Drug-drug interactions of NOACs with comedication: prevalence and implications for adverse events in patients with atrial fibrillation

Background and Aims The clinical relevance of drug-drug interactions associated with Non-vitamin K-antagonist oral anticoagulants (NOACs) in atrial fibrillation (AF) patients remains poorly understood. We examined the prevalence of pharmacokinetic and pharmacodynamic drug-drug interactions and their association with adverse clinical outcomes in AF patients receiving NOACs. Methods We analyzed patients from a prospective, multicenter cohort study. We employed frailty survival models to investigate the association of the different potential interactions with the respective clinical adverse outcomes (major bleeding, clinically relevant non-major bleeding, any bleeding, ischemic stroke/systemic embolism). Results Our analysis comprised 1732 AF patients (mean age 73 ± 8 years, 501 [29%] females) with a median follow-up period of 6 years. For 683 (39%) of these patients, we recorded at least one potential drug-drug interaction. In the multivariable adjusted model, the HR of drug-drug interaction was 1.21 (95% CI 0.84; 1.75, p = 0.31) for major bleeding, 1.22 (95% CI 0.92; 1.62, p = 0.17) for clinically relevant non-major bleeding, 1.22 (95% CI 0.97; 1.54, p = 0.09) for any bleeding, and 1.00 (95% CI 0.22; 4.53, p = 0.99) for ischemic stroke/systemic embolism. Conclusions In a large real-world cohort of AF patients, the prevalence of potential interactions of comedication with NOACs was high. We found no strong evidence supporting an association between such drug-drug interactions and an increased risk of major bleeding or ischemic stroke/systemic embolism, but there was a trend toward an increase in the risk of any bleeding.