Comparative Stroke, Bleeding, and Mortality

Comparative Stroke, Bleeding, and Mortality Risks in Older Medicare Patients Treated with Oral Anticoagulants for Nonvalvular Atrial Fibrillation David J. Graham, MD, MPH , a Elande Baro, PhD , b Rongmei Zhang, PhD , b Jiemin Liao, MA , c Michael Wernecke, BA , c Marsha E. Reichman, PhD , a Mao Hu, BS , c Onyekachukwu Illoh, OD, MPH , a Yuqin Wei, MS , c Margie R. Goulding, PhD , a Yoganand Chillarige, MPA , c Mary Ross Southworth, PharmD , d Thomas E. MaCurdy, PhD , c , e Jeffrey A. Kelman, MD, MMS c f a Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research; b Office of Biostatistics, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Md; c Acumen LLC, Burlingame, Calif; d Office of New Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Md; e Department of Economics, Stanford University, Stanford, Calif; f Centers for Medicare & Medicaid Services, Washington, DC. ABSTRACT BACKGROUND: Nonvitamin K antagonist oral anticoagulants (NOACs) are alternatives to warfarin in patients with nonvalvular atrial fibrillation. Randomized trials compared NOACs with warfarin, but none have compared individual NOACs against each other for safety and effectiveness. METHODS: We performed a retrospective new-user cohort study of patients with nonvalvular atrial fibrilla- tion enrolled in US Medicare who initiated warfarin (n = 183,318), or a standard dose of dabigatran (150 mg twice daily; n = 86,198), rivaroxaban (20 mg once daily; n = 106,389), or apixaban (5 mg twice daily; n = 73,039) between October 2010 and September 2015. Propensity score-adjusted Cox proportional hazards regression was used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for the outcomes of thromboembolic stroke, intracranial hemorrhage, major extracranial bleeding, and all- cause mortality, comparing each NOAC with warfarin, and with each other NOAC. RESULTS: Compared with warfarin, each NOAC was associated with reduced risks of thromboembolic stroke (20%-29% reduction; P = .002 [dabigatran], P < 0.001 [rivaroxaban, apixaban]), intracranial hemorrhage (35%-62% reduction; P < 0.001 [each NOAC]), and mortality (19%-34% reduction; P < .001 [each NOAC]). The NOACs were similar for thromboembolic stroke but rivaroxaban was associated with increased risks of intracranial hemorrhage (vs dabigatran: HR = 1.71; 95% CI, 1.35- 2.17), major extracranial bleeding (vs dabigatran: HR = 1.32; 95% CI, 1.21-1.45; vs apixaban: HR = 2.70; 95% CI, 2.38-3.05), and death (vs dabigatran: HR = 1.12; 95% CI, 1.01-1.24; vs apixaban: HR = 1.23; 95% CI, 1.09-1.38). Dabigatran was associated with reduced risk of intracranial hemor- rhage (HR = 0.70; 95% CI ,0.53-0.94) and increased risk of major extracranial bleeding (HR = 2.04; 95% CI, 1.78-2.32) compared with apixaban. CONCLUSIONS: Among patients treated with standard-dose NOAC for nonvalvular atrial fibrillation and warfarin users with similar baseline characteristics, dabigatran, rivaroxaban, and apixaban were associated with a more favorable benefit − harm profile than warfarin. Among NOAC users, dabigatran and apixaban were associated with a more favorable benefit − harm profile than rivaroxaban. 2019 Elsevier Inc. All rights reserved. The American Journal of Medicine (2019) 000:1 − 9 KEYWORDS: Anticoagulants; Apixaban; Atrial fibrillation; Comparative effectiveness; Comparative safety; Dabiga- tran; Rivaroxaban; Warfarin ARTICLE IN PRESS Funding: See last page of article. Conflict of Interest: See last page of article. Authorship: See last page of article. Requests for reprints should be addressed to David J. Graham, MD, MPH, Office of Surveillance and Epidemiology, 10903 New Hampshire Ave, Building 22, Room 4314, Silver Spring, MD, 20993-0002. E-mail address: david.graham1@fda.hhs.gov 0002-9343/ © 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.amjmed.2018.12.023 CLINICAL RESEARCH STUDY