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

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.

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.

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).

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.