Risk of major bleeding in patients with non-valvular atrial fibrillation treated with oral anticoagulants: a systematic review of real-world observational studies

Abstract

Objective: To conduct a systematic review of real-world (RWD) studies comparing the risk of major bleeding (MB) among patients with non-valvular atrial fibrillation (NVAF) on direct oral anticoagulants (DOACs) or warfarin.

Methods: MEDLINE, Embase, NHS-EED, and EconLit were searched for RWD studies published between January 2003 and November 2016 comparing MB risk among DOACs and warfarin. Proceedings of clinical conferences from 2012 to 2016 were reviewed.

Results: A total of 4218 citations were identified, 26 of which met eligibility criteria. Most studies were retrospective analyses of administrative claims databases and patient registries (n = 23 of 26); about half were based in the United States (n = 15). Apixaban showed a significantly lower risk of MB versus warfarin in all eight included studies. MB risk was either significantly lower (n = 9 of 16) or not significantly different (n = 7 of 16) between dabigatran and warfarin; there was no significant difference between rivaroxaban and warfarin in all seven included studies. The risk was significantly lower with apixaban versus rivaroxaban (n = 7 of 7) but not significantly different from dabigatran (n = 6 of 7). MB risk was significantly lower (n = 3 of 4) or not significantly different (n = 1 of 4) with dabigatran versus rivaroxaban. No evidence was identified for edoxaban.

Conclusion: DOACs were associated with similar or lower risks of MB versus warfarin. A lower MB risk was consistently observed for apixaban, but less consistently for dabigatran; MB risk was similar between rivaroxaban and warfarin. Among DOACs, the risk of MB with apixaban was consistently lower than with rivaroxaban, but similar to dabigatran.

Keywords:

• Direct oral anticoagulants (DOACs)
• novel oral anticoagulants (NOACs)
• vitamin K antagonists (VKAs)
• warfarin
• non-valvular atrial fibrillation (NVAF)
• major bleeding (MB)
• systematic review

Transparency

Declaration of funding

Funding for the study and this manuscript was provided by Pfizer Inc. and Bristol-Myers Squibb.

Author contributions: X.L., M.H., R.H. and A.A. were involved in the conception and design. All authors were involved in the synthesis of the data; the drafting of the paper or revising it critically for intellectual content; and the final approval of the version to be published; and all authors agree to be accountable for all aspects of the work.

Declaration of financial/other relationships

S.D. has disclosed that she/he is a consultant for Bayer/Janssen and Bristol Myers Squibb Company/Pfizer Inc., Daiichi-Sankyo, Portola, and Boehringer Ingelheim, and has been on the speakers’ bureau for Janssen and Bristol Myers Squibb Company/Pfizer Inc. X.L. has disclosed that she/he is an employee of Pfizer Inc., with ownership of stocks in Pfizer Inc. R.H. has disclosed that she/he is a former employee of Pfizer Inc., with ownership of stocks in Pfizer Inc. X.L., M.H. and L.V. have disclosed that they are employees of Bristol Myers Squibb Company with ownership of stocks in Bristol Myers Squibb Company. A.A. and C.F. have disclosed that they are employed by Evidera, which provides consulting and other research services to pharmaceutical, medical device, and related organizations. In their salaried positions, they work with a variety of companies and organizations, and are precluded from receiving payment or honoraria directly from these organizations for services rendered. Evidera received funding from Pfizer Inc. and Bristol-Myers Squibb to participate in the study and the development of this manuscript.

CMRO peer reviewers on this manuscript have received an honorarium from CMRO for their review work, but have no relevant financial or other relationships to disclose.