Real-World Polypharmacy and Drug-Drug Interactions in a Large Cohort of Direct Oral Anticoagulant Users With Atrial Fibrillation

Purpose: Despite their promising safety profile, use of direct oral anticoagulants (DOACs) presents challenges, particularly concerning polypharmacy and potential drug-drug interactions (DDIs). This study aimed to investigate real-world effects of polypharmacy and DDIs among DOAC users, focusing on patients with atrial fibrillation (AF). Methods: A retrospective cohort analysis was conducted using administrative health care data from the Caserta Local Health Unit (2012–2020). Incident DOAC users were categorized by type of anticoagulant (apixaban, dabigatran, rivaroxaban, and edoxaban). Polypharmacy and DDIs were analyzed before and after index date (ID), stratifying results by DOAC and therapeutic indication. The impact of DDIs on safety outcomes, particularly bleeding risk, was assessed. Bleeding outcomes were evaluated within 1 year after ID by multivariate regression models. Findings: Among 16,367 incident DOAC users, 68.9% were treated for AF. The number of interacting drugs increased in 55.2% of patients, with a higher prevalence of 3+ interacting drugs in low-dose users (35% vs 29.2% in high-dose users; P < 0.05). Before ID, 35.6% of the overall cohort had 0 interacting drugs compared with 15.2% after ID. Dabigatran users had the highest increase in interacting drugs (61.8%) compared with anti-Xa agents (56%). Patients with 6+ interacting drugs exhibited a 2.5% incidence of major bleeding after ID. Dabigatran use and low-dose DOAC regimens were independently associated with increased bleeding risks. Implications: Polypharmacy and DDIs are prevalent among real-world DOAC users, particularly in patients with AF. The observed association between DDIs and bleeding risk underscores the importance of personalized medication management strategies and routine DDI evaluations to optimize DOAC safety.