Thrombotic and Hemorrhagic Adverse Events of Direct Oral Anticoagulants: An Analysis of Sex-Related Differences Using Food and Drug Administration Adverse Event Reporting System.

BACKGROUND

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).

METHODS

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.

RESULTS

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).

CONCLUSIONS

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