4% with warfarin. Dual therapy and triple therapy were used in 36.9% and 4.9%, respectively. Vascular disease patients had increased risk of MACNE (adjusted hazard ratio [aHR] 1.83 [95%CIs 1.32-2.55]), but not major bleeding (aHR 1.24 [0.95-1.63]). Among patients with vascular disease, relative to those on warfarin, those treated with DOACs had similar risk for MACNE (aHR 1.20 [0.77-1.87]) but lower risks for bleeding, although it did not reach statistical significance (aHR 0.70 [0.43-1.15]). Concomitant antiplatelet therapy was associated with higher bleeding (aHR 2.27 [1.38-3.73]) with no apparent reduction in MACNE (aHR 1.50 [1.00-2.25]).CONCLUSIONS: Most patients with AF and vascular disease were managed with oral anticoagulation. About half of them were also treated with concomitant antiplatelet therapy, which was associated with increased risk of bleeding, without evidence of improved cardiovascular outcomes.

    View details for DOI 10.1016/j.ahj.2019.04.007

    View details for PubMedID 31129441

  • Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. The New England journal of medicine Perkovic, V., Jardine, M. J., Neal, B., Bompoint, S., Heerspink, H. J., Charytan, D. M., Edwards, R., Agarwal, R., Bakris, G., Bull, S., Cannon, C. P., Capuano, G., Chu, P., de Zeeuw, D., Greene, T., Levin, A., Pollock, C., Wheeler, D. C., Yavin, Y., Zhang, H., Zinman, B., Meininger, G., Brenner, B. M., Mahaffey, K. W., CREDENCE Trial Investigators 2019

    Abstract

    BACKGROUND: Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium-glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes.METHODS: In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin-angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically.RESULTS: The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture.CONCLUSIONS: In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years. (Funded by Janssen Research and Development; CREDENCE ClinicalTrials.gov number, NCT02065791.).

    View details for PubMedID 30990260

  • Efficacy and safety of rivaroxaban vs. warfarin in patients with non-valvular atrial fibrillation and a history of cancer: observations from ROCKETAF EUROPEAN HEART JOURNAL-QUALITY OF CARE AND CLINICAL OUTCOMES Chen, S. T., Hellkamp, A. S., Becker, R. C., Berkowitz, S. D., Breithardt, G., Fox, K. A., Hacke, W., Halperin, J. L., Hankey, G. J., Mahaffey, K., Nessel, C. C., Piccini, J. P., Singer, D. E., Patel, M. R., Melloni, C. 2019; 5 (2): 145–52
  • Effects of Canagliflozin on Heart Failure Outcomes Associated with Preserved and Reduced Ejection Fraction in Type 2 Diabetes: Results from the CANVAS Program. Circulation Figtree, G. A., Radholm, K., Barrett, T. D., Perkovic, V., Mahaffey, K. W., de Zeeuw, D., Fulcher, G., Matthews, D. R., Shaw, W., Neal, B. 2019

    Abstract

    Patients with type 2 diabetes mellitus are at high risk of developing heart failure (HF).1 Sodium glucose co-transporter 2 (SGLT2) inhibitors have been demonstrated, in large scale trials, to reduce the risk of HF events in patients with type 2 diabetes deemed to be at high risk based on established cardiovascular disease or multiple risk factors.2-4 However, it is unclear whether benefits are experienced across the broad spectrum of HF patients that includes those with preserved (HFpEF) as well as reduced ejection fraction (HFrEF).

    View details for PubMedID 30882240

  • EFFICACY OF A CENTRALIZED, BLENDED ELECTRONIC, AND HUMAN INTERVENTION TO IMPROVE DOAC ADHERENCE: THE SMARTADHERE TRIAL Turakhia, M. P., Sundaram, V., Smith, S., Ding, V., Ho, P., Kowey, P. R., Piccini, J., Foody, J., Birmingham, M., Ianus, J., Rajmane, A., Mahaffey, K. ELSEVIER SCIENCE INC. 2019: 510
  • Effects of canagliflozin on amputation risk in type 2 diabetes: the CANVAS Program. Diabetologia Matthews, D. R., Li, Q., Perkovic, V., Mahaffey, K. W., de Zeeuw, D., Fulcher, G., Desai, M., Hiatt, W. R., Nehler, M., Fabbrini, E., Kavalam, M., Lee, M., Neal, B. 2019

    Abstract

    AIMS/HYPOTHESIS: The primary analysis of the Canagliflozin cardioVascular Assessment Study (CANVAS) Program showed canagliflozin to have a beneficial effect on cardiovascular and renal outcomes in people with type 2 diabetes at high cardiovascular risk, but also an unexpected increased risk of major or minor lower extremity amputation. These secondary analyses explore this finding in more detail.METHODS: The effect of canagliflozin on amputation risk in the CANVAS Program was calculated for amputations of different types and proximate aetiologies and different canagliflozin doses. Univariate and multivariate associations of baseline characteristics with amputation risk were determined and proportional and absolute effects of canagliflozin were compared across subgroups.RESULTS: There were 187 (1.8%) participants with atraumatic lower extremity amputations (minor 71%, major 29%); as previously published, rates were 6.30 vs 3.37 per 1000 participant-years with canagliflozin vs placebo (HR 1.97 [95% CI 1.41, 2.75]). Risk was similar for ischaemic and infective aetiologies and for 100mg and 300mg doses. Overall amputation risk was strongly associated with baseline history of prior amputation (major or minor) (HR 21.31 [95% CI 15.40, 29.49]) and other established risk factors. No interactions between randomised treatment and participant characteristics explained the effect of canagliflozin on amputation risk. For every clinical subgroup studied, numbers of amputation events projected were smaller than numbers of major adverse cardiovascular events averted.CONCLUSIONS/INTERPRETATION: The CANVAS Program demonstrated that canagliflozin increased the risk of amputation (mainly minor) in this study population. Anticipated risk factors for amputation were identified, such as prior history of amputation, peripheral vascular disease and neuropathy, but no specific aetiological mechanism or at-risk subgroup for canagliflozin was identified.

    View details for PubMedID 30868176

  • B-type natriuretic peptide, disease progression and clinical outcomes in atrial fibrillation HEART Inohara, T., Kim, S., Pieper, K., Blanco, R. G., Allen, L. A., Fonarow, G. C., Gersh, B. J., Ezekowitz, M. D., Kowey, P. R., Reiffel, J. A., Naccarelli, G. V., Chan, P. S., Mahaffey, K. W., Singer, D. E., Freeman, J. V., Steinberg, B. A., Peterson, E. D., Piccini, J. P., ORBIT AF Patients & Investigators 2019; 105 (5): 370–77
  • Periprocedural Outcomes According to Timing of Clopidogrel Loading Dose in Patients Who Did Not Receive P2Y12 Inhibitor Pretreatment. Circulation. Cardiovascular interventions Abtan, J., Ducrocq, G., Steg, P. G., Stone, G. W., Mahaffey, K. W., Gibson, C. M., Hamm, C. W., Price, M. J., Prats, J., Deliargyris, E. N., White, H. D., Harrington, R. A., Bhatt, D. L. 2019; 12 (3): e007445

    Abstract

    BACKGROUND: In patients undergoing percutaneous coronary intervention (PCI), who did not receive P2Y12 inhibitor pretreatment, the optimal timing of P2Y12 inhibitor loading dose remains debated. We sought to examine whether the choice of administration of the clopidogrel loading dose before or after the start of PCI had an impact on periprocedural complications, including bleeding.METHODS AND RESULTS: The CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention) double-blind randomized trial compared cangrelor with clopidogrel loading dose at the time of PCI. Pretreatment with clopidogrel before randomization was not permitted per protocol. In the clopidogrel-only group (n=5438), a loading dose was given before (early load [EL]) or after the start of PCI (late load [LL]) according to physician choice. Overall, 3442 (63.3%) patients had EL and 1997 LL (36.7%). Median times were 5 minutes before and 20 minutes after the start of PCI, respectively. EL was more frequently used among patients with ST-segment-elevation myocardial infarction (84.4%) and non-ST-segment-elevation acute coronary syndromes (71.5%) than in stable patients (53.7%). At 48 hours, rates of the primary outcome of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis were similar (6.0% versus 5.4%) for EL versus LL, respectively (odds ratio [OR], 1.11 [95% CI, 0.87-1.41]; P=0.41), and remained so after adjustment for potential confounders, including clinical presentation (OR [95% CI], 1.39 [0.90-2.15]; P=0.14). Compared with clopidogrel, cangrelor consistently reduced the primary outcome in both EL (4.8% versus 6.0%; OR [95% CI], 0.80 [0.64-0.98]) and LL (4.3% versus 5.4%; OR [95% CI], 0.79 [0.59-1.06]; interaction P=0.99). Global Use of Strategies to Open Occluded Coronary Arteries severe/moderate bleeding rates were similar between treatment arms for both EL (OR [95% CI], 1.24 [0.58-2.66]) and LL (OR [95% CI], 2.53 [0.98-6.54]; interaction P=0.25).CONCLUSIONS: In a nonrandomized comparison of patients with clopidogrel loading before or after the start of PCI, the rates of periprocedural PCI complications, including bleeding, were similar, as were the benefits of cangrelor, regardless of the timing.CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01156571.

    View details for DOI 10.1161/CIRCINTERVENTIONS.118.007445

    View details for PubMedID 30871355

  • Characteristics of Digital Health Studies Registered in ClinicalTrials.gov. JAMA internal medicine Chen, C. E., Harrington, R. A., Desai, S. A., Mahaffey, K. W., Turakhia, M. P. 2019

    View details for PubMedID 30801617

  • Blood Pressure Control and Cardiovascular Outcomes in Patients With Atrial Fibrillation (From the ORBIT-AF Registry). The American journal of cardiology Vemulapalli, S., Inohara, T., Kim, S., Thomas, L., Piccini, J. P., Patel, M. R., Chang, P., Fonarow, G. C., Ezekowitz, M. D., Hylek, E., Go, A. S., Kowey, P. R., Mahaffey, K. W., Gersh, B. J., Peterson, E. D. 2019

    Abstract

    Systolic blood pressure (SBP) and its association with clinical outcomes in atrial fibrillation (AF) patients in community practice are poorly characterized. In patients with AF, we sought to (1) examine the prevalence of baseline uncontrolled hypertension and the overall change in SBP control, (2) identify predictors of uncontrolled SBP over 2 years of follow-up, and (3) determine the relation between SBP and clinical outcomes. We analyzed 10,132 patients with AF at 176 clinics in the ORBIT-AF registry between 2010 and 2014, classified as: (1) no history of hypertension; (2) controlled hypertension (baseline SBP <140 mm Hg); (3) and uncontrolled hypertension (baseline SBP >140 mm Hg). Predictors of SBP >140 mm Hg at baseline or in follow-up were identified with pooled logistic regression. Random effects Cox regression models were used to compare cardiovascular outcomes and major bleeding as a function of continuous, time-dependent SBP. Overall 8,383 (83%) of patients with AF had hypertension. Of these, 24.2% (n = 2032) had uncontrolled baseline SBP, with little change over 2 years. Predictors of elevated follow-up SBP included uncontrolled baseline SBP, females, previous percutaneous coronary intervention, and diabetes. For every 5 mm Hg increase in follow-up SBP, the adjusted risk of stroke or systemic embolism or transient ischemic attack (adjusted hazard ratio [aHR] 1.05, 95% confidence interval [CI] 1.01 to 1.08, p = 0.01), myocardial infarction (aHR 1.05, 95% CI 1.00 to 1.11, p = 0.04), and major bleeding (aHR 1.03, 95% CI 1.00 to 1.06, p = 0.04) increased modestly. In conclusion, in patients with AF, higher SBP was associated with increasing adverse events; therefore, more rigorous blood pressure control should be emphasized.

    View details for PubMedID 30846214

  • Appropriateness of Direct Oral Anticoagulant Dosing in Patients With Atrial Fibrillation: Insights From the Veterans Health Administration. Journal of pharmacy practice Leef, G. C., Perino, A. C., Askari, M., Fan, J., Ho, P. M., Olivier, C. B., Longo, L., Mahaffey, K. W., Turakhia, M. P. 2019: 897190019828270

    Abstract

    BACKGROUND:: Direct oral anticoagulants (DOACs) have strict dosing guidelines, but recent studies indicate that inappropriate dosing is common, particularly in chronic kidney disease (CKD), for which it has been reported to be as high as 43%. Since 2011, the Veterans Health Administration (VA) has implemented anticoagulation management programs for DOACs, generally led by pharmacists, which has previously been shown to improve medication adherence.OBJECTIVE:: We investigated the prevalence of overdosing and underdosing of DOACs in the VA.METHODS:: Using data from the TREAT-AF cohort study (The Retrospective Evaluation and Assessment of Therapies in AF), we identified VA patients with newly diagnosed atrial fibrillation (AF) and receipt of a DOAC between 2003 and 2015. We classified dosing as correct, overdosed, or underdosed based on the Food and Drug Administration-approved dosing criteria.RESULTS:: Of 230 762 patients, 5060 received dabigatran (77.3%) or rivaroxaban (22.7%) within 90 days of AF diagnosis (age 69 [10[ years; CHA2DS2-VASc 1.6 [1.4]), of which 1312 (25.9%) had CKD based on estimated glomerular filtration rate <60. Overall, 93.6% of patients, 83.2% with CKD, received appropriate DOAC dosing. Incorrect dosing increased with worsening renal function.CONCLUSION:: Compared to recent studies of commercial payers and health-care systems, incorrect dosing of DOACs is less common across the VA. Pharmacist-led DOAC management or similar anticoagulation management interventions may reduce the risk of incorrect dosing across health-care systems.

    View details for PubMedID 30791808

  • Frequency, Regional Variation, and Predictors of Undetermined Cause of Death in Cardiometabolic Clinical Trials: A Pooled Analysis of 9259 Deaths in 9 Trials CIRCULATION Fanaroff, A. C., Clare, R., Pieper, K. S., Mahaffey, K. W., Melloni, C., Green, J. B., Alexander, J. H., Jones, W., Harrison, R. W., Mehta, R. H., Povsic, T. J., Moreira, H. G., Ai-Khatib, S. M., Roe, M. T., Kong, D. F., Mathews, R., Tricoci, P., Holman, R. R., Wallentin, L., Held, C., Califf, R. M., Alexander, K. P., Lopes, R. D. 2019; 139 (7): 863–73
  • Alirocumab Reduces Total Nonfatal Cardiovascular and Fatal Events The ODYSSEY OUTCOMES Trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Szarek, M., White, H. D., Schwartz, G. G., Alings, M., Bhatt, D. L., Bittner, V. A., Chiang, C., Diaz, R., Edelberg, J. M., Goodman, S. G., Hanotin, C., Harrington, R. A., Jukema, J., Kimura, T., Kiss, R., Lecorps, G., Mahaffey, K. W., Moryusef, A., Pordy, R., Roe, M. T., Tricoci, P., Xavier, D., Zeiher, A. M., Steg, G., Schwartz, G. G., Steg, P., Bhatt, D. L., Bittner, V. A., Diaz, R., Goodman, S. G., Harrington, R. A., Jukema, J., Szarek, M., White, H. D., Zeiher, A. M., Tricoci, P., Roe, M. T., Mahaffey, K. W., Edelberg, J. M., Hanotin, C., Lecorps, G., Moryusef, A., Pordy, R., Sasiela, W. J., Tamby, J., Aylward, P. E., Drexel, H., Sinnaeve, P., Dilic, M., Gotcheva, N. N., Goodman, S. G., Prieto, J., Yong, H., Lopez-Jaramillo, P., Pecin, I., Reiner, Z., Ostadal, P., Poulsen, S., Viigimaa, M., Nieminen, M. S., Danchin, N., Chumburidze, V., Marx, N., Liberopoulos, E., Valdovinos, P., Tse, H., Kiss, R., Xavier, D., Zahger, D., Valgimigli, M., Kimura, T., Kim, H., Kim, S., Kedev, S., Erglis, A., Laucevicius, A., Yusoff, K., Lopez, R., Arturo, G., Alings, M., White, H. D., Halvorsen, S., Correa Flores, R. M., Sy, R. G., Budaj, A., Morais, J., Dorobantu, M., Karpov, Y., Ristic, A. D., Chua, T., Murin, J., Fras, Z., Dalby, A. J., Tunon, J., de Silva, H., Hagstrom, E., Muller, C., Chiang, C., Sritara, P., Guneri, S., Parkhomenko, A., Ray, K. K., Moriarty, P. M., Roe, M. T., Chaitman, B., Kelsey, S. F., Olsson, A. G., Rouleau, J., Simoons, M. L., Alexander, K., Meloni, C., Rosenson, R., Sijbrands, E. G., Alexander, J. H., Armaganijan, L., Bagai, A., Bahit, M., Brennan, J., Clifton, S., DeVore, A. D., Deloatch, S., Dickey, S., Dombrowski, K., Ducrocq, G., Eapen, Z., Endsley, P., Eppinger, A., Harrison, R. W., Hess, C., Hlatky, M. A., Jordan, J., Knowles, J. W., Kolls, B. J., Kong, D. F., Leonardi, S., Lillis, L., Maron, D. J., Marcus, J., Mathews, R., Mehta, R. H., Mentz, R. J., Moreira, H., Patel, C. B., Pereira, S., Perkins, L., Povsic, T. J., Puymirat, E., Jones, W., Shah, B. R., Sherwood, M. W., Stringfellow, K., Sujjavanich, D., Toma, M., Van Diepen, S. P., Wilson, M. D., Yan, A., Lopes, R. D., Trotter, C., Schiavi, L. B., Garrido, M., Alvarisqueta, A. F., Sassone, S. A., Bordonava, A. P., Alves De Lima, A. E., Schmidberg, J. M., Duronto, E. A., Caruso, O. C., Novaretto, L. P., Angel Hominal, M., Montana, O. R., Caccavo, A., Gomez Vilamajo, O. A., Lorenzatti, A. J., Cartasegna, L. R., Paterlini, G. A., Mackinnon, I. J., Caime, G. D., Amuchastegui, M., Salomone, R., Codutti, O. R., Jure, H. O., Bono, J. E., Hrabar, A. D., Vallejos, J. A., Ahuad Guerrero, R. A., Novoa, F., Patocchi, C. A., Zaidman, C. J., Giuliano, M. E., Dran, R. D., Vico, M. L., Carnero, G. S., Guzman, P. N., Medrano Allende, J. C., Garcia Brasca, D. F., Bustamante Labarta, M. H., Nani, S., Blumberg, E. S., Colombo, H. R., Liberman, A., Luciardi, H. L., Waisman, G. D., Berli, M. A., Duran, R., Cestari, H. G., Luquez, H. A., Giordano, J. A., Saavedra, S. S., Zapata, G., Costamagna, O., Llois, S., Waites, J. H., Collins, N., Soward, A., Aylward, P. E., Hii, C. S., Shaw, J., Arstall, M. A., Horowitz, J., Rogers, J. F., Colquhoun, D., Oqueli Flores, R. E., Roberts-Thomson, P., Raffel, O., Lehman, S. J., Aroney, C., Coverdale, S. M., Garrahy, P. J., Starmer, G., Sader, M., Carroll, P. A., Dick, R., Zweiker, R., Hoppe, U., Huber, K., Berger, R., Weidinger, F., Faes, D., Hermans, K., Pirenne, B., Leone, A., Hoffer, E., Vrolix, M. M., De Wolf, L., Wollaert, B., Castadot, M., Dujardin, K., Beauloye, C., Vervoort, G., Striekwold, H., Convens, C., Roosen, J., Barbato, E., Claeys, M., Cools, F., Terzic, I., Barakovic, F., Midzic, Z., Pojskic, B., Fazlibegovic, E., Durak-Nalbantic, A., Vulic, D., Muslibegovic, A., Goronja, B., Reis, G., Sousa, L., Nicolau, J. C., Giorgeto, F. E., Silva, R. P., Maia, L., Rech, R., Rossi, P. F., Cerqueira, M. G., Duda, N., Kalil, R., Kormann, A., Abrantes, J. M., Pimentel Filho, P., Soggia, A., de Santos, M. N., Neuenschwander, F., Bodanese, L. C., Michalaros, Y. L., Eliaschewitz, F. G., Vidotti, M. H., Leaes, P. E., Botelho, R. V., Kaiser, S., Fernandes Manenti, E. F., Precoma, D. B., Moura Jorge, J. C., Silva, P. B., Silveira, J. A., Saporito, W., Marin Neto, J. A., Feitosa, G. S., Ritt, L. F., de Souza, J. A., Costa, F., Souza, W. B., Reis, H. L., Machado, L., Aidar Ayoub, J., Todorov, G. V., Nikolov, F. P., Velcheva, E. S., Tzekova, M. L., Benov, H. O., Petranov, S. L., Tumbev, H. S., Shehova-Yankova, N. S., Markov, D. T., Raev, D. H., Mollov, M. N., Kichukov, K. N., Ilieva-Pandeva, K. A., Ivanova, R., Mincheva, V. M., Lazov, P. V., Dimov, B. I., Senaratne, M., Stone, J., Kornder, J., Pearce, S., Dion, D., Savard, D., Pesant, Y., Pandey, A., Robinson, S., Gosselin, G., Vizel, S., Hoag, G., Bourgeois, R., Morisset, A., Sabbah, E., Sussex, B., Kouz, S., MacDonald, P., Diaz, A., Michaud, N., Fell, D., Leung, R., Vuurmans, T., Lai, C., Nigro, F., Davies, R., Nogareda, G., Vijayaraghavan, R., Ducas, J., Lepage, S., Mehta, S., Cha, J., Dupuis, R., Fong, P., Rodes-Cabau, J., Fadlallah, H., Cleveland, D., Thao Huynh, Bata, I., Hameed, A., Pincetti, C., Potthoff, S., Prieto, J. C., Acevedo, M., Aguirre, A., Vejar, M., Yanez, M., Araneda, G., Fernandez, M., Perez, L., Varleta, P., Florenzano, F., Huidobro, L., Raffo, C. A., Olivares, C., Nahuelpan, L., Montecinos, H., Chen, J., Dong, Y., Huang, W., Wang, J., Huang, S., Yao, Z., Li, X., Cui, L., Lin, W., Sun, Y., Wang, J., Li, J., Zhang, X., Zhu, H., Chen, D., Huang, L., Dong, S., Su, G., Xu, B., Su, X., Cheng, X., Lin, J., Zong, W., Li, H., Feng, Y., Xu, D., Yang, X., Ke, Y., Lin, X., Zhang, Z., Zheng, Z., Luo, Z., Chen, Y., Ding, C., Zheng, Y., Li, X., Peng, D., Li, Y., Wei, M., Liu, S., Yu, Y., Qu, B., Jiang, W., Zhou, Y., Zhao, X., Yuan, Z., Guo, Y., Xu, X., Shi, X., Ge, J., Fu, G., Bai, F., Fang, W., Shou, X., Yang, X., Wang, J., Sun, Y., Lu, Q., Zhang, R., Zhu, J., Xu, Y., Fan, Z., Li, T., Wu, C., Jaramillo, N., Vallejo, G., Botia, D., Lopez, R., De Salazar, D., Bonfanti, A., Higuera, J., Silva, S., Lozada, H., Arroyo, J., Mendoza, J., Ruiz, R., Jatin, F., Herazo, A., Parada, J., Triana, M., Strozzi, M., Car, S., Milicic, D., Bencic, M., Pintaric, H., Prvulovic, D., Sikic, J., Persic, V., Mileta, D., Stambuk, K., Zdravko, B., Tomulic, V., Krstulovic, S., Starcevic, B., Spinar, J., Horak, D., Stasek, J., Alan, D., Machova, V., Linhart, A., Novotny, V., Kaucak, V., Rokyta, R., Naplava, R., Coufal, Z., Adamkova, V., Podpera, I., Zizka, J., Motovska, Z., Marusincova, I., Svab, P., Ostadal, P., Heinc, P., Kuchar, J., Povolny, P., Matuska, J., Raungaard, B., Clemmensen, P., Bang, L. E., May, O., Bottcher, M., Hove, J. D., Frost, L., Gislason, G., Larsen, J., Johansen, P., Hald, F., Jeppesen, J., Nielsen, T., Kristensen, K. S., Walichiewicz, P., Lomholdt, J. D., Klausen, I. C., Nielsen, P., Davidsen, F., Videbaek, L., Soots, M., Vahula, V., Hedman, A., Soopold, U., Martsin, K., Kristjan, A., Taskinen, M., Porthan, K., Airaksinen, J. K., Juonala, M., Kiviniemi, T., Vikman, S., Posio, P., Taurio, J., Huikuri, H., Kaikkonen, K., Coste, P., Ferrari, E., Morel, O., Montalescot, G., Barone-Rochette, G., Mansourati, J., Cottin, Y., Leclercq, F., Belhassane, A., Delarche, N., Boccara, F., Paganelli, F., Clerc, J., Schiele, F., Aboyans, V., Probst, V., Berland, J., Lefevre, T., Citron, B., Khintibidze, I., Shaburishvili, T., Pagava, Z., Ghlonti, R., Lominadze, Z., Khabeishvili, G., Hemetsberger, R., Rauch-Kroehnert, U., Stratmann, M., Appel, K., Schmidt, E., Omran, H., Stellbrink, C., Dorsel, T., Lianopoulos, E., Marx, R., Zirlik, A., Schellenberg, D., Heitzer, T., Laufs, U., Marx, N., Gielen, S., Winkelmann, B., Behrens, S., Sydow, K., Simonis, G., Muenzel, T., Werner, N., Leggewie, S., Boecker, D., Braun-Dullaeus, R., Toursarkissian, N., Jeserich, M., Weissbrodt, M., Schaeufele, T., Weil, J., Voeller, H., Waltenberger, J., Natour, M., Schmitt, S., Steiner, S., Heidenreich, L., Gremmler, U., Killat, H., Rieker, W., Patsilinakos, S., Kartalis, A., Manolis, A., Sionis, D., Liberopoulos, E., Skoumas, I., Athyros, V., Vardas, P., Parthenakis, F., Alexopoulos, D., Hahalis, G., Lekakis, J., Hatzitolios, A., Ovando, S., Valdovinos, P., Benecke, J., De Leon, E., Yan, B. Y., Siu, D. W., Turi, T., Merkely, B., Kiss, R., Ungi, I., Lupkovics, G., Nagy, L., Katona, A., Edes, I., Muller, G., Horvath, I., Kapin, T., Falukozy, J., Kumbla, M., Sandhu, M., Annam, S., Proddutur, N., Premchand, R. K., Mahajan, A., Abhyanakar, A. D., Kerkar, P., Govinda, R. A., Oomman, A., Sinha, D., Patil, S. N., Kahali, D., Sawhney, J., Joshi, A. B., Chaudhary, S., Harkut, P., Guha, S., Porwal, S., Jujjuru, S., Pothineni, R. B., Monteiro, M. R., Khan, A., Iyengar, S. S., Grewal, J., Chopda, M., Fulwani, M. C., Patange, A., Chopra, V. K., Goyal, N. K., Shinde, R., Manakshe, G. 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B., Berti, S., Cavallini, C., Puccioni, E., Galvani, M., Tespili, M., Piatti, P., Palvarini, M., De Luca, G., Violini, R., De Leo, A., Filardi, P., Ferratini, M., Ricca, V., Dai, K., Kamiya, H., Ando, K., Takeda, Y., Morino, Y., Hata, Y., Kimura, K., Kishi, K., Michishita, I., Uehara, H., Higashikata, T., Hirayama, A., Hirooka, K., Sakagami, S., Taguchi, S., Koike, A., Fujinaga, H., Koba, S., Kozuma, K., Kawasaki, T., Ono, Y., Shimizu, M., Katsuda, Y., Wada, A., Shinke, T., Kimura, T., Ako, J., Fujii, K., Takahashi, T., Sakamoto, T., Furukawa, Y., Sugino, H., Mano, T., Utsu, N., Ito, K., Haraguchi, T., Ueda, Y., Nishibe, A., Fujimoto, K., Masutani, M., Fujimoto, K., Yoon, J., Kim, S., Park, H., Chae, I., Kim, M., Jeong, M., Rha, S., Kim, C., Kim, H., Hong, T., Tahk, S., Kim, Y., Busmane, A., Pontaga, N., Strelnieks, A., Mintale, I., Sime, I., Petrulioniene, Z., Kavaliauskiene, R., Jurgaitiene, R., Sakalyte, G., Slapikas, R., Norkiene, S., Misonis, N., Kibarskis, A., Kubilius, R., Bojovski, S., Kedev, S., Lozance, N., Kjovkaroski, A., Doncovska, S., Ong, T., Kasim, S., Maskon, O., Kandasamy, B., Yusoff, K., Liew, H. B., Mohamed, W., ODYSSEY OUTCOMES Comm Investigator 2019; 73 (4): 387–96
  • Canagliflozin and Stroke in Type 2 Diabetes Mellitus Results From the Randomized CANVAS Program Trials STROKE Zhou, Z., Lindley, R. I., Radholm, K., Jenkins, B., Watson, J., Perkovic, V., Mahaffey, K. W., de Zeeuw, D., Fulcher, G., Shaw, W., Oh, R., Desai, M., Matthews, D. R., Neal, B. 2019; 50 (2): 396–404
  • Characterization of cardiovascular clinical events and impact of event adjudication on the treatment effect of darapladib versus placebo in patients with stable coronary heart disease: Insights from the STABILITY trial AMERICAN HEART JOURNAL Held, C., White, H. D., Stewart, R. H., Davies, R., Sampson, S., Chiswell, K., Silverstein, A., Lopes, R. D., Heldestad, U., Budaj, A., Mahaffey, K. W., Wallentin, L., STABILITY Investigators 2019; 208: 65–73
  • Association of frailty and cognitive impairment with benefits of oral anticoagulation in patients with atrial fibrillation. American heart journal Madhavan, M., Holmes, D. N., Piccini, J. P., Ansell, J. E., Fonarow, G. C., Hylek, E. M., Kowey, P. R., Mahaffey, K. W., Thomas, L., Peterson, E. D., Chan, P., Allen, L. A., Gersh, B. J., ORBIT AF Investigators 2019; 211: 77–89

    Abstract

    BACKGROUND: The incidence of cognitive impairment and frailty increase with age and may impact both therapy and outcomes in atrial fibrillation (AF).METHODS: We examined the prevalence of clinically recognized cognitive impairment and frailty (as defined by the American Geriatric Society Criteria) in the Outcomes Registry for Better Informed Care in AF (ORBIT AF) and associated adjusted outcomes via multivariable Cox regression. The interaction between cognitive impairment and frailty and oral anticoagulation (OAC) in determining outcomes was examined.RESULTS: Among 9749 patients with AF [median (IQR) age 75 (67-82) y, 57% male], cognitive impairment and frailty was identified in 293 (3.0%) and 575 (5.9%) patients respectively. Frail patients (68 vs 77%, P < .001) and those with cognitive impairment (70 vs 77%, P = .006) were both less likely to receive an OAC. Both cognitive impairment [HR (95% CI) 1.34 (1.05-1.72), P = .0198] and frailty [HR 1.29 (1.08-1.55), P = .0060] were associated with increased risk of death. Cognitive impairment and frailty were not associated with stroke/transient ischemic attack (TIA) or major bleeding. In multivariable analysis, there was no interaction between OAC use and cognitive impairment or frailty in their associations with mortality, major bleeding and a composite end point of stroke, non-central nervous system systemic embolism, TIA, myocardial infarction or cardiovascular death.CONCLUSION: Those with cognitive impairment or frailty in AF had higher predicted risk for stroke and higher observed mortality, yet were less likely to be treated with OAC. Despite this, the benefits of OAC were similar in patients with and without cognitive impairment or frailty.

    View details for PubMedID 30901602

  • Cohort profile: patient characteristics and quality-of-life measurements for newly-referred patients with atrial fibrillation-Keio interhospital Cardiovascular Studies-atrial fibrillation (KiCS-AF). BMJ open Ikemura, N. n., Spertus, J. A., Kimura, T. n., Mahaffey, K. n., Piccini, J. P., Inohara, T. n., Ueda, I. n., Tanimoto, K. n., Suzuki, M. n., Nakamura, I. n., Akaishi, M. n., Mitamura, H. n., Fukuda, K. n., Takatsuki, S. n., Kohsaka, S. n. 2019; 9 (12): e032746

    Abstract

    Besides the high rates of morbidity and mortality, atrial fibrillation (AF) is also associated with impairment of quality-of-life (QOL). However, reports covering non-selected AF population within Asian countries remain scarce. The objective of the Keio interhospital Cardiovascular Studies-atrial fibrillation (KiCS-AF) registry is to clarify the baseline and QOL profiles of the AF patients at the time of initial referral to identify areas for improvement and country-specific gaps.The KiCS-AF registry is a multicentre, prospective cohort study designed to specifically recruit AF patients newly referred to the 11 network hospitals within the Kanto area of Japan. The registry completed its enrolment in June 2018. All patients were requested to answer the Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire both at baseline and 1 year, with planned clinical follow-up for 5 years. The registry also assessed individual treatment strategies including rate and rhythm control, stroke prophylaxis, and their impacts on patient-reported QOL.As of December 2016, 2464 AF patients were registered; their mean age was 67.1 years (SD, 11.7), majority (69.7%; n=1717) were men and 49.2% presented with paroxysmal AF. The mean CHA2DS2-VASc (cardiac failure or dysfunction, hypertension, age ≥75 years, diabetes, stroke including vascular disease, age 65-74 years, and sex category [female]) score was 2.3 (SD, 1.6) and oral anticoagulant therapy was used for 88.6% of patients with CHA2DS2-VASc scores ≥2. The median AFEQT-overall summary score was 79.1 (IQR, 66.6-89.1). Roughly 50% had significantly impaired QOL (ie, AFEQT <80) at baseline. Currently, 2307 eligible patients (93.6%) have completed the 1-year follow-up, of which 2072 patients (89.8%) answered the second AFEQT questionnaire.The KiCS-AF allowed for extensive investigation of AF-related QOL in a non-selected population with long-term follow-up using a rigorously validated QOL assessment tool. Almost half of patients had impaired QOL at baseline. Further investigations aimed at providing care and improving patient-reported QOL are required.

    View details for DOI 10.1136/bmjopen-2019-032746

    View details for PubMedID 31857312

  • Canagliflozin and Renal Outcomes in Diabetic Nephropathy. Reply. The New England journal of medicine Jardine, M. J., Mahaffey, K. W., Perkovic, V. 2019; 381 (11): 1089–90

    View details for DOI 10.1056/NEJMc1909687

    View details for PubMedID 31509685

  • Site Variation and Outcomes for Antithrombotic Therapy in Atrial Fibrillation Patients After Percutaneous Coronary Intervention. Circulation. Cardiovascular interventions Olivier, C. B., Fan, J. n., Askari, M. n., Mahaffey, K. W., Heidenreich, P. A., Perino, A. C., Leef, G. C., Ho, P. M., Harrington, R. A., Turakhia, M. P. 2019; 12 (8): e007604

    Abstract

    Patients with atrial fibrillation (AF) treated with percutaneous coronary intervention (PCI) require multiple antithrombotic therapies. The optimal strategy is debated suggesting increased treatment variation. This study sought to characterize site-level variation in antithrombotic therapies in AF patients after PCI and determine the association with outcomes.Using the retrospective TREAT-AF study (The Retrospective Evaluation and Assessment of Therapies in AF) from the Veterans Health Administration, patients with newly diagnosed, nonvalvular AF between 2004 and 2015 followed by a PCI with a P2Y12-antagonist prescription were identified. Patients were grouped according to the therapy dispensed 7 days before until 30 days after the PCI: oral anticoagulation plus platelet inhibition (OAC+PI) or platelet inhibition only. A combined outcome of death, myocardial infarction, stroke, or major bleeding was assessed 1 year after PCI and Cox regression was performed to estimate hazard ratios.Of 230 762 patients with newly diagnosed AF, 4042 (1.8%) underwent PCI and received a P2Y12-antagonist during the observation period (age, 67±9 years; CHA2DS2-VASc, 2.7±1.7; HAS-BLED, 2.6±1.2). Among these, 47% were prescribed OAC+PI, and 53% platelet inhibition only 7 days before until 30 days after the PCI. Across 63 sites, the use of OAC+PI ranged from 19% to 66%. Prescription of OAC+PI was independently associated with a reduction in the combined outcome of death, myocardial infarction, stroke, or major bleeding compared with platelet inhibition only (adjusted hazard ratio, 0.85; 95% CI, 0.73-0.99; P=0.033).In patients with established AF undergoing PCI, the use of OAC+PI varied substantially across sites in the 30 days post-PCI. Anticoagulation appeared to be underutilized but was associated with improved outcomes. Strategies to promote OAC+PI and minimize site variation may be useful, particularly in light of recent randomized trials.

    View details for DOI 10.1161/CIRCINTERVENTIONS.118.007604

    View details for PubMedID 31416357

  • Incidence, Characteristics, and Outcomes of Myocardial Infarction in Patients With Peripheral Artery Disease Insights From the EUCLID Trial JAMA CARDIOLOGY Olivier, C. B., Mulder, H., Hiatt, W. R., Jones, W., Fowkes, F. R., Rockhold, F. W., Berger, J. S., Baumgartner, I., Held, P., Katona, B. G., Norgren, L., Blomster, J., Patel, M. R., Mahaffey, K. W. 2019; 4 (1): 7–15
  • Rationale and design of a large-scale, app-based study to identify cardiac arrhythmias using a smartwatch: The Apple Heart Study AMERICAN HEART JOURNAL Turakhia, M. P., Desai, M., Hedlin, H., Rajmane, A., Talati, N., Ferris, T., Desai, S., Nag, D., Patel, M., Kowey, P., Rumsfeld, J. S., Russo, A. M., Hills, M., Granger, C. B., Mahaffey, K. W., Perez, M. V. 2019; 207: 66–75
  • Eligibility of sodium-glucose co-transporter-2 inhibitors among patients with diabetes mellitus admitted for heart failure. ESC heart failure Sharma, A. n., Wu, J. n., Ezekowitz, J. A., Felker, G. M., Udell, J. A., Heidenreich, P. A., Fonarow, G. C., Mahaffey, K. W., Hernandez, A. F., DeVore, A. D. 2019

    Abstract

    Sodium-glucose co-transporter (SGLT)-2 inhibitors have been shown to reduce the risk of cardiovascular death and heart failure (HF) hospitalization in patients with type 2 diabetes mellitus (DM) and high cardiovascular risk in two large clinical outcome trials: empagliflozin in EMPA-REG OUTCOME and canagliflozin in CANVAS. The scope of eligibility for SGLT-2 inhibitors (empagliflozin and canagliflozin) among patients with type 2 DM and HF, based on clinical trial criteria and current US Food and Drug Administration (FDA) labelling criteria, remains unknown.Using data from the US Get With The Guidelines (GWTG)-Heart Failure registry, we evaluated the proportion of patients with DM and HF eligible for SGLT-2 inhibitor therapy based on the clinical trial criteria and the US FDA labelling criteria. The GWTG-HF registry is a quality improvement registry of patients admitted in hospital with HF in the USA. We included GWTG-HF registry participants meeting eligibility criteria hospitalized between August 2014 and 30 June 2017 from sites fully participating in the registry. The initial inclusion time point reflects when both drugs had FDA approval. Among the 139 317 patients (out of 407 317) with DM hospitalized with HF (in 460 hospitals; 2014 to 2017), the median age was 71 years, 47% (n = 65 685) were female, and 43% (n = 59 973) had HF with reduced ejection fraction. Overall, 43% (n = 59 943) were eligible for the EMPA-REG OUTCOME trial, 45% (n = 62 818) were eligible for the CANVAS trial, and 34% (n = 47 747) of patients were eligible for either SGLT-2 inhibitors based on the FDA labelling criteria. Among the FDA-eligible patients, 91.5% (n = 43 708) were eligible for either the EMPA-REG OUTCOME trial or the CANVAS trial. Patients who were FDA eligible, compared with those who were not, were younger (70.0 vs. 72.0 years of age), more likely to be male (57.7 vs. 50.3%), and had less burden of co-morbidities.The majority of patients with DM who are hospitalized with HF are not eligible for SGLT-2 inhibitor therapies. Ongoing studies evaluating the safety and efficacy of SGLT-2 inhibitors among patients with HF may potentially broaden the population that may benefit from these therapies.

    View details for DOI 10.1002/ehf2.12528

    View details for PubMedID 31747132

  • Clinical outcomes with canagliflozin according to baseline body mass index: results from post hoc analyses of the CANVAS Program. Diabetes, obesity & metabolism Ohkuma, T. n., Van Gaal, L. n., Shaw, W. n., Mahaffey, K. W., de Zeeuw, D. n., Matthews, D. R., Perkovic, V. n., Neal, B. n. 2019

    Abstract

    Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce several cardiovascular risk factors including plasma glucose, blood pressure, albuminuria and body weight. Long-term treatment lowers risks of cardiovascular and renal events. The objective of this post hoc analysis was to determine the effects of canagliflozin treatment versus placebo on clinical outcomes in relation to body mass index (BMI).The CANVAS Program randomized 10,142 participants with type 2 diabetes to canagliflozin or placebo. These analyses tested the consistency of canagliflozin treatment effects across BMI levels for cardiovascular, renal, safety, and body weight outcomes in 3 groups defined by baseline BMI: <25, 25-<30, and ≥30 kg/m2 .A total of 10,128 participants with baseline BMI measurements were included. There were 966 participants with BMI <25 kg/m2 , 3153 with BMI 25-<30 kg/m2 , and 6009 with BMI ≥30 kg/m2 . Mean body weight reduction with canagliflozin compared to placebo was greater at 12 months (-2.47 kg [95% CI: -2.64, -2.30]) than at 3 months (-1.53 kg [95% CI: -1.63, -1.44]). The HRs (95% CI) for canagliflozin compared with placebo control for the composite outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke were HR 1.03 (95% CI: 0.66, 1.59) in participants with BMI <25 kg/m2 , 0.97 (0.76, 1.23) with BMI 25-<30 kg/m2 , and 0.79 (0.67, 0.93) with BMI ≥30 kg/m2 (P for heterogeneity = 0.55). The effects of canagliflozin on each component of the composite were also similar across BMI subgroups, as were effects on heart failure, renal, and safety outcomes (all P for heterogeneity ≥0.15).Canagliflozin improved cardiovascular and renal outcomes consistently across patients with a broad range of BMI levels. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1111/dom.13920

    View details for PubMedID 31729107

  • Claims-based cardiovascular outcome identification for clinical research: Results from 7 large randomized cardiovascular clinical trials. American heart journal Brennan, J. M., Wruck, L. n., Pencina, M. J., Clare, R. M., Lopes, R. D., Alexander, J. H., O'Brien, S. n., Krucoff, M. n., Rao, S. V., Wang, T. Y., Curtis, L. H., Newby, L. K., Granger, C. B., Patel, M. n., Mahaffey, K. n., Ross, J. S., Normand, S. L., Eloff, B. C., Caños, D. A., Lokhnygina, Y. V., Roe, M. T., Califf, R. M., Marinac-Dabic, D. n., Peterson, E. D. 2019; 218: 110–22

    Abstract

    Medicare insurance claims may provide an efficient means to ascertain follow-up of older participants in clinical research. We sought to determine the accuracy and completeness of claims- versus site-based follow-up with clinical event committee (+CEC) adjudication of cardiovascular outcomes.We performed a retrospective study using linked Medicare and Duke Database of Clinical Trials data. Medicare claims were linked to clinical data from 7 randomized cardiovascular clinical trials. Of 52,476 trial participants, linking resulted in 5,839 (of 10,497 linkage-eligible) Medicare-linked trial participants with fee-for-service A and B coverage. Death, myocardial infarction (MI), stroke, and revascularization incidences were compared using Medicare inpatient claims only, site-reported events (+CEC) only, or a combination of the 2. Randomized treatment effects were compared as a function of whether claims-based, site-based (+CEC), or a combined system was used for event detection.Among the 5,839 study participants, the annual event rates were similar between claims- and site-based (+CEC) follow-up: death (overall rate 5.2% vs 5.2%; adjusted κ 0.99), MI (2.2% vs 2.3%; adjusted κ 0.96), stroke (0.7% vs 0.7%; adjusted κ 0.99), and any revascularization (7.4% vs 7.9%; adjusted κ 0.95). Of events detected by claims yet not reported by CEC, a minority were reported by sites but negatively adjudicated by CEC (39% of MIs and 18% of strokes). Differences in individual case concordance led to higher event rates when claims- and site-based (+CEC) systems were combined. Randomized treatment effects were similar among the 3 approaches for each outcome of interest.Claims- versus site-based (+CEC) follow-up identified similar overall cardiovascular event rates despite meaningful differences in the events detected. Randomized treatment effects were similar using the 2 methods, suggesting claims data could be used to support clinical research leveraging routinely collected data. This approach may lead to more effective evidence generation, synthesis, and appraisal of medical products and inform the strategic approaches toward the National Evaluation System for Health Technology.

    View details for DOI 10.1016/j.ahj.2019.09.002

    View details for PubMedID 31726314

  • Large-Scale Assessment of a Smartwatch to Identify Atrial Fibrillation. The New England journal of medicine Perez, M. V., Mahaffey, K. W., Hedlin, H., Rumsfeld, J. S., Garcia, A., Ferris, T., Balasubramanian, V., Russo, A. M., Rajmane, A., Cheung, L., Hung, G., Lee, J., Kowey, P., Talati, N., Nag, D., Gummidipundi, S. E., Beatty, A., Hills, M. T., Desai, S., Granger, C. B., Desai, M., Turakhia, M. P., Apple Heart Study Investigators, Perez, M. V., Turakhia, M. P., Lhamo, K., Smith, S., Berdichesky, M., Sharma, B., Mahaffey, K., Parizo, J., Olivier, C., Nguyen, M., Tallapalli, S., Kaur, R., Gardner, R., Hung, G., Mitchell, D., Olson, G., Datta, S., Gerenrot, D., Wang, X., McCoy, P., Satpathy, B., Jacobsen, H., Makovey, D., Martin, A., Perino, A., O'Brien, C., Gupta, A., Toruno, C., Waydo, S., Brouse, C., Dorfman, D., Stein, J., Huang, J., Patel, M., Fleischer, S., Doll, E., O'Reilly, M., Dedoshka, K., Chou, M., Daniel, H., Crowley, M., Martin, C., Kirby, T., Brumand, M., McCrystale, K., Haggerty, M., Newberger, J., Keen, D., Antall, P., Holbrook, K., Braly, A., Noone, G., Leathers, B., Montrose, A., Kosowsky, J., Lewis, D., Finkelmeier, J. R., Bemis, K., Mahaffey, K. W., Desai, M., Talati, N., Nag, D., Rajmane, A., Desai, S., Caldbeck, D., Cheung, L., Granger, C., Rumsfeld, J., Kowey, P. R., Hills, M. T., Russo, A., Rockhold, F., Albert, C., Alonso, A., Wruck, L., Friday, K., Wheeler, M., Brodt, C., Park, S., Rogers, A., Jones, R., Ouyang, D., Chang, L., Yen, A., Dong, J., Mamic, P., Cheng, P., Shah, R., Lorvidhaya, P. 2019; 381 (20): 1909–17

    Abstract

    BACKGROUND: Optical sensors on wearable devices can detect irregular pulses. The ability of a smartwatch application (app) to identify atrial fibrillation during typical use is unknown.METHODS: Participants without atrial fibrillation (as reported by the participants themselves) used a smartphone (Apple iPhone) app to consent to monitoring. If a smartwatch-based irregular pulse notification algorithm identified possible atrial fibrillation, a telemedicine visit was initiated and an electrocardiography (ECG) patch was mailed to the participant, to be worn for up to 7 days. Surveys were administered 90 days after notification of the irregular pulse and at the end of the study. The main objectives were to estimate the proportion of notified participants with atrial fibrillation shown on an ECG patch and the positive predictive value of irregular pulse intervals with a targeted confidence interval width of 0.10.RESULTS: We recruited 419,297 participants over 8 months. Over a median of 117 days of monitoring, 2161 participants (0.52%) received notifications of irregular pulse. Among the 450 participants who returned ECG patches containing data that could be analyzed - which had been applied, on average, 13 days after notification - atrial fibrillation was present in 34% (97.5% confidence interval [CI], 29 to 39) overall and in 35% (97.5% CI, 27 to 43) of participants 65 years of age or older. Among participants who were notified of an irregular pulse, the positive predictive value was 0.84 (95% CI, 0.76 to 0.92) for observing atrial fibrillation on the ECG simultaneously with a subsequent irregular pulse notification and 0.71 (97.5% CI, 0.69 to 0.74) for observing atrial fibrillation on the ECG simultaneously with a subsequent irregular tachogram. Of 1376 notified participants who returned a 90-day survey, 57% contacted health care providers outside the study. There were no reports of serious app-related adverse events.CONCLUSIONS: The probability of receiving an irregular pulse notification was low. Among participants who received notification of an irregular pulse, 34% had atrial fibrillation on subsequent ECG patch readings and 84% of notifications were concordant with atrial fibrillation. This siteless (no on-site visits were required for the participants), pragmatic study design provides a foundation for large-scale pragmatic studies in which outcomes or adherence can be reliably assessed with user-owned devices. (Funded by Apple; Apple Heart Study ClinicalTrials.gov number, NCT03335800.).

    View details for DOI 10.1056/NEJMoa1901183

    View details for PubMedID 31722151

  • Comparison of Patient-Reported Care Satisfaction, Quality of Warfarin Therapy, and Outcomes of Atrial Fibrillation: Findings From the ORBIT - AF Registry. Journal of the American Heart Association Perino, A. C., Shrader, P. n., Turakhia, M. P., Ansell, J. E., Gersh, B. J., Fonarow, G. C., Go, A. S., Kaiser, D. W., Hylek, E. M., Kowey, P. R., Singer, D. E., Thomas, L. n., Steinberg, B. A., Peterson, E. D., Piccini, J. P., Mahaffey, K. W. 2019; 8 (9): e011205

    Abstract

    Background Patient satisfaction with therapy is an important metric of care quality and has been associated with greater medication persistence. We evaluated the association of patient satisfaction with warfarin therapy to other metrics of anticoagulation care quality and clinical outcomes among patients with atrial fibrillation ( AF ). Methods and Results Using data from the ORBIT - AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) registry, patients were identified with AF who were taking warfarin and had completed an Anti-Clot Treatment Scale ( ACTS ) questionnaire, a validated metric of patient-reported burden and benefit of oral anticoagulation. Multivariate regressions were used to determine association of ACTS burden and benefit scores with time in therapeutic international normalized ratio range ( TTR ; both ≥75% and ≥60%), warfarin discontinuation, and clinical outcomes (death, stroke, major bleed, and all-cause hospitalization). Among 1514 patients with AF on warfarin therapy (75±10 years; 42% women; CHA 2 DS 2- VAS c 3.9±1.7), those most burdened with warfarin therapy were younger and more likely to be women, have paroxysmal AF , and to be treated with antiarrhythmic drugs. After adjustment for covariates, ACTS burden scores were independent of TTR ( TTR ≥75%: odds ratio, 1.01 [95% CI , 0.99-1.03]; TTR ≥60%: odds ratio, 1.01 [95% CI , 0.98-1.05]), warfarin discontinuation (odds ratio, 0.99; 95% CI , 0.97-1.01), or clinical outcomes. ACTS benefit scores were also not associated with TTR , warfarin discontinuation, or clinical outcomes. Conclusions In a large registry of patients with AF taking warfarin, ACTS scores provided independent information beyond other traditional metrics of oral anticoagulation care quality and identified patient groups at high risk for dissatisfaction with warfarin therapy.

    View details for PubMedID 31023126

  • Canagliflozin review - safety and efficacy profile in patients with T2DM DIABETES METABOLIC SYNDROME AND OBESITY-TARGETS AND THERAPY Jakher, H., Chang, T. I., Tan, M., Mahaffey, K. W. 2019; 12: 209–15
  • Impact of Procedural Bleeding in Peripheral Artery Disease: An Analysis From EUCLID Trial. Circulation. Cardiovascular interventions Kansal, A. n., Huang, Z. n., Rockhold, F. W., Baumgartner, I. n., Berger, J. S., Blomster, J. I., Fowkes, F. G., Katona, B. n., Mahaffey, K. W., Norgren, L. n., Hiatt, W. R., Patel, M. R., Jones, W. S. 2019; 12 (10): e008069

    Abstract

    The relationship between invasive vascular procedures and bleeding in patients with peripheral artery disease has not been well described in the literature. This post hoc analysis from the EUCLID trial (Examining Use of Ticagrelor in Peripheral Artery Disease) aimed to describe the incidence of major and minor postprocedural bleeding and characterize the timing and severity of bleeding events relative to the procedure.EUCLID was a multicenter, randomized controlled trial of 13 885 patients with symptomatic peripheral artery disease that tested the efficacy and safety of ticagrelor compared with clopidogrel for the prevention of major adverse cardiovascular events. A total of 2661 patients underwent 3062 coronary revascularization, peripheral revascularization, and amputation during the study. The primary safety end point was Thrombolysis in Myocardial Infarction major or minor bleeding. All bleeding events were formally adjudicated by a clinical end point classification group.Major bleeding events most often occurred ≤7 days following the procedure. The incidence of Thrombolysis in Myocardial Infarction major or minor bleeding ≤7 days following peripheral revascularization (3.3%; 95% CI, 2.5%-4.1%) was similar to rates after coronary revascularization (4.0%; 95% CI, 2.6%-5.4%) and lower extremity amputation (2.3%; 95% CI, 0.8%-3.8%). The severity of bleeding events (as graded by drop in hemoglobin, need for transfusion, bleeding in a critical location, and fatal bleeding) was also similar following peripheral, coronary revascularization, and lower extremity amputation.The incidence of Thrombolysis in Myocardial Infarction major/minor bleeding following peripheral revascularization is comparable to rates after coronary revascularization and lower extremity amputation, and the majority of bleeding events occur within 7 days following the procedure. The severity of periprocedural bleeding is also similar after procedures, with the most frequently adjudicated reason being a drop in hemoglobin ≥2 g/dL. Future studies should be performed to enhance our understanding of bleeding risk related to revascularization and amputation procedures in peripheral artery disease patients.

    View details for DOI 10.1161/CIRCINTERVENTIONS.119.008069

    View details for PubMedID 31581789

  • Canagliflozin review - safety and efficacy profile in patients with T2DM. Diabetes, metabolic syndrome and obesity : targets and therapy Jakher, H. n., Chang, T. I., Tan, M. n., Mahaffey, K. W. 2019; 12: 209–15

    Abstract

    Canagliflozin is a sodium glucose-cotransporter (SGLT) receptor inhibitor approved for the treatment of type 2 diabetes mellitus (T2DM). This article reviews the mechanism of action of SGLT-2 receptor inhibitors and the efficacy of canagliflozin as an antidiabetic agent, its cardiovascular and renal benefits, and safety profile. During the development of canagliflozin, Phase II trials showed an improvement in cardiac and renal biomarkers such as blood pressure, body weight, and albuminuria. The large CANVAS program showed that canagliflozin reduced the composite cardiovascular outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. The CANVAS program also showed a possible benefit of canagliflozin on a renal composite of sustained 40% reduction in estimated glomerular filtration rate, the need for renal replacement therapy, or death from renal causes. The safety profile of canagliflozin has been well characterized, and known side effects such as mycotic genital infections were confirmed in CANVAS. However, an increased risk of amputations was observed in CANVAS that requires further study. Overall, canagliflozin is an effective antidiabetic medication with cardiovascular and likely renal benefits, and with a generally well-tolerated safety profile. Results from the CREDENCE trial will further evaluate the safety and potential renal benefits of canagliflozin in patients with established diabetic nephropathy.

    View details for PubMedID 30787627

  • Effect of Alirocumab on Mortality After Acute Coronary Syndromes: An Analysis of the ODYSSEY OUTCOMES Randomized Clinical Trial. Circulation Steg, P. G., Szarek, M. n., Bhatt, D. L., Bittner, V. A., Brégeault, M. F., Dalby, A. J., Diaz, R. n., Edelberg, J. M., Goodman, S. G., Hanotin, C. n., Harrington, R. A., Jukema, J. W., Lecorps, G. n., Mahaffey, K. W., Moryusef, A. n., Ostadal, P. n., Parkhomenko, A. n., Pordy, R. n., Roe, M. T., Tricoci, P. n., Vogel, R. n., White, H. D., Zeiher, A. M., Schwartz, G. G. 2019

    Abstract

    Trials of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome (ACS).ODYSSEY OUTCOMES was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1-12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death.Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years' follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths ( P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events ( P<0.001) and thereby may have attenuated the number of noncardiovascular deaths. A post-hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined with achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend).Alirocumab added to intensive statin therapy has the potential to reduce death after ACS, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low.URL: https://www.clinicaltrials.gov. Unique Identifier: NCT01663402.

    View details for DOI 10.1161/CIRCULATIONAHA.118.038840

    View details for PubMedID 31117810

  • Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial. European heart journal White, H. D., Steg, P. G., Szarek, M. n., Bhatt, D. L., Bittner, V. A., Diaz, R. n., Edelberg, J. M., Erglis, A. n., Goodman, S. G., Hanotin, C. n., Harrington, R. A., Jukema, J. W., Lopes, R. D., Mahaffey, K. W., Moryusef, A. n., Pordy, R. n., Roe, M. T., Sritara, P. n., Tricoci, P. n., Zeiher, A. M., Schwartz, G. G. 2019

    Abstract

    The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin-kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI.Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77-0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77-0.99; P = 0.032) and Type 2 (0.77, 0.61-0.97; P = 0.025), but not Type 4 MI.After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.

    View details for DOI 10.1093/eurheartj/ehz299

    View details for PubMedID 31121022

  • Incremental prognostic value of renal function for stroke prediction in atrial fibrillation INTERNATIONAL JOURNAL OF CARDIOLOGY O'Brien, E. C., Holmes, D. N., Thomas, L., Singer, D. E., Fonarow, G. C., Mahaffey, K. W., Kowey, P. R., Hylek, E. M., Pokorney, S. D., Ansell, J. E., Pencina, M. J., Peterson, E. D., Piccini, J. P., ORBIT-AF Patients & Investigators 2019; 274: 152–57

    Abstract

    Renal function has been associated with an increased stroke risk in patients with atrial fibrillation (AF). However, whether renal function incrementally adds to risk prediction in both anticoagulated and non-anticoagulated patients with AF is unclear.We used data from the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF)-a national, prospective, outpatient AF registry in patients aged >18 years (2010-2011). The association between baseline renal function and risk of stroke/systemic embolism (SSE) was evaluated in proportional hazards models adjusting for stroke risk score components. We compared discrimination of 2-year outcomes using C-indices and evaluated calibration by comparing event rates in ORBIT-AF to published rates from an external clinical trial population (ROCKET AF) and an observational cohort (ATRIA).Among 9743 patients included in the analysis, the median age was 75 years (interquartile range [IQR] 67-82), 89.5% were white, 43% were female, and 76% were taking oral anticoagulation (OAC). Over a median follow-up of 2.3 years, 214 SSE events occurred (1.00 per 100 patient-years). Continuous creatinine clearance (CrCl) was not associated with SSE risk after adjusting for other clinical factors (components of CHADS2 or CHA2DS2-VASc). Discrimination for predicting stroke (C-index; 95% CI) was similar for R2CHADS2 (0.65; 0.61-0.69), CHADS2 (0.65; 0.61-0.69), and CHA2DS2-VASc (0.66; 0.62-0.70).In a community patient population with AF, renal dysfunction was not independently associated with embolic risk beyond other established risk factors in either OAC-treated or untreated patients. Additional study is needed to identify clinical factors that incrementally add to stroke risk prediction.

    View details for PubMedID 30144994

  • Major bleeding in patients with peripheral artery disease: Insights from the EUCLID trial. American heart journal Ward, R. n., Huang, Z. n., Rockhold, F. W., Baumgartner, I. n., Berger, J. S., Blomster, J. I., Fowkes, F. G., Katona, B. G., Mahaffey, K. W., Norgren, L. n., Vemulapalli, S. n., Povsic, T. J., Mehta, R. n., Hiatt, W. R., Patel, M. R., Jones, W. S. 2019; 220: 51–58

    Abstract

    Rates and predictors of major bleeding in patients with peripheral artery disease (PAD) treated with antiplatelets have not been well studied. This post hoc analysis of EUCLID aimed to determine the incidence of major/minor bleeding, predictors of major bleeding, and risk of major adverse cardiovascular events (MACE) following major bleeding events.EUCLID, a multicenter randomized controlled trial of 13,885 patients with symptomatic PAD, compared ticagrelor with clopidogrel for the prevention of MACE. The primary safety end point was Thrombolysis in Myocardial Infarction (TIMI) major bleeding. Baseline characteristics were used to develop a multivariable model to determine factors associated with TIMI major bleeding. The occurrence and timing of MACE relative to a first major bleeding event were determined.TIMI major bleeding occurred in 2.3% of participants overall (0.94 event/100 patient-years). There was no significant difference in major bleeding rates by treatment assignment. Factors associated with TIMI major bleeding included older age, geographic region, Rutherford class, and β-blocker use. Patients with TIMI major bleeding postrandomization had an increased risk of MACE (hazard ratio [HR] 4.46; 95% CI 3.40-5.84; P < .0001) compared with those without major bleeding; the association was strongest within 30 days after a bleeding event.In patients with symptomatic PAD, 0.94 major bleeding event/100 patient-years was observed and associated with older age, residing in North America, disease severity, and β-blocker use. Patients who had a major bleeding event were significantly more likely to experience MACE, especially within the first 30 days, when compared with patients who did not have major bleeding.

    View details for DOI 10.1016/j.ahj.2019.11.007

    View details for PubMedID 31783279

  • A Cluster Analysis of the Japanese Multicenter Outpatient Registry of Patients With Atrial Fibrillation. The American journal of cardiology Inohara, T. n., Piccini, J. P., Mahaffey, K. W., Kimura, T. n., Katsumata, Y. n., Tanimoto, K. n., Inagawa, K. n., Ikemura, N. n., Ueda, I. n., Fukuda, K. n., Takatsuki, S. n., Kohsaka, S. n. 2019

    Abstract

    Recently, cluster analysis was used to identify unique clinically relevant phenotypes of atrial fibrillation (AF) in a cohort from the United States (US) and classified clusters according to the presence of comorbid behavioral disorders, those with conduction disorders, or atherosclerotic comorbidities. Whether these phenotypes are consistent in AF cohorts outside the US remains unknown. Thus, we sought to conduct a cluster analysis in a cohort of Japanese AF patients. We conducted a cluster analysis of phenotypic data (46 variables) in an AF patient cohort recruited from 11 Japanese sites participating in the KiCS-AF Registry. Overall, 2,458 AF patients (median [IQR] age, 68.0 [60.0 to 76.0]; 30.3% female; median [IQR] CHA2DS2-Vasc, 2 [1, 3]) were analyzed. Similar to the US cohort, atherosclerotic comorbidities were identified as distinguishing factors to characterize clusters. Distribution of AF type and left atrial (LA) size substantially varied and was the key feature for cluster formation. CHA2DS2-Vasc score also contributed to cluster formation, although behavioral disorders and/or conduction disorders did not readily characterize clusters. Subsequently, the cohort was classified into 3 clusters: (1) Younger paroxysmal AF (n = 1,190); (2) Persistent/permanent AF with LA enlargement (n = 1,143); and (3) Atherosclerotic comorbid AF in elderly patients (N = 125). In conclusion, conventional classifications, such as atherosclerotic risk factors and CHA2DS2-Vasc score contributed to cluster formation in mutually, whereas in nonatherosclerotic clusters, AF type or LA size rather than the presence or absence of behavior risk factors or sinus node dysfunction (tachy-brady syndrome) seemed to contribute to cluster formation in the Japanese cohort.

    View details for DOI 10.1016/j.amjcard.2019.05.071

    View details for PubMedID 31350002

  • Chronic kidney disease and risk for cardiovascular and limb outcomes in patients with symptomatic peripheral artery disease: The EUCLID trial. Vascular medicine (London, England) Hopley, C. W., Kavanagh, S. n., Patel, M. R., Ostrom, C. n., Baumgartner, I. n., Berger, J. S., Blomster, J. I., Fowkes, F. G., Jones, W. S., Katona, B. G., Mahaffey, K. W., Norgren, L. n., Rockhold, F. W., Hiatt, W. R. 2019: 1358863X19864172

    Abstract

    In patients with symptomatic peripheral artery disease (PAD), the impact of chronic kidney disease (CKD) on major adverse cardiovascular events has not been fully evaluated. The Examining Use of Ticagrelor In PAD (EUCLID) trial randomized 13,885 patients with PAD to ticagrelor 90 mg twice daily or clopidogrel 75 mg daily. This post hoc analysis compared the incidence of the primary composite endpoint (cardiovascular death, myocardial infarction (MI), or ischemic stroke) in patients with CKD (eGFR < 60 mL/min/1.73 m2) with those without CKD (eGFR ⩾ 60 mL/min/1.73 m2). The primary safety endpoint was thrombolysis in MI (TIMI) major bleeding. A total of 13,483 patients were included; 3332 (25%) had CKD, of whom 237 had stage 4/5 disease. Median follow-up was approximately 30 months. After statistical adjustment, patients with CKD had a higher rate of the primary endpoint compared with those without CKD (6.75 vs 3.72 events/100 patient-years; adjusted hazard ratio (HR) 1.45, 95% CI 1.30-1.63). CKD was not associated with increased risk of hospitalization for acute limb ischemia (ALI) (adjusted HR 0.96, 95% CI 0.69-1.34) or major amputation (adjusted HR 0.92, 95% CI 0.66-1.28). CKD was not associated with a significantly increased risk of major bleeding (adjusted HR 1.21, 95% CI 0.89-1.64), but minor bleeding was significantly increased (adjusted HR 1.51, 95% CI 1.07-2.15). In conclusion, patients with PAD and CKD had higher rates of cardiovascular death, MI, and ischemic stroke, but similar rates of ALI, major amputation, and TIMI major bleeding when compared with patients without CKD. ClinicalTrials.gov Identifier: NCT01732822.

    View details for DOI 10.1177/1358863X19864172

    View details for PubMedID 31339474

  • Patient-Reported Satisfaction and Study Drug Discontinuation: Post-Hoc Analysis of Findings from ROCKET AF. Cardiology and therapy Ungar, L. n., Rodriguez, F. n., Hellkamp, A. S., Becker, R. C., Berkowitz, S. D., Breithardt, G. n., Fox, K. A., Hacke, W. n., Halperin, J. L., Hankey, G. J., Nessel, C. C., Singer, D. E., Patel, M. R., Piccini, J. P., Mahaffey, K. W. 2019

    Abstract

    Patient-reported outcomes (PROs) and satisfaction endpoints are increasingly important in clinical trials and may be associated with treatment adherence. In this post hoc substudy from ROCKET AF, we examined whether patient-reported satisfaction was associated with study drug discontinuation.ROCKET AF (n = 14,264) compared rivaroxaban with warfarin for prevention of stroke and systemic embolism in patients with atrial fibrillation. We analyzed treatment satisfaction scores: the Anti-Clot Treatment Scale (ACTS) and Treatment Satisfaction Questionnaire for Medication version II (TSQM II). We compared satisfaction with study drug between the two treatment arms, and examined the association between satisfaction and patient-driven study drug discontinuation (stopping study drug due to withdrawal of consent, noncompliance, or loss to follow-up).A total of 1577 (11%) patients participated in the Patient Satisfaction substudy; 1181 (8.3%) completed both the ACTS and TSQM II 4 weeks after starting study drug. Patients receiving rivaroxaban did not experience significant differences in satisfaction compared with those receiving warfarin. During a median follow-up of 1.6 years, 448 premature study drug discontinuations occurred (213 rivaroxaban group; 235 warfarin group), of which 116 (26%) were patient-driven (52 [24%] rivaroxaban group; 64 [27%] warfarin group). No significant differences were observed between satisfaction level and rates of patient-driven study drug discontinuation.Study drug satisfaction did not predict rate of study drug discontinuation. No significant difference was observed between satisfaction with warfarin and rivaroxaban, as expected given the double-blind trial design. Although these results are negative, the importance of PRO data will only increase, and these analyses may inform future studies that explore the relationship between drug-satisfaction PROs, adherence, and clinical outcomes. CLINICALTRIALS.GOV: NCT00403767.The ROCKET AF trial was funded by Johnson & Johnson and Bayer.

    View details for DOI 10.1007/s40119-019-00146-6

    View details for PubMedID 31376090

  • The efficacy and safety of cangrelor in single vessel vs multi vessel percutaneous coronary intervention: Insights from CHAMPION PHOENIX. Clinical cardiology Yong, C. M., Sundaram, V. n., Abnousi, F. n., Olivier, C. B., Yang, J. n., Stone, G. W., Steg, P. G., Michael Gibson, C. n., Hamm, C. W., Price, M. J., Deliargyris, E. N., Prats, J. n., White, H. D., Harrington, R. A., Bhatt, D. L., Mahaffey, K. W. 2019

    Abstract

    The intravenous, rapidly acting P2Y12 inhibitor cangrelor reduces the rate of ischemic events during PCI with no significant increase in severe bleeding. However, the efficacy and safety of cangrelor compared with clopidogrel in patients treated with single vessel (SV)-percutaneous coronary intervention (PCI) or multi vessel (MV)-PCI remains unexplored.We studied the modified intention-to-treat population of patients from the CHAMPION PHOENIX trial who were randomized to either cangrelor or clopidogrel. We used logistic regression and propensity score matching to evaluate the effect of cangrelor compared with clopidogrel on the primary efficacy outcome (composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis) at 48 hours. The safety outcome was moderate or severe Global Utilization of Streptokinase and tPA for Occluded Arteries bleeding at 48 hours.Cangrelor isas efficacious and safe as clopidogrel in both SVand MV PCI.Among 10 854 patients, 9204 (85%) underwent SV- and 1650 (15%) MV-PCI. After adjustment, cangrelor was associated with similar reductions vs clopidogrel in the primary efficacy outcome in patients undergoing SV-PCI (4.5% vs 5.2%; odds ratio [OR] 0.81 [0.66-0.98]) or MV-PCI (6.1% vs 9.8%, OR 0.59 [0.41-0.85]; Pint 0.14). Similar results were observed after propensity score matching (SV-PCI: 5.5% vs 5.9%, OR 0.93 [0.74-1.18]; MV-PCI: 6.2% vs 8.9%, OR 0.67 [0.44-1.01]; Pint 0.17). There was no evidence of heterogeneity in the treatment effect of cangrelor compared with clopidogrel for the safety outcome.In patients undergoing SV- or MV-PCI, cangrelor was associated with similar relative risk reductions in ischemic complications and no increased risk of significant bleeding compared with clopidogrel, which highlights the expanding repertoire of options for use in complex PCI.

    View details for DOI 10.1002/clc.23221

    View details for PubMedID 31254472

  • Central Adjudication Identified Additional and Prognostically Important Myocardial Infarctions in Patients Undergoing Percutaneous Coronary Intervention. Circulation. Cardiovascular interventions Olivier, C. B., Bhatt, D. L., Leonardi, S. n., Stone, G. W., Gibson, C. M., Steg, P. G., Hamm, C. W., Wilson, M. D., Mangum, S. n., Price, M. J., Prats, J. n., White, H. D., Lopes, R. D., Harrington, R. A., Mahaffey, K. W. 2019; 12 (7): e007342

    Abstract

    In the CHAMPION PHOENIX trial, cangrelor reduced the primary composite end point of death, myocardial infarction (MI), ischemia-driven revascularization, or stent thrombosis at 48 hours. This study aimed to explore the impact of event adjudication and the prognostic importance of MI reported by a clinical events committee (CEC) or site investigators (SIs).Data from the CHAMPION PHOENIX trial of patients undergoing elective or nonelective percutaneous coronary intervention were analyzed. A CEC systematically identified and adjudicated MI using predefined criteria, a computer algorithm to identify suspected events, and semilogarithmic plots to review biomarker changes. Thirty-day death was modeled using baseline characteristics. Of 10 942 patients, 462 (4.2%) patients had at least 1 MI by 48 hours identified by the CEC (207 [3.8%] cangrelor; 255 [4.7%] clopidogrel; odds ratio [OR] 0.80; 95% CI, 0.67-0.97; P=0.022), and 143 patients had at least 1 MI by 48 hours reported by the SI (60 [1.1%] cangrelor; 83 [1.5%] clopidogrel; OR, 0.72; 95% CI, 0.52-1.01; P=0.053). Of the 462 MIs identified by the CEC, 92 (20%) were reported by SI, and 370 (80%) were not. Of the 143 MI reported by the SI, 51 (36%) were not confirmed by CEC. All categories were associated with an increased adjusted risk for 30-day death (CEC: OR, 5.35; 95% CI, 2.56-11.2; P<0.001; SI: 9.08 [4.01-20.5]; P<0.001; CEC and SI: 10.9 [3.23-36.6]; P<0.001; CEC but not SI: 4.69 [1.94-11.3]; P<0.001; SI but not CEC: 15.4 [5.26-44.9]; P<0.001).In patients undergoing percutaneous coronary intervention, CEC procedures identified 3 times as many MIs as the SI reported. Compared with clopidogrel, cangrelor significantly reduced MIs identified by the CEC with a qualitatively similar relative risk reduction in MIs reported by the SI. MIs identified by CEC or reported by SI were independently associated with worse 30-day death. Central adjudication identified additional, prognostically important events.URL: https://www.clinicaltrials.gov . Unique identifier: NCT01156571.

    View details for DOI 10.1161/CIRCINTERVENTIONS.118.007342

    View details for PubMedID 31296081

  • Canagliflozin and Stroke in Type 2 Diabetes Mellitus. Stroke Zhou, Z., Lindley, R. I., Radholm, K., Jenkins, B., Watson, J., Perkovic, V., Mahaffey, K. W., de Zeeuw, D., Fulcher, G., Shaw, W., Oh, R., Desai, M., Matthews, D. R., Neal, B. 2018: STROKEAHA118023009

    Abstract

    Background and Purpose- This study reports the detailed effects of canagliflozin on stroke, stroke subtypes, and vascular outcomes in participants with and without cerebrovascular disease (stroke or transient ischemic attack) at baseline from the CANVAS (Canagliflozin Cardiovascular Assessment Study) Program. Methods- The CANVAS Program, comprising 2 similarly designed and conducted clinical trials, randomly assigned 10 142 participants with type 2 diabetes mellitus and high cardiovascular risk to canagliflozin or placebo. Its primary outcome was a composite of major adverse cardiovascular events. The main outcome of interest for this report was fatal or nonfatal stroke. Additional exploratory outcomes were stroke subtypes and other vascular outcomes defined according to standard criteria. Results- There were 1 958 (19%) participants with prior stroke or transient ischemic attack at baseline. These individuals were older, more frequently women, and had higher rates of heart failure, atrial fibrillation, and microvascular disease (all P<0.001) compared with those without such a history. There were 309 participants with stroke events during follow-up (123 had prior stroke or transient ischemic attack at baseline and 186 did not), at a rate of 7.93/1000 patient-years among those assigned canagliflozin and 9.62/1000 patient-years among placebo (hazard ratio, 0.87; 95% CI, 0.69-1.09). Analysis of stroke subtypes found no effect on ischemic stroke (n=253, hazard ratio, 0.95; 95% CI, 0.74-1.22), a significant reduction for hemorrhagic stroke (n=30, hazard ratio, 0.43; 95% CI, 0.20-0.89) and no effect on undetermined stroke (n=29, hazard ratio, 1.04; 95% CI, 0.48-2.22). Effects on other cardiovascular outcomes were comparable among participants with and without stroke or transient ischemic attack at baseline. Conclusions- There were too few events in the CANVAS Program to separately define the effects of canagliflozin on stroke, but benefit is more likely than harm. The observed possible protective effect for hemorrhagic stroke was based on small numbers but warrants further investigation. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01032629 and NCT01989754.

    View details for PubMedID 30591006

  • Cardiovascular and Limb Outcomes in Patients With Diabetes and PeripheralArtery Disease: The EUCLID Trial. Journal of the American College of Cardiology Low Wang, C. C., Blomster, J. I., Heizer, G., Berger, J. S., Baumgartner, I., Fowkes, F. G., Held, P., Katona, B. G., Norgren, L., Jones, W. S., Lopes, R. D., Olin, J. W., Rockhold, F. W., Mahaffey, K. W., Patel, M. R., Hiatt, W. R., EUCLID Trial Executive Committee and Investigators 2018; 72 (25): 3274–84

    Abstract

    BACKGROUND: Diabetes confers an increased risk for atherosclerotic cardiovascular disease, but less is known about the independent risk diabetes confers on major cardiovascular and limb events in patients with symptomatic peripheral artery disease (PAD) on contemporary management.OBJECTIVES: The authors sought to assess the risk of cardiovascular and limb events in patients with PAD and diabetes as compared with those with PAD alone.METHODS: In the EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) trial, 13,885 patients with symptomatic PAD were evaluated with a primary endpoint of an adjudicated composite of major adverse cardiovascular events (MACE) (cardiovascular death, myocardial infarction, ischemic stroke) followed over a median of 30months. The diabetes subgroup was analyzed compared with the subgroup without diabetes, and further examined for diabetes-specific factors such as glycosylated hemoglobin (HbA1c) that might affect risk for major cardiovascular and limb outcomes.RESULTS: A total of 5,345 patients (38.5%) had diabetes; the majority (n=5,134 [96.1%]) had type 2 diabetes. The primary endpoint occurred in 15.9% of patients with PAD and diabetes as compared with 10.4% of those without diabetes (absolute risk difference 5.5%; adjusted hazard ratio: 1.56; 95% confidence interval [CI]: 1.41 to 1.72; p< 0.001). Every 1% increase in HbA1c was associated with a 14.2% increased relative risk for MACE (95% CI: 1.09 to 1.20; p<0.0001).CONCLUSIONS: Patients with PAD and diabetes are at high risk for cardiovascular and limb ischemic events, even on contemporary therapies. Every 1% increase in HbA1c was associated with a 14.2% increased relative risk for MACE (95%CI: 1.09 to 1.20; p< 0.0001). (A Study Comparing Cardiovascular Effects of Ticagrelor and Clopidogrel in PatientsWith Peripheral Artery Disease [EUCLID]; NCT01732822).

    View details for PubMedID 30573030

  • Cardiovascular and Limb Outcomes in Patients With Diabetes and Peripheral Artery Disease The EUCLID Trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Wang, C., Blomster, J. I., Heizer, G., Berger, J. S., Baumgartner, I., Fowkes, F. R., Held, P., Katona, B. G., Norgren, L., Jones, W., Lopes, R. D., Olin, J. W., Rockhold, F. W., Mahaffey, K. W., Patel, M. R., Hiatt, W. R., EUCLID Trial Executive Comm Invest 2018; 72 (25): 3274–84
  • Stroke Outcomes With Vorapaxar Versus Placebo in Patients With Acute Coronary Syndromes: Insights From the TRACER Trial. Journal of the American Heart Association Ungar, L., Clare, R. M., Rodriguez, F., Kolls, B. J., Armstrong, P. W., Aylward, P., Held, C., Moliterno, D. J., Strony, J., Van de Werf, F., Wallentin, L., White, H. D., Tricoci, P., Harrington, R. A., Mahaffey, K. W., Melloni, C. 2018; 7 (24): e009609

    Abstract

    Background Vorapaxar, a protease-activated receptor-1 antagonist, is approved for secondary prevention of cardiovascular events but is associated with increased intracranial hemorrhage. Methods and Results TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) was a trial of vorapaxar versus placebo among patients with acute coronary syndrome. Strokes were adjudicated by a central events committee. Of 12944 patients, 199 (1.5%) had ≥1 stroke during the study period (median follow-up, 477days). Four patients had a single stroke of unknown type; 195 patients had ≥1 stroke classified as hemorrhagic or nonhemorrhagic (165 nonhemorrhagic, 28 hemorrhagic, and 2 both). Strokes occurred in 96 of 6473 patients (1.5%) assigned vorapaxar and 103 of 6471 patients (1.6%) assigned placebo. Kaplan-Meier incidence of stroke for vorapaxar versus placebo was higher for hemorrhagic stroke (0.45% versus 0.14% [hazard ratio, 2.74; 95% confidence interval, 1.22-6.15]), lower but not significantly different for nonhemorrhagic stroke (1.53% versus 1.98% at 2years [hazard ratio, 0.79; 95% confidence interval, 0.58-1.07]), and similar for stroke overall (1.93% versus 2.13% at 2years [hazard ratio, 0.94; 95% confidence interval, 0.71-1.24]). Conclusions Stroke occurred in <2% of patients. Vorapaxar-assigned patients had increased hemorrhagic stroke but a nonsignificant trend toward lower nonhemorrhagic stroke. Overall stroke frequency was similar with vorapaxar versus placebo.

    View details for PubMedID 30526198

  • Stroke Outcomes With Vorapaxar Versus Placebo in Patients With Acute Coronary Syndromes: Insights From the TRACER Trial JOURNAL OF THE AMERICAN HEART ASSOCIATION Ungar, L., Clare, R. M., Rodriguez, F., Kolls, B. J., Armstrong, P. W., Aylward, P., Held, C., Moliterno, D. J., Strony, J., Van de Werf, F., Wallentin, L., White, H. D., Tricoci, P., Harrington, R. A., Mahaffey, K. W., Melloni, C. 2018; 7 (24)
  • Cost-Effectiveness of Alirocumab Based on Evidence From a Large Multinational Outcome Trial: The ODYSSEY OUTCOMES Economics Study Bhatt, D. L., Briggs, A., Reed, S. D., Annemans, L., Szarek, M., Bittner, V. A., Diaz, R., Edelberg, J. M., Goodman, S. G., Hanotin, C., Harrington, R. A., Jukema, J., Mahaffey, K. W., Moryusef, A., Pordy, R., Roe, M. T., Sanchez, R., Higuchi, K., White, H. D., Zeiher, A. M., Schwartz, G. G., Steg, G., ODYSSEY OUTCOMES Investigators LIPPINCOTT WILLIAMS & WILKINS. 2018: E753–E754
  • Alirocumab Reduces Risk of Death after Acute Coronary Syndrome in Patients with Persistently Elevated Atherogenic Lipoproteins on Intensive Statin Treatment Schwartz, G. G., Szarek, M. M., Bhatt, D. L., Bittner, V. A., Bregeault, M., Dalby, A. J., Diaz, R., Edelberg, J. M., Goodman, S. G., Hanotin, C., Harrington, R. A., Jukema, J. W., Lecorps, G., Mahaffey, K. W., Moryusef, A., Ostadal, P., Parkhomenko, A., Pordy, R., Roe, M. T., Tricoci, P., Vogel, R., White, H. D., Zeiher, A. M., Steg, P. G. LIPPINCOTT WILLIAMS & WILKINS. 2018: E772–E773
  • Incidence, Characteristics, and Outcomes of Myocardial Infarction in Patients With Peripheral Artery Disease: Insights From the EUCLID Trial. JAMA cardiology Olivier, C. B., Mulder, H., Hiatt, W. R., Jones, W. S., Fowkes, F. G., Rockhold, F. W., Berger, J. S., Baumgartner, I., Held, P., Katona, B. G., Norgren, L., Blomster, J., Patel, M. R., Mahaffey, K. W. 2018

    Abstract

    Importance: Patients with peripheral artery disease (PAD) are at high risk for myocardial infarction (MI).Objective: To characterize the incidence and types of MI in a PAD population, identify factors associated with MI, and determine the association of MI with cardiovascular mortality and acute limb ischemia.Design, Setting, and Participants: The Study Comparing Cardiovascular Effects of Ticagrelor and Clopidogrel in Patients With Peripheral Artery Disease (EUCLID) was a double-blind randomized clinical trial conducted at 811 sites in 28 countries that randomized 13 885 patients with symptomatic PAD to monotherapy with ticagrelor or clopidogrel. Participants had an ankle-brachial index (ABI) of 0.80 or less or previous lower extremity revascularization. Median follow-up was 30 months. For these analyses, patients were evaluated for MI occurrence during follow-up irrespective of treatment. Data were analyzed from June 2017 to September 2018.Main Outcomes and Measures: An adjudication clinical events committee classified MI as type 1 (spontaneous), type 2 (secondary), type 3 (sudden cardiac death), type 4a (less than 48 hours after percutaneous coronary intervention), type 4b (definite stent thrombosis), or type 5 (less than 72 hours after coronary artery bypass graft). A multivariate regression model was developed by stepwise selection to identify factors associated with MI, and a time-dependent multivariate Cox regression analysis was performed to determine the association of MI with cardiovascular death and acute limb ischemia requiring hospitalization.Results: Of the 13 885 patients included in this analysis, 9997 (72.0%) were male, and the median (interquartile range) age was 66 (60-73) years. Myocardial infarction occurred in 683 patients (4.9%; 2.4 events per 100 patient-years) during a median follow-up of 30 months. Patients experiencing MI were older (median [interquartile range] age, 69 [62-75] vs 66 [60-72] years), more likely to have diabetes (349 of 683 [51.1%] vs 4996 of 13 202 [37.8%]) or a previous lower extremity revascularization (466 of 683 [68.2%] vs 7409 of 13 202 [56.1%]), and had a lower ABI (if included by ABI) compared with censored patients. Of the 683 patients with MI during follow-up, the most common MI type was type 1 (405 [59.3%]), followed by type 2 (236 [34.6%]), type 4a (14 [2.0%]), type 3 (12 [1.8%]), type 4b (11 [1.6%]), and type 5 (5 [0.7%]). Postrandomization MI was independently associated with cardiovascular death (adjusted hazard ratio, 9.0; 95% CI, 7.3-11.2; P<.001) and acute limb ischemia requiring hospitalization (adjusted hazard ratio, 2.5; 95% CI, 1.3-5.0; P=.008).Conclusions and Relevance: Approximately 5% of patients with symptomatic PAD had an MI during a median follow-up of 30 months. Type 1 MI (spontaneous) was the most common MI type; however, one-third of MIs were type 2 MI (secondary). More research is needed to identify therapies to reduce the risk of MI in patients with PAD and to improve management of type 2 MI.Trial Registration: ClinicalTrials.gov Identifier: NCT01732822.

    View details for PubMedID 30540355

  • Impact of lesion complexity on peri-procedural adverse events and the benefit of potent intravenous platelet adenosine diphosphate receptor inhibition after percutaneous coronary intervention: core laboratory analysis from 10854 patients from the CHAMPION PHOENIX trial. European heart journal Stone, G. W., Genereux, P., Harrington, R. A., White, H. D., Gibson, C. M., Steg, P. G., Hamm, C. W., Mahaffey, K. W., Price, M. J., Prats, J., Deliargyris, E. N., Bhatt, D. L. 2018; 39 (46): 4112–21

    Abstract

    Aims: In the CHAMPION PHOENIX trial, the potent, rapidly acting, intravenous platelet adenosine diphosphate receptor antagonist cangrelor reduced the 48-h incidence of major adverse cardiac events (MACE; death, myocardial infarction, stent thrombosis, or ischaemia-driven revascularization) compared with a loading dose of clopidogrel in patients undergoing percutaneous coronary intervention (PCI). We sought to determine whether the efficacy of cangrelor during PCI varies in patients with simple vs. complex target lesion coronary anatomy.Methods and results: Blinded angiographic core laboratory analysis was completed in 10854 of 10942 (99.2%) randomized patients in CHAMPION PHOENIX (13418 target lesions). Outcomes were analysed according to the number of angiographic PCI target lesion high-risk features (HRF) present (bifurcation, left main, thrombus, angulated, tortuous, eccentric, calcified, long, or multi-lesion treatment). The number of patients with 0, 1, 2, and ≥3 HRFs was 1817 (16.7%), 3442 (31.7%), 2901 (26.7%), and 2694 (24.8%), respectively. The 48-h MACE rate in clopidogrel-treated patients increased progressively with lesion complexity (from 3.3% to 4.4% to 6.9% to 8.7%, respectively, P<0.0001). Cangrelor reduced the 48-h rate of MACE by 21% {4.7% vs. 5.9%, odds ratio (OR) [95% confidence interval (95% CI)] 0.79 (0.67, 0.93), P=0.006} compared with clopidogrel, an effect which was consistent regardless of PCI lesion complexity (Pinteraction=0.66) and presentation with stable ischaemic heart disease (SIHD) or an acute coronary syndrome (ACS). By multivariable analysis, the number of high-risk PCI characteristics [OR (95% CI) 1.68 (1.20, 2.36), 2.78 (2.00, 3.87), and 3.23 (2.33, 4.48) for 1, 2, and 3 HRFs compared with 0 HRFs, all P<0.0001] and treatment with cangrelor vs. clopidogrel [OR (95% CI) 0.78 (0.66, 0.92), P=0.004] were independent predictors of the primary 48-h MACE endpoint. Major bleeding rates were unrelated to lesion complexity and were not increased by cangrelor.Conclusion: Peri-procedural MACE after PCI is strongly dependent on the number of treated high-risk target lesion features. Compared with a loading dose of clopidogrel, cangrelor reduced MACE occurring within 48h after PCI in patients with SIHD and ACS regardless of baseline lesion complexity. The absolute benefit:risk profile for cangrelor will therefore be greatest during PCI in patients with complex coronary anatomy.Clinicaltrials.gov identifier: NCT01156571.

    View details for PubMedID 30203006

  • Impact of lesion complexity on peri-procedural adverse events and the benefit of potent intravenous platelet adenosine diphosphate receptor inhibition after percutaneous coronary intervention: core laboratory analysis from 10 854 patients from the CHAMPIONPHOENIX trial EUROPEAN HEART JOURNAL Stone, G. W., Genereux, P., Harrington, R. A., White, H. D., Gibson, C., Steg, P., Hamm, C. W., Mahaffey, K. W., Price, M. J., Prats, J., Deliargyris, E. N., Bhatt, D. L. 2018; 39 (46): 4112–21
  • Reviewing the role of healthy volunteer studies in drug development. Journal of translational medicine Karakunnel, J. J., Bui, N., Palaniappan, L., Schmidt, K. T., Mahaffey, K. W., Morrison, B., Figg, W. D., Kummar, S. 2018; 16 (1): 336

    Abstract

    BACKGROUND: With the exception of genotoxic oncology drugs, first-in-human, Phase 1 clinical studies of investigational drugs have traditionally been conducted in healthy volunteers (HVs). The primary goal of these studies is to investigate the pharmacokinetics and pharmacodynamics of a novel drug candidate, determine appropriate dosing, and document safety and tolerability.MAIN BODY: When tailored to specific study objectives, HV studies are beneficial to manufacturers and patients alike and can be applied to both non-oncology and oncology drug development. Enrollment of HVs not only increases study accrual rates for dose-escalation studies but also alleviates the ethical concern of enrolling patients with disease in a short-term study at subtherapeutic doses when other studies (e.g. Phase 2 or Phase 3 studies) may be more appropriate for the patient. The use of HVs in non-oncology Phase 1 clinical trials is relatively safe but nonetheless poses ethical challenges because of the potential risks to which HVs are exposed. In general, most adverse events associated with non-oncology drugs are mild in severity, and serious adverse events are rare, but examples of severe toxicity have been reported. The use of HVs in the clinical development of oncology drugs is more limited but is nonetheless useful for evaluating clinical pharmacology and establishing an appropriate starting dose for studies in cancer patients. During the development of oncology drugs, clinical pharmacology studies in HVs have been used to assess pharmacokinetics, drug metabolism, food effects, potential drug-drug interactions, effects of hepatic and renal impairment, and other pharmacologic parameters vital for clinical decision-making in oncology. Studies in HVs are also being used to evaluate biosimilars versus established anticancer biologic agents.CONCLUSION: A thorough assessment of toxicity and pharmacology throughout the drug development process is critical to ensure the safety of HVs. With the appropriate safeguards, HVs will continue to play an important role in future drug development.

    View details for PubMedID 30509294

  • Reviewing the role of healthy volunteer studies in drug development JOURNAL OF TRANSLATIONAL MEDICINE Karakunnel, J. J., Bui, N., Palaniappan, L., Schmidt, K. T., Mahaffey, K. W., Morrison, B., Figg, W. D., Kummar, S. 2018; 16
  • Ticagrelor versus clopidogrel in patients with symptomatic peripheral artery disease and prior coronary artery disease: Insights from the EUCLID trial VASCULAR MEDICINE Berger, J. S., Abramson, B. L., Lopes, R. D., Heizer, G., Rockhold, F. W., Baumgartner, I., Fowkes, F. R., Held, P., Katona, B. G., Norgren, L., Jones, W., Millegard, M., Blomster, J., Reist, C., Hiatt, W. R., Patel, M. R., Mahaffey, K. W., EUCLID Trial Steering Comm Inve 2018; 23 (6): 523–30

    Abstract

    Patients with peripheral artery disease (PAD) are at heightened risk of cardiovascular morbidity and mortality. We sought to evaluate the risk of concomitant coronary artery disease (CAD) in patients with symptomatic PAD versus PAD without diagnosed CAD, and whether ticagrelor was superior to clopidogrel in reducing that risk. The EUCLID trial randomized 13,885 patients with PAD to antithrombotic monotherapy with ticagrelor or clopidogrel. CAD was defined as prior myocardial infarction (MI), percutaneous coronary intervention (PCI), or coronary artery bypass graft (CABG) surgery. Median follow-up was 30 months. Among 4032 (29%) patients with PAD and CAD, 63% had prior MI, 54% prior PCI, and 38% prior CABG. After adjustment for baseline characteristics, patients with PAD and CAD had significantly higher rates of the primary endpoint (cardiovascular death/MI/stroke, 15.3% vs 8.9%, hazard ratio (HR) 1.50, 95% CI: 1.13-1.99; p=0.005), but no statistically significant increase in acute limb ischemia (HR 1.28, 95% CI: 0.57-2.85; p=0.55) or major bleeding (HR 1.10, 95% CI: 0.49-2.48; p=0.81) versus PAD without CAD. Among patients with PAD and CAD, there was no differential treatment effect between ticagrelor versus clopidogrel for the primary efficacy endpoint (HR 1.02, 95% CI: 0.87-1.19; p=0.84), acute limb ischemia (HR 1.03, 95% CI: 0.63-1.69; p=0.89), or major bleeding (HR 1.06, 95% CI: 0.66-1.69; p=0.81). There was a statistically significant interaction between prior coronary stent placement and study treatment ( p=0.03) with a numerical reduction in the primary efficacy endpoint with ticagrelor versus clopidogrel (13.8% vs 16.8%, HR 0.82, 95% CI: 0.65-1.03; p=0.09). Patients with PAD and prior CAD had higher composite rates of cardiovascular death, MI, and ischemic stroke versus PAD without diagnosed CAD. There were no significant differences between ticagrelor and clopidogrel in cardiovascular events or major bleeding. ClinicalTrials.gov Identifier: NCT01732822.

    View details for PubMedID 29992857

  • Association of Race/Ethnicity With Oral Anticoagulant Use in Patients With Atrial Fibrillation Findings From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II JAMA CARDIOLOGY Essien, U. R., Holmes, D. N., Jackson, L. R., Fonarow, G. C., Mahaffey, K. W., Reiffel, J. A., Steinberg, B. A., Allen, L. A., Chan, P. S., Freeman, J., Blanco, R. G., Pieper, K. S., Piccini, J. P., Peterson, E. D., Singer, D. E. 2018; 3 (12): 1174–82
  • Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome NEW ENGLAND JOURNAL OF MEDICINE Schwartz, G. G., Steg, P. G., Szarek, M., Bhatt, D. L., Bittner, V. A., Diaz, R., Edelberg, J. M., Goodman, S. G., Hanotin, C., Harrington, R. A., Jukema, J. W., Lecorps, G., Mahaffey, K. W., Moryusef, A., Pordy, R., Quintero, K., Roe, M. T., Sasiela, W. J., Tamby, J., Tricoci, P., White, H. D., Zeiher, A. M., ODYSSEY OUTCOMES Comm Inv 2018; 379 (22): 2097–2107
  • Association of Race/Ethnicity With Oral Anticoagulant Use in Patients With Atrial Fibrillation: Findings From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II. JAMA cardiology Essien, U. R., Holmes, D. N., Jackson, L. R., Fonarow, G. C., Mahaffey, K. W., Reiffel, J. A., Steinberg, B. A., Allen, L. A., Chan, P. S., Freeman, J. V., Blanco, R. G., Pieper, K. S., Piccini, J. P., Peterson, E. D., Singer, D. E. 2018

    Abstract

    Importance: Black and Hispanic patients are less likely than white patients to use oral anticoagulants for atrial fibrillation. Little is known about racial/ethnic differences in use of direct-acting oral anticoagulants (DOACs) for atrial fibrillation.Objective: To assess racial/ethnic differences in the use of oral anticoagulants, particularly DOACs, in patients with atrial fibrillation.Design, Setting, and Participants: This cohort study used data from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II, a prospective, US-based registry of outpatients with nontransient atrial fibrillation 21 years and older who were followed up from February 2013 to July 2016. Data were analyzed from February 2017 to February 2018.Exposures: Self-reported race/ethnicity as white, black, or Hispanic.Main Outcomes and Measures: The primary outcome was use of any oral anticoagulant, particularly DOACs. Secondary outcomes included the quality of anticoagulation received and oral anticoagulant discontinuation at 1 year.Results: Of 12 417 patients, 11 100 were white individuals (88.6%), 646 were black individuals (5.2%), and 671 were Hispanic individuals (5.4%) with atrial fibrillation. After adjusting for clinical features, black individuals were less likely to receive any oral anticoagulant than white individuals (adjusted odds ratio [aOR], 0.75 [95% CI, 0.56, 0.99]) and less likely to receive DOACs if an anticoagulant was prescribed (aOR, 0.63 [95% CI, 0.49-0.83]). After further controlling for socioeconomic factors, oral anticoagulant use was no longer significantly different in black individuals (aOR, 0.78 [95% CI, 0.59-1.04]); among patients using oral anticoagulants, DOAC use remained significantly lower in black individuals (aOR, 0.73 [95% CI, 0.55-0.95]). There was no significant difference between white and Hispanic groups in use of oral anticoagulants. Among patients receiving warfarin, the median time in therapeutic range was lower in black individuals (57.1% [IQR, 39.9%-72.5%]) and Hispanic individuals (51.7% [interquartile range {IQR}, 39.1%-66.7%]) than white individuals (67.1% [IQR, 51.8%-80.6%]; P<.001). Black and Hispanic individuals treated with DOACs were more likely to receive inappropriate dosing than white individuals (black patients, 61 of 394 [15.5%]; Hispanic patients, 74 of 409 [18.1%]; white patients, 1003 of 7988 [12.6%]; P=.01). One-year persistence on oral anticoagulants was the same across groups.Conclusions and Relevance: After controlling for clinical and socioeconomic factors, black individuals were less likely than white individuals to receive DOACs for atrial fibrillation, with no difference between white and Hispanic groups. When atrial fibrillation was treated, the quality of anticoagulant use was lower in black and Hispanic individuals. Identifying modifiable causes of these disparities could improve the quality of care in atrial fibrillation.

    View details for PubMedID 30484833

  • Frequency, Regional Variation, and Predictors of Undetermined Cause of Death in Cardiometabolic Clinical Trials: A Pooled Analysis of 9,259 Deaths in 9 Trials. Circulation Fanaroff, A. C., Clare, R., Pieper, K. S., Mahaffey, K. W., Melloni, C., Green, J., Alexander, J. H., Jones, W. S., Harrison, R. W., Mehta, R. H., Povsic, T. J., Moreira, H. G., Al-Khatib, S. M., Roe, M. T., Kong, D. F., Mathews, R., Tricoci, P., Holman, R. R., Wallentin, L., Held, C., Califf, R. M., Alexander, K. P., Lopes, R. D. 2018

    Abstract

    BACKGROUND: Modern cardiometabolic clinical trials often include cardiovascular death as a component of a composite primary outcome, requiring central adjudication by a clinical events committee to classify cause of death. However, sometimes the cause of death cannot be determined from available data. The U.S. Food and Drug Administration has indicated that this circumstance should occur only rarely, but its prevalence has not been formally assessed.METHODS: Data from 9 global clinical trials (2009-2017) with long-term follow-up and blinded, centrally adjudicated cause of death were used to calculate the proportion of deaths attributed to CV, non-CV, or undetermined causes by therapeutic area (diabetes mellitus [DM]/pre-DM, stable atherosclerosis, atrial fibrillation, and acute coronary syndrome), region of patient enrollment, and year of trial manuscript publication. Patient- and trial-level variables associated with undetermined cause of death were identified using a logistic model.RESULTS: Across 127,049 enrolled participants from 9 trials, there were 9259 centrally adjudicated deaths: 5012 (54.1%) due to CV causes, 2800 (30.2%) due to non-CV causes, and 1447 (15.6%) due to undetermined causes. There was variability in the proportion of deaths ascribed to undetermined causes by trial therapeutic area, region of enrollment, and year of trial manuscript publication. On multivariable analysis, acute coronary syndrome or atrial fibrillation trial (versus atherosclerotic vascular disease or DM/pre-DM), longer time from enrollment to death, more recent trial manuscript publication year, enrollment in North America (versus Western Europe), female sex, and older age were associated with greater likelihood of death of undetermined cause.CONCLUSIONS: In 9 cardiometabolic clinical trials with long-term follow-up, approximately 16% of deaths had undetermined causes. This provides a baseline for quality assessment of clinical trials and informs operational efforts to potentially reduce the frequency of undetermined deaths in future clinical research.

    View details for PubMedID 30586739

  • Characteristics and outcomes of patients requiring bailout use of glycoprotein IIb/IIIa inhibitors for thrombotic complications of percutaneous coronary intervention: An analysis from the CHAMPION PHOENIX trial. International journal of cardiology Abtan, J., Ducrocq, G., Steg, P. G., Stone, G. W., Mahaffey, K. W., Gibson, C. M., Hamm, C., Price, M. J., Prats, J., Elkin, S., Deliargyris, E. N., White, H. D., Menozzi, A., Harrington, R. A., Bhatt, D. L., MPH on Behalf of the CHAMPION PHOENIX Investigators 2018

    Abstract

    AIMS: To describe the characteristics and outcomes of patients receiving bailout glycoprotein IIb/IIIa inhibitors (GPI) for thrombotic complications of percutaneous coronary intervention (PCI) in a large, contemporary trial.METHODS AND RESULTS: In the CHAMPION PHOENIX trial, the use of GPI was restricted to bailout for thrombotic complications. We describe the characteristics and outcomes of patients requiring bailout GPI compared to patients not receiving GPIs, with adjustment through propensity-score. A multivariable model was constructed to identify independent correlates associated with bailout GPI use. A total of 380 out of 10,942 patients received GPI (3.5%); GPI patients were younger, more frequently male, more likely to present with ST segment elevation myocardial infarction and less frequently treated with cangrelor. At 48 h, GPI patients experienced higher rates of the primary composite outcome of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis (ST) (19.2% vs 4.8%; adjusted OR: 5.65(4.08, 7.82), p < 0.0001) and a higher rate of GUSTO severe or moderate bleeding (2.6% vs 0.4% adjusted OR: 4.90 (1.98, 12.18), p = 0.0006) compared with non GPI patients. Independent correlates of GPI use were STEMI, use of unfractionated heparin, drug-eluting stents and longer procedure duration.CONCLUSIONS: In a large contemporary trial, patients receiving bailout GPI for thrombotic complications of PCI experienced very high risks of both ischemic and bleeding complications, suggesting that prevention of periprocedural complications rather than bailout GPI may be preferable.CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov identifier: NCT01156571.

    View details for DOI 10.1016/j.ijcard.2018.11.114

    View details for PubMedID 30563770

  • Embolic and Other Adverse Outcomes in Symptomatic Versus Asymptomatic Patients With Atrial Fibrillation (from the ORBIT-AF Registry) AMERICAN JOURNAL OF CARDIOLOGY Thind, M., Holmes, D. N., Badri, M., Pieper, K. S., Singh, A., Blanco, R. G., Steinberg, B. A., Fonarow, G. C., Gersh, B. J., Mahaffey, K. W., Peterson, E. D., Reiffel, J. A., Piccini, J. P., Kowey, P. R., ORBIT-AF Investigators Patients 2018; 122 (10): 1677–83

    Abstract

    Asymptomatic atrial fibrillation (AF) is being increasingly diagnosed via implantable devices, screening, and inpatient telemetry. Management of asymptomatic AF is controversial, in part, because the associated risks have not been well described. We examined the incidence of major adverse outcomes in patients with asymptomatic versus symptomatic AF using Outcomes Registry for Better Informed Treatment of Atrial, a nationwide US registry of AF patients. We compared stroke and/or non-central nervous system (CNS) embolism, major adverse cardiovascular and neurologic events, bleeding, and death in 9,319 asymptomatic (defined by European Heart Rhythm Association score = 1 or "no symptoms") versus symptomatic patients. Overall, median (interquartile) age was 75 (67 to 82) years, 3,944 (42%) were women, and 38% versus 37% were asymptomatic based on physician versus patient-reported symptoms. Compared with those with symptoms, physician-defined asymptomatic patients were less likely to be woman (35%/47%) or be on an antiarrhythmic agent (22%/33%), but were more likely to have permanent and/or persistent AF (51%/40%). CHA2DS2-VASc scores did not vary by symptom status. After adjustment, risk of first stroke and/or non-CNS embolism (hazard ratio [HR] 0.85 [95% confidence interval {CI} 0.63 to 1.16], p = 0.32), major adverse cardiovascular and neurologic events (HR 0.88 [95% CI 0.76 to 1.03], p = 0.11), bleeding (HR 0.85 [95% CI 0.72 to 1.00], p = 0.05), and death (HR 0.99 [95% CI 0.87 to 1.13], p = 0.88) were similar in asymptomatic (European Heart Rhythm Association = 1) and symptomatic AF, respectively. Prospective, randomized studies are needed to further define associated adverse events and delineate optimal prophylactic therapies in patients with asymptomatic AF.

    View details for PubMedID 30227964

  • Association of Multiple Biomarkers With Risk of All-Cause and Cause-Specific Mortality After Acute Coronary Syndromes: A Secondary Analysis of the PLATO Biomarker Study. JAMA cardiology Lindholm, D., James, S. K., Gabrysch, K., Storey, R. F., Himmelmann, A., Cannon, C. P., Mahaffey, K. W., Steg, P. G., Held, C., Siegbahn, A., Wallentin, L. 2018

    Abstract

    Importance: Mortality remains at about 5% within a year after an acute coronary syndrome event. Prior studies have assessed biomarkers in relation to all-cause or cardiovascular deaths but not across multiple causes.Objective: To assess if different biomarkers provide information about the risk for all-cause and cause-specific mortality.Design, Setting, and Participants: The Platelet Inhibition and Patient Outcomes (PLATO) trial randomized 18 624 patients with acute coronary syndrome to ticagrelor or clopidogrel from October 2006 through July 2008. In this secondary analysis biomarker substudy, 17 095 patients participated.Main Outcomes and Measures: Death due to myocardial infarction, heart failure, sudden cardiac death/arrhythmia, bleeding, procedures, other vascular causes, and nonvascular causes, as well as all-cause death.Exposures: At baseline, levels of cystatin-C, growth differentiation factor-15 (GDF-15), high-sensitivity C-reactive protein, high-sensitivity troponin I and T, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were determined.Results: The median (interquartile range) age of patients was 62.0 (54.0-71.0) years. Of 17 095 patients, 782 (4.6%) died during follow-up. The continuous associations between biomarkers and all-cause and cause-specific mortality were modeled using Cox models and presented as hazard ratio (HR) comparing the upper vs lower quartile. For all-cause mortality, NT-proBNP and GDF-15 were the strongest markers with adjusted HRs of 2.96 (95% CI, 2.33-3.76) and 2.65 (95% CI, 2.17-3.24), respectively. Concerning death due to heart failure, NT-proBNP was associated with an 8-fold and C-reactive protein, GDF-15, and cystatin-C, with a 3-fold increase in risk. Regarding sudden cardiac death/arrhythmia, NT-proBNP was associated with a 4-fold increased risk and GDF-15 with a doubling in risk. Growth differentiation factor-15 had the strongest associations with other vascular and nonvascular deaths and was possibly associated with death due to major bleeding (HR, 4.91; 95% CI, 1.39-17.43).Conclusions and Relevance: In patients with acute coronary syndrome, baseline levels of NT-proBNP and GDF-15 were strong markers associated with all-cause death based on their associations with death due to heart failure as well as due to arrhythmia and sudden cardiac death. Growth differentiation factor-15 had the strongest associations with death due to other vascular or nonvascular causes and possibly with death due to bleeding.Trial Registration: ClinicalTrials.gov Identifier: NCT00391872.

    View details for DOI 10.1001/jamacardio.2018.3811

    View details for PubMedID 30427997

  • Characterization of cardiovascular clinical events and impact of event adjudication on the treatment effect of darapladib versus placebo in patients with stable coronary heart disease: Insights from the STABILITY trial. American heart journal Held, C., White, H. D., Stewart, R. A., Davies, R., Sampson, S., Chiswell, K., Silverstein, A., Lopes, R. D., Heldestad, U., Budaj, A., Mahaffey, K. W., Wallentin, L., STABILITY Investigators 2018; 208: 65–73

    Abstract

    BACKGROUND: Clinical Endpoint Classification (CEC) in clinical trials allows FOR standardized, systematic, blinded, and unbiased adjudication of investigator-reported events. We quantified the agreement rates in the STABILITY trial on 15,828 patients with stable coronary heart disease.METHODS: Investigators were instructed to report all potential events. Each reported event was reviewed independently by 2 reviewers according to prespecified processes and prespecified end point definitions. Concordance between reported and adjudicated cardiovascular (CV) events was evaluated, as well as event classification influence on final study results.RESULTS: In total, CEC reviewed 7,096 events: 1,064 deaths (696 CV deaths), 958 myocardial infarctions (MI), 433 strokes, 182 transient ischemic attacks, 2,052 coronary revascularizations, 1,407 hospitalizations for unstable angina, and 967 hospitalizations for heart failure. In total, 71.8% events were confirmed by CEC. Concordance was high (>80%) for cause of death and nonfatal MI and lower for hospitalization for unstable angina (25%) and heart failure (50%). For the primary outcome (composite of CV death, MI, and stroke), investigators reported 2,086 events with 82.5% confirmed by CEC. The STABILITY trial treatment effect of darapladib versus placebo on the primary outcome was consistent using investigator-reported events (hazard ratio 0.96 [95% CI 0.87-1.06]) or adjudicated events (hazard ratio 0.94 [95% CI 0.85-1.03]).CONCLUSIONS: The primary outcome results of the STABILITY trial were consistent whether using investigator-reported or CEC-adjudicated events. The proportion of investigator-reported events confirmed by CEC varied by type of event. These results should help improve event identification in clinical trials to optimize ascertainment and adjudication.

    View details for PubMedID 30572273

  • Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. The New England journal of medicine Schwartz, G. G., Steg, P. G., Szarek, M., Bhatt, D. L., Bittner, V. A., Diaz, R., Edelberg, J. M., Goodman, S. G., Hanotin, C., Harrington, R. A., Jukema, J. W., Lecorps, G., Mahaffey, K. W., Moryusef, A., Pordy, R., Quintero, K., Roe, M. T., Sasiela, W. J., Tamby, J., Tricoci, P., White, H. D., Zeiher, A. M., ODYSSEY OUTCOMES Committees and Investigators 2018

    Abstract

    BACKGROUND: Patients who have had an acute coronary syndrome are at high risk for recurrent ischemic cardiovascular events. We sought to determine whether alirocumab, a human monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9), would improve cardiovascular outcomes after an acute coronary syndrome in patients receiving high-intensity statin therapy.METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled trial involving 18,924 patients who had an acute coronary syndrome 1 to 12 months earlier, had a low-density lipoprotein (LDL) cholesterol level of at least 70 mg per deciliter (1.8 mmol per liter), a non-high-density lipoprotein cholesterol level of at least 100 mg per deciliter (2.6 mmol per liter), or an apolipoprotein B level of at least 80 mg per deciliter, and were receiving statin therapy at a high-intensity dose or at the maximum tolerated dose. Patients were randomly assigned to receive alirocumab subcutaneously at a dose of 75 mg (9462 patients) or matching placebo (9462 patients) every 2 weeks. The dose of alirocumab was adjusted under blinded conditions to target an LDL cholesterol level of 25 to 50 mg per deciliter (0.6 to 1.3 mmol per liter). The primary end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization.RESULTS: The median duration of follow-up was 2.8 years. A composite primary end-point event occurred in 903 patients (9.5%) in the alirocumab group and in 1052 patients (11.1%) in the placebo group (hazard ratio, 0.85; 95% confidence interval [CI], 0.78 to 0.93; P<0.001). A total of 334 patients (3.5%) in the alirocumab group and 392 patients (4.1%) in the placebo group died (hazard ratio, 0.85; 95% CI, 0.73 to 0.98). The absolute benefit of alirocumab with respect to the composite primary end point was greater among patients who had a baseline LDL cholesterol level of 100 mg or more per deciliter than among patients who had a lower baseline level. The incidence of adverse events was similar in the two groups, with the exception of local injection-site reactions (3.8% in the alirocumab group vs. 2.1% in the placebo group).CONCLUSIONS: Among patients who had a previous acute coronary syndrome and who were receiving high-intensity statin therapy, the risk of recurrent ischemic cardiovascular events was lower among those who received alirocumab than among those who received placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; ODYSSEY OUTCOMES ClinicalTrials.gov number, NCT01663402 .).

    View details for PubMedID 30403574

  • Characteristics and outcomes of adults with chronic obstructive pulmonary disease and atrial fibrillation HEART Durheim, M. T., Holmes, D. N., Blanco, R. G., Allen, L. A., Chan, P. S., Freeman, J. V., Fonarow, G. C., Go, A. S., Hylek, E. M., Mahaffey, K. W., Pokorney, S. D., Reiffel, J. A., Singer, D. E., Peterson, E. D., Piccini, J. P. 2018; 104 (22): 1850–58

    Abstract

    Chronic obstructive pulmonary disease (COPD) is associated with the development of atrial fibrillation (AF), and may complicate treatment of AF. We examined the association between COPD and symptoms, quality of life (QoL), treatment and outcomes among patients with AF.We compared patients with and without a diagnosis of COPD in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation, a prospective registry that enrolled outpatients with AF not secondary to reversible causes, from both academic and community settings.Among 9749 patients with AF, 1605 (16%) had COPD. Relative to patients without COPD, those with COPD were more likely to be older, current/former smokers (73% vs 43%), have heart failure (54% vs 29%) and coronary artery disease (49% vs 34%). Oral anticoagulant and beta blocker use were similar, whereas digoxin use was more common among patients with COPD. Symptom burden was generally higher, and QoL worse, among patients with COPD (median Atrial Fibrillation Effect on QualiTy-of-Life score 76 vs 83). Patients with COPD had higher risk of all-cause mortality (adjusted HR 1.52 (95% CI 1.32 to 1.74)), cardiovascular mortality (adjusted HR 1.51 (95% CI 1.24 to 1.84)) and cardiovascular hospitalisation (adjusted HR 1.15 (95% CI 1.05 to 1.26)). Patients with COPD also had higher risk of major bleeding events (adjusted HR 1.25 (95% CI 1.05 to 1.50)). There did not appear to be associations between COPD and AF progression, ischaemic events or new-onset heart failure.Among patients with AF, COPD is associated with higher symptom burden, worse QoL, and worse cardiovascular and bleeding outcomes. These associations were not fully explained by cardiovascular risk factors, AF treatment or smoking history.NCT01165710.

    View details for PubMedID 29875139

  • Definitions of peri-procedural myocardial infarction and the association with one-year mortality: Insights from CHAMPION trials INTERNATIONAL JOURNAL OF CARDIOLOGY Olivier, C. B., Sundaram, V., Bhatt, D. L., Leonardi, S., Lopes, R. D., Ding, V. Y., Yang, L., Stone, G. W., Steg, P., Gibson, C., Hamm, C. W., Price, M. J., White, H. D., Desai, M., Lynch, D. R., Harrington, R. A., Mahaffey, K. W., CHAMPION PLATFORM & CHAM 2018; 270: 96–101
  • Early therapeutic persistence on dabigatran versus warfarin therapy in patients with atrial fibrillation: results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry JOURNAL OF THROMBOSIS AND THROMBOLYSIS Jackson, L. R., Kim, S., Shrader, P., Blanco, R., Thomas, L., Ezekowitz, M. D., Ansell, J., Fonarow, G. C., Gersh, B. J., Go, A. S., Kowey, P. R., Mahaffey, K. W., Hylek, E. M., Peterson, E. D., Piccini, J. P. 2018; 46 (4): 435–39

    Abstract

    Anticoagulation is highly effective for the prevention of stroke in patients with atrial fibrillation (AF) but it is dependent on patients continuing therapy. While studies have demonstrated suboptimal therapeutic persistence on warfarin, few have studied persistence rates with non vitamin K antagonist oral anticoagulants (NOACs) such as dabigatran. We examined rates of continued use of dabigatran versus warfarin over 1 year among AF patients in the ORBIT-AF registry between June 29, 2010 and August 09, 2011. Multivariable logistic regression analysis was used to identify characteristics associated with 1-year persistent use of dabigatran therapy or warfarin. At baseline, 6.4 and 93.6% of 7150 AF patients were on dabigatran and warfarin, respectively. At 12 months, dabigatran-treated patients were less likely to have continued their therapy than warfarin-treated patients [Adjusted persistence rates: 66% (95% CI 60-72) vs. 82% (95% CI 80-84), p < .0001]. Predictors of dabigatran persistence included: CHA2DS2-VASc risk scores ≥ 2 OR 5.69, (95% CI 1.50-21.6) and BMI greater than 25 mg/m2 but less than 38 kg/m2 1.05 (1.01-1.09). Predictors of persistence on warfarin included: African American race (vs. White) 1.53 (1.07-2.19), Hispanic ethnicity (vs. White) 1.66 (1.06-2.60), paroxysmal and persistent AF (vs. new-onset) 1.68 (1.21-2.33) and 1.91 (1.35-2.69) respectively, LVH 1.40 (1.08-1.81), and CHA2DS2-VASc risk scores ≥ 2 1.94 (1.18-3.19). While 1-year persistence rates for dabigatran were lower than warfarin, persistence rates for both agents were not ideal. Future studies evaluating contemporary persistence are needed in order to assist in better targeting interventions aimed to improve anticoagulation persistence.

    View details for PubMedID 30051164

  • Alirocumab Reduces Total Nonfatal Cardiovascular and Fatal Events in the ODYSSEY OUTCOMES Trial. Journal of the American College of Cardiology Szarek, M., White, H. D., Schwartz, G. G., Alings, M., Bhatt, D. L., Bittner, V. A., Chiang, C., Diaz, R., Edelberg, J. M., Goodman, S. G., Hanotin, C., Harrington, R. A., Jukema, J. W., Kimura, T., Kiss, R. G., Lecorps, G., Mahaffey, K. W., Moryusef, A., Pordy, R., Roe, M. T., Tricoci, P., Xavier, D., Zeiher, A. M., Steg, P. G., ODYSSEY OUTCOMES Committees and Investigators 2018

    Abstract

    BACKGROUND: The ODYSSEY OUTCOMES trial compared alirocumab with placebo, added to high-intensity or maximum tolerated statin treatment, after acute coronary syndrome (ACS) in 18,924 patients. Alirocumab reduced the first occurrence of the primary composite endpoint and was associated with fewer all-cause deaths.OBJECTIVES: This pre-specified analysis determined the extent to which alirocumab reduced total (first and subsequent) nonfatal cardiovascular events and all-cause deaths in ODYSSEY OUTCOMES.METHODS: Hazard functions for total nonfatal cardiovascular events (myocardial infarction, stroke, ischemia-driven coronary revascularization, and hospitalization for unstable angina or heart failure) and death were jointly estimated, linked by a shared frailty accounting for patient risk heterogeneity and correlated within-patient nonfatal events. An association parameter also quantified the strength of the linkage between risk of nonfatal events and death. The model provides accurate relative estimates of nonfatal event risk if nonfatal events are associated with increased risk for death.RESULTS: With 3,064 first and 5,425 total events, 190 fewer first and 385 fewer total nonfatal cardiovascular events or deaths were observed with alirocumab compared with placebo. Alirocumab reduced total nonfatal cardiovascular events (hazard ratio 0.87, 95% confidence interval 0.82 to 0.93) and death (hazard ratio 0.83, 95% confidence interval 0.71 to 0.97) in the presence of a strong association between nonfatal and fatal event risk.CONCLUSIONS: In patients with ACS, the total number of nonfatal cardiovascular events and deaths prevented with alirocumab was twice the number of first events prevented. Consequently, total event reduction is a more comprehensive metric to capture the totality of alirocumab clinical efficacy after ACS.

    View details for PubMedID 30428396

  • Cardiovascular and Renal Outcomes With Canagliflozin According to Baseline Kidney Function: Data From the CANVAS Program CIRCULATION Neuen, B. L., Ohkuma, T., Neal, B., Matthews, D. R., de Zeeuw, D., Mahaffey, K. W., Fulcher, G., Desai, M., Li, Q., Deng, H., Rosenthal, N., Jardine, M. J., Bakris, G., Perkovic, V. 2018; 138 (15): 1537–50

    Abstract

    Background : Canagliflozin is approved for glucose lowering in type 2 diabetes and confers cardiovascular and renal benefits. We sought to assess whether it had benefits in people with chronic kidney disease (CKD), including those with an estimated glomerular filtration rate (eGFR) between 30 and 45 mL/min/1.73 m2 in whom the drug is not currently approved for use. Methods : The CANagliflozin cardioVascular Assessment Study Program (CANVAS) randomized 10,142 participants with type 2 diabetes and eGFR greater than 30 mL/min/1.73 m2 to canagliflozin or placebo. The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, with other cardiovascular, renal, and safety outcomes. This secondary analysis describes outcomes in participants with and without CKD, defined as eGFR <60 and ≥60 mL/min/1.73 m2, and according to baseline kidney function (eGFR <45, 45-<60, 60-<90, and ≥90 mL/min/1.73 m2). Results : At baseline, 2039 (20.1%) participants had an eGFR <60 mL/min/1.73 m2, of whom 71.6% had a history of cardiovascular disease. The effect of canagliflozin on the primary outcome was similar in people with CKD (HR 0.70, 95% CI 0.55-0.90) and those with preserved kidney function (HR 0.92, 95% CI 0.79-1.07, P heterogeneity = 0.08). Relative effects on most cardiovascular and renal outcomes were similar across eGFR subgroups, with possible heterogeneity suggested only for the outcome of fatal/nonfatal stroke (P heterogeneity = 0.01), as were results for almost all safety outcomes. Conclusions : The effect of canagliflozin on cardiovascular and renal outcomes was not modified by baseline level of kidney function in people with type 2 diabetes and a history or high risk of cardiovascular disease down to eGFR levels of 30 mL/min/1.73 m2 Reassessing current limitations on the use of canagliflozin in CKD may allow additional individuals to benefit from this therapy. Clinical Trial Registration : URL: https://clinicaltrials.gov. Unique identifiers: NCT01032629, NCT01989754.

    View details for PubMedID 29941478

  • Cardiovascular Outcomes After Lower Extremity Endovascular or Surgical Revascularization JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Baumgartner, I., Norgren, L., Fowkes, F. R., Mulder, H., Patel, M. R., Berger, J. S., Jones, W., Rockhold, F. W., Katona, B. G., Mahaffey, K., Hiatt, W. R., Executive Comm Investigators EUCLI 2018; 72 (14): 1563–72

    Abstract

    Lower extremity revascularization (LER) is a common treatment in patients with peripheral artery disease (PAD), but long-term outcomes are poorly defined.The aim was to analyze LER in the EUCLID (Examining Use of tiCagreLor In paD) trial to determine predictors and cardiovascular outcomes.Patients were grouped according to whether they received a post-randomization LER (n = 1,738) or not (n = 12,147). All variables were assessed for significance in univariable and parsimonious multivariable models. The primary endpoint was myocardial infarction, ischemic stroke, or cardiovascular death; major adverse limb events (MALE) included acute limb ischemia or major amputation.A post-randomization LER occurred in 12.5% of patients and was an endovascular LER in 74.7%. Endovascular LERs were performed more often in North America, whereas surgical procedures occurred more frequently in Europe. Independent factors predicting LER were prior and type of prior LER, geographic region, limb symptoms, diabetes, and smoking. A post-randomization LER was associated with an increased risk for the primary endpoint (hazard ratio: 1.60; 95% confidence interval: 1.35 to 1.90; p < 0.0001) and MALE (hazard ratio: 12.0; 95% confidence interval: 9.47 to 15.30; p < 0.0001). Event rates for the primary endpoint after LER were numerically higher in the surgical subgroup, but MALE were similar between surgical and endovascular LER.In the EUCLID trial, LER was most often endovascular. Following LER, there was an increased hazard for the primary endpoint (with higher event rates in the surgical group) and a markedly increased risk for MALE events (with similar event rates between surgical and endovascular LER procedures). (A Study Comparing Cardiovascular Effects of Ticagrelor and Clopidogrel in Patients With Peripheral Artery Disease [EUCLID]; NCT01732822).

    View details for PubMedID 30261955

  • Academic health centers: integration of clinical research with healthcare and education. Comments on a workshop. Clinics (Sao Paulo, Brazil) Arai, R. J., Noronha, I. d., Nicolau, J. C., Schmidt, C., de Albuquerque, G. M., Mahaffey, K. W., Krieger, E. M., Auler Junior, J. O. 2018; 73 (suppl 1): e515s

    View details for PubMedID 30281697

  • B-type natriuretic peptide, disease progression and clinical outcomes in atrial fibrillation. Heart (British Cardiac Society) Inohara, T., Kim, S., Pieper, K., Blanco, R. G., Allen, L. A., Fonarow, G. C., Gersh, B. J., Ezekowitz, M. D., Kowey, P. R., Reiffel, J. A., Naccarelli, G. V., Chan, P. S., Mahaffey, K. W., Singer, D. E., Freeman, J. V., Steinberg, B. A., Peterson, E. D., Piccini, J. P., ORBIT AF Patients and Investigators 2018

    Abstract

    OBJECTIVE: The association with B-type natriuretic peptide (BNP), disease progression and outcomes in patients with atrial fibrillation (AF) has not been thoroughly investigated.METHODS: We evaluated the association between BNP levels and outcomes, including AF progression, composite outcome of major adverse cardiovascular or neurological events (MACNE) and major bleeding, via pooled logistic regression and Cox frailty models in Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II registry. AF progression was defined as either paroxysmal becoming persistent or permanent, or persistent becoming permanent at any follow-up.RESULTS: Among 13375 patients with AF, 2797 with BNP values at baseline (median age (IQR), 72.0 (63.0-80.0) years; 43.0% women; median BNP, 238 (102-502) ng/L; 42.3% prior heart failure) were included in the models evaluating the association between BNP levels and MACNE or major bleeding. Of these, 1282 patients with paroxysmal or persistent AF at baseline were analysed in AF progression model. The likelihood of AF progression (adjusted OR, 1.11 for every 100ng/mL; 95% CI 1.03 to 1.19) and MACNE (adjusted HR, 1.11 for every doubling in BNP values; 95%CI 1.01 to 1.22) increased with BNP concentration, while the elevated BNP values were not associated with increased risks of major bleeding. BNP values improved the risk prediction of AF progression and MACNE when added to conventional risk estimates.CONCLUSIONS: BNP levels are associated with increased risk of AF progression and cardiovascular outcomes in patients with AF. Further studies are required to assess whether biomarker-based risk stratification improves patient outcomes.CLINICAL TRIAL REGISTRATION: NCT01701817.

    View details for PubMedID 30228248

  • Pharmacotherapy for Atrial Fibrillation in Patients With Chronic Kidney Disease: Insights From ORBIT-AF JOURNAL OF THE AMERICAN HEART ASSOCIATION Washam, J. B., Holmes, D. N., Thomas, L. E., Pokorney, S. D., Hylek, E. M., Fonarow, G. C., Mahaffey, K. W., Gersh, B. J., Kowey, P. R., Ansell, J. E., Go, A. S., Reiffel, J. A., Freeman, J. V., Singer, D. E., Naccarelli, G., Blanco, R., Peterson, E. D., Piccini, J. P. 2018; 7 (18)
  • Pharmacotherapy for Atrial Fibrillation in Patients With Chronic Kidney Disease: Insights From ORBIT-AF. Journal of the American Heart Association Washam, J. B., Holmes, D. N., Thomas, L. E., Pokorney, S. D., Hylek, E. M., Fonarow, G. C., Mahaffey, K. W., Gersh, B. J., Kowey, P. R., Ansell, J. E., Go, A. S., Reiffel, J. A., Freeman, J. V., Singer, D. E., Naccarelli, G., Blanco, R., Peterson, E. D., Piccini, J. P. 2018; 7 (18): e008928

    Abstract

    Background Chronic kidney disease ( CKD ) is a common comorbidity in patients with atrial fibrillation. The presence of CKD complicates drug selection for stroke prevention and rhythm control. Methods and Results Patients enrolled in ORBIT AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) with baseline renal function and follow-up data were included (N=9019). CKD was defined as an estimated creatinine clearance <60 mL /min. Patient characteristics were compared by CKD status, and Cox proportional hazards modeling was used to examine the association between oral anticoagulant ( OAC ) use and outcomes and antiarrhythmic drug use and outcomes stratified by CKD stages. At enrollment, 3490 (39%) patients had an estimated creatinine clearance <60 mL /min. Patients with CKD were older and had higher CHA 2 DS 2 VAS c and Anticoagulant and Risk Factors in Atrial Fibrillation (ATRIA) scores. A rhythm control strategy was selected less frequently in patients with CKD , while OAC use was lower among Stage IV and V CKD patients. After adjustment, no significant interaction was noted for OAC and CKD on all-cause mortality ( P=0.5442) or cardiovascular death ( P=0.1233), although a trend for increased major bleeding ( P=0.0608) and stroke, systemic embolism or transient ischemic attack ( P=0.0671) was observed. No interaction was noted for antiarrhythmic drug use and CKD status on all-cause mortality ( P=0.9706), or stroke, systemic embolism or transient ischemic attack ( P=0.4218). Conclusions Patients with atrial fibrillation and CKD are less likely to be treated with rhythm control. Patients with advanced CKD are less likely to receive OAC . Finally, outcomes with OAC in patients with advanced CKD may be materially different with higher rates of both bleeding and stroke.

    View details for PubMedID 30371218

  • Efficacy and Safety of Rivaroxaban versus Warfarin in Patients with Nonvalvular Atrial Fibrillation and a History of Cancer: Observations from ROCKET AF. European heart journal. Quality of care & clinical outcomes Chen, S. T., Hellkamp, A. S., Becker, R. C., Berkowitz, S. D., Breithardt, G., Fox, K. A., Hacke, W., Halperin, J. L., Hankey, G. J., Mahaffey, K. W., Nessel, C. C., Piccini, J. P., Singer, D. E., Patel, M. R., Melloni, C. 2018

    Abstract

    Aims: The management of anticoagulation therapy in patients with atrial fibrillation (AF) and cancer is challenging due to increased thrombotic and bleeding risks. We sought to determine the safety and efficacy of rivaroxaban in patients with AF and a history of cancer.Methods and Results: ROCKET AF randomized 14,264 patients with AF to rivaroxaban or warfarin with a median follow-up of 1.9 years. Cox regression models were used to assess the association between cancer history and clinical outcomes, and the relative treatment effect of rivaroxaban versus warfarin in these patients. A total of 640 patients enrolled in ROCKET AF had a history of cancer, with the most common types being prostate (28.6%), colorectal (16.1%), and breast (14.7%) cancer. Patients with a history of cancer were older, more frequently male, more likely to have prior VKA use, and had higher rates of overall bleeding (HR 1.30 95% CI 1.16-1.47; p<0.0001) and non-cardiovascular death (HR 1.47 95% CI 1.04-2.07; p=0.031) compared with those with no cancer history. There were no significant associations between cancer history and stroke, venous thromboembolism, or myocardial infarction. The relative efficacy of rivaroxaban versus warfarin for prevention of stroke/systemic embolism was similar in those with and without a history of cancer (interaction p-value=0.21).Conclusion: In ROCKET AF, a history of cancer was associated with a higher risk of bleeding and non-cardiovascular death, but not ischemic events. The relative efficacy and safety of rivaroxaban compared with warfarin were not significantly different in patients with and without a history of cancer. The results of this study are exploratory and should be taken in context of the study population, which may not be generalizable to those with advanced malignancy. Further investigation is needed to understand optimal anticoagulation strategies in patients with AF and cancer.

    View details for PubMedID 30219887

  • Rationale and design of a large-scale, app-based study to identify cardiac arrhythmias using a smartwatch: The Apple Heart Study. American heart journal Turakhia, M. P., Desai, M., Hedlin, H., Rajmane, A., Talati, N., Ferris, T., Desai, S., Nag, D., Patel, M., Kowey, P., Rumsfeld, J. S., Russo, A. M., Hills, M. T., Granger, C. B., Mahaffey, K. W., Perez, M. V. 2018

    Abstract

    BACKGROUND: Smartwatch and fitness band wearable consumer electronics can passively measure pulse rate from the wrist using photoplethysmography (PPG). Identification of pulse irregularity or variability from these data has the potential to identify atrial fibrillation or atrial flutter (AF, collectively). The rapidly expanding consumer base of these devices allows for detection of undiagnosed AF at scale.METHODS: The Apple Heart Study is a prospective, single arm pragmatic study that has enrolled 419,093 participants (NCT03335800). The primary objective is to measure the proportion of participants with an irregular pulse detected by the Apple Watch (Apple Inc, Cupertino, CA) with AF on subsequent ambulatory ECG patch monitoring. The secondary objectives are to: 1) characterize the concordance of pulse irregularity notification episodes from the Apple Watch with simultaneously recorded ambulatory ECGs; 2) estimate the rate of initial contact with a health care provider within 3 months after notification of pulse irregularity. The study is conducted virtually, with screening, consent and data collection performed electronically from within an accompanying smartphone app. Study visits are performed by telehealth study physicians via video chat through the app, and ambulatory ECG patches are mailed to the participants.CONCLUSIONS: The results of this trial will provide initial evidence for the ability of a smartwatch algorithm to identify pulse irregularity and variability which may reflect previously unknown AF. The Apple Heart Study will help provide a foundation for how wearable technology can inform the clinical approach to AF identification and screening.

    View details for PubMedID 30392584

  • Effects of genetic variation in protease activated receptor 4 after an acute coronary syndrome: Analysis from the TRACER trial BLOOD CELLS MOLECULES AND DISEASES Tricoci, P., Neely, M., Whitley, M. J., Edelstein, L. C., Simon, L. M., Shaw, C., Fortina, P., Moliterno, D. J., Armstrong, P. W., Aylward, P., White, H., Van de Werf, F., Jennings, L. K., Wallentin, L., Held, C., Harrington, R. A., Mahaffey, K. W., Bray, P. F. 2018; 72: 37–43

    Abstract

    Variation in platelet response to thrombin may affect the safety and efficacy of PAR antagonism. The Thr120 variant of the common single nucleotide polymorphism (SNP) rs773902 in the protease-activated receptor (PAR) 4 gene is associated with higher platelet aggregation compared to the Ala120 variant. We investigated the relationship between the rs773902 SNP with major bleeding and ischemic events, safety, and efficacy of PAR1 inhibition in 6177 NSTE ACS patients in the TRACER trial. There was a lower rate of GUSTO moderate/severe bleeding in patients with the Thr120 variant. The difference was driven by a lower rate in the smaller homozygous group (recessive model, HR 0.13 [0.02-0.92] P = 0.042). No significant differences were observed in the ischemic outcomes. The excess in bleeding observed with PAR1 inhibition was attenuated in patients with the Thr120 variant, but the interactions were not statistically significant. In summary, lower major bleeding rates were observed in the overall TRACER cohort with the hyperreactive PAR4 Thr120 variant. The increase in bleeding with vorapaxar was attenuated with the Thr120 variant, but we could not demonstrate an interaction with PAR1 inhibition. These findings warrant further exploration, including those of African ancestry where the A allele (Thr120) frequency is ~65%.

    View details for PubMedID 30055940

    View details for PubMedCentralID PMC6097632

  • Association of Healthcare Plan with atrial fibrillation prescription patterns CLINICAL CARDIOLOGY Chang, A., Askari, M., Fan, J., Heidenreich, P. A., Ho, P., Mahaffey, K. W., Ullal, A., Perino, A., Turakhia, M. P. 2018; 41 (9): 1136–43

    View details for DOI 10.1002/clc.23042

    View details for Web of Science ID 000446429700004

  • Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials LANCET DIABETES & ENDOCRINOLOGY Perkovic, V., de Zeeuw, D., Mahaffey, K. W., Fulcher, G., Erondu, N., Shaw, W., Barrett, T. D., Weidner-Wells, M., Deng, H., Matthews, D. R., Neal, B. 2018; 6 (9): 691–704

    Abstract

    In the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program, canagliflozin reduced the rates of major adverse cardiovascular events and the results suggested a renal benefit in patients with type 2 diabetes who were at high risk for cardiovascular events, compared with those treated with placebo. Here we report the results of a prespecified exploratory analysis of the long-term effects of canagliflozin on a range of sustained and adjudicated renal outcomes.The CANVAS Program consists of two double-blind, randomised trials that assessed canagliflozin versus placebo in participants with type 2 diabetes who were at high risk of cardiovascular events, done at 667 centres in 30 countries. People with type 2 diabetes and an HbA1c of 7·0-10·5% (53-91 mmol/mol) who were aged at least 30 years and had a history of symptomatic atherosclerotic vascular disease, or who were aged at least 50 years and had at least two cardiovascular risk factors were eligible to participate. Participants in CANVAS were randomly assigned (1:1:1) to receive 300 mg canagliflozin, 100 mg canagliflozin, or matching placebo once daily. Participants in CANVAS-R were randomly assigned (1:1) to receive canagliflozin or matching placebo, at an initial dose of 100 mg daily, with optional uptitration to 300 mg from week 13 or matching placebo. Participants and all study staff were masked to treatment allocations until study completion. Prespecified outcomes reported here include a composite of sustained and adjudicated doubling in serum creatinine, end-stage kidney disease, or death from renal causes; the individual components of this composite outcome; annual reductions in estimated glomerular filtration rate (eGFR); and changes in urinary albumin-to-creatinine ratio (UACR). The trials are registered with ClinicalTrials.gov, numbers NCT01032629 (CANVAS) and NCT01989754 (CANVAS-R).Between Nov 17, 2009, and March 7, 2011 (CANVAS), and Jan 17, 2014, and May 29, 2015 (CANVAS-R), 15 494 people were screened, of whom 10 142 participants (with a baseline mean eGFR 76·5 mL/min per 1·73 m2, median UACR 12·3 mg/g, and 80% of whom were receiving renin-angiotensin system blockade) were randomly allocated to receive either canagliflozin or placebo. The composite outcome of sustained doubling of serum creatinine, end-stage kidney disease, and death from renal causes occurred less frequently in the canagliflozin group compared with the placebo group (1·5 per 1000 patient-years in the canagliflozin group vs 2·8 per 1000 patient-years in the placebo group; hazard ratio 0·53, 95% CI 0·33-0·84), with consistent findings across prespecified patient subgroups. Annual eGFR decline was slower (slope difference between groups 1·2 mL/min per 1·73 m2 per year, 95% CI 1·0-1·4) and mean UACR was 18% lower (95% CI 16-20) in participants treated with canagliflozin than in those treated with placebo. Total serious renal-related adverse events were similar between the canagliflozin and placebo groups (2·5 vs 3·3 per 1000 patient-years; HR 0·76, 95% CI 0·49-1·19).In a prespecified exploratory analysis, canagliflozin treatment was associated with a reduced risk of sustained loss of kidney function, attenuated eGFR decline, and a reduction in albuminuria, which supports a possible renoprotective effect of this drug in people with type 2 diabetes.Janssen Research & Development.

    View details for PubMedID 29937267

  • Prognostic Significance of Nuisance Bleeding in Anticoagulated Patients With Atrial Fibrillation CIRCULATION O'Brien, E. C., Holmes, D. N., Thomas, L. E., Fonarow, G. C., Allen, L. A., Gersh, B. J., Kowey, P. R., Singer, D. E., Ezekowitz, M. D., Naccarelli, G. V., Ansell, J. E., Chan, P. S., Mahaffey, K. W., Go, A. S., Freeman, J. V., Reiffel, J. A., Peterson, E. D., Piccini, J. P., Hylek, E. M. 2018; 138 (9): 889–97

    Abstract

    Background -Bleeding is commonly cited as a reason for stopping oral anticoagulants (OAC). Whether minor bleeding events ("nuisance bleeding", NB) in patients with atrial fibrillation (AF) on OAC are associated with OAC discontinuation, major bleeding and stroke/systemic embolism (SSE), is unknown. Methods -Within the ORBIT-AF prospective, outpatient registry, we identified 6771 patients ≥18 years of age at 172 sites with AF and eligible followup visits. NB was ascertained from the medical record and was defined as minor bleeding that did not require medical attention (e.g. bruising, hemorrhoidal bleeding). We used multivariable pooled logistic regression modeling to evaluate the associations between NB and major bleeding and SSE in the 180 days after documentation of NB. Our unit of analysis was the patient visit, occurring at approximately 6 month intervals for a median of 1.5 years following enrollment. Changes in anticoagulation treatment satisfaction after NB were examined descriptively in a subset of patients. Results -The median age of the overall population was 75.0 (IQR 67.0 - 81.0); 90.0% were white and 42.5% were female. Among 6771 patients (18,560 visits), n=1357 (20.0%) had documented NB, for an incidence rate of 14.8 events per 100 person-years. Over 96.4% of patients remained on OAC therapy after the NB event. Overall, 287 (4.3%) patients experienced major bleeding and 64 (0.96%) had a SSE event during follow-up. NB was not associated with a significant increased risk of major bleeding over 6 months models adjusting for the ATRIA bleeding score (OR 1.04; 95% CI 0.68-1.60; p=0.86). NB was also not associated with increased SSE risk over 6 months in or models adjusting for CHA2DS2-VASc risk score (OR 1.24; 95% CI 0.53-2.91; p=0.62). Conclusions -Nuisance bleeding is common among AF patients on OAC. However, NB was not associated with a higher risk of major bleeding or SSE over the next 6 months, suggesting its occurrence should not lead to changes in anticoagulation treatment strategies in OAC-treated patients. Clinical Trial Registration -URL: https://clinicaltrials.gov Unique Identifier: NCT01165710.

    View details for PubMedID 29678813

  • Stroke Risk and Treatment in Patients with Atrial Fibrillation and Low CHA2DS2-VASc Scores: Findings From the ORBIT-AF I and II Registries. Journal of the American Heart Association Jackson, L. R., Kim, S., Fonarow, G. C., Freeman, J. V., Gersh, B. J., Go, A. S., Hylek, E. M., Kowey, P. R., Mahaffey, K. W., Singer, D., Thomas, L., Blanco, R., Peterson, E. D., Piccini, J. P., Outcomes Registry for Better Informed Treatment of Atrial Fibrillation Patients and Investigators 2018; 7 (16): e008764

    Abstract

    Background Current American College of Cardiology/American Heart Association guidelines suggest that for patients with atrial fibrillation who are at low risk for stroke (CHA2DS2VASc=1) (or women with CHA2DS2VASc=2) a variety of treatment strategies may be considered. However, in clinical practice, patterns of treatment in these "low-risk" patients are not well described. The objective of this analysis is to define thromboembolic event rates and to describe treatment patterns in patients with low-risk CHA2DS2VASc scores. Methods and Results We compared characteristics, treatment strategies, and outcomes among patients with a CHA2DS2VASc=0, CHA2DS2VASc=1, females with a CHA2DS2VASc=2, and CHA2DS2VASc ≥2 in ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) I & II. Compared with CHA2DS2VASc ≥2 patients (84.2%), those with a CHA2DS2VASc=0 (60.3%), 1 (69.9%), and females with a CHA2DS2VASc score=2 (72.4%) were significantly less often treated with oral anticoagulation ( P<0.0001). Stroke rates were low overall and ranged from 0 per 100 patient-years in those with CHA2DS2VASc=0, 0.8 (95% confidence interval [CI] [0.5-1.2]) in those with CHA2DS2VASc=1, 0.8 (95% CI [0.4-1.6]) in females with a CHA2DS2VASc score=2, and 1.7 (95% CI [1.6-1.9]) in CHA2DS2VASc ≥2. All-cause mortality (per 100 patient-years) was highest in females with a CHA2DS2VASc score=2 (1.4) (95% CI [0.8-2.3]), compared with patients with a CHA2DS2VASc=0 (0.2) (95% CI [0.1-1.0]), and CHA2DS2VASc=1 (1.0) (95% CI [0.7-1.4]), but lower than patients with a CHA2DS2VASc ≥2 (5.7) (95% CI [5.4-6.0]). Conclusion The majority of CHA2DS2VASc=0-1 patients are treated with oral anticoagulation. In addition, the absolute risks of death and stroke/transient ischemic attack were low among both male and females CHA2DS2VASc=0-1 as well as among females with a CHA2DS2VASc score=2. Clinical Trial Registration URL: http://www.clinicaltrials.gov . Unique identifier: NCT01701817.

    View details for PubMedID 30369317

  • Initiating anticoagulation with the intention of cardioverting: does drug choice matter? EUROPEAN HEART JOURNAL Mahaffey, K. W., Turakhia, M. P. 2018; 39 (32): 2972–74
  • Stroke Risk and Treatment in Patients with Atrial Fibrillation and Low CHA(2)DS(2)-VASc Scores: Findings From the ORBIT-AF I and II Registries JOURNAL OF THE AMERICAN HEART ASSOCIATION Jackson, L. R., Kim, S., Fonarow, G. C., Freeman, J. V., Gersh, B. J., Go, A. S., Hylek, E. M., Kowey, P. R., Mahaffey, K. W., Singer, D., Thomas, L., Blanco, R., Peterson, E. D., Piccini, J. P., Outcomes Registry Better Informed 2018; 7 (16)
  • Letter by Matthews et al Regarding Article, "Class Effect for Sodium Glucose-Cotransporter-2 Inhibitors in Cardiovascular Outcomes: Implications for the Cardiovascular Disease Specialist" CIRCULATION Matthews, D. R., Perkovic, V., Mahaffey, K. W. 2018; 138 (6): 660–61
  • Selective Serotonin Reuptake Inhibitors and Bleeding Risk in Anticoagulated Patients With Atrial Fibrillation: An Analysis From the ROCKET AF Trial JOURNAL OF THE AMERICAN HEART ASSOCIATION Quinn, G. R., Hellkamp, A. S., Hankey, G. J., Becker, R. C., Berkowitz, S. D., Breithardt, G., Fava, M., Fox, K. A., Halperin, J. L., Mahaffey, K. W., Nessel, C. C., Patel, M. R., Piccini, J. P., Singer, D. E. 2018; 7 (15)
  • Selective Serotonin Reuptake Inhibitors and Bleeding Risk in Anticoagulated Patients With Atrial Fibrillation: An Analysis From the ROCKET AF Trial. Journal of the American Heart Association Quinn, G. R., Hellkamp, A. S., Hankey, G. J., Becker, R. C., Berkowitz, S. D., Breithardt, G., Fava, M., Fox, K. A., Halperin, J. L., Mahaffey, K. W., Nessel, C. C., Patel, M. R., Piccini, J. P., Singer, D. E. 2018; 7 (15): e008755

    Abstract

    Background There is concern that selective serotonin reuptake inhibitors ( SSRI s) substantially increase bleeding risk in patients taking anticoagulants. Methods and Results We studied 737 patients taking SSRI s in the ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Embolism and Stroke Trial in Atrial Fibrillation) trial of rivaroxaban compared with warfarin for the prevention of stroke/systemic embolism in patients with atrial fibrillation. These patients were propensity score matched 1:1 to 737 patients not taking SSRI s. The primary outcome measure was major and nonmajor clinically relevant bleeding events, the principal safety outcome in ROCKET AF . Over a mean 1.6years of follow-up, the rate of major/ nonmajor clinically relevant bleeding was 18.57 events/100 patient-years for SSRI users versus 16.84 events/100 patient-years for matched comparators, adjusted hazard ratio ( aHR ) of 1.16 (95% confidence interval [CI], 0.95-1.43). The aHR s were similar in patients taking rivaroxaban ( aHR 1.11 [95% CI, 0.82-1.51]) and those taking warfarin ( aHR 1.21 [95% CI, 0.91-1.60]). For the rarer outcome of major bleeding, the aHR for SSRI users versus those not taking SSRI s was 1.13 (95% CI, 0.62-2.06) for rivaroxaban; for warfarin, the aHR was higher, at 1.58 (95% CI , 0.96-2.60) but not statistically significantly elevated. Conclusions We found no significant increase in bleeding risk when SSRI s were combined with anticoagulant therapy, although there was a suggestion of increased bleeding risk with SSRI s added to warfarin. While physicians should be vigilant regarding bleeding risk, our results provide reassurance that SSRI s can be safely added to anticoagulants in patients with atrial fibrillation . Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 00403767.

    View details for PubMedID 30371223

  • Safety of ticagrelor in patients with baseline conduction abnormalities: A PLATO (Study of Platelet Inhibition and Patient Outcomes) analysis AMERICAN HEART JOURNAL Scirica, B. M., Bansilal, S., Davoudi, F., Armstrong, P. W., Clare, R. M., Schulte, P. J., Pieper, K. S., Becker, R. C., James, S. K., Storey, R. F., Steg, P., Held, C., Himmelmann, A., Mahaffey, K. W., Wallentin, L., Cannon, C. P., PLATO Steering Comm & Investigato 2018; 202: 54–60

    Abstract

    Although bradyarrhythmias have been observed with ticagrelor and its use with advanced atrioventricular block is not recommended, questions arise regarding its use in patients with mild conduction abnormalities. The objectives were to compare rates of clinically relevant arrhythmias in relation to any mild baseline conduction abnormality in patients with acute coronary syndrome randomized to ticagrelor versus clopidogrel.We included all subjects in the electrocardiographic (ECG) substudy of the Platelet Inhibition and Patient Outcomes trial, excluding those with missing baseline ECG or with a pacemaker at baseline (N = 15,460). Conduction abnormality was defined as sinus bradycardia, first-degree atrioventricular block, hemiblock, or bundle-branch block. The primary arrhythmic outcome was the composite of any symptomatic brady- or tachyarrhythmia, permanent pacemaker placement, or cardiac arrest through 12 months.Patients with baseline conduction abnormalities (n = 4,256, 27.5%) were older and more likely to experience the primary arrhythmic outcome. There were no differences by ticagrelor versus clopidogrel in the composite arrhythmic end point in those with baseline conduction disease (1-year cumulative incidence rate: 17% for both study arms; hazard ratio: 0.99 [0.86-1.15]) or without baseline conduction disease (1-year cumulative incidence rate: clopidogrel 12.8% vs ticagrelor 12.4%; hazard ratio: 0.98 (0.88-1.09). There were also no statistically significant differences between ticagrelor and clopidogrel in the rates of bradycardic (or any individual arrhythmic) events in patients with baseline conduction abnormalities.Ticagrelor compared to clopidogrel did not increase arrhythmic events even in subjects with acute coronary syndrome who present with mild conduction abnormalities on their baseline ECG.

    View details for PubMedID 29859968

  • Canagliflozin and Heart Failure in Type 2 Diabetes Mellitus: Results From the CANVAS Program CIRCULATION Radholm, K., Figtree, G., Perkovic, V., Solomon, S. D., Mahaffey, K. W., de Zeeuw, D., Fulcher, G., Barrett, T. D., Shaw, W., Desai, M., Matthews, D. R., Neal, B. 2018; 138 (5): 458–68

    Abstract

    BACKGROUND : Canagliflozin is a sodium glucose cotransporter 2 inhibitor that reduces the risk of cardiovascular events. We report the effects on heart failure and cardiovascular death overall, in those with and without a baseline history of heart failure, and in other participant subgroups. METHODS : The CANVAS Program (Canagliflozin Cardiovascular Assessment Study) enrolled 10 142 participants with type 2 diabetes mellitus and high cardiovascular risk. Participants were randomly assigned to canagliflozin or placebo and followed for a mean of 188 weeks. The primary end point for these analyses was adjudicated cardiovascular death or hospitalized heart failure. RESULTS : Participants with a history of heart failure at baseline (14.4%) were more frequently women, white, and hypertensive and had a history of prior cardiovascular disease (all P<0.001). Greater proportions of these patients were using therapies such as blockers of the renin angiotensin aldosterone system, diuretics, and β-blockers at baseline (all P<0.001). Overall, cardiovascular death or hospitalized heart failure was reduced in those treated with canagliflozin compared with placebo (16.3 versus 20.8 per 1000 patient-years; hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.67-0.91), as was fatal or hospitalized heart failure (HR, 0.70; 95% CI, 0.55-0.89) and hospitalized heart failure alone (HR, 0.67; 95% CI, 0.52-0.87). The benefit on cardiovascular death or hospitalized heart failure may be greater in patients with a prior history of heart failure (HR, 0.61; 95% CI, 0.46-0.80) compared with those without heart failure at baseline (HR, 0.87; 95% CI, 0.72-1.06; P interaction =0.021). The effects of canagliflozin compared with placebo on other cardiovascular outcomes and key safety outcomes were similar in participants with and without heart failure at baseline (all interaction P values >0.130), except for a possibly reduced absolute rate of events attributable to osmotic diuresis among those with a prior history of heart failure (P=0.03). CONCLUSIONS : In patients with type 2 diabetes mellitus and an elevated risk of cardiovascular disease, canagliflozin reduced the risk of cardiovascular death or hospitalized heart failure across a broad range of different patient subgroups. Benefits may be greater in those with a history of heart failure at baseline. CLINICAL TRIAL REGISTRATION : URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01032629 and NCT01989754.

    View details for PubMedID 29526832

  • International Validation of the Thrombolysis in Myocardial Infarction (TIMI) Risk Score for Secondary Prevention in Post-MI Patients: A Collaborative Analysis of the Chronic Kidney Disease Prognosis Consortium and the Risk Validation Scientific Committee JOURNAL OF THE AMERICAN HEART ASSOCIATION Mok, Y., Ballew, S. H., Bash, L. D., Bhatt, D. L., Boden, W. E., Bonaca, M. P., Carrero, J., Coresh, J., D'Agostino, R. B., Elley, C., Fowkes, F. R., Jee, S., Kovesdy, C. P., Mahaffey, K. W., Nadkarni, G., Peterson, E. D., Sang, Y., Matsushita, K. 2018; 7 (14)

    Abstract

    The Thrombolysis in Myocardial Infarction (TIMI) Risk Score for Secondary Prevention (TRS2°P), a 0-to-9-point system based on the presence/absence of 9 clinical factors, was developed to classify the risk of major adverse cardiovascular events (MACE) (a composite of cardiovascular death, recurrent myocardial infarction, or ischemic stroke) among patients with a recent myocardial infarction. Its performance has not been examined internationally outside of a clinical trial setting.We evaluated the performance of TRS2°P for predicting MACE in 53 599 patients with recent myocardial infarction in 5 international cohorts from New Zealand, South Korea, Sweden, and the United States participating in the Chronic Kidney Disease Prognosis Consortium. Overall, there were 19 444 cases of MACE across 5 cohorts over a mean follow-up of 5 years, and the overall MACE rate ranged from 5.0 to 18.4 (per 100 person-years). The TRS2°P showed modest calibration (Brier score ranged from 0.144 to 0.173) and discrimination (C-statistics >0.61 in all studies except 1 from Korea with 0.55) across cohorts relative to its original Brier score of 0.098 and C-statistic of 0.67 in the derived data set. Although there was some heterogeneity across cohorts, the 9 predictors in the TRS2°P were generally associated with higher MACE risk, with strongest associations observed (meta-analyzed adjusted hazard ratio 1.6-1.7) for history of heart failure, age ≥75 years, and prior stroke, followed by peripheral artery disease, kidney dysfunction, diabetes mellitus, and hypertension (hazard ratio 1.3-1.4). Prior coronary bypass graft surgery and smoking did not reach statistical significance (hazard ratio ≈1.1).TRS2°P, a simple scoring system with 9 routine clinical factors, was modestly predictive of secondary events when applied in patients with recent myocardial infarction from diverse clinical and geographic settings.

    View details for DOI 10.1161/JAHA.117.008426

    View details for Web of Science ID 000452803800010

    View details for PubMedID 29982232

    View details for PubMedCentralID PMC6064832

  • Discharge timing and outcomes after uncomplicated non-ST-segment elevation acute myocardial infarction AMERICAN HEART JOURNAL Rymer, J. A., Tempelhof, M. W., Clare, R. M., Pieper, K. S., Granger, C. B., Van de Werf, F., Moliterno, D. J., Harrington, R. A., White, H. D., Armstrong, P. W., Lopes, R. D., Mahaffey, K. W., Newby, L. 2018; 201: 103–10

    Abstract

    Length of stay after non-ST-segment elevation myocardial infarction (NSTEMI) continues to decrease, but information to guide duration of hospitalization is limited.We used landmark analyses, in which the landmark defined potential days of discharge, to estimate complication rates on the first day the patient would have been out of the hospital, and estimated associations between timing of discharge and 30-day and 1-year event-free survival after discharge among NSTEMI patients.Among 20,410 NSTEMI patients, median length of stay was 7 (4, 12) days; 3,209 (15.7%) experienced a cardiac complication on days 0 to 2 and 1,322 (6.5%) were discharged without complications during hospital days 0 to 2. At the start of day 3, 15,879 patients (77.8%) were still hospitalized without complications. Of these, 1,689 (10.6%) were discharged event-free on day 3. Adjusted event-free survival rates of death or myocardial infarction from day 4 to 30 days after among the 1,689 patients was 99.1% compared with 93.1% for the 14,190 who remained hospitalized at the end of day 3. For 1-year mortality, these rates were 98.1% and 96.4%, respectively. Among 13,334 patients hospitalized without complications at the start of day 4, 1,706 were discharged event-free that day. Adjusted survival rates among these patients, compared with those still hospitalized at the end of day 4, were 98.0% versus 93.7% for 30-day death or myocardial infarction and 97.8% versus 96.1% for 1-year mortality.Patients with NSTEMI who had no serious complications during the first 2 hospital days were at low risk of subsequent short- and intermediate-term death or ischemic events.

    View details for PubMedID 29910048

  • Incidence, timing, and type of first and recurrent ischemic events in patients with and without peripheral artery disease after an acute coronary syndrome AMERICAN HEART JOURNAL Inohara, T., Pieper, K., Wojdyla, D. M., Patel, M. R., Jones, W., Tricoci, P., Mahaffey, K. W., James, S. K., Alexander, J. H., Lopes, R. D., Wallentin, L., Oilman, E., Roe, M. T., Vemulapalli, S. 2018; 201: 25–32

    Abstract

    Patients with peripheral artery disease (PAD) are known to have an increased risk of ischemic cardiovascular events. However, the influence of concomitant PAD on first and subsequent recurrent ischemic events after an acute coronary syndrome (ACS) remains poorly characterized.We analyzed the combined data set from 4 randomized trials (PLATO, APPRAISE-2, TRA-CER, and TRILOGY ACS) in ACS for a follow-up length of 1 year. Using multivariable regression, we examined the association between PAD and major adverse cardiovascular events, a composite of cardiovascular death, myocardial infarction, and stroke. Among patients with a nonfatal first event, we evaluated the incidence and type of a second recurrent event.A total of 4,098 of 48,094 (8.5%) post-ACS patients had a history of PAD. The unadjusted frequency of major adverse cardiovascular events was 2-fold higher in patients with PAD (14.3% vs 7.5%) over a median (25th-75th) follow-up of 353 (223-365) days with an adjusted hazard ratio of 1.63 (95% CI: 1.48-1.78; P < .001). The frequency of recurrent ischemic events among those patients with a first, nonfatal event was higher among those with PAD (40.0% vs 27.7%). The relative frequency of each event type (cardiovascular death, noncardiovascular death, myocardial infarction, or stroke) within first and subsequent ischemic events was similar regardless of PAD status at baseline.Patients with PAD have a significantly higher risk of first and recurrent ischemic events in the post-ACS setting. These findings highlight the opportunity for improved treatments in patients with PAD who experience an ACS.

    View details for PubMedID 29910052

  • Therapeutic Strategies Following Major, Clinically Relevant Nonmajor, and Nuisance Bleeding in Atrial Fibrillation: Findings From ORBIT-AF JOURNAL OF THE AMERICAN HEART ASSOCIATION O'Brien, E. C., Holmes, D. N., Thomas, L., Fonarow, G. C., Kowey, P. R., Ansell, J. E., Mahaffey, K. W., Gersh, B. J., Peterson, E. D., Piccini, J. P., Hylek, E. M. 2018; 7 (12)

    Abstract

    Oral anticoagulation (OAC) reduces stroke risk in atrial fibrillation, but bleeding is a frequent side effect. The decision to discontinue or modify medication regimens in response to a bleeding event may differ according to bleeding site and severity.We used data from a large, national outpatient registry, ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation; 2010-2011), to evaluate event characteristics and OAC management following the first bleeding event occurring during follow-up. Bleeding events were classified into 3 categories: (1) International Society of Thrombosis and Hemostasis major bleeding, (2) clinically relevant nonmajor bleeding requiring medical attention, and (3) nuisance bleeding not requiring medical attention (eg, bruising, hemorrhoidal bleeding). Of 9743 patients enrolled in ORBIT-AF with follow-up data, 510 (3.23/100 subject-years) experienced a major bleed, 615 (3.90/100 subject-years), experienced a clinically relevant nonmajor bleed, and 1558 (9.87/100 subject-years) experienced a nuisance bleed, among first bleeds over 2 years. Nearly one third of patients (31.6%) discontinued OAC therapy following a major bleeding event, 12.7% following a clinically relevant nonmajor bleed, and 4.5% following a nuisance bleed. Compared with those who experienced a clinically relevant nonmajor or nuisance bleed, patients who experienced a major bleed were more likely to be black and female and to have a history of heart failure and stroke. Those who discontinued were more likely to have central nervous system or gastrointestinal bleeding than those who persisted on OAC therapy.Overall, 1 in 3 patients who experienced a major bleed was no longer anticoagulated after the event. Those who discontinued OAC were more likely to have central nervous system or gastrointestinal bleeding than those who persisted on OAC.

    View details for PubMedID 29886422

  • Definitions of peri-procedural myocardial infarction and the association with one-year mortality: Insights from CHAMPION trials. International journal of cardiology Olivier, C. B., Sundaram, V., Bhatt, D. L., Leonardi, S., Lopes, R. D., Ding, V. Y., Yang, L., Stone, G. W., Steg, P. G., Gibson, C. M., Hamm, C. W., Price, M. J., White, H. D., Desai, M., Lynch, D. R., Harrington, R. A., Mahaffey, K. W., CHAMPION PLATFORM and CHAMPION PCI Investigators 2018

    Abstract

    BACKGROUND: Controversies exist over the appropriate definition for peri-procedural myocardial infarction (PPMI) and its association with mortality. This study aims to evaluate one-year survival following percutaneous coronary intervention (PCI) and the association of different definitions of PPMI with survival among patients with stable angina (SA) or acute coronary syndrome (ACS) in the contemporary era.METHODS: We used data from the CHAMPION PLATFORM and CHAMPION PCI trials of patients undergoing PCI and conducted univariable and multivariable Cox proportional hazard regression models to evaluate mortality risk during the first year after PCI. A blinded events committee adjudicated suspected PPMI defined by biomarker elevations ≥3* the upper limit of normal (ULN) or new Q-waves. We further analyzed PPMI by the magnitude of CK-MB elevation ([a] 3 to <5* ULN, [b] 5 to <10* ULN, [c] ≥10* ULN) or by the 2nd universal definition of myocardial infarction (UDMICK-MB) excluding patients with evidence of myocardial infarction (MI) prior to PCI.RESULTS: Of 13,968 patients, 11% initially presented with SA, and 89% with ACS. One-year mortality was 3.4% (SA: 1.5%; ACS: 3.6%). PPMI occurred in 6.3% of the patients (3 to <5* ULN: 2.5%; 5 to <10* ULN: 2.1%; ≥10* ULN: 1.6%; UDMICK-MB: 2.7%). After multivariable adjustment, a significantly higher risk of one-year mortality was observed for patients with PPMI compared with patients without PPMI (HR 2.35 [1.74-3.18], p < 0.001; 3 to <5* ULN: 1.55 [0.92-2.62], p = 0.10; 5 to <10* ULN: 1.22 [0.67-2.20], p = 0.52; ≥10* ULN: 4.78 [3.06-7.47], p < 0.001; UDMICK-MB: 2.19 [1.29-3.73], p = 0.004).CONCLUSION: PPMI occurred in 6.3% of the patients and was associated with increased risk of death within one year. Survival was not significantly impacted by PPMI if defined by periprocedural CK-MB elevations <10* ULN alone and without additional evaluation of symptoms or evidence of ischemia. These findings highlight the importance of PPMI for long-term outcome in the contemporary era and of its definition in the planning and interpretation of clinical trials.

    View details for PubMedID 29937301

  • Initiating anticoagulation with the intention of cardioverting: does drug choice matter? European heart journal Mahaffey, K. W., Turakhia, M. P. 2018

    View details for PubMedID 29873723

  • Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular disease, death and safety outcomes in type 2 diabetes - A systematic review DIABETES RESEARCH AND CLINICAL PRACTICE Radholm, K., Wu, J. Y., Wong, M., Foote, C., Fulcher, G., Mahaffey, K. W., Perkovic, V., Neal, B. 2018; 140: 118–28

    Abstract

    Sodium glucose co-transporter 2 (SGLT2) inhibitors appear to protect against increased risks of cardiovascular and kidney disease in patients with type 2 diabetes but also cause some harms. Whether effects are comparable across drug class or specific to individual compounds is unclear. This meta-analysis assessed the class and individual compound effects of SGLT2 inhibition versus control on cardiovascular events, death, kidney disease and safety outcomes in patients with type 2 diabetes.MEDLINE, EMBASE, the Cochrane Library and regulatory databases were systematically searched for data from randomized clinical trials that included reporting of cardiovascular events, deaths or safety outcomes. We used fixed effects models and inverse variance weighting to calculate relative risks with the 95% confidence intervals.The analyses included data from 82 trials, four overviews and six regulatory reports and there were 1,968 major cardiovascular events identified for analysis. Patients randomly assigned to SGLT2 had lower risks of major cardiovascular events (RR 0.85, 95%CI 0.77-0.93), heart failure (RR 0.67, 95%CI 0.55-0.80), all-cause death (RR 0.79, 95%CI 0.70-0.88) and serious decline in kidney function (RR 0.59, 0.49-0.71). Significant adverse effects were observed for genital infections (RR 3.06, 95%CI 2.73-4.43), volume depletion events (RR 1.24, 95%CI 1.07-1.43) and amputation (RR 1.44 95%CI 1.13-1.83). There was a high likelihood of differences in the associations of the individual compounds with cardiovascular death, hypoglycaemia and amputation (all I2 > 80%) and a moderate likelihood of differences in the associations with non-fatal stroke, all-cause death, urinary tract infection and fracture (all I2 > 30%).There are strong overall associations of SGLT2 inhibition with protection against major cardiovascular events, heart failure, serious decline in kidney function and all-cause death. SGLT2 inhibitors were also associated with infections, volume depletion effects and amputation. Some associations appear to differ between compounds.

    View details for PubMedID 29604389

  • Impact of polyvascular disease on patients with atrial fibrillation: Insights from ROCKET AF AMERICAN HEART JOURNAL Chen, S. T., Hellkamp, A. S., Becker, R. C., Berkowitz, S. D., Breithardt, G., Fox, K. A., Hacke, W., Halperin, J. L., Hankey, G. J., Mahaffey, K. W., Nessel, C. C., Piccini, J. P., Singer, D. E., Patel, M. R. 2018; 200: 102–9

    Abstract

    We investigated the impact of polyvascular disease in patients enrolled in ROCKET AF.Cox regression models were used to assess clinical outcomes and treatment effects of rivaroxaban compared with warfarin in patients with atrial fibrillation and coronary, peripheral, or carotid artery disease, or any combination of the 3.A total of 655 (4.6%) patients had polyvascular disease (≥2 disease locations), and 3,391 (23.8%) had single-arterial bed disease. Patients with polyvascular disease had similar rates of stroke/systemic embolism but higher rates of cardiovascular and bleeding events when compared with those without vascular disease. Use of rivaroxaban compared with warfarin was associated with higher rates of stroke in patients with polyvascular disease (hazard ratio [HR] 2.41, 95% CI 1.05-5.54); however, this was not seen in patients with single-bed (HR 0.90, 95% CI 0.64-1.28) or no vascular disease (HR 0.85, 95% CI 0.69-1.04; interaction P = .058). There was a significant interaction for major or nonmajor clinically relevant bleeding in patients with polyvascular (HR 1.23, 95% CI 0.91-1.65) and single-bed vascular disease (HR 1.30, 95% CI 1.13-1.49) treated with rivaroxaban compared with warfarin when compared with those without vascular disease (HR 0.95, 95% CI 0.87-1.04; interaction P = .0006). Additional antiplatelet therapy in this population did not improve stroke or cardiovascular outcomes.The use of rivaroxaban compared with warfarin was associated with a higher risk of stroke and bleeding in patients with polyvascular disease enrolled in ROCKET AF. Further studies are needed to understand the optimal management of this high-risk population.

    View details for PubMedID 29898836

  • Prognostic and Practical Validation of Current Definitions of Myocardial Infarction Associated With Percutaneous Coronary Intervention JACC-CARDIOVASCULAR INTERVENTIONS Tricoci, P., Newby, L., Clare, R. M., Leonardi, S., Gibson, C., Giugliano, R. P., Armstrong, P. W., Van de Werf, F., Montalescot, G., Moliterno, D. J., Held, C., Aylward, P. E., Wallentin, L., Harrington, R. A., Braunwald, E., Mahaffey, K. W., White, H. D. 2018; 11 (9): 856-+

    Abstract

    In 13,038 patients with non-ST-segment elevation acute coronary syndrome undergoing index percutaneous coronary intervention (PCI) in the EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome) and TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) trials, the relationship between PCI-related myocardial infarction (MI) and 1-year mortality was assessed.The definition of PCI-related MI is controversial. The third universal definition of PCI-related MI requires cardiac troponin >5 times the 99th percentile of the normal reference limit from a stable or falling baseline and PCI-related clinical or angiographic complications. The definition from the Society for Cardiovascular Angiography and Interventions (SCAI) requires creatine kinase-MB elevation >10 times the upper limit of normal (or 5 times if new electrocardiographic Q waves are present). Implications of these definitions on prognosis, prevalence, and implementation are not established.In our cohort of patients undergoing PCI, PCI-related MIs were classified using the third universal type 4a MI definition and SCAI criteria. In the subgroup of patients included in the angiographic core laboratory (ACL) substudy of EARLY ACS (n = 1,401) local investigator- versus ACL-reported angiographic complications were compared.Altogether, 2.0% of patients met third universal definition of PCI-related MI criteria, and 1.2% met SCAI criteria. One-year mortality was 3.3% with the third universal definition (hazard ratio: 1.96; 95% confidence interval: 1.24 to 3.10) and 5.3% with SCAI criteria (hazard ratio: 2.79; 95% confidence interval: 1.69 to 4.58; p < 0.001). Agreement between ACL and local investigators in detecting angiographic complications during PCI was overall moderate (κ = 0.53).The third universal definition of MI and the SCAI definition were both associated with significant risk for mortality at 1 year. Suboptimal concordance was observed between ACL and local investigators in identifying patients with PCI complications detected on angiography. (Trial to Assess the Effects of Vorapaxar [SCH 530348; MK-5348] in Preventing Heart Attack and Stroke in Participants With Acute Coronary Syndrome [TRA·CER] [Study P04736]; NCT00527943; EARLY ACS: Early Glycoprotein IIb/IIIa Inhibition in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome [Study P03684AM2]; NCT00089895).

    View details for PubMedID 29747915

  • External validation of the TIMI risk score for secondary cardiovascular events among patients with recent myocardial infarction ATHEROSCLEROSIS Williams, B. A., Chagin, K. M., Bash, L. D., Boden, W. E., Duval, S., Fowkes, F. R., Mahaffey, K. W., Patel, M. D., D'Agostino, R. B., Peterson, E. D., Kattan, M. W., Bhatt, D. L., Bonaca, M. P. 2018; 272: 80–86

    Abstract

    Risk stratification of patients with recent myocardial infarction (MI) for subsequent cardiovascular (CV) events helps identify patients most likely to benefit from secondary prevention therapies. This study externally validated a new risk score (TRS2˚P) for secondary events derived from the TRA2°P-TIMI 50 trial among post-MI patients from two large health care systems.This retrospective cohort study included 9618 patients treated for acute MI at either the Cleveland Clinic (CC) or Geisinger Health System (GHS) between 2008 and 2013. Patients with a clinic visit within 2-52 weeks of MI were included and followed for CV death, repeat MI, and ischemic stroke through electronic medical records (EMR). The TRS2˚P is based on nine factors determined through EMR documentation. Discrimination and calibration of the TRS2˚P were quantified in both patient populations.MI patients at CC and GHS were older, had more comorbidities, received fewer medications, and had higher 3-year event rates compared to subjects in the TRA2°P trial: 31% (CC), 33% (GHS), and 10% (TRA2°P-TIMI 50). The proposed risk score had similar discrimination across the three cohorts with c-statistics of 0.66 (CC), 0.66 (GHS), and 0.67 (TRA2°P-TIMI 50). A strong graded relationship between the risk score and event rates was observed in all cohorts, though 3-year event rates were consistently higher within TRS2°P strata in the CC and GHS cohorts relative to TRA2˚P-TIMI 50.The TRS2˚P demonstrated consistent risk discrimination across trial and non-trial patients with recent MI, but event rates were consistently higher in the non-trial cohorts.

    View details for PubMedID 29579671

  • Mineralocorticoid Receptor Antagonism in Patients With Atrial Fibrillation: Findings From the ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) Registry JOURNAL OF THE AMERICAN HEART ASSOCIATION Fudim, M., Liu, P. R., Shrader, P., Blanco, R. G., Allen, L. A., Fonarow, G. C., Gersh, B. J., Kowey, P. R., Mahaffey, K. W., Hylek, E., Go, A. S., Thomas, L., Peterson, E. D., Piccini, J. P. 2018; 7 (8)

    Abstract

    Mineralocorticoid receptor antagonist (MRA) therapy may be beneficial to patients with atrial fibrillation (AF), but little is known about their use in patients with AF and subsequent outcomes.In order to better understand MRA use and subsequent outcomes, we performed a retrospective cohort study of the contemporary ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) registry. AF progression and cardiovascular outcomes were compared using propensity-matched Cox proportional hazards modeling according to MRA use at baseline and new MRA use at follow-up versus patients with no MRA use. Among 7012 patients with nonpermanent AF, 320 patients were taking MRA at enrollment, and 416 patients initiated MRA use during follow-up. The mean patient age was 72.5 years, 56.3% were men, and 70.4% had paroxysmal AF. Among all patients taking MRAs, 434 (59.0%) had heart failure, 655 (89.0%) had hypertension, and 380 (51.6%) had both. After adjustment, new MRA use was not associated with reduced AF progression (hazard ratio, 1.18; 95% confidence interval, 0.88-1.58; P=0.27) but showed a trend towards lower risk of stroke, transient ischemic attack, or systemic embolism (hazard ratio, 0.17; 95% confidence interval, 0.02-1.23; P=0.08). Results were similar for a comparison of new MRA users and baseline MRA users compared with nonusers.In community-based outpatients with AF, the majority of MRA use was for heart failure and hypertension. MRA use also trended towards lower adjusted stroke risk. Future studies should test the hypothesis that MRA use may decrease the risk of stroke in patients with AF.

    View details for PubMedID 29654203

  • Net clinical benefit of rivaroxaban compared with warfarin in atrial fibrillation: Results from ROCKET AF INTERNATIONAL JOURNAL OF CARDIOLOGY Barnett, A. S., Cyr, D. D., Goodman, S. G., Levitan, B. S., Yuan, Z., Hankey, G. J., Singer, D. E., Becker, R. C., Breithardt, G., Berkowitz, S. D., Halperin, J. L., Hacke, W., Mahaffey, K. W., Nessel, C. C., Fox, K. A., Patel, M. R., Piccini, J. P. 2018; 257: 78–83

    Abstract

    The aim of this study was to determine the net clinical benefit (NCB) of rivaroxaban compared with warfarin in patients with atrial fibrillation.This was a retrospective analysis of 14,236 patients included in ROCKET AF who received at least one dose of study drug. We analyzed NCB using four different methods: (1) composite of death, stroke, systemic embolism, myocardial infarction, and major bleeding; (2) method 1 with fatal or critical organ bleeding substituted for major bleeding; (3) difference between the rate of ischemic stroke or systemic embolism minus 1.5 times the difference between the rate of intracranial hemorrhage; and (4) weighted sum of differences between rates of death, ischemic stroke or systemic embolism, intracranial hemorrhage, and major bleeding.Rivaroxaban was associated with a lower risk of the composite outcome of death, myocardial infarction, stroke, or systemic embolism (rate difference per 10,000 patient-years [RD]=-86.8 [95% CI -143.6 to -30.0]) and fatal or critical organ bleeding (-41.3 [-68 to -14.7]). However, rivaroxaban was associated with a higher risk of major bleeding other than fatal or critical organ bleeding (55.9 [14.7 to 97.2]). Method 1 showed no difference between treatments (-35.5 [-108.4 to 37.3]). Methods 2-4 favored treatment with rivaroxaban (2: -96.8 [-157.0 to -36.8]; 3: -65.2 [-112.3 to -17.8]; 4: -54.8 [-96.0 to -10.2]).Rivaroxaban was associated with favorable NCB compared with warfarin. The NCB was attributable to lower rates of ischemic events and fatal or critical organ bleeding.

    View details for PubMedID 29506743

  • Incidence, Predictors, and Outcomes of Acquired Thrombocytopenia After Percutaneous Coronary Intervention: A Pooled, Patient-Level Analysis of the CHAMPION Trials (Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition). Circulation. Cardiovascular interventions Groves, E. M., Bhatt, D. L., Steg, P. G., Deliargyris, E. N., Stone, G. W., Gibson, C. M., Hamm, C. W., Mahaffey, K. W., White, H. D., Angiolillo, D., Prats, J., Harrington, R. A., Price, M. J. 2018; 11 (4): e005635

    Abstract

    BACKGROUND: The influence of cangrelor on the incidence and outcomes of post-percutaneous coronary intervention (PCI) thrombocytopenia is not defined. We aimed to explore the incidence, predictors, and clinical impact of thrombocytopenia after PCI in cangrelor-treated patients.METHODS AND RESULTS: This was a pooled, patient-level analysis of the CHAMPION trials (Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition), which compared cangrelor with clopidogrel for prevention of thrombotic complications during and after PCI. Acquired thrombocytopenia was defined as either a drop in platelet count to <100 000 after PCI or a drop of >50% between baseline and a follow-up. The main efficacy outcome was major adverse cardiac events. The primary safety outcome was noncoronary artery bypass grafting-related Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries-defined severe bleeding at 48 hours. Patients (23 783) were enrolled, and 3009 (12.7%) received a GPI (glycoprotein IIb/IIIa inhibitor). Acquired thrombocytopenia occurred in 200 patients (0.8%). The adjusted rate of major adverse cardiovascular events at 48 hours was significantly higher in patients who developed thrombocytopenia compared with those who did not (odds ratio, 3.00; 95% confidence interval, 1.89-4.69; P<0.001), as was major bleeding (odds ratio, 14.71; 95% confidence interval, 5.96-36.30; P<0.001). GPI use was the strongest independent predictor of acquired thrombocytopenia (odds ratio, 2.93; 95% confidence interval, 2.15-3.97; P<0.0001). There was no difference in the rate of acquired thrombocytopenia in patients randomized to cangrelor or clopidogrel.CONCLUSIONS: Acquired thrombocytopenia after PCI is strongly associated with substantial early morbidity and mortality, as well as major bleeding. GPI use is a significant predictor of thrombocytopenia. Cangrelor is not associated with acquired thrombocytopenia, and its clinical efficacy and safety is consistent irrespective of thrombocytopenia occurrence.CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT00305162, NCT00385138, and NCT01156571.

    View details for PubMedID 29632238

  • Incidence, Predictors, and Outcomes of Acquired Thrombocytopenia After Percutaneous Coronary Intervention A Pooled, Patient-Level Analysis of the CHAMPION Trials (Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition) CIRCULATION-CARDIOVASCULAR INTERVENTIONS Groves, E. M., Bhatt, D. L., Steg, P., Deliargyris, E. N., Stone, G. W., Gibson, C., Hamm, C. W., Mahaffey, K. W., White, H. D., Angiolillo, D., Prats, J., Harrington, R. A., Price, M. J., CHAMPION Investigators 2018; 11 (4)
  • Optimised care of elderly patients with acute coronary syndrome EUROPEAN HEART JOURNAL-ACUTE CARDIOVASCULAR CARE Leonardi, S., Bueno, H., Ahrens, I., Hassager, C., Bonnefoy, E., Lettino, M. 2018; 7 (3): 287–95
  • THE EFFICACY AND SAFETY OF CANGRELOR FOR PATIENTS UNDERGOING SINGLE VESSEL VERSUS MULTI VESSEL PERCUTANEOUS CORONARY INTERVENTION: INSIGHTS FROM THE CHAMPION PHOENIX TRIAL Olivier, C., Abnousi, F., Sundaram, V., Yang, J., Stone, G., Steg, P., Gibson, C., Hamm, C., Price, M., Deliargyris, E., Prats, J., White, H., Harrington, R., Bhatt, D., Mahaffey, K., Yong, C., CHAMPION PHOENIX Investigators ELSEVIER SCIENCE INC. 2018: 29
  • 2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Hicks, K. A., Mahaffey, K. W., Mehran, R., Nissen, S. E., Wiviott, S. D., Dunn, B., Solomon, S. D., Marler, J. R., Teerlink, J. R., Farb, A., Morrow, D. A., Targum, S. L., Sila, C. A., Hai, M., Jaff, M. R., Joffe, H. V., Cutlip, D. E., Desai, A. S., Lewis, E. F., Gibson, C., Landray, M. J., Lincoff, A., White, C. J., Brooks, S. S., Rosenfield, K., Domanski, M. J., Lansky, A. J., McMurray, J. V., Tcheng, J. E., Steinhubl, S. R., Burton, P., Mauri, L., O'Connor, C. M., Pfeffer, M. A., Hung, H., Stockbridge, N. L., Chaitman, B. R., Temple, R. J., Standardized Data Collection 2018; 71 (9): 1021–34

    Abstract

    This publication describes uniform definitions for cardiovascular and stroke outcomes developed by the Standardized Data Collection for Cardiovascular Trials Initiative and the U.S. Food and Drug Administration (FDA). The FDA established the Standardized Data Collection for Cardiovascular Trials Initiative in 2009 to simplify the design and conduct of clinical trials intended to support marketing applications. The writing committee recognizes that these definitions may be used in other types of clinical trials and clinical care processes where appropriate. Use of these definitions at the FDA has enhanced the ability to aggregate data within and across medical product development programs, conduct meta-analyses to evaluate cardiovascular safety, integrate data from multiple trials, and compare effectiveness of drugs and devices. Further study is needed to determine whether prospective data collection using these common definitions improves the design, conduct, and interpretability of the results of clinical trials.

    View details for PubMedID 29495982

  • Disease understanding in patients newly diagnosed with atrial fibrillation HEART Kaufman, B. G., Kim, S., Pieper, K., Allen, L. A., Gersh, B. J., Naccarelli, G. V., Ezekowitz, M. D., Fonarow, G. C., Mahaffey, K. W., Singer, D. E., Chan, P. S., Freeman, J. V., Ansell, J., Kowey, P. R., Rieffel, J. A., Piccini, J., Peterson, E., O'Brien, E. C. 2018; 104 (6): 494–501

    Abstract

    To describe self-reported disease understanding for newly diagnosed patients with atrial fibrillation (AF) and assess (1) how disease understanding changes over the first 6 months after diagnosis and (2) the relationship between patient understanding of therapies at baseline and treatment receipt at 6 months among treatment-naïve patients.We analysed survey data from SATELLITE (Survey of Patient Knowledge and Personal Priorities for Treatment), a substudy of patients with new-onset AF enrolled in the national Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT) II registry across 56 US sites. Patients were surveyed at the baseline and 6-month follow-up clinic visits using Likert scales.Among 1004 baseline survey responses, patients' confidence in their understanding of rhythm control, ablation, anticoagulation and cardioversion was suboptimal, with 'high' understanding ranging from 8.5% for left atrial appendage closure to 71.3% for rhythm therapy. Of medical history and demographic factors, education level was the strongest predictor of reporting 'high' disease understanding. Among the 786 patients with 6-month survey data, significant increases in the proportion reporting high understanding were observed (p<0.05) only for warfarin and direct oral anticoagulants (DOACs). With the exception of ablation, high understanding for a given therapeutic option was not associated with increased use of that therapy at 6 months.About half of patients with new-onset AF understood the benefits of oral anticoagulant at the time of diagnosis and understanding improved over the first 6 months. However, understanding of AF treatment remains suboptimal at 6 months. Our results suggest a need for ongoing patient education.Clinicaltrials.gov. Identifier: NCT01701817.

    View details for DOI 10.1136/heartjnl-2017-311800

    View details for Web of Science ID 000428906600011

    View details for PubMedID 28790169

    View details for PubMedCentralID PMC5861387

  • 2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials CIRCULATION Hicks, K. A., Mahaffey, K. W., Mehran, R., Nissen, S. E., Wiviott, S. D., Dunn, B., Solomon, S. D., Mar-Ler, J. R., Teerlink, J. R., Farb, A., Morrow, D. A., Targum, S. L., Sila, C. A., Hai, M., Jaff, M. R., Joffe, H. V., Cutlip, D. E., Desai, A. S., Lewis, E. F., Gibson, C., Landray, M. J., Lincoff, A., White, C. J., Brooks, S. S., Rosenfield, K., Domanski, M. J., Lansky, A. J., McMurray, J. V., Tcheng, J. E., Steinhubl, S. R., Burton, P., Mauri, L., O'Connor, C. M., Pfeffer, M. A., Hung, H., Stockbridge, N. L., Chaitman, B. R., Temple, R. J., Standardized Data Collection 2018; 137 (9): 961–72

    Abstract

    This publication describes uniform definitions for cardiovascular and stroke outcomes developed by the Standardized Data Collection for Cardiovascular Trials Initiative and the US Food and Drug Administration (FDA). The FDA established the Standardized Data Collection for Cardiovascular Trials Initiative in 2009 to simplify the design and conduct of clinical trials intended to support marketing applications. The writing committee recognizes that these definitions may be used in other types of clinical trials and clinical care processes where appropriate. Use of these definitions at the FDA has enhanced the ability to aggregate data within and across medical product development programs, conduct meta-analyses to evaluate cardiovascular safety, integrate data from multiple trials, and compare effectiveness of drugs and devices. Further study is needed to determine whether prospective data collection using these common definitions improves the design, conduct, and interpretability of the results of clinical trials.

    View details for PubMedID 29483172

  • Frequency and Outcomes of Reduced Dose Non-Vitamin K Antagonist Anticoagulants: Results From ORBIT-AF II (The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II) JOURNAL OF THE AMERICAN HEART ASSOCIATION Steinberg, B. A., Shrader, P., Pieper, K., Thomas, L., Allen, L. A., Ansell, J., Chan, P. S., Ezekowitz, M. D., Fonarow, G. C., Freeman, J. V., Gersh, B. J., Kowey, P. R., Mahaffey, K. W., Naccarelli, G. V., Reiffel, J. A., Singer, D. E., Peterson, E. D., Piccini, J. P., Outcomes Registry Better Informed 2018; 7 (4)

    Abstract

    Non-vitamin K antagonist oral anticoagulants (NOACs) are indicated for stroke prevention in atrial fibrillation (AF) but require lower doses in certain patients. We sought to describe the frequency, appropriateness (according to Food and Drug Administration labeling), and outcomes of patients prescribed reduced doses of NOACs in community practice.We analyzed data from the ORBIT-AF II (The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II) registry, a prospective, national, observational registry of AF patients. Among 7925 AF patients receiving NOACs, we assessed patterns of use of reduced NOAC doses and associated cardiovascular and bleeding outcomes at median follow-up of 1 year. Overall, 6636 patients (84%) received a NOAC at standard dose, which was consistent with US Food and Drug Administration labeling in 6376 (96%). Reduced NOAC dose was prescribed to 1289 (16% overall), which was consistent with Food and Drug Administration labeling in only 555 patients (43%). Compared with those whose NOAC dose was appropriately reduced, patients receiving inappropriate dose reductions were younger (median age 79 versus 84, P<0.0001) and had lower ORBIT bleeding risk scores (26% ≥4 versus 45%, P<0.0001). Compared with those appropriately receiving standard dosing, patients receiving inappropriately reduced-dose NOACs had higher unadjusted rates of thromboembolic events (2.11 versus 1.35 events per 100 patient years, hazard ratio 1.56, 95% confidence interval 0.92-2.67) and death (6.77 versus 2.60, hazard ratio 2.61, 95% confidence interval 1.86-3.67). After adjustment, outcomes were not significantly different but tended to favor patients dosed appropriately.The majority of dose reductions of NOACs in AF are inconsistent with US Food and Drug Administration recommendations. There appear to be opportunities to improve current NOAC dosing in community practice.URL: http://www.clinicaltrials.gov. Unique identifier: NCT01701817.

    View details for PubMedID 29453305

  • Short- and long-term mortality following bleeding events in patients undergoing percutaneous coronary intervention: insights from four validated bleeding scales in the CHAMPION trials EUROINTERVENTION Vaduganathan, M., Harrington, R. A., Stone, G. W., Steg, P., Gibson, C., Hamm, C. W., Price, M. J., Lopes, R. D., Leonardi, S., Deliargyris, E. N., Prats, J., Mahaffey, K. W., White, H. D., Bhatt, D. L., CHAMPION Investigators 2018; 13 (15): 1841–49

    Abstract

    The aim of this study was to determine the prognostic significance of periprocedural bleeding based on various definitions on 30-day and one-year all-cause mortality in patients undergoing routine or urgent percutaneous coronary intervention (PCI).In this exploratory analysis of 25,107 patients enrolled in the three phase-3 CHAMPION trials, we assessed the prognostic impact of four bleeding scales (GUSTO, TIMI, ACUITY, and BARC) at 48 hrs. Follow-up all-cause mortality data were available at 30 days in all three trials, and at one year in CHAMPION PCI and CHAMPION PLATFORM. Bleeding rates within 48 hrs of PCI were variably identified by each clinical definition (range: <0.5% to >3.5%). Severe/major bleeding, measured by all bleeding scales, and blood transfusion requirement were independently associated with increased mortality at 30 days and one year after PCI (p<0.001 for all associations). Mild/minor bleeding was not independently predictive of one-year mortality (p>0.07 for all associations). Each bleeding definition demonstrated only modest ability to discriminate 30-day and one-year mortality (adjusted C-statistics range: 0.49 to 0.67).Commonly employed clinical definitions variably identify rates of bleeding after PCI. Severe or major, but not mild or minor, bleeding is independently associated with increased 30-day and one-year mortality. These data may aid in selection of appropriate bleeding metrics in future clinical trials.

    View details for DOI 10.4244/EIJ-D-17-00723

    View details for Web of Science ID 000424328100020

    View details for PubMedID 28988157

  • Ischaemic Events and Stent Thrombosis following Planned Discontinuation of Study Treatment with Ticagrelor or Clopidogrel in the PLATO Study THROMBOSIS AND HAEMOSTASIS Storey, R. F., Ardissino, D., Vignali, L., Cairns, R., Becker, R. C., Cannon, C. P., Mahaffey, K. W., Himmelmann, A., Katus, H. A., James, S. K., Wallentin, L., PLATO Investigators 2018; 118 (2): 427–29

    View details for PubMedID 29443375

  • Clinical features and outcomes of patients with type 2 myocardial infarction: Insights from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial AMERICAN HEART JOURNAL Guimaraes, P. O., Leonardi, S., Huang, Z., Wallentin, L., Van de Werf, F., Aylward, P. E., Held, C., Harrington, R. A., Moliterno, D. J., Armstrong, P. W., White, H. D., Alexander, K. P., Lopes, R. D., Mahaffey, K. W., Tricoci, P. 2018; 196: 28–35

    Abstract

    Type 2 myocardial infarction (MI) is characterized by an imbalance between myocardial blood supply and demand, leading to myocardial ischemia without coronary plaque rupture, but its diagnosis is challenging.In the TRACER trial, patients with non-ST-segment elevation acute coronary syndromes were included. We aimed to describe provoking factors, cardiac biomarker profiles, treatment patterns, and clinical outcomes of patients with type 2 MIs. MI events during trial follow-up were adjudicated by an independent clinical events classification committee (CEC) and were classified according to the Third Universal Definition of MI. Using available source documents retrieved as part of the CEC process, we performed a retrospective chart abstraction to collect details on the type 2 MIs. Cox regression models were used to explore the association between MI type (type 1 or type 2) and cardiovascular death.Overall, 10.3% (n=1327) of TRACER participants had a total of 1579 adjudicated MIs during a median follow-up of 502 days (25th and 75th percentiles [IQR] 349-667). Of all MIs, 5.2% (n=82) were CEC-adjudicated type 2 MIs, occurring in 76 patients. The incidence of type 2 MI was higher in the first month following randomization, after which the distribution became more scattered. The most frequent potential provoking factors for type 2 MIs were tachyarrhythmias (38.2%), anemia/bleeding (21.1%), hypotension/shock (14.5%), and hypertensive emergencies (11.8%). Overall, 36.3% had a troponin increase >10× the upper limit of normal. Coronary angiography was performed in 22.4% (n=17) of patients during hospitalizations due to type 2 MIs. The hazard of cardiovascular death was numerically higher following type 2 MI (vs. no MI, adj. HR 11.82, 95% CI 5.71-24.46; P<.0001) than that of type 1 MI (vs. no MI, adj. HR 8.90, 95% CI 6.93-11.43; P<.0001).Type 2 MIs were more prevalent in the first month after ACS, were characterized by the presence of triggers and infrequent use of an invasive strategy, and were associated with a high risk of death. Further efforts are needed to better define the role and implications of type 2 MI in both clinical practice and research.

    View details for PubMedID 29421012

  • Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events: Results From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study) CIRCULATION Mahaffey, K. W., Neal, B., Perkovic, V., de Zeeuw, D., Fulcher, G., Erondu, N., Shaw, W., Fabbrini, E., Sun, T., Li, Q., Desai, M., Matthews, D. R., CANVAS Program Collaborative Grp 2018; 137 (4): 323–34

    Abstract

    Canagliflozin is a sodium glucose cotransporter 2 inhibitor that significantly reduces the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in patients with type 2 diabetes mellitus and elevated cardiovascular risk. The comparative effects among participants with and without a history of cardiovascular disease (secondary versus primary prevention) were prespecified for evaluation.The CANVAS Program (Canagliflozin Cardiovascular Assessment Study) randomly assigned 10 142 participants with type 2 diabetes mellitus to canagliflozin or placebo. The primary prevention cohort comprised individuals ≥50 years of age with ≥2 risk factors for cardiovascular events but with no prior cardiovascular event, and the secondary prevention cohort comprised individuals ≥30 years of age with a prior cardiovascular event. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included heart failure hospitalization and a renal composite (40% reduction in estimated glomerular filtration rate, renal replacement therapy, or renal death).Primary prevention participants (N=3486; 34%) were younger (63 versus 64 years of age), were more often female (45% versus 31%), and had a longer duration of diabetes mellitus (14 versus 13 years) compared with secondary prevention participants (N=6656; 66%). The primary end point event rate was higher in the secondary prevention group compared with the primary prevention group (36.9 versus 15.7/1000 patient-years, P<0.001). In the total cohort, the primary end point was reduced with canagliflozin compared with placebo (26.9 versus 31.5/1000 patient-years; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.75-0.97; P<0.001 for noninferiority, P=0.02 for superiority) with no statistical evidence of heterogeneity (interaction P value=0.18) between the primary (HR, 0.98; 95% CI, 0.74-1.30) and secondary prevention (HR, 0.82; 95% CI, 0.72-0.95) cohorts. Renal outcomes (HR, 0.59; 95% CI, 0.44-0.79 versus HR, 0.63; 95% CI, 0.39-1.02; interaction P value=0.73) and heart failure hospitalization (HR, 0.68; 95% CI, 0.51-0.90 versus HR, 0.64; 95% CI, 0.35-1.15; interaction P value=0.91) were similarly reduced in the secondary and primary prevention cohorts, respectively. Lower extremity amputations were similarly increased in the secondary and primary prevention cohorts (HR, 2.07; 95% CI, 1.43-3.00 versus HR, 1.52; 95% CI, 0.70-3.29; interaction P value=0.63).Patients with type 2 diabetes mellitus and prior cardiovascular events had higher rates of cardiovascular outcomes compared with the primary prevention patients. Canagliflozin reduced cardiovascular and renal outcomes with no statistical evidence of heterogeneity of the treatment effect across the primary and secondary prevention groups. Additional studies will provide further insights into the effects of canagliflozin in these patient populations.URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01032629 and NCT01989754.

    View details for PubMedID 29133604

    View details for PubMedCentralID PMC5777572

  • Cangrelor compared with clopidogrel in patients with prior myocardial infarction - Insights from the CHAMPION trials INTERNATIONAL JOURNAL OF CARDIOLOGY Eisen, A., Harrington, R. A., Stone, G. W., Steg, P., Gibson, C., Hamm, C. W., Price, M. J., Prats, J., Deliargyris, E. N., Mahaffey, K. W., White, H. D., Bhatt, D. L., CHAMPION Investigators 2018; 250: 49–55

    Abstract

    Patients who have had a prior myocardial infarction (MI) are at increased risk for adverse outcomes after subsequent percutaneous coronary intervention (PCI).The objective of this study is to examine the efficacy and safety of cangrelor, a potent intravenous P2Y12 inhibitor, in patients with prior MI.Pooled data from the CHAMPION trials were examined. Prior MI was defined as a history of MI, excluding MI events at baseline. The primary endpoint was a composite of death, MI, ischemia-driven revascularization, or stent thrombosis at 48-h post-randomization. The primary safety endpoint was GUSTO-defined severe bleeding at 48h.Out of 24,691 patients, 5699 (23%) had a prior MI. The primary endpoint was higher in patients with vs. without prior MI (4.9% vs. 4.0%, p=0.002). The primary endpoint was 4.2% with cangrelor vs. 5.7% with clopidogrel (absolute risk reduction=1.5%; OR 0.72 [95%CI 0.57-0.92]) in patients with prior MI and 3.7% with cangrelor vs. 4.3% with clopidogrel (absolute risk reduction=0.6%; OR 0.85 [95%CI 0.74-0.99]) in patients without prior MI (P-interaction=0.25). The rate of GUSTO-defined severe bleeding was 0.1% with cangrelor vs. 0.1% with clopidogrel (OR 1.39 [95%CI 0.31-6.24]) in patients with prior MI, and 0.2% with cangrelor vs. 0.2% with clopidogrel (OR 1.18 [95%CI 0.65-2.14]) in patients without prior MI (P-interaction=0.84).In the CHAMPION trials, patients with prior MI had higher rates of ischemic outcomes within 48h after PCI. Cangrelor reduced ischemic events with no significant increase in GUSTO-defined severe bleeding in patients with or without prior MI.

    View details for PubMedID 29030140

  • Academic health centers: integration of clinical research with healthcare and education. Comments on a workshop CLINICS Arai, R., Noronha, I., Nicolau, J., Schmidt, C., de Albuquerque, G., Mahaffey, K. W., Krieger, E., Costa Auler Junior, J. 2018; 73
  • Letter by Matthews et al Regarding Article, "Class Effect for Sodium Glucose-Cotransporter-2 Inhibitors in Cardiovascular Outcomes: Implications for the Cardiovascular Disease Specialist". Circulation Matthews, D. R., Perkovic, V. n., Mahaffey, K. W. 2018; 138 (6): 660–61

    View details for PubMedID 30354619

  • Polyvascular Disease and Risk of Major Adverse Cardiovascular Events in Peripheral Artery Disease: A Secondary Analysis of the EUCLID Trial. JAMA network open Gutierrez, J. A., Mulder, H. n., Jones, W. S., Rockhold, F. W., Baumgartner, I. n., Berger, J. S., Blomster, J. I., Fowkes, F. G., Held, P. n., Katona, B. G., Mahaffey, K. W., Norgren, L. n., Hiatt, W. R., Patel, M. R. 2018; 1 (7): e185239

    Abstract

    The effect of polyvascular disease on cardiovascular outcomes in the background of peripheral artery disease (PAD) is unclear.To determine the risk of ischemic events (both cardiac and limb) among patients with PAD and polyvascular disease.In this post hoc secondary analysis of the international Examining Use of Ticagrelor in Peripheral Artery Disease (EUCLID) trial, outcomes were compared among 13 885 enrolled patients with PAD alone, PAD + coronary artery disease (CAD), PAD + cerebrovascular disease (CVD), and PAD + CAD + CVD. Adjusted Cox proportional hazards regression models were implemented to determine the risk associated with polyvascular disease and outcomes, and intention-to-treat analysis was performed. The EUCLID trial was conducted from December 31, 2012, to March 7, 2014; the present post hoc analysis was performed from June 1, 2017, to February 5, 2018.EUCLID evaluated ticagrelor vs clopidogrel in preventing major adverse cardiac events (cardiovascular death, myocardial infarction [MI], or ischemic stroke) and major bleeding in patients with PAD.The primary end point was a composite of cardiovascular death, MI, or ischemic stroke. Key secondary end points included the individual components of the primary end point and acute limb ischemia leading to hospitalization, major amputation, and lower-extremity revascularization. The primary end point of Thrombolysis in Myocardial Infarction (TIMI) major bleeding was also evaluated.The EUCLID trial randomized 13 885 patients with a median age of 66 years (interquartile range, 60-73 years), of whom 3888 (28.0%) were women. At baseline, 7804 patients (56.2%) had PAD alone; 2639 (19.0%) had PAD + CAD; 2049 (14.8%) had PAD + CVD; and 1393 (10.0%) had PAD + CAD + CVD. Compared with patients with isolated PAD, the adjusted hazard ratios (aHRs) for major adverse cardiac events were 1.34 (95% CI, 1.15-1.57; P < .001) for PAD + CVD, 1.65 (95% CI, 1.43-1.91; P < .001) for PAD + CAD, and 1.99 (95% CI, 1.69-2.34; P < .001) for PAD + CAD + CVD. The aHRs for lower-extremity revascularization were 1.17 (95% CI, 1.03-1.34; P = .01) for PAD + CAD, 1.17 (95% CI, 1.02-1.35; P = .02) for PAD + CVD, and 1.34 (95% CI, 1.15-1.57; P < .001) for PAD + CAD + CVD. Polyvascular disease was not associated with an increased risk of acute limb ischemia (aHR for PAD + CVD, 0.91; 95% CI, 0.62-1.34, P = .63; PAD + CAD, 0.93; 95% CI, 0.64-1.34, P = .69; and PAD + CAD + CVD, 0.98; 95% CI, 0.63-1.53, P = .93), major amputation (aHR for PAD + CVD, 0.83; 95% CI, 0.54-1.27, P = .40; PAD + CAD, 0.74; 95% CI, 0.47-1.16, P = .19; and PAD + CAD + CVD, 1.12; 95% CI, 0.69-1.80, P = .65), or TIMI major bleeding (PAD + CVD, 0.98; 0.66-1.44, P = .91; PAD + CAD, 1.04; 0.74-1.48, P = .81; and PAD + CAD + CVD, 0.96; 95% CI, 0.62-1.51, P = .88).Compared with patients with PAD alone, the risk of major adverse cardiac events and lower-extremity revascularization increased with multiple vascular bed involvement. There was no clear increased risk of bleeding associated with polyvascular disease.

    View details for PubMedID 30646395

    View details for PubMedCentralID PMC6324381

  • Association of Healthcare Plan with Atrial Fibrillation Prescription Patterns. Clinical cardiology Chang, A. Y., Askari, M. n., Fan, J. n., Heidenreich, P. A., Ho, P. M., Mahaffey, K. W., Ullal, A. J., Perino, A. C., Turakhia, M. P. 2018

    Abstract

    Atrial fibrillation (AF) is treated by many types of physician specialists, including primary care physicians (PCPs). Health plans have different policies for how patients encounter these providers, and these may affect selection of AF treatment strategy.We hypothesized that healthcare plans with PCP-gatekeeping to specialist access may be associated with different pharmacologic treatments for AF.We performed a retrospective cohort study using a commercial pharmaceutical claims database. We utilized logistic regression models to compare odds of prescription of oral anticoagulant (OAC), non-vitamin K-dependent oral anticoagulant (NOAC), rate control, and rhythm control medications used to treat AF between patients with PCP-gated healthcare plans (e.g. HMO, EPO, POS) and patients with non-PCP-gated healthcare plans (e.g. PPO, CHDP, HDHP, Comprehensive) between 2007 and 2012. We also calculated median time to receipt of therapy within 90 days of index AF diagnosis.We found similar odds of OAC prescription at 90 days following new AF diagnosis in patients with PCP-gated plans compared to those with non-PCP-gated plans (OR: OAC 1.01, p=0.84; warfarin 1.05, p=0.08). Relative odds were similar for rate control (1.17, p<0.01) and rhythm control agents (0.93, p=0.03). However, PCP-gated plan patients had slightly lower likelihood of being prescribed NOACs (0.82, p=0.001) than non-gated plan patients. Elapsed time until receipt of medication was similar between PCP-gated and non-gated groups across drug classes.Pharmaceutical claims data do not suggest that PCP-gatekeeping by healthcare plans is a structural barrier to AF therapy, although it was associated with lower use of NOACs.

    View details for PubMedID 30098034

  • Outcomes of Patients with Critical Limb Ischaemia in the EUCLID Trial EUROPEAN JOURNAL OF VASCULAR AND ENDOVASCULAR SURGERY Norgren, L., Patel, M. R., Hiatt, W. R., Wojdyla, D. M., Fowkes, F. R., Baumgartner, I., Mahaffey, K. W., Berger, J. S., Jones, W., Katona, B. G., Held, P., Blomster, J. I., Rockhold, F. W., Bjoerck, M., EUCLID Steering Comm & Investiga 2018; 55 (1): 109–17

    Abstract

    Critical limb ischaemia (CLI) implies an increased risk of cardiovascular morbidity and mortality, and the optimal antithrombotic treatment is not established.The EUCLID trial investigated the effect of monotherapy with ticagrelor versus clopidogrel in 13,885 patients with peripheral artery disease (PAD); the primary endpoint was cardiovascular death, myocardial infarction, or ischaemic stroke. Patients planned for revascularisation or amputation within 3 months, were excluded. This analysis focuses on the subgroup with CLI, defined by rest pain (58.8%), major (9.0%) or minor (32.2%) tissue loss.In EUCLID, 643 patients (4.6%) had CLI at baseline. Diabetes mellitus was more common in the CLI group, while coronary disease, carotid disease, and hypertension were more common in the non-CLI group. A majority of CLI patients (62.1%) had only lower extremity PAD. In patients enrolled on the ankle brachial index (ABI) criteria, ABI was 0.55 ± 0.21 (mean ± SD) for those with CLI versus 0.63 ± 0.15 for those without CLI. The primary efficacy endpoint significantly increased among patients with CLI compared with those without CLI with a rate of 8.85 versus 4.28/100 patient years (adjusted for baseline characteristics hazard ratio [HR] 1.43 [95% CI 1.16-1.76]; p = 0.0009). When acute limb ischaemia requiring hospitalisation was added to the model, significant differences remained (adjusted HR 1.38, [95% CI 1.13-1.69]; p = 0.0016). The 1 year mortality was 8.9%. A trend towards increased lower limb revascularisation among those with CLI was observed. Bleeding (TIMI major, fatal, intracranial) did not differ between those with and without CLI.Nearly 5% of patients enrolled in EUCLID had CLI at baseline. Milder forms of CLI dominated, a result of the trial design. Patients with CLI had a significantly higher rate of cardiovascular mortality and morbidity versus those without CLI. Further efforts are required to reduce the risk of cardiovascular events in PAD, especially in patients with CLI. CLINICALTRIALS.GOV: NCT01732822.

    View details for PubMedID 29273390

  • Efficacy and safety of rivaroxaban compared with warfarin in patients with carotid artery disease and nonvalvular atrial fibrillation: Insights from the ROCKET AF trial CLINICAL CARDIOLOGY Kochar, A., Hellkamp, A. S., Lokhnygina, Y., Jones, W., Becker, R. C., Berkowitz, S. D., Breithardt, G., Fox, K. A., Halperin, J. L., Hankey, G. J., Mahaffey, K. W., Nessel, C. C., Singer, D. E., Piccini, J. P., Patel, M. R. 2018; 41 (1): 39–45

    Abstract

    Atrial fibrillation (AF) increases risk of stroke 5-fold. Carotid artery disease (CD) also augments the risk of stroke, yet there are limited data about the interplay of these 2 diseases and clinical outcomes in patients with comorbid AF and CD.Among patients with both AF and CD, use of rivaroxaban when compared with warfarin is associated with a lower risk of stroke.This post hoc analysis from ROCKET AF aimed to determine absolute rates of stroke/systemic embolism (SE) and bleeding, and the efficacy and safety of rivaroxaban compared with warfarin in patients with AF and CD (defined as history of carotid occlusive disease or carotid revascularization [endarterectomy and/or stenting]).A total of 593 (4.2%) patients had CD at enrollment. Patients with and without CD had similar rates of stroke or SE (adjusted hazard ratio [HR]: 0.99, 95% confidence interval [CI]: 0.66-1.48, P = 0.96), and there was no difference in major or nonmajor clinically relevant bleeding (adjusted HR: 1.04, 95% CI: 0.88-1.24, P = 0.62). The efficacy of rivaroxaban compared with warfarin for the prevention of stroke/SE was not statistically significant in patients with vs those without CD (interaction P = 0.25). The safety of rivaroxaban vs warfarin for major or nonmajor clinically relevant bleeding was similar in patients with and without CD (interaction P = 0.64).Patients with CD in ROCKET AF had similar risk of stroke/SE compared with patients without CD. Additionally, there was no interaction between CD and the treatment effect of rivaroxaban or warfarin for stroke prevention or safety endpoints.

    View details for PubMedID 29389037

  • Anticoagulant and antiplatelet therapy choices for patients with atrial fibrillation one year after coronary stenting or acute coronary syndrome EXPERT OPINION ON DRUG SAFETY Olivier, C. B., Turakhia, M. P., Mahaffey, K. W. 2018; 17 (3): 251–58

    Abstract

    Guidelines recommend a combined anticoagulant and antiplatelet approach for patients with atrial fibrillation (AF) after coronary stenting (CS) or acute coronary syndrome (ACS). Finding the optimal balance of reducing ischemic risk and minimizing bleeding risk is challenging. Recent trials have evaluated a variety of regimens for up to one year for AF patients after CS/ACS. Little empiric evidence exists about the best antithrombotic strategy beyond one year. Areas covered: In this review two key areas are covered. First, a summary of the overall risk and benefits of anticoagulant and antiplatelet therapy in patients with AF and CS or ACS is provided. Second, despite limited empiric evidence to guide therapeutic decisions for combined anticoagulant and antiplatelet therapy in patients with AF one year after CS/ACS we provide guidance for shared patient-physician decision making. Expert opinion: The evidence is limited. For all patients with AF and stable CAD (≥1 year after CS or ACS) the risk for thromboembolism, cardiovascular events and bleeding should be assessed individually. For patients with low bleeding risk and high risk for cardiovascular events, antiplatelet therapy might be added to anticoagulant therapy.

    View details for PubMedID 29363352

  • Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events in Type 2 Diabetes: Results From the CANVAS Program Mahaffey, K. W., Neal, B., Perkovic, V., de Zeeuw, D., Fulcher, G., Erondu, N., Shaw, W., Sun, T., Desai, M., Matthews, D. R., CANVAS Program Collaborative Grp LIPPINCOTT WILLIAMS & WILKINS. 2017: E454–E455
  • International trends in clinical characteristics and oral anticoagulation treatment for patients with atrial fibrillation: Results from the GARFIELD-AF, ORBIT-AF I, and ORBIT-AF II registries AMERICAN HEART JOURNAL Steinberg, B. A., Gao, H., Shrader, P., Pieper, K., Thomas, L., Camm, A., Ezekowitz, M. D., Fonarow, G. C., Gersh, B. J., Goldhaber, S., Haas, S., Hacke, W., Kowey, P. R., Ansell, J., Mahaffey, K. W., Naccarelli, G., Reiffel, J. A., Turpie, A., Verheugt, F., Piccini, J. P., Kakkar, A., Peterson, E. D., Fox, K. A., GARFIELD-AF ORBIT-AF Investigators 2017; 194: 132–40
  • Prevalence, Characteristics, and Outcomes of Valvular Heart Disease in Patients With Atrial Fibrillation: Insights From the ORBIT-AF (Outcomes Registry for Better Informed Treatment for Atrial Fibrillation) JOURNAL OF THE AMERICAN HEART ASSOCIATION Thomas, K. L., Jackson, L. R., Shrader, P., Ansell, J., Fonarow, G. C., Gersh, B., Kowey, P. R., Mahaffey, K. W., Singer, D. E., Thomas, L., Piccini, J. P., Peterson, E. D. 2017; 6 (12)
  • Outcome of Patients Receiving Thrombolytic Therapy While on Rivaroxaban for Nonvalvular Atrial Fibrillation (from Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) AMERICAN JOURNAL OF CARDIOLOGY Chen, S. T., Hellkamp, A. S., Becker, R. C., Berkowitz, S. D., Breithardt, G., Fox, K. A., Hacke, W., Halperin, J. L., Hankey, G. J., Mahaffey, K. W., Nessel, C. C., Piccini, J. P., Singer, D. E., Patel, M. R. 2017; 120 (10): 1837–40

    Abstract

    The safety of intravenous thrombolysis in patients taking rivaroxaban has not been well established. We retrospectively analyzed the outcomes of all patients who received thrombolytic therapy in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). A review of medical and adverse event records for patients receiving thrombolytic therapy while enrolled in ROCKET AF was performed to determine their baseline characteristics, indications for thrombolysis, and type of agent used. Safety end points were 30-day post-thrombolytic rates of stroke, bleeding, and mortality. A total of 28 patients in ROCKET AF received thrombolytic therapy, with 19 patients on rivaroxaban and 9 patients on warfarin. Ischemic stroke was the most common indication for thrombolysis (n = 10), and alteplase was the most commonly used fibrinolytic agent (n = 14). Of the 19 patients in the rivaroxaban group, there were 2 nonfatal bleeding events and 2 deaths, mostly occurring when thrombolytic therapy was administered within 48 hours of the last rivaroxaban dose. Of the 9 patients in the warfarin group, there was 1 nonfatal bleeding event and 3 deaths, most occurring when thrombolytic therapy was administered outside of 48 hours from the last warfarin dose. In conclusion, these observations suggest that careful assessment of the time since the last dose may be of clinical significance in patients on novel oral anticoagulants who require emergent thrombolysis.

    View details for PubMedID 28886856

  • Treatment of Atrial Fibrillation and Concordance With the American Heart Association/American College of Cardiology/Heart Rhythm Society Guidelines: Findings From ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation). Circulation. Arrhythmia and electrophysiology Barnett, A. S., Kim, S., Fonarow, G. C., Thomas, L. E., Reiffel, J. A., Allen, L. A., Freeman, J. V., Naccarelli, G., Mahaffey, K. W., Go, A. S., Kowey, P. R., Ansell, J. E., Gersh, B. J., Hylek, E. M., Peterson, E. D., Piccini, J. P. 2017; 10 (11)

    Abstract

    BACKGROUND: It is unclear how frequently patients with atrial fibrillation receive guideline-concordant (GC) care and whether guideline concordance is associated with improved outcomes.METHODS AND RESULTS: Using data from ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation), we determined how frequently patients received care that was concordant with 11 recommendations from the 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society atrial fibrillation guidelines pertaining to antithrombotic therapy, rate control, and antiarrhythmic medications. We also analyzed the association between GC care and clinical outcomes at both the patient level and center level. A total of 9570 patients were included. The median age was 75 years (interquartile range, 67-82), and the median CHA2DS2-VASc score was 4 (interquartile range, 3-5). A total of 5977 patients (62.5%) received care that was concordant with all guideline recommendations for which they were eligible. Rates of GC care were higher in patients treated by providers with greater specialization in arrhythmias (60.0%, 62.4%, and 67.0% for primary care physicians, cardiologists, and electrophysiologists, respectively; P<0.001). During a median of 30 months of follow-up, patients treated with GC care had a higher risk of bleeding hospitalization (hazard ratio=1.21; P=0.021) but a similar risk of death, stroke, major bleeding, and all-cause hospitalization.CONCLUSIONS: Over a third of patients with atrial fibrillation in this large outpatient registry received care that differed in some respect from guideline recommendations. There was no apparent association between GC care and improved risk-adjusted outcomes.

    View details for PubMedID 29141842

  • Treatment of Atrial Fibrillation and Concordance With the American Heart Association/American College of Cardiology/Heart Rhythm Society Guidelines Findings From ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY Barnett, A. S., Kim, S., Fonarow, G. C., Thomas, L. E., Reiffel, J. A., Allen, L. A., Freeman, J. V., Naccarelli, G., Mahaffey, K. W., Go, A. S., Kowey, P. R., Ansell, J. E., Gersh, B. J., Hylek, E. M., Peterson, E. D., Piccini, J. P. 2017; 10 (11)
  • Cangrelor Versus Clopidogrel on a Background of Unfractionated Heparin (from CHAMPION PHOENIX) AMERICAN JOURNAL OF CARDIOLOGY Vaduganathan, M., Harrington, R. A., Stone, G. W., Steg, P., Gibson, C., Hamm, C. W., Price, M. J., Deliargyris, E. N., Prats, J., Mahaffey, K. W., White, H. D., Bhatt, D. L., CHAMPION PHOENIX Investigators 2017; 120 (7): 1043–48

    Abstract

    Cangrelor is approved for use during percutaneous coronary intervention (PCI) and is administered with different parenteral anticoagulants. We examined the efficacy and safety of cangrelor in the subgroup of patients who received unfractionated heparin (UFH) during PCI in the modified intention-to-treat population of the randomized CHAMPION PHOENIX trial (cangrelor vs clopidogrel; n = 10,939). The primary efficacy end point was the composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis (ST) at 48 hours. The key secondary efficacy end point was ST. UFH was used in 69.2% (7,569/10,939) of patients. In the UFH subgroup, cangrelor reduced the primary composite efficacy end point at 48 hours compared with clopidogrel (4.8% vs 5.9%; odds ratio [OR] 0.80 [0.65 to 0.98]; p = 0.03). Cangrelor consistently reduced ST at 2 hours (0.7% vs 1.3%; OR 0.56 [0.35 to 0.90]; p = 0.01) and 48 hours (0.9% vs 1.4%; OR 0.70 [0.45 to 1.07]; p = 0.10). There was no difference in GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries)-defined severe or life-threatening bleeding (0.1% vs 0.1%; OR 1.24 [0.33 to 4.61]; p = 0.75) or blood transfusion requirement at 48 hours (0.4% vs 0.2%; OR 1.87 [0.83 to 4.21]; p = 0.12). In conclusion, cangrelor reduces early ischemic periprocedural complications without increasing severe bleeding compared with clopidogrel in patients undergoing PCI with UFH.

    View details for PubMedID 28802512

  • Care Patterns and Outcomes in Atrial Fibrillation Patients With and Without Diabetes ORBIT-AF Registry JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Echouffo-Tcheugui, J. B., Shrader, P., Thomas, L., Gersh, B. J., Kowey, P. R., Mahaffey, K. W., Singer, D. E., Hylek, E. M., Go, A. S., Peterson, E. D., Piccini, J. P., Fonarow, G. C. 2017; 70 (11): 1325–35

    Abstract

    Diabetes is a well-established risk factor for thromboembolism in patients with atrial fibrillation (AF), but less is known about how diabetes influences outcomes among AF patients.This study assessed whether symptoms, health status, care, and outcomes differ between AF patients with and without diabetes.The cohort study included 9,749 patients from the ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) registry, a prospective, nationwide, outpatient registry of patients with incident and prevalent AF. Outcomes included symptoms, health status, and AF treatment, as well as 2-year risk of death, hospitalization, thromboembolic events, heart failure (HF), and AF progression.Patients with diabetes (29.5%) were younger, more likely to have hypertension, chronic kidney disease, HF, coronary heart disease, and stroke. Compared to patients without diabetes, patients with diabetes also had a lower Atrial Fibrillation Effects on Quality of Life score of 80 (interquartile range [IQR]: 62.5 to 92.6) versus 82.4 (IQR: 67.6 to 93.5; p = 0.025) and were more likely to receive anticoagulation (p < 0.001). Diabetes was associated with higher mortality risk, including overall (adjusted hazard ratio [aHR]: 1.63; 95% confidence interval [CI]: 1.04 to 2.56, for age <70 years vs. aHR: 1.25; 95% CI: 1.09 to 1.44, for age ≥70 years) and cardiovascular (CV) mortality (aHR: 2.20; 95% CI: 1.22 to 3.98, for age <70 years vs. 1.24; 95% CI: 1.02 to 1.51 for age ≥70 years). Diabetes conferred a higher risk of non-CV death, sudden cardiac death, hospitalization, CV hospitalization, and non-CV and nonbleeding-related hospitalization, but no increase in risks of thromboembolic events, bleeding-related hospitalization, new-onset HF, and AF progression.Among AF patients, diabetes was associated with worse AF symptoms and lower quality of life, and increased risk of death and hospitalizations, but not thromboembolic or bleeding events.

    View details for PubMedID 28882229

  • Efficacy and Safety of Rivaroxaban Versus Warfarin in Patients Taking Nondihydropyridine Calcium Channel Blockers for Atrial Fibrillation (from the ROCKET AF Trial) AMERICAN JOURNAL OF CARDIOLOGY Washam, J. B., Hellkamp, A. S., Lokhnygina, Y., Piccini, J. P., Berkowitz, S. D., Nessel, C. C., Becker, R. C., Breithardt, G., Fox, K. A., Halperin, J. L., Hankey, G. J., Mahaffey, K. W., Singer, D. E., Patel, M. R., ROCKET AF Steering Comm & Investig 2017; 120 (4): 588–94

    Abstract

    Non-dihydropyridine calcium channel blockers (non-DHP CCBs) possess combined P-glycoprotein and moderate CYP3A4 inhibition, which may lead to increased exposure of medications that are substrates for these metabolic pathways, such as rivaroxaban. We evaluated the use and outcomes of non-DHP CCBs in patients with atrial fibrillation (AF) in Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). We assessed clinical outcomes in patients who received non-DHP CCBs and the impact on the efficacy and safety of rivaroxaban compared with warfarin. Stroke or noncentral nervous system (CNS) systemic embolism (SE), major or nonmajor clinically relevant (NMCR) bleeding, all-cause death, and major bleeding were compared according to non-DHP CCB use. At randomization, 1,308 patients (9.2%) were taking a non-DHP CCB. They were more likely to be women, have diabetes and COPD, and less likely to have heart failure and had a lower mean CHADS2 score (3.3 vs 3.5). Non-DHP CCB use was not associated with an increased risk of stroke/non-CNS SE (p = 0.11) or the composite outcome of NMCR or major bleeding (p = 0.087). Non-DHP CCB use was associated with an increased risk of major bleeding (adjusted hazard ratio 1.50, 95% CI 1.11 to 2.04) and intracranial hemorrhage (adjusted hazard ratio 2.84, 95% CI 1.53 to 5.29). No significant difference was observed in the primary efficacy (stroke or non-CNS SE; adjusted interaction p value = 0.38) or safety outcome (NMCR or major bleeding; adjusted interaction p value = 0.14) between rivaroxaban and warfarin with non-DHP CCB use. In conclusion, although the overall use of non-DHP CCBs was associated with an increased risk of major bleeding and intracranial hemorrhage, the use was not associated with a significant change in the safety or efficacy of rivaroxaban compared with warfarin observed in ROCKET AF.

    View details for PubMedID 28645473

  • Cangrelor in Older Patients Undergoing Percutaneous Coronary Intervention Findings From CHAMPION PHOENIX CIRCULATION-CARDIOVASCULAR INTERVENTIONS Cavender, M. A., Bhatt, D. L., Stone, G. W., Steg, P., Gibson, C., Hamm, C. W., Price, M. J., Prats, J., Elkin, S., Deliargyris, E. N., Mahaffey, K. W., White, H. D., Harrington, R. A. 2017; 10 (8)

    Abstract

    Older patients treated with percutaneous coronary intervention are at increased risk of periprocedural events.CHAMPION (cangrelor versus standard therapy to achieve optimal management of platelet inhibition) PHOENIX randomized 11 145 patients to cangrelor or clopidogrel. We sought to determine the outcomes in the prespecified subgroup of patients ≥75 years old (n=2010; 18%). Cangrelor resulted in directionally consistent effects on the primary end point (death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis) in patients ≥75 years old (odds ratio [OR], 0.71; 95% confidence interval [CI], 0.50-1.02) and in those <75 years old (OR, 0.81; 95% CI, 0.67-0.98; P [interaction]=0.55). Age ≥75 years was an independent predictor of GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) moderate/severe bleeding (1.0% versus 0.3%; adjusted OR, 2.94; 95% CI, 1.28-6.77; P=0.01) when compared with patients <75 years old. There was no significant difference in GUSTO moderate/severe bleeding with cangrelor versus clopidogrel (1.1% versus 1.0%; OR, 1.07; 95% CI 0.45-2.53) in patients ≥75 years old or in those <75 years old (0.4% versus 0.2%; OR, 2.24; 95% CI, 1.02-4.93; P [interaction]=0.21). For the net composite end point of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis plus GUSTO moderate/severe bleeding, the OR for cangrelor in those ≥75 years old was 0.75 (6.4% versus 8.3%; 95% CI, 0.54-1.05; P=0.09). The effects were similar in those <75 years old (4.9% versus 5.8%; OR, 0.85; 95% CI, 0.70-1.02; P=0.08; P [interaction]=0.53).Patients ≥75 years old have an overall ≈3-fold increased odds of moderate/severe bleeding. Cangrelor, when compared with clopidogrel, provides similar efficacy and in patients ≥75 years old as in those <75 years old but does not increase the risk of major bleeding.URL: https://www.clinicaltrials.gov. Unique identifier: NCT01156571.

    View details for PubMedID 28801539

  • Use of troponin assay 99th percentile as the decision level for myocardial infarction diagnosis AMERICAN HEART JOURNAL Bagai, A., Alexander, K. P., Berger, J. S., Senior, R., Sajeev, C., Pracon, R., Mavromatis, K., Luis Lopez-Sendon, J., Gosselin, G., Diaz, A., Perna, G., Drozdz, J., Humen, D., Petrauskiene, B., Cheema, A. N., Phaneuf, D., Banerjee, S., Miller, T. D., Kedev, S., Schuchlenz, H., Stone, G. W., Goodman, S. G., Mahaffey, K. W., Jaffe, A. S., Rosenberg, Y. D., Bangalore, S., Newby, L., Maron, D. J., Hochman, J. S., Chaitman, B. R. 2017; 190: 135–39

    Abstract

    The Universal Definition of Myocardial Infarction recommends the 99th percentile concentration of cardiac troponin in a normal reference population as part of the decision threshold to diagnose type 1 spontaneous myocardial infarction. Adoption of this recommendation in contemporary worldwide practice is not well known.We performed a cohort study of 276 hospital laboratories in 31 countries participating in the National Heart, Lung, and Blood Institute-sponsored International Study of Comparative Health Effectiveness with Medical and Invasive Approaches trial. Each hospital laboratory's troponin assay manufacturer and model, the recommended assay's 99th percentile upper reference limit (URL) from the manufacturer's package insert, and the troponin concentration used locally as the decision level to diagnose myocardial infarction were ascertained.Twenty-one unique troponin assays from 9 manufacturers were used by the surveyed hospital laboratories. The ratio of the troponin concentration used locally to diagnose myocardial infarction to the assay manufacturer-determined 99th percentile URL was <1 at 19 (6.6%) laboratories, equal to 1 at 91 (31.6%) laboratories, >1 to ≤5 at 101 (35.1%) laboratories, >5 to ≤10 at 34 (11.8%) laboratories, and >10 at 43 (14.9%) laboratories. The variability in troponin decision level for myocardial infarction relative to the assay 99th percentile URL was present for laboratories in and outside of the United States, as well as for high- and standard-sensitivity assays.There is substantial hospital-level variation in the troponin threshold used to diagnose myocardial infarction; only one-third of hospital laboratories currently follow the Universal Definition of Myocardial Infarction consensus recommendation for use of troponin concentration at the 99th percentile of a normal reference population as the decision level to diagnose myocardial infarction. This variability across laboratories has important implications for both the diagnosis of myocardial infarction in clinical practice as well as adjudication of myocardial infarction in clinical trials.

    View details for PubMedID 28760208

  • Management and outcomes of patients with atrial fibrillation and a history of cancer: the ORBIT-AF registry EUROPEAN HEART JOURNAL-QUALITY OF CARE AND CLINICAL OUTCOMES Melloni, C., Shrader, P., Carver, J., Piccini, J. P., Thomas, L., Fonarow, G. C., Ansell, J., Gersh, B., Go, A. S., Hylek, E., Herling, I. M., Mahaffey, K. W., Yu, A. F., Peterson, E. D., Kowey, P. R., ORBIT-AF Steering Comm 2017; 3 (3): 192–97

    Abstract

    The presence of cancer can complicate treatment choices for patients with atrial fibrillation (AF) increasing both the risk of thrombotic and bleeding events.Using data from Outcomes Registry for Better Informed Treatment of Atrial Fibrillation, we aimed to characterize AF patients with cancer, to describe their management and to assess the association between cancer and cardiovascular (CV) outcomes. Among 9749 patients, 23.8% had history of cancer (57% solid malignancy, 1.3% leukaemia, 3.3% lymphoma, 40% other type, and 2.2% metastatic cancer). Patients with history of cancer were older, more likely to have CV disease, CV risk factors, and prior gastrointestinal bleeding. No difference in antiarrhythmic and antithrombotic therapy was observed between those with and without cancer. Patients with history of cancer had a significantly higher risk of death (7.8 vs. 4.9 deaths per 100 patient-years follow-up, P = 0.0003) mainly driven by non-CV death (4.2 vs. 2.4 per 100 patient-years follow-up; P = 0.0004) and higher risk of major bleeding (5.1 vs. 3.5 per 100 patient-years follow-up; P = 0.02) compared with non-cancer patients; no differences were observed in risks of strokes/non-central nervous system embolism (1.96 vs. 1.48, P = 0.74) and CV death (2.89 vs. 2.07, P = 0.35) between the two groups.A history of cancer is common among AF patients with up to one in four patients having both. Antithrombotic therapy, rates of cerebrovascular accident, other thrombotic events and cardiac death were similar in AF patients with or without a history of cancer. Patients with cancer, however, were at higher risk of major bleeding and non-CV death.

    View details for PubMedID 28838088

  • Factors associated with non-vitamin K antagonist oral anticoagulants for stroke prevention in patients with new-onset atrial fibrillation: Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II (ORBIT-AF II) AMERICAN HEART JOURNAL Steinberg, B. A., Shrader, P., Thomas, L., Ansell, J., Fonarow, G. C., Gersh, B. J., Hylek, E., Kowey, P. R., Mahaffey, K. W., O'Brien, E. C., Singer, D. E., Peterson, E. D., Piccini, J. P., Outcomes Registry Better Informed 2017; 189: 40–47

    Abstract

    Several non-vitamin K antagonist oral anticoagulant (NOAC) alternatives to warfarin are available for stroke prevention in atrial fibrillation (AF). We aimed to describe the factors associated with selection of NOACs versus warfarin in patients with new onset AF.The ORBIT-AF II study is a national, US, prospective, observational, cohort study of anticoagulation treatment in patients with AF receiving NOACs or warfarin in the United States from 2013 to 2016. We measured factors associated with oral anticoagulant selection in 4,670 patients recently diagnosed with AF.At baseline, 1,169 (25%) patients were started on warfarin and 3,501 (75%) on NOACs: of these latter, 259 (6%) were started on dabigatran, 1858 (40%) on rivaroxaban, and 1384 (30%) on apixaban. Those receiving NOACs were slightly younger patients (median age 71 vs 72, P<.0001); were less likely to have prior stroke (5.3% vs 8.6%; P<.0001) or prior bleeding (2.7% vs 4.4%; P=.005); had better kidney function (mean estimated glomerular filtration rate 91 mL/min vs 80 mL/min, P<.0001); and had fewer patients at high stroke risk (CHA2DS2-VASc score [Congestive heart failure, Hypertension, Age ≥75years, Diabetes mellitus, Prior stroke, transient ischemic attack {TIA}, or thromboembolism,Vascular disease, Age 65-74years, Sex category {female}] ≥2 in 86% vs 93%; P<.0001). In multivariable analysis, factors associated with NOAC selection versus warfarin included renal function, prior stroke or valve replacement, rhythm control AF management strategy, treatment by a cardiologist, and higher patient education level.In contemporary clinical practice, up to three-fourths of patients with new-onset AF are now initially treated with a NOAC for stroke prevention. Those selected for NOAC treatment had lower stroke and bleeding risk profiles, were more likely treated by cardiologists, and had higher socioeconomic status.clinicaltrials.gov Identifier: NCT01701817.

    View details for PubMedID 28625380

  • Relation of Risk of Stroke in Patients With Atrial Fibrillation to Body Mass Index (from Patients Treated With Rivaroxaban and Warfarin in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation Trial). American journal of cardiology Balla, S. R., Cyr, D. D., Lokhnygina, Y., Becker, R. C., Berkowitz, S. D., Breithardt, G., Fox, K. A., Hacke, W., Halperin, J. L., Hankey, G. J., Mahaffey, K. W., Nessel, C. C., Piccini, J. P., Singer, D. E., Patel, M. R. 2017; 119 (12): 1989-1996

    Abstract

    We investigated stroke outcomes in normal weight (body mass index [BMI] 18.50 to 24.99 kg/m(2)), overweight (BMI 25.00 to 29.99 kg/m(2)), and obese (BMI ≥30 kg/m(2)) patients with atrial fibrillation treated with rivaroxaban and warfarin. We compared the incidence of stroke and systemic embolic events as well as bleeding events in normal weight (n = 3,289), overweight (n = 5,535), and obese (n = 5,206) patients in a post hoc analysis of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation trial. Stroke and systemic embolic event rates per 100 patient-years were 2.93 in the normal weight group (reference group), 2.28 in the overweight group (adjusted hazard ratio [HR] 0.81, 95% CI 0.66 to 0.99, p = 0.04) and 1.88 in the obese group (adjusted HR 0.69, 95% CI 0.55 to 0.86, p <0.001). The risk of stroke was statistically significantly lower for obese patients with BMI ≥35 than that for normal weight patients in both the rivaroxaban and warfarin groups (rivaroxaban: HR 0.62, 95% CI 0.40 to 0.96, p = 0.033; warfarin: HR 0.48, 95% CI 0.31 to 0.74, p <0.001). In conclusion, in patients with atrial fibrillation treated with anticoagulant therapy, increased BMI was associated with decreased stroke risk. Warfarin and the novel anticoagulant rivaroxaban are effective in stroke prevention in all subgroups of obese patients.

    View details for DOI 10.1016/j.amjcard.2017.03.028

    View details for PubMedID 28477860

  • Cangrelor reduces the risk of ischemic complications in patients with single-vessel and multi-vessel disease undergoing percutaneous coronary intervention: Insights from the CHAMPION PHOENIX trial. American heart journal Abnousi, F., Sundaram, V., Yong, C. M., Prats, J., Deliargyris, E. N., Stone, G. W., Hamm, C. W., Steg, P. G., Gibson, C. M., White, H. D., Price, M. J., Généreux, P., Desai, M., Yang, L., Ding, V. Y., Harrington, R. A., Bhatt, D. L., Mahaffey, K. W. 2017; 188: 147-155

    Abstract

    To examine the safety and efficacy of cangrelor in patients with single-vessel disease (SVD) and multi-vessel disease (MVD).Cangrelor, an intravenous, rapidly acting P2Y12 inhibitor, is superior to clopidogrel in reducing ischemic events among patients receiving percutaneous coronary intervention (PCI).We studied a modified intention to treat population of patients with SVD and MVD from the CHAMPION PHOENIX trial. The primary efficacy outcome was the composite of death, myocardial infarction (MI), ischemia-driven revascularization (IDR), and stent thrombosis (ST) at 48hours. The key safety outcome was non-coronary artery bypass grafting GUSTO severe bleeding at 48hours.Among 10,921 patients, 5,220 (48%) had SVD and 5,701 (52%) had MVD. MVD patients were older and more often had diabetes, hyperlipidemia, hypertension, prior stroke, and prior MI. After adjustment, MVD patients had similar rates of 48-hour death/MI/IDR/ST (6.3% vs 4.2%, adjusted odds ratio [OR] 1.6 [95% CI 0.42-6.06]) and GUSTO severe bleeding (0.1% vs 0.2%, P=.67) compared with SVD patients. Consistent with overall trial findings, cangrelor use reduced ischemic complications in patients with both SVD (3.9% vs 4.5%; OR 0.86, 95% CI 0.65-1.12) and MVD (5.5% vs 7.2%; OR 0.74, 95% CI 0.6-0.92, P-interaction=.43). GUSTO severe bleeding outcomes were not significantly increased with cangrelor or clopidogrel in either SVD or MVD patients.In the CHAMPION PHOENIX trial, MVD and SVD patients had similar ischemic outcomes at 48hours and 30days. Cangrelor consistently reduced ischemic complications in both SVD and MVD patients without a significant increase in GUSTO severe bleeding. CLINICAL PERSPECTIVES.

    View details for DOI 10.1016/j.ahj.2017.02.031

    View details for PubMedID 28577670

  • Characteristics of dyspnoea and associated clinical outcomes in the CHAMPION PHOENIX study THROMBOSIS AND HAEMOSTASIS Parker, W. A., Bhatt, D. L., Prats, J., Day, J. S., Steg, P., Stone, G. W., Hamm, C. W., Mahaffey, K. W., Price, M. J., Gibson, C., White, H. D., Storey, R. F., CHAMPION PHOENIX Investigators 2017; 117 (6): 1093–1100

    Abstract

    Dyspnoea may be induced by some reversibly-binding P2Y12 inhibitors, including cangrelor and ticagrelor. Dyspnoea was not associated with any compromise to the efficacy of ticagrelor in the PLATO study. The CHAMPION PHOENIX study (NCT01156571) compared initial treatment with cangrelor versus initial treatment with clopidogrel in patients undergoing PCI. We investigated the incidence, characteristics, and associated clinical outcomes in patients with dyspnoea in CHAMPION PHOENIX. Adverse events (AEs) of dyspnoea to 48 hours were recorded in patients randomised to cangrelor or clopidogrel in CHAMPION PHOENIX. The composite primary endpoint of death, myocardial infarction, ischaemia-driven revascularisation, or stent thrombosis as well its individual components were assessed in patients who did or did not report dyspnoea. A total of 68 (1.2 %) cangrelor-treated patients and 18 (0.3 %) clopidogrel-treated patients reported dyspnoea (p<0.001). Most dyspnoea events in cangrelor-treated patients were considered mild (71 %) or moderate (28 %) and only one event was considered severe and led to discontinuation of cangrelor. The dyspnoea events in the clopidogrel-treated patients were mild (78 %) or moderate (22 %). Characteristics of dyspnoea were consistent with those seen in the CHAMPION programme as a whole. In the modified intention-to-treat population, rates of the composite primary outcome and its individual components were not affected by the presence of dyspnoea in cangrelor-treated patients. Cangrelor-related dyspnoea is transient, usually mild or moderate, and unlikely to lead to discontinuation of therapy. The occurrence of dyspnoea does not seem to be associated with any reduction in the efficacy of cangrelor compared with clopidogrel as initial therapy in PCI patients.

    View details for DOI 10.1160/TH16-12-0958

    View details for Web of Science ID 000402591300009

    View details for PubMedID 28382371

  • Safety and Efficacy of Rivaroxaban in Patients With Cardiac Implantable Electronic Devices: Observations From the ROCKET AF Trial JOURNAL OF THE AMERICAN HEART ASSOCIATION Leef, G. C., Hellkamp, A. S., Patel, M. R., Becker, R. C., Berkowitz, S. D., Breithardt, G., Halperin, J. L., Hankey, G. J., Hacke, W., Nessel, C. C., Singer, D. E., Fox, K. A., Mahaffey, K. W., Piccini, J. P. 2017; 6 (6)

    Abstract

    Although implantation of cardiac implantable electronic devices (CIEDs) in patients receiving warfarin is well studied, limited data are available on the use of oral factor Xa inhibitors in this setting.Using data from Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) (n=14 264), we compared baseline characteristics and clinical outcomes in patients with atrial fibrillation randomized to rivaroxaban versus warfarin who did and did not undergo CIED implantation or revision. In this post-hoc, postrandomization, on-treatment analysis, only the first intervention per patient was analyzed. During a median follow-up of 2.2 years, 453 patients (242 rivaroxaban group; 211 warfarin group) underwent de novo CIED implantation (64.2%) or revision procedures (35.8%). Patients who received CIEDs were older, more likely to be male, and more likely to have past myocardial infarction, but had similar stroke risk compared to patients who did not receive CIEDs. Most patients who received a device had study drug interrupted for the procedure and did not receive bridging anticoagulation. During the 30-day postprocedural period, 11 patients (4.55%) in the rivaroxaban group experienced bleeding complications compared with 15 (7.13%) in the warfarin group. Thromboembolic complications occurred in 3 patients (1.26%) in the rivaroxaban group and 1 (0.48%) in the warfarin group. Event rates were too low for formal hypothesis testing.Bleeding and thromboembolic events were low in both rivaroxaban- and warfarin-treated patients. Periprocedural use of oral factor Xa inhibitors in CIED implantation requires further study in prospective, randomized trials.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00403767.

    View details for PubMedID 28615214

  • Effect of Atrial Fibrillation on Mortality, Stroke Risk, and Quality-of-Life Scores in Patients With Heart Failure (from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation [ORBIT-AF]). American journal of cardiology Cherian, T. S., Shrader, P., Fonarow, G. C., Allen, L. A., Piccini, J. P., Peterson, E. D., Thomas, L., Kowey, P. R., Gersh, B. J., Mahaffey, K. W. 2017; 119 (11): 1763-1769

    Abstract

    The degree to which clinical outcomes are worsened in patients with atrial fibrillation (AF) with heart failure (HF) compared with those without HF is not well described. This study aimed to determine the impact of HF on clinical outcomes in patients with AF. We analyzed data from Outcomes Registry for Better Informed Treatment of Atrial Fibrillation, a national registry of 10,135 patients with AF to determine associations between HF and left ventricular ejection fraction (LVEF) and outcomes, including stroke, mortality, and hospitalization using Cox multivariable modeling. Atrial Fibrillation Effect on Quality-of-Life Questionnaire (AFEQT) scores between groups were also compared. Overall, 33% (n = 3,203) of patients had HF; of these 33% (n = 985) had LVEF ≤40%. Oral anticoagulation was prescribed more commonly in patients with HF (81% vs 74%). Compared with patients without HF, those with HF had similar rate of stroke (1.28 vs 0.88 per 100-patient years, hazard ratio [HR] 1.11, confidence interval [CI] 0.83 to 1.48, p = 0.47) but higher mortality (HR 1.69, CI 1.49 to 1.92, p <0.001) and hospitalization (HR 1.31, CI 1.23 to 1.39, p <0.0001). Patients with LVEF ≤40% had similar stroke risk (HR 1.06, CI 0.67 to 1.67) but higher mortality (HR 2.06, CI 1.74 to 2.44) and hospitalization (HR 1.38, CI 1.25 to 1.51). AFEQT overall score was significantly lower (76.9 vs 83.3, p <0.0001) in patients with HF. In conclusion, HF was associated with increased risk of death and hospitalization and worse quality of life, but similar rates of thromboembolism regardless of LVEF among patients with AF. These findings highlight the need to develop therapeutic strategies targeting functional status and survival for patients with HF and AF.

    View details for DOI 10.1016/j.amjcard.2017.02.050

    View details for PubMedID 28416199

  • Levosimendan in Patients with Left Ventricular Dysfunction Undergoing Cardiac Surgery NEW ENGLAND JOURNAL OF MEDICINE Mehta, R. H., Leimberger, J. D., van Diepen, S., Meza, J., Wang, A., Jankowich, R., Harrison, R. W., Hay, D., Fremes, S., Duncan, A., Soltesz, E. G., Luber, J., Park, S., Argenziano, M., Murphy, E., Marcel, R., Kalavrouziotis, D., Nagpal, D., Bozinovski, J., Toller, W., Heringlake, M., Goodman, S. G., Levy, J. H., Harrington, R. A., Anstrom, K. J., Alexander, J. H., LEVO-CTS Investigators 2017; 376 (21): 2032–42

    Abstract

    Levosimendan is an inotropic agent that has been shown in small studies to prevent or treat the low cardiac output syndrome after cardiac surgery.In a multicenter, randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of levosimendan in patients with a left ventricular ejection fraction of 35% or less who were undergoing cardiac surgery with the use of cardiopulmonary bypass. Patients were randomly assigned to receive either intravenous levosimendan (at a dose of 0.2 μg per kilogram of body weight per minute for 1 hour, followed by a dose of 0.1 μg per kilogram per minute for 23 hours) or placebo, with the infusion started before surgery. The two primary end points were a four-component composite of death through day 30, renal-replacement therapy through day 30, perioperative myocardial infarction through day 5, or use of a mechanical cardiac assist device through day 5; and a two-component composite of death through day 30 or use of a mechanical cardiac assist device through day 5.A total of 882 patients underwent randomization, 849 of whom received levosimendan or placebo and were included in the modified intention-to-treat population. The four-component primary end point occurred in 105 of 428 patients (24.5%) assigned to receive levosimendan and in 103 of 421 (24.5%) assigned to receive placebo (adjusted odds ratio, 1.00; 99% confidence interval [CI], 0.66 to 1.54; P=0.98). The two-component primary end point occurred in 56 patients (13.1%) assigned to receive levosimendan and in 48 (11.4%) assigned to receive placebo (adjusted odds ratio, 1.18; 96% CI, 0.76 to 1.82; P=0.45). The rate of adverse events did not differ significantly between the two groups.Prophylactic levosimendan did not result in a rate of the short-term composite end point of death, renal-replacement therapy, perioperative myocardial infarction, or use of a mechanical cardiac assist device that was lower than the rate with placebo among patients with a reduced left ventricular ejection fraction who were undergoing cardiac surgery with the use of cardiopulmonary bypass. (Funded by Tenax Therapeutics; LEVO-CTS ClinicalTrials.gov number, NCT02025621 .).

    View details for PubMedID 28316276

  • Oral anticoagulation management in patients with atrial fibrillation undergoing cardiac implantable electronic device implantation. Clinical cardiology Black-Maier, E., Kim, S., Steinberg, B. A., Fonarow, G. C., Freeman, J. V., Kowey, P. R., Ansell, J., Gersh, B. J., Mahaffey, K. W., Naccarelli, G., Hylek, E. M., Go, A. S., Peterson, E. D., Piccini, J. P. 2017

    Abstract

    Oral anticoagulation (OAC) therapy is associated with increased periprocedural risks after cardiac implantable electronic device (CIED) implantation. Patterns of anticoagulation management involving non-vitamin K antagonist oral anticoagulants (NOACs) have not been characterized.Anticoagulation strategies and outcomes differ by anticoagulant type in patients undergoing CIED implantation.Using the nationwide Outcomes Registry for Better Informed Treatment of Atrial Fibrillation, we assessed how atrial fibrillation (AF) patients undergoing CIED implantation were cared for and their subsequent outcomes. Outcomes were compared by oral anticoagulant therapy (none, warfarin, or NOAC) as well as by anticoagulation interruption status.Among 9129 AF patients, 416 (5%) underwent CIED implantation during a median follow-up of 30 months (interquartile range, 24-36). Of these, 60 (14%) had implantation on a NOAC. Relative to warfarin therapy, those on a NOAC were younger (70.5 years [range, 65-77.5 years] vs 77 years [range, 70-82 years]), had less valvular heart disease (15.0% vs 31.3%), higher creatinine clearance (67.3 [range, 59.7-99.0] vs 65.8 [range, 50.0-91.6]), were more likely to have persistent AF (26.7% vs 22.9%), and use concomitant aspirin (51.7% vs 35.2%). OAC therapy was commonly interrupted for CIED in 64% (n = 183 of 284) of warfarin patients and 65% (n = 39 of 60) of NOAC patients. Many interrupted patients received intravenous bridging anticoagulation: 33/183 (18%) interrupted warfarin and 4/39 (10%) interrupted NOAC patients. Thirty-day periprocedure bleeding and stroke adverse events were infrequent.Management of anticoagulation among AF patients undergoing CIED implantation is highly variable, with OAC being interrupted in more than half of both warfarin- and NOAC-treated patients. Bleeding and stroke events were infrequent in both warfarin and NOAC-treated patients.

    View details for DOI 10.1002/clc.22726

    View details for PubMedID 28543401

  • Management of Major Bleeding in Patients With Atrial Fibrillation Treated With Non-Vitamin K Antagonist Oral Anticoagulants Compared With Warfarin in Clinical Practice (from Phase II of the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation [ORBIT-AF II]). American journal of cardiology Steinberg, B. A., Simon, D. N., Thomas, L., Ansell, J., Fonarow, G. C., Gersh, B. J., Kowey, P. R., Mahaffey, K. W., Peterson, E. D., Piccini, J. P. 2017; 119 (10): 1590-1595

    Abstract

    Non-vitamin K antagonist oral anticoagulants (NOACs) are effective at preventing stroke in patients with atrial fibrillation (AF). However, little is known about the management of bleeding in contemporary, clinical use of NOACs. We aimed to assess the frequency, management, and outcomes of major bleeding in the setting of community use of NOACs. Using the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II registry, we analyzed rates of International Society on Thrombosis and Haemostasis major bleeding and subsequent outcomes in patients treated with NOACs versus warfarin. Outcomes of interest included acute and chronic bleeding management, recurrent bleeding, thromboembolic events, and death. In total, 344 patients with atrial fibrillation experienced major bleeding events over a median follow-up of 360 days follow-up: n = 273 on NOAC (3.3 per 100 patient-years) and n = 71 on warfarin (3.5 per 100 patient-years). Intracranial bleeding was uncommon but similar (0.34 per 100 patient-years for NOAC vs 0.44 for warfarin, p = 0.5), as was gastrointestinal bleeding (1.8 for NOAC vs 1.3 for warfarin, p = 0.1). Blood products and correction agents were less commonly used in NOAC patients with major bleeds compared with warfarin-treated patients (53% vs 76%, p = 0.0004 for blood products; 0% vs 1.5% for recombinant factor; p = 0.0499); no patients received pharmacologic hemostatic agents (aminocaproic acid, tranexamic acid, desmopressin, aprotinin). Within 30 days, 23 NOAC-treated patients (8.4%) died versus 5 (7.0%) on warfarin (p = 0.7). At follow-up, 126 NOAC-treated (46%) and 29 warfarin-treated patients (41%) were not receiving any anticoagulation. In conclusion, rates of major bleeding are similar in warfarin and NOAC-treated patients in clinical practice. However, NOAC-related bleeds require less blood product administration and rarely require factor replacement.

    View details for DOI 10.1016/j.amjcard.2017.02.015

    View details for PubMedID 28363354

  • Adjuvant Antithrombotic Therapy in TAVR CURRENT CARDIOLOGY REPORTS O'Malley, R. G., Mahaffey, K. W., Fearon, W. F. 2017; 19 (5)

    Abstract

    Transcatheter aortic valve replacement (TAVR) has developed into an important alternative to surgical aortic valve replacement (SAVR) for patients with severe aortic stenosis (AS). Adjuvant antithrombotic therapies are commonly used during and after TAVR to decrease the risk of valve thrombosis and thromboembolic cerebrovascular events (CVEs) but consequently increase the risk of bleeding. This article reviews the past and current clinical data regarding adjuvant antithrombotic therapies in TAVR.Cerebrovascular and bleeding events during and after TAVR are associated with substantial morbidity and mortality. Bivalirudin, a direct thrombin inhibitor, has been shown to be safe alternative to unfractionated heparin (UFH) as procedural anticoagulation during TAVR; however, sparse evidence exists to guide use of antiplatelet and anticoagulant therapies in patients after TAVR. Multiple studies comparing different antithrombotic regimens in the post-TAVR setting are currently underway. Current guidelines recommend intra-procedural anticoagulation with UFH for during TAVR and with dual antiplatelet therapy (DAPT) after TAVR. There is a need to better understand the role of adjuvant antithrombotic therapies in TAVR. The results of ongoing studies are needed to develop evidence-based guidance for the use of adjuvant antithrombotic therapies after TAVR.

    View details for DOI 10.1007/s11886-017-0850-1

    View details for PubMedID 28391560

  • Noncentral Nervous System Systemic Embolism in Patients With Atrial Fibrillation Results From ROCKET AF (Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Orgel, R., Wojdyla, D., Huberman, D., Halperin, J. L., Breithardt, G., Singer, D. E., Fox, K. A., Hankey, G. J., Mahaffey, K. W., Jones, W. S., Patel, M. R. 2017; 10 (5)
  • An examination of the relationship between serum uric acid level, a clinical history of gout, and cardiovascular outcomes among patients with acute coronary syndrome. American heart journal Pagidipati, N. J., Hess, C. N., Clare, R. M., Akerblom, A., Tricoci, P., Wojdyla, D., Keenan, R. T., James, S., Held, C., Mahaffey, K. W., Klein, A. B., Wallentin, L., Roe, M. T. 2017; 187: 53-61

    Abstract

    Studies have suggested a relationship between higher baseline serum uric acid (sUA) levels and an elevated risk of subsequent ischemic cardiovascular outcomes among acute coronary syndrome (ACS) patients; this relationship may be modified by a clinical history of gout and has not been studied in large patient cohorts. We sought to understand the effect of sUA and gout on ACS outcomes.Using PLATO and TRACER data on 27,959 ACS patients, we evaluated baseline sUA levels in relation to a composite of cardiovascular death, myocardial infarction (MI), or stroke. We assessed interaction terms to determine if a baseline clinical diagnosis of gout modified this putative relationship; 46% (n=12,882) had sUA levels elevated >6.0 mg/dL.Patients with elevated levels were more often male with a history of prior MI, diabetes, and heart failure compared with those with sUA <6.0 mg/dL. The unadjusted risk of the composite endpoint increased with corresponding elevations in sUA levels (per 1 mg/dL increase) (HR=1.23 [95% CI: 1.20-1.26]) above the statistical inflection point of 5.0 mg/dL. After adjustment, the association between sUA level and the composite outcome remained significant (HR=1.07 [95% CI: 1.04-1.10]), and baseline gout did not modify this relationship.In patients with ACS, increasing levels of sUA are associated with an elevated risk of cardiovascular events, regardless of a clinical diagnosis of gout. Further investigation is warranted to determine the mechanism behind this relationship and to delineate whether sUA is an appropriate therapeutic target to reduce cardiovascular risk.

    View details for DOI 10.1016/j.ahj.2017.02.023

    View details for PubMedID 28454808

  • Differential occurrence, profile, and impact of first recurrent cardiovascular events after an acute coronary syndrome. American heart journal Hess, C. N., Clare, R. M., Neely, M. L., Tricoci, P., Mahaffey, K. W., James, S. K., Alexander, J. H., Held, C., Lopes, R. D., Fox, K. A., White, H. D., Wallentin, L., Armstrong, P. W., Harrington, R. A., Ohman, E. M., Roe, M. T. 2017; 187: 194-203

    Abstract

    Acute coronary syndrome (ACS) trials typically use a composite primary outcome (myocardial infarction [MI], stroke, or cardiovascular death), but differential patient characteristics, timing, and consequences associated with individual component end points as first events have not been well studied. We compared patient characteristics and prognostic significance associated with first cardiovascular events in the post-ACS setting for initially stabilized patients.We combined patient-level data from 4 trials of post-ACS antithrombotic therapies (PLATO, APPRAISE-2, TRACER, and TRILOGY ACS) to characterize the timing of and characteristics associated with first cardiovascular events (MI, stroke, or cardiovascular death). Landmark analysis at 7 days after index ACS presentation was used to focus on spontaneous, postdischarge events that were not confounded by in-hospital procedural complications. Using a competing risk framework, we tested for differential associations between prespecified covariates and the occurrence of nonfatal stroke vs MI as the first event, and we examined subsequent events after the first nonfatal event.Among 46,694 patients with a median follow-up of 358 (25th, 75th percentiles 262, 486) days, a first ischemic event occurred in 4,307 patients (9.2%) as follows: MI in 5.8% (n = 2,690), stroke in 1.0% (n = 477), and cardiovascular death in 2.4% (n = 1,140). Older age, prior stroke/transient ischemic attack, prior atrial fibrillation, and higher diastolic blood pressure were associated with a significantly greater risk of stroke vs MI, whereas prior percutaneous coronary intervention was associated with a greater risk of MI vs stroke. Second events occurred in 32% of those with a first nonfatal stroke at a median of 13 (3, 59) days after the first event and in 32% of those with a first nonfatal MI at a median of 35 (5, 137) days after the first event. The most common second event was a recurrent MI among those with MI as the first event and cardiovascular death among those with stroke as the first event.Approximately 9% of patients experienced a first cardiovascular event in the post-ACS setting during a median follow-up of 1 year. Although the profile and prognostic implications of stroke vs MI as the first nonfatal event differ substantially, approximately one-third of these patients experienced a second event, typically soon after the first event. These findings have implications for improving post-ACS care and influencing the design of future cardiovascular trials.

    View details for DOI 10.1016/j.ahj.2017.01.016

    View details for PubMedID 28454804

  • Efficacy and safety of rivaroxaban versus warfarin in patients from mainland China with nonvalvular atrial fibrillation: A subgroup analysis from the ROCKET AF trial. Thrombosis research Sun, Y., Hu, D., Stevens, S., Lokhnygina, Y., Becker, R. C., Berkowitz, S. D., Breithardt, G., Hacke, W., Halperin, J. L., Hankey, G. J., Mahaffey, K. W., Nessel, C. C., Piccini, J. P., Singer, D. E., Fox, K. A., Patel, M. R. 2017

    Abstract

    The ROCKET AF study evaluated once-daily rivaroxaban versus dose-adjusted warfarin for the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF). In this analysis, we compared rivaroxaban with warfarin in patients with AF from China, East Asia, and the rest of the world (ROW).We assessed baseline demographics and interaction of treatment effects of rivaroxaban versus warfarin among patients from mainland China, other East Asian countries, and ROW. Of the 14,236 patients enrolled in the per-protocol population, 495 were from mainland China, 433 from other East-Asian regions, and 13,308 from the rest of the world (ROW). At baseline, patients from China had significantly higher rates of previous stroke/transient ischemic attack (TIA) compared with patients from other East Asian regions and ROW (79.6%, 44.6%, 51.6% respectively; p<0.0001) and lower rates of VKA use (33.7%, 66.7%, 63.4%, respectively; p<0.0001). The rates of stroke or systemic embolism among those on warfarin while on treatment was 5.23% in patients from China, 1.82% in those from other East Asian regions, and 2.07% from ROW; on rivaroxaban, the rates were 2.29% in patients from China, 1.86% in those from other east Asian regions, and 1.67% from ROW. There were no significant treatment-by-region interactions for any efficacy or safety outcome (all p>0.12). Numerically higher rates of intracranial bleeding were seen in patients from China receiving warfarin versus rivaroxaban.In patients from China, rates of intracranial hemorrhage were numerically lower among those receiving rivaroxaban and consistent with the overall trial.URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00403767.

    View details for DOI 10.1016/j.thromres.2017.04.010

    View details for PubMedID 28433206

  • Obesity, Diabetes, and Acute Coronary Syndrome: Differences Between Asians and Whites. The American journal of medicine Koshizaka, M., Lopes, R. D., Newby, L. K., Clare, R. M., Schulte, P. J., Tricoci, P., Mahaffey, K. W., Ogawa, H., Moliterno, D. J., Giugliano, R. P., Huber, K., James, S., Harrington, R. A., Alexander, J. H. 2017

    Abstract

    Most diabetes and cardiovascular studies have been conducted in white patients, with data being extrapolated to other population groups.For this analysis, patient-level data were extracted from 5 randomized clinical trials in patients with acute coronary syndrome; we compared obesity levels between Asian and white populations, stratified by diabetes status. By using an adjusted Cox proportional hazards model, hazard ratios (HRs) for cardiovascular outcomes after an acute coronary syndrome were determined.We identified 49,224 patient records from the 5 trials, with 3176 Asians and 46,048 whites. Whites with diabetes had higher body mass index values than those without diabetes (median 29.3 vs 27.2 kg/m(2); P < .0001), whereas Asians with diabetes and without diabetes had similar body mass index (24.7 vs 24.2 kg/m(2)). Asians with diabetes (HR, 1.63; 95% confidence interval [CI], 1.32-2.02), whites with diabetes (HR, 1.15; 95% CI, 1.06-1.25), and Asians without diabetes (HR, 1.36; 95% CI, 1.14-1.64) had higher rates of the composite of death, myocardial infarction, or stroke at 30 days than whites without diabetes. Asians with diabetes (HR, 1.84; 95% CI, 1.47-2.31), whites with diabetes (HR, 1.47; 95% CI, 1.33-1.62), and Asians without diabetes (HR, 1.38; 95% CI, 1.11-1.73) had higher rates of death at 1 year compared with whites without diabetes. There were no significant interactions between race and diabetes for ischemic outcomes.Although Asians with diabetes and acute coronary syndrome are less likely to be obese than their white counterparts, their risk for death or recurrent ischemic events was not lower.

    View details for DOI 10.1016/j.amjmed.2017.03.030

    View details for PubMedID 28396226

  • Predicting the risk of bleeding during dual antiplatelet therapy after acute coronary syndromes. Heart (British Cardiac Society) Alfredsson, J., Neely, B., Neely, M. L., Bhatt, D. L., Goodman, S. G., Tricoci, P., Mahaffey, K. W., Cornel, J. H., White, H. D., Fox, K. A., Prabhakaran, D., Winters, K. J., Armstrong, P. W., Ohman, E. M., Roe, M. T. 2017

    Abstract

    Dual antiplatelet therapy (DAPT) with aspirin + a P2Y12 inhibitor is recommended for at least 12 months for patients with acute coronary syndrome (ACS), with shorter durations considered for patients with increased bleeding risk. However, there are no decision support tools available to predict an individual patient's bleeding risk during DAPT treatment in the post-ACS setting.To develop a longitudinal bleeding risk prediction model, we analysed 9240 patients with unstable angina/non-ST segment elevation myocardial infarction (NSTEMI) from the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trial, who were managed without revascularisation and treated with DAPT for a median of 14.8 months.We identified 10 significant baseline predictors of non-coronary artery bypass grafting (CABG)-related Global Use of Strategies to Open Occluded Arteries (GUSTO) severe/life-threatening/moderate bleeding: age, sex, weight, NSTEMI (vs unstable angina), angiography performed before randomisation, prior peptic ulcer disease, creatinine, systolic blood pressure, haemoglobin and treatment with beta-blocker. The five significant baseline predictors of Thrombolysis In Myocardial Infarction (TIMI) major or minor bleeding included age, sex, angiography performed before randomisation, creatinine and haemoglobin. The models showed good predictive accuracy with Therneau's C-indices: 0.78 (SE=0.024) for the GUSTO model and 0.67 (SE=0.023) for the TIMI model. Internal validation with bootstrapping gave similar C-indices of 0.77 and 0.65, respectively. External validation demonstrated an attenuated C-index for the GUSTO model (0.69) but not the TIMI model (0.68).Longitudinal bleeding risks during treatment with DAPT in patients with ACS can be reliably predicted using selected baseline characteristics. The TRILOGY ACS bleeding models can inform risk-benefit considerations regarding the duration of DAPT following ACS.ClinicalTrials.gov identifier: https://clinicaltrials.gov/ct2/show/NCT00699998.

    View details for DOI 10.1136/heartjnl-2016-310090

    View details for PubMedID 28381584

  • Data monitoring committees: Promoting best practices to address emerging challenges CLINICAL TRIALS Fleming, T. R., DeMets, D. L., Roe, M. T., Wittes, J., Calis, K. A., Vora, A. N., Meisel, A., Bain, R. P., Konstam, M. A., Pencina, M. J., Gordon, D. J., Mahaffey, K. W., Hennekens, C. H., Neaton, J. D., Pearson, G. D., Andersson, T. L., Pfeffer, M. A., Ellenberg, S. S. 2017; 14 (2): 115-123

    Abstract

    Data monitoring committees are responsible for safeguarding the interests of study participants and assuring the integrity and credibility of clinical trials. The independence of data monitoring committees from sponsors and investigators is essential in achieving this mission. Creative approaches are needed to address ongoing and emerging challenges that potentially threaten data monitoring committees' independence and effectiveness.An expert panel of representatives from academia, industry and government sponsors, and regulatory agencies discussed these challenges and proposed best practices and operating principles for effective functioning of contemporary data monitoring committees.Prospective data monitoring committee members need better training. Options could include didactic instruction as well as apprenticeships to provide real-world experience. Data monitoring committee members should be protected against legal liability arising from their service. While avoiding breaches in confidentiality of interim data remains a high priority, data monitoring committees should have access to unblinded efficacy and safety data throughout the trial to enable informed judgments about risks and benefits. Because overly rigid procedures can compromise their independence, data monitoring committees should have the flexibility necessary to best fulfill their responsibilities. Data monitoring committee charters should articulate principles that guide the data monitoring committee process rather than list a rigid set of requirements. Data monitoring committees should develop their recommendations by consensus rather than through voting processes. The format for the meetings of the data monitoring committee should maintain the committee's independence and clearly establish the leadership of the data monitoring committee chair. The independent statistical group at the Statistical Data Analysis Center should have sufficient depth of knowledge about the study at hand and experience with trials in general to ensure that the data monitoring committee has access to timely, reliable, and readily interpretable insights about emerging evidence in the clinical trial. Contracts engaging data monitoring committee members for industry-sponsored trials should have language customized to the unique responsibilities of data monitoring committee members rather than use language appropriate to consultants for product development. Regulatory scientists would benefit from experiencing data monitoring committee service that does not conflict with their regulatory responsibilities.

    View details for DOI 10.1177/1740774516688915

    View details for Web of Science ID 000397934800001

    View details for PubMedID 28359194

  • Absence of Oral Anticoagulation and Subsequent Outcomes Among Outpatients with Atrial Fibrillation AMERICAN JOURNAL OF MEDICINE Hess, P. L., Kim, S., Fonarow, G. C., Thomas, L., Singer, D. E., Freeman, J. V., Gersh, B. J., Ansell, J., Kowey, P. R., Mahaffey, K. W., Chan, P. S., Steinberg, B. A., Peterson, E. D., Piccini, J. P. 2017; 130 (4): 449-456

    Abstract

    Prior studies have shown a treatment gap in oral anticoagulation (OAC) use among patients with atrial fibrillation yet have incompletely characterized factors associated with failure to treat and subsequent outcomes in contemporary practice.Using data collected between June 2010 and August 2011 from 174 ambulatory care sites in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation, we identified factors associated with absence of OAC via stratified logistic regression. Using weighted Cox regression, we assessed the association between OAC non-use and subsequent outcomes over 2.5 years.Among 9553 patients, 2202 (23.0%) were not on OAC. Among OAC nonrecipients, 1846 (83.8%) had a CHA2DS2-VASc score ≥2. Factors independently associated with OAC non-use included atrial fibrillation type (paroxysmal odds ratio [OR] 0.73, 95% confidence interval [CI] 0.54-0.99; persistent OR 0.14, 95% CI 0.10-0.21; permanent OR 0.35, 95% CI 0.25-0.49; reference = new-onset), left atrial diameter enlargement (mild OR 0.80, 95% CI 0.66-0.97; moderate 0.58, 95% CI 0.47-0.73; severe 0.53, 95% CI 0.42-0.68; reference = normal diameter), and age >80 years (OR 1.04, 95% CI 1.02-1.08). Untreated patients had a higher risk of death (adjusted hazard ratio [HR] 1.22, 95% CI 1.05-1.41), a lower bleeding risk (adjusted HR 0.35, 95% CI 0.15-0.81), and a nonsignificant trend toward higher risk of stroke/non-central nervous system embolism/transient ischemic attack than those treated (adjusted HR 1.18, 95% CI 0.91-1.54).A majority of atrial fibrillation patients not treated with an OAC in current community practice meet guideline indications for treatment. Atrial fibrillation burden, chronicity, and comorbidity are associated with nontreatment. Untreated patients are at increased risk for adverse outcomes.

    View details for DOI 10.1016/j.amjmed.2016.11.001

    View details for Web of Science ID 000400462300035

  • CANGRELOR VERSUS CLOPIDOGREL ON A BACKGROUND OF UNFRACTIONATED HEPARIN INSIGHTS FROM CHAMPION PHOENIX Vaduganathan, M., Harrington, R., Stone, G., Steg, P., Gibson, C., Hamm, C., Price, M., Deliargyris, E., Prats, J., Mahaffey, K., White, H., Bhatt, D. ELSEVIER SCIENCE INC. 2017: 1345
  • ONE-YEAR MORTALITY INCREASED IN PATIENTS WITH PERI-PROCEDURAL MYOCARDIAL INFARCTION: INSIGHTS FROM THE CHAMPION TRIALS Olivier, C., Sundaram, V., Ding, V., Yang, L., Leonardi, S., Lopes, R., Bhatt, D., Stone, G., Steg, P., Gibson, C., Hamm, C., Price, M., White, H., Desai, M., Harrington, R., Lynch, D. R., Mahaffey, K., CHAMPION Investigators ELSEVIER SCIENCE INC. 2017: 7
  • IMPACT OF PERIPROCEDURAL MYOCARDIAL INFARCTION IN CONTEMPORARY PCI: POOLED PATIENT-LEVEL DATA FROM THE CHAMPION TRIALS Vaduganathan, M., Harrington, R., Stone, G., Steg, P., Gibson, C., Hamm, C., Price, M., Deliargyris, E., Prats, J., Mahaffey, K., White, H., Bhatt, D. ELSEVIER SCIENCE INC. 2017: 112
  • Trade-off of myocardial infarction vs. bleeding types on mortality after acute coronary syndrome: lessons from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) randomized trial EUROPEAN HEART JOURNAL Valgimigli, M., Costa, F., Lokhnygina, Y., Clare, R. M., Wallentin, L., Moliterno, D. J., Armstrong, P. W., White, H. D., Held, C., Aylward, P. E., Van de Werf, F., Harrington, R. A., Mahaffey, K. W., Tricoci, P. 2017; 38 (11): 804-?

    Abstract

    Dual antiplatelet therapy reduces non-fatal ischaemic events after acute coronary syndrome (ACS) but increases bleeding to a similar extent. We sought to determine the prognostic impact of myocardial infarction (MI) vs. bleeding during an extended follow-up period to gain insight into the trade-off between efficacy and safety among patients after ACS.In 12 944 patients with non-ST-segment elevation ACS from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial, we investigated the relative impact of MI and bleeding occurring >30 days post-ACS and subsequent all-cause mortality. Bleeding was graded according to Bleeding Academic Research Consortium (BARC) criteria. MI was associated with a five-fold increase in mortality. BARC type 2 and 3, but not type 1, bleeding had a significant impact on mortality. MI was associated with a greater risk of mortality compared with BARC 2 [relative risk (RR) 3.5; 95% confidence interval (CI) 2.08-4.77; P < 0.001] and BARC 3a bleeding (RR 2.23; 95% CI 1.36-3.64; P = 0.001), and a risk similar to BARC 3b bleeding (RR 1.37; 95% CI 0.81-2.30; P = 0.242). Risk of death after MI was significantly lower than after BARC 3c bleeding (RR 0.22; 95% CI 0.13-0.36; P < 0.001). MI and bleeding had similar time-associations with mortality, which remained significant for several months, still being higher early after the event.In patients treated with antiplatelet therapy after ACS, both MI and bleeding significantly impacted mortality with similar time-dependency. Although BARC 2 and 3a bleeding were less prognostic for death than MI, the risk of mortality was equivalent between BARC 3b bleeding and MI, and was higher following BARC 3c bleeding.

    View details for DOI 10.1093/eurheartj/ehw525

    View details for Web of Science ID 000396777300005

    View details for PubMedID 28363222

  • Treatment Consistency Across Levels of Baseline Renal Function With Rivaroxaban or Warfarin A ROCKET AF (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) Analysis CIRCULATION Lindner, S. M., Fordyce, C. B., Hellkamp, A. S., Lokhnygina, Y., Piccini, J. P., Breithardt, G., Mahaffey, K. W., Singer, D. E., Hacke, W., Halperin, J. L., Hankey, G. J., Berkowitz, S. D., Nessel, C. C., Becker, R. C., Fox, K. A., Patel, M. R., ROCKET AF Steering Comm 2017; 135 (10): 1001–3

    View details for PubMedID 28264892

  • Results of a curtailed randomized controlled trial, evaluating the efficacy and safety of azimilide in patients with implantable cardioverter-defibrillators: The SHIELD-2 trial. American heart journal Robinson, V. M., Bharucha, D. B., Mahaffey, K. W., Dorian, P., Kowey, P. R. 2017; 185: 43-51

    Abstract

    Frequent hospital attendances in patients with implantable cardioverter-defibrillators (ICDs) result in significant morbidity and health care costs. Current drugs to reduce ICD shocks and hospital visits have limited efficacy and considerable toxicity. We evaluated the efficacy and safety of azimilide, a novel oral class III antiarrhythmic, for use in ICD patients.A total of 240 patients were enrolled in a prospective, randomized, double-blind, placebo-controlled trial to evaluate the effect of oral azimilide 75 mg daily in ICD patients with previously documented ventricular tachycardia or ventricular fibrillation, and a left ventricular ejection fraction ≤40%. The primary outcome metric was the adjudicated time-to-first unplanned cardiovascular (CV) hospitalization, or CV emergency department (ED) visit, or CV death. The trial was prematurely discontinued due to withdrawal of study sponsorship.Azimilide demonstrated numerical but statistically nonsignificant reductions in the primary composite outcome (odds ratio [OR] 0.79, 95% CI 0.44-1.44), unplanned CV hospitalizations (OR 0.75, 95% CI 0.41-1.38), ED visits (OR 0.68, 95% CI 0.35-1.31), and all-cause shocks (OR 0.58, 95% CI 0.32-1.05). The incidence of adverse events was lower in the azimilide group. Neutropenia was not observed (absolute neutrophil count <1000 μ/L), and there was one possible torsade de pointes case that led to a successful ICD discharge.The SHIELD-2 trial was statistically underpowered due to early trial termination and did not meet its primary objective. Despite this limitation, azimilide showed promise as a safe and effective drug in reducing all-cause shocks, unplanned hospitalizations, and ED visits in ICD patients.

    View details for DOI 10.1016/j.ahj.2016.10.025

    View details for PubMedID 28267474

  • Rationale, design and baseline characteristics of the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R): A randomized, placebo-controlled trial. Diabetes, obesity & metabolism Neal, B., Perkovic, V., Matthews, D. R., Mahaffey, K. W., Fulcher, G., Meininger, G., Erondu, N., Desai, M., Shaw, W., Vercruysse, F., Yee, J., Deng, H., de Zeeuw, D. 2017; 19 (3): 387-393

    Abstract

    The primary aim of the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R) is to determine whether the favourable effects of inhibition of the sodium glucose co-transporter 2 (SGLT2) on blood glucose, blood pressure and body weight are accompanied by protection against adverse renal outcomes.CANVAS-R is a prospective, randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes with a history or high risk of cardiovascular events. Patients were randomly assigned to once-daily placebo or canagliflozin 100 mg (with optional uptitration to 300 mg) for a planned average of 2.5 years of follow-up. The primary outcome is kidney disease progression, defined by class change in albuminuria. The two secondary outcomes are the composite of hospitalized heart failure or cardiovascular death, and cardiovascular death alone. Effects on end-stage renal disease and a range of other outcomes will also be explored.A total of 5812 participants were recruited at 422 sites in 24 countries between January 2014 and May 2015. The mean baseline age was 64 years, mean duration of diabetes was 14 years, mean glycated haemoglobin level was 8.3% and mean body mass index was 32 kg/m(2) . Of these participants, 37% were women, 71% had a history of cardiovascular disease, 22.3% had microalbuminuria and 8.7% had macroalbuminuria. The mean baseline estimated glomerular filtration rate was 76 mL/min/1.73 m(2) . The study will have at least 90% power ( P = .05) to detect a 22% or greater reduction in the risk of progression of albuminuria.The trial should define the potential renoprotective effect of canagliflozin and will provide additional important new data about its effects on vascular outcomes, death and kidney failure.

    View details for DOI 10.1111/dom.12829

    View details for PubMedID 28120497

    View details for PubMedCentralID PMC5348724

  • Cardioversion and subsequent quality of life and natural history of atrial fibrillation. American heart journal Pokorney, S. D., Kim, S., Thomas, L., Fonarow, G. C., Kowey, P. R., Gersh, B. J., Mahaffey, K. W., Peterson, E. D., Piccini, J. P. 2017; 185: 59-66

    Abstract

    Cardioversion is a class I procedure for patients with symptomatic atrial fibrillation (AF) pursuing rhythm control. There are few contemporary reports on quality of life and outcomes after cardioversion.Using the nationwide prospective ORBIT-AF registry, cardioversion patients were propensity matched 3:1 to noncardioverted patients and Cox proportional hazards modeling evaluated hospitalization at 1 year in those with and without cardioversion. Cardiovascular outcomes, AF progression, and quality of life were evaluated for the matched cohorts with and without cardioversion.Among 9,642 patients, 817 patients (8%) underwent 906 cardioversions during a median follow-up of 12 (interquartile range 6-18) months. Among matched cardioverted and noncardioverted patients, 1-year cardiovascular hospitalization rates were 43% vs 21% (adjusted hazard ratio 2.2, 95% CI 1.8-2.8, P<.001), and sinus rhythm at both first and second follow-ups was 36% vs 27% (P=.042), respectively. Findings were similar among first-time cardioversion patients. Matched cardioversion patients did not exhibit greater symptom improvement (34% vs 42%) or less symptomatic progression (15% vs 4%) by European Heart Rhythm Association scores. Cardioversion was associated with AF progression with an odds ratio of 1.6 (95% CI 1.2-2.2, P=.001) after cardioversion and 2.7 (P<.001) after first cardioversion vs matched noncardioversion patients. After cardioversion, only 18% of patients not previously on an antiarrhythmic started one, less than 5% underwent ablation, and 22% stopped their antiarrhythmic.Cardioversion was not associated with improved AF-related quality of life or less progression. Many patients who undergo cardioversion do not receive adjunctive rhythm control therapies. These findings may help to better inform therapeutic decision making.

    View details for DOI 10.1016/j.ahj.2016.10.018

    View details for PubMedID 28267476

  • Optimising the analysis strategy for the CANVAS Program - a pre-specified plan for the integrated analyses of the CANVAS and CANVAS-R trials. Diabetes, obesity & metabolism Neal, B., Perkovic, V., Mahaffey, K. W., Fulcher, G., Erondu, N., Desai, M., Shaw, W., Law, G., Walton, M. K., Rosenthal, N., Zeeuw, D. d., Matthews, D. R. 2017

    Abstract

    Two large cardiovascular outcome trials of canagliflozin, comprising the CANVAS Program, will complete in early 2017: the CANagliflozin cardioVascular Assessment Study (CANVAS) and the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R). Accruing data for the sodium glucose co-transporter 2 (SGLT2) inhibitor class has identified questions and opportunities that were not apparent when the trials were designed. Accordingly, a series of modifications have been made to the planned analyses. These updates will ensure that the data from the CANVAS Program will maximize advances in scientific knowledge and patient care. The specification of the analysis strategy prior to knowledge of the trial results, their design by the independent scientific trial Steering Committee, the detailed a priori definition of the analysis plans, and the external review provided by the US Food and Drug Administration all provide maximally efficient and robust utilization of the data. The CANVAS Program should significantly advance our understanding of the effects of canagliflozin, and the broader SGLT2 inhibitor class, on a range of important efficacy and safety outcomes.

    View details for DOI 10.1111/dom.12924

    View details for PubMedID 28244644

  • Evaluation of Ischemic and Bleeding Risks Associated With 2 Parenteral Antiplatelet Strategies Comparing Cangrelor With Glycoprotein IIb/IIIa Inhibitors: An Exploratory Analysis From the CHAMPION Trials. JAMA cardiology Vaduganathan, M., Harrington, R. A., Stone, G. W., Deliargyris, E. N., Steg, P. G., Gibson, C. M., Hamm, C. W., Price, M. J., Menozzi, A., Prats, J., Elkin, S., Mahaffey, K. W., White, H. D., Bhatt, D. L. 2017; 2 (2): 127-135

    Abstract

    In the context of contemporary pharmacotherapy, optimal antiplatelet management with percutaneous coronary intervention (PCI) has not been well established.To compare the ischemic and bleeding risks associated with glycoprotein IIb/IIIa inhibitors (GPIs) and a potent P2Y12 antagonist, cangrelor, in patients undergoing PCI.An exploratory analysis of pooled patient-level data from the 3 phase 3 Cangrelor vs Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION PCI, CHAMPION PLATFORM, and CHAMPION PHOENIX) trials of patients undergoing elective or nonelective PCI. The participants included 10 929 patients assigned to cangrelor but not receiving GPIs (cangrelor alone) and 1211 patients assigned to clopidogrel (or placebo) and receiving routine GPIs (clopidogrel-GPI). Patients requiring bailout or rescue GPI therapy were excluded. To account for risk imbalances, 1:1 propensity score matching based on 16 baseline clinical variables yielded 1021 unique matched pairs. The present study's data analysis was conducted from October 28, 2015, to August 6, 2016.The primary efficacy end point was the composite of all-cause mortality, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours. Safety was assessed by 3 validated bleeding scales (Global Use of Strategies to Open Occluded Coronary Arteries [GUSTO], Thrombolysis in Myocardial Infarction [TIMI], and Acute Catheterization and Urgent Intervention Triage) and requirement for blood transfusions.Of the 12 140 patients included in the analysis, 8779 were men (72.3%), and the mean (SD) age was 63.2 (11.3) years. Patients in the clopidogrel-GPI group were more likely to be male (75.6% vs 71.9%), younger (median, 60 [range, 23-91] years vs 64 [range, 26-95] years), enrolled from the United States (77.9% vs 40.0%), and present with an acute coronary syndrome, but they had lower comorbid disease burden and were less likely to receive bivalirudin (8.8% vs 27.3%). In the matched cohorts, the rates of the primary efficacy end point were not significantly different between the cangrelor alone and clopidogrel-GPI groups (2.6% vs 3.3%; odds ratio [OR], 0.79; 95% CI, 0.48-1.32). There was a nonsignificant trend toward lower rates of GUSTO-defined severe/life-threatening bleeding with cangrelor alone compared with clopidogrel-GPI (0.3% vs 0.7%; OR, 0.43; 95% CI, 0.11-1.66). Rates of TIMI-defined major or minor bleeding were significantly lower in patients treated with cangrelor alone (0.7% vs 2.4%; OR, 0.29; 95% CI, 0.13-0.68).Based on a pooled analysis from the 3 phase 3 CHAMPION trials, cangrelor alone was associated with similar ischemic risk and lower risk-adjusted bleeding risk compared with clopidogrel-GPIs.clinicaltrials.gov Identifiers: NCT00305162, NCT00385138, and NCT01156571.

    View details for DOI 10.1001/jamacardio.2016.4556

    View details for PubMedID 27902833

  • Cangrelor With and Without Glycoprotein IIb/IIIa Inhibitors in Patients Undergoing Percutaneous Coronary Intervention JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Vaduganathan, M., Harrington, R. A., Stone, G. W., Deliargyris, E. N., Steg, P. G., Gibson, C. M., Hamm, C. W., Price, M. J., Menozzi, A., Prats, J., Elkin, S., Mahaffey, K. W., White, H. D., Bhatt, D. L. 2017; 69 (2): 176-185

    Abstract

    Cangrelor, an intravenous, reversible P2Y12 antagonist, is approved for use in patients undergoing percutaneous coronary intervention (PCI).This study sought to evaluate the efficacy and safety of cangrelor compared with clopidogrel in subgroups that did and did not receive glycoprotein IIb/IIIa inhibitors (GPIs).This pooled, patient-level analysis of the 3 CHAMPION (Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition) trials analyzed all randomized patients who underwent PCI and received the study drug (n = 24,902). Only bailout/rescue GPI use was permitted, except in CHAMPION PCI, in which routine or bailout/rescue GPI use was at the site investigator's discretion. The primary efficacy endpoint was the composite of all-cause mortality, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 h after randomization.Overall, 3,173 patients (12.7%) received a GPI, most commonly eptifibatide (69.4%). Despite variation in indications for GPIs, baseline characteristics were well balanced between the cangrelor and clopidogrel arms in subsets receiving and not receiving GPIs. Rates of the primary composite endpoint were lower with cangrelor compared with clopidogrel in patients who did (4.9% vs. 6.5%; odds ratio [OR]: 0.74; 95% confidence interval [CI]: 0.55 to 1.01) or did not receive a GPI (3.6% vs. 4.4%; OR: 0.82; 95% CI: 0.72 to 0.94; Pint = 0.55). Cangrelor did not increase the primary safety endpoint, GUSTO-defined severe/life-threatening bleeding, in patients who did (0.4% vs. 0.5%; OR: 0.71; 95% CI: 0.25 to 1.99) or did not receive GPIs (0.2% vs. 0.1%; OR: 1.56; 95% CI: 0.80 to 3.04; Pint = 0.21). GPI use was associated with increased risk of bleeding in both treatment arms.Cangrelor's efficacy in reducing ischemic complications in patients undergoing PCI was maintained irrespective of GPI administration. GPI use was associated with substantially higher bleeding rates, regardless of the randomization to cangrelor or clopidogrel. (A Clinical Trial to Demonstrate the Efficacy of Cangrelor [PCI]: NCT00305162; Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition [PLATFORM]: NCT00385138; A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI] [CHAMPION PHOENIX] [CHAMPION]: NCT01156571).

    View details for DOI 10.1016/j.jacc.2016.10.055

    View details for Web of Science ID 000392993100009

    View details for PubMedID 28081827

  • Ticagrelor Compared With Clopidogrel in Patients With Prior Lower Extremity Revascularization for Peripheral Artery Disease CIRCULATION Jones, W. S., Baumgartner, I., Hiatt, W. R., Heizer, G., Conte, M. S., White, C. J., Berger, J. S., Held, P., Katona, B. G., Mahaffey, K. W., Norgren, L., Blomster, J., Millegard, M., Reist, C., Patel, M. R., Fowkes, F. G. 2017; 135 (3): 241-?

    Abstract

    In patients with symptomatic peripheral artery disease with a history of limb revascularization, the optimal antithrombotic regimen for long-term management is unknown.The EUCLID trial (Examining Use of Ticagrelor In PAD) randomized 13 885 patients with peripheral artery disease to treatment with ticagrelor 90 mg twice daily or clopidogrel 75 mg daily. Patients were enrolled based on an abnormal ankle-brachial index ≤0.80 or a previous lower extremity revascularization. This analysis focuses on the 7875 (57%) patients enrolled based on the previous lower extremity revascularization criterion. Patients could not be enrolled within 30 days of most recent revascularization, and patients with an indication for dual antiplatelet therapy were excluded. The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or ischemic stroke. The primary safety end point was major bleeding.Patients with a previous revascularization had a mean age of 66 years, 73% were male, and the median baseline ankle-brachial index was 0.78. After adjustment for baseline characteristics, patients enrolled based on previous revascularization had similar rates of the primary composite end point (hazard ratio [HR] 1.10, 95% confidence interval [CI] 0.98-1.23, P=0.12) and statistically significantly higher rates of myocardial infarction (HR 1.29, 95% CI 1.08-1.55, P=0.005) and acute limb ischemia (HR 4.23, 95% CI 2.86-6.25, P<0.001) when compared with patients enrolled based on ankle-brachial index criteria. No differences in ticagrelor- versus clopidogrel-treated patients were found for the primary efficacy end point (11.4% vs 11.3%; HR 1.01, 95% CI 0.88-1.15; P=0.90), all-cause mortality (9.2% vs 9.2%; HR 0.99, 95% CI 0.86-1.15; P=0.93), acute limb ischemia (2.5% vs 2.5%; HR 1.03, 95% CI 0.78-1.36; P=0.84), or major bleeding (1.9% vs 1.8%; HR 1.15, 95% CI 0.83-1.59; P=0.41). The median duration of follow-up was ≈30 months.After adjustment for baseline characteristics, patients enrolled based on previous revascularization for peripheral artery disease had higher rates of myocardial infarction and acute limb ischemia, with similar composite rates of cardiovascular death, myocardial infarction, and stroke when compared with patients enrolled based on the ankle-brachial index criterion. No significant differences were found between ticagrelor and clopidogrel for reduction of cardiovascular or acute limb events.URL: http://www.clinicaltrials.gov. Unique identifier: NCT01732822.

    View details for DOI 10.1161/CIRCULATIONAHA.116.025880

    View details for Web of Science ID 000392291000009

    View details for PubMedID 27840336

  • Ticagrelor versus Clopidogrel in Symptomatic Peripheral Artery Disease NEW ENGLAND JOURNAL OF MEDICINE Hiatt, W. R., Fowkes, F. G., Heizer, G., Berger, J. S., Baumgartner, I., Held, P., Katona, B. G., Mahaffey, K. W., Norgren, L., Jones, W. S., Blomster, J., Millegard, M., Reist, C., Patel, M. R. 2017; 376 (1): 32-40

    Abstract

    Peripheral artery disease is considered to be a manifestation of systemic atherosclerosis with associated adverse cardiovascular and limb events. Data from previous trials have suggested that patients receiving clopidogrel monotherapy had a lower risk of cardiovascular events than those receiving aspirin. We wanted to compare clopidogrel with ticagrelor, a potent antiplatelet agent, in patients with peripheral artery disease.In this double-blind, event-driven trial, we randomly assigned 13,885 patients with symptomatic peripheral artery disease to receive monotherapy with ticagrelor (90 mg twice daily) or clopidogrel (75 mg once daily). Patients were eligible if they had an ankle-brachial index (ABI) of 0.80 or less or had undergone previous revascularization of the lower limbs. The primary efficacy end point was a composite of adjudicated cardiovascular death, myocardial infarction, or ischemic stroke. The primary safety end point was major bleeding. The median follow-up was 30 months.The median age of the patients was 66 years, and 72% were men; 43% were enrolled on the basis of the ABI and 57% on the basis of previous revascularization. The mean baseline ABI in all patients was 0.71, 76.6% of the patients had claudication, and 4.6% had critical limb ischemia. The primary efficacy end point occurred in 751 of 6930 patients (10.8%) receiving ticagrelor and in 740 of 6955 (10.6%) receiving clopidogrel (hazard ratio, 1.02; 95% confidence interval [CI], 0.92 to 1.13; P=0.65). In each group, acute limb ischemia occurred in 1.7% of the patients (hazard ratio, 1.03; 95% CI, 0.79 to 1.33; P=0.85) and major bleeding in 1.6% (hazard ratio, 1.10; 95% CI, 0.84 to 1.43; P=0.49).In patients with symptomatic peripheral artery disease, ticagrelor was not shown to be superior to clopidogrel for the reduction of cardiovascular events. Major bleeding occurred at similar rates among the patients in the two trial groups. (Funded by AstraZeneca; EUCLID ClinicalTrials.gov number, NCT01732822 .).

    View details for DOI 10.1056/NEJMoa1611688

    View details for PubMedID 27959717

  • Impact of Cerebrovascular Events Older Than One Year on Ischemic and Bleeding Outcomes With Cangrelor in Percutaneous Coronary Intervention CIRCULATION-CARDIOVASCULAR INTERVENTIONS Sawlani, N. N., Harrington, R. A., Stone, G. W., Steg, P. G., Gibson, C. M., Hamm, C. W., Price, M. J., Prats, J., Deliargyris, E. N., Mahaffey, K. W., White, H. D., Bhatt, D. L. 2017; 10 (1)

    Abstract

    Cangrelor is a potent intravenous adenosine diphosphate-receptor antagonist that in the CHAMPION trials reduced the 48-hour and 30-day rates of ischemic events during percutaneous coronary intervention without an increase in severe bleeding.CHAMPION PCI (A Clinical Trial to Demonstrate the Efficacy of Cangrelor), CHAMPION PLATFORM (Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition), and CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention) were 3 randomized, double-blind, double-dummy trials in which cangrelor was compared with clopidogrel during percutaneous coronary intervention. The effect of cangrelor on ischemic events and bleeding was analyzed in the subgroup of patients with a history of cerebrovascular events at least 1 year prior to randomization; the Breslow-Day test was used to test for interaction of treatment effect in subgroups with and without such a history. The primary efficacy end point was a composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours. Among 24 910 randomized patients, 1270 patients (5.1%) had a cerebrovascular event >1 year old, including 650 assigned to cangrelor and 620 assigned to clopidogrel. Consistent with the overall trial results, the rate of the primary efficacy end point was 4.3% in the cangrelor group versus 5.3% in the clopidogrel group (odds ratio 0.80; 95% confidence interval 0.48-1.34; P=0.40; P for interaction =0.97), and the rate of GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) severe bleeding was 0.3% in both groups (P=0.97; P for interaction =0.81).Among patients in the CHAMPION trials with a prior cerebrovascular event at least 1 year before the percutaneous coronary intervention, the efficacy and bleeding profile of cangrelor compared with clopidogrel was similar to that in the overall trial.

    View details for DOI 10.1161/CIRCINTERVENTIONS.116.004380

    View details for Web of Science ID 000393178000006

    View details for PubMedID 28039321

  • Navigating the Future of Cardiovascular Drug Development-Leveraging Novel Approaches to Drive Innovation and Drug Discovery: Summary of Findings from the Novel Cardiovascular Therapeutics Conference. Cardiovascular drugs and therapy Povsic, T. J., Scott, R. n., Mahaffey, K. W., Blaustein, R. n., Edelberg, J. M., Lefkowitz, M. P., Solomon, S. D., Fox, J. C., Healy, K. E., Khakoo, A. Y., Losordo, D. W., Malik, F. I., Monia, B. P., Montgomery, R. L., Riesmeyer, J. n., Schwartz, G. G., Zelenkofske, S. L., Wu, J. C., Wasserman, S. M., Roe, M. T. 2017; 31 (4): 445–58

    Abstract

    The need for novel approaches to cardiovascular drug development served as the impetus to convene an open meeting of experts from the pharmaceutical industry and academia to assess the challenges and develop solutions for drug discovery in cardiovascular disease.The Novel Cardiovascular Therapeutics Summit first reviewed recent examples of ongoing or recently completed programs translating basic science observations to targeted drug development, highlighting successes (protein convertase sutilisin/kexin type 9 [PCSK9] and neprilysin inhibition) and targets still under evaluation (cholesteryl ester transfer protein [CETP] inhibition), with the hope of gleaning key lessons to successful drug development in the current era. Participants then reviewed the use of innovative approaches being explored to facilitate rapid and more cost-efficient evaluations of drug candidates in a short timeframe.We summarize observations gleaned from this summit and offer insight into future cardiovascular drug development.The rapid development in genetic and high-throughput drug evaluation technologies, coupled with new approaches to rapidly evaluate potential cardiovascular therapies with in vitro techniques, offer opportunities to identify new drug targets for cardiovascular disease, study new therapies with better efficiency and higher throughput in the preclinical setting, and more rapidly bring the most promising therapies to human testing. However, there must be a critical interface between industry and academia to guide the future of cardiovascular drug development. The shared interest among academic institutions and pharmaceutical companies in developing promising therapies to address unmet clinical needs for patients with cardiovascular disease underlies and guides innovation and discovery platforms that are significantly altering the landscape of cardiovascular drug development.

    View details for PubMedID 28735360

  • Cardiovascular adverse events in the drug-development program of bupropion for smoking cessation: A systematic retrospective adjudication effort. Clin Cardiol. 2017 Jun 12. Kittle, J., et al 2017: 899–906

    Abstract

    In 2011, the US Food and Drug Administration requested that GlaxoSmithKline perform retrospective adjudication of cardiovascular (CV) events reported in the bupropion drug-development trials for smoking cessation.Retrospective adjudication of clinical trial data will not increase the identification of adverse events.We performed a comprehensive retrospective analysis of adverse events in 19 previously completed controlled US clinical trials of bupropion marketed for the treatment of smoking cessation, yielding 9479 subjects (5290 bupropion, 2927 placebo, 1018 active control [ACT], and 244 treated concurrently with bupropion and ACT). All adverse events were sent to the Duke Clinical Research Institute for adjudication by Clinical Events Classification (CEC) physician reviewers. The primary endpoint was a composite of major adverse CV events: CV death, nonfatal myocardial infarction (MI), and nonfatal stroke.Overall, 416 nonfatal CV events in 366 subjects, and 22 deaths, were identified and processed for adjudication. Of these, 7 nonfatal MIs (4 bupropion, 3 placebo, 0 ACT), 5 nonfatal strokes (1 bupropion, 3 placebo, 1 ACT), and 9 CV deaths (4 bupropion, 4 placebo, 1 ACT) were confirmed by the CEC Committee. The primary endpoint occurred in 3/4297 (0.07%) subjects in the bupropion group and in 4/2927 (0.14%) subjects in the placebo group (log-rank P value: 0.613).CV events in bupropion clinical trials for smoking cessation were uncommon, with no observed increase among subjects assigned to bupropion vs placebo. However, this effort was limited by a paucity of quality data.

    View details for DOI 10.1002/clc.22744

  • International trends in clinical characteristics and oral anticoagulation treatment for patients with atrial fibrillation: Results from the GARFIELD-AF, ORBIT-AF I, and ORBIT-AF II registries. American heart journal Steinberg, B. A., Gao, H. n., Shrader, P. n., Pieper, K. n., Thomas, L. n., Camm, A. J., Ezekowitz, M. D., Fonarow, G. C., Gersh, B. J., Goldhaber, S. n., Haas, S. n., Hacke, W. n., Kowey, P. R., Ansell, J. n., Mahaffey, K. W., Naccarelli, G. n., Reiffel, J. A., Turpie, A. n., Verheugt, F. n., Piccini, J. P., Kakkar, A. n., Peterson, E. D., Fox, K. A. 2017; 194: 132–40

    Abstract

    Atrial fibrillation (AF) is the most common cardiac arrhythmia in the world. We aimed to provide comprehensive data on international patterns of AF stroke prevention treatment.Demographics, comorbidities, and stroke risk of the patients in the GARFIELD-AF (n=51,270), ORBIT-AF I (n=10,132), and ORBIT-AF II (n=11,602) registries were compared (overall N=73,004 from 35 countries). Stroke prevention therapies were assessed among patients with new-onset AF (≤6 weeks).Patients from GARFIELD-AF were less likely to be white (63% vs 89% for ORBIT-AF I and 86% for ORBIT-AF II) or have coronary artery disease (19% vs 36% and 27%), but had similar stroke risk (85% CHA2DS2-VASc ≥2 vs 91% and 85%) and lower bleeding risk (11% with HAS-BLED ≥3 vs 24% and 15%). Oral anticoagulant use was 46% and 57% for patients with a CHA2DS2-VASc=0 and 69% and 87% for CHA2DS2-VASc ≥2 in GARFIELD-AF and ORBIT-AF II, respectively, but with substantial geographic heterogeneity in use of oral anticoagulant (range: 31%-93% [GARFIELD-AF] and 66%-100% [ORBIT-AF II]). Among patients with new-onset AF, non-vitamin K antagonist oral anticoagulant use increased over time to 43% in 2016 for GARFIELD-AF and 71% for ORBIT-AF II, whereas use of antiplatelet monotherapy decreased from 36% to 17% (GARFIELD-AF) and 18% to 8% (ORBIT-AF I and II).Among new-onset AF patients, non-vitamin K antagonist oral anticoagulant use has increased and antiplatelet monotherapy has decreased. However, anticoagulation is used frequently in low-risk patients and inconsistently in those at high risk of stroke. Significant geographic variability in anticoagulation persists and represents an opportunity for improvement.

    View details for PubMedID 29223431

  • Prevalence, Characteristics, and Outcomes of Valvular Heart Disease in Patients With Atrial Fibrillation: Insights From the ORBIT-AF (Outcomes Registry for Better Informed Treatment for Atrial Fibrillation). Journal of the American Heart Association Thomas, K. L., Jackson, L. R., Shrader, P. n., Ansell, J. n., Fonarow, G. C., Gersh, B. n., Kowey, P. R., Mahaffey, K. W., Singer, D. E., Thomas, L. n., Piccini, J. P., Peterson, E. D. 2017; 6 (12)

    Abstract

    The presence of valvular heart disease (VHD) may affect the risk of stroke and mortality in patients with atrial fibrillation (AF). Community-based estimates of prevalence and outcomes of specific forms of VHD in patients with AF are lacking.We examined the prevalence of VHD, anticoagulation use, mortality, stroke/transient ischemic attack, and bleeding among a community cohort of patients with AF. Significant VHD was defined as follows: (1) moderate/severe mitral stenosis or mechanical valve; (2) bioprosthetic valve, surgical repair, or balloon valvuloplasty; and (3) moderate/severe aortic regurgitation or stenosis, mitral regurgitation, or tricuspid regurgitation. Proportional hazards models were performed to test the association between VHD groups and outcomes. Among 9748 patients with AF, 2705 (27.7%) had significant VHD. Anticoagulation use was highest among patients with mitral stenosis/mechanical valve (91.8%). Compared with individuals with no significant VHD, individuals with aortic regurgitation/aortic stenosis, mitral regurgitation, or tricuspid regurgitation (hazard ratio, 1.23; 95% confidence interval, 1.07-1.42) had the highest risk of death. There were no differences in stroke or transient ischemic attack and major bleeding among individuals with and without significant VHD. Patients with AF and aortic stenosis had the highest risk of death (hazard ratio, 1.32; 95% confidence interval, 1.08-1.62).Significant VHD is common among patients with AF in community practice. In a community cohort of patients with AF and CHA2DS2-VASc score ≥2, most were anticoagulated. Individuals with AF and moderate-to-severe biological VHD have more comorbidities and a higher mortality risk; however, stroke and major bleeding are similar among those with and without significant VHD.

    View details for PubMedID 29273635

    View details for PubMedCentralID PMC5778999

  • Cardiovascular adverse events in the drug-development program of bupropion for smoking cessation: A systematic retrospective adjudication effort. Clinical cardiology Kittle, J. n., Lopes, R. D., Huang, M. n., Marquess, M. L., Wilson, M. D., Ascher, J. n., Krishen, A. n., Hasselblad, V. n., Kolls, B. J., Roe, M. T., McGuire, D. K., Russell, S. D., Mahaffey, K. W. 2017; 40 (10): 899–906

    Abstract

    In 2011, the US Food and Drug Administration requested that GlaxoSmithKline perform retrospective adjudication of cardiovascular (CV) events reported in the bupropion drug-development trials for smoking cessation.Retrospective adjudication of clinical trial data will not increase the identification of adverse events.We performed a comprehensive retrospective analysis of adverse events in 19 previously completed controlled US clinical trials of bupropion marketed for the treatment of smoking cessation, yielding 9479 subjects (5290 bupropion, 2927 placebo, 1018 active control [ACT], and 244 treated concurrently with bupropion and ACT). All adverse events were sent to the Duke Clinical Research Institute for adjudication by Clinical Events Classification (CEC) physician reviewers. The primary endpoint was a composite of major adverse CV events: CV death, nonfatal myocardial infarction (MI), and nonfatal stroke.Overall, 416 nonfatal CV events in 366 subjects, and 22 deaths, were identified and processed for adjudication. Of these, 7 nonfatal MIs (4 bupropion, 3 placebo, 0 ACT), 5 nonfatal strokes (1 bupropion, 3 placebo, 1 ACT), and 9 CV deaths (4 bupropion, 4 placebo, 1 ACT) were confirmed by the CEC Committee. The primary endpoint occurred in 3/4297 (0.07%) subjects in the bupropion group and in 4/2927 (0.14%) subjects in the placebo group (log-rank P value: 0.613).CV events in bupropion clinical trials for smoking cessation were uncommon, with no observed increase among subjects assigned to bupropion vs placebo. However, this effort was limited by a paucity of quality data.

    View details for PubMedID 28605035

  • The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) Study Rationale, Design, and Baseline Characteristics AMERICAN JOURNAL OF NEPHROLOGY Jardine, M. J., Mahaffey, K. W., Neal, B., Agarwal, R., Bakris, G. L., Brenner, B. M., Bull, S., Cannon, C. P., Charytan, D. M., de Zeeuw, D., Edwards, R., Greene, T., Heerspink, H. L., Levin, A., Pollock, C., Wheeler, D. C., Xie, J., Zhang, H., Zinman, B., Desai, M., Perkovic, V., CREDENCE Study Investigators 2017; 46 (6): 462–72

    Abstract

    People with diabetes and kidney disease have a high risk of cardiovascular events and progression of kidney disease. Sodium glucose co-transporter 2 inhibitors lower plasma glucose by reducing the uptake of filtered glucose in the kidney tubule, leading to increased urinary glucose excretion. They have been repeatedly shown to induce modest natriuresis and reduce HbA1c, blood pressure, weight, and albuminuria in patients with type 2 diabetes. However, the effects of these agents on kidney and cardiovascular events have not been extensively studied in patients with type 2 diabetes and established kidney disease.The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial aims to compare the efficacy and safety of canagliflozin -versus placebo at preventing clinically important kidney and cardiovascular outcomes in patients with diabetes and established kidney disease. CREDENCE is a randomized, double-blind, event-driven, placebo-controlled trial set in in 34 countries with a projected duration of ∼5.5 years and enrolling 4,401 adults with type 2 diabetes, estimated glomerular filtration rate ≥30 to <90 mL/min/1.73 m2, and albuminuria (urinary albumin:creatinine ratio >300 to ≤5,000 mg/g). The study has 90% power to detect a 20% reduction in the risk of the primary outcome (α = 0.05), the composite of end-stage kidney disease, doubling of serum creatinine, and renal or cardiovascular death.CREDENCE will provide definitive evidence about the effects of canagliflozin on renal (and cardiovascular) outcomes in patients with type 2 diabetes and established kidney disease.EudraCT number: 2013-004494-28; ClinicalTrials.gov identifier: NCT02065791.

    View details for PubMedID 29253846

    View details for PubMedCentralID PMC5804835

  • Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. The New England journal of medicine Neal, B. n., Perkovic, V. n., Mahaffey, K. W., de Zeeuw, D. n., Fulcher, G. n., Erondu, N. n., Shaw, W. n., Law, G. n., Desai, M. n., Matthews, D. R. 2017; 377 (7): 644–57

    Abstract

    Background Canagliflozin is a sodium-glucose cotransporter 2 inhibitor that reduces glycemia as well as blood pressure, body weight, and albuminuria in people with diabetes. We report the effects of treatment with canagliflozin on cardiovascular, renal, and safety outcomes. Methods The CANVAS Program integrated data from two trials involving a total of 10,142 participants with type 2 diabetes and high cardiovascular risk. Participants in each trial were randomly assigned to receive canagliflozin or placebo and were followed for a mean of 188.2 weeks. The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Results The mean age of the participants was 63.3 years, 35.8% were women, the mean duration of diabetes was 13.5 years, and 65.6% had a history of cardiovascular disease. The rate of the primary outcome was lower with canagliflozin than with placebo (occurring in 26.9 vs. 31.5 participants per 1000 patient-years; hazard ratio, 0.86; 95% confidence interval [CI], 0.75 to 0.97; P<0.001 for noninferiority; P=0.02 for superiority). Although on the basis of the prespecified hypothesis testing sequence the renal outcomes are not viewed as statistically significant, the results showed a possible benefit of canagliflozin with respect to the progression of albuminuria (hazard ratio, 0.73; 95% CI, 0.67 to 0.79) and the composite outcome of a sustained 40% reduction in the estimated glomerular filtration rate, the need for renal-replacement therapy, or death from renal causes (hazard ratio, 0.60; 95% CI, 0.47 to 0.77). Adverse reactions were consistent with the previously reported risks associated with canagliflozin except for an increased risk of amputation (6.3 vs. 3.4 participants per 1000 patient-years; hazard ratio, 1.97; 95% CI, 1.41 to 2.75); amputations were primarily at the level of the toe or metatarsal. Conclusions In two trials involving patients with type 2 diabetes and an elevated risk of cardiovascular disease, patients treated with canagliflozin had a lower risk of cardiovascular events than those who received placebo but a greater risk of amputation, primarily at the level of the toe or metatarsal. (Funded by Janssen Research and Development; CANVAS and CANVAS-R ClinicalTrials.gov numbers, NCT01032629 and NCT01989754 , respectively.).

    View details for PubMedID 28605608

  • A 15-year review of the Stanford Internal Medicine Residency Program: predictors of resident satisfaction and dissatisfaction ADVANCES IN MEDICAL EDUCATION AND PRACTICE Kahn, J. S., Witteles, R. M., Mahaffey, K. W., Desai, S. A., Ozdalga, E., Heidenreich, P. A. 2017; 8: 559–66

    Abstract

    Satisfaction with training and with educational experiences represents important internal medicine (IM) programmatic goals. Graduates from IM residency programs are uniquely poised to provide insights into their educational and training experiences and to assess whether these experiences were satisfactory and relevant to their current employment.We surveyed former IM residents from the training program held during the years 2000-2015 at the Department of Medicine, Stanford University. The first part of the survey reviewed the IM residency program and the second part sought identifying data regarding gender, race, ethnicity, work, relationships, and financial matters. The primary outcome was satisfaction with the residency experience.Of the 405 individuals who completed the Stanford IM residency program in the study period, we identified 384 (95%) former residents with a known email address. Two hundred and one (52%) former residents responded to the first part and 185 (48%) answered both the parts of the survey. The mean age of the respondents was 36.9 years; 44% were female and the mean time from IM residency was 6.1 (±4.3) years. Fifty-eight percent reported extreme satisfaction with their IM residency experience. Predictors associated with being less than extremely satisfied included insufficient outpatient experience, insufficient international experience, insufficient clinical research experience, and insufficient time spent with family and peers.The residents expressed an overall high satisfaction rate with their IM training. The survey results provided insights for improving satisfaction with IM residency training that includes diversifying and broadening IM training experiences.

    View details for PubMedID 28814910

  • Rejoinder. Clinical trials Fleming, T. R., DeMets, D. L., Roe, M. T., Wittes, J., Calis, K. A., Vora, A. N., Meisel, A., Bain, R. P., Konstam, M. A., Pencina, M. J., Gordon, D. J., Mahaffey, K. W., Hennekens, C. H., Neaton, J. D., Pearson, G. D., Andersson, T. L., Pfeffer, M. A., Ellenberg, S. S. 2017: 1740774516688917-?

    View details for DOI 10.1177/1740774516688917

    View details for PubMedID 28135837

    View details for PubMedCentralID PMC5376229

  • Predictors and Prognostic Implications of Incident Heart Failure in Patients With Prevalent Atrial Fibrillation JACC-HEART FAILURE Pandey, A., Kim, S., Moore, C., Thomas, L., Gersh, B., Allen, L. A., Kowey, P. R., Mahaffey, K. W., Hylek, E., Peterson, E. D., Piccini, J. P., Fonarow, G. C. 2017; 5 (1): 44-52

    Abstract

    The purpose of this study was to determine the significant clinical predictors of incident heart failure (HF) and its prognostic effect on long-term outcomes among community-based patients with established atrial fibrillation (AF).AF is associated with an increased risk of HF. However, in this population, little focus is placed on risk stratification for and the prevention of HF.Patients with AF but without HF at baseline enrolled in the ORBIT-AF (Outcomes Registry for Informed Treatment of Atrial Fibrillation) registry were included. Separate multivariable-adjusted Cox frailty regression models were used to identify significant predictors of HF incidence and determine the associated risk of adverse clinical events.The study included 6,545 participants with AF from 173 participating sites. Incident HF developed in 236 participants (3.6%) over the 2-year follow-up period; ejection fraction was preserved (>40%) in 64%, reduced (≤40%) in 13.5%, and missing in 22.5%. In multivariable analysis, traditional HF risk factors (age, coronary artery disease, renal dysfunction, and valvular disease), presence of permanent AF (hazard ratio [HR]: 1.60 [95% confidence interval (CI): 1.18 to 2.16]; reference group: paroxysmal AF), and elevated baseline heart rate (HR: 1.07 [95% CI: 1.02 to 1.13] per 5 beats/min higher heart rate) were independently associated with incident HF risk. Incident HF among patients with AF was independently associated with higher risk of mortality, all-cause hospitalization, and bleeding events.Incident HF among patients with AF is common, is more likely to be HF with preserved ejection fraction, and is associated with poor long-term outcomes. Traditional HF risk factors, AF type, and baseline heart rate are independent clinical predictors of incident HF.

    View details for DOI 10.1016/j.jchf.2016.09.016

    View details for Web of Science ID 000391520500007

    View details for PubMedID 28034376

  • Off-Label Dosing of Non-Vitamin K Antagonist Oral Anticoagulants and Adverse Outcomes The ORBIT-AF II Registry JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Steinberg, B. A., Shrader, P., Thomas, L., Ansell, J., Fonarow, G. C., Gersh, B. J., Kowey, P. R., Mahaffey, K. W., Naccarelli, G., Reiffel, J., Singer, D. E., Peterson, E. D., Piccini, J. P. 2016; 68 (24): 2597-2604

    Abstract

    Although non-vitamin K antagonist oral anticoagulants (NOACs) do not require frequent laboratory monitoring, each compound requires dose adjustments on the basis of certain clinical criteria.This study assessed the frequency of off-label NOAC doses among AF patients and the associations between off-label dose therapy and clinical outcomes in community practice.We evaluated 5,738 patients treated with a NOAC at 242 ORBIT-AF II (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation phase II) sites. NOAC doses were classified as either underdosed or overdosed, consistent with Food and Drug Administration labeling. Longitudinal outcomes (median follow-up: 0.99 years) included stroke or systemic embolism, myocardial infarction, major bleeding (International Society of Thrombosis and Haemostasis criteria), cause-specific hospitalization, and all-cause mortality.Overall, 541 NOAC-treated patients (9.4%) were underdosed, 197 were overdosed (3.4%), and 5,000 were dosed according to U.S. labeling (87%). Compared with patients receiving the recommended dose, those who were receiving off-label doses were older (median: 79 and 80 years of age vs. 70 years of age, respectively; p < 0.0001), more likely female (48% and 67% vs. 40%, respectively; p < 0.0001), less likely to be treated by an electrophysiologist (18% and 19% vs. 27%, respectively; p < 0.0001), and had higher CHA2DS2-VASc scores (96% and 97% ≥2 vs. 86%, respectively; p < 0.0001) and higher ORBIT bleeding scores (25% and 31% >4 vs. 11%, respectively; p < 0.0001). After dose adjustment, NOAC overdosing was associated with increased all-cause mortality compared with recommended doses (adjusted hazard ratio: 1.91; 95% confidence interval [CI]: 1.02 to 3.60; p = 0.04). Underdosing was associated with increased cardiovascular hospitalization (adjusted hazard ratio: 1.26; 95% CI: 1.07 to 1.50; p = 0.007).A significant minority (almost 1 in 8) of U.S. patients in the community received NOAC doses inconsistent with labeling. NOAC over- and underdosing are associated with increased risk for adverse events. (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II [ORBIT-AF II]; NCT01701817).

    View details for DOI 10.1016/j.jacc.2016.09.966

    View details for Web of Science ID 000389593000001

    View details for PubMedID 27978942

  • Effects of Ticagrelor Compared With Clopidogrel in Patients With Peripheral Artery Disease (EUCLID) Patel, M. R., Fowkes, F. R., Berger, J. S., Norgren, L., Heizer, G., Baumgartner, I., Mahaffey, K. W., Katona, B. G., Held, P., Blomster, J., Jones, W., Reisr, C., Millegard, M., Hiatt, W. R. LIPPINCOTT WILLIAMS & WILKINS. 2016: E703
  • Relation of Post Coronary Artery Bypass Graft Creatine Kinase-MB Elevations and New Q Waves With Long-Term Cardiovascular Death in Patients With Diabetes Mellitus and Multivessel Coronary Artery Disease AMERICAN JOURNAL OF CARDIOLOGY Domanski, M., Farkouh, M. E., Zak, V., French, J., Alexander, J. H., Bochenek, A., Hamon, M., Mahaffey, K., Puskas, J., Smith, P., Shrader, P., Fuster, V. 2016; 118 (11): 1655-1660

    Abstract

    Associations of early creatine phosphokinase-MB (CK-MB) elevation and new Q waves and their association with cardiovascular death (CVD) after coronary artery bypass grafting (CABG) have been reported, but this association has not been studied in a large population of patients with diabetes mellitus. In this study, we examine the association of periprocedural CK-MB elevations and new Q waves with CVD in the Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease trial. Cox proportional hazards regression was used to assess the relation of CK-MB elevations and new Q waves in the first 24 hours after procedure and their relation to CVD; logistic regression was used to assess odds ratios of these variables. Hazard ratios, 95% confidence intervals, and p values associated with Wald chi-square test are reported. CK-MB elevation in first 24 hours after procedure was independently associated with CVD. CVD hazard increased by 6% (p <0.001) with each multiple of CK-MB above the upper reference limit (URL); odds of new post-CABG Q waves increased by a factor of 1.08 (p <0.001); at 7× CK-MB URL, HR was >2. CK-MB URL multiples of 7, 12, and 15 were associated with new Q-wave odds ratios of 9, 16, and 27 times, respectively (p ≤0.001, C-statistic >0.70). New Q waves were independently associated with survival in the multivariate model only when CK-MB was excluded (p = 0.01). In conclusion, independent associations included (1) CVD and early post-CABG CK-MB elevation; (2) new Q waves with early post-CABG CK-MB elevation; (3) CVD with new Q waves only when CK-MB elevation is excluded from analysis.

    View details for DOI 10.1016/j.amjcard.2016.08.041

    View details for Web of Science ID 000389686100008

    View details for PubMedID 27816118

  • Absence of Oral Anticoagulation and Subsequent Outcomes Among Outpatients with Atrial Fibrillation. American journal of medicine Hess, P. L., Kim, S., Fonarow, G. C., Thomas, L., Singer, D. E., Freeman, J. V., Gersh, B. J., Ansell, J., Kowey, P. R., Mahaffey, K. W., Chan, P. S., Steinberg, B. A., Peterson, E. D., Piccini, J. P. 2016

    Abstract

    Prior studies have shown a treatment gap in oral anticoagulation (OAC) use among patients with atrial fibrillation yet have incompletely characterized factors associated with failure to treat and subsequent outcomes in contemporary practice.Using data collected between June 2010 and August 2011 from 174 ambulatory care sites in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation, we identified factors associated with absence of OAC via stratified logistic regression. Using weighted Cox regression, we assessed the association between OAC non-use and subsequent outcomes over 2.5 years.Among 9553 patients, 2202 (23.0%) were not on OAC. Among OAC nonrecipients, 1846 (83.8%) had a CHA2DS2-VASc score ≥2. Factors independently associated with OAC non-use included atrial fibrillation type (paroxysmal odds ratio [OR] 0.73, 95% confidence interval [CI] 0.54-0.99; persistent OR 0.14, 95% CI 0.10-0.21; permanent OR 0.35, 95% CI 0.25-0.49; reference = new-onset), left atrial diameter enlargement (mild OR 0.80, 95% CI 0.66-0.97; moderate 0.58, 95% CI 0.47-0.73; severe 0.53, 95% CI 0.42-0.68; reference = normal diameter), and age >80 years (OR 1.04, 95% CI 1.02-1.08). Untreated patients had a higher risk of death (adjusted hazard ratio [HR] 1.22, 95% CI 1.05-1.41), a lower bleeding risk (adjusted HR 0.35, 95% CI 0.15-0.81), and a nonsignificant trend toward higher risk of stroke/non-central nervous system embolism/transient ischemic attack than those treated (adjusted HR 1.18, 95% CI 0.91-1.54).A majority of atrial fibrillation patients not treated with an OAC in current community practice meet guideline indications for treatment. Atrial fibrillation burden, chronicity, and comorbidity are associated with nontreatment. Untreated patients are at increased risk for adverse outcomes.

    View details for DOI 10.1016/j.amjmed.2016.11.001

    View details for PubMedID 27888051

  • Vorapaxar: emerging evidence and clinical questions in a new era of PAR-1 inhibition. Coronary artery disease Ungar, L., Rodriguez, F., Mahaffey, K. W. 2016; 27 (7): 604-615

    Abstract

    Despite the use of therapies recommended in practice guidelines for secondary prevention in patients with atherosclerotic coronary artery disease, the residual risk for cardiovascular events remains high. Some of the residual risk is believed to result from incomplete platelet inhibition with current therapy. Vorapaxar is a first-in-class, novel antiplatelet agent that acts by antagonizing the PAR-1 receptor, inhibiting thrombin-mediated platelet activation. Vorapaxar was recently approved by the Food and Drug Administration for secondary prevention of cardiovascular events in patients with a history of myocardial infarction or peripheral artery disease who do not have a history of transient ischemic attack or stroke. We review the data from two key phase III cardiovascular outcome trials with vorapaxar: TRACER and TRA 2P-TIMI 50. We will focus on identifying the key patient populations that should be identified for treatment, highlight practical clinical issues when prescribing vorapaxar, and review unanswered questions. Vorapaxar should be considered in patients at high risk for recurrent ischemic events and low risk of bleeding.

    View details for DOI 10.1097/MCA.0000000000000409

    View details for PubMedID 27398626

  • How well does physician risk assessment predict stroke and bleeding in atrial fibrillation? Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). American heart journal Steinberg, B. A., Shrader, P., Kim, S., Thomas, L., Fonarow, G. C., Ansell, J., Kowey, P. R., Singer, D. E., Gersh, B. J., Mahaffey, K. W., Peterson, E. D., Piccini, J. P. 2016; 181: 145-152

    Abstract

    Assessments of stroke and bleeding risks are essential to selecting oral anticoagulation in patients with atrial fibrillation (AF). We aimed to assess outcomes according to physician assessed risk, with comparison to empirical risk scores.This was a prospective, observational study of 9,715 outpatients with AF enrolled in ORBIT-AF, a US national registry. Stroke and bleeding risks were quantified by physician assignment, CHADS2 and CHA2DS2-VASc stroke scores, and ATRIA and HAS-BLED bleeding scores. Outcomes were stroke or systemic embolism and major bleeding during a median follow-up of 28 months.Physician-assigned risk was associated with thromboembolic events: low risk (0.71 per 100 patient-years [95% CI 0.56-0.91], n=3,991), intermediate risk (0.98 [95% CI 0.79-1.20], n=4,148), and high risk (1.84 [95% CI 1.43-2.37], n=1,576, P<.0001), and major bleeding: low (3.43 [95% CI 3.07-3.82], n=4,250), intermediate (4.55 [95% CI 4.03-5.15], n=2,702), and high (5.76 [95% CI 4.42-7.50], n=468; P<.0001). Discrimination of stroke risk was similar with CHADS2 (c=0.59, 95% CI 0.57-0.61) vs physician assessment (c=0.58, 95% CI 0.55-0.62). Among patients on oral anticoagulation, bleeding risk discrimination was higher with ATRIA (c=0.63, 95% CI 0.61-0.65) and HAS-BLED (c=0.60, 95% CI 0.59-0.62) than with physician assessment (0.55, 95% CI 0.53-0.57). Physician-assessed risk categories did not add significantly to empirical risk scores, in Cox models for outcomes (Padjusted>.05 for all physician assessments vs Padjusted<.05 for empirical scores).Physician-assigned risk showed a graded relationship with outcomes, and both physician-based and empirical scores yielded only moderate discrimination. Although empirical scores provided valuable risk stratification information (with or without physician judgment), physician assessment added little to existing scores. These data support the use of empirical scores for stroke and bleeding risk stratification, and the need for novel approaches to risk stratification in this population.

    View details for DOI 10.1016/j.ahj.2016.07.026

    View details for PubMedID 27823686

  • Influence of Kidney Function Estimation Methods on Eligibility for Edoxaban Population Impact of the US Food and Drug Administration's Approach for Its Product Labeling CIRCULATION Pokorney, S. D., Shrader, P., Thomas, L., Fonarow, G. C., Kowey, P. R., Singer, D. E., Ansell, J., Gersh, B. J., Mahaffey, K. W., Hylek, E. M., Go, A. S., Piccini, J. P., Peterson, E. D., Outcomes Registry Better Informed 2016; 134 (15): 1122–24

    View details for PubMedID 27753615

  • Temporal changes in biomarkers and their relationships to reperfusion and to clinical outcomes among patients with ST segment elevation myocardial infarction. Journal of thrombosis and thrombolysis van Diepen, S., Alemayehu, W. G., Zheng, Y., Theroux, P., Newby, L. K., Mahaffey, K. W., Granger, C. B., Armstrong, P. W. 2016; 42 (3): 376-385

    Abstract

    Coronary plaque rupture mediating acute ST segment elevation myocardial infarction (STEMI) is associated with a systemic inflammatory response. Whether early temporal changes in inflammatory biomarkers are associated with angiographic and electrocardiographic markers of reperfusion and subsequent clinical outcomes is unclear. In the APEX-AMI biomarker substudy, 376 patients with STEMI had inflammatory biomarkers measured at the time of hospital presentation and 24 h later. The primary outcome was the 90-day composite of death, shock, or heart failure. Secondary reperfusion outcomes were (1) worst least residual ST segment elevation (ST-E: <1 mm, 1 to <2 mm, ≥2 mm) and (2) post-percutaneous coronary intervention (PCI) TIMI flow grade (0/1/2 vs 3) and TIMI myocardial perfusion grade (TMPG 0/1 vs 2/3). The 90-day incidence of death, shock or heart failure was 21.3 % in this cohort. Electrocardiographic reperfusion (worst residual ST-E <1 mm, 1 to <2 mm, ≥2 mm) was associated with differences in 24 h change in N-terminal proB-type natriuretic peptide (NT-proBNP) (1192.8, 1332.5, 1859.0 ng/mL; p = 0.043) and the pro-inflammatory cytokines Interleukin (IL)-6 (14.0, 13.6, 22.1 pg/mL; p = 0.016), IL-12 (-0.5, -0.9, -0.1 pg/mL; p = 0.013), and tumor necrosis factor α (TNFα) (1.0, 0.6, 3.6 pg/mL; p = 0.023). Angiographic reperfusion (TMPG 0/1 vs 2/3) was associated with changes in median NT-proBNP (2649.3, 1382.7 ng/mL; p = 0.002) and IL-6 (28.7, 15.1; p = 0.040). After adjustment for baseline covariates, the 24 h change in the pro-inflammatory cytokine TNFα [hazard ratio (HR) 0.49; 95 % CI 0.26-0.95; p = 0.035] and the anti-inflammatory cytokine IL 10 (HR 1.41; 95 % CI 1.06-1.87; p = 0.018) were independently associated with the primary composite outcome. Successful coronary reperfusion was associated with less systemic inflammatory response and greater temporal inflammatory changes were independently associated with higher 90-day composite of death, shock, or heart failure. These findings provide support for an association between success of reperfusion, an acute STEMI inflammatory response and subsequent clinical outcomes.

    View details for DOI 10.1007/s11239-016-1390-z

    View details for PubMedID 27324144

  • Efficacy and Safety of Cangrelor in Preventing Periprocedural Complications in Patients With Stable Angina and Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention The CHAMPION PHOENIX Trial JACC-CARDIOVASCULAR INTERVENTIONS Abtan, J., Steg, P. G., Stone, G. W., Mahaffey, K. W., Gibson, C. M., Hamm, C. W., Price, M. J., Abnousi, F., Prats, J., Deliargyris, E. N., White, H. D., Harrington, R. A., Bhatt, D. L. 2016; 9 (18): 1905-1913

    Abstract

    The purpose of this study was to examine the safety and efficacy of cangrelor in patients with stable angina (SA) or acute coronary syndrome (ACS).The CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention) trial demonstrated that cangrelor significantly reduced periprocedural ischemic events in all-comer percutaneous coronary intervention with a modest increase in mild and moderate bleeding. Whether this benefit is consistent across SA and ACS has not been explored fully.The CHAMPION PHOENIX trial compared periprocedural administration of cangrelor or clopidogrel, with either a 300- or 600-mg loading dose for the prevention of periprocedural complications in patients undergoing percutaneous coronary intervention. Among the 10,942 patients in the modified intention to treat population, 6,358 patients were classified as having SA, and 4,584 patients had ACS (including unstable angina, non ST-segment elevation myocardial infarction and ST-segment elevation myocardial infarction) at randomization. The primary composite endpoint was death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 h. A key secondary endpoint was stent thrombosis, and the primary safety endpoint was GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) severe bleeding.Cangrelor consistently reduced the primary endpoint in SA and ACS (odds ratio [OR]: 0.83 [95% confidence interval (CI): 0.67 to 1.01] and OR: 0.71 [95% CI: 0.52 to 0.96], respectively; interaction p = 0.41). Cangrelor also consistently reduced stent thrombosis in SA and ACS (OR: 0.55 [95% CI: 0.30 to 1.01] and OR: 0.67 [95% CI: 0.42 to 1.06], respectively; interaction p = 0.62). The impact of cangrelor on GUSTO severe/moderate bleeding was also similar for SA and ACS (OR: 1.49 [95% CI: 0.67 to 3.33] and OR: 1.79 [95% CI: 0.79 to 4.07], respectively; interaction p = 0.75).The benefits and risks of cangrelor were consistent in patients with SA and ACS. (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI] [CHAMPION PHOENIX] [CHAMPION]; NCT01156571).

    View details for DOI 10.1016/j.jcin.2016.06.046

    View details for Web of Science ID 000385713800010

    View details for PubMedID 27659566

  • Consistent Reduction in Periprocedural Myocardial Infarction With Cangrelor as Assessed by Multiple Definitions: Findings From CHAMPION PHOENIX (Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition). Circulation Cavender, M. A., Bhatt, D. L., Stone, G. W., White, H. D., Steg, P. G., Gibson, C. M., Hamm, C. W., Price, M. J., Leonardi, S., Prats, J., Deliargyris, E. N., Mahaffey, K. W., Harrington, R. A. 2016; 134 (10): 723-733

    Abstract

    Cangrelor is an intravenous P2Y12 inhibitor approved to reduce periprocedural ischemic events in patients undergoing percutaneous coronary intervention not pretreated with a P2Y12 inhibitor.A total of 11 145 patients were randomized to cangrelor or clopidogrel in the CHAMPION PHOENIX trial (Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition). We explored the effects of cangrelor on myocardial infarction (MI) using different definitions and performed sensitivity analyses on the primary end point of the trial.A total of 462 patients (4.2%) undergoing percutaneous coronary intervention had an MI as defined by the second universal definition. The majority of these MIs (n=433, 93.7%) were type 4a. Treatment with cangrelor reduced the incidence of MI at 48 hours (3.8% versus 4.7%; odds ratio [OR], 0.80; 95% confidence interval [CI], 0.67-0.97; P=0.02). When the Society of Coronary Angiography and Intervention definition of periprocedural MI was applied to potential ischemic events, there were fewer total MIs (n=134); however, the effects of cangrelor on MI remained significant (OR, 0.65; 95% CI, 0.46-0.92; P=0.01). Similar effects were seen in the evaluation of the effects of cangrelor on MIs with peak creatinine kinase-MB ≥10 times the upper limit of normal (OR, 0.64; 95% CI, 0.45-0.91) and those with peak creatinine kinase-MB ≥10 times the upper limit of normal, ischemic symptoms, or ECG changes (OR, 0.63; 95% CI, 0.48-0.84). MIs defined by any of these definitions were associated with increased risk of death at 30 days. Treatment with cangrelor reduced the composite end point of death, MI (Society of Coronary Angiography and Intervention definition), ischemia-driven revascularization, or Academic Research Consortium definite stent thrombosis (1.4% versus 2.1%; OR, 0.69; 95% CI, 0.51-0.92).MI in patients undergoing percutaneous coronary intervention, regardless of definition, remains associated with increased risk of death in the current era. Cangrelor compared with clopidogrel significantly reduces MI regardless of the definition.URL: http://clinicaltrials.gov. Unique identifier: NCT01156571.

    View details for DOI 10.1161/CIRCULATIONAHA.115.020829

    View details for PubMedID 27482008

    View details for PubMedCentralID PMC5006794

  • Use of concomitant aspirin in patients with atrial fibrillation: Findings from the ROCKET AF trial AMERICAN HEART JOURNAL Shah, R., Hellkamp, A., Lokhnygina, Y., Becker, R. C., Berkowitz, S. D., Breithardt, G., Backe, W., Halperin, J. L., Hankey, G. J., Fox, K. A., Nessel, C. C., Mahaffey, K. W., Piccini, J. P., Singer, D. E., Patel, M. R. 2016; 179: 77-86

    Abstract

    We aimed to investigate the relationship between aspirin use and clinical outcomes in patients enrolled in Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), in particular, those with known coronary artery disease (CAD).Patients in ROCKET AF, comparing rivaroxaban and warfarin, were analyzed. Aspirin use was assessed at baseline. Stroke and systemic embolism, myocardial infarction, death, and major or nonmajor clinically relevant (NMCR) bleeding were compared between groups. Multivariable modeling was done adjusting for baseline risk factors.A total of 5,205 (36.5%) patients were receiving aspirin at baseline (mean dose 99.2mg); 30.6% of those had known CAD. Patients receiving aspirin were more likely to have prior myocardial infarction (22% vs 14%; P<.001) and heart failure (68% vs 59%; P<.001). Relative efficacy of rivaroxaban versus warfarin was similar with and without aspirin use for both stroke/systemic embolism (P=.95 for interaction), and major or NMCR bleeding (P=.76 for interaction). After adjustment, aspirin use was associated with similar rates of stroke/systemic embolism (hazard ratio [HR] 1.16, 95% CI 0.98-1.37; P=.094) but higher rates of all-cause death (HR 1.27, 95% CI 1.13-1.42; P<.0001) and major or NMCR bleeding (HR 1.32, 95% CI 1.21-1.43; P<.0001). There was a significant interaction between no CAD at baseline and aspirin for all-cause death (P=.009).Aspirin use at baseline was associated with an increased risk for bleeding and all-cause death in ROCKET AF, a risk most pronounced in patients without known CAD. Although these findings may reflect unmeasured clinical factors, further investigation is warranted to determine optimal aspirin use in patients with AF.

    View details for DOI 10.1016/j.ahj.2016.05.019

    View details for Web of Science ID 000383112100009

  • Use of concomitant aspirin in patients with atrial fibrillation: Findings from the ROCKET AF trial. American heart journal Shah, R., Hellkamp, A., Lokhnygina, Y., Becker, R. C., Berkowitz, S. D., Breithardt, G., Hacke, W., Halperin, J. L., Hankey, G. J., Fox, K. A., Nessel, C. C., Mahaffey, K. W., Piccini, J. P., Singer, D. E., Patel, M. R. 2016; 179: 77-86

    Abstract

    We aimed to investigate the relationship between aspirin use and clinical outcomes in patients enrolled in Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), in particular, those with known coronary artery disease (CAD).Patients in ROCKET AF, comparing rivaroxaban and warfarin, were analyzed. Aspirin use was assessed at baseline. Stroke and systemic embolism, myocardial infarction, death, and major or nonmajor clinically relevant (NMCR) bleeding were compared between groups. Multivariable modeling was done adjusting for baseline risk factors.A total of 5,205 (36.5%) patients were receiving aspirin at baseline (mean dose 99.2mg); 30.6% of those had known CAD. Patients receiving aspirin were more likely to have prior myocardial infarction (22% vs 14%; P<.001) and heart failure (68% vs 59%; P<.001). Relative efficacy of rivaroxaban versus warfarin was similar with and without aspirin use for both stroke/systemic embolism (P=.95 for interaction), and major or NMCR bleeding (P=.76 for interaction). After adjustment, aspirin use was associated with similar rates of stroke/systemic embolism (hazard ratio [HR] 1.16, 95% CI 0.98-1.37; P=.094) but higher rates of all-cause death (HR 1.27, 95% CI 1.13-1.42; P<.0001) and major or NMCR bleeding (HR 1.32, 95% CI 1.21-1.43; P<.0001). There was a significant interaction between no CAD at baseline and aspirin for all-cause death (P=.009).Aspirin use at baseline was associated with an increased risk for bleeding and all-cause death in ROCKET AF, a risk most pronounced in patients without known CAD. Although these findings may reflect unmeasured clinical factors, further investigation is warranted to determine optimal aspirin use in patients with AF.

    View details for DOI 10.1016/j.ahj.2016.05.019

    View details for PubMedID 27595682

  • Use of Dual Antiplatelet Therapy and Patient Outcomes in Those Undergoing Percutaneous Coronary Intervention: The ROCKET AF Trial. JACC. Cardiovascular interventions Sherwood, M. W., Cyr, D. D., Jones, W. S., Becker, R. C., Berkowitz, S. D., Washam, J. B., Breithardt, G., Fox, K. A., Halperin, J. L., Hankey, G. J., Singer, D. E., Piccini, J. P., Nessel, C. C., Mahaffey, K. W., Patel, M. R. 2016; 9 (16): 1694-1702

    Abstract

    The authors assessed the use of dual antiplatelet therapy (DAPT) and outcomes in patients undergoing percutaneous coronary intervention (PCI) during the ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation).The frequency, patterns, and outcomes when adding DAPT to non-vitamin K antagonist oral anticoagulants in the setting of PCI in patients with AF are largely unknown.The study population included all patients in the treatment group of the ROCKET AF trial divided by the receipt of PCI during follow-up. Clinical characteristics, PCI frequency, and rates of DAPT were reported. Clinical outcomes were adjudicated independently as part of the trial.Among 14,171 patients, 153 (1.1%) underwent PCI during a median 806 days of follow-up. Patients treated with rivaroxaban were significantly less likely to undergo PCI compared with warfarin-treated patients (61 vs. 92; p = 0.01). Study drug was continued during PCI in 81% of patients. Long-term DAPT (≥30 days) was used in 37% and single antiplatelet therapy in 34%. A small number switched from DAPT to monotherapy within 30 days of PCI (n = 19 [12.3%]) and 15% of patients received no antiplatelet therapy after PCI. Rates of stroke/systemic embolism and major bleeding events were high in post-PCI patients (4.5/100 patient-years and 10.2/100 patient-years) in both treatment groups.In patients with AF at moderate to high risk for stroke, PCI occurred in <1% per year. DAPT was used in a variable manner, with the majority of patients remaining on study drug after PCI. Rates of both thrombotic and bleeding events were high after PCI, highlighting the need for studies to determine the optimal antithrombotic therapy.

    View details for DOI 10.1016/j.jcin.2016.05.039

    View details for PubMedID 27539689

  • Implications of different criteria for percutaneous coronary intervention-related myocardial infarction on study results of three large phase III clinical trials: The CHAMPION experience. European heart journal. Acute cardiovascular care Leonardi, S., Lopes, R. D., Steg, P. G., Abnousi, F., Menozzi, A., Prats, J., Mangum, S., Wilson, M., Todd, M., Stone, G. W., Gibson, C. M., Hamm, C. W., Price, M. J., White, H. D., Harrington, R. A., Bhatt, D. L., Mahaffey, K. W. 2016

    Abstract

    The purpose of this study was to test whether different results between Cangrelor versus standard therapy to acHieve optimal Management of Platelet InhibitiON (CHAMPION) PCI/PLATFORM and PHOENIX trials are due in part to different definitions of percutaneous coronary intervention (PCI)-related myocardial infarction (MI).In patients with acute coronary syndrome (ACS), the definition of MI was identical in CHAMPION PCI and PLATFORM and did not require an assessment of baseline cardiac biomarker status, while in PHOENIX specific MI criteria were associated with different patient presentations. The same MI criteria were used in PCI, PLATFORM, and PHOENIX for patients with stable angina. Logistic regression assessed the effect of cangrelor on MI (PCI- and non-PCI related) in the combined PCI/PLATFORM population and in PHOENIX. Consistency of cangrelor's effect in PCI/PLATFORM and in PHOENIX in patients with stable angina and in those with an ACS (with or without ST elevation) was evaluated. Overall, the incidence of PCI-related MI at 48 h was 6.3% in PCI/PLATFORM and 4.0% in PHOENIX. In patients with ACS, MI incidence was 6.4% in PCI/PLATFORM and 1.7% in PHOENIX, and 6.3% and 5.6%, respectively in stable angina patients. Cangrelor's effect on PCI-related MI differed between PCI/PLATFORM (odds ratio (OR) 1.03, 95% confidence interval (CI) 0.90-1.17) and PHOENIX (OR 0.80, 95% CI 0.66-0.98) with pINT=0.04. This difference was mostly evident in patients with ACS (pINT= 0.06) while the effect was consistent in patients with stable angina (pINT=0.81). Results were similar when all MIs were analyzed.The definition of PCI-related MI has important implications for event rates, treatment effect, and study results. This illustrates the importance of a rigorous assessment of PCI-related MI in clinical trials of patients with an ACS.

    View details for PubMedID 27485140

  • Blood pressure control and stroke or bleeding risk in anticoagulated patients with atrial fibrillation: Results from the ROCKET AF Trial. American heart journal Vemulapalli, S., Hellkamp, A. S., Jones, W. S., Piccini, J. P., Mahaffey, K. W., Becker, R. C., Hankey, G. J., Berkowitz, S. D., Nessel, C. C., Breithardt, G., Singer, D. E., Fox, K. A., Patel, M. R. 2016; 178: 74-84

    Abstract

    We conducted a retrospective analysis examining the association between systolic blood pressure (SBP) or hypertension bracket and stroke risk in patients with atrial fibrillation (AF).The study included 14,256 anticoagulated patients in the ROCKET AF trial. Cox proportional hazards models were used to compare the risk of adverse outcomes by European Society of Cardiology hypertension bracket and screening SBP.In total, 90.5% of patients had hypertension (55.8% controlled, 34.6% uncontrolled). The adjusted risk of stroke or systemic embolism (SE) increased significantly for every 10-mm Hg increase in screening SBP (hazard ratio [HR] 1.07, 95% CI 1.02-1.13). There was a trend toward an increased adjusted risk of stroke or SE in patients with controlled (HR 1.22, 95% CI 0.89-1.66) and uncontrolled hypertension (HR 1.42, 95% CI 1.03-1.95) (P = .06). In contrast, the adjusted risk of major bleeding was similar between hypertensive brackets and did not vary significantly by screening SBP. The benefit of rivaroxaban versus warfarin in preventing stroke or SE was consistent among patients regardless of SBP (P interaction = .69).In a trial of anticoagulated patients with AF, increasing screening SBP was independently associated with stroke and SE, and one-third of patients had uncontrolled hypertension. The relative effectiveness and safety of rivaroxaban versus warfarin were consistent across all levels of screening SBP. A single SBP may be an important factor in reducing the overall risk of stroke and SE in anticoagulated patients with AF.

    View details for DOI 10.1016/j.ahj.2016.05.001

    View details for PubMedID 27502854

  • Arterial access site and outcomes in patients undergoing percutaneous coronary intervention with and without vorapaxar. Catheterization and cardiovascular interventions Déry, J., Mahaffey, K. W., Tricoci, P., White, H. D., Podder, M., Westerhout, C. M., Moliterno, D. J., Harrington, R. A., Chen, E., Strony, J., Van de Werf, F., Ziada, K. M., Held, C., Aylward, P. E., Armstrong, P. W., Rao, S. V. 2016; 88 (2): 163-173

    Abstract

    We evaluated outcomes associated with transradial vs. transfemoral approaches and vorapaxar in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) in the TRACER trial.Vorapaxar reduces ischemic events but increases the risk of major bleeding.We compared 30-day and 2-year major adverse cardiac events (MACE: cardiovascular death, myocardial infarction, stroke, recurrent ischemia with rehospitalization, and urgent coronary revascularization) and noncoronary artery bypass graft (CABG)-related bleedings in 2,192 transradial and 4,880 transfemoral patients undergoing PCI after adjusting for confounding variables, including propensity for transradial access.Overall, 30-day GUSTO moderate/severe and non-CABG TIMI major/minor bleeding occurred less frequently in transradial (0.9% vs. 2.0%, P = 0.001) vs. transfemoral (1.1% vs. 2.5%, P = 0.005) patients. A similar reduction was seen at 2 years (3.3% vs. 4.7%, P = 0.008; 3.3% vs. 4.9%, P < 0.001, respectively). Transradial was associated with an increased risk of ischemic events at 30 days (OR 1.38, 95% CI 1.11-1.72; P = 0.004), driven primarily by increased periprocedural myocardial infarctions. At 2 years, rates of MACE were comparable (HR 1.14, 95% CI 0.98-1.33; P = 0.096). Although bleeding rates were higher with vorapaxar in transfemoral vs. transradial patients, there was no significant treatment interaction. Also, the access site did not modulate the association between vorapaxar and MACE.Transradial access was associated with lower bleeding rates and similar long-term ischemic outcomes, suggesting transradial access is safer than transfemoral access among ACS patients receiving potent antiplatelet therapies. Because of the nonrandomized allocation of arterial access, these results should be considered exploratory. © 2015 Wiley Periodicals, Inc.

    View details for DOI 10.1002/ccd.26335

    View details for PubMedID 26698636

  • Albuminuria and cardiovascular events in patients with acute coronary syndromes: Results from the TRACER trial. American heart journal Åkerblom, A., Clare, R. M., Lokhnygina, Y., Wallentin, L., Held, C., Van de Werf, F., Moliterno, D. J., Patel, U. D., Leonardi, S., Armstrong, P. W., Harrington, R. A., White, H. D., Aylward, P. E., Mahaffey, K. W., Tricoci, P. 2016; 178: 1-8

    Abstract

    Albuminuria is associated with cardiovascular (CV) outcomes. We evaluated albuminuria, alone and in combination with estimated glomerular filtration rate (eGFR), as a predictor of mortality and CV morbidity in 12,944 patients with non-ST-segment elevation acute coronary syndromes.Baseline serum creatinine and urinary dipsticks were obtained, with albuminuria stratified into no/trace albuminuria, microalbuminuria (≥30 but <300 mg/dL), or macroalbuminuria (≥300 mg/dL). Kaplan-Meier rates and proportional Cox hazards models of CV death, overall mortality, CV death or myocardial infarction (MI), and bleeding were calculated. Incidence of acute kidney injury, identified by adverse event reporting and creatinine increase (absolute ≥0.3 mg/dL or relative ≥50%), was descriptively reported.Both dipstick albuminuria and creatinine values were available in 9473 patients (73.2%). More patients with macroalbuminuria, versus no/trace albuminuria, had diabetes (66% vs 27%) or hypertension (86% vs 68%). Rates for CV death and overall mortality per strata were 3.1% and 4.8% (no/trace albuminuria); 5.8% and 9.0% (microalbuminuria); and 7.7% and 12.6% (macroalbuminuria) at 2 years of follow-up. Corresponding rates for CV death or MI were 12.2%, 16.9%, and 23.5%, respectively. Observed acute kidney injury rates were 0.6%, 1.2%, and 2.9% (n = 79), respectively. Adjusted HRs for macroalbuminuria on CV mortality were 1.65 (95% CI 1.15-2.37), and after adjustment with eGFR, 1.37 (95% CI 0.93-2.01). Corresponding HRs for overall mortality were 1.82 (95% CI 1.37-2.42) and 1.47 (95% CI 1.08-1.98).High-risk patients with non-ST-segment elevation acute coronary syndromes and albuminuria have increased morbidity and increased overall mortality independent of eGFR.

    View details for DOI 10.1016/j.ahj.2016.04.013

    View details for PubMedID 27502846

  • Effect of age on efficacy and safety of vorapaxar in patients with non-ST-segment elevation acute coronary syndrome: Insights from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial. American heart journal Armaganijan, L. V., Alexander, K. P., Huang, Z., Tricoci, P., Held, C., Van de Werf, F., Armstrong, P. W., Aylward, P. E., White, H. D., Moliterno, D. J., Wallentin, L., Chen, E., Harrington, R. A., Strony, J., Mahaffey, K. W., Lopes, R. D. 2016; 178: 176-184

    Abstract

    Antithrombotic therapy plays an important role in the treatment of non-ST-segment elevation acute coronary syndromes (NSTE ACS) but is associated with bleeding risk. Advanced age may modify the relationship between efficacy and safety.Efficacy and safety of vorapaxar (a protease-activated receptor 1 antagonist) was analyzed across ages as a continuous and a categorical variable in the 12,944 patients with NSTE ACS enrolled in the TRACER trial. To evaluate the effect of age, Cox regression models were developed to estimate hazard ratios (HRs) with the adjustment of other baseline characteristics and randomized treatment for the primary efficacy composite of cardiovascular death, myocardial infarction (MI), stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization, and the primary safety composite of moderate or severe Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) bleeding.The median age of the population was 64years (25th, 75th percentiles = 58, 71). Also, 1,791 patients (13.8%) were ≤54years of age, 4,968 (38.4%) were between 55 and 64 years, 3,979 (30.7%) were between 65 and 74 years, and 2,206 (17.1%) were 75years or older. Older patients had higher rates of hypertension, renal insufficiency, and previous stroke and worse Killip class. The oldest age group (≥75years) had substantially higher 2-year rates of the composite ischemic end point and moderate or severe GUSTO bleeding compared with the youngest age group (≤54years). The relationships between treatment assignment (vorapaxar vs placebo) and efficacy outcomes did not vary by age. For the primary efficacy end point, the HRs (95% CIs) comparing vorapaxar and placebo in the 4 age groups were as follows: 1.12 (0.88-1.43), 0.88 (0.76-1.02), 0.89 (0.76-1.04), and 0.88 (0.74-1.06), respectively (P value for interaction = .435). Similar to what was observed for efficacy outcomes, we did not observe any interaction between vorapaxar and age on bleeding outcomes. For the composite of moderate or severe bleeding according to the GUSTO classification, the HRs (95% CIs) comparing vorapaxar and placebo in the 4 age groups were 1.73 (0.89-3.34), 1.39 (1.04-1.86), 1.10 (0.85-1.42), and 1.73 (1.29-2.33), respectively (P value for interaction = .574).Older patients had a greater risk for ischemic and bleeding events; however, the efficacy and safety of vorapaxar in NSTE ACS were not significantly influenced by age.

    View details for DOI 10.1016/j.ahj.2016.05.012

    View details for PubMedID 27502866

  • Hospitalizations in patients with atrial fibrillation: an analysis from ROCKET AF. Europace DeVore, A. D., Hellkamp, A. S., Becker, R. C., Berkowitz, S. D., Breithardt, G., Hacke, W., Halperin, J. L., Hankey, G. J., Mahaffey, K. W., Nessel, C. C., Singer, D. E., Fox, K. A., Patel, M. R., Piccini, J. P. 2016; 18 (8): 1135-1142

    Abstract

    The high costs associated with treatment for atrial fibrillation (AF) are primarily due to hospital care, but there are limited data to understand the reasons for and predictors of hospitalization in patients with AF.The ROCKET AF trial compared rivaroxaban with warfarin for stroke prophylaxis in AF. We described the frequency of and reasons for hospitalization during study follow-up and utilized Cox proportional hazards models to assess for baseline characteristics associated with all-cause hospitalization. Of 14 171 patients, 14% were hospitalized at least once. Of 2614 total hospitalizations, 41% were cardiovascular including 4% for AF; of the remaining, 12% were for bleeding. Compared with patients not hospitalized, hospitalized patients were older (74 vs. 72 years), and more frequently had diabetes (46 vs. 39%), prior MI (23 vs. 16%), and paroxysmal AF (19 vs. 17%), but less frequently had prior transient ischaemic attack/stroke (49 vs. 56%). After multivariable adjustment, lung disease [hazard ratio (HR) 1.46, 95% confidence interval (CI) 1.29-1.66], diabetes [1.22, (1.11-1.34)], prior MI [1.27, (1.13-1.42)], and renal dysfunction [HR 1.07 per 5 unit GFR < 65 mL/min, (1.04-1.10)] were associated with increased hospitalization risk. Treatment assignment was not associated with differential rates of hospitalization.Nearly 1 in 7 of the moderate-to-high-risk patients with AF enrolled in this trial was hospitalized within 2 years, and both AF and bleeding were rare causes of hospitalization. Further research is needed to determine whether care pathways directed at comorbid conditions among AF patients could reduce the need for and costs associated with hospitalization.

    View details for DOI 10.1093/europace/euv404

    View details for PubMedID 27174904

    View details for PubMedCentralID PMC4974633

  • Management of Patients With NSTE-ACS A Comparison of the Recent AHA/ACC and ESC Guidelines JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Rodriguez, F., Mahaffey, K. W. 2016; 68 (3): 313-321

    Abstract

    Non-ST-segment elevation acute coronary syndromes (NSTE-ACS) are the leading cause of morbidity and mortality from cardiovascular disease worldwide. The American Heart Association/American College of Cardiology and the European Society of Cardiology periodically release practice guidelines to guide clinicians in the management of NSTE-ACS, most recently in in 2014 and 2015, respectively. The present review compares and contrasts the 2 guidelines, with a focus on the strength of recommendation and level of evidence in the approach to initial presentation and diagnosis of NSTE-ACS, risk assessment, treatments, and systems of care. Important differences include the use of a rapid rule-out protocol with high-sensitivity troponin assays, a preference for prasugrel/ticagrelor and fondaparinux for anticoagulation therapy, and a preference for radial arterial access in the European Society of Cardiology guidelines compared with the American Heart Association/American College of Cardiology guidelines. We also highlight the similarities and differences in the guidelines for special patient populations and suggest areas of further study.

    View details for DOI 10.1016/j.jacc.2016.03.599

    View details for Web of Science ID 000379518600012

    View details for PubMedID 27417010

  • Response by Piccini et al to Letters Regarding Article, "Polypharmacy and the Efficacy and Safety of Rivaroxaban Versus Warfarin in the Prevention of Stroke in Patients With Nonvalvular Atrial Fibrillation" CIRCULATION Piccini, J. P., Hellkamp, A. S., Washam, J. B., Becker, R. C., Breithardt, G., Berkowitz, S. D., Halperin, J. L., Hankey, G. J., Hacke, W., Mahaffey, K. W., Nessel, C. C., Singer, D. E., Fox, K. A., Patel, M. R. 2016; 134 (2): E7–E8

    View details for PubMedID 27400902

  • On-Treatment Outcomes in Patients With Worsening Renal Function With Rivaroxaban Compared With Warfarin Insights From ROCKET AF CIRCULATION Fordyce, C. B., Hellkamp, A. S., Lokhnygina, Y., Lindner, S. M., Piccini, J. P., Becker, R. C., Berkowitz, S. D., Breithardt, G., Fox, K. A., Mahaffey, K. W., Nessel, C. C., Singer, D. E., Patel, M. R. 2016; 134 (1): 37-?

    Abstract

    Despite rapid clinical adoption of novel anticoagulants, it is unknown whether outcomes differ among patients with worsening renal function (WRF) taking these new drugs compared with warfarin. We aimed to determine whether the primary efficacy (stroke or systemic embolism) and safety (major bleeding and nonmajor clinically relevant bleeding) end points from the ROCKET AF trial (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation trial) differed among participants with WRF taking rivaroxaban and those taking warfarin.After excluding patients without at least 1 follow-up creatinine measurement (n=1624), we included all remaining patients (n=12 612) randomly assigned to either rivaroxaban or dose-adjusted warfarin. On-treatment WRF (a decrease of >20% from screening creatinine clearance measurement at any time point during the study) was evaluated as a time-dependent covariate in Cox proportional hazards models.Baseline characteristics were generally similar between patients with stable renal function (n=9292) and WRF (n=3320). Rates of stroke or systemic embolism, myocardial infarction, and bleeding were also similar, but WRF patients experienced a higher incidence of vascular death versus stable renal function (2.21 versus 1.41 events per 100 patient-years; P=0.026). WRF patients who were randomized to receive rivaroxaban had a reduction in stroke or systemic embolism compared with those taking warfarin (1.54 versus 3.25 events per 100 patient-years) that was not seen in patients with stable renal function who were randomized to receive rivaroxaban (P=0.050 for interaction). There was no difference in major or nonmajor clinically relevant bleeding among WRF patients randomized to warfarin versus rivaroxaban.Among patients with on-treatment WRF, rivaroxaban was associated with lower rates of stroke and systemic embolism compared with warfarin, without an increase in the composite bleeding end point.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00403767.

    View details for DOI 10.1161/CIRCULATIONAHA.116.021890

    View details for Web of Science ID 000378900300008

    View details for PubMedID 27358435

  • Cinacalcet, dialysate calcium concentration, and cardiovascular events in the EVOLVE trial HEMODIALYSIS INTERNATIONAL Pun, P. H., Abdalla, S., Block, G. A., Chertow, G. M., Correa-Rotter, R., Dehmel, B., Drueke, T. B., Floege, J., Goodman, W. G., Herzog, C. A., London, G. M., Mahaffey, K. W., Moe, S. M., Parfrey, P. S., Wheeler, D. C., Middleton, J. P. 2016; 20 (3): 421-431

    Abstract

    Among patients receiving hemodialysis, abnormalities in calcium regulation have been linked to an increased risk of cardiovascular events. Cinacalcet lowers serum calcium concentrations through its effect on parathyroid hormone secretion and has been hypothesized to reduce the risk of cardiovascular events. In observational cohort studies, prescriptions of low dialysate calcium concentration and larger observed serum-dialysate calcium gradients have been associated with higher risks of in-dialysis facility or peri-dialytic sudden cardiac arrest. We performed this study to examine the risks associated with dialysate calcium and serum-dialysate gradients among participants in the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial. In EVOLVE, 3883 hemodialysis patients were randomized 1:1 to cinacalcet or placebo. Dialysate calcium was administered at the discretion of treating physicians. We examined whether baseline dialysate calcium concentration or the serum-dialysate calcium gradient modified the effect of cinacalcet on the following adjudicated endpoints: (1) primary composite endpoint (death or first non-fatal myocardial infarction, hospitalization for unstable angina, heart failure, or peripheral vascular event); (2) cardiovascular death; and (3) sudden death. In EVOLVE, use of higher dialysate calcium concentrations was more prevalent in Europe and Latin America compared with North America. There was a significant fall in serum calcium concentration in the cinacalcet group; dialysate calcium concentrations were changed infrequently in both groups. There was no association between baseline dialysate calcium concentration or serum-dialysate calcium gradient and the endpoints examined. Neither the baseline dialysate calcium nor the serum-dialysate calcium gradient significantly modified the effects of cinacalcet on the outcomes examined. The effects of cinacalcet on cardiovascular death and major cardiovascular events are not altered by the dialysate calcium prescription and serum-dialysate calcium gradient.

    View details for DOI 10.1111/hdi.12382

    View details for PubMedID 26564024

  • Native valve disease in patients with non-valvular atrial fibrillation on warfarin or rivaroxaban HEART Breithardt, G., Baumgartner, H., Berkowitz, S. D., Hellkamp, A. S., Piccini, J. P., Lokhnygina, Y., Halperin, J. L., Singer, D. E., Hankey, G. J., Hacke, W., Becker, R. C., Nessel, C. C., Mahaffey, K. W., Califf, R. M., Fox, K. A., Patel, M. R. 2016; 102 (13): 1036-1043

    Abstract

    To compare the characteristics and outcomes of patients with atrial fibrillation (AF) and aortic stenosis (AS) with patients with AF with mitral regurgitation (MR) or aortic regurgitation (AR) and patients without significant valve disease (no SVD).Using Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) data, we analysed efficacy and safety outcomes, adjusting hazard ratios (HRs) for potential confounders using Cox regression analysis.Among 14 119 intention-to-treat ROCKET AF trial patients, a trial that excluded patients with mitral stenosis or artificial valve prosthesis, 214 had AS with or without other valve abnormalities, 1726 had MR or AR and 12 179 had no SVD. After adjusting for prognostic factors, the composite of stroke, systemic embolism or vascular death increased approximately twofold in patients with AS (AS 10.84, MR or AR 4.54 and no SVD 4.31 events per 100 patient-years, p=0.0001). All-cause death also significantly increased (AS 11.22, MR or AR 4.90 and no SVD 4.39 events per 100 patient-years, p=0.0003). Major bleeding occurred more frequently in AS (adjusted HR 1.61, confidence intervals (CI) 1.03 to 2.49, p<0.05) and MR or AR (HR 1.30, 1.07 to 1.57, p<0.01) than in no SVD, but there was no difference between AS and MR or AR (HR 1.24, 0.78 to 1.97). The relative efficacy of rivaroxaban versus warfarin was consistent among patients with and without valvular disease. Rivaroxaban was associated with higher rates of major bleeding than warfarin in patients with MR or AR (HR 1.63, 1.15 to 2.31).We found that patients with AF and AS on oral anticoagulants may have distinctly different efficacy and safety outcomes than patients with MR or AR or no SVD.NCT00403767; Post-results.

    View details for DOI 10.1136/heartjnl-2015-308120

    View details for PubMedID 26888572

    View details for PubMedCentralID PMC4941167

  • Variation in Patient Profiles and Outcomes in US and Non-US Subgroups of the Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION) PHOENIX Trial CIRCULATION-CARDIOVASCULAR INTERVENTIONS Vaduganathan, M., Harrington, R. A., Stone, G. W., Steg, P. G., Gibson, C. M., Hamm, C. W., Price, M. J., Prats, J., Deliargyris, E. N., Mahaffey, K. W., White, H. D., Bhatt, D. L. 2016; 9 (6)

    Abstract

    The Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION) PHOENIX trial demonstrated superiority of cangrelor in reducing ischemic events at 48 hours in patients undergoing percutaneous coronary intervention compared with clopidogrel.We analyzed all patients included in the modified intention-to-treat analysis in US (n=4097; 37.4%) and non-US subgroups (n=6845; 62.6%). The US cohort was older, had a higher burden of cardiovascular risk factors, and had more frequently undergone prior cardiovascular procedures. US patients more frequently underwent percutaneous coronary intervention for stable angina (77.9% versus 46.2%). Almost all US patients (99.1%) received clopidogrel loading doses of 600 mg, whereas 40.5% of non-US patients received 300 mg. Bivalirudin was more frequently used in US patients (56.7% versus 2.9%). At 48 hours, rates of the primary composite end point were comparable in the US and non-US cohorts (5.5% versus 5.2%; P=0.53). Cangrelor reduced rates of the primary composite end point compared with clopidogrel in US (4.5% versus 6.4%; odds ratio 0.70 [95% confidence interval 0.53-0.92]) and in non-US patients (4.8% versus 5.6%; odds ratio 0.85 [95% confidence interval 0.69-1.05]; interaction P=0.26). Similarly, rates of the key secondary end point, stent thrombosis, were reduced by cangrelor in both regions. Rates of Global Use of Strategies to Open Occluded Arteries (GUSTO)-defined severe bleeding were low and not significantly increased by cangrelor in either region.Despite broad differences in clinical profiles and indications for percutaneous coronary intervention by region in a large global cardiovascular clinical trial, cangrelor consistently reduced rates of ischemic end points compared with clopidogrel without an excess in severe bleeding in both the US and non-US subgroups.URL: http://www.clinicaltrials.gov. Unique identifier: NCT01156571.

    View details for DOI 10.1161/CIRCINTERVENTIONS.116.003612

    View details for Web of Science ID 000378134200013

    View details for PubMedID 27313282

    View details for PubMedCentralID PMC4920208

  • Association of Body Mass Index WithCareand Outcomes in Patients WithAtrialFibrillation: Results From the ORBIT-AF Registry. JACC. Clinical electrophysiology Pandey, A., Gersh, B. J., McGuire, D. K., Shrader, P., Thomas, L., Kowey, P. R., Mahaffey, K. W., Hylek, E., Sun, S., Burton, P., Piccini, J., Peterson, E., Fonarow, G. C. 2016; 2 (3): 355–63

    Abstract

    OBJECTIVES: This study sought to determine the association between body mass index (BMI) and clinical outcomes among patients with prevalent atrial fibrillation (AF).BACKGROUND: Higher BMI is an independent risk factor for incident AF. However, its impact on management strategies and clinical outcomes among patients with prevalent AF is unclear.METHODS: Patients with AF enrolled in the ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) registry from June 2010 through August 2011 were stratified into BMI-based categories as normal weight, overweight, class I obese, class II obese, and class III obese. Unadjusted and adjusted Cox frailty models were constructed to assess the association of BMI with clinical outcomes over a 2-year follow-up.RESULTS: We evaluated 9,606 patients with AF (42% women; 78% overweight/obese) from 174 ORBIT participating practices in the United States. Higher BMI patients were younger and had a greater prevalence of diabetes, hypertension, and obstructive sleep apnea (OSA). Use of anticoagulation and rhythm control strategies was significantly greater among higher BMI patients. Rates for all-cause mortality and thromboembolic events decreased in a near linear fashion across increasing BMI categories (p< 0.001). After multivariable adjustment, higher BMI was associated with lower risk for all-cause mortality with lowest risk among class I obese patients (hazard ratio [HR]: 0.65; 95% CI: 0.54 to 0.78); reference: normal weight). For every 5-kg/m2 increase in BMI, the odds of risk-adjusted mortality were 7% lower. Incontrast, BMI was not associated with adjusted risk for thromboembolic events and AF progression.CONCLUSIONS: Although AF patients with higher BMI were significantly younger, higher BMI in AF patients was associated with similar or better clinical outcomes.

    View details for PubMedID 29766895

  • Triple vs Dual Antithrombotic Therapy in Patients with Atrial Fibrillation and Coronary Artery Disease AMERICAN JOURNAL OF MEDICINE Lopes, R. D., Rao, M., Simon, D. N., Thomas, L., Ansell, J., Fonarow, G. C., Gersh, B. J., Go, A. S., Hylek, E. M., Kowey, P., Piccini, J. P., Singer, D. E., Chang, P., Peterson, E. D., Mahaffey, K. W. 2016; 129 (6): 592-U197

    Abstract

    The role of triple antithrombotic therapy vs dual antithrombotic therapy in patients with both atrial fibrillation and coronary artery disease remains unclear. This study explores the differences in treatment practices and outcomes between triple antithrombotic therapy and dual antithrombotic therapy in patients with atrial fibrillation and coronary artery disease.Using the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (n = 10,135), we analyzed outcomes in patients with coronary artery disease (n = 1827) according to treatment with triple antithrombotic therapy (defined as concurrent therapy with an oral anticoagulant, a thienopyridine, and aspirin) or dual antithrombotic therapy (comprising either an oral anticoagulant and one antiplatelet agent [OAC plus AA] or 2 antiplatelet drugs and no anticoagulant [DAP]).The use of triple antithrombotic therapy, OAC plus AA, and DAP at baseline was 8.5% (n = 155), 80.4% (n = 1468), and 11.2% (n = 204), respectively. Among patients treated with OAC plus AA, aspirin was the most common antiplatelet agent used (90%), followed by clopidogrel (10%) and prasugrel (0.1%). The use of triple antithrombotic therapy was not affected by patient risk of either stroke or bleeding. Patients treated with triple antithrombotic therapy at baseline were hospitalized for all causes (including cardiovascular) more often than patients on OAC plus AA (adjusted hazard ratio 1.75; 95% confidence interval, 1.35-2.26; P <.0001) or DAP (hazard ratio 1.82; 95% confidence interval, 1.25-2.65; P = .0018). Rates of major bleeding or a combined cardiovascular outcome were not significantly different by treatment group.Choice of antithrombotic therapy in patients with atrial fibrillation and coronary artery disease was not affected by patient stroke or bleeding risks. Triple antithrombotic therapy-treated patients were more likely to be hospitalized for all causes than those on OAC plus AA or on DAP.

    View details for DOI 10.1016/j.amjmed.2015.12.026

    View details for Web of Science ID 000376499100030

    View details for PubMedID 26797080

  • Validation of BARC Bleeding Criteria in Patients With Acute Coronary Syndromes The TRACER Trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Vranckx, P., White, H. D., Huang, Z., Mahaffey, K. W., Armstrong, P. W., Van de Werf, F., Moliterno, D. J., Wallentin, L., Held, C., Aylward, P. E., Cornel, J. H., Bode, C., Huber, K., Nicolau, J. C., Ruzyllo, W., Harrington, R. A., Tricoci, P. 2016; 67 (18): 2135-2144

    Abstract

    The Bleeding Academic Research Consortium (BARC) scale has been proposed to standardize bleeding endpoint definitions and reporting in cardiovascular trials. Validation in large cohorts of patients is needed.This study sought to investigate the relationship between BARC-classified bleeding and mortality and compared its prognostic value against 2 validated bleeding scales: TIMI (Thrombolysis In Myocardial Infarction) and GUSTO (Global Use of Strategies to Open Occluded Arteries).We analyzed bleeding in 12,944 patients with acute coronary syndromes without ST-segment elevation, with or without early invasive strategy. The main outcome measure was all-cause death.During follow-up (median: 502 days), noncoronary artery bypass graft (CABG) bleeding occurred in 1,998 (15.4%) patients according to BARC (grades 2, 3, or 5), 484 (3.7%) patients according to TIMI minor/major, and 514 (4.0%) patients according to GUSTO moderate/severe criteria. CABG-related bleeding (BARC 4) occurred in 155 (1.2%) patients. Patients with BARC (2, 3, or 4) bleeding had a significant increase in risk of death versus patients without bleeding (BARC 0 or 1); the hazard was highest in the 30 days after bleeding (hazard ratio: 7.35; 95% confidence interval: 5.59 to 9.68; p < 0.0001) and remained significant up to 1 year. The hazard of mortality increased progressively with non-CABG BARC grades. BARC 4 bleeds were significantly associated with mortality within 30 days (hazard ratio: 10.05; 95% confidence interval: 5.41 to 18.69; p < 0.0001), but not thereafter. Inclusion of BARC (2, 3, or 4) bleeding in the 1-year mortality model with baseline characteristics improved it to an extent comparable to TIMI minor/major and GUSTO moderate/severe bleeding.In patients with acute coronary syndromes without ST-segment elevation, bleeding assessed with the BARC scale was significantly associated with risk of subsequent death up to 1 year after the event and risk of mortality increased gradually with higher BARC grades. Our results support adoption of the BARC bleeding scale in ACS clinical trials. (Trial to Assess the Effects of Vorapaxar [SCH 530348; MK-5348] in Preventing Heart Attack and Stroke in Participants With Acute Coronary Syndrome [TRACER] [Study P04736]; NCT00527943).

    View details for DOI 10.1016/j.jacc.2016.02.056

    View details for Web of Science ID 000375406100007

    View details for PubMedID 27151345

  • Lack of Concordance Between Local Investigators, Angiographic Core Laboratory, and Clinical Event Committee in the Assessment of Stent Thrombosis Results From the TRACER Angiographic Substudy CIRCULATION-CARDIOVASCULAR INTERVENTIONS Popma, C. J., Sheng, S., Korjian, S., Daaboul, Y., Chi, G., Tricoci, P., Huang, Z., Moliterno, D. J., White, H. D., Van de Werf, F., Harrington, R. A., Wallentin, L., Held, C., Armstrong, P. W., Aylward, P. E., Strony, J., Mahaffey, K. W., Gibson, C. M. 2016; 9 (5)

    Abstract

    Stent thrombosis (ST) is an important end point in cardiovascular clinical trials. Adjudication is traditionally based on clinical event committee (CEC) review of case report forms and source documentation rather than angiograms. However, the degree to which this method of adjudication is concordant with the review of independent angiographic core laboratories (ACLs) has not been studied. This report represents the first assessment of variability between local investigators (LIs), a CEC, and an ACL.Serial angiograms of 329 patients with acute coronary syndrome without ST-segment-elevation who underwent percutaneous coronary intervention at entry in the Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Particpants With Acute Coronary Syndrome (TRACER) and who met criteria for possible ST subsequent to the index event were reviewed by an ACL. The ACL was blinded to the assessment by both LIs and the CEC regarding the presence or absence of ST. CEC adjudication was based on Academic Research Consortium definitions of ST, using case report form data and source documents, including catheterization laboratory reports. The ACL, CEC, and LIs agreed on the presence or absence of ST in 52.9% events (κ=0.32; 95% confidence interval, 0.26-0.39). The ACL and CEC agreed on 82.7% of events (κ=0.57; 95% confidence interval, 0.47-0.67); the ACL and LIs agreed on 61.1% of events (κ=0.25; 95% confidence interval, 0.16-0.34); and the CEC and LIs agreed on 62% of events (κ=0.28; 95% confidence interval, 0.21-0.36).ST reporting by an ACL, a CEC, and LIs is discordant. The assessment of ST is more often detected by direct review of angiograms by an ACL.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00527943.

    View details for DOI 10.1161/CIRCINTERVENTIONS.115.003114

    View details for Web of Science ID 000376742000002

    View details for PubMedID 27162212

  • Clinical Characteristics, Oral Anticoagulation Patterns, and Outcomes of Medicaid Patients With Atrial Fibrillation: Insights From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF I) Registry. Journal of the American Heart Association O'Brien, E. C., Kim, S., Thomas, L., Fonarow, G. C., Kowey, P. R., Mahaffey, K. W., Gersh, B. J., Piccini, J. P., Peterson, E. D. 2016; 5 (5)

    Abstract

    Whereas insurance status has been previously associated with care patterns, little is currently known about the association between Medicaid insurance and the clinical characteristics, treatment, or outcomes of patients with atrial fibrillation (AF).We used data from adults with AF enrolled in the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF), a national outpatient registry conducted at 176 community, multispecialty sites. The primary outcome of interest was the proportion of patients prescribed any oral anticoagulation (OAC; warfarin or novel oral anticoagulants [NOAC]). Secondary outcomes of interest included the proportion of patients prescribed NOACs (dabigatran or rivaroxaban); time in therapeutic range (TTR) for warfarin users, all-cause mortality, stroke/systemic embolism, and major bleed. Of 10 133 patients, N=470 (4.6%) had Medicaid insurance. Medicaid patients were similarly likely to receive OAC at baseline (72.8% vs 76.3%; unadjusted P=0.079), but less likely to receive NOAC at baseline or follow-up (12.1% vs 16.3%; unadjusted P=0.019). After risk adjustment, Medicaid status was associated with lower use of OAC at baseline among patients with high stroke risk (odds ratio [OR]=0.68; 95% CI=0.49, 0.94), but was not associated with OAC use overall (OR=0.82; 95% CI=0.61, 1.09). Among warfarin users, median TTR was lower among Medicaid patients (60% vs 68%; P<0.0001; adjusted TTR difference, -2.9; 95% CI=-5.7, -0.2; P=0.04). Use of an NOAC over 2 years of follow-up was not statistically different by insurance. Compared with non-Medicaid patients, Medicaid patients had higher unadjusted rates of mortality, stroke/systemic embolism, and major bleeding; however, these differences were attenuated following adjustment for clinical characteristics.In a contemporary AF cohort, use of OAC overall and use of NOACs were not significantly lower among Medicaid patients relative to others. However, among warfarin users, Medicaid patients spent less time in therapeutic range compared with those with other forms of insurance.

    View details for DOI 10.1161/JAHA.115.002721

    View details for PubMedID 27146448

    View details for PubMedCentralID PMC4889165

  • North American Thrombosis Forum, AF Action Initiative Consensus Document AMERICAN JOURNAL OF MEDICINE Ruff, C. T., Ansell, J. E., Becker, R. C., Benjamin, E. J., Deicicchi, D. J., Estes, N. A., Ezekowitz, M. D., Fanikos, J., Fareed, J., Garcia, D., Giugliano, R. P., Goldhaber, S. Z., Granger, C., Healey, J. S., Hull, R., Hylek, E. M., Libby, P., Lopes, R. D., Mahaffey, K. W., Mega, J., Piazza, G., Sasahara, A. A., Sorond, F. A., Spyropoulos, A. C., Walenga, J. M., Weitz, J. I. 2016; 129 (5): S1-S29

    Abstract

    The North American Thrombosis Forum Atrial Fibrillation Action Initiative consensus document is a comprehensive yet practical briefing document focusing on stroke and bleeding risk assessment in patients with atrial fibrillation, as well as recommendations regarding anticoagulation options and management. Despite the breadth of clinical trial data and guideline recommendation updates, many clinicians continue to struggle to synthesize the disparate information available. This problem slows the uptake and utilization of updated risk prediction tools and adoption of new oral anticoagulants. This document serves as a practical and educational reference for the entire medical community involved in the care of patients with atrial fibrillation.

    View details for DOI 10.1016/j.amjmed.2016.02.001

    View details for PubMedID 27126598

  • Design and rationale for the Effects of Ticagrelor and Clopidogrel in Patients with Peripheral Artery Disease (EUCLID) trial AMERICAN HEART JOURNAL Berger, J. S., Katona, B. G., Jones, W. S., Patel, M. R., Norgren, L., Baumgartner, I., Blomster, J., Mahaffey, K. W., Held, P., Millegard, M., Heizer, G., Reist, C., Fowkes, F. G., Hiatt, W. R. 2016; 175: 86-93

    Abstract

    Despite overwhelming data demonstrating the efficacy of antiplatelet therapy in heart disease and stroke, data in peripheral artery disease (PAD) are less compelling. Aspirin has modest evidence supporting a reduction in cardiovascular events in patients with PAD, whereas clopidogrel monotherapy may be more effective in PAD. Ticagrelor, a potent, reversibly binding P2Y12 receptor antagonist, is beneficial in patients with acute coronary syndrome and prior myocardial infarction. The EUCLID trial is designed to address the need for effective antiplatelet therapy in PAD to decrease the risk of cardiovascular events.EUCLID is a randomized, double-blind, parallel-group, multinational clinical trial designed to evaluate the efficacy and safety of ticagrelor compared with clopidogrel for the prevention of major adverse cardiovascular events in subjects with symptomatic PAD. Subjects with established PAD will be randomized in a 1:1 fashion to ticagrelor 90 mg twice daily or clopidogrel 75 mg daily. The primary end point is a composite of cardiovascular death, myocardial infarction, or ischemic stroke. Other end points address limb events including acute leg ischemia, need for revascularization, disease progression by ankle-brachial index, and quality of life. The primary safety objective is Thrombolysis in Myocardial Infarction-defined major bleeding. Recruitment began in December 2012 and was completed in March 2014; 13,887 patients were randomized. The trial will continue until at least 1,364 adjudicated primary end points occur.The EUCLID study is investigating whether treatment with ticagrelor versus clopidogrel, given as antiplatelet monotherapy, will reduce the incidence of cardiovascular and limb-specific events in patients with symptomatic PAD.

    View details for DOI 10.1016/j.ahj.2016.01.018

    View details for Web of Science ID 000375655200011

    View details for PubMedID 27179727

  • Family history of atrial fibrillation is associated with earlier-onset and more symptomatic atrial fibrillation: Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry AMERICAN HEART JOURNAL Gundlund, A., Fosbol, E. L., Kim, S., Fonarow, G. C., Gersh, B. J., Kowey, P. R., Hylek, E., Mahaffey, K. W., Thomas, L., Piccini, J. P., Peterson, E. D. 2016; 175: 28-35

    Abstract

    We addressed whether patients with a family history of atrial fibrillation (AF) were diagnosed as having AF earlier in life, were more symptomatic, and had worse outcomes compared with those without a family history of AF.Using the ORBIT-AF, we compared symptoms and disease characteristics in those with and without a family history of AF. A family history of AF was defined as AF in a first-degree family member and obtained by patient self-reporting. Multivariable Cox proportional hazard analyses were performed to compare the incidence of cardiovascular outcomes, AF progression, all-cause hospitalization, and all-cause death.Among 9,999 patients with AF from 176 US outpatient clinics, 1,481 (14.8%) had a family history of AF. Relative to those without, those with a family history of AF developed AF 5 years earlier on average (median age 65 vs 70 years, P < .01), with less comorbidity, and had more severe AF-related symptoms. No differences were found between the 2 groups in the risk of AF progression (adjusted hazard ratio [HR] 0.98, 95% CI 0.85-1.14), stroke, non-central nervous system embolism, or transient ischemic attack (adjusted HR 0.95, 95% CI 0.67-1.34), all-cause hospitalization (adjusted HR 1.03, 95% CI 0.94-1.12), and all-cause death (adjusted HR 1.05, 95% CI 0.86-1.27).Patients with a family history of AF developed AF at a younger age, had less comorbidity, and were more symptomatic. Once AF developed, no significantly increased risks of AF progression and thromboembolism were associated with a family history of AF compared with no family history.

    View details for DOI 10.1016/j.ahj.2016.01.020

    View details for Web of Science ID 000375655200005

    View details for PubMedID 27179721

  • Trends in Enrollment, Clinical Characteristics, Treatment, and Outcomes According to Age in Non-ST-Segment-Elevation Acute Coronary Syndromes Clinical Trials CIRCULATION Kragholm, K., Goldstein, S. A., Yang, Q., Lopes, R. D., Schulte, P. J., Bernacki, G. M., White, H. D., Mahaffey, K. W., Giugliano, R. P., Armstrong, P. W., Harrington, R. A., Tricoci, P., Van de Werf, F., Alexander, J. H., Alexander, K. P., Newby, L. K. 2016; 133 (16): 1560-?

    Abstract

    Representation by age ensures appropriate translation of clinical trial results to practice, but, historically, older patients have been underrepresented in clinical trial populations. As the general population has aged, it is unknown whether clinical trial enrollment has changed in parallel.We studied time trends in enrollment, clinical characteristics, treatment, and outcomes by age among 76 141 patients with non-ST-segment-elevation acute coronary syndrome enrolled in 11 phase III clinical trials over 17 years (1994-2010). Overall, 19.7% of patients were ≥75 years; this proportion increased from 16% during 1994 to 1997 to 21% during 1998 to 2001 and 23.2% during 2002 to 2005, but declined to 20.2% in 2006 to 2010. The number of comorbidities increased with successive time periods irrespective of age. There were substantial increases in the use of evidence-based medication in-hospital and at discharge regardless of age. Although predicted 6-month mortality increased slightly over time, observed 6-month mortality declined significantly in all age strata (1994-1997 versus 2006-2010: <65 years: 3.0% versus 1.9%; 65-74 years: 7.5% versus 3.4%; 75-79 years: 13.0% versus 6.5%; 80-84 years: 17.6% versus 8.2%; and ≥85 years: 24.8% versus 12.6%).The distribution of enrollment by age in phase III non-ST-segment-elevation acute coronary syndrome trials was unchanged over time. Irrespective of age, post-myocardial infarction mortality decreased significantly over time, concurrent with increased evidence-based care and despite increasing comorbidities.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00089895.

    View details for DOI 10.1161/CIRCULATIONAHA.115.017299

    View details for Web of Science ID 000374553400011

    View details for PubMedID 26957532

    View details for PubMedCentralID PMC4856566

  • The effect of cangrelor and access site on ischaemic and bleeding events: insights from CHAMPION PHOENIX EUROPEAN HEART JOURNAL Gutierrez, J. A., Harrington, R. A., Blankenship, J. C., Stone, G. W., Steg, P. G., Gibson, C. M., Hamm, C. W., Price, M. J., Genereux, P., Prats, J., Deliargyris, E. N., Mahaffey, K., White, H. D., Bhatt, D. L. 2016; 37 (14): 1122-1130

    Abstract

    To assess whether the use of the femoral or radial approach for percutaneous coronary intervention (PCI) interacted with the efficacy and safety of cangrelor, an intravenous P2Y12 inhibitor, in CHAMPION PHOENIX.A total of 11 145 patients were randomly assigned in a double-dummy, double-blind manner either to a cangrelor bolus and 2-h infusion or to clopidogrel at the time of PCI. The primary endpoint, a composite of death, myocardial infarction, ischaemia-driven revascularization, or stent thrombosis, and the primary safety endpoint, Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) defined severe bleeding, were evaluated at 48 h. Of the patients undergoing PCI and receiving study drug treatment, a total of 8064 (74%) and 2855 (26%) patients underwent femoral or radial PCI, respectively. Among the femoral cohort, the primary endpoint rate was 4.8% with cangrelor vs. 6.0% with clopidogrel (odds ratio, OR [95% confidence interval, CI] = 0.79 [0.65-0.96]); among the radial cohort, the primary endpoint was 4.4% with cangrelor vs. 5.7% with clopidogrel (OR [95% CI] = 0.76 [0.54-1.06]), P-interaction 0.83. The rate of GUSTO severe bleeding in the femoral cohort was 0.2% with cangrelor vs. 0.1% with clopidogrel (OR [95% CI] = 1.73 [0.51-5.93]). Among the radial cohort, the rate of GUSTO severe bleeding was 0.1% with cangrelor vs. 0.1% with clopidogrel (OR [95% CI] = 1.02 [0.14-7.28]), P-interaction 0.65. The evaluation of safety endpoints with the more sensitive ACUITY-defined bleeding found major bleeding in the femoral cohort to be 5.2% with cangrelor vs. 3.1% with clopidogrel (OR [95% CI] = 1.69 [1.35-2.12]); among the radial cohort the rate of ACUITY major bleeding was 1.5% with cangrelor vs. 0.7% with clopidogrel (OR [95% CI] = 2.17 [1.02-4.62], P-interaction 0.54).In CHAMPION PHOENIX, cangrelor reduced ischaemic events with no significant increase in GUSTO-defined severe bleeding. The absolute rates of bleeding, regardless of the definition, tended to be lower when PCI was performed via the radial artery.http://www.clinicaltrials.gov identifier: NCT01156571.

    View details for DOI 10.1093/eurheartj/ehv498

    View details for Web of Science ID 000373558500011

    View details for PubMedID 26400827

    View details for PubMedCentralID PMC4823635

  • THE EFFICACY AND SAFETY OF CANGRELOR WITH AND WITHOUT GLYCOPROTEIN IIB/IIIA INHIBITORS IN PATIENTS UNDERGOING PERCUTANEOUS CORONARY INTERVENTION: A POOLED ANALYSIS OF THE CHAMPION TRIALS Vaduganathan, M., Harrington, R., Stone, G., Steg, P., Gibson, C., Hamm, C., Price, M., Menozzi, A., Prats, J., Deliargyris, E., Mahaffey, K., White, H., Bhatt, D. ELSEVIER SCIENCE INC. 2016: 452
  • Racial/ethnic differences in atrial fibrillation symptoms, treatment patterns, and outcomes: Insights from Outcomes Registry for Better Informed Treatment for Atrial Fibrillation Registry AMERICAN HEART JOURNAL Golwala, H., Jackson, L. R., Simon, D. N., Piccini, J. P., Gersh, B., Go, A. S., Hylek, E. M., Kowey, P. R., Mahaffey, K. W., Thomas, L., Fonarow, G. C., Peterson, E. D., Thomas, K. L. 2016; 174: 29-36

    Abstract

    Significant racial/ethnic differences exist in the incidence of atrial fibrillation (AF). However, less is known about racial/ethnic differences in quality of life (QoL), treatment, and outcomes associated with AF.Using data from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation, we compared clinical characteristics, QoL, management strategies, and long-term outcomes associated with AF among various racial/ethnic groups.We analyzed 9,542 participants with AF (mean age 74 ± 11 years, 43% women, 91% white, 5% black, 4% Hispanic) from 174 centers. Compared with AF patients identified as white race, patients identified as Hispanic ethnicity and those identified as black race were younger, were more often women, and had more cardiac and noncardiac comorbidities. Black patients were more symptomatic with worse QoL and were less likely to be treated with a rhythm control strategy than other racial/ethnic groups. There were no significant racial/ethnic differences in CHA2DS2-VASc stroke or ATRIA bleeding risk scores and rates of oral anticoagulation use were similar. However, racial and ethnic minority populations treated with warfarin spent a lower median time in therapeutic range of international normalized ratio (59% blacks vs 68% whites vs 62% Hispanics, P < .0001). There was no difference in long-term outcomes associated with AF between the 3 groups at a median follow-up of 2.1 years.Relative to white and Hispanic patients, black patients with AF had more symptoms, were less likely to receive rhythm control interventions, and had lower quality of warfarin management. Despite these differences, clinical events at 2 years were similar by race and ethnicity.

    View details for DOI 10.1016/j.ahj.2015.10.028

    View details for Web of Science ID 000372538500007

  • Rhythm Control Versus Rate Control andClinical Outcomes in Patients WithAtrial Fibrillation: Results From the ORBIT-AF Registry. JACC. Clinical electrophysiology Noheria, A., Shrader, P., Piccini, J. P., Fonarow, G. C., Kowey, P. R., Mahaffey, K. W., Naccarelli, G., Noseworthy, P. A., Reiffel, J. A., Steinberg, B. A., Thomas, L. E., Peterson, E. D., Gersh, B. J., ORBIT-AF Investigators and Patients 2016; 2 (2): 221–29

    Abstract

    OBJECTIVES: The study sought to evaluate clinical outcomes in clinical practice with rhythm control versus rate control strategy for management of atrial fibrillation (AF).BACKGROUND: Randomized trials have not demonstrated significant differences in stroke, heart failure, or mortality between rhythm and rate control strategies. The comparative outcomes in contemporary clinical practice are not well described.METHODS: Patients managed with a rhythm control strategy targeting maintenance of sinus rhythm were retrospectively compared with a strategy of rate control alone in a AF registry across various U.S. practice settings. Unadjusted and adjusted (inverse-propensity weighted) outcomes were estimated.RESULTS: The overall study population (N= 6,988) had a median of 74 (65 to 81) years of age, 56% were males, 77% had first detected or paroxysmal AF, and 68% had CHADS2 score≥2. In unadjusted analyses, rhythm control was associated with lower all-cause death, cardiovascular death, first stroke/non-central nervous system systemic embolization/transient ischemic attack, or first major bleeding event (all p< 0.05); no difference in new onset heart failure (p=0.28); and more frequent cardiovascular hospitalizations (p= 0.0006). There was no difference in the incidence of pacemaker, defibrillator, or cardiac resynchronization device implantations (p= 0.99). In adjusted analyses, there were no statistical differences in clinical outcomes between rhythm control and rate control treated patients (all p > 0.05); however, rhythm control was associated with more cardiovascular hospitalizations (hazard ratio: 1.24; 95% confidence interval: 1.10 to 1.39; p= 0.0003).CONCLUSIONS: Among patients with AF, rhythm control was not superior to rate control strategy for outcomes of stroke, heart failure, or mortality, but was associated with more cardiovascular hospitalizations.

    View details for PubMedID 29766874

  • Sudden Cardiac Death After Non-ST-Segment Elevation Acute Coronary Syndrome. JAMA cardiology Hess, P. L., Wojdyla, D. M., Al-Khatib, S. M., Lokhnygina, Y., Wallentin, L., Armstrong, P. W., Roe, M. T., Ohman, E. M., Harrington, R. A., Alexander, J. H., White, H. D., Van de Werf, F., Piccini, J. P., Held, C., Aylward, P. E., Moliterno, D. J., Mahaffey, K. W., Tricoci, P. 2016; 1 (1): 73-79

    Abstract

    In the current therapeutic era, the risk for sudden cardiac death (SCD) after non-ST-segment elevation acute coronary syndrome (NSTE ACS) has not been characterized completely.To determine the cumulative incidence of SCD during long-term follow-up after NSTE ACS, to develop a risk model and risk score for SCD after NSTE ACS, and to assess the association between recurrent events after the initial ACS presentation and the risk for SCD.This pooled cohort analysis merged individual data from 48 286 participants in 4 trials: the Apixaban for Prevention of Acute Ischemic Events 2 (APPRAISE-2), Study of Platelet Inhibition and Patient Outcomes (PLATO), Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER), and Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trials. The cumulative incidence of SCD and cardiovascular death was examined according to time after NSTE ACS. Using competing risk and Cox proportional hazards models, clinical factors at baseline and after the index event that were associated with SCD after NSTE ACS were identified. Baseline factors were used to develop a risk model. Data were analyzed from January 2, 2014, to December 11, 2015.Sudden cardiac death.Of the initial 48 286 patients, 37 555 patients were enrolled after NSTE ACS (67.4% men; 32.6% women; median [interquartile range] age, 65 [57-72] years). Among these, 2109 deaths occurred after a median follow-up of 12.1 months. Of 1640 cardiovascular deaths, 513 (31.3%) were SCD. At 6, 18, and 30 months, the cumulative incidence estimates of SCD were 0.79%, 1.65%, and 2.37%, respectively. Reduced left ventricular ejection fraction, older age, diabetes mellitus, lower estimated glomerular filtration rate, higher heart rate, prior myocardial infarction, peripheral artery disease, Asian race, male sex, and high Killip class were significantly associated with SCD. A model developed to calculate the risk for SCD in trials with systematic collection of left ventricular ejection fraction had a C index of 0.77. An integer-based score was developed from this model and yielded a calculated SCD probability ranging from 0.1% to 56.7% (C statistic, 0.75). In a multivariable model that included time-dependent clinical events occurring after the index hospitalization for ACS, SCD was associated with recurrent myocardial infarction (hazard ratio [HR], 2.95; 95% CI, 2.29-3.80; P < .001) and any hospitalization (HR, 2.45; 95% CI, 1.98-3.03; P < .001), whereas coronary revascularization had a negative relationship with SCD (HR, 0.75; 95% CI, 0.58-0.98; P = .03).In the current therapeutic era, SCD accounts for about one-third of cardiovascular deaths after NSTE ACS. Risk stratification can be performed with good accuracy using commonly collected clinical variables. Clinical events occurring after the index hospitalization are underappreciated but important risk factors.

    View details for DOI 10.1001/jamacardio.2015.0359

    View details for PubMedID 27437658

  • Racial/ethnic differences in atrial fibrillation symptoms, treatment patterns, and outcomes: Insights from Outcomes Registry for Better Informed Treatment for Atrial Fibrillation Registry. American heart journal Golwala, H., Jackson, L. R., Simon, D. N., Piccini, J. P., Gersh, B., Go, A. S., Hylek, E. M., Kowey, P. R., Mahaffey, K. W., Thomas, L., Fonarow, G. C., Peterson, E. D., Thomas, K. L. 2016; 174: 29-36

    Abstract

    Significant racial/ethnic differences exist in the incidence of atrial fibrillation (AF). However, less is known about racial/ethnic differences in quality of life (QoL), treatment, and outcomes associated with AF.Using data from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation, we compared clinical characteristics, QoL, management strategies, and long-term outcomes associated with AF among various racial/ethnic groups.We analyzed 9,542 participants with AF (mean age 74 ± 11 years, 43% women, 91% white, 5% black, 4% Hispanic) from 174 centers. Compared with AF patients identified as white race, patients identified as Hispanic ethnicity and those identified as black race were younger, were more often women, and had more cardiac and noncardiac comorbidities. Black patients were more symptomatic with worse QoL and were less likely to be treated with a rhythm control strategy than other racial/ethnic groups. There were no significant racial/ethnic differences in CHA2DS2-VASc stroke or ATRIA bleeding risk scores and rates of oral anticoagulation use were similar. However, racial and ethnic minority populations treated with warfarin spent a lower median time in therapeutic range of international normalized ratio (59% blacks vs 68% whites vs 62% Hispanics, P < .0001). There was no difference in long-term outcomes associated with AF between the 3 groups at a median follow-up of 2.1 years.Relative to white and Hispanic patients, black patients with AF had more symptoms, were less likely to receive rhythm control interventions, and had lower quality of warfarin management. Despite these differences, clinical events at 2 years were similar by race and ethnicity.

    View details for DOI 10.1016/j.ahj.2015.10.028

    View details for PubMedID 26995367

  • Pooled analysis of adverse event collection from 4 acute coronary syndrome trials. American heart journal Zimerman, A., Lopes, R. D., Stebbins, A. L., Guimarães, P. O., Haque, G., Melloni, C., Trollinger, K., James, S. K., Alexander, J. H., Tricoci, P., Roe, M. T., Ohman, E. M., Mahaffey, K. W., Held, C., Tinga, B., Pieper, K. S., Alexander, K. P. 2016; 174: 60-67

    Abstract

    Adverse event collection in randomized clinical trials establishes drug safety. Although costly and regulated, it is rarely studied.Adverse event data from 4 clinical trials (APPRAISE-2, PLATO, TRACER, TRILOGY ACS) comprising 48,118 participants with acute coronary syndromes were pooled to compare patterns and determinants of reporting. Events were classified as serious (SAE) or nonserious (AE) from hospital discharge to 1 year; study end points were excluded.In total, 84,901 events were reported. Of those, 12,266 (14.4%) were SAEs and 72,635 (85.6%) were AEs. Of all participants, 7,823 (16.3%) had SAEs, 18,124 (37.7%) had only AEs, and 22,171 (46.1%) had neither. Nonserious adverse events were distributed across system organ classes: general disorders (11%), infection (10%), gastrointestinal (10%), respiratory (9%), cardiovascular (8.4%), and other (35%). Serious adverse events had a higher proportion of cardiovascular causes (14.0%). Event reporting was highest after hospital discharge, decreasing rapidly during the following 3 months. In a Cox proportional hazards model, chronic obstructive pulmonary disease (hazard ratio 1.58, 95% CI 1.44-1.74), heart failure (1.55, 1.40-1.70), older age, and female sex were independent predictors of more SAEs, whereas enrollment in Eastern Europe (0.63, 0.58-0.69) or Asia (0.84, 0.75-0.94) were independent predictors of fewer SAEs.Half of all participants reported adverse events in the year after acute coronary syndrome; most were AEs and occurred within 3 months. The high volume of events, as well as the variation in SAE reporting by characteristics and enrollment region, indicates that efforts to refine event collection in large trials are warranted.

    View details for DOI 10.1016/j.ahj.2016.01.003

    View details for PubMedID 26995371

  • Pooled analysis of adverse event collection from 4 acute coronary syndrome trials AMERICAN HEART JOURNAL Zimerman, A., Lopes, R. D., Stebbins, A. L., Guimaraes, P. O., Haque, G., Melloni, C., Trollinger, K., James, S. K., Alexander, J. H., Tricoci, P., Roe, M. T., Ohman, E. M., Mahaffey, K. W., Held, C., Tinga, B., Pieper, K. S., Alexander, K. P. 2016; 174: 60-67

    Abstract

    Adverse event collection in randomized clinical trials establishes drug safety. Although costly and regulated, it is rarely studied.Adverse event data from 4 clinical trials (APPRAISE-2, PLATO, TRACER, TRILOGY ACS) comprising 48,118 participants with acute coronary syndromes were pooled to compare patterns and determinants of reporting. Events were classified as serious (SAE) or nonserious (AE) from hospital discharge to 1 year; study end points were excluded.In total, 84,901 events were reported. Of those, 12,266 (14.4%) were SAEs and 72,635 (85.6%) were AEs. Of all participants, 7,823 (16.3%) had SAEs, 18,124 (37.7%) had only AEs, and 22,171 (46.1%) had neither. Nonserious adverse events were distributed across system organ classes: general disorders (11%), infection (10%), gastrointestinal (10%), respiratory (9%), cardiovascular (8.4%), and other (35%). Serious adverse events had a higher proportion of cardiovascular causes (14.0%). Event reporting was highest after hospital discharge, decreasing rapidly during the following 3 months. In a Cox proportional hazards model, chronic obstructive pulmonary disease (hazard ratio 1.58, 95% CI 1.44-1.74), heart failure (1.55, 1.40-1.70), older age, and female sex were independent predictors of more SAEs, whereas enrollment in Eastern Europe (0.63, 0.58-0.69) or Asia (0.84, 0.75-0.94) were independent predictors of fewer SAEs.Half of all participants reported adverse events in the year after acute coronary syndrome; most were AEs and occurred within 3 months. The high volume of events, as well as the variation in SAE reporting by characteristics and enrollment region, indicates that efforts to refine event collection in large trials are warranted.

    View details for DOI 10.1016/j.ahj.2016.01.003

    View details for Web of Science ID 000372538500011

  • Lessons Learned from EVOLVE for Planning of Future Randomized Trials in Patients on Dialysis CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Parfrey, P. S., Block, G. A., Correa-Rotter, R., Drueeke, T. B., Floege, J., Herzog, C. A., London, G. M., Mahaffey, K. W., Moe, S. M., Wheeler, D. C., Chertow, G. M. 2016; 11 (3): 539-546

    Abstract

    The effect of the calcimimetic cinacalcet on cardiovascular disease in patients undergoing hemodialysis with secondary hyperparathyroidism was assessed in the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events trial. This was the largest (in size) and longest (in duration) randomized controlled clinical trial undertaken in this population. During planning, execution, analysis, and reporting of the trial, many lessons were learned, including those related to the use of a composite cardiovascular primary endpoint, definition of endpoints (particularly heart failure and severe unremitting hyperparathyroidism), importance of age for optimal stratification at randomization, use of unadjusted and adjusted intention-to-treat analysis for the primary outcome, how to respond to a lower-than-predicted event rate during the trial, development of a prespecified analytic plan that accounted for nonadherence and for cointerventions that diminished the power of the trial to observe a treatment effect, determination of the credibility of a subgroup effect, use of adverse effects database to investigate rare diseases, collection of blood for biomarker measurement not designated before trial initiation, and interpretation of the benefits-to-harms ratio for individual patients. It is likely that many of these issues will arise in the planning of future trials in CKD.

    View details for DOI 10.2215/CJN.06370615

    View details for Web of Science ID 000371453100023

    View details for PubMedID 26614406

  • The effects of cinacalcet on blood pressure, mortality and cardiovascular endpoints in the EVOLVE trial JOURNAL OF HUMAN HYPERTENSION Chang, T. I., AbdAlla, S., London, G. M., Block, G. A., Correa-Rotter, R., Drueeke, T. B., Floege, J., Herzog, C. A., Mahaffey, K. W., Moe, S. M., Parfrey, P. S., Wheeler, D. C., Dehmel, B., Goodman, W. G., Chertow, G. M. 2016; 30 (3): 204-209

    Abstract

    Patients with end-stage renal disease often have derangements in calcium and phosphorus homeostasis and resultant secondary hyperparathyroidism (sHPT), which may contribute to the high prevalence of arterial stiffness and hypertension. We conducted a secondary analysis of the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial, in which patients receiving hemodialysis with sHPT were randomly assigned to receive cinacalcet or placebo. We sought to examine whether the effect of cinacalcet on death and major cardiovascular events was modified by baseline pulse pressure as a marker of arterial stiffness, and whether cinacalcet yielded any effects on blood pressure. As reported previously, an unadjusted intention-to-treat analysis failed to conclude that randomization to cinacalcet reduces the risk of the primary composite end point (all-cause mortality or non-fatal myocardial infarction, heart failure, hospitalization for unstable angina or peripheral vascular event). However, after prespecified adjustment for baseline characteristics, patients randomized to cinacalcet experienced a nominally significant 13% lower adjusted risk (95% confidence limit 4-20%) of the primary composite end point. The effect of cinacalcet was not modified by baseline pulse pressure (Pinteraction=0.44). In adjusted models, at 20 weeks cinacalcet resulted in a 2.2 mm Hg larger average decrease in systolic blood pressure (P=0.002) and a 1.3 mm Hg larger average decrease in diastolic blood pressure (P=0.002) compared with placebo. In summary, in the EVOLVE trial, the effect of cinacalcet on death and major cardiovascular events was independent of baseline pulse pressure.

    View details for DOI 10.1038/jhh.2015.56

    View details for PubMedID 26040438

  • Use of thienopyridine prior to presentation with non-ST-segment elevation acute coronary syndrome and association with safety and efficacy of vorapaxar: insights from the TRACER trial. European heart journal. Acute cardiovascular care Harskamp, R. E., Clare, R. M., Ambrosio, G., Held, C., Lokhnygina, Y., Moliterno, D. J., White, H. D., Aylward, P. E., Armstrong, P. W., Mahaffey, K. W., Harrington, R. A., Van de Werf, F., Wallentin, L., Strony, J., Tricoci, P. 2016

    Abstract

    Vorapaxar is effective in the prevention of secondary atherothrombotic events, although the efficacy/safety balance appears less favorable in the treatment of patients with non-ST-segment elevation (NSTE) acute coronary syndrome (ACS). We hypothesized that patients with NSTE ACS already receiving thienopyridine prior to the ACS event may show differential efficacy/safety effects with vorapaxar vs. placebo added to their standard care.We studied 12,944 patients from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial with respect to thienopyridine use before admission for the index NSTE ACS event. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, rehospitalization for ischemia, and urgent revascularization. The key secondary endpoint was a composite of cardiovascular death, myocardial infarction, and stroke. Safety endpoints were bleeding complications.Only 1513 patients (11.7%) were receiving thienopyridine before admission for the index NSTE ACS event. In these patients, Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) moderate/severe bleeding occurred in 5.7% treated with vorapaxar and 5.3% treated with a placebo (hazards ratio (HR) 1.10, 95% confidence interval (CI) 0.70-1.71); in thienopyridine-naïve patients, the rates were 5.7% and 4.1%, respectively (HR 1.32, 95% CI 1.11-1.57; Pint=0.45). GUSTO severe bleeding in the prior thienopyridine group occurred in 0.5% of patients treated with vorapaxar and 1.3% of patients treated with placebo (HR 0.34, 95% CI 0.09-1.30); in thienopyridine-naïve patients, the rates were 2.0% and 1.0%, respectively (HR 1.89, 95% CI 1.36-2.62; Pint=0.01). No interaction was observed between vorapaxar efficacy and prior thienopyridine use on the primary (adjusted Pint=0.53) or key secondary endpoints ( Pint=0.61).TRACER was largely conducted in thienopyridine-naïve patients with unknown tolerance to multiple antiplatelet treatments. Patients receiving thienopyridine before the index event may have had an attenuated increase in bleeding when adding vorapaxar, whereas concomitantly adding vorapaxar and thienopyridine in naïve patients may have uncovered a latent susceptibility to bleeding.

    View details for PubMedID 26895973

  • Sinus Node Dysfunction Is Associated With Higher Symptom Burden and Increased Comorbid Illness: Results From the ORBIT-AF Registry CLINICAL CARDIOLOGY Jackson, L. R., Kim, S. H., Piccini, J. P., Gersh, B. J., Naccarelli, G. V., Reiffel, J. A., Freeman, J., Thomas, L., Chang, P., Fonarow, G. C., Go, A. S., Mahaffey, K. W., Peterson, E. D., Kowey, P. R. 2016; 39 (2): 119-125

    Abstract

    Patients with sinus node dysfunction (SND) have increased risk of atrial tachyarrhythmias, including atrial fibrillation (AF). To date, treatment patterns and outcomes of patients with SND and AF have not been well described.Patients with SND and AF have higher risk of adverse cardiovascular outcomes.Sinus node dysfunction was defined clinically, based on treating physician. Treatment patterns were described and logistic regression analysis performed to assess outcomes.Overall, 1710 (17.7%) out of 9631 patients had SND at enrollment. Patients with SND and AF had increased comorbid medical illnesses, more severe symptoms (European Heart Rhythm Association class IV: 17.5% vs 13.9%; P = 0.0007), and poorer quality of life (median 12-month Atrial Fibrillation Effect on Quality of Life score: 79.6 vs 85.2; P = 0.0008). There were no differences in AF management strategy between patients with SND and those without (rate control, 69.7% vs 67.7%; rhythm control, 30.0% vs 32.0%; P = 0.11). After adjustment, patients with SND were more likely than those without SND to progress from paroxysmal AF at baseline to persistent or permanent AF at any follow-up, or persistent AF at baseline to permanent AF at any follow-up (odds ratio: 1.23, 95% confidence interval: 1.01-1.49, P = 0.035). However, there was no association between SND and major risk-adjusted outcomes.Sinus node dysfunction is present in 1 of 6 patients with AF and is associated with increased comorbidities and higher symptom burden. However, SND is not associated with an increase in major risk-adjusted outcomes.

    View details for DOI 10.1002/clc.22504

    View details for Web of Science ID 000371415400008

    View details for PubMedID 26720750

    View details for PubMedCentralID PMC4784163

  • Polypharmacy and the Efficacy and Safety of Rivaroxaban Versus Warfarin in the Prevention of Stroke in Patients With Nonvalvular Atrial Fibrillation. Circulation Piccini, J. P., Hellkamp, A. S., Washam, J. B., Becker, R. C., Breithardt, G., Berkowitz, S. D., Halperin, J. L., Hankey, G. J., Hacke, W., Mahaffey, K. W., Nessel, C. C., Singer, D. E., Fox, K. A., Patel, M. R. 2016; 133 (4): 352-360

    Abstract

    Patients with atrial fibrillation (AF) often take multiple medications.We examined characteristics and compared adjusted outcomes between rivaroxaban and warfarin according to number of concomitant baseline medications and the presence of combined cytochrome P450 3A4 and P-glycoprotein inhibitors in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study. At baseline, 5101 patients (36%) were on 0 to 4 medications, 7298 (51%) were on 5 to 9, and 1865 (13%) were on ≥ 10. Although polypharmacy was not associated with higher risk of stroke or non-central nervous system embolism (adjusted hazard ratio, 1.02 for ≥ 10 versus 0-4 medications; 95% confidence interval, 0.76-1.38), it was associated with higher risks of the combined end point of stroke, non-central nervous system embolism, vascular death, or myocardial infarction (adjusted hazard ratio, 1.41 for ≥ 10 versus 0-4 medications; 95% confidence interval, 1.18-1.68) and nonmajor clinically relevant or major bleeding (adjusted hazard ratio, 1.47 for ≥ 10 versus 0-4 medications; 95% confidence interval, 1.31-1.65). There was no significant difference in primary efficacy (adjusted interaction P=0.99) or safety outcomes (adjusted interaction P=0.87) between treatment groups by number of medications. Patients treated with 0 to 4 medications had lower rates of major bleeding with rivaroxaban (adjusted hazard ratio, 0.71; 95% confidence interval, 0.52-0.95; interaction P=0.0074). There was no evidence of differential outcomes in those treated with ≥ 1 combined cytochrome P450 3A4 and P-glycoprotein inhibitors.In a population of patients with atrial fibrillation, two thirds were on ≥ 5 medications. Increasing medication use was associated with higher risk of bleeding but not stroke. Rivaroxaban was tolerated across complex patients on multiple medications.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00403767.

    View details for DOI 10.1161/CIRCULATIONAHA.115.018544

    View details for PubMedID 26673560

  • Efficacy and Safety of Cangrelor in Women Versus Men During Percutaneous Coronary Intervention Insights From the Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION PHOENIX) Trial CIRCULATION O'Donoghue, M. L., Bhatt, D. L., Stone, G. W., Steg, P. G., Gibson, C. M., Hamm, C. W., Price, M. J., Prats, J., Liu, T., Deliargyris, E. N., Mahaffey, K. W., White, H. D., Harrington, R. A. 2016; 133 (3): 248-255

    Abstract

    Cangrelor is an intravenous ADP receptor antagonist that leads to potent and reversible inhibition of platelet aggregation. The relative safety and efficacy of some antiplatelet drugs in women has been disputed.The Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION PHOENIX) trial randomized 11,145 patients undergoing elective or urgent percutaneous coronary intervention to cangrelor or clopidogrel. The primary efficacy end point was the composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours; the key secondary end point was stent thrombosis at 48 hours. The primary safety end point was GUSTO severe bleeding at 48 hours. Of subjects analyzed, 3051 (28%) were female. Cangrelor reduced the odds of the primary end point by 35% in women (adjusted odds ratio [OR], 0.65; 95% confidence interval [CI], 0.48-0.89) and by 14% in men (OR, 0.86; 95% CI, 0.70-1.05; P interaction=0.23) compared with clopidogrel. Cangrelor reduced the odds of stent thrombosis by 61% in women (OR, 0.39; 95% CI, 0.20-0.77) and 16% in men (OR, 0.84; 95% CI, 0.53-1.33; P interaction=0.11). The odds of severe bleeding were similar in both women and men treated with cangrelor (0.3% versus 0.2%, P=0.30 [women]; 0.1% versus 0.1%, P=0.41 [men]; P interaction=0.88) versus clopidogrel. Cangrelor increased the odds of moderate bleeding in women (0.9% versus 0.3%, P=0.02), but not in men (0.2% versus 0.2%, P=0.68; P interaction=0.040). The net clinical benefit (primary efficacy and safety end point) favored cangrelor in both women (OR, 0.68; 95% CI, 0.50-0.92) and men (OR, 0.87; 95% CI, 0.71-1.06; P interaction=0.26).In CHAMPION PHOENIX, cangrelor reduced the odds of major adverse cardiovascular events and stent thrombosis in women and men and appeared to offer greater net clinical benefit than clopidogrel.URL: http://www.clinicaltrials.gov. Unique identifier: NCT01156571.

    View details for DOI 10.1161/CIRCULATIONAHA.115.017300

    View details for Web of Science ID 000368540900004

    View details for PubMedCentralID PMC4894784

  • Efficacy and safety of canagliflozin when used in conjunction with incretin-mimetic therapy in patients with type 2 diabetes DIABETES OBESITY & METABOLISM Fulcher, G., Matthews, D. R., Perkovic, V., de Zeeuw, D., Mahaffey, K. W., Mathieu, C., Woo, V., Wysham, C., Capuano, G., Desai, M., Shaw, W., Vercruysse, F., Meininger, G., Neal, B. 2016; 18 (1): 82-91

    Abstract

    To assess the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes enrolled in the CANagliflozin cardioVascular Assessment Study (CANVAS) who were on an incretin mimetic [dipeptidyl peptidase-4 (DPP-4) inhibitor or glucagon-like peptide-1 (GLP-1) receptor agonist].CANVAS is a double-blind, placebo-controlled study that randomized participants to canagliflozin 100 or 300 mg or placebo added to routine therapy. The present post hoc analysis assessed the efficacy and safety of canagliflozin 100 and 300 mg compared with placebo in subsets of patients from CANVAS who were taking background DPP-4 inhibitors or GLP-1 receptor agonists with or without other antihyperglycaemic agents at week 18.Of the 4330 patients in CANVAS, 316 were taking DPP-4 inhibitors and 95 were taking GLP-1 receptor agonists. At 18 weeks, canagliflozin 100 and 300 mg provided larger placebo-subtracted reductions in glycated haemoglobin (HbA1c) in patients taking DPP-4 inhibitors [-0.56% (95% confidence interval [CI]: -0.77, -0.35), and -0.75% (95% CI: -0.95, -0.54), respectively] and GLP-1 receptor agonists [-1.00% (95% CI: -1.35, -0.65), and -1.06% (95% CI: -1.43, -0.69), respectively]. Body weight and blood pressure (BP) reductions were seen with canagliflozin versus placebo in both subsets. Higher incidences of genital mycotic infections and osmotic diuresis-related adverse events (AEs) were seen with canagliflozin compared with placebo. The incidence of hypoglycaemia was numerically higher with canagliflozin versus placebo; nearly all events occurred in patients on background insulin or insulin secretagogues.In patients on background incretin mimetics, canagliflozin improved HbA1c, body weight and BP, with an increased incidence of AEs related to SGLT2 inhibition.

    View details for DOI 10.1111/dom.12589

    View details for Web of Science ID 000367233900011

  • Racial Differences in Quality of Anticoagulation Therapy for Atrial Fibrillation (from the TREAT-AF Study). The American journal of cardiology Yong, C. n., Azarbal, F. n., Abnousi, F. n., Heidenreich, P. A., Schmitt, S. n., Fan, J. n., Than, C. T., Ullal, A. J., Yang, F. n., Phibbs, C. S., Frayne, S. M., Ho, P. M., Shore, S. n., Mahaffey, K. W., Turakhia, M. P. 2016; 117 (1): 61–68

    Abstract

    The influence of race on quality of anticoagulation control is not well described. We examined the association between race, international normalized ratio (INR) monitoring intensity, and INR control in warfarin-treated patients with atrial fibrillation (AF). Using data from the Veterans Health Administration (VHA), we performed a retrospective cohort study of 184,161 patients with a new diagnosis of AF/flutter from 2004 to 2012 who received any VHA prescription within 90 days of diagnosis. The primary predictor was race, ascertained from multiple VHA and linked Medicare demographic files. The primary outcome was first-year and long-term time in therapeutic range (TTR) of INR 2.0 to 3.0. Secondary outcomes were INR monitoring intensity and warfarin persistence. Of the 116,021 patients who received warfarin in the cohort, INR monitoring intensity was similar across racial groups. However, TTR was lowest in blacks and highest in whites (first year 0.49 ± 0.23 vs 0.57 ± 0.21, p <0.001; long term 0.52 ± 0.20 vs 0.59 ± 0.18, p <0.001); 64% of whites and 49% of blacks had long-term TTR >55% (p <0.001). After adjusting for site and patient-level covariates, black race was associated with lower first-year and long-term TTRs (4.2% and 4.1% below the conditional mean, relative to whites; p <0.0001 for both). One-year warfarin persistence was slightly lower in blacks compared to whites (58% vs 60%, p <0.0001). In conclusion, in patients with AF anticoagulated with warfarin, differences in INR control are most evident among blacks, underscoring the need to determine if other types of intensive management or warfarin alternatives may be necessary to improve anticoagulation among vulnerable AF populations.

    View details for PubMedID 26552504

  • Efficacy and Safety of Cangrelor in Women Versus Men During Percutaneous Coronary Intervention: Insights From the Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION PHOENIX) Trial. Circulation O'Donoghue, M. L., Bhatt, D. L., Stone, G. W., Steg, P. G., Gibson, C. M., Hamm, C. W., Price, M. J., Prats, J. n., Liu, T. n., Deliargyris, E. N., Mahaffey, K. W., White, H. D., Harrington, R. A. 2016; 133 (3): 248–55

    Abstract

    Cangrelor is an intravenous ADP receptor antagonist that leads to potent and reversible inhibition of platelet aggregation. The relative safety and efficacy of some antiplatelet drugs in women has been disputed.The Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION PHOENIX) trial randomized 11,145 patients undergoing elective or urgent percutaneous coronary intervention to cangrelor or clopidogrel. The primary efficacy end point was the composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours; the key secondary end point was stent thrombosis at 48 hours. The primary safety end point was GUSTO severe bleeding at 48 hours. Of subjects analyzed, 3051 (28%) were female. Cangrelor reduced the odds of the primary end point by 35% in women (adjusted odds ratio [OR], 0.65; 95% confidence interval [CI], 0.48-0.89) and by 14% in men (OR, 0.86; 95% CI, 0.70-1.05; P interaction=0.23) compared with clopidogrel. Cangrelor reduced the odds of stent thrombosis by 61% in women (OR, 0.39; 95% CI, 0.20-0.77) and 16% in men (OR, 0.84; 95% CI, 0.53-1.33; P interaction=0.11). The odds of severe bleeding were similar in both women and men treated with cangrelor (0.3% versus 0.2%, P=0.30 [women]; 0.1% versus 0.1%, P=0.41 [men]; P interaction=0.88) versus clopidogrel. Cangrelor increased the odds of moderate bleeding in women (0.9% versus 0.3%, P=0.02), but not in men (0.2% versus 0.2%, P=0.68; P interaction=0.040). The net clinical benefit (primary efficacy and safety end point) favored cangrelor in both women (OR, 0.68; 95% CI, 0.50-0.92) and men (OR, 0.87; 95% CI, 0.71-1.06; P interaction=0.26).In CHAMPION PHOENIX, cangrelor reduced the odds of major adverse cardiovascular events and stent thrombosis in women and men and appeared to offer greater net clinical benefit than clopidogrel.URL: http://www.clinicaltrials.gov. Unique identifier: NCT01156571.

    View details for PubMedID 26762525

    View details for PubMedCentralID PMC4894784

  • High-degree atrioventricular block, asystole, and electro-mechanical dissociation complicating non-ST-segment elevation myocardial infarction AMERICAN HEART JOURNAL Pokorney, S. D., Radder, C., Schulte, P. J., Al-Khatib, S. M., Tricocci, P., Van de Werf, F., James, S. K., Cannon, C. P., Armstrong, P. W., White, H. D., Califf, R. M., Gibson, C. M., Giugliano, R. P., Wallentin, L., Mahaffey, K. W., Harrington, R. A., Newby, L. K., Piccini, J. P. 2016; 171 (1): 25-32

    Abstract

    Non-ST-segment myocardial infarction (NSTEMI) can be complicated by high-degree atrioventricular (AV) block, asystole, or electromechanical dissociation (EMD), but these events are not well characterized in the contemporary era. This analysis assesses the incidence of and factors associated with these dysrhythmias in acute NSTEMIs.Patients with NSTEMI in the EARLY ACS, PLATO, and TRACER trials were included in the pooled cohort (N = 29,677). Logistic regression was used to identify factors associated with in-hospital high-degree AV block and asystole or EMD, and Kaplan-Meier methods were used to assess mortality.High-degree AV block occurred in 112 (0.4%) patients, asystole in 157 (0.5%), and EMD in 38 (0.1%). Pacemakers were inserted in 241 patients (0.8%) during the index hospitalization: 30 (12%) for AV block. Among patients with high-degree AV block, we observed more frequent right coronary artery lesions (47% vs 29%). Age, diabetes, lower heart rate, and lower blood pressure were associated with high-degree AV block. Higher Killip class, ST-segment depression, prior myocardial infarction, and peripheral vascular disease were most strongly associated with asystole or EMD. Ten-day unadjusted survival was 90% for patients with high-degree AV block and 43% for those with asystole or EMD.Although high-degree AV block, asystole, and EMD were infrequent complications of NSTEMI, they were associated with substantial short-term mortality. Only 1 in 8 pacemakers placed in NSTEMI patients during the acute hospitalization was for high-degree AV block.

    View details for DOI 10.1016/j.ahj.2015.09.004

    View details for Web of Science ID 000367126200004

    View details for PubMedID 26699597

    View details for PubMedCentralID PMC4692180

  • Racial Differences in Quality of Anticoagulation Therapy for Atrial Fibrillation (from the TREAT-AF Study) AMERICAN JOURNAL OF CARDIOLOGY Yong, C., Azarbal, F., Abnousi, F., Heidenreich, P. A., Schmitt, S., Fan, J., Than, C. T., Ullal, A. J., Yang, F., Phibbs, C. S., Frayne, S. M., Ho, P. M., Shore, S., Mahaffey, K. W., Turakhia, M. P. 2016; 117 (1): 61-68

    Abstract

    The influence of race on quality of anticoagulation control is not well described. We examined the association between race, international normalized ratio (INR) monitoring intensity, and INR control in warfarin-treated patients with atrial fibrillation (AF). Using data from the Veterans Health Administration (VHA), we performed a retrospective cohort study of 184,161 patients with a new diagnosis of AF/flutter from 2004 to 2012 who received any VHA prescription within 90 days of diagnosis. The primary predictor was race, ascertained from multiple VHA and linked Medicare demographic files. The primary outcome was first-year and long-term time in therapeutic range (TTR) of INR 2.0 to 3.0. Secondary outcomes were INR monitoring intensity and warfarin persistence. Of the 116,021 patients who received warfarin in the cohort, INR monitoring intensity was similar across racial groups. However, TTR was lowest in blacks and highest in whites (first year 0.49 ± 0.23 vs 0.57 ± 0.21, p <0.001; long term 0.52 ± 0.20 vs 0.59 ± 0.18, p <0.001); 64% of whites and 49% of blacks had long-term TTR >55% (p <0.001). After adjusting for site and patient-level covariates, black race was associated with lower first-year and long-term TTRs (4.2% and 4.1% below the conditional mean, relative to whites; p <0.0001 for both). One-year warfarin persistence was slightly lower in blacks compared to whites (58% vs 60%, p <0.0001). In conclusion, in patients with AF anticoagulated with warfarin, differences in INR control are most evident among blacks, underscoring the need to determine if other types of intensive management or warfarin alternatives may be necessary to improve anticoagulation among vulnerable AF populations.

    View details for DOI 10.1016/j.amjcard.2015.09.047

    View details for Web of Science ID 000368048900010

  • Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation: Data From ROCKET AF. Journal of the American Heart Association Pokorney, S. D., Piccini, J. P., Stevens, S. R., Patel, M. R., Pieper, K. S., Halperin, J. L., Breithardt, G., Singer, D. E., Hankey, G. J., Hacke, W., Becker, R. C., Berkowitz, S. D., Nessel, C. C., Mahaffey, K. W., Fox, K. A., Califf, R. M. 2016; 5 (3)

    Abstract

    Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions.In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS2 score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P<0.0001) and age ≥75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P<0.0001) were associated with higher all-cause mortality. Multiple additional characteristics were independently associated with higher mortality, with decreasing creatinine clearance, chronic obstructive pulmonary disease, male sex, peripheral vascular disease, and diabetes being among the most strongly associated (model C-index 0.677).In a large population of patients anticoagulated for nonvalvular atrial fibrillation, ≈7 in 10 deaths were cardiovascular, whereas <1 in 10 deaths were caused by nonhemorrhagic stroke or systemic embolism. Optimal prevention and treatment of heart failure, renal impairment, chronic obstructive pulmonary disease, and diabetes may improve survival.URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00403767.

    View details for DOI 10.1161/JAHA.115.002197

    View details for PubMedID 26955859

  • The ORBIT bleeding score: a simple bedside score to assess bleeding risk in atrial fibrillation. European heart journal O'Brien, E. C., Simon, D. N., Thomas, L. E., Hylek, E. M., Gersh, B. J., Ansell, J. E., Kowey, P. R., Mahaffey, K. W., Chang, P., Fonarow, G. C., Pencina, M. J., Piccini, J. P., Peterson, E. D. 2015; 36 (46): 3258-3264

    Abstract

    Therapeutic decisions in atrial fibrillation (AF) are often influenced by assessment of bleeding risk. However, existing bleeding risk scores have limitations.We sought to develop and validate a novel bleeding risk score using routinely available clinical information to predict major bleeding in a large, community-based AF population.We analysed data from Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF), a prospective registry that enrolled incident and prevalent AF patients at 176 US sites. Using Cox proportional hazards regression, we identified factors independently associated with major bleeding among patients taking oral anticoagulation (OAC) over a median follow-up of 2 years (interquartile range = 1.6-2.5). We also created a numerical bedside risk score that included the five most predictive risk factors weighted according to their strength of association with major bleeding. The predictive performance of the full model, the simple five-item score, and two existing risk scores (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly, drugs/alcohol concomitantly, HAS-BLED, and anticoagulation and risk factors in atrial fibrillation, ATRIA) were then assessed in both the ORBIT-AF cohort and a separate clinical trial population, Rivaroxaban Once-daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET-AF).Among 7411 ORBIT-AF patients taking OAC, the rate of major bleeding was 4.0/100 person-years. The full continuous model (12 variables) and five-factor ORBIT risk score (older age [75+ years], reduced haemoglobin/haematocrit/history of anaemia, bleeding history, insufficient kidney function, and treatment with antiplatelet) both had good ability to identify those who bled vs. not (C-index 0.69 and 0.67, respectively). These scores both had similar discrimination, but markedly better calibration when compared with the HAS-BLED and ATRIA scores in an external validation population from the ROCKET-AF trial.The five-element ORBIT bleeding risk score had better ability to predict major bleeding in AF patients when compared with HAS-BLED and ATRIA risk scores. The ORBIT risk score can provide a simple, easily remembered tool to support clinical decision making.

    View details for DOI 10.1093/eurheartj/ehv476

    View details for PubMedID 26424865

    View details for PubMedCentralID PMC4670965

  • Lost to Follow-up and Withdrawal of Consent in Contemporary Global Cardiovascular Randomized Clinical Trials. Critical pathways in cardiology Rodriguez, F., Harrison, R. W., Wojdyla, D., Mahaffey, K. W. 2015; 14 (4): 150-153

    Abstract

    High rates of lost to follow-up (LTFU) and withdrawal of consent (WDC) may introduce uncertainty around the validity of the results of clinical trials. We sought to better understand published proportions of LTFU and WDC in large contemporary cardiovascular clinical trials.Large (>5000 randomized subjects) cardiovascular clinical trials published between 2007 and 2012 in N Engl J Med were systematically reviewed. Data regarding LTFU and WDC were extracted from the primary manuscripts and supplementary online material.Twenty-five published randomized trials were identified. Trials ranged in size from 5518 to 26449 subjects. All trials reported LTFU with 15 separately reporting WDC. The duration of follow-up ranged from 30 days to 6.2 years. The number of subjects LTFU ranged from 8 to 905, and the median proportion of subjects LTFU was 0.23% (interquartile range: 0.12%-0.58%). Individual LTFU proportions varied 300-fold, from 0.03% to 9.7%. Proportions of WDC ranged from 0.02% to 8.3%-a 400-fold difference-with a median of 1.1% (interquartile range: 0.2%-2.6%). WDC occurred more frequently than LTFU in all but 2 studies.Contemporary cardiovascular clinical trials typically have low proportions of LTFU or WDC, but some trials have approximately 10% of subjects with LTFU or WDC. WDC occurred more frequently than LTFU but was only reported in 60% of the trials. These results emphasize the need to standardize reporting of LTFU and WDC as important trial metrics of quality and to develop strategies to minimize their occurrence.

    View details for DOI 10.1097/HPC.0000000000000055

    View details for PubMedID 26569655

  • Cytokines profile in hypertensive patients with left ventricular remodeling and dysfunction. Journal of the American Society of Hypertension Kuznetsova, T., Haddad, F., Knez, J., Rosenberg-Hasson, Y., Sung, J., Cauwenberghs, N., Thijs, L., Karakikes, I., Maecker, H., Mahaffey, K. W., Wu, J. C., Staessen, J. A. 2015; 9 (12): 975-984 e3

    Abstract

    There is strong evidence that inflammatory mediators play a key role in the progression to heart failure in patients with systemic hypertension (HTN). The present study aimed to identify a set of cytokines that are associated with early left ventricular (LV) remodeling and dysfunction as captured by echocardiography in patients with HTN in a cross-sectional case-control study nested within the FLEMish study on ENvironment, Genes and Health Outcome. We identified three groups of participants from the cohort: normotensive subjects (normotension; n = 30), HTN with normal LV structure and function (HTN [LV-]; n = 30), and HTN with evidence of adverse LV remodeling (HTN [LV+]; n = 50). We measured cytokines using a 63-plex Luminex platform. Using partial least squares-discriminant analysis, we constructed three latent variables from the measured cytokines that explained 35%-45% of the variance between groups. We identified five common cytokines (interleukin 18, monokine induced by gamma interferon, hepatocyte growth factor, epithelial neutrophil-activating peptide 78, and vascular endothelial growth factor D) with a stable signal which had a major impact on the construction of the latent variables. Among these cytokines, after adjustment for confounders, interleukin 18 remained significantly different between HTN participants with and without LV involvement (P = .02). Moreover, granulocyte-macrophage colony-stimulating factor and leptin showed a consistent upward trend in all HTN patients compared with normotensive subjects. In conclusion, in HTN patients with LV remodeling or/and dysfunction, we identified a set of cytokines strongly associated with LV maladaptation. We also found a distinct profile of inflammatory biomarkers that characterize HTN.

    View details for DOI 10.1016/j.jash.2015.10.003

    View details for PubMedID 26565110

  • Cytokines profile in hypertensive patients with left ventricular remodeling and dysfunction JOURNAL OF THE AMERICAN SOCIETY OF HYPERTENSION Kuznetsova, T., Haddad, F., Knez, J., Rosenberg-Hasson, Y., Sung, J., Cauwenberghs, N., Thijs, L., Karakikes, I., Maecker, H., Mahaffey, K. W., Wu, J. C., Staessen, J. A. 2015; 9 (12): 975-984

    Abstract

    There is strong evidence that inflammatory mediators play a key role in the progression to heart failure in patients with systemic hypertension (HTN). The present study aimed to identify a set of cytokines that are associated with early left ventricular (LV) remodeling and dysfunction as captured by echocardiography in patients with HTN in a cross-sectional case-control study nested within the FLEMish study on ENvironment, Genes and Health Outcome. We identified three groups of participants from the cohort: normotensive subjects (normotension; n = 30), HTN with normal LV structure and function (HTN [LV-]; n = 30), and HTN with evidence of adverse LV remodeling (HTN [LV+]; n = 50). We measured cytokines using a 63-plex Luminex platform. Using partial least squares-discriminant analysis, we constructed three latent variables from the measured cytokines that explained 35%-45% of the variance between groups. We identified five common cytokines (interleukin 18, monokine induced by gamma interferon, hepatocyte growth factor, epithelial neutrophil-activating peptide 78, and vascular endothelial growth factor D) with a stable signal which had a major impact on the construction of the latent variables. Among these cytokines, after adjustment for confounders, interleukin 18 remained significantly different between HTN participants with and without LV involvement (P = .02). Moreover, granulocyte-macrophage colony-stimulating factor and leptin showed a consistent upward trend in all HTN patients compared with normotensive subjects. In conclusion, in HTN patients with LV remodeling or/and dysfunction, we identified a set of cytokines strongly associated with LV maladaptation. We also found a distinct profile of inflammatory biomarkers that characterize HTN.

    View details for DOI 10.1016/j.jash.2015.10.003

    View details for Web of Science ID 000367214500014

    View details for PubMedID 26565110

  • Gastrointestinal Bleeding in Patients With Atrial Fibrillation Treated With Rivaroxaban or Warfarin ROCKET AF Trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Sherwood, M. W., Nessel, C. C., Hellkamp, A. S., Mahaffey, K. W., Piccini, J. P., Suh, E., Becker, R. C., Singer, D. E., Halperin, J. L., Hankey, G. J., Berkowitz, S. D., Fox, K. A., Patel, M. R. 2015; 66 (21): 2271-2281

    Abstract

    Gastrointestinal (GI) bleeding is a common complication of oral anticoagulation.This study evaluated GI bleeding in patients who received at least 1 dose of the study drug in the on-treatment arm of the ROCKET AF (Rivaroxaban Once-daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial.The primary outcome was adjudicated GI bleeding reported from first to last drug dose + 2 days. Multivariable modeling was performed with pre-specified candidate predictors.Of 14,236 patients, 684 experienced GI bleeding during follow-up. These patients were older (median age 75 years vs. 73 years) and less often female. GI bleeding events occurred in the upper GI tract (48%), lower GI tract (23%), and rectum (29%) without differences between treatment arms. There was a significantly higher rate of major or nonmajor clinical GI bleeding in rivaroxaban- versus warfarin-treated patients (3.61 events/100 patient-years vs. 2.60 events/100 patient-years; hazard ratio: 1.42; 95% confidence interval: 1.22 to 1.66). Severe GI bleeding rates were similar between treatment arms (0.47 events/100 patient-years vs. 0.41 events/100 patient-years; p = 0.39; 0.01 events/100 patient-years vs. 0.04 events/100 patient-years; p = 0.15, respectively), and fatal GI bleeding events were rare (0.01 events/100 patient-years vs. 0.04 events/100 patient-years; 1 fatal events vs. 5 fatal events total). Independent clinical factors most strongly associated with GI bleeding were baseline anemia, history of GI bleeding, and long-term aspirin use.In the ROCKET AF trial, rivaroxaban increased GI bleeding compared with warfarin. The absolute fatality rate from GI bleeding was low and similar in both treatment arms. Our results further illustrate the need for minimizing modifiable risk factors for GI bleeding in patients on oral anticoagulation.

    View details for DOI 10.1016/j.jacc.2015.09.024

    View details for Web of Science ID 000365099600001

    View details for PubMedID 26610874

  • Efficacy of Cangrelor in Lesions with High-Risk and Low-Risk Angiographic Characteristics: The CHAMPION PHOENIX trial Stone, G. W., Genereux, P., White, H. D., Gibson, C., Hamm, C., Mahaffey, K., Price, M. J., Prats, J., Harrington, R., Bhatt, D. L. ELSEVIER SCIENCE INC. 2015: B36–B37
  • Cangrelor Improves Ischemic Outcomes In Patients With Multivessel Disease And Single Vessel Disease Undergoing PCI: Insights From The CHAMPION PHOENIX Trial Abnousi, F., Sundaram, V., Prats, J., Deliargyris, E. N., Stone, G. W., Hamm, C., Steg, P. G., Gibson, C., White, H. D., Price, M. J., Yong, C., Desai, M., Harrington, R., Bhatt, D. L., Mahaffey, K. ELSEVIER SCIENCE INC. 2015: B35
  • Impact of cangrelor overdosing on bleeding complications in patients undergoing percutaneous coronary intervention: insights from the CHAMPION trials JOURNAL OF THROMBOSIS AND THROMBOLYSIS Angiolillo, D. J., Bhatt, D. L., Steg, P. G., Stone, G. W., White, H. D., Gibson, C. M., Hamm, C. W., Price, M. J., Prats, J., Liu, T., Mahaffey, K. W., Harrington, R. A. 2015; 40 (3): 317-322

    Abstract

    Overdosing of parenteral antithrombotic therapies can increase the risk of bleeding. Cangrelor is a potent intravenous platelet P2Y12 receptor antagonist with rapid onset and offset of action. In patients undergoing percutaneous coronary interventions (PCI), compared with control, cangrelor (30 µg/kg bolus, followed immediately by a 4 µg/kg per minute infusion for 2-4 h or until the conclusion of the index PCI, whichever was longer) reduces periprocedural thrombotic complications without an increase in major bleeding complications, although minor bleeding is increased. The impact of cangrelor overdosing on bleeding is unknown and represented the aim of this analysis. Patients with cangrelor overdosing were identified among safety population patients enrolled in the CHAMPION program (n = 25,107). Overdose was defined as administration of an excess >20 % of the bolus dose (30 μg/kg) and/or infusion rate (4 μg/kg per min). Bleeding complications were assessed. Among the safety analysis population in the CHAMPION program, 12,565 patients received cangrelor. A total of 36 overdosed cangrelor patients (0.29 %) were identified in this pooled analysis (20 with both bolus and infusion, 5 with bolus only, and 11 with infusion only). In the majority of patients, the dose did not exceed 2.5 times the recommended dose. Bleeding events were balanced between treatment arms and were consistent with those in the overall CHAMPION program. Only one overdosed patient experienced a serious bleed. There was no correlation between bleeding and magnitude of cangrelor overdose. In a large clinical trial program of patients undergoing PCI, cangrelor overdosing was rare and not associated with an increase in bleeding complications, an observation that may be attributed to its very short-half life and rapid offset of action.

    View details for DOI 10.1007/s11239-015-1233-3

    View details for Web of Science ID 000360193200010

  • 2014 ACC/AHA Key Data Elements and Definitions for Cardiovascular Endpoint Events in Clinical Trials: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Cardiovascular Endpoints Data Standards). Journal of nuclear cardiology Hicks, K. A., Tcheng, J. E., Bozkurt, B., Chaitman, B. R., Cutlip, D. E., Farb, A., Fonarow, G. C., Jacobs, J. P., Jaff, M. R., Lichtman, J. H., Limacher, M. C., Mahaffey, K. W., Mehran, R., Nissen, S. E., Smith, E. E., Targum, S. L. 2015; 22 (5): 1041-1144

    View details for DOI 10.1007/s12350-015-0209-1

    View details for PubMedID 26204990

  • Efficacy and safety of rivaroxaban in patients with diabetes and nonvalvular atrial fibrillation: The Rivaroxaban Once-daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF Trial). American heart journal Bansilal, S., Bloomgarden, Z., Halperin, J. L., Hellkamp, A. S., Lokhnygina, Y., Patel, M. R., Becker, R. C., Breithardt, G., Hacke, W., Hankey, G. J., Nessel, C. C., Singer, D. E., Berkowitz, S. D., Piccini, J. P., Mahaffey, K. W., Fox, K. A. 2015; 170 (4): 675-682 e8

    Abstract

    The prevalence of both atrial fibrillation (AF) and diabetes mellitus (DM) are rising, and these conditions often occur together. Also, DM is an independent risk factor for stroke in patients with AF. We aimed to examine the safety and efficacy of rivaroxaban vs warfarin in patients with nonvalvular AF and DM in a prespecified secondary analysis of the ROCKET AF trial.We stratified the ROCKET AF population by DM status, assessed associations with risk of outcomes by DM status and randomized treatment using Cox proportional hazards models, and tested for interactions between randomized treatments. For efficacy, primary outcomes were stroke (ischemic or hemorrhagic) or non-central nervous system embolism. For safety, the primary outcome was major or nonmajor clinically relevant bleeding.The 5,695 patients with DM (40%) in ROCKET AF were younger, were more obese, and had more persistent AF, but fewer had previous stroke (the CHADS2 score includes DM and stroke). The relative efficacy of rivaroxaban and warfarin for prevention of stroke and systemic embolism was similar in patients with (1.74 vs 2.14/100 patient-years, hazard ratio [HR] 0.82) and without (2.12 vs 2.32/100 patient-years, HR 0.92) DM (interaction P = .53). The safety of rivaroxaban vs warfarin regarding major bleeding (HRs 1.00 and 1.12 for patients with and without DM, respectively; interaction P = .43), major or nonmajor clinically relevant bleeding (HRs 0.98 and 1.09; interaction P = .17), and intracerebral hemorrhage (HRs 0.62 and 0.72; interaction P = .67) was independent of DM status. Adjusted exploratory analyses suggested 1.3-, 1.5-, and 1.9-fold higher 2-year rates of stroke, vascular mortality, and myocardial infarction in DM patients.The relative efficacy and safety of rivaroxaban vs warfarin was similar in patients with and without DM, supporting use of rivaroxaban as an alternative to warfarin in diabetic patients with AF.

    View details for DOI 10.1016/j.ahj.2015.07.006

    View details for PubMedID 26386791

  • Increased Heart Rate Is Associated With Higher Mortality in Patients With Atrial Fibrillation (AF): Results From the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF) JOURNAL OF THE AMERICAN HEART ASSOCIATION Steinberg, B. A., Kim, S., Thomas, L., Fonarow, G. C., Gersh, B. J., Holmqvist, F., Hylek, E., Kowey, P. R., Mahaffey, K. W., Naccarelli, G., Reiffel, J. A., Chang, P., Peterson, E. D., Piccini, J. P. 2015; 4 (9)

    Abstract

    Most patients with atrial fibrillation (AF) require rate control; however, the optimal target heart rate remains under debate. We aimed to assess rate control and subsequent outcomes among patients with permanent AF.We studied 2812 US outpatients with permanent AF in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation. Resting heart rate was measured longitudinally and used as a time-dependent covariate in multivariable Cox models of all-cause and cause-specific mortality during a median follow-up of 24 months. At baseline, 7.4% (n=207) had resting heart rate <60 beats per minute (bpm), 62% (n=1755) 60 to 79 bpm, 29% (n=817) 80 to 109 bpm, and 1.2% (n=33) ≥110 bpm. Groups did not differ by age, previous cerebrovascular disease, heart failure status, CHA2DS2-VASc scores, renal function, or left ventricular function. There were significant differences in race (P=0.001), sinus node dysfunction (P=0.004), and treatment with calcium-channel blockers (P=0.006) and anticoagulation (P=0.009). In analyses of continuous heart rates, lower heart rate ≤65 bpm was associated with higher all-cause mortality (adjusted hazard ratio [HR], 1.15 per 5-bpm decrease; 95% CI, 1.01 to 1.32; P=0.04). Similarly, increasing heart rate >65 bpm was associated with higher all-cause mortality (adjusted HR, 1.10 per 5-bpm increase; 95% CI, 1.05 to 1.15; P<0.0001). This relationship was consistent across endpoints and in a broader sensitivity analysis of permanent and nonpermanent AF patients.Among patients with permanent AF, there is a J-shaped relationship between heart rate and mortality. These data support current guideline recommendations, and clinical trials are warranted to determine optimal rate control.URL: http://clinicaltrials.gov/. Unique identifier: NCT01165710.

    View details for DOI 10.1161/JAHA.115.002031

    View details for Web of Science ID 000364152100007

    View details for PubMedID 26370445

  • Efficacy and Safety of Canagliflozin Used in Conjunction with Sulfonylurea in Patients with Type 2 Diabetes Mellitus: A Randomized, Controlled Trial. Diabetes therapy : research, treatment and education of diabetes and related disorders Fulcher, G., Matthews, D. R., Perkovic, V., de Zeeuw, D., Mahaffey, K. W., Weiss, R., Rosenstock, J., Capuano, G., Desai, M., Shaw, W., Vercruysse, F., Meininger, G., Neal, B. 2015; 6 (3): 289-302

    Abstract

    The efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, was evaluated in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on sulfonylurea monotherapy.The CANagliflozin cardioVascular Assessment Study (CANVAS) is a double-blind, placebo-controlled cardiovascular outcomes study that randomized participants to placebo or canagliflozin 100 or 300 mg once daily in addition to routine therapy. Participants in the CANVAS trial are men and women aged ≥30 years with T2DM and a history or high risk of cardiovascular disease, and inadequate glycemic control (glycated hemoglobin [HbA1c] ≥7.0% and ≤10.5%) on current antihyperglycemic therapies. The primary objective of this prespecified substudy was to assess change from baseline to 18 weeks in HbA1c among patients on sulfonylurea monotherapy.Of the 4330 patients enrolled in CANVAS, 127 met the entry criteria for the sulfonylurea monotherapy substudy (placebo, n = 45; canagliflozin 100 mg, n = 42; canagliflozin 300 mg, n = 40). At 18 weeks, placebo-subtracted changes (95% confidence interval) in HbA1c were -0.74% (-1.15, -0.33; P < 0.001) and -0.83% (-1.24, -0.42; P < 0.001) with canagliflozin 100 and 300 mg, respectively. Relative to placebo, canagliflozin 100 and 300 mg also decreased fasting plasma glucose (FPG; -2.1 mmol/L [-3.0, -1.2] and -2.7 mmol/L [-3.6, -1.7], respectively). Body weight was lower with canagliflozin 300 mg (-1.8% [-3.2, -0.4]; P = 0.014) but unchanged with canagliflozin 100 mg (-0.4% [-1.8, 1.0]; P = 0.557). Canagliflozin 300 mg increased hypoglycemia episodes compared to canagliflozin 100 mg and placebo (15%, 0%, and 4.4%, respectively). Adverse events (AEs) of male and female genital mycotic infections, pollakiuria, and thirst were more common with canagliflozin.Canagliflozin added to ongoing sulfonylurea monotherapy produced improvements in HbA1c, FPG, and body weight, with an increased incidence of AEs consistent with the mechanism of action of SGLT2 inhibition.Janssen Research & Development, LLC.ClinicalTrials.gov NCT01032629.

    View details for DOI 10.1007/s13300-015-0117-z

    View details for PubMedID 26081793

    View details for PubMedCentralID PMC4575303

  • Heart Failure is Associated With Worse Quality of Life and Survival But Similar Stroke Risk in Atrial Fibrillation Cherian, T. S., Shrader, P., Fonarow, G. C., Allen, L. A., Peterson, E. D., Piccini, J., Thomas, L., Kowey, P. R., Burton, P., Gersh, B. J., Mahaffey, K. W. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2015: S115–S116
  • 2014 ACC/AHA Key Data Elements and Definitions for Cardiovascular Endpoint Events in Clinical Trials A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Cardiovascular Endpoints Data Standards) JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Hicks, K. A., Tcheng, J. E., Bozkurt, B., Chaitman, B. R., Cutlip, D. E., Farb, A., Fonarow, G. C., Jacobs, J. P., Jaff, M. R., Lichtman, J. H., Limacher, M. C., Mahaffey, K. W., Mehran, R., Nissen, S. E., Smith, E. E., Targum, S. L., Weintraub, W. S., Bozkurt, B., Fonarow, G. C., Hendel, R. C., Jacobs, J. P., Jneid, H. H., Kutcher, M. A., Lichtman, J. H., Smith, E. E., Tcheng, J. E., Wang, T. Y. 2015; 66 (4): 403-469
  • 2014 ACC/AHA Key Data Elements and Definitions for Cardiovascular Endpoint Events in Clinical Trials: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Cardiovascular Endpoints Data Standards). Circulation Hicks, K. A., Tcheng, J. E., Bozkurt, B., Chaitman, B. R., Cutlip, D. E., Farb, A., Fonarow, G. C., Jacobs, J. P., Jaff, M. R., Lichtman, J. H., Limacher, M. C., Mahaffey, K. W., Mehran, R., Nissen, S. E., Smith, E. E., Targum, S. L. 2015; 132 (4): 302-361

    View details for DOI 10.1161/CIR.0000000000000156

    View details for PubMedID 25547519

  • 2014 ACC/AHA Key Data Elements and Definitions for Cardiovascular Endpoint Events in Clinical Trials: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Cardiovascular Endpoints Data Standards). Journal of the American College of Cardiology Hicks, K. A., Tcheng, J. E., Bozkurt, B., Chaitman, B. R., Cutlip, D. E., Farb, A., Fonarow, G. C., Jacobs, J. P., Jaff, M. R., Lichtman, J. H., Limacher, M. C., Mahaffey, K. W., Mehran, R., Nissen, S. E., Smith, E. E., Targum, S. L. 2015; 66 (4): 403-469

    View details for DOI 10.1016/j.jacc.2014.12.018

    View details for PubMedID 25553722

  • 2014 ACC/AHA Key Data Elements and Definitions for Cardiovascular Endpoint Events in Clinical Trials A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards ( Writing Committee to Develop Cardiovascular Endpoints Data Standards) CIRCULATION Hicks, K. A., Tcheng, J. E., Bozkurt, B., Chaitman, B. R., Cutlip, D. E., Farb, A., Fonarow, G. C., Jacobs, J. P., Jaff, M. R., Lichtman, J. H., Limacher, M. C., Mahaffey, K. W., Mehran, R., Nissen, S. E., Smith, E. E., Targum, S. L., Weintraub, W. S., Bozkurt, B., Fonarow, G. C., Hendel, R. C., Jacobs, J. P., Jneid, H. H., Kutcher, M. A., Lichtman, J. H., Smith, E. E., Tcheng, J. E., Wang, T. Y. 2015; 132 (4): 302-361
  • Cinacalcet, Fibroblast Growth Factor-23, and Cardiovascular Disease in Hemodialysis The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial CIRCULATION Moe, S. M., Chertow, G. M., Parfrey, P. S., Kubo, Y., Block, G. A., Correa-Rotter, R., Drueeke, T. B., Herzog, C. A., London, G. M., Mahaffey, K. W., Wheeler, D. C., Stolina, M., Dehmel, B., Goodman, W. G., Floege, J. 2015; 132 (1): 27-39

    Abstract

    Patients with kidney disease have disordered bone and mineral metabolism, including elevated serum concentrations of fibroblast growth factor-23 (FGF23). These elevated concentrations are associated with cardiovascular and all-cause mortality. The objective was to determine the effects of the calcimimetic cinacalcet (versus placebo) on reducing serum FGF23 and whether changes in FGF23 are associated with death and cardiovascular events.This was a secondary analysis of a randomized clinical trial comparing cinacalcet to placebo in addition to conventional therapy (phosphate binders/vitamin D) in patients receiving hemodialysis with secondary hyperparathyroidism (intact parathyroid hormone ≥300 pg/mL). The primary study end point was time to death or a first nonfatal cardiovascular event (myocardial infarction, hospitalization for angina, heart failure, or a peripheral vascular event). This analysis included 2985 patients (77% of randomized) with serum samples at baseline and 2602 patients (67%) with samples at both baseline and week 20. The results demonstrated that a significantly larger proportion of patients randomized to cinacalcet had ≥30% (68% versus 28%) reductions in FGF23. Among patients randomized to cinacalcet, a ≥30% reduction in FGF23 between baseline and week 20 was associated with a nominally significant reduction in the primary composite end point (relative hazard, 0.82; 95% confidence interval, 0.69-0.98), cardiovascular mortality (relative hazard, 0.66; 95% confidence interval, 0.50-0.87), sudden cardiac death (relative hazard, 0.57; 95% confidence interval, 0.37-0.86), and heart failure (relative hazard, 0.69; 95% confidence interval, 0.48-0.99).Treatment with cinacalcet significantly lowers serum FGF23. Treatment-induced reductions in serum FGF23 are associated with lower rates of cardiovascular death and major cardiovascular events.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00345839.

    View details for DOI 10.1161/CIRCULATIONAHA.114.013876

    View details for Web of Science ID 000357498100005

  • Cinacalcet, Fibroblast Growth Factor-23, and Cardiovascular Disease in Hemodialysis: The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial. Circulation Moe, S. M., Chertow, G. M., Parfrey, P. S., Kubo, Y., Block, G. A., Correa-Rotter, R., Drüeke, T. B., Herzog, C. A., London, G. M., Mahaffey, K. W., Wheeler, D. C., Stolina, M., Dehmel, B., Goodman, W. G., Floege, J. 2015; 132 (1): 27-39

    Abstract

    Patients with kidney disease have disordered bone and mineral metabolism, including elevated serum concentrations of fibroblast growth factor-23 (FGF23). These elevated concentrations are associated with cardiovascular and all-cause mortality. The objective was to determine the effects of the calcimimetic cinacalcet (versus placebo) on reducing serum FGF23 and whether changes in FGF23 are associated with death and cardiovascular events.This was a secondary analysis of a randomized clinical trial comparing cinacalcet to placebo in addition to conventional therapy (phosphate binders/vitamin D) in patients receiving hemodialysis with secondary hyperparathyroidism (intact parathyroid hormone ≥300 pg/mL). The primary study end point was time to death or a first nonfatal cardiovascular event (myocardial infarction, hospitalization for angina, heart failure, or a peripheral vascular event). This analysis included 2985 patients (77% of randomized) with serum samples at baseline and 2602 patients (67%) with samples at both baseline and week 20. The results demonstrated that a significantly larger proportion of patients randomized to cinacalcet had ≥30% (68% versus 28%) reductions in FGF23. Among patients randomized to cinacalcet, a ≥30% reduction in FGF23 between baseline and week 20 was associated with a nominally significant reduction in the primary composite end point (relative hazard, 0.82; 95% confidence interval, 0.69-0.98), cardiovascular mortality (relative hazard, 0.66; 95% confidence interval, 0.50-0.87), sudden cardiac death (relative hazard, 0.57; 95% confidence interval, 0.37-0.86), and heart failure (relative hazard, 0.69; 95% confidence interval, 0.48-0.99).Treatment with cinacalcet significantly lowers serum FGF23. Treatment-induced reductions in serum FGF23 are associated with lower rates of cardiovascular death and major cardiovascular events.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00345839.

    View details for DOI 10.1161/CIRCULATIONAHA.114.013876

    View details for PubMedID 26059012

  • Sex-Stratified Trends in Enrollment, Patient Characteristics, Treatment, and Outcomes Among Non-ST-Segment Elevation Acute Coronary Syndrome Patients Insights From Clinical Trials Over 17 Years CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Kragholm, K., Halim, S. A., Yang, Q., Schulte, P. J., Hochman, J. S., Melloni, C., Mahaffey, K. W., Moliterno, D. J., Harrington, R. A., White, H. D., Armstrong, P. W., Ohman, E. M., Van de Werf, F., Tricoci, P., Alexander, J. H., Giugliano, R. P., Newby, L. K. 2015; 8 (4): 357-367

    Abstract

    Adequate representation by sex in trials allows generalizability of results. We examined representation of women in clinical trials during a 17-year period in which inclusion criteria were broadened and federal mandates for representativeness were launched.Using mixed models, we studied sex-stratified temporal trends in enrollment, clinical characteristics, treatment, and outcomes among 76 148 non-ST-segment elevation acute coronary syndrome patients using patient-level data merged from 11 phase III trials conducted from 1994 to 2010. Overall, 33.3% of patients were women, which changed minimally over time. Women were consistently 4 to 5 years older than men (median age 68 [interquartile range 61-75] versus 64 [interquartile range 56-72] years) and more frequently had diabetes mellitus, hypertension, and heart failure; men more frequently had prior myocardial infarction and revascularization. GRACE risk scores increased over time for both sexes with the inclusion of older patients with more comorbidities. Use of percutaneous coronary intervention, in-hospital and discharge angiotensin-converting enzyme inhibitor/angiotensin II receptor blockers, β-blockers, and lipid-lowering drugs also increased among both sexes. Kaplan-Meier estimates of 6-month mortality declined from 7.0% [95% confidence interval 6.5%-7.6%] to 4.5% [95% confidence interval 4.0%-5.0%] among women and 6.3% [95% confidence interval 6.0%-6.7%] to 3.1% [95% confidence interval 2.9%-3.4%] among men during the 17-year period.The relative proportion of women in non-ST-segment elevation acute coronary syndrome trials changed minimally over time. Nevertheless, in parallel with men, use of evidence-based care and outcomes improved significantly over time among women.

    View details for DOI 10.1161/CIRCOUTCOMES.114.001615

    View details for Web of Science ID 000358214000007

    View details for PubMedCentralID PMC4512844

  • Cardiac Safety Research Consortium (CSRC): Cardiovascular Safety and Adverse Event Case Report Forms THERAPEUTIC INNOVATION & REGULATORY SCIENCE Sabol, M., Finkle, J., Krucoff, M., Stockbridge, N., Parkhill, N., Shinagawa, K., Mahaffey, K., Tcheng, J., Lenihan, D., Melloni, C., Todaro, T., Michelson, E., Munley, J., Zander, J., Oh, R. 2015; 49 (4): 511–13

    Abstract

    Detection of off-target cardiovascular (CV) effects remains a significant challenge to drug development. Documentation of CV events in non-CV trials is often inadequate to interpret imbalances between treatment arms, which may lead to concerns about potential CV safety "signals." The Cardiac Safety Research Consortium (CSRC) public-private partnership has developed CV case report forms (CRFs) for adverse CV events, including death. These CRFs are intended to encourage collection, as near to the occurrence of an event as possible, of the minimum information necessary to assess, or possibly adjudicate, the event. A broad range of stakeholders (representing industry, academia, and regulatory authorities) developed these forms with the goal of balancing the collection of key information with the resources likely to be available. Use of these forms is optional, and sponsors may modify them. These forms have not undergone any type of "validation" process. The CSRC will continue to sponsor a working group to invite public comment and feedback on these forms.

    View details for PubMedID 30222439

  • Association Between Atrial Fibrillation Symptoms, Quality of Life, and Patient Outcomes: Results From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). Circulation. Cardiovascular quality and outcomes Freeman, J. V., Simon, D. N., Go, A. S., Spertus, J., Fonarow, G. C., Gersh, B. J., Hylek, E. M., Kowey, P. R., Mahaffey, K. W., Thomas, L. E., Chang, P., Peterson, E. D., Piccini, J. P. 2015; 8 (4): 393-402

    Abstract

    Instruments to assess symptom burden and quality of life among patients with atrial fibrillation (AF) have not been well evaluated in community practice or associated with patient outcomes.Using data from 10 087 AF patients in the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF), symptom severity was evaluated using the European Heart Rhythm Association (EHRA) classification system, and quality of life was assessed using the Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire. The association between AF-related symptoms, quality of life, and outcomes was assessed using Cox regression. The majority of AF patients (61.8%) were symptomatic (EHRA >2) and 16.5% had severe or disabling symptoms (EHRA 3-4). EHRA symptom class was well correlated with the AFEQT score (Spearman correlation coefficient -0.39). Over 1.8 years of follow-up, AF symptoms were associated with a higher risk of hospitalization (adjusted hazard ratio for EHRA ≥2 versus EHRA 1 1.23, 95% confidence interval, 1.15-1.31) and a borderline higher risk of major bleeding. Lower quality of life was associated with a higher risk of hospitalization (adjusted hazard ratio for lowest quartile of AFEQT versus highest 1.49, 95% confidence interval, 1.2-1.84), but not other major adverse events, including death.In a community-based study, most patients with AF were symptomatic and had impaired quality of life. Quality of life measured by the AFEQT correlated closely with symptom severity measured by the EHRA class. AF symptoms and lower quality of life were associated with higher risk of hospitalization but not mortality during follow-up.

    View details for DOI 10.1161/CIRCOUTCOMES.114.001303

    View details for PubMedID 26058720

  • Sex-Stratified Trends in Enrollment, Patient Characteristics, Treatment, and Outcomes Among Non-ST-Segment Elevation Acute Coronary Syndrome Patients: Insights From Clinical Trials Over 17 Years. Circulation. Cardiovascular quality and outcomes Kragholm, K., Halim, S. A., Yang, Q., Schulte, P. J., Hochman, J. S., Melloni, C., Mahaffey, K. W., Moliterno, D. J., Harrington, R. A., White, H. D., Armstrong, P. W., Ohman, E. M., Van de Werf, F., Tricoci, P., Alexander, J. H., Giugliano, R. P., Newby, L. K. 2015; 8 (4): 357-367

    Abstract

    Adequate representation by sex in trials allows generalizability of results. We examined representation of women in clinical trials during a 17-year period in which inclusion criteria were broadened and federal mandates for representativeness were launched.Using mixed models, we studied sex-stratified temporal trends in enrollment, clinical characteristics, treatment, and outcomes among 76 148 non-ST-segment elevation acute coronary syndrome patients using patient-level data merged from 11 phase III trials conducted from 1994 to 2010. Overall, 33.3% of patients were women, which changed minimally over time. Women were consistently 4 to 5 years older than men (median age 68 [interquartile range 61-75] versus 64 [interquartile range 56-72] years) and more frequently had diabetes mellitus, hypertension, and heart failure; men more frequently had prior myocardial infarction and revascularization. GRACE risk scores increased over time for both sexes with the inclusion of older patients with more comorbidities. Use of percutaneous coronary intervention, in-hospital and discharge angiotensin-converting enzyme inhibitor/angiotensin II receptor blockers, β-blockers, and lipid-lowering drugs also increased among both sexes. Kaplan-Meier estimates of 6-month mortality declined from 7.0% [95% confidence interval 6.5%-7.6%] to 4.5% [95% confidence interval 4.0%-5.0%] among women and 6.3% [95% confidence interval 6.0%-6.7%] to 3.1% [95% confidence interval 2.9%-3.4%] among men during the 17-year period.The relative proportion of women in non-ST-segment elevation acute coronary syndrome trials changed minimally over time. Nevertheless, in parallel with men, use of evidence-based care and outcomes improved significantly over time among women.

    View details for DOI 10.1161/CIRCOUTCOMES.114.001615

    View details for PubMedID 26152683

    View details for PubMedCentralID PMC4512844

  • Patients' time in therapeutic range on warfarin among US patients with atrial fibrillation: Results from ORBIT-AF registry AMERICAN HEART JOURNAL Pokorney, S. D., Simon, D. N., Thomas, L., Fonarow, G. C., Kowey, P. R., Chang, P., Singer, D. E., Ansell, J., Blanco, R. G., Gersh, B., Mahaffey, K. W., Hylek, E. M., Go, A. S., Piccini, J. P., Peterson, E. D. 2015; 170 (1): 141-U194

    Abstract

    Time in therapeutic range (TTR) of international normalized ratio (INR) of 2.0 to 3.0 is important for the safety and effectiveness of warfarin anticoagulation. There are few data on TTR among patients with atrial fibrillation (AF) in community-based clinical practice.Using the US Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF), we examined TTR (using a modified Rosendaal method) among 5,210 patients with AF on warfarin and treated at 155 sites. Patients were grouped into quartiles based on TTR data. Multivariable logistic regression modeling with generalized estimating equations was used to determine patient and provider factors associated with the lowest (worst) TTR.Overall, 59% of the measured INR values were between 2.0 and 3.0, with an overall mean and median TTR of 65% ± 20% and 68% (interquartile range [IQR] 53%-79%). The median times below and above the therapeutic range were 17% (IQR 8%-29%) and 10% (IQR 3%-19%), respectively. Patients with renal dysfunction, advanced heart failure, frailty, prior valve surgery, and higher risk for bleeding (ATRIA score) or stroke (CHA2DS2-VASc score) had significantly lower TTR (P < .0001 for all). Patients treated at anticoagulation clinics had only slightly higher median TTR (69%) than those not (66%) (P < .0001).Among patients with AF in US clinical practices, TTR on warfarin is suboptimal, and those at highest predicted risks for stroke and bleeding were least likely to be in therapeutic range.

    View details for DOI 10.1016/j.ahj.2015.03.017

    View details for Web of Science ID 000356452700018

    View details for PubMedID 26093875

  • Association Between Atrial Fibrillation Symptoms, Quality of Life, and Patient Outcomes Results From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Freeman, J. V., Simon, D. N., Go, A. S., Spertus, J., Fonarow, G. C., Gersh, B. J., Hylek, E. M., Kowey, P. R., Mahaffey, K. W., Thomas, L. E., Chang, P., Peterson, E. D., Piccini, J. P. 2015; 8 (4): 393-402

    Abstract

    Instruments to assess symptom burden and quality of life among patients with atrial fibrillation (AF) have not been well evaluated in community practice or associated with patient outcomes.Using data from 10 087 AF patients in the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF), symptom severity was evaluated using the European Heart Rhythm Association (EHRA) classification system, and quality of life was assessed using the Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire. The association between AF-related symptoms, quality of life, and outcomes was assessed using Cox regression. The majority of AF patients (61.8%) were symptomatic (EHRA >2) and 16.5% had severe or disabling symptoms (EHRA 3-4). EHRA symptom class was well correlated with the AFEQT score (Spearman correlation coefficient -0.39). Over 1.8 years of follow-up, AF symptoms were associated with a higher risk of hospitalization (adjusted hazard ratio for EHRA ≥2 versus EHRA 1 1.23, 95% confidence interval, 1.15-1.31) and a borderline higher risk of major bleeding. Lower quality of life was associated with a higher risk of hospitalization (adjusted hazard ratio for lowest quartile of AFEQT versus highest 1.49, 95% confidence interval, 1.2-1.84), but not other major adverse events, including death.In a community-based study, most patients with AF were symptomatic and had impaired quality of life. Quality of life measured by the AFEQT correlated closely with symptom severity measured by the EHRA class. AF symptoms and lower quality of life were associated with higher risk of hospitalization but not mortality during follow-up.

    View details for DOI 10.1161/CIRCOUTCOMES.114.001303

    View details for Web of Science ID 000358214000011

  • Digoxin Use and Subsequent Outcomes Among Patients in a Contemporary Atrial Fibrillation Cohort JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Allen, L. A., Fonarow, G. C., Simon, D. N., Thomas, L. E., Marzec, L. N., Pokorney, S. D., Gersh, B. J., Go, A. S., Hylek, E. M., Kowey, P. R., Mahaffey, K. W., Chang, P., Peterson, E. D., Piccini, J. P. 2015; 65 (25): 2691-2698

    Abstract

    Although digoxin has long been used to treat atrial fibrillation (AF) and heart failure (HF), its safety remains controversial.This study sought to describe digoxin use over time in patients with AF who were stratified by the presence or absence of HF, to characterize the predictors of digoxin use and initiation, and to correlate digoxin use with outcomes.Longitudinal patterns of digoxin use and its association with a variety of outcomes were assessed in a prospective outpatient registry conducted at 174 U.S. sites with enrollment from June 2010 to August 2011.Among 9,619 patients with AF and serial follow-up every 6 months for up to 3 years, 2,267 (23.6%) received digoxin at study enrollment, 681 (7.1%) were initiated on digoxin during follow-up, and 6,671 (69.4%) were never prescribed digoxin. After adjusting for other medications, heart rate was 72.9 beats/min among digoxin users and 71.5 beats/min among nonusers (p < 0.0001). Prevalent digoxin use at registry enrollment was not associated with subsequent onset of symptoms, hospitalization, or mortality (in patients with HF, adjusted hazard ratio [HR] for death: 1.04; without HF, HR: 1.22). Incident digoxin use during follow-up was not associated with subsequent death in patients with HF (propensity adjusted HR: 1.05), but was associated with subsequent death in those without HF (propensity adjusted HR: 1.99).After adjustment for detailed clinical factors, digoxin use in registry patients with AF had a neutral association with outcomes under most circumstances. Because of the multiple conflicting observational reports about digoxin's safety and possible concerns in specific clinical situations, a large pragmatic trial of digoxin therapy in AF is needed.

    View details for DOI 10.1016/j.jacc.2015.04.045

    View details for Web of Science ID 000356775100003

    View details for PubMedID 26112191

    View details for PubMedCentralID PMC4483195

  • Digoxin use in patients with atrial fibrillation and adverse cardiovascular outcomes: a retrospective analysis of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) LANCET Washam, J. B., Stevens, S. R., Lokhnygina, Y., Halperin, J. L., Breithardt, G., Singer, D. E., Mahaffey, K. W., Hankey, G. J., Berkowitz, S. D., Nessel, C. C., Fox, K. A., Califf, R. M., Piccini, J. P., Patel, M. R. 2015; 385 (9985): 2363-2370

    Abstract

    Digoxin is a widely used drug for ventricular rate control in patients with atrial fibrillation (AF), despite a scarcity of randomised trial data. We studied the use and outcomes of digoxin in patients in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF).For this retrospective analysis, we included and classified patients from ROCKET AF on the basis of digoxin use at baseline and during the study. Patients in ROCKET AF were recruited from 45 countries and had AF and risk factors putting them at moderate-to-high risk of stroke, with or without heart failure. We used Cox proportional hazards regression models adjusted for baseline characteristics and drugs to investigate the association of digoxin with all-cause mortality, vascular death, and sudden death. ROCKET AF was registered with ClinicalTrials.gov, number NCT00403767.In 14,171 randomly assigned patients, digoxin was used at baseline in 5239 (37%). Patients given digoxin were more likely to be female (42% vs 38%) and have a history of heart failure (73% vs 56%), diabetes (43% vs 38%), and persistent AF (88% vs 77%; p<0·0001 for each comparison). After adjustment, digoxin was associated with increased all-cause mortality (5·41 vs 4·30 events per 100 patients-years; hazard ratio 1·17; 95% CI 1·04-1·32; p=0·0093), vascular death (3·55 vs 2·69 per 100 patient-years; 1·19; 1·03-1·39, p=0·0201), and sudden death (1·68 vs 1·12 events per 100 patient-years; 1·36; 1·08-1·70, p=0·0076).Digoxin treatment was associated with a significant increase in all-cause mortality, vascular death, and sudden death in patients with AF. This association was independent of other measured prognostic factors, and although residual confounding could account for these results, these data show the possibility of digoxin having these effects. A randomised trial of digoxin in treatment of AF patients with and without heart failure is needed.Janssen Research & Development and Bayer HealthCare AG.

    View details for DOI 10.1016/S0140-6736(14)61836-5

    View details for Web of Science ID 000356003700029

    View details for PubMedID 25749644

  • Effects of Cinacalcet on Fracture Events in Patients Receiving Hemodialysis: The EVOLVE Trial. Journal of the American Society of Nephrology Moe, S. M., Abdalla, S., Chertow, G. M., Parfrey, P. S., Block, G. A., Correa-Rotter, R., Floege, J., Herzog, C. A., London, G. M., Mahaffey, K. W., Wheeler, D. C., Dehmel, B., Goodman, W. G., Drüeke, T. B. 2015; 26 (6): 1466-1475

    Abstract

    Fractures are frequent in patients receiving hemodialysis. We tested the hypothesis that cinacalcet would reduce the rate of clinical fractures in patients receiving hemodialysis using data from the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events trial, a placebo-controlled trial that randomized 3883 hemodialysis patients with secondary hyperparathyroidism to receive cinacalcet or placebo for ≤64 months. This study was a prespecified secondary analysis of the trial whose primary end point was all-cause mortality and non-fatal cardiovascular events, and one of the secondary end points was first clinical fracture event. Clinical fractures were observed in 255 of 1935 (13.2%) patients randomized to placebo and 238 of 1948 (12.2%) patients randomized to cinacalcet. In an unadjusted intention-to-treat analysis, the relative hazard for fracture (cinacalcet versus placebo) was 0.89 (95% confidence interval [95% CI], 0.75 to 1.07). After adjustment for baseline characteristics and multiple fractures, the relative hazard was 0.83 (95% CI, 0.72 to 0.98). Using a prespecified lag-censoring analysis (a measure of actual drug exposure), the relative hazard for fracture was 0.72 (95% CI, 0.58 to 0.90). When participants were censored at the time of cointerventions (parathyroidectomy, transplant, or provision of commercial cinacalcet), the relative hazard was 0.71 (95% CI, 0.58 to 0.87). Fracture rates were higher in older compared with younger patients and the effect of cinacalcet appeared more pronounced in older patients. In conclusion, using an unadjusted intention-to-treat analysis, cinacalcet did not reduce the rate of clinical fracture. However, when accounting for differences in baseline characteristics, multiple fractures, and/or events prompting discontinuation of study drug, cinacalcet reduced the rate of clinical fracture by 16%-29%.

    View details for DOI 10.1681/ASN.2014040414

    View details for PubMedID 25505257

    View details for PubMedCentralID PMC4446874

  • The future of cardiovascular clinical research in North America and beyond-addressing challenges and leveraging opportunities through unique academic and grassroots collaborations. American heart journal Roe, M. T., Mahaffey, K. W., Ezekowitz, J. A., Alexander, J. H., Goodman, S. G., Hernandez, A., Temple, T., Berdan, L., Califf, R. M., Harrington, R. A., Peterson, E. D., Armstrong, P. W. 2015; 169 (6): 743-750

    Abstract

    Recent developments have highlighted the challenges facing cardiovascular clinical research in global contemporary practice, particularly in North America, including shifting priorities for drug development targets, increasing regulatory requirements, and expensive operational approaches for conducting randomized clinical trials. Nonetheless, emerging trends such as the consolidation of practices and hospitals into integrated health systems, the integration of electronic health records from thousands of practices into large data repositories to support prospective research studies, and streamlined operational approaches such as registry-based trials and risk-based monitoring have created numerous opportunities to disrupt the clinical research paradigm. Within this context, academic research organizations around the globe, particularly a strengthened collaboration of 3 established academic research organizations in North America, are uniquely positioned to promote and develop grassroots collaborations across all types of clinical practices, to delineate successful solutions to obstacles that limit clinical research initiatives, and to guide the future of cardiovascular research in the global research environment.

    View details for DOI 10.1016/j.ahj.2015.03.002

    View details for PubMedID 26027610

  • Effects of Cinacalcet on Fracture Events in Patients Receiving Hemodialysis: The EVOLVE Trial JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Moe, S. M., Abdalla, S., Chertow, G. M., Parfrey, P. S., Block, G. A., Correa-Rotter, R., Floege, J., Herzog, C. A., London, G. M., Mahaffey, K. W., Wheeler, D. C., Dehmel, B., Goodman, W. G., Drueeke, T. B. 2015; 26 (6): 1466-1475

    Abstract

    Fractures are frequent in patients receiving hemodialysis. We tested the hypothesis that cinacalcet would reduce the rate of clinical fractures in patients receiving hemodialysis using data from the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events trial, a placebo-controlled trial that randomized 3883 hemodialysis patients with secondary hyperparathyroidism to receive cinacalcet or placebo for ≤64 months. This study was a prespecified secondary analysis of the trial whose primary end point was all-cause mortality and non-fatal cardiovascular events, and one of the secondary end points was first clinical fracture event. Clinical fractures were observed in 255 of 1935 (13.2%) patients randomized to placebo and 238 of 1948 (12.2%) patients randomized to cinacalcet. In an unadjusted intention-to-treat analysis, the relative hazard for fracture (cinacalcet versus placebo) was 0.89 (95% confidence interval [95% CI], 0.75 to 1.07). After adjustment for baseline characteristics and multiple fractures, the relative hazard was 0.83 (95% CI, 0.72 to 0.98). Using a prespecified lag-censoring analysis (a measure of actual drug exposure), the relative hazard for fracture was 0.72 (95% CI, 0.58 to 0.90). When participants were censored at the time of cointerventions (parathyroidectomy, transplant, or provision of commercial cinacalcet), the relative hazard was 0.71 (95% CI, 0.58 to 0.87). Fracture rates were higher in older compared with younger patients and the effect of cinacalcet appeared more pronounced in older patients. In conclusion, using an unadjusted intention-to-treat analysis, cinacalcet did not reduce the rate of clinical fracture. However, when accounting for differences in baseline characteristics, multiple fractures, and/or events prompting discontinuation of study drug, cinacalcet reduced the rate of clinical fracture by 16%-29%.

    View details for DOI 10.1681/ASN.2014040414

    View details for Web of Science ID 000355386100024

    View details for PubMedCentralID PMC4446874

  • Magnitude of troponin elevation and long-term clinical outcomes in acute coronary syndrome patients treated with and without revascularization. Circulation. Cardiovascular interventions Bagai, A., Huang, Z., Lokhnygina, Y., Harrington, R. A., Armstrong, P. W., Strony, J., White, H. D., Leonardi, S., Held, C., Van de Werf, F., Wallentin, L., Tricoci, P., Mahaffey, K. W. 2015; 8 (6)

    Abstract

    In patients with non-ST-segment-elevation acute coronary syndrome (NSTE ACS), elevated troponin levels identify patients at high risk for adverse outcomes; however, it is unknown whether the magnitude of troponin elevation during hospitalization remains predictive of subsequent events in patients undergoing coronary revascularization.We studied 12 635 patients with NSTE ACS in the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) study with at least 1 troponin measurement during index hospitalization. Cox proportional hazards regression was used to examine the relationship between peak troponin level (standardized as the ratio of peak troponin value measured during hospitalization and local laboratory upper reference limit [URL]) and revascularization on all-cause mortality at 2 years. Revascularization (percutaneous coronary intervention or coronary artery bypass graft) was performed during index hospitalization in 8586 patients (68.0%); revascularized patients had higher peak troponin ratios (median, 23 versus 9.5× URL). Among patients that did not undergo revascularization, the mortality rate at 2 years increased in a curvilinear fashion with increasing levels of peak troponin. In contrast, the mortality rate at 2 years remained constant irrespective of peak troponin levels among revascularized patients (P for interaction=0.004). This relationship was unchanged after multivariable adjustment.There is a differential relationship between the magnitude of troponin elevation and long-term mortality in ACS patients treated with and without revascularization. Although prognostically important in patients treated without revascularization, the prognostic implications of peak troponin level seem to be minimal in revascularized patients.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00527943.

    View details for DOI 10.1161/CIRCINTERVENTIONS.115.002314

    View details for PubMedID 26025218

  • Meta-Analysis of Intracranial Hemorrhage in Acute Coronary Syndromes: Incidence, Predictors, and Clinical Outcomes JOURNAL OF THE AMERICAN HEART ASSOCIATION Mahaffey, K. W., Hager, R., Wojdyla, D., White, H. D., Armstrong, P. W., Alexander, J. H., Tricoci, P., Lopes, R. D., Ohman, E. M., Roe, M. T., Harrington, R. A., Wallentin, L. 2015; 4 (6)

    Abstract

    Little is known about the incidence, predictors, or outcomes of intracranial hemorrhage (ICH) in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS). We aimed to determine the incidence and timing of ICH, characterize the location of ICH, and identify independent baseline predictors of ICH in NSTE ACS patients.We pooled patient-level data from 4 contemporary antithrombotic therapy trials. Multivariable modeling identified independent predictors of ICH. ICHs were adjudicated by a clinical events committee. Of 37 815 patients, 135 (0.4%) had an ICH. The median (25th, 75th percentiles) follow-up was 332 (184, 434) days but differed across trials. Locations of ICH were intracerebral (50%), subdural (31%), subarachnoid (18.5%), and intraventricular (11%). Independent predictors of ICH were older age (HR per 10 years, 1.61; 95% CI, 1.35 to 1.91); prior stroke/transient ischemic attack; HR, 1.95; 95% CI, 1.14 to 3.35), higher systolic blood pressure; HR per 10 mm Hg increase, 1.09; 95% CI, 1.01 to 1.18), and larger number of antithrombotic agents (HR per each additional agent, 2.06; 95% CI, 1.49 to 2.84). Of all ICHs, 45 (33%) were fatal.In patients with NSTE ACS enrolled in recent clinical trials of antithrombotic therapies, ICH was uncommon. Patients with older age, prior transient ischemic attack/stroke, higher systolic blood pressure, or larger number of antithrombotic agents were at increased risk. One-third of patients with ICH died. These data may be useful to trialists and data and safety monitoring committees for trial conduct and monitoring.URL: https://www.clinicaltrials.gov/. Unique identifiers: TRACER: NCT00527943, PLATO: NCT00391872, APPRAISE-2: NCT00831441, TRILOGY ACS: NCT00699998.

    View details for DOI 10.1161/JAHA.114.001512

    View details for Web of Science ID 000357025100007

    View details for PubMedID 26089177

  • Heart rate is associated with progression of atrial fibrillation, independent of rhythm HEART Holmqvist, F., Kim, S., Steinberg, B. A., Reiffel, J. A., Mahaffey, K. W., Gersh, B. J., Fonarow, G. C., Naccarelli, G. V., Chang, P., Freeman, J. V., Kowey, P. R., Thomas, L., Peterson, E. D., Piccini, J. P. 2015; 101 (11): 894-899

    Abstract

    Atrial fibrillation (AF) often progresses from paroxysmal or persistent to more sustained forms, but the rate and predictors of AF progression in clinical practice are not well described.Using the Outcomes Registry for Better Informed Treatment of AF, we analysed the incidence and predictors of progression and tested the discrimination and calibration of the HATCH (hypertension, age, TIA/stroke, chronic obstructive pulmonary disease, heart failure) and CHA₂DS₂VASc scores for identifying AF progression.Among 6235 patients with paroxysmal or persistent AF at baseline, 1479 progressed, during follow-up (median 18 (IQR 12-24) months). These patients were older and had more comorbidities than patients who did not progress (CHADS₂ 2.3±1.3 vs 2.1±1.3, p<0.0001). At baseline, patients with AF progression were more often on a rate control as opposed to a rhythm control strategy (66 vs 56%, p<0.0001) and had higher heart rate (72(64-80) vs 68(60-76) bpm, p<0.0001). The strongest predictors of AF progression were AF on the baseline ECG (OR 2.30, 95% CI 1.95 to 2.73, p<0.0001) and increasing age (OR 1.16, 95% CI1.09 to 1.24, p<0.0001, per 10 increase), while patients with lower heart rate (OR 0.84, 95% CI 0.79 to 0.89, p<0.0001, per 10 decrease ≤80) were less likely to progress. There was no significant interaction between rhythm on baseline ECG and heart rate (p=0.71). The HATCH and CHA₂DS₂VASc scores had modest discriminatory power for AF progression (C-indices 0.55 (95% CI 0.53 to 0.58) and 0.55 (95% CI 0.52 to 0.57)).Within 1.5 years, almost a quarter of the patients with paroxysmal or persistent AF progress to a more sustained form. Progression is strongly associated with heart rate, and age.

    View details for DOI 10.1136/heartjnl-2014-307043

    View details for Web of Science ID 000354277600014

    View details for PubMedID 25732748

    View details for PubMedCentralID PMC4453487

  • Cardiovascular events in acute coronary syndrome patients with peripheral arterial disease treated with ticagrelor compared with clopidogrel: Data from the PLATO Trial EUROPEAN JOURNAL OF PREVENTIVE CARDIOLOGY Patel, M. R., Becker, R. C., Wojdyla, D. M., Emanuelsson, H., Hiatt, W. R., Horrow, J., Husted, S., Mahaffey, K. W., Steg, P. G., Storey, R. F., Wallentin, L., James, S. K. 2015; 22 (6): 734-742

    Abstract

    To determine the effect of ticagrelor compared to clopidogrel in patients with peripheral artery disease (PAD) and acute coronary syndromes (ACS).PLATO (n = 18,624) was a multicentre, double-blind, randomized trial in ACS, that showed a 16% reduction in cardiovascular death (CV-death), myocardial infarction (MI) and stroke with ticagrelor compared with clopidogrel, without significant increase in overall major bleeding. We performed a post-hoc analysis of cardiovascular and bleeding outcomes in PLATO according to reported PAD status at baseline. At one year, CV death, MI or stroke occurred in 19.3% of patients with PAD (n = 1144) compared to 10.2% in patients without PAD (p < 0.001). The Kaplan-Meier one year event rate for the primary endpoint of CV death, MI or stroke in PAD patients treated with ticagrelor as compared with clopidogrel, was 18% vs 20.6% (HR: 0.85 95% CI 0.64-1.11; for PAD status by treatment interaction, p = 0.99) and for death from any cause 8.7% vs 11.9%, (HR: 0.74 95% CI 0.50-1.08; interaction p = 0.73). PLATO-defined major bleeding event rates at one year were 14.8% for ticagrelor compared to 17.9% for clopidogrel, (HR: 0.81 95% CI 0.59-1.10; interaction p = 0.09).PAD patients have a high rate of ischaemic and bleeding events post ACS. The reduction of CV death, MI or stroke with ticagrelor compared with clopidogrel in PAD patients was consistent with the overall trial result although it did not reach statistical significance. Overall major bleeding was similar between the therapies.

    View details for DOI 10.1177/2047487314533215

    View details for Web of Science ID 000354129500006

    View details for PubMedID 24830710

  • The future of cardiovascular clinical research in North America and beyond-addressing challenges and leveraging opportunities through unique academic and grassroots collaborations AMERICAN HEART JOURNAL Roe, M. T., Mahaffey, K. W., Ezekowitz, J. A., Alexander, J. H., Goodman, S. G., Hernandez, A., Temple, T., Berdan, L., Califf, R. M., Harrington, R. A., Peterson, E. D., Armstrong, P. W. 2015; 169 (6): 743-750

    Abstract

    Recent developments have highlighted the challenges facing cardiovascular clinical research in global contemporary practice, particularly in North America, including shifting priorities for drug development targets, increasing regulatory requirements, and expensive operational approaches for conducting randomized clinical trials. Nonetheless, emerging trends such as the consolidation of practices and hospitals into integrated health systems, the integration of electronic health records from thousands of practices into large data repositories to support prospective research studies, and streamlined operational approaches such as registry-based trials and risk-based monitoring have created numerous opportunities to disrupt the clinical research paradigm. Within this context, academic research organizations around the globe, particularly a strengthened collaboration of 3 established academic research organizations in North America, are uniquely positioned to promote and develop grassroots collaborations across all types of clinical practices, to delineate successful solutions to obstacles that limit clinical research initiatives, and to guide the future of cardiovascular research in the global research environment.

    View details for DOI 10.1016/j.ahj.2015.03.002

    View details for Web of Science ID 000355213300001

  • Glycoprotein IIb/IIIa Receptor Inhibitors in Combination With Vorapaxar, a Platelet Thrombin Receptor Antagonist, Among Patients With Non-ST-Segment Elevation Acute Coronary Syndromes (from the TRACER Trial) AMERICAN JOURNAL OF CARDIOLOGY Cornel, J. H., Tricoci, P., Lokhnygina, Y., Moliterno, D. J., Wallentin, L., Armstrong, P. W., Aylward, P. E., Clare, R. M., Chen, E., Leonardi, S., de Werf, F. V., White, H. D., Held, C., Strony, J., Mahaffey, K. W., Harrington, R. A. 2015; 115 (10): 1325-1332

    Abstract

    We evaluated the interaction between protease-activated receptor-1 antagonist vorapaxar and concomitant glycoprotein (GP) IIb/IIIa receptor inhibitors in patients with non-ST-segment elevation acute coronary syndromes who underwent PCI. In Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome trial, 12,944 patients with non-ST-segment elevation acute coronary syndromes were randomized to vorapaxar or placebo. Administration of GP IIb/IIIa receptor inhibitors was allowed at the treating physician's discretion. We investigated whether use of GP IIb/IIIa receptor inhibitors modified vorapaxar's effect on non-coronary artery bypass grafting (CABG)-related bleeding at 7 days and ischemic events at 30 days. In total, 7,455 patients underwent PCI during index hospitalization. Of these, 2,023 patients (27.1%) received inhibitors and 5,432 (72.9%) did not. Vorapaxar was associated with a numerically higher rate of non-CABG-related moderate/severe Global Use of Strategies to Open Occluded Arteries (GUSTO) bleeding at 7 days compared with placebo in those who did (1.3% vs 1.0%) and did not (0.6% vs 0.4%) receive GP IIb/IIIa receptor inhibitors. Ischemic end point rates at 30 days were not significantly lower with vorapaxar versus placebo. Increased rates of non-CABG GUSTO moderate/severe bleeding were observed in patients who received GP IIb/IIIa receptor inhibitors versus those who did not (adjusted hazard ratio [HR] 1.77, 95% confidence interval [CI] 0.43 to 7.35 in placebo arm; adjusted HR 2.02, 95% CI 0.62 to 6.61 in vorapaxar arm) and in those who received vorapaxar versus placebo (adjusted HR 1.54, 95% CI 0.36 to 6.56 in the GP IIb/IIIa group; adjusted HR 1.34, 95% CI 0.44 to 4.07 in the no-GP IIb/IIIa group). No interaction was found between vorapaxar and inhibitor use up to 7 days (P interaction = 0.89) nor at the end of the treatment (P interaction = 0.74); however, the event rate was low. Also, no interaction was observed for efficacy end points after PCI at 30 days or at the end of the treatment. In conclusion, GP IIb/IIIa receptor inhibitor use plus dual antiplatelet therapy in a population with non-ST-segment elevation myocardial infarction planned for PCI was frequent but did not interact with vorapaxar's efficacy or safety. Nonetheless, GP IIb/IIIa receptor inhibitors and vorapaxar were associated with increased bleeding risk, and their combined use may result in additive effects on bleeding rates.

    View details for DOI 10.1016/j.amjcard.2015.02.043

    View details for Web of Science ID 000354422500001

  • Glycoprotein IIb/IIIa Receptor Inhibitors in Combination With Vorapaxar, a Platelet Thrombin Receptor Antagonist, Among Patients With Non-ST-Segment Elevation Acute Coronary Syndromes (from the TRACER Trial). American journal of cardiology Cornel, J. H., Tricoci, P., Lokhnygina, Y., Moliterno, D. J., Wallentin, L., Armstrong, P. W., Aylward, P. E., Clare, R. M., Chen, E., Leonardi, S., Van de Werf, F., White, H. D., Held, C., Strony, J., Mahaffey, K. W., Harrington, R. A. 2015; 115 (10): 1325-1332

    Abstract

    We evaluated the interaction between protease-activated receptor-1 antagonist vorapaxar and concomitant glycoprotein (GP) IIb/IIIa receptor inhibitors in patients with non-ST-segment elevation acute coronary syndromes who underwent PCI. In Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome trial, 12,944 patients with non-ST-segment elevation acute coronary syndromes were randomized to vorapaxar or placebo. Administration of GP IIb/IIIa receptor inhibitors was allowed at the treating physician's discretion. We investigated whether use of GP IIb/IIIa receptor inhibitors modified vorapaxar's effect on non-coronary artery bypass grafting (CABG)-related bleeding at 7 days and ischemic events at 30 days. In total, 7,455 patients underwent PCI during index hospitalization. Of these, 2,023 patients (27.1%) received inhibitors and 5,432 (72.9%) did not. Vorapaxar was associated with a numerically higher rate of non-CABG-related moderate/severe Global Use of Strategies to Open Occluded Arteries (GUSTO) bleeding at 7 days compared with placebo in those who did (1.3% vs 1.0%) and did not (0.6% vs 0.4%) receive GP IIb/IIIa receptor inhibitors. Ischemic end point rates at 30 days were not significantly lower with vorapaxar versus placebo. Increased rates of non-CABG GUSTO moderate/severe bleeding were observed in patients who received GP IIb/IIIa receptor inhibitors versus those who did not (adjusted hazard ratio [HR] 1.77, 95% confidence interval [CI] 0.43 to 7.35 in placebo arm; adjusted HR 2.02, 95% CI 0.62 to 6.61 in vorapaxar arm) and in those who received vorapaxar versus placebo (adjusted HR 1.54, 95% CI 0.36 to 6.56 in the GP IIb/IIIa group; adjusted HR 1.34, 95% CI 0.44 to 4.07 in the no-GP IIb/IIIa group). No interaction was found between vorapaxar and inhibitor use up to 7 days (P interaction = 0.89) nor at the end of the treatment (P interaction = 0.74); however, the event rate was low. Also, no interaction was observed for efficacy end points after PCI at 30 days or at the end of the treatment. In conclusion, GP IIb/IIIa receptor inhibitor use plus dual antiplatelet therapy in a population with non-ST-segment elevation myocardial infarction planned for PCI was frequent but did not interact with vorapaxar's efficacy or safety. Nonetheless, GP IIb/IIIa receptor inhibitors and vorapaxar were associated with increased bleeding risk, and their combined use may result in additive effects on bleeding rates.

    View details for DOI 10.1016/j.amjcard.2015.02.043

    View details for PubMedID 25776457

  • The Effects of Cinacalcet in Older and Younger Patients on Hemodialysis: The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial. Clinical journal of the American Society of Nephrology Parfrey, P. S., Drüeke, T. B., Block, G. A., Correa-Rotter, R., Floege, J., Herzog, C. A., London, G. M., Mahaffey, K. W., Moe, S. M., Wheeler, D. C., Kubo, Y., Dehmel, B., Goodman, W. G., Chertow, G. M. 2015; 10 (5): 791-799

    Abstract

    The calcimimetic cinacalcet reduced the risk of death or cardiovascular (CV) events in older, but not younger, patients with moderate to severe secondary hyperparathyroidism (HPT) who were receiving hemodialysis. To determine whether the lower risk in younger patients might be due to lower baseline CV risk and more frequent use of cointerventions that reduce parathyroid hormone (kidney transplantation, parathyroidectomy, and commercial cinacalcet use), this study examined the effects of cinacalcet in older (≥65 years, n=1005) and younger (<65 years, n=2878) patients.Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) was a global, multicenter, randomized placebo-controlled trial in 3883 prevalent patients on hemodialysis, whose outcomes included death, major CV events, and development of severe unremitting HPT. The age subgroup analysis was prespecified.Older patients had higher baseline prevalence of diabetes mellitus and CV comorbidity. Annualized rates of kidney transplantation and parathyroidectomy were >3-fold higher in younger relative to older patients and were more frequent in patients randomized to placebo. In older patients, the adjusted relative hazard (95% confidence interval) for the primary composite (CV) end point (cinacalcet versus placebo) was 0.70 (0.60 to 0.81); in younger patients, the relative hazard was 0.97 (0.86 to 1.09). Corresponding adjusted relative hazards for mortality were 0.68 (0.51 to 0.81) and 0.99 (0.86 to 1.13). Reduction in the risk of severe unremitting HPT was similar in both groups.In the EVOLVE trial, cinacalcet decreased the risk of death and of major CV events in older, but not younger, patients with moderate to severe HPT who were receiving hemodialysis. Effect modification by age may be partly explained by differences in underlying CV risk and differential application of cointerventions that reduce parathyroid hormone.

    View details for DOI 10.2215/CJN.07730814

    View details for PubMedID 25710802

  • Impact of obstructive sleep apnea and continuous positive airway pressure therapy on outcomes in patients with atrial fibrillation-Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) AMERICAN HEART JOURNAL Holmqvist, F., Guan, N., Zhu, Z., Kowey, P. R., Allen, L. A., Fonarow, G. C., Hylek, E. M., Mahaffey, K. W., Freeman, J. V., Chang, P., Holmes, D. N., Peterson, E. D., Piccini, J. P., Gersh, B. J. 2015; 169 (5): 647-U93

    Abstract

    Obstructive sleep apnea (OSA) is common in patients with atrial fibrillation (AF). Little is known about the impact of OSA on AF treatment and long-term outcomes. We studied whether patients with OSA have a greater likelihood of progressing to more persistent forms of AF or require more hospitalizations and/or worse outcomes compared with patients without OSA.A total of 10,132 patients were enrolled between June 2010 and August 2011 in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) and followed for up to 2 years. The prevalence of OSA and continuous positive airway pressure (CPAP) treatment was captured at baseline. The association between OSA and major cardiovascular outcomes was analyzed using multivariable hierarchical logistic regression modeling and Cox frailty regression model.Of the 10,132 patients with AF, 1,841 had OSA. Patients with OSA were more symptomatic (22% vs 16% severe/disabling symptoms; P < .0001) and more often on rhythm control therapy (35% vs 31%; P = .0037). In adjusted analyses, patients with OSA had higher risk of hospitalization (hazard ratio [HR], 1.12; 95% CI, 1.03-1.22; P = .0078), but no difference in the risks of death (HR, 0.94; 95% CI, 0.77-1.15; P = .54); the composite of CV death, myocardial infarction, and stroke/transient ischemic attack (HR, 1.07; 95% CI, 0.85-1.34; P = .57); major bleeding (HR, 1.18; 95% CI, 0.96-1.46; P = .11); or AF progression (HR, 1.06; 95% CI, 0.89-1.28; P = .51). Patients with OSA on CPAP treatment were less likely to progress to more permanent forms of AF compared with patients without CPAP (HR, 0.66; 95% CI, 0.46-0.94; P = .021).Compared with those without, AF patients with OSA have worse symptoms and higher risks of hospitalization, but similar mortality, major adverse cardiovascular outcome, and AF progression rates.NCT01165710 (http://www.clinicaltrials.gov).

    View details for DOI 10.1016/j.ahj.2014.12.024

    View details for Web of Science ID 000354172400011

    View details for PubMedID 25965712

  • Assessing the treatment effect in a randomized controlled trial with extensive non-adherence: the EVOLVE trial PHARMACEUTICAL STATISTICS Kubo, Y., Sterling, L. R., Parfrey, P. S., Gill, K., Mahaffey, K. W., Gioni, I., Trotman, M., Dehmel, B., Chertow, G. M. 2015; 14 (3): 242-251

    Abstract

    Intention-to-treat (ITT) analysis is widely used to establish efficacy in randomized clinical trials. However, in a long-term outcomes study where non-adherence to study drug is substantial, the on-treatment effect of the study drug may be underestimated using the ITT analysis. The analyses presented herein are from the EVOLVE trial, a double-blind, placebo-controlled, event-driven cardiovascular outcomes study conducted to assess whether a treatment regimen including cinacalcet compared with placebo in addition to other conventional therapies reduces the risk of mortality and major cardiovascular events in patients receiving hemodialysis with secondary hyperparathyroidism. Pre-specified sensitivity analyses were performed to assess the impact of non-adherence on the estimated effect of cinacalcet. These analyses included lag-censoring, inverse probability of censoring weights (IPCW), rank preserving structural failure time model (RPSFTM) and iterative parameter estimation (IPE). The relative hazard (cinacalcet versus placebo) of mortality and major cardiovascular events was 0.93 (95% confidence interval 0.85, 1.02) using the ITT analysis; 0.85 (0.76, 0.95) using lag-censoring analysis; 0.81 (0.70, 0.92) using IPCW; 0.85 (0.66, 1.04) using RPSFTM and 0.85 (0.75, 0.96) using IPE. These analyses, while not providing definitive evidence, suggest that the intervention may have an effect while subjects are receiving treatment. The ITT method remains the established method to evaluate efficacy of a new treatment; however, additional analyses should be considered to assess the on-treatment effect when substantial non-adherence to study drug is expected or observed.

    View details for DOI 10.1002/pst.1680

    View details for PubMedID 25851955

  • The Effects of Cinacalcet in Older and Younger Patients on Hemodialysis: The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Parfrey, P. S., Drueeke, T. B., Block, G. A., Correa-Rotter, R., Floege, J., Herzog, C. A., London, G. M., Mahaffey, K. W., Moe, S. M., Wheeler, D. C., Kubo, Y., Dehmel, B., Goodman, W. G., Chertow, G. M. 2015; 10 (5): 791-799

    Abstract

    The calcimimetic cinacalcet reduced the risk of death or cardiovascular (CV) events in older, but not younger, patients with moderate to severe secondary hyperparathyroidism (HPT) who were receiving hemodialysis. To determine whether the lower risk in younger patients might be due to lower baseline CV risk and more frequent use of cointerventions that reduce parathyroid hormone (kidney transplantation, parathyroidectomy, and commercial cinacalcet use), this study examined the effects of cinacalcet in older (≥65 years, n=1005) and younger (<65 years, n=2878) patients.Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) was a global, multicenter, randomized placebo-controlled trial in 3883 prevalent patients on hemodialysis, whose outcomes included death, major CV events, and development of severe unremitting HPT. The age subgroup analysis was prespecified.Older patients had higher baseline prevalence of diabetes mellitus and CV comorbidity. Annualized rates of kidney transplantation and parathyroidectomy were >3-fold higher in younger relative to older patients and were more frequent in patients randomized to placebo. In older patients, the adjusted relative hazard (95% confidence interval) for the primary composite (CV) end point (cinacalcet versus placebo) was 0.70 (0.60 to 0.81); in younger patients, the relative hazard was 0.97 (0.86 to 1.09). Corresponding adjusted relative hazards for mortality were 0.68 (0.51 to 0.81) and 0.99 (0.86 to 1.13). Reduction in the risk of severe unremitting HPT was similar in both groups.In the EVOLVE trial, cinacalcet decreased the risk of death and of major CV events in older, but not younger, patients with moderate to severe HPT who were receiving hemodialysis. Effect modification by age may be partly explained by differences in underlying CV risk and differential application of cointerventions that reduce parathyroid hormone.

    View details for DOI 10.2215/CJN.07730814

    View details for Web of Science ID 000354144900011

    View details for PubMedCentralID PMC4422239

  • Efficacy and safety of canagliflozin, an inhibitor of sodium-glucose cotransporter 2, when used in conjunction with insulin therapy in patients with type 2 diabetes. Diabetes care Neal, B., Perkovic, V., de Zeeuw, D., Mahaffey, K. W., Fulcher, G., Ways, K., Desai, M., Shaw, W., Capuano, G., Alba, M., Jiang, J., Vercruysse, F., Meininger, G., Matthews, D. 2015; 38 (3): 403-411

    Abstract

    There are limited data about the effects of sodium-glucose cotransporter 2 inhibitors when used with insulin. We report the efficacy and safety of canagliflozin in patients with type 2 diabetes using insulin.The CANagliflozin CardioVascular Assessment Study is a double-blind, placebo-controlled study that randomized participants to placebo, canagliflozin 100 mg, or canagliflozin 300 mg once daily, added to a range of therapies. The primary end point of this substudy was the change in HbA1c from baseline at 18 weeks among patients using insulin; 52-week effects were also examined.Individuals receiving insulin at baseline were randomized to receive placebo (n = 690), canagliflozin 100 mg (n = 692), or canagliflozin 300 mg (n = 690). These individuals were 66% male and had a median age of 63 years, mean HbA1c of 8.3% (67 mmol/mol), BMI of 33.1 kg/m(2), estimated glomerular filtration rate of 75 mL/min/1.73 m(2), fasting plasma glucose of 9.2 mmol/L, and a median daily insulin dose of 60 IU. Most individuals were using basal/bolus insulin. Reductions in HbA1c with canagliflozin 100 and 300 mg versus placebo were -0.62% (95% CI -0.69, -0.54; -6.8 mmol/mol [95% CI -7.5, -5.9]; P < 0.001) and -0.73% (95% CI -0.81, -0.65; -8.0 mmol/mol [95% CI -8.9, -7.1]; P < 0.001) at 18 weeks and -0.58% (95% CI -0.68, -0.48; -6.3 mmol/mol [95% CI -7.4, -5.2]) and -0.73% (95% CI -0.83, -0.63; -8.0 mmol/mol [95% CI -9.1, -6.9]) at 52 weeks. There were significant falls in fasting plasma glucose, body weight, and blood pressure at both time points and there was a greater incidence of hypoglycemia, genital mycotic infections, and hypovolemia with both canagliflozin doses.Canagliflozin added to insulin therapy improved glycemic control and decreased body weight. There was a greater frequency of several anticipated side effects, although few led to discontinuation of treatment.

    View details for DOI 10.2337/dc14-1237

    View details for PubMedID 25468945

  • Outcomes With Cangrelor Versus Clopidogrel on a Background of Bivalirudin Insights From the CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI]) JACC-CARDIOVASCULAR INTERVENTIONS White, H. D., Bhatt, D. L., Gibson, C. M., Hamm, C. W., Mahaffey, K. W., Price, M. J., Steg, P. G., Stone, G. W., Cortese, B., Wilensky, M., Deliargyris, E. N., Liu, T., Prats, J., Harrington, R. A. 2015; 8 (3): 424-433

    Abstract

    The aim of this study was to examine the efficacy and bleeding outcomes of cangrelor in patients in the CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI]) who underwent percutaneous coronary intervention with bivalirudin.Cangrelor is a potent intravenous P2Y12 inhibitor with rapid onset and offset. In the CHAMPION PHOENIX, cangrelor compared with clopidogrel significantly reduced 48-h ischemic events including stent thrombosis, without increasing major bleeding. Bivalirudin has demonstrated ischemic outcomes similar to those with heparin plus glycoprotein IIb/IIIa inhibition, with reduced bleeding but increased early stent thrombosis.In the modified intent-to-treat population, 2,059 patients (18.8%) received bivalirudin, with 1,014 patients in the cangrelor treatment arm and 1,045 in the clopidogrel treatment arm.At 48 h, the primary endpoint of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis was lower with cangrelor versus clopidogrel (48 [4.7%] vs. 70 [6.7%]; odds ratio [OR]: 0.68, p = 0.047). Death was similar in both arms (2 [0.2%] vs. 2 [0.2%]). Myocardial infarction was reduced by cangrelor (37 [3.6%] vs. 59 [5.6%]; OR: 0.63, p = 0.03), as was death/myocardial infarction (39 [3.8%] vs. 61 [5.8%]; OR: 0.65, p = 0.04). Cangrelor was associated with a nonsignificant trend toward less stent thrombosis (7 [0.7%] vs. 15 [1.4%]; OR: 0.48, p = 0.10), which was evident within 2 h after percutaneous coronary intervention (p = 0.057). GUSTO (Global Use of Strategies to Open Occluded Arteries) severe bleeding was similar in both arms (2 of 1,021 [0.2%] vs. 2 of 1,055 [0.2%]) as were other bleeding definitions and transfusions. Efficacy and safety results were consistent in patients with stable angina, non-ST-segment elevation acute coronary syndrome, and ST-segment elevation myocardial infarction (p for interaction: 0.62 and 0.29).Cangrelor may offer an attractive benefit risk profile when used in combination with bivalirudin.

    View details for DOI 10.1016/j.jcin.2014.09.025

    View details for Web of Science ID 000351221300014

    View details for PubMedID 25703887

  • Use and Outcomes Associated With Bridging During Anticoagulation Interruptions in Patients With Atrial Fibrillation: Findings From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). Circulation Steinberg, B. A., Peterson, E. D., Kim, S., Thomas, L., Gersh, B. J., Fonarow, G. C., Kowey, P. R., Mahaffey, K. W., Sherwood, M. W., Chang, P., Piccini, J. P., Ansell, J. 2015; 131 (5): 488-494

    Abstract

    Temporary interruption of oral anticoagulation for procedures is often required, and some propose using bridging anticoagulation. However, the use and outcomes of bridging during oral anticoagulation interruptions in clinical practice are unknown.The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry is a prospective, observational registry study of US outpatients with atrial fibrillation. We recorded incident temporary interruptions of oral anticoagulation for a procedure, including the use and type of bridging therapy. Outcomes included multivariable-adjusted rates of myocardial infarction, stroke or systemic embolism, major bleeding, cause-specific hospitalization, and death within 30 days. Of 7372 patients treated with oral anticoagulation, 2803 overall interruption events occurred in 2200 patients (30%) at a median follow-up of 2 years. Bridging anticoagulants were used in 24% (n=665), predominantly low-molecular-weight heparin (73%, n=487) and unfractionated heparin (15%, n=97). Bridged patients were more likely to have had prior cerebrovascular events (22% versus 15%; P=0.0003) and mechanical valve replacements (9.6% versus 2.4%; P<0.0001); however, there was no difference in CHA2DS2-VASc scores (scores ≥2 in 94% versus 95%; P=0.5). Bleeding events were more common in bridged than nonbridged patients (5.0% versus 1.3%; adjusted odds ratio, 3.84; P<0.0001). The incidence of myocardial infarction, stroke or systemic embolism, major bleeding, hospitalization, or death within 30 days was also significantly higher in patients receiving bridging (13% versus 6.3%; adjusted odds ratio, 1.94; P=0.0001).Bridging anticoagulation is used in one quarter of anticoagulation interruptions and is associated with higher risk for bleeding and adverse events. These data do not support the use of routine bridging, and additional data are needed to identify best practices concerning anticoagulation interruptions.http://www.clinicaltrials.gov. Unique identifier: NCT01165710.

    View details for DOI 10.1161/CIRCULATIONAHA.114.011777

    View details for PubMedID 25499873

    View details for PubMedCentralID PMC4315748

  • Centralized adjudication of cardiovascular end points in cardiovascular and noncardiovascular pharmacologic trials: A report from the Cardiac Safety Research Consortium AMERICAN HEART JOURNAL Seltzer, J. H., Turner, J. R., Geiger, M. J., Rosano, G., Mahaffey, K. W., White, W. B., Sabol, M. B., Stockbridge, N., Sager, P. T. 2015; 169 (2): 197-204

    Abstract

    This white paper provides a summary of presentations and discussions at a cardiovascular (CV) end point adjudication think tank cosponsored by the Cardiac Safety Research Committee and the US Food and Drug Administration (FDA) that was convened at the FDA's White Oak headquarters on November 6, 2013. Attention was focused on the lack of clarity concerning the need for end point adjudication in both CV and non-CV trials: there is currently an absence of widely accepted academic or industry standards and a definitive regulatory policy on how best to structure and use clinical end point committees (CECs). This meeting therefore provided a forum for leaders in the fields of CV clinical trials and CV safety to develop a foundation of initial best practice recommendations for use in future CEC charters. Attendees included representatives from pharmaceutical companies, regulatory agencies, end point adjudication specialist groups, clinical research organizations, and active, academically based adjudicators. The manuscript presents recommendations from the think tank regarding when CV end point adjudication should be considered in trials conducted by cardiologists and by noncardiologists as well as detailing key issues in the composition of a CEC and its charter. In addition, it presents several recommended best practices for the establishment and operation of CECs. The science underlying CV event adjudication is evolving, and suggestions for additional areas of research will be needed to continue to advance this science. This manuscript does not constitute regulatory guidance.

    View details for DOI 10.1016/j.ahj.2014.11.003

    View details for Web of Science ID 000349212800003

  • Higher risk of death and stroke in patients with persistent vs. paroxysmal atrial fibrillation: results from the ROCKET-AF Trial. European heart journal Steinberg, B. A., Hellkamp, A. S., Lokhnygina, Y., Patel, M. R., Breithardt, G., Hankey, G. J., Becker, R. C., Singer, D. E., Halperin, J. L., Hacke, W., Nessel, C. C., Berkowitz, S. D., Mahaffey, K. W., Fox, K. A., Califf, R. M., Piccini, J. P. 2015; 36 (5): 288-296

    Abstract

    Anticoagulation prophylaxis for stroke is recommended for at-risk patients with either persistent or paroxysmal atrial fibrillation (AF). We compared outcomes in patients with persistent vs. paroxysmal AF receiving oral anticoagulation.Patients randomized in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial (n = 14 264) were grouped by baseline AF category: paroxysmal or persistent. Multivariable adjustment was performed to compare thrombo-embolic events, bleeding, and death between groups, in high-risk subgroups, and across treatment assignment (rivaroxaban or warfarin). Of 14 062 patients, 11 548 (82%) had persistent AF and 2514 (18%) had paroxysmal AF. Patients with persistent AF were marginally older (73 vs. 72, P = 0.03), less likely female (39 vs. 45%, P < 0.0001), and more likely to have previously used vitamin K antagonists (64 vs. 56%, P < 0.0001) compared with patients with paroxysmal AF. In patients randomized to warfarin, time in therapeutic range was similar (58 vs. 57%, P = 0.94). Patients with persistent AF had higher adjusted rates of stroke or systemic embolism (2.18 vs. 1.73 events per 100-patient-years, P = 0.048) and all-cause mortality (4.78 vs. 3.52, P = 0.006). Rates of major bleeding were similar (3.55 vs. 3.31, P = 0.77). Rates of stroke or systemic embolism in both types of AF did not differ by treatment assignment (rivaroxaban vs. warfarin, Pinteraction = 0.6).In patients with AF at moderate-to-high risk of stroke receiving anticoagulation, those with persistent AF have a higher risk of thrombo-embolic events and worse survival compared with paroxysmal AF.

    View details for DOI 10.1093/eurheartj/ehu359

    View details for PubMedID 25209598

    View details for PubMedCentralID PMC4313363

  • Effects of Cinacalcet on Atherosclerotic and Nonatherosclerotic Cardiovascular Events in Patients Receiving Hemodialysis: The EValuation Of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) Trial JOURNAL OF THE AMERICAN HEART ASSOCIATION Wheeler, D. C., London, G. M., Parfrey, P. S., Block, G. A., Correa-Rotter, R., Dehmel, B., Drueeke, T. B., Floege, J., Kubo, Y., Mahaffey, K. W., Goodman, W. G., Moe, S. M., Trotman, M., Abdalla, S., Chertow, G. M., Herzog, C. A. 2015; 4 (1)
  • Centralized adjudication of cardiovascular end points in cardiovascular and noncardiovascular pharmacologic trials: a report from the Cardiac Safety Research Consortium. American heart journal Seltzer, J. H., Turner, J. R., Geiger, M. J., Rosano, G. n., Mahaffey, K. W., White, W. B., Sabol, M. B., Stockbridge, N. n., Sager, P. T. 2015; 169 (2): 197–204

    Abstract

    This white paper provides a summary of presentations and discussions at a cardiovascular (CV) end point adjudication think tank cosponsored by the Cardiac Safety Research Committee and the US Food and Drug Administration (FDA) that was convened at the FDA's White Oak headquarters on November 6, 2013. Attention was focused on the lack of clarity concerning the need for end point adjudication in both CV and non-CV trials: there is currently an absence of widely accepted academic or industry standards and a definitive regulatory policy on how best to structure and use clinical end point committees (CECs). This meeting therefore provided a forum for leaders in the fields of CV clinical trials and CV safety to develop a foundation of initial best practice recommendations for use in future CEC charters. Attendees included representatives from pharmaceutical companies, regulatory agencies, end point adjudication specialist groups, clinical research organizations, and active, academically based adjudicators. The manuscript presents recommendations from the think tank regarding when CV end point adjudication should be considered in trials conducted by cardiologists and by noncardiologists as well as detailing key issues in the composition of a CEC and its charter. In addition, it presents several recommended best practices for the establishment and operation of CECs. The science underlying CV event adjudication is evolving, and suggestions for additional areas of research will be needed to continue to advance this science. This manuscript does not constitute regulatory guidance.

    View details for PubMedID 25641528

  • Efficacy and Safety of Vorapaxar in Non-ST-Segment Elevation Acute Coronary Syndrome Patients Undergoing Noncardiac Surgery. Journal of the American Heart Association van Diepen, S., Tricoci, P., Podder, M., Westerhout, C. M., Aylward, P. E., Held, C., Van de Werf, F., Strony, J., Wallentin, L., Moliterno, D. J., White, H. D., Mahaffey, K. W., Harrington, R. A., Armstrong, P. W. 2015; 4 (12)

    Abstract

    Perioperative antiplatelet agents potentially increase bleeding after non-ST-segment elevation (NSTE) acute coronary syndromes (ACS). The protease-activated receptor 1 antagonist vorapaxar reduced cardiovascular events and was associated with increased bleeding versus placebo in NSTE ACS, but its efficacy and safety in noncardiac surgery (NCS) remain unknown. We aimed to evaluate ischemic, bleeding, and long-term outcomes of vorapaxar in NCS after NSTE ACS.In the TRACER trial, 2202 (17.0%) patients underwent major or minor NCS after NSTE ACS over 1.5 years (median); continuing study treatment perioperatively was recommended. The primary ischemic end point for this analysis was cardiovascular death, myocardial infarction, stent thrombosis, or urgent revascularization within 30 days of NCS. Safety outcomes included 30-day NCS bleeding and GUSTO moderate/severe bleeding. Overall, 1171 vorapaxar and 1031 placebo patients underwent NCS. Preoperative aspirin and thienopyridine use was 96.8% versus 97.7% (P=0.235) and 89.1% versus 86.1% (P=0.036) for vorapaxar versus placebo, respectively. Within 30 days of NCS, no differences were observed in the primary ischemic end point between vorapaxar and placebo groups (3.4% versus 3.9%; adjusted odds ratio 0.81, 95% CI 0.50 to 1.33, P=0.41). Similarly, no differences in NCS bleeding (3.9% versus 3.4%; adjusted odds ratio 1.41, 95% CI 0.87 to 2.31, P=0.17) or GUSTO moderate/severe bleeding (4.2% versus 3.7%; adjusted odds ratio 1.15, 95% CI, 0.72 to 1.83, P=0.55) were observed. In a 30-day landmarked analysis, NCS patients had a higher long-term risk of the ischemic end point (adjusted hazard ratio 1.62, 95% CI 1.33 to 1.97, P<0.001) and GUSTO moderate/severe bleeding (adjusted hazard ratio 5.63, 95% CI 3.98 to 7.97, P<0.001) versus patients who did not undergo NCS, independent of study treatment.NCS after NSTE ACS is common and associated with more ischemic outcomes and bleeding. Vorapaxar after NSTE ACS was not associated with increased perioperative ischemic or bleeding events in patients undergoing NCS.

    View details for DOI 10.1161/JAHA.115.002546

    View details for PubMedID 26672080

    View details for PubMedCentralID PMC4845287

  • Alternative Calculations of Individual Patient Time in Therapeutic Range While Taking Warfarin: Results From the ROCKET AF Trial. Journal of the American Heart Association Singer, D. E., Hellkamp, A. S., Yuan, Z., Lokhnygina, Y., Patel, M. R., Piccini, J. P., Hankey, G. J., Breithardt, G., Halperin, J. L., Becker, R. C., Hacke, W., Nessel, C. C., Mahaffey, K. W., Fox, K. A., Califf, R. M. 2015; 4 (3)

    Abstract

    In the ROCKET AF (Rivaroxaban-Once-daily, oral, direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) trial, marked regional differences in control of warfarin anticoagulation, measured as the average individual patient time in the therapeutic range (iTTR) of the international normalized ratio (INR), were associated with longer inter-INR test intervals. The standard Rosendaal approach can produce biased low estimates of TTR after an appropriate dose change if the follow-up INR test interval is prolonged. We explored the effect of alternative calculations of TTR that more immediately account for dose changes on regional differences in mean iTTR in the ROCKET AF trial.We used an INR imputation method that accounts for dose change. We compared group mean iTTR values between our dose change-based method with the standard Rosendaal method and determined that the differences between approaches depended on the balance of dose changes that produced in-range INRs ("corrections") versus INRs that were out of range in the opposite direction ("overshoots"). In ROCKET AF, the overall mean iTTR of 55.2% (Rosendaal) increased up to 3.1% by using the dose change-based approach, depending on assumptions. However, large inter-regional differences in anticoagulation control persisted.TTR, the standard measure of control of warfarin anticoagulation, depends on imputing daily INR values for the vast majority of follow-up days. Our TTR calculation method may better reflect the impact of warfarin dose changes than the Rosendaal approach. In the ROCKET AF trial, this dose change-based approach led to a modest increase in overall mean iTTR but did not materially affect the large inter-regional differences previously reported.ClinicalTrials.gov. Unique identifier: NCT00403767.

    View details for DOI 10.1161/JAHA.114.001349

    View details for PubMedID 25736441

  • Clinical characteristics and outcomes with rivaroxaban vs. warfarin in patients with non-valvular atrial fibrillation but underlying native mitral and aortic valve disease participating in the ROCKET AF trial EUROPEAN HEART JOURNAL Breithardt, G., Baumgartner, H., Berkowitz, S. D., Hellkamp, A. S., Piccini, J. P., Stevens, S. R., Lokhnygina, Y., Patel, M. R., Halperin, J. L., Singer, D. E., Hankey, G. J., Hacke, W., Becker, R. C., Nessel, C. C., Mahaffey, K. W., Fox, K. A., Califf, R. M. 2014; 35 (47): 3377-3385

    Abstract

    We investigated clinical characteristics and outcomes of patients with significant valvular disease (SVD) in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial.ROCKET AF excluded patients with mitral stenosis or artificial valve prostheses. We used Cox regression to adjust comparisons for potential confounders. Among 14 171 patients, 2003 (14.1%) had SVD; they were older and had more comorbidities than patients without SVD. The rate of stroke or systemic embolism with rivaroxaban vs. warfarin was consistent among patients with SVD [2.01 vs. 2.43%; hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.55-1.27] and without SVD (1.96 vs. 2.22%; HR 0.89, 95% CI 0.75-1.07; interaction P = 0.76). However, rates of major and non-major clinically relevant bleeding with rivaroxaban vs. warfarin were higher in patients with SVD (19.8% rivaroxaban vs. 16.8% warfarin; HR 1.25, 95% CI 1.05-1.49) vs. those without (14.2% rivaroxaban vs. 14.1% warfarin; HR 1.01, 95% CI 0.94-1.10; interaction P = 0.034), even when controlling for risk factors and potential confounders. In intracranial haemorrhage, there was no interaction between patients with and without SVD where the overall rate was lower among those randomized to rivaroxaban.Many patients with 'non-valvular atrial fibrillation' have significant valve lesions. Their risk of stroke is similar to that of patients without SVD after controlling for stroke risk factors. Efficacy of rivaroxaban vs. warfarin was similar in patients with and without SVD; however, the observed risk of bleeding was higher with rivaroxaban in patients with SVD but was the same among those without SVD. Atrial fibrillation patients with and without SVD experience the same stroke-preventive benefit of oral anticoagulants.

    View details for DOI 10.1093/eurheartj/ehu305

    View details for Web of Science ID 000346406800016

    View details for PubMedID 25148838

  • Effects of Cinacalcet on Atherosclerotic and Nonatherosclerotic Cardiovascular Events in Patients Receiving Hemodialysis: The EValuation Of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) Trial JOURNAL OF THE AMERICAN HEART ASSOCIATION Wheeler, D. C., London, G. M., Parfrey, P. S., Block, G. A., Correa-Rotter, R., Dehmel, B., Drueeke, T. B., Floege, J., Kubo, Y., Mahaffey, K. W., Goodman, W. G., Moe, S. M., Trotman, M., Abdalla, S., Chertow, G. M., Herzog, C. A. 2014; 3 (6)

    Abstract

    Premature cardiovascular disease limits the duration and quality of life on long-term hemodialysis. The objective of this study was to define the frequency of fatal and nonfatal cardiovascular events attributable to atherosclerotic and nonatherosclerotic mechanisms, risk factors for these events, and the effects of cinacalcet, using adjudicated data collected during the EValuation of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) Trial.EVOLVE was a randomized, double-blind, placebo-controlled clinical trial that randomized 3883 hemodialysis patients with moderate to severe secondary hyperparathyroidism to cinacalcet or matched placebo for up to 64 months. For this post hoc analysis, the outcome measure was fatal and nonfatal cardiovascular events reflecting atherosclerotic and nonatherosclerotic cardiovascular diseases. During the trial, 1518 patients experienced an adjudicated cardiovascular event, including 958 attributable to nonatherosclerotic disease. Of 1421 deaths during the trial, 768 (54%) were due to cardiovascular disease. Sudden death was the most frequent fatal cardiovascular event, accounting for 24.5% of overall mortality. Combining fatal and nonfatal cardiovascular events, randomization to cinacalcet reduced the rates of sudden death and heart failure. Patients randomized to cinacalcet experienced fewer nonatherosclerotic cardiovascular events (adjusted relative hazard 0.84, 95% CI 0.74 to 0.96), while the effect of cinacalcet on atherosclerotic events did not reach statistical significance.Accepting the limitations of post hoc analysis, any benefits of cinacalcet on cardiovascular disease in the context of hemodialysis may result from attenuation of nonatherosclerotic processes.Unique identifier: NCT00345839. URL: ClinicalTrials.gov.

    View details for DOI 10.1161/JAHA.114.001363

    View details for Web of Science ID 000345067600025

  • Effects of cinacalcet on atherosclerotic and nonatherosclerotic cardiovascular events in patients receiving hemodialysis: the EValuation Of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) trial. Journal of the American Heart Association Wheeler, D. C., London, G. M., Parfrey, P. S., Block, G. A., Correa-Rotter, R., Dehmel, B., Drüeke, T. B., Floege, J., Kubo, Y., Mahaffey, K. W., Goodman, W. G., Moe, S. M., Trotman, M., Abdalla, S., Chertow, G. M., Herzog, C. A. 2014; 3 (6)

    Abstract

    Premature cardiovascular disease limits the duration and quality of life on long-term hemodialysis. The objective of this study was to define the frequency of fatal and nonfatal cardiovascular events attributable to atherosclerotic and nonatherosclerotic mechanisms, risk factors for these events, and the effects of cinacalcet, using adjudicated data collected during the EValuation of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) Trial.EVOLVE was a randomized, double-blind, placebo-controlled clinical trial that randomized 3883 hemodialysis patients with moderate to severe secondary hyperparathyroidism to cinacalcet or matched placebo for up to 64 months. For this post hoc analysis, the outcome measure was fatal and nonfatal cardiovascular events reflecting atherosclerotic and nonatherosclerotic cardiovascular diseases. During the trial, 1518 patients experienced an adjudicated cardiovascular event, including 958 attributable to nonatherosclerotic disease. Of 1421 deaths during the trial, 768 (54%) were due to cardiovascular disease. Sudden death was the most frequent fatal cardiovascular event, accounting for 24.5% of overall mortality. Combining fatal and nonfatal cardiovascular events, randomization to cinacalcet reduced the rates of sudden death and heart failure. Patients randomized to cinacalcet experienced fewer nonatherosclerotic cardiovascular events (adjusted relative hazard 0.84, 95% CI 0.74 to 0.96), while the effect of cinacalcet on atherosclerotic events did not reach statistical significance.Accepting the limitations of post hoc analysis, any benefits of cinacalcet on cardiovascular disease in the context of hemodialysis may result from attenuation of nonatherosclerotic processes.Unique identifier: NCT00345839. URL: ClinicalTrials.gov.

    View details for DOI 10.1161/JAHA.114.001363

    View details for PubMedID 25404192

  • Vorapaxar with or without clopidogrel after non-ST-segment elevation acute coronary syndromes: Results from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome trial AMERICAN HEART JOURNAL Tricoci, P., Lokhnygina, Y., Huang, Z., Van de Werf, F., Cornel, J. H., Chen, E., Wallentin, L., Held, C., Aylward, P. E., Moliterno, D. J., Jennings, L. K., White, H. D., Armstrong, P. W., Harrington, R. A., Strony, J., Mahaffey, K. W. 2014; 168 (6): 869-?

    Abstract

    Protease-activated receptor 1 antagonism with vorapaxar represents a novel strategy for platelet inhibition. In TRACER, vorapaxar was compared with placebo plus standard of care among 12,944 patients with non-ST-segment elevation acute coronary syndromes. We anticipated that most patients would have received clopidogrel as part of standard care. We investigated the modification of vorapaxar's effect associated with clopidogrel use over time.The marginal structural model method was used to estimate causal modification of vorapaxar effect by use of clopidogrel over time. The primary outcomes were the composite of cardiovascular death, myocardial infarction, or stroke and Global Use of Strategies to Open Occluded Coronary Arteries moderate or severe bleeding. The event accrual period excluded the time during which clopidogrel was clinically warranted.Among 12,887 patients who received study medication, 11,117 (86.3%) received clopidogrel before randomization, of whom 38.5% stopped later in the trial (median time to stoppage 200 days with placebo; interquartile range [IQR] 14-367) (186 days with vorapaxar; IQR 17-366). In total, 1,770 (13.7%) patients were not on clopidogrel at randomization, of whom 47.8% started afterward (median time to start 2 days; IQR 2-4). During the period of event accrual, vorapaxar was associated with a 26% reduction in the composite of cardiovascular death, myocardial infarction, or stroke when used with clopidogrel (hazard ratio [HR] 0.74; 95% CI 0.60-0.91) and a 24% reduction when used without clopidogrel (HR 0.76; 95% CI 0.56-1.02) (interaction; P = .89). The hazard of Global Use of Strategies to Open Occluded Coronary Arteries bleeding with vorapaxar was not significantly different without clopidogrel (HR 1.33; 95% CI 0.81-2.20) or with clopidogrel (HR 1.09; 95% CI 0.76-1.56) (interaction; P = .53).We observed no interaction between vorapaxar and clopidogrel after non-ST-segment elevation acute coronary syndromes on efficacy or safety outcomes, supporting a complementary role of protease-activated receptor 1 and P2Y12 antagonism.

    View details for DOI 10.1016/j.ahj.2014.09.002

    View details for Web of Science ID 000345506100009

  • Causes of mortality with ticagrelor compared with clopidogrel in acute coronary syndromes HEART Varenhorst, C., Alstrom, U., Braun, O. O., Storey, R. F., Mahaffey, K. W., Bertilsson, M., Cannon, C. P., Scirica, B. M., Himmelmann, A., James, S. K., Wallentin, L., Held, C. 2014; 100 (22): 1762-?

    Abstract

    To describe specific causes of death and evaluate whether bleeding events and infection contributed to mortality in all ticagrelor-treated and clopidogrel-treated patients with acute coronary syndromes.In the PLATelet inhibition and patient Outcomes (PLATO) trial, ticagrelor significantly reduced rates of vascular and total death compared with clopidogrel. In the 905 patients who died postenrolment in the PLATO trial (n=18 624), reviewers, blinded to study treatment, subclassified direct causes of death and evaluated whether infection or bleeding events contributed to fatal events.Among vascular deaths, there were significantly fewer sudden deaths (63 (0.7%) vs 98 (1.1%), p<0.01) but no significant difference in deaths caused by acute myocardial infarction (179 (1.9%) vs 194 (2.1%), p=0.43) or heart failure (31 (0.3%) vs 42 (0.5%), p=0.20) with ticagrelor compared with clopidogrel. For non-vascular deaths, there was no difference between treatments in deaths directly caused by infection. Although, patients treated with ticagrelor were at lower risk for death where infection was either a direct cause or contributed to death (51 (0.5%) vs 76 (0.8%), HR 0.67 (0.47 to 0.95), p<0.05) but not for bleeding (42 (0.5%) vs 42 (0.5%), HR 0.99 (0.65 to 1.53), p=0.98).In this post hoc analysis, ticagrelor compared with clopidogrel reduced total and cardiovascular mortality, which appeared to be mainly mediated by a reduction in sudden death. Importantly, bleeding causing or contributing to death did not differ between treatments.NCT00391872 (http://www.clinicaltrial.gov).

    View details for DOI 10.1136/heartjnl-2014-305619

    View details for Web of Science ID 000345450400007

  • Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: Rationale and design of the ODYSSEY Outcomes trial AMERICAN HEART JOURNAL Schwartz, G. G., Bessac, L., Berdan, L. G., Bhatt, D. L., Bittner, V., Diaz, R., Goodman, S. G., Hanotin, C., Harrington, R. A., Jukema, J. W., Mahaffey, K. W., Moryusef, A., Pordy, R., Roe, M. T., Rorick, T., Sasiela, W. J., Shirodaria, C., Szarek, M., Tamby, J., Tricoci, P., White, H., Zeiher, A., Steg, P. G. 2014; 168 (5): 682-689

    Abstract

    Following acute coronary syndrome (ACS), the risk for future cardiovascular events is high and is related to levels of low-density lipoprotein cholesterol (LDL-C) even within the setting of intensive statin treatment. Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates LDL receptor expression and circulating levels of LDL-C. Antibodies to PCSK9 can produce substantial and sustained reductions of LDL-C. The ODYSSEY Outcomes trial tests the hypothesis that treatment with alirocumab, a fully human monoclonal antibody to PCSK9, improves cardiovascular outcomes after ACS.This Phase 3 study will randomize approximately 18,000 patients to receive biweekly injections of alirocumab (75-150 mg) or matching placebo beginning 1 to 12 months after an index hospitalization for acute myocardial infarction or unstable angina. Qualifying patients are treated with atorvastatin 40 or 80 mg daily, rosuvastatin 20 or 40 mg daily, or the maximum tolerated and approved dose of one of these agents and fulfill one of the following criteria: LDL-C ≥ 70 mg/dL, non-high-density lipoprotein cholesterol ≥ 100 mg/dL, or apolipoprotein B ≥ 80 mg/dL. The primary efficacy measure is time to first occurrence of coronary heart disease death, acute myocardial infarction, hospitalization for unstable angina, or ischemic stroke. The trial is expected to continue until 1613 primary end point events have occurred with minimum follow-up of at least 2 years, providing 90% power to detect a 15% hazard reduction. Adverse events of special interest include allergic events and injection site reactions. Interim analyses are planned when approximately 50% and 75% of the targeted number of primary end points have occurred.ODYSSEY Outcomes will determine whether the addition of the PCSK9 antibody alirocumab to intensive statin therapy reduces cardiovascular morbidity and mortality after ACS.

    View details for DOI 10.1016/j.ahj.2014.07.028

    View details for Web of Science ID 000344434300010

  • Challenges and solutions to pre- and post-randomization subgroup analyses. Current cardiology reports Desai, M., Pieper, K. S., Mahaffey, K. 2014; 16 (10): 531-?

    Abstract

    Subgroup analyses are commonly performed in the clinical trial setting with the purpose of illustrating that the treatment effect was consistent across different patient characteristics or identifying characteristics that should be targeted for treatment. There are statistical issues involved in performing subgroup analyses, however. These have been given considerable attention in the literature for analyses where subgroups are defined by a pre-randomization feature. Although subgroup analyses are often performed with subgroups defined by a post-randomization feature--including analyses that estimate the treatment effect among compliers--discussion of these analyses has been neglected in the clinical literature. Such analyses pose a high risk of presenting biased descriptions of treatment effects. We summarize the challenges of doing all types of subgroup analyses described in the literature. In particular, we emphasize issues with post-randomization subgroup analyses. Finally, we provide guidelines on how to proceed across the spectrum of subgroup analyses.

    View details for DOI 10.1007/s11886-014-0531-2

    View details for PubMedID 25135344

  • Prognostic implications of creatine kinase-MB measurements in ST-segment elevation myocardial infarction patients treated with primary percutaneous coronary intervention AMERICAN HEART JOURNAL Bagai, A., Schulte, P. J., Granger, C. B., Mahaffey, K. W., Christenson, R. H., Bell, G., Lopes, R. D., Green, C. L., Lincoff, A. M., Armstrong, P. W., Roe, M. T. 2014; 168 (4): 503-?

    Abstract

    Peak creatine kinase (CK)-MB concentration is related to reperfusion success and clinical outcomes after fibrinolytic therapy for acute myocardial infarction. However, prognostic implications of CK-MB measurements after primary percutaneous coronary intervention (PCI), which provides more predictable and consistent reperfusion, are unknown.We pooled 2,042 primary PCI-treated ST-segment elevation myocardial infarction (STEMI) patients from 3 trials with serial core laboratory-determined CK-MB measurements; 1,799 patients (88.1%) who survived to 36 hours and had ≥4 CK-MB measurements were studied. Cox regression modeling was performed to quantify the association between peak CK-MB concentration (and area under the time-concentration curve [AUC]) and mortality at 6 months, and death or congestive heart failure at 90 days.The median (25th-75th percentiles) peak CK-MB concentration and AUC measurement through 36 hours were 239 (109-429) ng/mL and 4,263 (2,081-7,124) ng/(mL h), respectively. By multivariable analysis, peak CK-MB concentration and AUC measurement were independently associated with 6-month mortality (adjusted hazard ratio [HR] 1.15, 95% CI 1.05-1.25, per 100-ng/mL increase, P = .002; and adjusted HR 1.09, 95% CI 1.03-1.14, per 1,000-ng/[mL h] increase, P < .001, respectively) and 90-day death or congestive heart failure (adjusted HR 1.26, 95% CI 1.18-1.34, P < .001; and adjusted HR 1.15, 95% CI 1.11-1.19, P < .001, respectively).Peak CK-MB concentration and AUC measurement are independent predictors of 3- to 6-month cardiovascular outcomes in primary PCI-treated STEMI patients. Our findings guide application of these measurements as efficacy end points in early-phase studies evaluating new therapies for STEMI.

    View details for DOI 10.1016/j.ahj.2014.06.008

    View details for Web of Science ID 000343096900016

    View details for PubMedID 25262260

  • Reasons for warfarin discontinuation in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) AMERICAN HEART JOURNAL O'Brien, E. C., Simon, D. N., Allen, L. A., Singer, D. E., Fonarow, G. C., Kowey, P. R., Thomas, L. E., Ezekowitz, M. D., Mahaffey, K. W., Chang, P., Piccini, J. P., Peterson, E. D. 2014; 168 (4): 487-494

    Abstract

    Warfarin reduces thromboembolic risks in atrial fibrillation (AF), but therapeutic durability remains a concern.We used clinical data from ORBIT-AF, a nationwide outpatient AF registry conducted at 176 sites with follow-up data at 6 and 12 months, to examine longitudinal patterns of warfarin discontinuation. We estimated associations between patient and provider characteristics and report of any warfarin discontinuation using discrete time proportional odds models.Of 10,132 AF patients enrolled in ORBIT-AF from June 2010 to August 2011, 6,110 (60.3%) were prescribed warfarin, had follow-up data, and were not switched to an alternative oral anticoagulant enrolled from June 2010 to August 2011. Over 1 year, 617 patients (10.1% of baseline warfarin users) discontinued warfarin therapy. Among incident warfarin users (starting therapy within 1 year of baseline survey), warfarin discontinuation rates rose to 17.1%. The most commonly reported reasons for warfarin discontinuation were physician preference (47.7%), patient refusal/preference (21.1%), bleeding event (20.2%), frequent falls/frailty (10.8%), high bleeding risk (9.8%), and patient inability to adhere to/monitor therapy (4.7%). In multivariable analysis, the factors most strongly associated with warfarin discontinuation were bleeding hospitalization during follow-up (odds ratio 10.91, 95% CI 7.91-15.03), prior catheter ablation (1.83, 1.37-2.45), noncardiovascular/nonbleeding hospitalization (1.77, 1.40-2.24), cardiovascular hospitalization (1.64, 1.33-2.03), and permanent AF (0.25, 0.17-0.36).Discontinuation of warfarin is common among patients with AF, particularly among incident users. Warfarin is most commonly discontinued because of physician preference, patient refusal, and bleeding events.

    View details for DOI 10.1016/j.ahj.2014.07.002

    View details for Web of Science ID 000343096900014

  • Vorapaxar in patients with peripheral artery disease and acute coronary syndrome: Insights from Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) AMERICAN HEART JOURNAL Jones, W. S., Tricoci, P., Huang, Z., Moliterno, D. J., Harrington, R. A., Sinnaeve, P. R., Strony, J., Van de Werf, F., White, H. D., Held, C., Armstrong, P. W., Aylward, P. E., Chen, E., Patel, M. R., Mahaffey, K. W. 2014; 168 (4): 588-596

    Abstract

    In the TRACER trial, vorapaxar, a protease-activated receptor-1 antagonist, plus standard care in non-ST-segment elevation acute coronary syndrome (NSTE ACS) patients did not significantly reduce the primary composite end point but reduced a key secondary end point and significantly increased bleeding. History of peripheral artery disease (PAD) was a risk-enrichment inclusion criterion. We investigated the efficacy and safety of vorapaxar in NSTE ACS patients with documented PAD.TRACER was a double-blind, randomized trial comparing vorapaxar with placebo in 12,944 patients with NSTE ACS.In total, 936 (7.2%) patients had a history of PAD. Ischemic events occurred more frequently among patients with PAD (25.3%) versus no PAD (12.2%, P < .001), and Global Use of Strategies to Open Occluded Coronary Arteries moderate/severe bleeding was more common in PAD (9.1%) versus no PAD (5.0%, P = .004). Similar rates of the composite end point (cardiovascular death, myocardial infarction, or stroke) occurred in patients with PAD treated with vorapaxar and placebo (21.7% vs 24.8%, P interaction = .787). Patients with PAD treated with vorapaxar, when compared with placebo, also had a numerical reduction in peripheral revascularization procedures (8.1% vs 9.0%, P = .158) and a lower extremity amputation rate (0.9% vs 1.5%, P = .107). Vorapaxar increased Global Use of Strategies to Open Occluded Coronary Arteries moderate/severe bleeding similarly in patients with PAD (hazard ratio 1.47, 95% CI 0.89-2.45) and without (hazard ratio 1.48, 95% CI 1.22-1.79; P interaction = .921).Patients with NSTE ACS and PAD were at increased risk for ischemic events. Lower rates of ischemic end points, peripheral revascularization, and amputation with vorapaxar did not reach statistical significance but warrant further investigation. Vorapaxar increased bleeding in both patients with and without PAD at a similar magnitude of risk.

    View details for DOI 10.1016/j.ahj.2014.06.017

    View details for Web of Science ID 000343096900026

  • Challenges and Priorities for Research A Report From the National Heart, Lung, and Blood Institute (NHLBI)/National Institutes of Health (NIH) Working Group on Thrombosis in Pediatric Cardiology and Congenital Heart Disease CIRCULATION McCrindle, B. W., Li, J. S., Manlhiot, C., Tweddell, J. S., Giglia, T. M., Massicotte, M. P., Monagle, P., Krishnamurthy, R., Mahaffey, K. W., Michelson, A. D., Verdun, N., Almond, C. S., Newburger, J. W., Brandao, L. R., Esmon, C. T., Manco-Johnson, M. J., Ichord, R., Ortel, T. L., Chan, A. K., Portman, R., Rose, M., Strony, J., Kaltman, J. R. 2014; 130 (14): 1192-1203
  • Effect of Cangrelor on Ischemic Endpoints: Further Analyses from CHAMPION PHOENIX Bhatt, D. L., Stone, G. W., Mahaffey, K., Gibson, C., Steg, P. G., Hamm, C., Price, M. J., Liu, T., Deliargyris, E. N., Skerjanec, S., Prats, J., White, H. D., Harrington, R. ELSEVIER SCIENCE INC. 2014: B142
  • Vorapaxar, a platelet thrombin-receptor antagonist, in medically managed patients with non-ST-segment elevation acute coronary syndrome: results from the TRACER trial. European heart journal. Acute cardiovascular care Held, C., Tricoci, P., Huang, Z., Van de Werf, F., White, H. D., Armstrong, P. W., Ambrosio, G., Aylward, P. E., Moliterno, D. J., Wallentin, L., Chen, E., Erkan, A., Jiang, L., Strony, J., Harrington, R. A., Mahaffey, K. W. 2014; 3 (3): 246-256

    Abstract

    This study characterized a medically managed population in a non-ST-segment elevation acute coronary syndrome (NSTEACS) cohort and evaluated prognosis and outcomes of vorapaxar vs. placebo.In the TRACER study, 12,944 NSTEACS patients were treated with standard care and vorapaxar (a novel platelet protease-activated receptor-1 antagonist) or placebo. Of those, 4194 patients (32.4%) did not undergo revascularization during index hospitalization, and 8750 (67.6%) underwent percutaneous coronary intervention or coronary artery bypass grafting. Patients managed medically were heterogeneous with different risk profiles, including 1137 (27.1%) who did not undergo coronary angiography. Patients who underwent angiography but were selected for medical management included those without evidence of significant coronary artery disease (CAD), with prior CAD but no new significant lesions, and with significant lesions who were not treated with revascularization.Cardiovascular event rates were highest among those without angiography and lowest in the group with angiography but without CAD. In the medically managed cohort, 2-year primary outcome (cardiovascular death, myocardial infarction, stroke, recurrent ischaemia with rehospitalization, urgent coronary revascularization) event rates were 16.3% with vorapaxar and 17.0% with placebo (HR 0.99, 95% CI 0.83-1.17), with no interaction between drug and management strategy (p=0.75). Key secondary endpoint (cardiovascular death, myocardial infarction, stroke) rates were 13.4% with vorapaxar and 14.9% with placebo (HR 0.89, 95% CI 0.74-1.07), with no interaction (p=0.58). Vorapaxar increased GUSTO moderate/severe bleeding numerically in medically managed patients (adjusted HR 1.46, 95% CI 0.99-2.15).NSTEACS patients who were initially medically managed had a higher risk-factor burden, and one-third had normal coronary arteries. Outcome in the medically managed cohort was significantly related to degree of CAD, highlighting the importance of coronary angiography. Efficacy and safety of vorapaxar appeared consistent with the overall trial results.

    View details for DOI 10.1177/2048872614527838

    View details for PubMedID 24627331

  • No misrepresentation of vital status follow-up in PLATO: Predefined analyses guarantee the integrity of the benefits of ticagrelor over clopidogrel in the PLATO trial Commentary on: DiNicolantonio JJ, Tomek A, Misrepresentation of vital status follow-up: Challenging the integrity of the PLATO trial and the claimed mortality benefit of ticagrelor versus clopidogrel, International Journal of Cardiology, 2013 Serebruany VL. Discrepancies in the primary PLATO trial publication and the FDA reviews, International Journal of Cardiology, 2014 INTERNATIONAL JOURNAL OF CARDIOLOGY Wallentin, L., Becker, R. C., Cannon, C. P., Held, C., Himmelmann, A., Husted, S., James, S. K., Katus, H. A., Mahaffey, K. M., Pieper, K. S., Storey, R. F., Steg, P., Harrington, R. A., PLATO Investigators 2014; 176 (1): 300–302

    View details for PubMedID 25005338

  • Usefulness and Safety of Vorapaxar in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention (from the TRACER Trial). American journal of cardiology Valgimigli, M., Tricoci, P., Huang, Z., Aylward, P. E., Armstrong, P. W., Van de Werf, F., Leonardi, S., White, H. D., Widimsky, P., Harrington, R. A., Cequier, A., Chen, E., Lokhnygina, Y., Wallentin, L., Strony, J., Mahaffey, K. W., Moliterno, D. J. 2014; 114 (5): 665-673

    Abstract

    The therapeutic potential of vorapaxar in patients with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention (PCI) is unknown. This prespecified analysis of a postrandomization subgroup evaluated the effects of vorapaxar compared with placebo among Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) participants undergoing PCI, focusing on the implanted stent type (drug-eluting stent [DES] vs bare-metal stent [BMS]). Among 12,944 recruited patients, 7,479 (57.8%) underwent PCI during index hospitalization, and 3,060 (40.9%) of those patients received exclusively BMS, whereas 4,015 (53.7%) received DES. The median (twenty-fifth, seventy-fifth percentiles) duration of thienopyridine therapy was 133 days (47, 246) with BMS and 221 days (88, 341) with DES. At 2 years among patients undergoing PCI, the primary (cardiovascular death, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization) and secondary (cardiovascular death, myocardial infarction, or stroke) end points did not differ between vorapaxar and placebo groups, which was consistent with the treatment effect observed in the overall study population (p value for interaction = 0.540). However, the treatment effect trended greater (p value for interaction = 0.069) and the risk for bleeding in patients taking vorapaxar versus placebo appeared attenuated in BMS-only recipients. After adjustment for confounders, the interaction was no longer significant (p value = 0.301). The covariate that mostly explained the stent-type-by-treatment interaction was the duration of clopidogrel therapy. In conclusion, among patients with PCI, the effect of vorapaxar is consistent with the overall TRACER results. Patients who received a BMS underwent shorter courses of clopidogrel therapy and displayed trends toward greater ischemic benefit from vorapaxar and lesser bleeding risk, compared with patients who received a DES.

    View details for DOI 10.1016/j.amjcard.2014.05.054

    View details for PubMedID 25129064

  • Independent data monitoring committees: Preparing a path for the future. American heart journal Hess, C. N., Roe, M. T., Gibson, C. M., J Temple, R., Pencina, M. J., Zarin, D. A., Anstrom, K. J., Alexander, J. H., Sherman, R. E., Fiedorek, F. T., Mahaffey, K. W., Lee, K. L., Chow, S., Armstrong, P. W., Califf, R. M. 2014; 168 (2): 135-141 e1

    Abstract

    Independent data monitoring committees (IDMCs) were introduced to monitor patient safety and study conduct in randomized clinical trials (RCTs), but certain challenges regarding the utilization of IDMCs have developed. First, the roles and responsibilities of IDMCs are expanding, perhaps due to increasing trial complexity and heterogeneity regarding medical, ethical, legal, regulatory, and financial issues. Second, no standard for IDMC operating procedures exists, and there is uncertainty about who should determine standards and whether standards should vary with trial size and design. Third, considerable variability in communication pathways exist across IDMC interfaces with regulatory agencies, academic coordinating centers, and sponsors. Finally, there has been a substantial increase in the number of RCTs using IDMCs, yet there is no set of qualifications to help guide the training and development of the next generation of IDMC members. Recently, an expert panel of representatives from government, industry, and academia assembled at the Duke Clinical Research Institute to address these challenges and to develop recommendations for the future utilization of IDMCs in RCTs.

    View details for DOI 10.1016/j.ahj.2014.05.003

    View details for PubMedID 25066551

  • Long-term outcomes associated with hospital acquired thrombocytopenia among patients with non-ST-segment elevation acute coronary syndrome AMERICAN HEART JOURNAL Vora, A. N., Chenier, M., Schulte, P. J., Goodman, S., Peterson, E. D., Pieper, K., Jolicoeur, M. E., Mahaffey, K. W., White, H., Wang, T. Y. 2014; 168 (2): 189-?

    Abstract

    Acquired thrombocytopenia after a non-ST-segment-elevation-acute coronary syndrome (NSTE-ACS) has been associated with increased in-hospital mortality and hemorrhagic complications, but longer term outcomes are unclear. We examined the association between thrombocytopenia and long-term outcomes after accounting for thrombocytopenia severity and discharge medication use.Data from 7,435 NSTE-ACS patients enrolled in the SYNERGY trial were analyzed. Severe thrombocytopenia was defined as a nadir platelet count <100 × 10(9)/L or a ≥ 50% drop from baseline. Mild thrombocytopenia was defined as a nadir platelet count between 100 and 149 × 10(9)/L with a <50% drop from baseline. The primary outcomes of interest were in-hospital GUSTO moderate-severe bleeding and 1-year mortality.Overall, 675 patients (9.1%) developed mild thrombocytopenia and 139 patients (1.9%) developed severe thrombocytopenia. In-hospital bleeding risks were higher in patients with mild (7.7%, adjusted HR 1.63, 95% CI 1.16-2.29) or severe (28.2%, adjusted HR 6.93, 95% CI 4.55-10.56) thrombocytopenia than in patients without thrombocytopenia (5.2%). One-year mortality rates were 6.5%, 8.1%, and 28.1% among patients with no, mild, and severe thrombocytopenia, respectively (log rank P < 0.001) but only severe thrombocytopenia remained significantly associated with increased mortality after adjustment: HR 4.07, 95% CI 2.86-5.78. Patients who developed severe thrombocytopenia were less likely to be discharged on guideline-recommended antiplatelet therapy. The relationship between severe thrombocytopenia and mortality was attenuated by but persisted after adjusting for discharge medication use (HR 2.83, 95% CI 1.49-5.38).Thrombocytopenia occurs commonly during the course of NSTE-ACS care; even mild decreases are associated with clinically meaningful bleeding. Patients who developed severe thrombocytopenia were less likely to be discharged on guideline-recommended antiplatelet therapy; this may contribute to their higher associated long-term mortality.

    View details for DOI 10.1016/j.ahj.2014.04.010

    View details for Web of Science ID 000340207700013

    View details for PubMedID 25066558

  • Population Pharmacokinetics and Pharmacodynamics of Rivaroxaban in Patients with Non-valvular Atrial Fibrillation: Results from ROCKET AF JOURNAL OF CLINICAL PHARMACOLOGY Girgis, I. G., Patel, M. R., Peters, G. R., Moore, K. T., Mahaffey, K. W., Nessel, C. C., Halperin, J. L., Califf, R. M., Fox, K. A., Becker, R. C. 2014; 54 (8): 917-927

    Abstract

    Two once-daily rivaroxaban dosing regimens were compared with warfarin for stroke prevention in patients with non-valvular atrial fibrillation in ROCKET AF: 20 mg for patients with normal/mildly impaired renal function and 15 mg for patients with moderate renal impairment. Rivaroxaban population pharmacokinetic (PK)/pharmacodynamic (PD) modeling data from ROCKET AF patients (n = 161) are reported and are used to confirm established rivaroxaban PK and PK/PD models and to re-estimate values of the models' parameters for the current AF population. An oral one-compartment model with first-order absorption adequately described rivaroxaban PK. Age, renal function, and lean body mass influenced the PK model. Prothrombin time and prothrombinase-induced clotting time exhibited a near-linear relationship with rivaroxaban plasma concentration; inhibitory effects were observed through to 24 hours post-dose. Rivaroxaban plasma concentration and factor Xa activity had an inhibitory maximum-effect (Emax ) relationship. Renal function (on prothrombin time; prothrombinase-induced clotting time) and age (on factor Xa activity) had moderate effects on PK/PD models. PK and PK/PD models were shown to be adequate for describing the current dataset. These findings confirm the modeling and empirical results that led to the selection of doses tested against warfarin in ROCKET AF.

    View details for DOI 10.1002/jcph.288

    View details for Web of Science ID 000339163200013

    View details for PubMedID 24668660

  • Outcomes registry for better informed treatment of atrial fibrillation II: Rationale and design of the ORBIT-AF II registry. American heart journal Steinberg, B. A., Blanco, R. G., Ollis, D., Kim, S., Holmes, D. N., Kowey, P. R., Fonarow, G. C., Ansell, J., Gersh, B., Go, A. S., Hylek, E., Mahaffey, K. W., Thomas, L., Chang, P., Peterson, E. D., Piccini, J. P. 2014; 168 (2): 160-167

    Abstract

    Recent clinical trials have demonstrated the safety and efficacy of several non-vitamin K oral anticoagulants (NOACs) for the treatment of atrial fibrillation (AF). However, there are limited data on their use and outcomes in routine clinical practice, particularly among patients newly diagnosed as having AF and patients with AF recently transitioned to a NOAC.ORBIT-AF II is a multicenter, national registry of patients with AF that is enrolling up to 15,000 newly diagnosed patients with AF and/or those with AF recently transitioned to a NOAC from 300 US outpatient practices. These patients will be followed for up to 2 years, including clinical status, outcomes (major adverse cardiovascular events, bleeding), and management of anticoagulation surrounding bleeding events. In addition, detailed data regarding the use of these agents in and around cardiac procedures, their complications, and management of such complications will be collected.The ORBIT-AF II registry will provide valuable insights into the safety and effectiveness of NOACs used in AF in community practice settings.

    View details for DOI 10.1016/j.ahj.2014.04.005

    View details for PubMedID 25066554

  • Management of major bleeding events in patients treated with rivaroxaban vs. warfarin: results from the ROCKET AF trial. European heart journal Piccini, J. P., Garg, J., Patel, M. R., Lokhnygina, Y., Goodman, S. G., Becker, R. C., Berkowitz, S. D., Breithardt, G., Hacke, W., Halperin, J. L., Hankey, G. J., Nessel, C. C., Mahaffey, K. W., Singer, D. E., Califf, R. M., Fox, K. A. 2014; 35 (28): 1873-1880

    Abstract

    There are no data regarding management and outcomes of major bleeding events in patients treated with oral factor Xa inhibitors.Using data from ROCKET AF, we analysed the management and outcomes of major bleeding overall and according to the randomized treatment. During a median follow-up of 1.9 years, 779 (5.5%) patients experienced major bleeding at a rate of 3.52 events/100 patient-years with a similar event rate in each arm (n = 395 rivaroxaban vs. n = 384 warfarin). The median number of transfused packed red blood cells (PRBC) per episode was similar in both arms [2 (25th, 75th: 2, 4) units]. Overall, few transfusions of whole blood (n = 14), platelets (n = 10), or cryoprecipitate (n = 2) were used. Transfusion of fresh frozen plasma (FFP) was significantly less in the rivaroxaban arm (n = 45 vs. n = 81 units) after adjustment for covariates [odds ratio (OR) 0.43 (95% CI 0.29-0.66); P < 0.0001]. Prothrombin complex concentrates (PCC) were administered less in the rivaroxaban arm (n = 4 vs. n = 9). Outcomes after major bleeding, including stroke or non-central nervous system embolism (4.7% rivaroxaban vs. 5.4% warfarin; HR 0.89; 95% CI 0.42-1.88) and all-cause death (20.4% rivaroxaban vs. 26.1% warfarin; HR 0.69, 95% CI 0.46-1.04) were similar in patients treated with rivaroxaban and warfarin (interaction P = 0.51 and 0.11).Among high-risk patients with atrial fibrillation who experienced major bleeding in ROCKET AF, the use of FFP and PCC was less among those allocated rivaroxaban compared with warfarin. However, use of PRBCs and outcomes after bleeding were similar among patients randomized to rivaroxaban or to warfarin.

    View details for DOI 10.1093/eurheartj/ehu083

    View details for PubMedID 24658769

  • Efficacy and Safety of Rivaroxaban Compared With Warfarin Among Elderly Patients With Nonvalvular Atrial Fibrillation in the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) CIRCULATION Halperin, J. L., Hankey, G. J., Wojdyla, D. M., Piccini, J. P., Lokhnygina, Y., Patel, M. R., Breithardt, G., Singer, D. E., Becker, R. C., Hacke, W., Paolini, J. F., Nessel, C. C., Mahaffey, K. W., Califf, R. M., Fox, K. A. 2014; 130 (2): 138-U45

    Abstract

    Nonvalvular atrial fibrillation is common in elderly patients, who face an elevated risk of stroke but difficulty sustaining warfarin treatment. The oral factor Xa inhibitor rivaroxaban was noninferior to warfarin in the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). This prespecified secondary analysis compares outcomes in older and younger patients.There were 6229 patients (44%) aged ≥75 years with atrial fibrillation and ≥2 stroke risk factors randomized to warfarin (target international normalized ratio=2.0-3.0) or rivaroxaban (20 mg daily; 15 mg if creatinine clearance <50 mL/min), double blind. The primary end point was stroke and systemic embolism by intention to treat. Over 10 866 patient-years, older participants had more primary events (2.57% versus 2.05%/100 patient-years; P=0.0068) and major bleeding (4.63% versus 2.74%/100 patient-years; P<0.0001). Stroke/systemic embolism rates were consistent among older (2.29% rivaroxaban versus 2.85% warfarin per 100 patient-years; hazard ratio=0.80; 95% confidence interval, 0.63-1.02) and younger patients (2.00% versus 2.10%/100 patient-years; hazard ratio=0.95; 95% confidence interval, 0.76-1.19; interaction P=0.313), as were major bleeding rates (≥75 years: 4.86% rivaroxaban versus 4.40% warfarin per 100 patient-years; hazard ratio=1.11; 95% confidence interval, 0.92-1.34; <75 years: 2.69% versus 2.79%/100 patient-years; hazard ratio=0.96; 95% confidence interval, 0.78-1.19; interaction P=0.336). Hemorrhagic stroke rates were similar in both age groups; there was no interaction between age and rivaroxaban response.Elderly patients had higher stroke and major bleeding rates than younger patients, but the efficacy and safety of rivaroxaban relative to warfarin did not differ with age, supporting rivaroxaban as an alternative for the elderly.

    View details for DOI 10.1161/CIRCULATIONAHA.113.005008

    View details for Web of Science ID 000338717500009

  • Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). Circulation Halperin, J. L., Hankey, G. J., Wojdyla, D. M., Piccini, J. P., Lokhnygina, Y., Patel, M. R., Breithardt, G., Singer, D. E., Becker, R. C., Hacke, W., Paolini, J. F., Nessel, C. C., Mahaffey, K. W., Califf, R. M., Fox, K. A. 2014; 130 (2): 138-146

    Abstract

    Nonvalvular atrial fibrillation is common in elderly patients, who face an elevated risk of stroke but difficulty sustaining warfarin treatment. The oral factor Xa inhibitor rivaroxaban was noninferior to warfarin in the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). This prespecified secondary analysis compares outcomes in older and younger patients.There were 6229 patients (44%) aged ≥75 years with atrial fibrillation and ≥2 stroke risk factors randomized to warfarin (target international normalized ratio=2.0-3.0) or rivaroxaban (20 mg daily; 15 mg if creatinine clearance <50 mL/min), double blind. The primary end point was stroke and systemic embolism by intention to treat. Over 10 866 patient-years, older participants had more primary events (2.57% versus 2.05%/100 patient-years; P=0.0068) and major bleeding (4.63% versus 2.74%/100 patient-years; P<0.0001). Stroke/systemic embolism rates were consistent among older (2.29% rivaroxaban versus 2.85% warfarin per 100 patient-years; hazard ratio=0.80; 95% confidence interval, 0.63-1.02) and younger patients (2.00% versus 2.10%/100 patient-years; hazard ratio=0.95; 95% confidence interval, 0.76-1.19; interaction P=0.313), as were major bleeding rates (≥75 years: 4.86% rivaroxaban versus 4.40% warfarin per 100 patient-years; hazard ratio=1.11; 95% confidence interval, 0.92-1.34; <75 years: 2.69% versus 2.79%/100 patient-years; hazard ratio=0.96; 95% confidence interval, 0.78-1.19; interaction P=0.336). Hemorrhagic stroke rates were similar in both age groups; there was no interaction between age and rivaroxaban response.Elderly patients had higher stroke and major bleeding rates than younger patients, but the efficacy and safety of rivaroxaban relative to warfarin did not differ with age, supporting rivaroxaban as an alternative for the elderly.

    View details for DOI 10.1161/CIRCULATIONAHA.113.005008

    View details for PubMedID 24895454

  • Use and outcomes of antiarrhythmic therapy in patients with atrial fibrillation receiving oral anticoagulation: Results from the ROCKET AF trial. Heart rhythm Steinberg, B. A., Hellkamp, A. S., Lokhnygina, Y., Halperin, J. L., Breithardt, G., Passman, R., Hankey, G. J., Patel, M. R., Becker, R. C., Singer, D. E., Hacke, W., Berkowitz, S. D., Nessel, C. C., Mahaffey, K. W., Fox, K. A., Califf, R. M., Piccini, J. P. 2014; 11 (6): 925-932

    Abstract

    Antiarrhythmic drugs (AADs) and anticoagulation are mainstays of atrial fibrillation (AF) treatment.To study the use and outcomes of AAD therapy in anticoagulated patients with AF.Patients in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation trial (N = 14,264) were stratified by AAD use at baseline: amiodarone, other AAD, or no AAD. Multivariable adjustment was performed to compare stroke, bleeding, and death across AAD groups as well as across treatment assignment (rivaroxaban or warfarin).Of 14,264 patients randomized, 1681 (11.8%) were treated with an AAD (1144 [8%] with amiodarone and 537 [3.8%] with other AADs). Amiodarone-treated patients were less often female (38% vs 48%), had more persistent AF (64% vs 40%), and more concomitant heart failure (71% vs 41%) than were patients receiving other AADs. Patients receiving no AAD more closely resembled amiodarone-treated patients. Time in therapeutic range was significantly lower in warfarin-treated patients receiving amiodarone than in those receiving no AAD (50% vs 58%; P < .0001). Compared with no AAD, neither amiodarone (adjusted hazard ratio [HR] 0.98; 95% confidence interval [CI] 0.74-1.31; P = .9) nor other AADs (adjusted HR 0.66; 95% CI 0.37-1.17; P = .15) were associated with increased mortality. Similar results were observed for embolic and bleeding outcomes. Treatment effects of rivaroxaban vs warfarin in patients receiving no AAD were consistent with results from the overall trial (primary end point: adjusted HR 0.82; 95% CI 0.68-0.98; Pinteraction = .06; safety end point: adjusted HR 1.12; 95% CI 0.90-1.24; Pinteraction = .33).Treatment with AADs was not associated with increased morbidity or mortality in anticoagulated patients with AF. The effect of amiodarone on outcomes in patients receiving rivaroxaban requires further investigation.

    View details for DOI 10.1016/j.hrthm.2014.03.006

    View details for PubMedID 24833235

    View details for PubMedCentralID PMC4035424

  • Comparison of clinical trial outcome patterns in patients following acute coronary syndromes and in patients with chronic stable atherosclerosis. Clinical cardiology Mahaffey, K. W., Wojdyla, D. M., Pieper, K. S., Tricoci, P., Alexander, J. H., Lincoff, A. M., Brennan, D. M., Bhatt, D. L., Wallentin, L., Harrington, R. A. 2014; 37 (6): 337-342

    Abstract

    The transition of patients with atherosclerotic vascular disease from the acute phase of the disease to the chronic stable atherosclerosis (CSA) phase has not been well characterized. We sought to compare ischemic and bleeding outcomes in hospitalized patients enrolled in clinical trials of non-ST-elevation acute coronary syndrome (ACS) with patients enrolled in outpatient trials of CSA.The risk for recurrent events will differ between the 2 populations.Patient-level outcome data were evaluated from 3 consecutive trials of patients with ACS with long-term follow-up and 2 trials of patients with CSA. Kaplan-Meier curves were generated for ischemic and bleeding outcomes.In total, 37 370 patients were included in these analyses. Of these, 28 489 (76.2%) were from ACS trials and 8881 (23.8%) from chronic trials. During the first year of follow-up, 1353 deaths, 1081 cardiovascular (CV) deaths, 2113 myocardial infarctions (MIs), and 397 strokes occurred across the trials. Six-month Kaplan-Meier event rates for CV death, MI, or stroke were higher in the ACS trials compared with the CSA trials (8.6% vs 2.7%), as were the 1-year CV death rate (3.6% vs 1.7%) and 1-year rates for GUSTO moderate or severe bleeding (6.0% vs 1.3%). Qualitatively, the Kaplan-Meier curves appear to show an early increased risk as well as a continued increased risk over time.Patients with ACS enrolled while in the hospital appear to have different risk profiles for ischemic and bleeding outcomes compared with outpatients enrolled with CSA, including those patients with ACS after the acute phase.

    View details for DOI 10.1002/clc.22255

    View details for PubMedID 24615711

  • Rivaroxaban for Stroke Prevention in East Asian Patients From the ROCKET AF Trial STROKE Wong, K. S., Hu, D. Y., Oomman, A., Tan, R., Patel, M. R., Singer, D. E., Breithardt, G., Mahaffey, K. W., Becker, R. C., Califf, R., Fox, K. A., Berkowitz, S. D., Hacke, W., Hankey, G. J. 2014; 45 (6): 1739-?

    Abstract

    In Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial, rivaroxaban was noninferior to dose-adjusted warfarin in preventing stroke or systemic embolism among patients with nonvalvular atrial fibrillation at moderate to high stroke risk. Because of differences in patient demographics, epidemiology, and stroke risk management in East Asia, outcomes and relative effects of rivaroxaban versus warfarin were assessed to determine consistency among East Asians versus other ROCKET AF participants.Baseline demographics and interaction of treatment effects of rivaroxaban and warfarin among patients within East Asia and outside were assessed.A total of 932 (6.5%) ROCKET AF participants resided in East Asia. At baseline, East Asians had lower weight, creatinine clearance, and prior vitamin K antagonist use; higher prevalence of prior stroke; and less congestive heart failure and prior myocardial infarction than other participants. Despite higher absolute event rates for efficacy and safety outcomes in East Asians, the relative efficacy of rivaroxaban (20 mg once daily; 15 mg once daily for creatinine clearance of 30-49 mL/min) versus warfarin with respect to the primary efficacy end point (stroke/systemic embolism) was consistent among East Asians and non-East Asians (interaction P=0.666). Relative event rates for the major or nonmajor clinically relevant bleeding in patients treated with rivaroxaban and warfarin were consistent among East Asians and non-East Asians (interaction P=0.867).Observed relative efficacy and safety of rivaroxaban versus warfarin were similar among patients within and outside East Asia. Rivaroxaban, 20 mg once daily, is an alternative to warfarin for stroke prevention in East Asians with nonvalvular atrial fibrillation.http://www.clinicaltrials.gov. Unique identifier: NCT00123456.

    View details for DOI 10.1161/STROKEAHA.113.002968

    View details for Web of Science ID 000337090700034

    View details for PubMedID 24763930

  • Comparison of Clinical Trial Outcome Patterns in Patients Following Acute Coronary Syndromes and in Patients With Chronic Stable Atherosclerosis CLINICAL CARDIOLOGY Mahaffey, K. W., Wojdyla, D. M., Pieper, K. S., Tricoci, P., Alexander, J. H., Lincoff, A. M., Brennan, D. M., Bhatt, D. L., Wallentin, L., Harrington, R. A. 2014; 37 (6): 337-342

    Abstract

    The transition of patients with atherosclerotic vascular disease from the acute phase of the disease to the chronic stable atherosclerosis (CSA) phase has not been well characterized. We sought to compare ischemic and bleeding outcomes in hospitalized patients enrolled in clinical trials of non-ST-elevation acute coronary syndrome (ACS) with patients enrolled in outpatient trials of CSA.The risk for recurrent events will differ between the 2 populations.Patient-level outcome data were evaluated from 3 consecutive trials of patients with ACS with long-term follow-up and 2 trials of patients with CSA. Kaplan-Meier curves were generated for ischemic and bleeding outcomes.In total, 37 370 patients were included in these analyses. Of these, 28 489 (76.2%) were from ACS trials and 8881 (23.8%) from chronic trials. During the first year of follow-up, 1353 deaths, 1081 cardiovascular (CV) deaths, 2113 myocardial infarctions (MIs), and 397 strokes occurred across the trials. Six-month Kaplan-Meier event rates for CV death, MI, or stroke were higher in the ACS trials compared with the CSA trials (8.6% vs 2.7%), as were the 1-year CV death rate (3.6% vs 1.7%) and 1-year rates for GUSTO moderate or severe bleeding (6.0% vs 1.3%). Qualitatively, the Kaplan-Meier curves appear to show an early increased risk as well as a continued increased risk over time.Patients with ACS enrolled while in the hospital appear to have different risk profiles for ischemic and bleeding outcomes compared with outpatients enrolled with CSA, including those patients with ACS after the acute phase.

    View details for DOI 10.1002/clc.22255

    View details for Web of Science ID 000337597900003

  • Lack of concordance between empirical scores and physician assessments of stroke and bleeding risk in atrial fibrillation: results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry. Circulation Steinberg, B. A., Kim, S., Thomas, L., Fonarow, G. C., Hylek, E., Ansell, J., Go, A. S., Chang, P., Kowey, P., Gersh, B. J., Mahaffey, K. W., Singer, D. E., Piccini, J. P., Peterson, E. D. 2014; 129 (20): 2005-2012

    Abstract

    Physicians treating patients with atrial fibrillation (AF) must weigh the benefits of anticoagulation in preventing stroke versus the risk of bleeding. Although empirical models have been developed to predict such risks, the degree to which these coincide with clinicians' estimates is unclear.We examined 10 094 AF patients enrolled in the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF) registry between June 2010 and August 2011. Empirical stroke and bleeding risks were assessed by using the congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and previous stroke or transient ischemic attack (CHADS2) and Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) scores, respectively. Separately, physicians were asked to categorize their patients' stroke and bleeding risks: low risk (<3%); intermediate risk (3%-6%); and high risk (>6%). Overall, 72% (n=7251) in ORBIT-AF had high-risk CHADS2 scores (≥2). However, only 16% were assessed as high stroke risk by physicians. Although 17% (n=1749) had high ATRIA bleeding risk (score ≥5), only 7% (n=719) were considered so by physicians. The associations between empirical and physician-estimated stroke and bleeding risks were low (weighted Kappa 0.1 and 0.11, respectively). Physicians weighed hypertension, heart failure, and diabetes mellitus less significantly than empirical models in estimating stroke risk; physicians weighted anemia and dialysis less significantly than empirical models when estimating bleeding risks. Anticoagulation use was highest among patients with high stroke risk, assessed by either empirical model or physician estimates. In contrast, physician and empirical estimates of bleeding had limited impact on treatment choice.There is little agreement between provider-assessed risk and empirical scores in AF. These differences may explain, in part, the current divergence of anticoagulation treatment decisions from guideline recommendations.http://www.clinicaltrials.gov. Unique identifier: NCT01165710.

    View details for DOI 10.1161/CIRCULATIONAHA.114.008643

    View details for PubMedID 24682387

  • Lack of Concordance Between Empirical Scores and Physician Assessments of Stroke and Bleeding Risk in Atrial Fibrillation: Results From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Registry. Circulation Steinberg, B. A., Kim, S., Thomas, L., Fonarow, G. C., Hylek, E., Ansell, J., Go, A. S., Chang, P., Kowey, P., Gersh, B. J., Mahaffey, K. W., Singer, D. E., Piccini, J. P., Peterson, E. D. 2014; 129 (20): 2005-2012

    Abstract

    Physicians treating patients with atrial fibrillation (AF) must weigh the benefits of anticoagulation in preventing stroke versus the risk of bleeding. Although empirical models have been developed to predict such risks, the degree to which these coincide with clinicians' estimates is unclear.We examined 10 094 AF patients enrolled in the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF) registry between June 2010 and August 2011. Empirical stroke and bleeding risks were assessed by using the congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and previous stroke or transient ischemic attack (CHADS2) and Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) scores, respectively. Separately, physicians were asked to categorize their patients' stroke and bleeding risks: low risk (<3%); intermediate risk (3%-6%); and high risk (>6%). Overall, 72% (n=7251) in ORBIT-AF had high-risk CHADS2 scores (≥2). However, only 16% were assessed as high stroke risk by physicians. Although 17% (n=1749) had high ATRIA bleeding risk (score ≥5), only 7% (n=719) were considered so by physicians. The associations between empirical and physician-estimated stroke and bleeding risks were low (weighted Kappa 0.1 and 0.11, respectively). Physicians weighed hypertension, heart failure, and diabetes mellitus less significantly than empirical models in estimating stroke risk; physicians weighted anemia and dialysis less significantly than empirical models when estimating bleeding risks. Anticoagulation use was highest among patients with high stroke risk, assessed by either empirical model or physician estimates. In contrast, physician and empirical estimates of bleeding had limited impact on treatment choice.There is little agreement between provider-assessed risk and empirical scores in AF. These differences may explain, in part, the current divergence of anticoagulation treatment decisions from guideline recommendations.http://www.clinicaltrials.gov. Unique identifier: NCT01165710.

    View details for DOI 10.1161/CIRCULATIONAHA.114.008643

    View details for PubMedID 24682387

    View details for PubMedCentralID PMC4050636

  • Response to Letter Regarding Article, "Stent Thrombosis With Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes: An Analysis From the Prospective, Randomized PLATO Trial" CIRCULATION Steg, P., Harrington, R. A., Emanuelsson, H., Katus, H. A., Mahaffey, K. W., Meier, B., Storey, R. F., Wojdyla, D. M., Lewis, B. S., Maurer, G., Wallentin, L., James, S. K. 2014; 129 (19): E494–E495
  • Outcomes of Temporary Interruption of Rivaroxaban Compared With Warfarin in Patients With Nonvalvular Atrial Fibrillation: Results From the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). Circulation Sherwood, M. W., Douketis, J. D., Patel, M. R., Piccini, J. P., Hellkamp, A. S., Lokhnygina, Y., Spyropoulos, A. C., Hankey, G. J., Singer, D. E., Nessel, C. C., Mahaffey, K. W., Fox, K. A., Califf, R. M., Becker, R. C. 2014; 129 (18): 1850-1859

    Abstract

    During long-term anticoagulation in atrial fibrillation, temporary interruptions (TIs) of therapy are common, but the relationship between patient outcomes and TIs has not been well studied. We sought to determine reasons for TI, the characteristics of patients undergoing TI, and the relationship between anticoagulant and outcomes among patients with TI.In the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), a randomized, double-blind, double-dummy study of rivaroxaban and warfarin in nonvalvular atrial fibrillation, baseline characteristics, management, and outcomes, including stroke, non-central nervous system systemic embolism, death, myocardial infarction, and bleeding, were reported in participants who experienced TI (3-30 days) for any reason. The at-risk period for outcomes associated with TI was from TI start to 30 days after resumption of study drug. In 14 236 participants who received at least 1 dose of study drug, 4692 (33%) experienced TI. Participants with TI were similar to the overall ROCKET AF population in regard to baseline clinical characteristics. Only 6% (n=483) of TI incidences involved bridging therapy. Stroke/systemic embolism rates during the at-risk period were similar in rivaroxaban-treated and warfarin-treated participants (0.30% versus 0.41% per 30 days; hazard ratio [confidence interval]=0.74 [0.36-1.50]; P=0.40). Risk of major bleeding during the at-risk period was also similar in rivaroxaban-treated and warfarin-treated participants (0.99% versus 0.79% per 30 days; hazard ratio [confidence interval]=1.26 [0.80-2.00]; P=0.32).TI of oral anticoagulation is common and is associated with substantial stroke risks and bleeding risks that were similar among patients treated with rivaroxaban or warfarin. Further investigation is needed to determine the optimal management strategy in patients with atrial fibrillation requiring TI of anticoagulation.http://www.clinicaltrials.gov. Unique identifier: NCT00403767.

    View details for DOI 10.1161/CIRCULATIONAHA.113.005754

    View details for PubMedID 24552831

  • Outcomes of Temporary Interruption of Rivaroxaban Compared With Warfarin in Patients With Nonvalvular Atrial Fibrillation CIRCULATION Sherwood, M. W., Douketis, J. D., Patel, M. R., Piccini, J. P., Hellkamp, A. S., Lokhnygina, Y., Spyropoulos, A. C., Hankey, G. J., Singer, D. E., Nessel, C. C., Mahaffey, K. W., Fox, K. A., Califf, R. M., Becker, R. C. 2014; 129 (18): 1850-1859

    Abstract

    During long-term anticoagulation in atrial fibrillation, temporary interruptions (TIs) of therapy are common, but the relationship between patient outcomes and TIs has not been well studied. We sought to determine reasons for TI, the characteristics of patients undergoing TI, and the relationship between anticoagulant and outcomes among patients with TI.In the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), a randomized, double-blind, double-dummy study of rivaroxaban and warfarin in nonvalvular atrial fibrillation, baseline characteristics, management, and outcomes, including stroke, non-central nervous system systemic embolism, death, myocardial infarction, and bleeding, were reported in participants who experienced TI (3-30 days) for any reason. The at-risk period for outcomes associated with TI was from TI start to 30 days after resumption of study drug. In 14 236 participants who received at least 1 dose of study drug, 4692 (33%) experienced TI. Participants with TI were similar to the overall ROCKET AF population in regard to baseline clinical characteristics. Only 6% (n=483) of TI incidences involved bridging therapy. Stroke/systemic embolism rates during the at-risk period were similar in rivaroxaban-treated and warfarin-treated participants (0.30% versus 0.41% per 30 days; hazard ratio [confidence interval]=0.74 [0.36-1.50]; P=0.40). Risk of major bleeding during the at-risk period was also similar in rivaroxaban-treated and warfarin-treated participants (0.99% versus 0.79% per 30 days; hazard ratio [confidence interval]=1.26 [0.80-2.00]; P=0.32).TI of oral anticoagulation is common and is associated with substantial stroke risks and bleeding risks that were similar among patients treated with rivaroxaban or warfarin. Further investigation is needed to determine the optimal management strategy in patients with atrial fibrillation requiring TI of anticoagulation.http://www.clinicaltrials.gov. Unique identifier: NCT00403767.

    View details for DOI 10.1161/CIRCULATIONAHA.113.005754

    View details for Web of Science ID 000335367500012

  • Effects of vorapaxar on platelet reactivity and biomarker expression in non-ST-elevation acute coronary syndromes. The TRACER Pharmacodynamic Substudy. Thrombosis and haemostasis Storey, R. F., Kotha, J., Smyth, S. S., Moliterno, D. J., Rorick, T. L., Moccetti, T., Valgimigli, M., Dery, J. P., Cornel, J. H., Thomas, G. S., Huber, K., Harrington, R. A., Hord, E., Judge, H. M., Chen, E., Strony, J., Mahaffey, K. W., Tricoci, P., Becker, R. C., Jennings, L. K. 2014; 111 (5): 883-891

    Abstract

    Vorapaxar is an antagonist of the protease activated receptor-1 (PAR-1), the principal platelet thrombin receptor. The Thrombin Receptor Antagonist for Clinical Event Reduction (TRACER) trial evaluated vorapaxar compared to placebo in non-ST-elevation (NSTE)-acute coronary syndrome (ACS) patients. It was the study's objective to assess the pharmacodynamic effects of vorapaxar versus placebo that included aspirin or a thienopyridine or, frequently, a combination of both agents in NSTE-ACS patients. In a substudy involving 249 patients, platelet aggregation was assessed by light transmittance aggregometry (LTA) in 85 subjects (41 placebo, 44 vorapaxar) using the agonists thrombin receptor activating peptide (TRAP, 15 μM), adenosine diphosphate (ADP, 20 μM), and the combination of collagen-related peptide (2.5 μg/ml) + ADP (5 μM) + TRAP (15 μM) (CAT). VerifyNow® IIb/IIIa and vasodilator-stimulated phosphoprotein (VASP) phosphorylation assays were performed, and platelet PAR-1 expression, plasma platelet/endothelial and inflammatory biomarkers were determined before and during treatment. LTA responses to TRAP and CAT and VerifyNow results were markedly inhibited by vorapaxar. Maximal LTA response to TRAP (median, interquartile range) 2 hours post loading dose: placebo 68% (53-75%) and vorapaxar 3% (2-6%), p<0.0001. ADP inhibition was greater in the vorapaxar group at 4 hours and one month (p<0.01). In contrast to the placebo group, PAR-1 receptor number in the vorapaxar group at one month was significantly lower than the baseline (179 vs 225; p=0.004). There were significant changes in selected biomarker levels between the two treatment groups. In conclusion, vorapaxar caused a potent inhibition of PAR-1-mediated platelet aggregation. Further studies are needed to explore vorapaxar effect on P2Y12 inhibition, PAR-1 expression and biomarkers and its contribution to clinical outcomes.

    View details for DOI 10.1160/TH13-07-0624

    View details for PubMedID 24402559

  • Intracranial hemorrhage among patients with atrial fibrillation anticoagulated with warfarin or rivaroxaban: the rivaroxaban once daily, oral, direct factor xa inhibition compared with vitamin k antagonism for prevention of stroke and embolism trial in atrial fibrillation. Stroke; a journal of cerebral circulation Hankey, G. J., Stevens, S. R., Piccini, J. P., Lokhnygina, Y., Mahaffey, K. W., Halperin, J. L., Patel, M. R., Breithardt, G., Singer, D. E., Becker, R. C., Berkowitz, S. D., Paolini, J. F., Nessel, C. C., Hacke, W., Fox, K. A., Califf, R. M. 2014; 45 (5): 1304-1312

    Abstract

    Intracranial hemorrhage (ICH) is a life-threatening complication of anticoagulation.We investigated the rate, outcomes, and predictors of ICH in 14 264 patients with atrial fibrillation from Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). Cox proportional hazards modeling was used.During 1.94 years (median) of follow-up, 172 patients (1.2%) experienced 175 ICH events at a rate of 0.67% per year. The significant, independent predictors of ICH were race (Asian: hazard ratio, 2.02; 95% CI, 1.39-2.94; black: hazard ratio, 3.25; 95% CI, 1.43-7.41), age (1.35; 1.13-1.63 per 10-year increase), reduced serum albumin (1.39; 1.12-1.73 per 0.5 g/dL decrease), reduced platelet count below 210×10(9)/L (1.08; 1.02-1.13 per 10×10(9)/L decrease), previous stroke or transient ischemic attack (1.42; 1.02-1.96), and increased diastolic blood pressure (1.17; 1.01-1.36 per 10 mm Hg increase). Predictors of a reduced risk of ICH were randomization to rivaroxaban (0.60; 0.44-0.82) and history of congestive heart failure (0.65; 0.47-0.89). The ability of the model to discriminate individuals with and without ICH was good (C-index, 0.69; 95% CI, 0.64-0.73).Among patients with atrial fibrillation treated with anticoagulation, the risk of ICH was higher among Asians, blacks, the elderly, and in those with previous stroke or transient ischemic attack, increased diastolic blood pressure, and reduced platelet count or serum albumin at baseline. The risk of ICH was significantly lower in patients with heart failure and in those who were randomized to rivaroxaban instead of warfarin. The external validity of these findings requires testing in other atrial fibrillation populations.

    View details for DOI 10.1161/STROKEAHA.113.004506

    View details for PubMedID 24743444

  • Darapladib for Preventing Ischemic Events in Stable Coronary Heart Disease NEW ENGLAND JOURNAL OF MEDICINE White, H. D., Held, C., Stewart, R., Tarka, E., Brown, R., Davies, R. Y., Budaj, A., Harrington, R. A., Steg, P. G., Ardis-Sino, D., Armstrong, P. W., Avezum, A., Aylward, P. E., Bryce, A., Chen, H., Chen, M., Corbalan, R., Dalby, A. J., Danchin, N., de Winter, R. J., Denchev, S., Diaz, R., Elisaf, M., Flather, M. D., Goudev, A. R., Granger, C. B., Grinfeld, L., Hochman, J. S., Husted, S., Kim, H., Koenig, W., Linhart, A., Lonn, E., Lopez-Sendon, J., Manolis, A. J., Mohler, E. R., Nicolau, J. C., Pais, P., Parkhomenko, A., Pedersen, T. R., Pella, D., Ramos-Corrales, M. A., Ruda, M., Sereg, M., Siddique, S., Sinnaeve, P., Smith, P., Sritara, P., Swart, H. P., Sy, R. G., Teramoto, T., Tse, H., Watson, D., Weaver, W. D., Weiss, R., Viigimaa, M., Vinereanu, D., Zhu, J., Cannon, C. P., Wallentin, L. 2014; 370 (18): 1702-1711

    Abstract

    Elevated lipoprotein-associated phospholipase A2 activity promotes the development of vulnerable atherosclerotic plaques, and elevated plasma levels of this enzyme are associated with an increased risk of coronary events. Darapladib is a selective oral inhibitor of lipoprotein-associated phospholipase A2.In a double-blind trial, we randomly assigned 15,828 patients with stable coronary heart disease to receive either once-daily darapladib (at a dose of 160 mg) or placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included the components of the primary end point as well as major coronary events (death from coronary heart disease, myocardial infarction, or urgent coronary revascularization for myocardial ischemia) and total coronary events (death from coronary heart disease, myocardial infarction, hospitalization for unstable angina, or any coronary revascularization).During a median follow-up period of 3.7 years, the primary end point occurred in 769 of 7924 patients (9.7%) in the darapladib group and 819 of 7904 patients (10.4%) in the placebo group (hazard ratio in the darapladib group, 0.94; 95% confidence interval [CI], 0.85 to 1.03; P=0.20). There were also no significant between-group differences in the rates of the individual components of the primary end point or in all-cause mortality. Darapladib, as compared with placebo, reduced the rate of major coronary events (9.3% vs. 10.3%; hazard ratio, 0.90; 95% CI, 0.82 to 1.00; P=0.045) and total coronary events (14.6% vs. 16.1%; hazard ratio, 0.91; 95% CI, 0.84 to 0.98; P=0.02).In patients with stable coronary heart disease, darapladib did not significantly reduce the risk of the primary composite end point of cardiovascular death, myocardial infarction, or stroke. (Funded by GlaxoSmithKline; STABILITY ClinicalTrials.gov number, NCT00799903.).

    View details for DOI 10.1056/NEJMoa1315878

    View details for Web of Science ID 000335405200008

    View details for PubMedID 24678955

  • Effects of vorapaxar on platelet reactivity and biomarker expression in non-ST-elevation acute coronary syndromes THROMBOSIS AND HAEMOSTASIS Storey, R. F., Kotha, J., Smyth, S. S., Moliterno, D. J., Rorick, T. L., Moccetti, T., Valgimigli, M., Dery, J. P., Cornel, J. H., Thomas, G. S., Huber, K., Harrington, R. A., Hord, E., Judge, H. M., Chen, E., Strony, J., Mahaffey, K. W., Tricoci, P., Becker, R. C., Jennings, L. K. 2014; 111 (5): 883-891
  • Drivers of hospitalization for patients with atrial fibrillation: Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) AMERICAN HEART JOURNAL Steinberg, B. A., Kim, S., Fonarow, G. C., Thomas, L., Ansell, J., Kowey, P. R., Mahaffey, K. W., Gersh, B. J., Hylek, E., Naccarelli, G., Go, A. S., Reiffel, J., Chang, P., Peterson, E. D., Piccini, J. P. 2014; 167 (5): 735-U131

    Abstract

    Atrial fibrillation (AF) is the most common cardiac dysrhythmia and contributes significantly to health care expenditures. We sought to assess the frequency and predictors of hospitalization in patients with AF.The ORBIT-AF registry is a prospective, observational study of outpatients with AF enrolled from June 29, 2010, to August 9, 2011. The current analysis included 9,484 participants with 1-year follow-up. Multivariable, logistic regression was used to identify baseline characteristics that were associated with first cause-specific hospitalization.Overall, 31% of patients with AF studied (n = 2,963) had 1 or more hospitalizations per year and 10% (n = 983) had 2 or more. The most common hospitalization cause was cardiovascular (20 per 100 patient-years vs 3.3 bleeding vs 17 noncardiovascular, nonbleeding). Compared with those not hospitalized, hospitalized patients were more likely to have concomitant heart failure (42% vs 28%, P < .0001), higher mean CHADS2 (1 point for congestive heart failure, hypertension, age ≥75, or diabetes; 2 points for prior stroke or transient ischemic attack) scores (2.5 vs 2.2, P < .0001), and more symptoms (baseline European Heart Rhythm Association class severe symptoms 18% vs 13%, P < .0001). In multivariable analysis, heart failure (adjusted hazard ratio [HR] 1.57 for New York Heart Association III/IV vs none, P < .0001), heart rate at baseline (adjusted HR 1.11 per 10-beats/min increase >66, P < .0001), and AF symptom class (adjusted HR 1.37 for European Heart Rhythm Association severe vs none, P < .0001) were the major predictors of incident hospitalization.Hospitalization is common in outpatients with AF and is independently predicted by heart failure and AF symptoms. Improved symptom control, rate control, and comorbid condition management should be evaluated as strategies to reduce health care use in these patients.

    View details for DOI 10.1016/j.ahj.2014.02.003

    View details for Web of Science ID 000335447800015

    View details for PubMedID 24766985

    View details for PubMedCentralID PMC4006943

  • Drivers of hospitalization for patients with atrial fibrillation: Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). American heart journal Steinberg, B. A., Kim, S., Fonarow, G. C., Thomas, L., Ansell, J., Kowey, P. R., Mahaffey, K. W., Gersh, B. J., Hylek, E., Naccarelli, G., Go, A. S., Reiffel, J., Chang, P., Peterson, E. D., Piccini, J. P. 2014; 167 (5): 735-42 e2

    Abstract

    Atrial fibrillation (AF) is the most common cardiac dysrhythmia and contributes significantly to health care expenditures. We sought to assess the frequency and predictors of hospitalization in patients with AF.The ORBIT-AF registry is a prospective, observational study of outpatients with AF enrolled from June 29, 2010, to August 9, 2011. The current analysis included 9,484 participants with 1-year follow-up. Multivariable, logistic regression was used to identify baseline characteristics that were associated with first cause-specific hospitalization.Overall, 31% of patients with AF studied (n = 2,963) had 1 or more hospitalizations per year and 10% (n = 983) had 2 or more. The most common hospitalization cause was cardiovascular (20 per 100 patient-years vs 3.3 bleeding vs 17 noncardiovascular, nonbleeding). Compared with those not hospitalized, hospitalized patients were more likely to have concomitant heart failure (42% vs 28%, P < .0001), higher mean CHADS2 (1 point for congestive heart failure, hypertension, age ≥75, or diabetes; 2 points for prior stroke or transient ischemic attack) scores (2.5 vs 2.2, P < .0001), and more symptoms (baseline European Heart Rhythm Association class severe symptoms 18% vs 13%, P < .0001). In multivariable analysis, heart failure (adjusted hazard ratio [HR] 1.57 for New York Heart Association III/IV vs none, P < .0001), heart rate at baseline (adjusted HR 1.11 per 10-beats/min increase >66, P < .0001), and AF symptom class (adjusted HR 1.37 for European Heart Rhythm Association severe vs none, P < .0001) were the major predictors of incident hospitalization.Hospitalization is common in outpatients with AF and is independently predicted by heart failure and AF symptoms. Improved symptom control, rate control, and comorbid condition management should be evaluated as strategies to reduce health care use in these patients.

    View details for DOI 10.1016/j.ahj.2014.02.003

    View details for PubMedID 24766985

  • Ticagrelor Effects on Myocardial Infarction and the Impact of Event Adjudication in the PLATO (Platelet Inhibition and Patient Outcomes) Trial. Journal of the American College of Cardiology Mahaffey, K. W., Held, C., Wojdyla, D. M., James, S. K., Katus, H. A., Husted, S., Steg, P. G., Cannon, C. P., Becker, R. C., Storey, R. F., Khurmi, N. S., Nicolau, J. C., Yu, C., Ardissino, D., Budaj, A., Morais, J., Montgomery, D., Himmelmann, A., Harrington, R. A., Wallentin, L. 2014; 63 (15): 1493-1499

    Abstract

    This study sought to report the treatment effect of ticagrelor on myocardial infarction (MI) and the strategy for and impact of event adjudication in the PLATO (Platelet Inhibition and Patient Outcomes) trial.In PLATO, ticagrelor reduced cardiovascular death, MI, or stroke in patients with acute coronary syndromes (ACS).A clinical events committee (CEC) prospectively defined and adjudicated all suspected MI events, on the basis of events reported by investigators and by triggers on biomarkers. Treatment comparisons used CEC-adjudicated data, and per protocol, excluded silent MI.Overall, 1,299 (610 ticagrelor, 689 clopidogrel) MIs reported by the CEC occurred during the trial. Of these, 1,097 (504 ticagrelor, 593 clopidogrel) contributed to the primary composite endpoint. Site investigators reported 1,198 (580 ticagrelor, 618 clopidogrel) MIs. Ticagrelor significantly reduced overall MI rates (12-month CEC-adjudicated Kaplan-Meier rates: 5.8% ticagrelor, 6.9% clopidogrel; hazard ratio [HR]: 0.84; 95% confidence interval [CI]: 0.75 to 0.95). Nonprocedural MI (HR: 0.86; 95% CI: 0.74 to 1.01) and MI related to percutaneous coronary intervention or stent thrombosis tended to be lower with ticagrelor. MIs related to coronary artery bypass graft surgery were few, but numerical excess was observed in patients assigned ticagrelor. Analyses of overall MIs using investigator-reported data showed similar results but did not reach statistical significance (HR: 0.88; 95% CI: 0.78 to 1.00).In patients with ACS, ticagrelor significantly reduced the incidence of MI compared with clopidogrel, with consistent results across most MI subtypes. CEC procedures identified more MI endpoints compared with site investigators. (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872).

    View details for DOI 10.1016/j.jacc.2014.01.038

    View details for PubMedID 24561148

  • Physician practices regarding contraindications to oral anticoagulation in atrial fibrillation: findings from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry. American heart journal O'Brien, E. C., Holmes, D. N., Ansell, J. E., Allen, L. A., Hylek, E., Kowey, P. R., Gersh, B. J., Fonarow, G. C., Koller, C. R., Ezekowitz, M. D., Mahaffey, K. W., Chang, P., Peterson, E. D., Piccini, J. P., Singer, D. E. 2014; 167 (4): 601-609 e1

    Abstract

    Oral anticoagulation (OAC) therapy reduces the risk of thromboembolic events associated with atrial fibrillation (AF), yet a substantial proportion of patients with AF are not prescribed OAC. The aim of this study is to describe the frequencies of and factors associated with OAC contraindications in contemporary clinical practice.We analyzed data from the ORBIT-AF study, a national, prospective, outpatient registry of incident and prevalent AF. Oral anticoagulation contraindications were uniformly collected at enrollment by site personnel using a predefined list. Baseline patient and provider characteristics were compared between participants with and without documented OAC contraindications.From June 2010 to August 2011, 10,130 patients 18 years or older with electrocardiographically documented AF were enrolled at 176 practices. Of these, 1,330 (13.1%) had contraindications documented at the baseline visit: prior bleed (27.7%), patient refusal/preference (27.5%), high bleeding risk (18.0%), frequent falls/frailty (17.6%), need for dual antiplatelet therapy (10.4%), unable to adhere/monitor warfarin (6.0%), comorbid illness (5.3%), prior intracranial hemorrhage (5.0%), allergy (2.4%), occupational risk (0.8%), pregnancy (0.2%), and other (12.6%). Among patients with reported contraindications, 30.3% were taking warfarin or dabigatran, as compared with 83.0% of those without reported contraindications. Besides "patient refusal/preference," being labeled as having frequent falls or being frail was associated with the lowest OAC use among patients with high stroke risk.Contraindications to OAC therapy among patients with AF are common but subjective. Many patients with reported contraindications were receiving OAC, suggesting that the perceived benefit outweighed the potential harm posed by the relative contraindication.

    View details for DOI 10.1016/j.ahj.2013.12.014

    View details for PubMedID 24655711

  • REDUCED DEATH, MYOCARDIAL INFARCTION, AND EARLY STENT THROMBOSIS WITH CANGRELOR VERSUS CLOPIDOGREL ON A BACKGROUND OF BIVALIRUDIN: INSIGHTS FROM CHAMPION PHOENIX White, H. D., Bhatt, D. L., Gibson, C., Hamm, C. W., Mahaffey, K. W., Price, M. J., Steg, P., Stone, G. W., Cortese, B., Wilensky, M., Deliargyris, E. N., Liu, T., Prats, J., Harrington, R. A. ELSEVIER SCIENCE INC. 2014: A36
  • Relationship Between Time in Therapeutic Range and Comparative Treatment Effect of Rivaroxaban and Warfarin: Results From the ROCKET AF Trial JOURNAL OF THE AMERICAN HEART ASSOCIATION Piccini, J. P., Hellkamp, A. S., Lokhnygina, Y., Patel, M. R., Harrell, F. E., Singer, D. E., Becker, R. C., Breithardt, G., Halperin, J. L., Hankey, G. J., Berkowitz, S. D., Nessel, C. C., Mahaffey, K. W., Fox, K. A., Califf, R. M. 2014; 3 (2)

    Abstract

    Time in therapeutic range (TTR) is a standard quality measure of the use of warfarin. We assessed the relative effects of rivaroxaban versus warfarin at the level of trial center TTR (cTTR) since such analysis preserves randomized comparisons.TTR was calculated using the Rosendaal method, without exclusion of international normalized ratio (INR) values performed during warfarin initiation. Measurements during warfarin interruptions >7 days were excluded. INRs were performed via standardized finger-stick point-of-care devices at least every 4 weeks. The primary efficacy endpoint (stroke or non-central nervous system embolism) was examined by quartiles of cTTR and by cTTR as a continuous function. Centers with the highest cTTRs by quartile had lower-risk patients as reflected by lower CHADS2 scores (P<0.0001) and a lower prevalence of prior stroke or transient ischemic attack (P<0.0001). Sites with higher cTTR were predominantly from North America and Western Europe. The treatment effect of rivaroxaban versus warfarin on the primary endpoint was consistent across a wide range of cTTRs (P value for interaction=0.71). The hazard of major and non-major clinically relevant bleeding increased with cTTR (P for interaction=0.001), however, the estimated reduction by rivaroxaban compared with warfarin in the hazard of intracranial hemorrhage was preserved across a wide range of threshold cTTR values.The treatment effect of rivaroxaban compared with warfarin for the prevention of stroke and systemic embolism is consistent regardless of cTTR.

    View details for DOI 10.1161/JAHA.113.000521

    View details for Web of Science ID 000336798000039

    View details for PubMedID 24755148

  • Physician practices regarding contraindications to oral anticoagulation in atrial fibrillation: Findings from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry AMERICAN HEART JOURNAL O'Brien, E. C., Holmes, D. N., Ansell, J. E., Allen, L. A., Hylek, E., Kowey, P. R., Gersh, B. J., Fonarow, G. C., Koller, C. R., Ezekowitz, M. D., Mahaffey, K. W., Chang, P., Peterson, E. D., Piccini, J. P., Singer, D. E. 2014; 167 (4): 601-U229

    Abstract

    Oral anticoagulation (OAC) therapy reduces the risk of thromboembolic events associated with atrial fibrillation (AF), yet a substantial proportion of patients with AF are not prescribed OAC. The aim of this study is to describe the frequencies of and factors associated with OAC contraindications in contemporary clinical practice.We analyzed data from the ORBIT-AF study, a national, prospective, outpatient registry of incident and prevalent AF. Oral anticoagulation contraindications were uniformly collected at enrollment by site personnel using a predefined list. Baseline patient and provider characteristics were compared between participants with and without documented OAC contraindications.From June 2010 to August 2011, 10,130 patients 18 years or older with electrocardiographically documented AF were enrolled at 176 practices. Of these, 1,330 (13.1%) had contraindications documented at the baseline visit: prior bleed (27.7%), patient refusal/preference (27.5%), high bleeding risk (18.0%), frequent falls/frailty (17.6%), need for dual antiplatelet therapy (10.4%), unable to adhere/monitor warfarin (6.0%), comorbid illness (5.3%), prior intracranial hemorrhage (5.0%), allergy (2.4%), occupational risk (0.8%), pregnancy (0.2%), and other (12.6%). Among patients with reported contraindications, 30.3% were taking warfarin or dabigatran, as compared with 83.0% of those without reported contraindications. Besides "patient refusal/preference," being labeled as having frequent falls or being frail was associated with the lowest OAC use among patients with high stroke risk.Contraindications to OAC therapy among patients with AF are common but subjective. Many patients with reported contraindications were receiving OAC, suggesting that the perceived benefit outweighed the potential harm posed by the relative contraindication.

    View details for DOI 10.1016/j.ahj.2013.12.014

    View details for Web of Science ID 000333170900025

    View details for PubMedID 24655711

  • Vorapaxar in Acute Coronary Syndrome Patients Undergoing Coronary Artery Bypass Graft Surgery: Subgroup Analysis From the TRACER Trial (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome). Journal of the American College of Cardiology Whellan, D. J., Tricoci, P., Chen, E., Huang, Z., Leibowitz, D., Vranckx, P., Marhefka, G. D., Held, C., Nicolau, J. C., Storey, R. F., Ruzyllo, W., Huber, K., Sinnaeve, P., Weiss, A. T., Dery, J., Moliterno, D. J., Van de Werf, F., Aylward, P. E., White, H. D., Armstrong, P. W., Wallentin, L., Strony, J., Harrington, R. A., Mahaffey, K. W. 2014; 63 (11): 1048-1057

    Abstract

    This study evaluated effects of protease-activated receptor-1 antagonist vorapaxar (Merck, Whitehouse Station, New Jersey) versus placebo among the TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) study patients with non-ST-segment elevation acute coronary syndromes undergoing coronary artery bypass grafting (CABG).Platelet activation may play a key role in graft occlusion, and antiplatelet therapies may reduce ischemic events, but perioperative bleeding risk remains a major concern. Although the TRACER study did not meet the primary quintuple composite outcome in the overall population with increased bleeding, an efficacy signal with vorapaxar was noted on major ischemic outcomes, and preliminary data suggest an acceptable surgical bleeding profile. We aimed to assess efficacy and safety of vorapaxar among CABG patients.Associations between treatment and ischemic and bleeding outcomes were assessed using time-to-event analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the Cox hazards model. Event rates were estimated using the Kaplan-Meier method.Among 12,944 patients, 1,312 (10.1%) underwent CABG during index hospitalization, with 78% on the study drug at the time of surgery. Compared with placebo CABG patients, vorapaxar-treated patients had a 45% lower rate of the primary endpoint (i.e., a composite of death, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization during index hospitalization) (HR: 0.55; 95% CI: 0.36 to 0.83; p = 0.005), with a significant interaction (p = 0.012). The CABG-related Thrombolysis In Myocardial Infarction major bleeding was numerically higher with vorapaxar, but not significantly different between vorapaxar and placebo (9.7% vs. 7.3%; HR: 1.36; 95% CI: 0.92 to 2.02; p = 0.12), with no excess in fatal bleeding (0% vs. 0.3%) or need for reoperation (4.7% vs. 4.6%).In non-ST-segment elevation acute coronary syndrome patients undergoing CABG, vorapaxar was associated with a significant reduction in ischemic events and no significant increase in major CABG-related bleeding. These data show promise for protease-activated receptor 1 antagonism in patients undergoing CABG and warrant confirmatory evidence in randomized trials. (Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Acute Coronary Syndrome [TRA·CER] [Study P04736AM3]; NCT00527943).

    View details for DOI 10.1016/j.jacc.2013.10.048

    View details for PubMedID 24211500

  • Vorapaxar in Acute Coronary Syndrome Patients Undergoing Coronary Artery Bypass Graft Surgery JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Whellan, D. J., Tricoci, P., Chen, E., Huang, Z., Leibowitz, D., Vranckx, P., Marhefka, G. D., Held, C., Nicolau, J. C., Storey, R. F., Ruzyllo, W., Huber, K., Sinnaeve, P., Weiss, A. T., Dery, J., Moliterno, D. J., Van de Werf, F., Aylward, P. E., White, H. D., Armstrong, P. W., Wallentin, L., Strony, J., Harrington, R. A., Mahaffey, K. W. 2014; 63 (11): 1048-1057

    Abstract

    This study evaluated effects of protease-activated receptor-1 antagonist vorapaxar (Merck, Whitehouse Station, New Jersey) versus placebo among the TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) study patients with non-ST-segment elevation acute coronary syndromes undergoing coronary artery bypass grafting (CABG).Platelet activation may play a key role in graft occlusion, and antiplatelet therapies may reduce ischemic events, but perioperative bleeding risk remains a major concern. Although the TRACER study did not meet the primary quintuple composite outcome in the overall population with increased bleeding, an efficacy signal with vorapaxar was noted on major ischemic outcomes, and preliminary data suggest an acceptable surgical bleeding profile. We aimed to assess efficacy and safety of vorapaxar among CABG patients.Associations between treatment and ischemic and bleeding outcomes were assessed using time-to-event analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the Cox hazards model. Event rates were estimated using the Kaplan-Meier method.Among 12,944 patients, 1,312 (10.1%) underwent CABG during index hospitalization, with 78% on the study drug at the time of surgery. Compared with placebo CABG patients, vorapaxar-treated patients had a 45% lower rate of the primary endpoint (i.e., a composite of death, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization during index hospitalization) (HR: 0.55; 95% CI: 0.36 to 0.83; p = 0.005), with a significant interaction (p = 0.012). The CABG-related Thrombolysis In Myocardial Infarction major bleeding was numerically higher with vorapaxar, but not significantly different between vorapaxar and placebo (9.7% vs. 7.3%; HR: 1.36; 95% CI: 0.92 to 2.02; p = 0.12), with no excess in fatal bleeding (0% vs. 0.3%) or need for reoperation (4.7% vs. 4.6%).In non-ST-segment elevation acute coronary syndrome patients undergoing CABG, vorapaxar was associated with a significant reduction in ischemic events and no significant increase in major CABG-related bleeding. These data show promise for protease-activated receptor 1 antagonism in patients undergoing CABG and warrant confirmatory evidence in randomized trials. (Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Acute Coronary Syndrome [TRA·CER] [Study P04736AM3]; NCT00527943).

    View details for DOI 10.1016/j.jacc.2013.10.048

    View details for Web of Science ID 000333090700004

  • Association of Aspirin Dose and Vorapaxar Safety and Efficacy in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome (from the TRACER Trial). American journal of cardiology Mahaffey, K. W., Huang, Z., Wallentin, L., Storey, R. F., Jennings, L. K., Tricoci, P., White, H. D., Armstrong, P. W., Aylward, P. E., Moliterno, D. J., Van de Werf, F., Chen, E., Leonardi, S., Rorick, T., Held, C., Strony, J., Harrington, R. A. 2014; 113 (6): 936-944

    Abstract

    Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial compared vorapaxar and placebo in 12,944 high-risk patients with non-ST-segment elevation acute coronary syndrome. We explored aspirin (ASA) use and its association with outcomes. Kaplan-Meier event rates were compared in groups defined by ASA dose (low, medium, and high). Landmark analyses with covariate adjustment were performed for 0 to 30, 31 to 180, and 181 to 365 days. Of 12,515 participants, 7,523, 1,049, and 3,943 participants were treated with low-, medium-, and high-dose ASA at baseline, respectively. Participants enrolled in North America versus elsewhere were more often treated with a high dose at baseline (66% vs 19%) and discharge (60% vs 3%). Unadjusted cardiovascular death, myocardial infarction, stroke, hospitalization for ischemia, or urgent revascularization event rates tended to be higher with higher baseline ASA (18.45% low, 19.13% medium, and 20.27% high; p for trend = 0.15573). Unadjusted and adjusted hazard ratios (95% confidence intervals) for effect of vorapaxar on cardiovascular (unadjusted p for interaction = 0.065; adjusted p for interaction = 0.140) and bleeding (unadjusted p for interaction = 0.915; adjusted p for interaction = 0.954) outcomes were similar across groups. Landmark analyses showed similar safety and efficacy outcomes with vorapaxar and placebo by ASA dose at each time point except for 0 to 30 days, when vorapaxar tended to be worse for efficacy (hazard ratio 1.13, 95% confidence interval 0.89 to 1.44, p for interaction = 0.0157). In conclusion, most TRACER participants were treated with low-dose ASA, although a high dose was common in North America. High-dose participants tended to have higher rates of ischemic and bleeding outcomes. Although formal statistical testing did not reveal heterogeneity in vorapaxar's effect across dose subgroups, consistent trends support use of low-dose ASA with other antiplatelet therapies.

    View details for DOI 10.1016/j.amjcard.2013.11.052

    View details for PubMedID 24444781

  • Factors Associated With Major Bleeding Events JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Goodman, S. G., Wojdyla, D. M., Piccini, J. P., White, H. D., Paolini, J. F., Nessel, C. C., Berkowitz, S. D., Mahaffey, K. W., Patel, M. R., Sherwood, M. W., Becker, R. C., Halperin, J. L., Hacke, W., Singer, D. E., Hankey, G. J., Breithardt, G., Fox, K. A., Califf, R. M. 2014; 63 (9): 891-900
  • Factors associated with major bleeding events: insights from the ROCKET AF trial (rivaroxaban once-daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation). Journal of the American College of Cardiology Goodman, S. G., Wojdyla, D. M., Piccini, J. P., White, H. D., Paolini, J. F., Nessel, C. C., Berkowitz, S. D., Mahaffey, K. W., Patel, M. R., Sherwood, M. W., Becker, R. C., Halperin, J. L., Hacke, W., Singer, D. E., Hankey, G. J., Breithardt, G., Fox, K. A., Califf, R. M. 2014; 63 (9): 891-900

    Abstract

    This study sought to report additional safety results from the ROCKET AF (Rivaroxaban Once-daily oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation).The ROCKET AF trial demonstrated similar risks of stroke/systemic embolism and major/nonmajor clinically relevant bleeding (principal safety endpoint) with rivaroxaban and warfarin.The risk of the principal safety and component bleeding endpoints with rivaroxaban versus warfarin were compared, and factors associated with major bleeding were examined in a multivariable model.The principal safety endpoint was similar in the rivaroxaban and warfarin groups (14.9 vs. 14.5 events/100 patient-years; hazard ratio: 1.03; 95% confidence interval: 0.96 to 1.11). Major bleeding risk increased with age, but there were no differences between treatments in each age category (<65, 65 to 74, ≥75 years; pinteraction = 0.59). Compared with those without (n = 13,455), patients with a major bleed (n = 781) were more likely to be older, current/prior smokers, have prior gastrointestinal (GI) bleeding, mild anemia, and a lower calculated creatinine clearance and less likely to be female or have a prior stroke/transient ischemic attack. Increasing age, baseline diastolic blood pressure (DBP) ≥90 mm Hg, history of chronic obstructive pulmonary disease or GI bleeding, prior acetylsalicylic acid use, and anemia were independently associated with major bleeding risk; female sex and DBP <90 mm Hg were associated with a decreased risk.Rivaroxaban and warfarin had similar risk for major/nonmajor clinically relevant bleeding. Age, sex, DBP, prior GI bleeding, prior acetylsalicylic acid use, and anemia were associated with the risk of major bleeding. (An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation: NCT00403767).

    View details for DOI 10.1016/j.jacc.2013.11.013

    View details for PubMedID 24315894

  • Impact of Intraprocedural Stent Thrombosis During Percutaneous Coronary Intervention: Insights From the CHAMPION PHOENIX Trial (Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention). Journal of the American College of Cardiology Généreux, P., Stone, G. W., Harrington, R. A., Gibson, C. M., Steg, P. G., Brener, S. J., Angiolillo, D. J., Price, M. J., Prats, J., Lasalle, L., Liu, T., Todd, M., Skerjanec, S., Hamm, C. W., Mahaffey, K. W., White, H. D., Bhatt, D. L. 2014; 63 (7): 619-629

    Abstract

    This study sought to evaluate the clinical impact of intraprocedural stent thrombosis (IPST), a relatively new endpoint.In the prospective, double-blind, active-controlled CHAMPION PHOENIX (Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention) trial, cangrelor significantly reduced periprocedural and 30-day ischemic events in patients undergoing percutaneous coronary intervention (PCI), including IPST.An independent core laboratory blinded to treatment assignment performed a frame-by-frame angiographic analysis in 10,939 patients for the development of IPST, defined as new or worsening thrombus related to stent deployment at any time during the procedure. Adverse events were adjudicated by an independent, blinded clinical events committee.IPST developed in 89 patients (0.8%), including 35 of 5,470 (0.6%) and 54 of 5,469 (1.0%) patients in the cangrelor and clopidogrel arms, respectively (odds ratio: 0.65; 95% confidence interval: 0.42 to 0.99; p = 0.04). Compared to patients without IPST, IPST was associated with a marked increase in composite ischemia (death, myocardial infarction [MI], ischemia-driven revascularization, or new-onset out-of-laboratory stent thrombosis [Academic Research Consortium]) at 48 h and at 30 days (29.2% vs. 4.5% and 31.5% vs. 5.7%, respectively; p < 0.0001 for both). After controlling for potential confounders, IPST remained a strong predictor of all adverse ischemic events at both time points.In the large-scale CHAMPION PHOENIX trial, the occurrence of IPST was strongly predictive of subsequent adverse cardiovascular events. The potent intravenous adenosine diphosphate antagonist cangrelor substantially reduced IPST, contributing to its beneficial effects at 48 h and 30 days. (Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI] [CHAMPION PHOENIX]; NCT01156571).

    View details for DOI 10.1016/j.jacc.2013.10.022

    View details for PubMedID 24184169

  • Impact of Intraprocedural Stent Thrombosis During Percutaneous Coronary Intervention JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Genereux, P., Stone, G. W., Harrington, R. A., Gibson, C. M., Steg, P. G., Brener, S. J., Angiolillo, D. J., Price, M. J., Prats, J., Lasalle, L., Liu, T., Todd, M., Skerjanec, S., Hamm, C. W., Mahaffey, K. W., White, H. D., Bhatt, D. L. 2014; 63 (7): 619-629

    Abstract

    This study sought to evaluate the clinical impact of intraprocedural stent thrombosis (IPST), a relatively new endpoint.In the prospective, double-blind, active-controlled CHAMPION PHOENIX (Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention) trial, cangrelor significantly reduced periprocedural and 30-day ischemic events in patients undergoing percutaneous coronary intervention (PCI), including IPST.An independent core laboratory blinded to treatment assignment performed a frame-by-frame angiographic analysis in 10,939 patients for the development of IPST, defined as new or worsening thrombus related to stent deployment at any time during the procedure. Adverse events were adjudicated by an independent, blinded clinical events committee.IPST developed in 89 patients (0.8%), including 35 of 5,470 (0.6%) and 54 of 5,469 (1.0%) patients in the cangrelor and clopidogrel arms, respectively (odds ratio: 0.65; 95% confidence interval: 0.42 to 0.99; p = 0.04). Compared to patients without IPST, IPST was associated with a marked increase in composite ischemia (death, myocardial infarction [MI], ischemia-driven revascularization, or new-onset out-of-laboratory stent thrombosis [Academic Research Consortium]) at 48 h and at 30 days (29.2% vs. 4.5% and 31.5% vs. 5.7%, respectively; p < 0.0001 for both). After controlling for potential confounders, IPST remained a strong predictor of all adverse ischemic events at both time points.In the large-scale CHAMPION PHOENIX trial, the occurrence of IPST was strongly predictive of subsequent adverse cardiovascular events. The potent intravenous adenosine diphosphate antagonist cangrelor substantially reduced IPST, contributing to its beneficial effects at 48 h and 30 days. (Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI] [CHAMPION PHOENIX]; NCT01156571).

    View details for DOI 10.1016/j.jacc.2013.10.022

    View details for Web of Science ID 000331719800003

  • Release kinetics of circulating cardiac myosin binding protein-C following cardiac injury AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY Kuster, D. W., Cardenas-Ospina, A., Miller, L., Liebetrau, C., Troidl, C., Nef, H. M., Moellmann, H., Hamm, C. W., Pieper, K. S., Mahaffey, K. W., Kleiman, N. S., Stuyvers, B. D., Marian, A. J., Sadayappan, S. 2014; 306 (4): H547-H556

    Abstract

    Diagnosis of myocardial infarction (MI) is based on ST-segment elevation on electrocardiographic evaluation and/or elevated plasma cardiac troponin (cTn) levels. However, troponins lack the sensitivity required to detect the onset of MI at its earliest stages. Therefore, to confirm its viability as an ultra-early biomarker of MI, this study investigates the release kinetics of cardiac myosin binding protein-C (cMyBP-C) in a porcine model of MI and in two human cohorts. Release kinetics of cMyBP-C were determined in a porcine model of MI (n = 6, pigs, either sex) by measuring plasma cMyBP-C level serially from 30 min to 14 days after coronary occlusion, with use of a custom-made immunoassay. cMyBP-C plasma levels were increased from baseline (76 ± 68 ng/l) at 3 h (767 ± 211 ng/l) and peaked at 6 h (2,418 ± 780 ng/l) after coronary ligation. Plasma cTnI, cTnT, and myosin light chain-3 levels were all increased 6 h after ligation. In a cohort of patients (n = 12) with hypertrophic obstructive cardiomyopathy undergoing transcoronary ablation of septal hypertrophy, cMyBP-C was significantly increased from baseline (49 ± 23 ng/l) in a time-dependent manner, peaking at 4 h (560 ± 273 ng/l). In a cohort of patients with non-ST segment elevation MI (n = 176) from the SYNERGY trial, cMyBP-C serum levels were significantly higher (7,615 ± 4,514 ng/l) than those in a control cohort (416 ± 104 ng/l; n = 153). cMyBP-C is released in the blood rapidly after cardiac damage and therefore has the potential to positively mark the onset of MI.

    View details for DOI 10.1152/ajpheart.00846.2013

    View details for Web of Science ID 000331895000009

    View details for PubMedID 24337456

  • Biomarkers in Relation to the Effects of Ticagrelor in Comparison With Clopidogrel in Non-ST-Elevation Acute Coronary Syndrome Patients Managed With or Without In-Hospital Revascularization A Substudy From the Prospective Randomized Platelet Inhibition and Patient Outcomes (PLATO) Trial CIRCULATION Wallentin, L., Lindholm, D., Siegbahn, A., Wernroth, L., Becker, R. C., Cannon, C. P., Cornel, J. H., Himmelmann, A., Giannitsis, E., Harrington, R. A., Held, C., Husted, S., Katus, H. A., Mahaffey, K. W., Steg, P. G., Storey, R. F., James, S. K. 2014; 129 (3): 293-303

    Abstract

    Risk stratification and the use of specific biomarkers have been proposed for tailoring treatment in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS). We investigated the prognostic importance of high-sensitivity troponin T (hs-TnT), N-terminal pro-brain natriuretic peptide (NT-proBNP), and growth differentiation factor-15 (GDF-15) in relation to randomized treatment (ticagrelor versus clopidogrel) and management strategy (with or without revascularization) in the NSTE-ACS subgroup of the Platelet Inhibition and Patient Outcomes (PLATO) trial.Of 18 624 patients in the PLATO trial, 9946 had an entry diagnosis of NSTE-ACS and baseline blood samples available. During index hospitalization, 5357 were revascularized, and 4589 were managed without revascularization. Hs-TnT, NT-proBNP, and GDF-15 were determined and assessed according to predefined cutoff levels. Median follow-up was 9.1 months. Increasing levels of hs-TnT were associated with increasing risk of cardiovascular death, myocardial infarction, and stroke in medically managed patients (P<0.001), but not in those managed invasively. NT-proBNP and GDF-15 levels were associated with the same events independent of management strategy. Ticagrelor versus clopidogrel reduced the rate of cardiovascular death, myocardial infarction, and stroke in patients with NSTE-ACS and hs-TnT ≥14.0 ng/L in both invasively and noninvasively managed patients; in patients with hs-TnT <14.0 ng/L, there was no difference between ticagrelor and clopidogrel in the noninvasive groupHs-TnT, NT-proBNP, and GDF-15 are predictors of cardiovascular death, myocardial infarction, and stroke in patients with NSTE-ACS managed noninvasively, and NT-proBNP and GDF-15 also in those managed invasively. Elevated hs-TnT predicts substantial benefit of ticagrelor over clopidogrel both in invasively and noninvasively managed patients, but no apparent benefit was seen at normal hs-TnT.URL:http://www.clinicaltrials.gov. Unique identifier: NCT00391872.

    View details for DOI 10.1161/CIRCULATIONAHA.113.004420

    View details for Web of Science ID 000329880700006

    View details for PubMedID 24170388

  • Ischaemic cardiac outcomes in patients with atrial fibrillation treated with vitamin K antagonism or factor Xa inhibition: results from the ROCKET AF trial. European heart journal Mahaffey, K. W., Stevens, S. R., White, H. D., Nessel, C. C., Goodman, S. G., Piccini, J. P., Patel, M. R., Becker, R. C., Halperin, J. L., Hacke, W., Singer, D. E., Hankey, G. J., Califf, R. M., Fox, K. A., Breithardt, G. 2014; 35 (4): 233-241

    Abstract

    We investigated the prevalence of prior myocardial infarction (MI) and incidence of ischaemic cardiovascular (CV) events among atrial fibrillation (AF) patients.In ROCKET AF, 14 264 patients with nonvalvular AF were randomized to rivaroxaban or warfarin. The key efficacy outcome for these analyses was CV death, MI, and unstable angina (UA). This pre-specified analysis was performed on patients while on treatment. Rates are per 100 patient-years. Overall, 2468 (17%) patients had prior MI at enrollment. Compared with patients without prior MI, these patients were more likely to be male (75 vs. 57%), on aspirin at baseline (47 vs. 34%), have prior congestive heart failure (78 vs. 59%), diabetes (47 vs. 39%), hypertension (94 vs. 90%), higher mean CHADS2 score (3.64 vs. 3.43), and fewer prior strokes or transient ischaemic attacks (46 vs. 54%). CV death, MI, or UA rates tended to be lower in patients assigned rivaroxaban compared with warfarin [2.70 vs. 3.15; hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.73-1.00; P = 0.0509]. CV death, MI, or UA rates were higher in those with prior MI compared with no prior MI (6.68 vs. 2.19; HR 3.04, 95% CI 2.59-3.56) with consistent results for CV death, MI, or UA for rivaroxaban compared with warfarin in prior MI compared with no prior MI (P interaction = 0.10).Prior MI was common and associated with substantial risk for subsequent cardiac events. Patients with prior MI assigned rivaroxaban compared with warfarin had a non-significant 14% reduction of ischaemic cardiac events.

    View details for DOI 10.1093/eurheartj/eht428

    View details for PubMedID 24132190

  • Review of the accumulated PLATO documentation supports reliable and consistent superiority of ticagrelor over clopidogrel in patients with acute coronary syndrome: Commentary on: DiNicolantonio JJ, Tomek A, Inactivations, deletions, non-adjudications, and downgrades of clinical endpoints on ticagrelor: serious concerns over the reliability of the PLATO trial, International Journal of Cardiology, 2013. International journal of cardiology Wallentin, L., Becker, R. C., Cannon, C. P., Held, C., Himmelmann, A., Husted, S., James, S. K., Katus, H. S., Mahaffey, K. W., Pieper, K. S., Storey, R. F., Steg, P. G., Harrington, R. A. 2014; 170 (3): e59-62

    View details for DOI 10.1016/j.ijcard.2013.11.003

    View details for PubMedID 24299581

  • Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. American heart journal Schwartz, G. G., Bessac, L. n., Berdan, L. G., Bhatt, D. L., Bittner, V. n., Diaz, R. n., Goodman, S. G., Hanotin, C. n., Harrington, R. A., Jukema, J. W., Mahaffey, K. W., Moryusef, A. n., Pordy, R. n., Roe, M. T., Rorick, T. n., Sasiela, W. J., Shirodaria, C. n., Szarek, M. n., Tamby, J. F., Tricoci, P. n., White, H. n., Zeiher, A. n., Steg, P. G. 2014; 168 (5): 682–89

    Abstract

    Following acute coronary syndrome (ACS), the risk for future cardiovascular events is high and is related to levels of low-density lipoprotein cholesterol (LDL-C) even within the setting of intensive statin treatment. Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates LDL receptor expression and circulating levels of LDL-C. Antibodies to PCSK9 can produce substantial and sustained reductions of LDL-C. The ODYSSEY Outcomes trial tests the hypothesis that treatment with alirocumab, a fully human monoclonal antibody to PCSK9, improves cardiovascular outcomes after ACS.This Phase 3 study will randomize approximately 18,000 patients to receive biweekly injections of alirocumab (75-150 mg) or matching placebo beginning 1 to 12 months after an index hospitalization for acute myocardial infarction or unstable angina. Qualifying patients are treated with atorvastatin 40 or 80 mg daily, rosuvastatin 20 or 40 mg daily, or the maximum tolerated and approved dose of one of these agents and fulfill one of the following criteria: LDL-C ≥ 70 mg/dL, non-high-density lipoprotein cholesterol ≥ 100 mg/dL, or apolipoprotein B ≥ 80 mg/dL. The primary efficacy measure is time to first occurrence of coronary heart disease death, acute myocardial infarction, hospitalization for unstable angina, or ischemic stroke. The trial is expected to continue until 1613 primary end point events have occurred with minimum follow-up of at least 2 years, providing 90% power to detect a 15% hazard reduction. Adverse events of special interest include allergic events and injection site reactions. Interim analyses are planned when approximately 50% and 75% of the targeted number of primary end points have occurred.ODYSSEY Outcomes will determine whether the addition of the PCSK9 antibody alirocumab to intensive statin therapy reduces cardiovascular morbidity and mortality after ACS.

    View details for PubMedID 25440796

  • Challenges and priorities for research: a report from the National Heart, Lung, and Blood Institute (NHLBI)/National Institutes of Health (NIH) Working Group on thrombosis in pediatric cardiology and congenital heart disease. Circulation McCrindle, B. W., Li, J. S., Manlhiot, C. n., Tweddell, J. S., Giglia, T. M., Massicotte, M. P., Monagle, P. n., Krishnamurthy, R. n., Mahaffey, K. W., Michelson, A. D., Verdun, N. n., Almond, C. S., Newburger, J. W., Brandão, L. R., Esmon, C. T., Manco-Johnson, M. J., Ichord, R. n., Ortel, T. L., Chan, A. K., Portman, R. n., Rose, M. n., Strony, J. n., Kaltman, J. R. 2014; 130 (14): 1192–1203

    View details for PubMedID 25266860

  • Vorapaxar in patients with peripheral artery disease and acute coronary syndrome: insights from Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER). American heart journal Jones, W. S., Tricoci, P. n., Huang, Z. n., Moliterno, D. J., Harrington, R. A., Sinnaeve, P. R., Strony, J. n., Van de Werf, F. n., White, H. D., Held, C. n., Armstrong, P. W., Aylward, P. E., Chen, E. n., Patel, M. R., Mahaffey, K. W. 2014; 168 (4): 588–96

    Abstract

    In the TRACER trial, vorapaxar, a protease-activated receptor-1 antagonist, plus standard care in non-ST-segment elevation acute coronary syndrome (NSTE ACS) patients did not significantly reduce the primary composite end point but reduced a key secondary end point and significantly increased bleeding. History of peripheral artery disease (PAD) was a risk-enrichment inclusion criterion. We investigated the efficacy and safety of vorapaxar in NSTE ACS patients with documented PAD.TRACER was a double-blind, randomized trial comparing vorapaxar with placebo in 12,944 patients with NSTE ACS.In total, 936 (7.2%) patients had a history of PAD. Ischemic events occurred more frequently among patients with PAD (25.3%) versus no PAD (12.2%, P < .001), and Global Use of Strategies to Open Occluded Coronary Arteries moderate/severe bleeding was more common in PAD (9.1%) versus no PAD (5.0%, P = .004). Similar rates of the composite end point (cardiovascular death, myocardial infarction, or stroke) occurred in patients with PAD treated with vorapaxar and placebo (21.7% vs 24.8%, P interaction = .787). Patients with PAD treated with vorapaxar, when compared with placebo, also had a numerical reduction in peripheral revascularization procedures (8.1% vs 9.0%, P = .158) and a lower extremity amputation rate (0.9% vs 1.5%, P = .107). Vorapaxar increased Global Use of Strategies to Open Occluded Coronary Arteries moderate/severe bleeding similarly in patients with PAD (hazard ratio 1.47, 95% CI 0.89-2.45) and without (hazard ratio 1.48, 95% CI 1.22-1.79; P interaction = .921).Patients with NSTE ACS and PAD were at increased risk for ischemic events. Lower rates of ischemic end points, peripheral revascularization, and amputation with vorapaxar did not reach statistical significance but warrant further investigation. Vorapaxar increased bleeding in both patients with and without PAD at a similar magnitude of risk.

    View details for PubMedID 25262270

  • Vorapaxar with or without clopidogrel after non-ST-segment elevation acute coronary syndromes: results from the thrombin receptor antagonist for clinical event reduction in acute coronary syndrome trial. American heart journal Tricoci, P. n., Lokhnygina, Y. n., Huang, Z. n., Van de Werf, F. n., Cornel, J. H., Chen, E. n., Wallentin, L. n., Held, C. n., Aylward, P. E., Moliterno, D. J., Jennings, L. K., White, H. D., Armstrong, P. W., Harrington, R. A., Strony, J. n., Mahaffey, K. W. 2014; 168 (6): 869–77.e1

    Abstract

    Protease-activated receptor 1 antagonism with vorapaxar represents a novel strategy for platelet inhibition. In TRACER, vorapaxar was compared with placebo plus standard of care among 12,944 patients with non-ST-segment elevation acute coronary syndromes. We anticipated that most patients would have received clopidogrel as part of standard care. We investigated the modification of vorapaxar's effect associated with clopidogrel use over time.The marginal structural model method was used to estimate causal modification of vorapaxar effect by use of clopidogrel over time. The primary outcomes were the composite of cardiovascular death, myocardial infarction, or stroke and Global Use of Strategies to Open Occluded Coronary Arteries moderate or severe bleeding. The event accrual period excluded the time during which clopidogrel was clinically warranted.Among 12,887 patients who received study medication, 11,117 (86.3%) received clopidogrel before randomization, of whom 38.5% stopped later in the trial (median time to stoppage 200 days with placebo; interquartile range [IQR] 14-367) (186 days with vorapaxar; IQR 17-366). In total, 1,770 (13.7%) patients were not on clopidogrel at randomization, of whom 47.8% started afterward (median time to start 2 days; IQR 2-4). During the period of event accrual, vorapaxar was associated with a 26% reduction in the composite of cardiovascular death, myocardial infarction, or stroke when used with clopidogrel (hazard ratio [HR] 0.74; 95% CI 0.60-0.91) and a 24% reduction when used without clopidogrel (HR 0.76; 95% CI 0.56-1.02) (interaction; P = .89). The hazard of Global Use of Strategies to Open Occluded Coronary Arteries bleeding with vorapaxar was not significantly different without clopidogrel (HR 1.33; 95% CI 0.81-2.20) or with clopidogrel (HR 1.09; 95% CI 0.76-1.56) (interaction; P = .53).We observed no interaction between vorapaxar and clopidogrel after non-ST-segment elevation acute coronary syndromes on efficacy or safety outcomes, supporting a complementary role of protease-activated receptor 1 and P2Y12 antagonism.

    View details for PubMedID 25458650

  • Causes of mortality with ticagrelor compared with clopidogrel in acute coronary syndromes. Heart (British Cardiac Society) Varenhorst, C. n., Alström, U. n., Braun, O. Ö., Storey, R. F., Mahaffey, K. W., Bertilsson, M. n., Cannon, C. P., Scirica, B. M., Himmelmann, A. n., James, S. K., Wallentin, L. n., Held, C. n. 2014; 100 (22): 1762–69

    Abstract

    To describe specific causes of death and evaluate whether bleeding events and infection contributed to mortality in all ticagrelor-treated and clopidogrel-treated patients with acute coronary syndromes.In the PLATelet inhibition and patient Outcomes (PLATO) trial, ticagrelor significantly reduced rates of vascular and total death compared with clopidogrel. In the 905 patients who died postenrolment in the PLATO trial (n=18 624), reviewers, blinded to study treatment, subclassified direct causes of death and evaluated whether infection or bleeding events contributed to fatal events.Among vascular deaths, there were significantly fewer sudden deaths (63 (0.7%) vs 98 (1.1%), p<0.01) but no significant difference in deaths caused by acute myocardial infarction (179 (1.9%) vs 194 (2.1%), p=0.43) or heart failure (31 (0.3%) vs 42 (0.5%), p=0.20) with ticagrelor compared w