Bleeding-related interactions between DOACs and cardiovascular drugs: Insights from FDA adverse event reporting system

BACKGROUND: Patients receiving direct-oral anticoagulants (DOACs) often have multiple cardiovascular disorders and are frequently exposed to polypharmacy. This study aimed to identify bleeding-related drug interactions between DOACs and cardiovascular drugs in the context of polypharmacy using the FDA Adverse Event Reporting System (FAERS). METHODS: Individual case safety reports involving apixaban, dabigatran, edoxaban, or rivaroxaban were extracted from FAERS. DOAC-related reports were classified according to exposure to concomitant use of predefined 15 drug classes of interest-ten cardiovascular drug classes, three classes of pharmacokinetic modifiers, anti-platelets, and non-steroidal anti-inflammatory drugs-and bleeding events. Bleeding events were defined at three levels: hemorrhage-related events, actual bleeding events, and major bleeding. Major bleeding was further classified by anatomical site. Exact matching and logistic regression were performed to estimate adjusted reporting odds ratios (RORs). RESULTS: A total of 317,583 eligible reports were included. Fifteen DOAC-drug combinations were consistently identified as significant interaction signals across the three bleeding definitions, with adjusted RORs ranging from 1.06 to 2.36. Diuretics showed consistent interaction signals across DOACs and bleeding definitions, while the strongest interaction signals were observed with digitalis glycosides, non-dihydropyridine calcium channel blockers, and amiodarone analogs. Site-stratified major bleeding analyses identified 64 significant interaction signals, with rivaroxaban accounting for the largest proportion, whereas edoxaban showed a relatively less extensive interaction signal profile. CONCLUSIONS: These findings suggest that consideration of polypharmacy and potential drug interactions may improve DOAC selection and risk stratification, particularly with concomitant cardiovascular drugs and site-specific bleeding risk, supporting closer monitoring.