Major Bleeding Risk During Concomitant Use of Antiarrhythmic Drugs and Oral Factor Xa Inhibitors: A Nationwide Self-Controlled Case Series Study

Abstract Bleeding risk may increase when factor Xa (FXa) inhibitors are co-administered with antiarrhythmic drugs (AADs) due to pharmacokinetic interactions, but real-world evidence on these interactions is inconsistent and limited, particularly for edoxaban. The aim of this study was to evaluate the overall and temporal risk of major bleeding associated with concomitant use of AADs (amiodarone, dronedarone, diltiazem, verapamil) and FXa inhibitors (apixaban, edoxaban, rivaroxaban) using the self-controlled case series (SCCS) method. An SCCS study was conducted using the Korean National Health Insurance Service database. Patients who initiated FXa inhibitors between July 2018 and December 2020, had AAD co-administration, and experienced major bleeding were included. Incidence rate ratios (IRRs) for major bleeding were estimated using conditional Poisson regression, adjusting for time-varying covariates. A total of 963 patients were analyzed. Concomitant use of amiodarone (IRR 2.16; 95% CI 1.73–2.70), diltiazem (IRR 1.96; 95% CI 1.63–2.35), and verapamil (IRR 1.72; 95% CI 1.15–2.59) was associated with an increased major bleeding risk, while dronedarone was not (IRR 1.20; 95% CI 0.69–2.06). The findings were consistent across different FXa inhibitors. Bleeding risk was highest during the first month of co-administration and decreased over time, remaining significant beyond 3 months for amiodarone. Concomitant use of FXa inhibitors with amiodarone, diltiazem, or verapamil was related to an increased incidence of major bleeding, particularly during the first month of co-administration. Close monitoring during this period may be warranted for patients at high risk of bleeding.