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

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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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.

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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.

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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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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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