Thrombotic and Hemorrhagic Adverse Events of Direct Oral Anticoagulants: An Analysis of Sex-Related Differences Using...

Sex-related differences in the safety profiles of direct oral anticoagulants (DOACs) remain insufficiently understood. This study aimed to evaluate sex-specific differences in the most frequently reported hemorrhagic and thrombotic adverse events (AEs) associated with DOAC therapy using data from the Food and Drug Administration Adverse Event Reporting System (FAERS).

A retrospective pharmacovigilance analysis was conducted using FAERS reports from each DOAC's approval date through 2024. Only cases in which a single DOAC was designated as the primary suspect and the report was submitted by a healthcare professional were included. Six major AEs were evaluated: gastrointestinal hemorrhage, intracerebral hemorrhage, pulmonary embolism (PE), deep vein thrombosis, ischemic stroke, and myocardial infarction (MI). Dabigatran served as the reference comparator. Reporting odds ratios (RORs) with 95% CIs were calculated to identify disproportionate reporting signals.

Hemorrhagic and thrombotic AE patterns demonstrated notable sex differences. Gastrointestinal hemorrhage risk was higher with apixaban (ROR = 2.32, P < .001, 95% CI: 2.20-2.45) and edoxaban (ROR = 2.95, P < .001, 95% CI: 2.54-3.42) compared with dabigatran, while female dabigatran users reported these events more frequently (P < .001). Intracranial hemorrhage was reported more often among males using dabigatran and rivaroxaban (P = .003 and P = .004). All DOACs were associated with increased MI reports (e.g., apixaban ROR = 2.37, P < .001, 95% CI: 2.08-2.71), particularly among males. Conversely, PE and ischemic stroke were more frequently reported in female rivaroxaban users (P < .001 and P = .018).

Significant sex-specific differences exist in DOAC safety profiles. Recognizing these patterns may inform individualized anticoagulant selection and enhance pharmacovigilance-driven personalized medicine.