A Major Knowledge Gap in Women's Health: The Combined Effect of Antifibrinolytics and Estrogen on Risk of Thromboembolism - a Scoping Review

Background:Up to 30% of women of reproductive age will seek medical attention for heavy menstrual bleeding (HMB), which negatively affects health-related quality of life. Both estrogen-containing oral contraceptives and antifibrinolytic agents are essential first-line treatments for HMB. Anecdotally, these agents appear synergistically effective when used in combination. Despite the strong evidence for the independent efficacy and safety of these agents for HMB as well as the use of antifibrinolytics in other high-estrogen states such as the post-partum state, prescribers are frequently uncomfortable prescribing them in combination due to the theoretical increased risk of thrombosis.

Objective:To systematically evaluate the literature that explores the combined effect of pharmacologic or high physiologic estrogen and antifibrinolytic agents on risk of thromboembolism in women of reproductive age when used for heavy menstrual or post-partum bleeding.

Methods:A literature search was performed on Medline, EMBASE, CINAHL, and Scopus from inception to July 2020. References of included articles were screened and a grey literature search was conducted to identify additional sources. Studies written in English that explored the risk of thromboembolism in women of reproductive age prescribed antifibrinolytic agents alongside estrogen-containing contraceptives or with a physiologic high-estrogen state were included. A thromboembolic event was defined as formation of a blood clot/thrombus in any arterial or venous structure with or without travel to a site distal to its point of origin, confirmed by appropriate diagnostic imaging/testing (including but not limited to deep vein thrombosis, superficial vein thrombosis, pulmonary embolism, ischemic stroke, myocardial infarction, mesenteric ischemia, ischemic colitis, kidney/spleen/liver infarct, or critical limb ischemia). Screening and data abstraction were performed by two independent reviewers (DM, DL) and conflicts were adjudicated by a third reviewer (MS).

Results:A total of 2389 title and abstracts were identified from the literature. Of those, a total of 33 studies with 27933 participants were extracted for full text review. Of these studies, 31 investigatedantifibrinolytic use for post-partum bleeding: 22 randomized controlled trials (RCT), 3 retrospective cohort studies, 1 combined prospective-retrospective cohort study, 2 case series, and 3 case reports. Almost all (29/31) of these studies found no increased rate/risk of thromboembolism. However, only 4 of these studies were powered to make this assessment, all of which were RCTs. The 2 studies that described thromboembolism with antifibrinolytic use in the postpartum period were a case report and case series (N=18), respectively. We found only 2 case reports published describing thromboembolism withconcomitant estrogen-containing contraceptives and antifibrinolytic use, both of which reported thromboembolism in women using both agents for less than 3 months.

Conclusions:We found no clear evidence that intermittent use of antifibrinolytics in either high physiologic or pharmacologic estrogenic states results in higher rates of thromboembolism. Prospective studies are warranted, particularly in the area of combined estrogen-containing contraceptive and antifibrinolytic use, to provide an accurate assessment of risk and properly inform prescribing practices.