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Association of Rivaroxaban vs Apixaban With Major Ischemic or Hemorrhagic Events in Patients With Atrial Fibrillation

Educational Objective
To understand the comparative effectiveness of oral anticoagulants for ischemic stroke prevention in patients with atrial fibrillation.
1 Credit CME
Key Points

Question  Is there a difference in risk of major ischemic or hemorrhagic events in patients with atrial fibrillation treated with rivaroxaban vs apixaban?

Findings  In this retrospective cohort study that included 581 451 patients 65 years or older enrolled in Medicare with atrial fibrillation, the adjusted incidence of major ischemic or hemorrhagic events was 16.1 per 1000 person-years for rivaroxaban vs 13.4 per 1000 person-years for apixaban, a difference that was statistically significant.

Meaning  Among older adults with atrial fibrillation, treatment with rivaroxaban compared with apixaban was associated with a significantly increased risk of major ischemic or hemorrhagic events.


Importance  The comparative effectiveness of rivaroxaban and apixaban, the most frequently prescribed oral anticoagulants for ischemic stroke prevention in patients with atrial fibrillation, is uncertain.

Objective  To compare major ischemic and hemorrhagic outcomes in patients with atrial fibrillation treated with rivaroxaban or apixaban.

Design, Setting, and Participants  Retrospective cohort study using computerized enrollment and claims files for US Medicare beneficiaries 65 years or older. Between January 1, 2013, and November 30, 2018, a total of 581 451 patients with atrial fibrillation began rivaroxaban or apixaban treatment and were followed up for 4 years, through November 30, 2018.

Exposures  Rivaroxaban (n = 227 572) and apixaban (n = 353 879), either standard or reduced dose.

Main Outcomes and Measures  The primary outcome was a composite of major ischemic (stroke/systemic embolism) and hemorrhagic (intracerebral hemorrhage/other intracranial bleeding/fatal extracranial bleeding) events. Secondary outcomes were nonfatal extracranial bleeding and total mortality (fatal ischemic/hemorrhagic event or other death during follow-up). Rates, hazard ratios (HRs), and rate differences (RDs) were adjusted for baseline differences in comorbidity with inverse probability of treatment weighting.

Results  Study patients (mean age, 77.0 years; 291 966 [50.2%] women; 134 393 [23.1%] receiving reduced dose) had 474 605 person-years of follow-up (median [IQR] of 174 [62-397] days). The adjusted primary outcome rate for rivaroxaban was 16.1 per 1000 person-years vs 13.4 per 1000 person-years for apixaban (RD, 2.7 [95% CI, 1.9-3.5]; HR, 1.18 [95% CI, 1.12-1.24]). The rivaroxaban group had increased risk for both major ischemic events (8.6 vs 7.6 per 1000 person-years; RD, 1.1 [95% CI, 0.5-1.7]; HR, 1.12 [95% CI, 1.04-1.20]) and hemorrhagic events (7.5 vs 5.9 per 1000 person-years; RD, 1.6 [95% CI, 1.1-2.1]; HR, 1.26 [95% CI, 1.16-1.36]), including fatal extracranial bleeding (1.4 vs 1.0 per 1000 person-years; RD, 0.4 [95% CI, 0.2-0.7]; HR, 1.41 [95% CI, 1.18-1.70]). Patients receiving rivaroxaban had increased risk of nonfatal extracranial bleeding (39.7 vs 18.5 per 1000 person-years; RD, 21.1 [95% CI, 20.0-22.3]; HR, 2.07 [95% CI, 1.99-2.15]), fatal ischemic/hemorrhagic events (4.5 vs 3.3 per 1000 person-years; RD, 1.2 [95% CI, 0.8-1.6]; HR, 1.34 [95% CI, 1.21-1.48]), and total mortality (44.2 vs 41.0 per 1000 person-years; RD, 3.1 [95% CI, 1.8-4.5]; HR, 1.06 [95% CI, 1.02-1.09]). The risk of the primary outcome was increased for rivaroxaban in both those receiving the reduced dose (27.4 vs 21.0 per 1000 person-years; RD, 6.4 [95% CI, 4.1-8.7]; HR, 1.28 [95% CI, 1.16-1.40]) and the standard dose (13.2 vs 11.4 per 1000 person-years; RD, 1.8 [95% CI, 1.0-2.6]; HR, 1.13 [95% CI, 1.06-1.21]) groups.

Conclusions and Relevance  Among Medicare beneficiaries 65 years or older with atrial fibrillation, treatment with rivaroxaban compared with apixaban was associated with a significantly increased risk of major ischemic or hemorrhagic events.

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Article Information

Corresponding Author: Wayne A. Ray, PhD, Department of Health Policy, 2525 West End Ave, Room 717, Nashville, TN 37203 (wayne.ray@vumc.org).

Accepted for Publication: November 8, 2021.

Correction: This article was corrected on April 5, 2022, to correct an error in the 95% CIs for the hazard ratios for hemorrhagic events and nonfatal extracranial

bleeding in Figure 3.

Author Contributions: Dr Ray had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Ray, Chung, Stein, Smalley, Zimmerman, Hung, Murray.

Acquisition, analysis, or interpretation of data: Ray, Chung, Stein, Zimmerman, Dupont, Daugherty, Dickson, Murray.

Drafting of the manuscript: Ray, Dickson, Murray.

Critical revision of the manuscript for important intellectual content: Ray, Chung, Stein, Smalley, Zimmerman, Dupont, Hung, Daugherty, Murray.

Statistical analysis: Ray, Zimmerman, Dupont.

Obtained funding: Ray.

Administrative, technical, or material support: Ray, Chung, Zimmerman, Hung, Daugherty, Dickson, Murray.

Supervision: Ray.

Conflict of Interest Disclosures: Dr Ray reported receiving grants from the National Heart, Lung, and Blood Institute (NHLBI) during the conduct of the study. Dr Chung reported receiving grants from the National Institutes of Health and grants from Veterans Affairs during the conduct of the study. Mr Daugherty reported receiving grants from NHLBI during the conduct of the study. Dr Hung reported receiving grants from Veterans Affairs during the conduct of the study. Dr Murray reported a patent pending with Vanderbilt University Medical Center from Metabolic Technologies outside the submitted work. No other disclosures were reported.

Funding/Support: The study was supported by a grant from the NHLBI (#HL151523). Access to study data was provided by the Virtual Research Data Center of the Centers for Medicare & Medicaid Services.

Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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