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Arrhythmias and sudden death
Original article
Non-major bleeding with apixaban versus warfarin in patients with atrial fibrillation
  1. M Cecilia Bahit1,
  2. Renato D Lopes2,
  3. Daniel M Wojdyla2,
  4. Claes Held3,
  5. Michael Hanna4,
  6. Dragos Vinereanu5,
  7. Elaine M Hylek6,
  8. Freek Verheugt7,
  9. Shinya Goto8,
  10. John H Alexander2,
  11. Lars Wallentin3,
  12. Christopher B Granger2
  1. 1INECO Neurociencias Oroño, Rosario, Santa Fe, Argentina
  2. 2Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina, USA
  3. 3Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden
  4. 4Bristol-Myers Squibb, Princeton, New Jersey, USA
  5. 5University of Medicine and Pharmacy Carol Davila, Bucharest, Romania
  6. 6Boston University Medical Center, Boston, Massachusetts, USA
  7. 7Heartcenter, Onze Lieve Vrouwe Gasthuis (OLVG), Amsterdam, Netherlands
  8. 8Tokai University School of Medicine, Isehara, Japan
  1. Correspondence to Dr Renato D Lopes, Duke Clinical Research Institute, Room 0311 Terrace Level, 2400 Pratt Street, Durham, NC 27705, USA; renato.lopes{at}duke.edu

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.

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/heartjnl-2016-309901

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    Footnotes

    • Contributors MCB and RDL had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The authors, independent of the sponsor, are responsible for the design and conduct of the study; collection, management, analysis and interpretation of the data; and preparation, review and approval of the manuscript. The sponsor had the right to review the manuscript, but did not have any input into the decision to submit the manuscript for publication.

    • Funding The ARISTOTLE study was supported by Bristol-Myers Squibb, Princeton, NJ and Pfizer, New York, NY.

    • 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.

    • Ethics approval Ethics committees at all sites approved the study.

    • Provenance and peer review Not commissioned; externally peer reviewed.