Bleeding rates of Veterans taking apixaban or rivaroxaban for atrial fibrillation or venous thromboembolism

  • Zachary HoweEmail author
  • Chad Naville-Cook
  • Derek Cole


This study examined potential differences in bleeding between apixaban and rivaroxaban, the most commonly utilized direct oral anticoagulants at the Richard L. Roudebush VA Medical Center. Additionally, the analysis included a comparison between observed and literature-reported bleeding rates. This retrospective chart review examined 452 (39%) Veterans receiving rivaroxaban and 716 (61%) Veterans receiving apixaban. Bleeding rates were expressed per 100 patient-years and the overall rates were analyzed as the primary analysis. Secondary objectives included comparisons based on indication and severity, as well as comparisons to literature-reported bleed rates, time to bleeding event, and location of the bleed. The analysis did not detect any statistically significant differences between apixaban and rivaroxaban in terms of overall, (ARR 0.90% per 100 patient-years, 95% CI − 0.58 to 2.38%, p > 0.05) major, (ARR 0.22% per 100 patient-years, 95% CI − 0.74 to 1.17%, p > 0.05) or non-major clinically relevant (ARR 0.35% per 100 patient-years, 95% CI − 0.57 to 1.27%, p > 0.05) bleeding. Observed bleeding for both rivaroxaban and apixaban in the Veteran population exceeded the rates reported by the literature when used for atrial fibrillation (1.96% vs. 0.15%, p < 0.05; 1.08% vs. 0.16%, p < 0.05) but the opposite was seen for long term venous thromboembolism (VTE) treatment (3.97% vs. 8.03%, p < 0.0001; 0.14% vs. 15.51%, p < 0.0001) or extended VTE prophylaxis (0.07% vs 5.98%, p < 0.0001; 0.07% vs 1.88%, p < 0.01). Results from this study suggest these agents impart similar levels of risk, but variations in bleeding risk between the Veteran population and the patients in the original clinical trials may exist.


Direct oral anticoagulants (DOAC) Novel oral anticoagulants (NOAC) Veterans affairs Apixaban Rivaroxaban 



We would like to thank Andrea Kingsolver, PharmD and the members of the Pharmacy Therapeutics Workgroup at the Richard L Roudebush VA Medical Center for assistance with manuscript editing and study facilitation, respectively. This material is the result of work supported with resources and the use of facilities at the Richard L Roudebush VA Medical Center, Indianapolis, IN. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.

Compliance with ethical standards

Conflict of interest

The author(s) declared no potential conflict of interest with respect to the research, authorship, and/or publication of this article.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study formal consent is not required.

Supplementary material

11239_2018_1770_MOESM1_ESM.pdf (136 kb)
Supplementary material 1 (PDF 135 KB)
11239_2018_1770_MOESM2_ESM.pdf (134 kb)
Supplementary material 2 (PDF 133 KB)


  1. 1.
    Kearon C, Ald EA, Ornelas J et al (2016) Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. CHEST 149(2):315–352. CrossRefPubMedGoogle Scholar
  2. 2.
    Castellucci LA, Cameron C, Le Gal G et al (2014) Clinical and safety outcomes associated with treatment of acute venous thromboembolism: a systematic review and meta-analysis. JAMA 312(11):1122–1135. CrossRefPubMedGoogle Scholar
  3. 3.
    Kang N, Sobieraj DM (2014) Indirect comparison of new oral anticoagulants for the treatment of acute venous thromboembolism. Throm Res 133:1145–1151. CrossRefGoogle Scholar
  4. 4.
    Castellucci LA (2018) Comparison of bleeding risk between rivaroxaban and apixaban (COBRRA pilot). NCT02559856. Posted September 24, 2015. Updated April 17, Accessed 16 July 2018Google Scholar
  5. 5.
    Castellucci LA, Carrier M (2018) Comparison of bleeding risk between rivaroxaban and apixaban for the treatment of acute venous thromboembolism (COBRRA). NCT03266783. Posted August 30, 2017. Updated July 10, Accessed 16 July 2018Google Scholar
  6. 6.
    Chao TH, Chen JY et al (2016) Comparison of efficacy and safety among dabigatran, rivaroxaban, and apixaban in non-valvular atrial fibrillation (DARING-AF). NCT02666157. Posted January 28, 2016. Updated February 17, Accessed 16 July 2018Google Scholar
  7. 7.
    Agnelli G, Buller HR, Cohen A et al (2013) Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 369(9):799–809. CrossRefPubMedGoogle Scholar
  8. 8.
    Agnelli G, Buller HR, Cohen A et al (2013) Apixaban for extended treatment of venous thromboembolism. N Engl J Med 368(8):699–709. CrossRefPubMedGoogle Scholar
  9. 9.
    Bauersachs R, Berkowitz SD, Brenner B et al (2010) Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 363:2499–2510. CrossRefPubMedGoogle Scholar
  10. 10.
    Granger CB, Alexander JH, McMurray JJV et al (2011) Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 365:981–992. CrossRefPubMedGoogle Scholar
  11. 11.
    Patel MR, Mahaffey KW, Garg J et al (2011) Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 365(10):883–891. CrossRefPubMedGoogle Scholar
  12. 12.
    Weitz JK, Lensing AWA, Prins MH et al (2017) Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med 376(13):1211–1223. CrossRefPubMedGoogle Scholar
  13. 13.
    Westat (2010) National survey of veterans, active duty service members, demobilized national guard and reserve members, family members, and surviving spouses. Studies/NVSSurveyFinalWeightedReport.pdf
  14. 14.
    Institute of Medicine (2009) Combating tobacco use in military and veteran populations. The National Academies Press, Washington, DCGoogle Scholar
  15. 15.
    Kurth T, Kase CS, Berger K et al (2003) Smoking and the risk of hemorrhagic stroke in men. Stroke 34:1151–1155. CrossRefPubMedGoogle Scholar
  16. 16.
    Pemberton MR, Forman-Hoffman VL, Lipari RN et al (2016) Prevalence of past year substance use and mental illness by veteran status in a nationally representative sample. CBHSQ.
  17. 17.
    Shoeb M, Fang MC (2013) Assessing bleeding risk in patients taking anticoagulants. J Thromb Thrombolysis 35(3):312–319. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Milling T Jr, Frontera J (2017) Exploring indications for the use of direct oral anticoagulants and the associated risks of major bleeding. Am J Manag Care 23(4 Suppl):S67–S80PubMedPubMedCentralGoogle Scholar
  19. 19.
    Activase [package insert] (1987) Genentech, Inc., South San FranciscoGoogle Scholar
  20. 20.
    Kcentra [package insert] (2013) CSL Behring GmbH, MargburgGoogle Scholar
  21. 21.
    Wilate [package insert] (2009) Octapharma Pharmazeutika Produktionsges, Vienna. m.b.HGoogle Scholar
  22. 22.
    Blood Safety Basics (2013) Centers for Disease Control and Prevention: Updated January 31, Accessed 26 June 2018
  23. 23.
    Ghate SR, Biskupiak J, Ye X, Kwong WJ, Brixner DI (2011) All-cause and bleeding-related health care costs in warfarin-treated patients with atrial fibrillation. J Manag Care Pharm 17(9):672–684. CrossRefPubMedGoogle Scholar
  24. 24.
    Andexxa [package insert] (2018) Portola Pharmaceuticals, Inc., South San FranciscoGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Pharmacy ServiceRichard L. Roudebush VA Medical CenterIndianapolisUSA
  2. 2.Butler University College of Pharmacy and Health SciencesIndianapolisUSA

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