Concomitant Drug Interactions With Non–Vitamin K Oral Anticoagulants Are Associated With Bleeding and Mortality Risk in Patients With Nonvalvular Atrial Fibrillation

Background Non–vitamin K oral anticoagulants prevent stroke and systemic embolism in patients with nonvalvular atrial fibrillation. However, potential drug interactions with concomitant medications may compromise their efficacy and escalate the risk of adverse effects. Methods and Results We conducted a territory‐wide retrospective cohort study in Hong Kong, focusing on nonvalvular atrial fibrillation prescribed non–vitamin K oral anticoagulants. The objective was to investigate the associated risk of gastrointestinal bleeding, intracranial hemorrhage, hospitalization for major bleeding, and all‐cause mortality in relation to various concomitant medications. Our analysis included 22 568 patients with nonvalvular atrial fibrillation (aged 75.7 ± 10.8 years; 51.2% men) taking non–vitamin K oral anticoagulants from January 1, 2017, to December 31, 2020, totaling 40 317 patient‐years. It was found that amiodarone (hazard ratio [HR], 1.53), digoxin (HR, 1.30), diltiazem (HR, 1.18), clarithromycin (HR, 4.98), and fluconazole (HR, 2.38) were associated with increased gastrointestinal bleeding, whereas amiodarone (HR, 2.20) and digoxin (HR, 1.61) were associated with increased intracranial hemorrhage. Furthermore, amiodarone (HR, 1.64), digoxin (HR, 1.35), clarithromycin (HR, 4.18), and fluconazole (HR, 2.40) were associated with increased hospitalization for major bleeding. Additionally, amiodarone (HR, 2.65), digoxin (HR, 1.85), diltiazem (HR, 1.44), verapamil (HR, 1.80), antidepressants (HR, 1.31), and fluconazole (HR, 3.27) were associated with increased all‐cause mortality. Conversely, dronedarone (HR, 0.56) and atorvastatin (HR, 0.86) were associated with a significant reduction in all‐cause mortality. Conclusions For patients with nonvalvular atrial fibrillation taking non–vitamin K oral anticoagulants, several concurrent medications were associated with increased risks of intracranial hemorrhage, major bleeding hospitalizations, and overall mortality.