Comparison of major bleeding risk in patients with non-valvular atrial fibrillation receiving direct oral anticoagulants in the real-world setting: a network meta-analysis

Abstract

Objective: To conduct a systematic literature review (SLR) and network meta-analysis (NMA) of real-world studies comparing major bleeding risk among patients with non-valvular atrial fibrillation (NVAF) on direct oral anticoagulants (DOACs) or warfarin.

Methods: Systematic searches were conducted in MEDLINE and Embase for full-text articles published between January 1, 2003 and March 18, 2017. Eligible studies compared at least two of the following in a real-world setting: warfarin, apixaban, dabigatran, rivaroxaban, or edoxaban. A Bayesian NMA was conducted to estimate hazard ratios (HRs) for major bleeding using a random-effects model.

Results: Eleven studies were included in the NMA. Nine studies included DOACs vs Warfarin comparisons, and four studies included DOACs vs DOACs comparisons (two studies included both comparisons). Median follow-up duration ranged from 2.6–31.2 months. No evidence was identified for edoxaban. Apixaban was associated with a significantly lower risk of major bleeding compared to other oral anticoagulants (warfarin HR = 0.58; 95% credible interval [CrI] = 0.48–0.69; dabigatran = 0.73; 0.61–0.87; rivaroxaban = 0.55; 0.46–0.66). Dabigatran was associated with a significantly lower risk than warfarin (0.79; 0.71–0.88) and rivaroxaban (0.76; 0.67–0.85), and rivaroxaban was not statistically different from warfarin (1.05; 0.91–1.19). Sensitivity analyses with standard dose and sponsorship showed consistent results.

Conclusion: DOACs were associated with lower or similar risk of major bleeding compared with warfarin in NVAF patients. Apixaban was associated with a significantly lower risk of major bleeding than other DOACs. Dabigatran was associated with a significantly lower risk of major bleeding compared to rivaroxaban and warfarin.

Keywords:

• Direct oral anticoagulants (DOACs)
• Novel oral anticoagulants (NOACs)
• Warfarin
• Non-valvular atrial fibrillation (NVAF)
• major bleeding
• Network meta-analysis (NMA)
• systematic review

Transparency

Declaration of funding

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

Declaration of financial/other relationship

S.D. is a consultant for Bayer/Janssen, 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. Luo and J.M. are employees of Pfizer Inc., with ownership of stocks in Pfizer Inc. X.m Li and L.V. are employees of Bristol-Myers Squibb Company with ownership of stocks in Bristol-Myers Squibb Company. A.A., C.F., and K.F. are employed by Evidera Inc., 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. A.A., C.F., and K.F. are employees of Evidera who were paid consultants to Pfizer and Bristol-Myers Squibb Company and in connection with the development of this manuscript. Evidera received funding from Pfizer Inc. and Bristol-Myers Squibb Company to participate in the study and the development of this manuscript. Peer reviewers on this manuscript have received an honorarium from CMRO for their review work, but have no other relevant financial relationships to disclose.