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Risk of Severe Abnormal Uterine Bleeding Associated with Rivaroxaban Compared with Apixaban, Dabigatran and Warfarin

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Abstract

Introduction

There have been reports of clinically relevant uterine bleeding events among women of reproductive age exposed to rivaroxaban.

Objective

The aim of this study was to compare the risk of severe abnormal uterine bleeding (SAUB) resulting in transfusion or surgical intervention among women on rivaroxaban versus apixaban, dabigatran and warfarin.

Methods

We conducted a retrospective cohort study in the FDA’s Sentinel System (10/2010–09/2015) among females aged 18+ years with venous thromboembolism (VTE), or atrial flutter/fibrillation (AF) who newly initiated a direct oral anticoagulant (DOAC; rivaroxaban, apixaban, dabigatran) or warfarin. We followed women from dispensing date until the earliest of transfusion or surgery following vaginal bleeding, disenrollment, exposure or study end date, or recorded death. We estimated hazard ratios (HRs) using Cox proportional hazards regression via propensity score stratification. Four pairwise comparisons were conducted for each intervention.

Results

Overall, there was an increased risk of surgical intervention with rivaroxaban when compared with dabigatran (HR 1.19; 95% CI 1.03–1.38), apixaban (1.23; 1.04–1.47), and warfarin (1.34; 1.22–1.47). No difference in risk for surgical intervention was observed for dabigatran–apixaban comparisons. Increased risk of transfusion was observed for rivaroxaban compared with dabigatran (1.49; 1.03–2.17) only. For patients with no gynecological history, rivaroxaban was associated with risk of surgical intervention compared with dabigatran (1.22; 1.05–1.42), apixaban (1.25; 1.04–1.49), and warfarin (1.36; 1.23–1.50).

Conclusion

Our study found increased SAUB risk with rivaroxaban use compared with other DOACs or warfarin. Increased risk with rivaroxaban was present among women without underlying gynecological conditions. Women on anticoagulant therapy should be aware of a risk of SAUB.

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References

  1. Cohen H, Arachchillage DRJ, Beyer-Westendorf J, Middeldorp S, Kadir RA. Direct oral anticoagulants and women. Semin Thromb Hemost. 2016;42(07):789–97.

    Article  CAS  Google Scholar 

  2. Myers B, Webster A. Heavy menstrual bleeding on rivaroxaban—comparison with apixaban. Br J Haematol. 2017;176(5):833–5.

    Article  Google Scholar 

  3. Beyer-Westendorf J, Michalski F, Tittl L, Hauswald-Dörschel S, Marten S. Management and outcomes of vaginal bleeding and heavy menstrual bleeding in women of reproductive age on direct oral anti-factor Xa inhibitor therapy: a case series. Lancet Haematol. 2016;3(10):e480–8.

    Article  Google Scholar 

  4. Ferreira M. Direct oral anti-Xa inhibitors and vaginal bleeding. Lancet Haematol. 2016;3(10):e451–2.

    Article  Google Scholar 

  5. Ferreira M, Barsam S, Patel JP, Czuprynska J, Roberts LN, Patel RK, et al. Heavy menstrual bleeding on rivaroxaban. Br J Haematol. 2016;173(2):314–5.

    Article  Google Scholar 

  6. Bryk AH, Piróg M, Plens K, Undas A. Heavy menstrual bleeding in women treated with rivaroxaban and vitamin K antagonists and the risk of recurrent venous thromboembolism. Vasc Pharmacol. 2016;87:242–7.

    Article  CAS  Google Scholar 

  7. De Crem N, Peerlinck K, Vanassche T, Vanheule K, Debaveye B, Middeldorp S, et al. Abnormal uterine bleeding in VTE patients treated with rivaroxaban compared to vitamin K antagonists. Thromb Res. 2015;136(4):749–53.

    Article  Google Scholar 

  8. Huq FY, Tvarkova K, Arafa A, Kadir RA. Menstrual problems and contraception in women of reproductive age receiving oral anticoagulation. Contraception. 2011;84(2):128–32.

    Article  CAS  Google Scholar 

  9. Cheong Y, Cameron IT, Critchley HOD. Abnormal uterine bleeding. Br Med Bull. 2017;123(1):103–14.

    Article  Google Scholar 

  10. Singh S, Best C, Dunn S, Leyland N, Wolfman WL. Abnormal uterine bleeding in pre-menopausal women. J Obstetr Gynaecol Canada. 2013;35(5):473–5.

    Article  Google Scholar 

  11. Tobenkin AMM, Munoz M. Accepted abstract: direct oral anticoagulants and menorrhagia in premenopausal women: data from the food and drug administration adverse event reporting system and US drug utilization. Haemophilia. 2017;23(S3):3–49.

    Google Scholar 

  12. Martinelli I, Lensing AW, Middeldorp S, Levi M, Beyer-Westendorf J, van Bellen B, et al. Recurrent venous thromboembolism and abnormal uterine bleeding with anticoagulant and hormone therapy use. Blood. 2016;127(11):1417–25.

    Article  CAS  Google Scholar 

  13. Brekelmans MP, Scheres LJ, Bleker SM, Hutten BA, Timmermans A, Buller HR, et al. Abnormal vaginal bleeding in women with venous thromboembolism treated with apixaban or warfarin. Thromb Haemost. 2017;117(4):809–15.

    Article  Google Scholar 

  14. Munro MG, Critchley HOD, Fraser IS. The two FIGO systems for normal and abnormal uterine bleeding symptoms and classification of causes of abnormal uterine bleeding in the reproductive years: 2018 revisions. Int J Gynaecol Obstet. 2018;143(3):393–408.

    Article  Google Scholar 

  15. Connolly JG, Wang SV, Fuller CC, Toh S, Panozzo CA, Cocoros N, et al. Development and application of two semi-automated tools for targeted medical product surveillance in a distributed data network. Curr Epidemiol Rep. 2017;4(4):298–306.

    Article  Google Scholar 

  16. Curtis LH, Weiner MG, Boudreau DM, Cooper WO, Daniel GW, Nair VP, et al. Design considerations, architecture, and use of the Mini-Sentinel distributed data system. Pharmacoepidemiol Drug Saf. 2012;21(Suppl 1):23–31.

    Article  Google Scholar 

  17. Sentinel Operations Center. Sentinel Common Data Model. [cited 2020 March 1, 2020]; Available from: https://www.sentinelinitiative.org/sentinel/data/distributed-database-common-data-model/sentinel-common-data-model

  18. McGraw D, Rosati K, Evans B. A policy framework for public health uses of electronic health data. Pharmacoepidemiol Drug Saf. 2012;21(Suppl 1):18–22.

    Article  Google Scholar 

  19. Forrow S, Campion DM, Herrinton LJ, Nair VP, Robb MA, Wilson M, et al. The organizational structure and governing principles of the Food and Drug Administration’s Mini-Sentinel pilot program. Pharmacoepidemiol Drug Saf. 2012;21(Suppl 1):12–7.

    Article  Google Scholar 

  20. Gagne JJ, Glynn RJ, Avorn J, Levin R, Schneeweiss S. A combined comorbidity score predicted mortality in elderly patients better than existing scores. J Clin Epidemiol. 2011;64(7):749–59.

    Article  Google Scholar 

  21. Fireman B, Lee J, Lewis N, Bembom O, van der Laan M, Baxter R. Influenza vaccination and mortality: differentiating vaccine effects from bias. Am J Epidemiol. 2009;170(5):650–6.

    Article  Google Scholar 

  22. Zhou M, Wang SV, Leonard CE, Gagne JJ, Fuller C, Hampp C, et al. Sentinel modular program for propensity-score matched cohort analyses: application to glyburide, glipizide, and serious hypoglycemia. Epidemiology. 2017.

  23. Graham DJ, Baro E, Zhang R, Liao J, Wernecke M, Reichman ME, et al. Comparative stroke, bleeding, and mortality risks in older medicare patients treated with oral anticoagulants for nonvalvular atrial fibrillation. Am J Med. 2019;132(5):596-604.e11.

    Article  Google Scholar 

  24. Deitelzweig S, Luo X, Gupta K, Trocio J, Mardekian J, Curtice T, et al. Comparison of effectiveness and safety of treatment with apixaban vs other oral anticoagulants among elderly nonvalvular atrial fibrillation patients. Curr Med Res Opin. 2017;33(10):1745–54.

    Article  CAS  Google Scholar 

  25. Hernandez I, Zhang Y, Saba S. Comparison of the effectiveness and safety of apixaban, dabigatran, rivaroxaban, and warfarin in newly diagnosed atrial fibrillation. Am J Cardiol. 2017;120(10):1813–9.

    Article  CAS  Google Scholar 

  26. 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  CAS  Google Scholar 

  27. FDA Administration. Meeting Materials, Cardiovascular and Renal Drugs Advisory Committee. 2011.

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Acknowledgements

The authors thank the Sentinel Data Partners who provided data used in the analysis: Aetna, a CVS Health company, Blue Bell, PA; Duke University School of Medicine, Department of Population Health Sciences, Durham, NC, through the Centers for Medicare and Medicaid Services which provided data; HealthCore, Inc., Translational Research for Affordability and Quality, Alexandria, VA; Humana, Inc., Healthcare Research, Miramar, FL; and OptumInsight, Life Sciences Inc., Boston, MA. The authors thank Andrew Petrone, MPH, Rajani Rajbhandari, MS, Elizabeth Dee, MPH, Joy Kolonoski, MPH, Judith C. Maro, PhD, and Anita Wagner, PhD at the Sentinel Operations Center for their programming, operational, and clinical review assistance.

Author information

Authors and Affiliations

  1. Division of Epidemiology, U.S. Food and Drug Administration, Silver Spring, MD, 20993, USA

    Efe Eworuke & David Moeny

  2. Department of Population Medicine, Harvard Medical School, Harvard Pilgrim Health+ Care Institute, Boston, MA, USA

    Laura Hou & Ting-Ying Huang

  3. Division of Biometrics, U.S. Food and Drug Administration, Silver Spring, MD, USA

    Rongmei Zhang

  4. Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA

    Hui-Lee Wong

  5. Division of Pharmacovigilance, U.S. Food and Drug Administration, Silver Spring, MD, USA

    Peter Waldron

  6. Division of Urology, Obstetrics and Gynecology, Office of New Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA

    Abby Anderson & Audrey Gassman

Authors
  1. Efe Eworuke
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  2. Laura Hou
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Corresponding author

Correspondence to Efe Eworuke.

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Authors' contribution

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by LH and T-YH. The first draft of the manuscript was written by EE and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding

The Sentinel Initiative is funded by the U.S. Food and Drug Administration through the Department of Health and Human Services contract number HHSF223200910006I.

Data availability

The datasets generated during and/or analyzed during the current study are not publicly available due to confidentiality agreements.

Conflict of interest

All authors have no conflict of interest to disclose.

Ethics approval

This study was conducted as part of the public health surveillance activities under the auspices of the Food and Drug Administration and therefore not under the purview of Institutional Review Boards.

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Not applicable.

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Code availability (software application or custom code)

https://dev.sentinelsystem.org/projects/AP/repos/sentinel-analytic-packages/browse?at=refs%2Fheads%2Fcder_mpl2p_wp018. The views expressed in this publication are those of the authors and do not necessarily reflect the official policy of the US Food and Drug Administration.

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Eworuke, E., Hou, L., Zhang, R. et al. Risk of Severe Abnormal Uterine Bleeding Associated with Rivaroxaban Compared with Apixaban, Dabigatran and Warfarin. Drug Saf 44, 753–763 (2021). https://doi.org/10.1007/s40264-021-01072-0

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