Skip to main content
SpringerLink
Log in

Evaluation of rivaroxaban-, apixaban- and dabigatran-associated hemorrhagic events using the FDA-Adverse event reporting system (FAERS) database

  • Research Article
  • Published:
International Journal of Clinical Pharmacy Aims and scope Submit manuscript

Abstract

Background Rivaroxaban, apixaban and dabigatran are non-vitamin K antagonist oral anticoagulants (NOACs) that are widely used for treatment or prevention of venous thromboembolism and stroke in patients with atrial fibrillation. Objective To estimate and compare hemorrhagic events report of rivaroxaban, apixaban and dabigatran. Setting FDA Adverse Event Reporting System (FAERS) database. Methods The reporting odds ratio (ROR) was used to assess the signal of hemorrhagic events of different NOACs. Main outcome measure The overall hemorrhagic events and hemorrhagic events in different physiological systems. Results From January 1, 2014 to December 31, 2019, the total number of reports of hemorrhage related to rivaroxaban was 53,085, and the numbers of apixaban and dabigatran were 13,151 and 14,100 respectively. The overall ROR (95% CI) of hemorrhagic events reporting for rivaroxaban versus dabigatran and apixaban versus dabigatran were 1.58 (1.54–1.62) and 0.47 (0.46–0.48) respectively. The ROR (95% CI) for rivaroxaban versus dabigatran in gastrointestinal system, nervous system, renal and urinary system, skin and subcutaneous tissue, and eye system was 1.38 (1.34–1.42), 0.94 (0.90–0.98), 1.07 (1.01–1.13), 0.80 (0.70–0.90), and 1.38 (1.19–1.60) respectively. The RORs (95% CI) for apixaban versus dabigatran in gastrointestinal system, nervous system, renal and urinary system, skin and subcutaneous tissue, and eye system were 0.28 (0.27–0.29), 0.69 (0.66–0.73), 0.31 (0.29–0.34), 0.98 (0.86–1.12), and 1.18 (1.00–1.39), respectively. Conclusions Overall, we found a moderate signal of higher frequency of reporting hemorrhage in rivaroxban compared with dabigatran and decreased hemorrhagic event reporting in apixaban compared with dabigatran. While this potential signal has not been confirmed in clinical trials or observational studies, in clinical practice, attention should be paid to the risk of potential hemorrhage when the patients switch from apixaban to dabigatran or rivaroxban.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149(2):315–52.

    Article  Google Scholar 

  2. Enea I, Roncon L, Gulizia MM, Azzarito M, Becattini C, Bongarzoni A, et al. ANMCO Position Paper: the use of non-vitamin K dependent new oral anticoagulant(s) in pulmonary embolism therapy and prevention. Eur Heart J Suppl. 2017;19(Suppl D):D293–308.

    Article  CAS  Google Scholar 

  3. January CT, Wann LS, Calkins H, Field ME, Chen LY, Furie KL, et al. 2019 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation. Circulation. 2019;140(2):e125–51.

    Article  Google Scholar 

  4. Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383:955–62.

    Article  CAS  Google Scholar 

  5. Yao X, Abraham NS, Alexander GC, Crown W, Montori VM, Sangaralingham LR, et al. Effect of adherence to oral anticoagulants on risk of stroke and major bleeding among patients with atrial fibrillation. J Am Heart Assoc. 2016;5(2):e003074.

    Article  Google Scholar 

  6. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139–51.

    Article  CAS  Google Scholar 

  7. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883–91.

    Article  CAS  Google Scholar 

  8. Kapil N, Datta YH, Alakbarova N, Bershad E, Selim M, Liebeskind DS, et al. Antiplatelet and anticoagulant therapies for prevention of ischemic stroke. Clin Appl Thromb Hemost. 2017;23(4):301–18.

    Article  CAS  Google Scholar 

  9. Fontaine GV, Mathews KD, Woller SC, Stevens SM, Lloyd JF, Evans RS. Major bleeding with dabigatran and rivaroxaban in patients with atrial fibrillation: a real-world setting. Clin Appl Thromb Hemost. 2014;20(7):665–72.

    Article  Google Scholar 

  10. Graham DJ, Reichman ME, Wernecke M, Hsueh YH, Izem R, Southworth MR, et al. Stroke, bleeding, and mortality risks in elderly medicare beneficiaries treated with dabigatran or rivaroxaban for nonvalvular atrial fibrillation. JAMA Intern Med. 2016;176(11):1662–71.

    Article  Google Scholar 

  11. Prins MH, Bauersachs R, Bellen B, Bellen B, Bounameaux H, Brighton TA, et al. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J. 2013;11(1):21.

    Article  Google Scholar 

  12. Abe J, Umetsu R, Kato Y, Ueda N, Nakayama Y, Suzuki Y, et al. Evaluation of dabigatran- and warfarin-associated hemorrhagic events using the FDA-adverse event reporting system database stratified by age. Int J Med Sci. 2015;12(4):312–21.

    Article  CAS  Google Scholar 

  13. Alshammari TM, Ata SI, Mahmoud MA, Alhawassi TM, Aljadhey HS. Signals of bleeding among direct-acting oral anticoagulant users compared to those among warfarin users: analyses of the post-marketing FDA adverse event Reporting system (FAERs) database, 2010–2015. Ther Clin Risk Manag. 2018;14:803–9.

    Article  Google Scholar 

  14. DeLoughery EP, Shatzel JJ. A comparative analysis of the safety profile of direct oral anticoagulants using the FDA adverse event reporting system. Eur J Haematol. 2019;103(1):43–6.

    Article  Google Scholar 

  15. Shimada K, Hasegawa S, Nakao S, Mukai R, Sasaoka S, Ueda N, et al. Adverse reaction profiles of hemorrhagic adverse reactions caused by direct oral anticoagulants analyzed using the Food and Drug Administration Adverse Event Reporting System (FAERS) database and the Japanese Adverse Drug Event Report (JADER) database. Int J Med Sci. 2019;16(9):1295–303.

    Article  CAS  Google Scholar 

  16. Yokoyama S, Tanaka Y, Nakagita K, Hosomi K, Takada M. Bleeding risk of warfarin and direct oral anticoagulants in younger population: a historical cohort study using a Japanese Claims Database. Int J Med Sci. 2018;15(14):1686–93.

    Article  CAS  Google Scholar 

  17. Rothman KJ, Lanes S, Sacks ST. The reporting odds ratio and its advantages over the proportional reporting ratio. Pharmacoepidemiol Drug Saf. 2004;13(8):519–23.

    Article  Google Scholar 

  18. Patrick B, Caroline DP, Yves C, Jacques B, Patrick M, Abdelilah A, et al. Comparative effectiveness and safety of standard or reduced dose dabigatran versus rivaroxaban in non-valvular atrial fibrillation. Clin Pharmacol Ther. 2019;105(6):1439–55.

    Article  Google Scholar 

  19. Douros A, Durand M, Doyle CM, Yoon S, Reynier P, Filion KB. Comparative effectiveness and safety of direct oral anticoagulants in patients with atrial fibrillation: a systematic review and meta-analysis of observational studies. Drug Saf. 2019;42(10):1135–48.

    Article  Google Scholar 

  20. Kreutz R. A clinical and pharmacologic assessment of once-daily versus twice-daily dosing for rivaroxaban. J Thromb Thrombolysis. 2014;38(2):137–49.

    Article  CAS  Google Scholar 

  21. Gu ZC, Wei AH, Zhang C, Wang XH, Zhang L, Shen L, et al. Risk of major gastrointestinal bleeding with new vs conventional oral anticoagulants: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2020;18:792–9.

    Article  CAS  Google Scholar 

  22. Abraham NS, Noseworthy PA, Yao X, Sangaralingham LR, Shah ND. Gastrointestinal safety of direct oral anticoagulants: a large population-based study. Gastroenterology. 2017;152(5):1014-22.e1.

    Article  Google Scholar 

  23. Deitelzweig S, Keshishian A, Li XY, Kang A, Dhamane AD, Luo XM, et al. Comparisons between oral anticoagulants among older nonvalvular atrial fibrillation patients. J Am Geriatr Soc. 2019;67(8):1662–71.

    Article  Google Scholar 

  24. Barnes GD, Lucas E, Alexander GC, Goldberger ZD. National trends in ambulatory oral anticoagulant use. Am J Med. 2015;128(12):1300-5.e2.

    Article  Google Scholar 

Download references

Acknowledgements

The authors were involved at all stages of manuscript development. The authors received no direct compensation related to the development of the manuscript.

Funding

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Conflicts of interest

The authors report no conflict of interest relevant to the subject of this article.

Author information

Authors and Affiliations

  1. Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, No. 95 Yongan Road, Xicheng District, Beijing, China

    Mingxing Guo, Ying Zhao, Wanyi Xu & Xiangli Cui

  2. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, 2101 McGavran-Greenberg Hall, Campus Box 7453, Chapel Hill, NC, 27599 , USA

    Sydney Thai & Tiansheng Wang

  3. Public Health Department, Aix-Marseille University, Marseille, France

    Junwen Zhou

  4. Department of Epidemiology, Milken Institute School of Public Health, George Washington University, Washington, DC, USA

    Jingkai Wei

Authors
  1. Mingxing Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sydney Thai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Junwen Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jingkai Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ying Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wanyi Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tiansheng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiangli Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Tiansheng Wang or Xiangli Cui.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guo, M., Thai, S., Zhou, J. et al. Evaluation of rivaroxaban-, apixaban- and dabigatran-associated hemorrhagic events using the FDA-Adverse event reporting system (FAERS) database. Int J Clin Pharm 43, 1508–1515 (2021). https://doi.org/10.1007/s11096-021-01273-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11096-021-01273-8

Keywords

Search

Navigation