Abstract
BACKGROUND: Several antiarrhythmic drugs can interact with direct oral anticoagulants (DOACs) through pharmacokinetic mechanisms increasing DOAC levels. Our multinational cohort study assessed the effectiveness and safety of concomitant use of DOACs and interacting antiarrhythmic drugs among patients with non-valvular atrial fibrillation (NVAF). METHODS: We used United Kingdom's Clinical Practice Research Datalink and Quebec administrative claims data assembling two cohorts of patients with NVAF who initiated DOACs and added-on antiarrhythmic drugs. We assessed the risk of ischemic stroke and major bleeding associated with concomitant use of DOACs and interacting antiarrhythmic drugs (amiodarone, diltiazem, dronedarone, verapamil) versus concomitant use of DOACs and non-interacting antiarrhythmic drugs (flecainide, propafenone, sotalol) using an as-treated exposure definition. Cox models yielded hazard ratios (HRs) and 95% confidence intervals (CIs) after inverse-probability-of-treatment-weighting. We pooled site-specific estimates together using random-effects models. Secondary analyses stratified by age, sex, and individual DOACs. RESULTS: Our study cohort included 54,078 NVAF patients initiating DOACs and adding-on antiarrhythmic drugs. Concomitant use of DOACs and interacting antiarrhythmic drugs versus concomitant use of DOACs and non-interacting antiarrhythmic drugs was not associated with the risk of ischemic stroke (pooled HR, 1.04; 95% CI, 0.88-1.21; I(2) = 0%) but with an increased risk of major bleeding (pooled HR, 1.30; 95% CI, 1.19-1.41; I(2) = 58%), especially among patients < 70 years (pooled HR, 1.56; 95% CI, 1.31-1.86; I(2) = 0%). There was no effect modification by sex or individual DOAC. CONCLUSIONS: Concomitant use of interacting antiarrhythmic drugs does not seem to affect the effectiveness of DOACs but may increase their risk of major bleeding.