Background: Bleeding risk may increase when Factor Xa (FXa) inhibitors are co-administered with anti-arrhythmic drugs (AADs) due to pharmacokinetic interactions but real-world evidence on these interactions is inconsistent and limited, particularly for edoxaban.

Objective: The aim of this study is 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.

Methods: A 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.

Results: A total of 963 patients were analyzed. Concomitant use of amiodarone (IRR 2.20; 95% CI 1.76–2.75), diltiazem (IRR 1.98; 95% CI 1.65–2.38), and verapamil (IRR 1.70; 95% CI 1.13–2.56) significantly increased major bleeding risk, while dronedarone did not (IRR 1.28; 95% CI 0.74–2.19). 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 three months for amiodarone.

Conclusions: Concomitant use of FXa inhibitors with amiodarone, diltiazem, or verapamil increases the risk of major bleeding, particularly during the first month of co-administration. Close monitoring during this period is recommended to mitigate bleeding complications.