Incidence of uterine bleeding following oral anticoagulant use in Food and Drug Administration’s Sentinel System

Abstract

To better understand the occurrence of uterine bleeding (UB) events requiring intervention in women treated with oral anticoagulants (OAs), we examined the incidence of UB events in the Food and Drug Administration’s (FDA) Sentinel System. The FDA’s Sentinel System,1Platt R. Brown J.S. Robb M. et al.The FDA Sentinel Initiative - an evolving national resource.N Engl J Med. 2018; 379: 2091-2093Crossref PubMed Scopus (91) Google Scholar, 2Ball R. Robb M. Anderson S.A. Dal Pan G. The FDA’s sentinel initiative--a comprehensive approach to medical product surveillance.Clin Pharmacol Ther. 2016; 99: 265-268Crossref PubMed Scopus (131) Google Scholar, 3Platt R. Carnahan R.M. Brown J.S. et al.The U.S. Food and Drug Administration’s Mini-Sentinel program: status and direction.Pharmacoepidemiol Drug Saf. 2012; 21: 1-8PubMed Google Scholar, 4Behrman R.E. Benner J.S. Brown J.S. McClellan M. Woodcock J. Platt R. Developing the Sentinel System--a national resource for evidence development.N Engl J Med. 2011; 364: 498-499Crossref PubMed Scopus (255) Google Scholar allows drug safety surveillance using real-world postmarketing data. It is comprised of 17 public and commercial health insurers and integrated delivery networks, contributing medical encounter and outpatient pharmacy claims data. Women with a diagnosis of venous thromboembolism and atrial fibrillation in the 183 days before (baseline) and on the day of dispensing of warfarin or nonvitamin K oral anticoagulants were identified during the study period from October 2010 to September 2015. We excluded women with hysterectomy, joint replacement, or the outcome of interest during the baseline period. From OA dispensing date, we followed women until the earliest of: end of treatment exposure, disenrollment from medical or prescription drug coverage, death, end of the study period, or study outcome. We focused on UB events resulting in medical, transfusion, or surgical interventions that reflect clinically relevant morbidity. Thus, we examined same-day insertion of an intrauterine system or vaginal packing or oral contraceptive or antifibrinolytic use (medical management), same-day red blood cell transfusion (transfusion) as UB diagnosis, and surgical intervention (hysterectomy, polypectomy, myomectomy, dilation and curettage, endometrial ablation, uterine artery embolization) occurring within 30 days of UB diagnosis (surgical management). We estimated incidence rates of these outcomes overall and stratified by age group. This study was exempt from the purview of institutional review boards. In 1,050,192 new users of OA, the overall UB incidence rates were 0.6, 1.7, and 5.0 per 1000 person-years for outcomes with medical, transfusion, and surgical management, respectively (Table). When stratified by age group, UB incidence rates among users younger than 50 years were increased to 11.8, 13.7, and 33.0 per 1000 person-years; all estimates were consistently higher than those observed in users older than 50 years. UB with surgical management was notably more common than UB with medical or transfusion management in all ages. Overall, 2.8% of women had a reported gynecologic disorder (adenomyosis, endometrial hyperplasia, endometriosis, gynecologic cancers, ovarian cyst, uterine fibroids, uterine or cervical polyp) before treatment.TableIncidence (per 1000 person-years) of UB requiring intervention among Novel Oral Anticoagulants (NOAC)aNOAC: rivaroxaban, apixaban and dabigatran. and warfarin usersManagement after uterine bleedOverall≤50 y51+ yMedical management within 24 h0.611.80.2Medical management within 5 d0.712.80.2Same-day transfusion management1.713.71.2Surgical management within 30 d5.033.03.9Surgical management within 60 d5.334.04.2Medical management: insertion of an intrauterine system or vaginal packing or initiation of an oral contraceptive or antifibrinolytic agent after UB diagnosis.Transfusion management: same-day red blood cell transfusion after UB diagnosis.Surgical management: surgical intervention, including hysterectomy, polypectomy, myomectomy, dilation and curettage, endometrial ablation, and uterine artery embolization occurring after UB diagnosis. NOAC drugs include rivaroxaban, apixaban, and dabigatran.Anderson. Incidence of uterine bleeding following oral anticoagulant use in Food and Drug Administration’s Sentinel System. Am J Obstet Gynecol 2021.a NOAC: rivaroxaban, apixaban and dabigatran. Open table in a new tab Medical management: insertion of an intrauterine system or vaginal packing or initiation of an oral contraceptive or antifibrinolytic agent after UB diagnosis. Transfusion management: same-day red blood cell transfusion after UB diagnosis. Surgical management: surgical intervention, including hysterectomy, polypectomy, myomectomy, dilation and curettage, endometrial ablation, and uterine artery embolization occurring after UB diagnosis. NOAC drugs include rivaroxaban, apixaban, and dabigatran. Anderson. Incidence of uterine bleeding following oral anticoagulant use in Food and Drug Administration’s Sentinel System. Am J Obstet Gynecol 2021. The extent of medical or surgical intervention from UB events may not be appreciated in clinical trials as they typically enroll a small proportion of reproductive-aged women. Gynecologists should be aware of the risks of UB in women on OAs, especially those in the reproductive years. Detailed guidance on the management of reproductive-aged women on OA will help inform healthcare providers of the risk of UB events and allow earlier interventions that could mitigate morbidity from UB events in women on OA therapy.