Early Bleeding Risk After DOAC Initiation With Concomitant Amiodarone in Older Adults With Atrial Fibrillation

Background Amiodarone is frequently co‐prescribed with direct oral anticoagulants (DOACs) in atrial fibrillation (AF), but its impact on early bleeding risk after DOAC initiation in older adults remains uncertain. We evaluated short‐term safety outcomes associated with concomitant amiodarone use at the time of DOAC initiation. Methods We performed a retrospective propensity score matched cohort study using the TriNetX US Research Network (2015 to 2025). Adults aged 75 years or older with nonvalvular AF newly initiating a DOAC were included. Exposure was defined as amiodarone prescription or administration within 30 days before or on the DOAC start date. Patients were matched 1:1 on demographics, comorbidities, and baseline cardiovascular medications. Follow‐up began 1 day after DOAC initiation and continued for 90 days. Primary outcomes were gastrointestinal (GI) bleeding and intracranial hemorrhage (ICH). Ischemic stroke was a secondary outcome. Results After matching, 136,806 patients were included (68,403 per cohort), with all standardized mean differences < 0.1. Index‐date DOAC exposures were predominantly apixaban (82.7%) and rivaroxaban (16.5%). Concomitant amiodarone use was associated with higher early bleeding risk. GI bleeding occurred in 2.3% vs 1.9% (HR 1.30, 95% CI 1.20 to 1.40), and ICH occurred in 0.4% vs 0.3% (HR 1.28, 95% CI 1.07 to 1.52). There was no significant difference in ischemic stroke (1.3% vs 1.5%; HR 0.91, 95% CI 0.83 to 1.01). Conclusions Among adults aged 75 years or older initiating DOAC therapy, concomitant amiodarone exposure was associated with a modest but significant increase in 90‐day GI bleeding and ICH without a detectable increase in ischemic stroke. These findings support careful medication review, dose selection, and early bleeding counseling when amiodarone is used with a DOAC in older adults.