Efficacy and Safety Outcomes of Direct Oral Anticoagulants and Amiodarone in Patients with Atrial Fibrillation

Background: Direct oral anticoagulants (DOACs) and amiodarone are widely used in the treatment of nonvalvular atrial fibrillation. The DOACs are P-glycoprotein (P-gp) and cytochrome p-450 (CYP3A4) substrates. Direct oral anticoagulant levels may be increased by the concomitant use of potent dual P-gp/CYP3A4 inhibitors, such as amiodarone, which can potentially translate into adverse clinical outcomes. We aimed to assess the efficacy and safety of drug–drug interaction by the concomitant use of DOACs and amiodarone. Methods: We performed a systematic review of MEDLINE, the Cochrane Central Register of Clinical Trials, and Embase, limiting our search to randomized controlled trials of patients with atrial fibrillation that have compared DOACs versus warfarin for prophylaxis of stroke or systemic embolism, to analyze the impact on stroke or systemic embolism, major bleeding, and intracranial bleeding risk in patients with concomitant use of amiodarone. Risk ratio (RR) 95% confidence intervals were measured using the Mantel-Haenszel method. The fixed effects model was used owing to heterogeneity (I²) < 25%. Results: Four trials with a total of 71,683 patients were analyzed, from which 5% of patients (n = 3212) were concomitantly taking DOAC and amiodarone. We found no statistically significant difference for any of the clinical outcomes (stroke or systemic embolism [RR 0.85; 95% CI, 0.67-1.06], major bleeding [RR 0.91; 95% CI, 0.77-1.07], or intracranial bleeding [RR 1.10; 95% CI, 0.68-1.78]) among patients taking DOAC and amiodarone versus DOAC without amiodarone. Conclusion: On the basis of the results of this meta-analysis, co-administration of DOACs and amiodarone, a dual P-gp/CYP3A4 inhibitor, does not seem to affect efficacy or safety outcomes in patients with atrial fibrillation.