Non-major bleeding with apixaban versus warfarin in patients with atrial fibrillation

Abstract

Objective: We describe the incidence, location and management of non-major bleeding, and assess the association between non-major bleeding and clinical outcomes in patients with atrial fibrillation (AF) receiving anticoagulation therapy enrolled in Apixaban for Reduction in Stroke and other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE).

Methods: We included patients who received ≥1 dose of study drug (n=18 140). Non-major bleeding was defined as the first bleeding event considered to be clinically relevant non-major (CRNM) or minor bleeding, and not preceded by a major bleeding event.

Results: Non-major bleeding was three times more common than major bleeding (12.1% vs 3.8%). Like major bleeding, non-major bleeding was less frequent with apixaban (6.4 per 100 patient-years) than warfarin (9.4 per 100 patient-years) (adjusted HR 0.69, 95% CI 0.63 to 0.75). The most frequent sites of non-major bleeding were haematuria (16.4%), epistaxis (14.8%), gastrointestinal (13.3%), haematoma (11.5%) and bruising/ecchymosis (10.1%). Medical or surgical intervention was similar among patients with non-major bleeding on warfarin versus apixaban (24.7% vs 24.5%). A change in antithrombotic therapy (58.6% vs 50.0%) and permanent study drug discontinuation (5.1% (61) vs 3.6% (30), p=0.10) was numerically higher with warfarin than apixaban. CRNM bleeding was independently associated with an increased risk of overall death (adjusted HR 1.70, 95% CI 1.32 to 2.18) and subsequent major bleeding (adjusted HR 2.18, 95% CI 1.56 to 3.04).

Conclusions: In ARISTOTLE, non-major bleeding was common and substantially less frequent with apixaban than with warfarin. CRNM bleeding was independently associated with a higher risk of death and subsequent major bleeding. Our results highlight the importance of any severity of bleeding in patients with AF treated with anticoagulation therapy and suggest that non-major bleeding, including minor bleeding, might not be minor.

Trial registration number: NCT00412984; post-results.

Conflict of interest statement

Competing interests: MCB: Research grants from Bristol-Myers Squibb, Bayer and Boehringer Ingelheim. RDL: Research grants from Bristol-Myers Squibb, GlaxoSmithKline; Consulting for Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Pfyzer and Portola. CH: Research grants from GlaxoSmithKline, Merck, Roche, Bristol-Myers Squibb, AstraZeneca; Speakers bureau for AstraZeneca. MH: Employee of Bristol-Myers Squibb. DV: Nothing to report. EMH: Consulting fees/honoraria from Bristol-Myers Squibb, Daiichi Sankyo, Boehringer Ingelheim, Johnson & Johnson, Pfizer and Bayer; and Research grants from Bristol-Myers Squibb. FV: Honoraria from and consulting/advisory board for Bristol-Myers Squibb and Pfizer. SG: Research grant from the Ministry of Education and Science, Sports and Culture, Japan as a Grant-in-Aid for Scientific Research in Japan (19590871, 21590911, 24390202); a grant for the Next-Generation Supercomputer Research and Development Program supported by RIKEN; Research grants from Sanofi-Aventis, Eisai and Boehringer Ingelheim; participated in consultancy or advisory board for Eisai, Sanofi-Aventis and Otsuka. JHA: Institutional research grants from Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Pfizer, Sanofi, Regado Biosciences, Tenax, Vivus; consulting fee/honoraria from Bristol-Myers Squibb, CSL Behring, Daiichi Sankyo, GlaxoSmithKlein, Jannsen, Pfizer, Portola, Sohmalution, Xoma. LW: Research grants from Bristol-Myers Squibb, Pfizer, AstraZeneca, Merck & Co., Boehringer Ingelheim, GlaxoSmithKline; Consultant/advisory board for Bristol-Myers Squibb, Pfizer, Abbott, AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim; Other from Bristol-Myers Squibb, Pfizer, Abbott, AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim. CBG: Available at https://http://www.dcri.org/about-us/conflict-of-interest/COI-Granger_2015.pdf.

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Figures

Figure 1

Cumulative incidence curves of first non-major bleeding event by treatment.

Figure 2

(A) Distribution of most common location of first non-major or minor bleeding events (1 patient with missing location; 11 patients had 2 bleeding locations reported); (B) non-major gastrointestinal bleeding location.

Figure 3

Effect of different severities of bleeding on subsequent outcomes (HR (95% CI) for yes vs no). CR, clinically relevant.