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Déjà vu all over again: a recurrent flaw in anticoagulant study design
Bethany Samuelson Bannow1, Alison Edelman2, Marc Carrier3
1The Hemostasis and Thrombosis Center at Oregon Health & Science University, Portland, Oregon, USA; Division of Hematology/Oncology, Department of Medicine, The Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, USA.
Abstract:
The availability of direct oral anticoagulants rapidly changed the landscape of anticoagulation between 2010 and the present. Randomized controlled trials demonstrating efficacy with similar or superior safety compared with warfarin led to the widespread use of direct oral anticoagulants in male and female patients of all ages. Years later, postmarketing data demonstrated a markedly increased rate of heavy menstrual bleeding (HMB) with rivaroxaban that had gone undetected in registry trials. Factor (F)XI inhibitors are currently being investigated as another alternative to available anticoagulation agents. While generally mild, the phenotype of inherited FXI deficiency includes bleeding in tissues with enhanced fibrinolysis, including HMB. Thus, we aimed to perform a systematic review of published studies on FXI inhibitors in order to estimate rates of HMB. However, we found that few studies included menstruating individuals, and even fewer specifically reported on uterine bleeding, highlighting once again a flaw in our approach to conducting trials of new anticoagulants.
Insights
Direct oral anticoagulants, like rivaroxaban, have shown increased rates of heavy menstrual bleeding (HMB). Current trials for new anticoagulants, such as Factor XI inhibitors, need to better include and report on HMB in menstruating individuals.
Area of Science:
- Pharmacology
- Hematology
- Clinical Trials
Background:
- Direct oral anticoagulants (DOACs) have largely replaced warfarin for anticoagulation since 2010.
- Postmarketing data revealed a significant increase in heavy menstrual bleeding (HMB) with rivaroxaban, which was not detected in initial trials.
- Factor XI (FXI) inhibitors are emerging as a new class of anticoagulants, with FXI deficiency phenotypes including bleeding in highly fibrinolytic tissues like the uterus.
Approach:
- A systematic review was conducted on published studies of FXI inhibitors.
- The review aimed to estimate the rates of HMB associated with FXI inhibitors.
- The analysis identified limitations in existing research regarding the inclusion and reporting of HMB in trials.
Key Points:
- Few studies on FXI inhibitors have included menstruating individuals.
- Even fewer studies specifically reported on uterine bleeding or HMB.
- This highlights a critical gap in the evaluation of new anticoagulants.
Conclusions:
- Current trial designs for anticoagulants may not adequately capture the risk of HMB.
- Further research is needed to specifically assess HMB risk with FXI inhibitors.
- Improved methodologies are required for future anticoagulant trials to ensure comprehensive safety evaluations.
