Patients with atrial fibrillation (AF) who experience ischemic stroke despite oral anticoagulation (OAC) face a high early risk of recurrent stroke and adverse outcomes. A retrospective analysis from the ASPERA-R study, published in Neurology, evaluated whether competing stroke etiologies are associated with 90-day outcomes after breakthrough ischemic stroke in this population.
The study included 1,649 adults with AF and imaging-confirmed ischemic stroke occurring during continuous OAC use across 35 centers between February 2020 and February 2025.

Competing etiologies, defined as additional stroke mechanisms coexisting with cardioembolism, were present in 24.3% of patients, most commonly large artery atherosclerosis (59.9%). After inverse probability weighting, recurrent ischemic stroke at 90 days occurred more frequently in patients with competing etiologies (6.0% vs 2.7%; adjusted hazard ratio [aHR] 2.62, 95% CI 2.01-3.42; p<0.001).

Competing etiologies were also associated with worse disability (adjusted odds ratio 1.30, 95% CI 1.08-1.55; p=0.005), higher all-cause mortality (aHR 1.58, 95% CI 1.18-2.12; p=0.002), and increased moderate-to-severe bleeding (aHR 1.82, 95% CI 1.08-3.09; p=0.026), while 24-hour hemorrhagic transformation was less frequent (adjusted risk difference −4.3%, 95% CI −7.8% to −0.7%; p=0.020). Other outcomes did not differ.

The retrospective design and incomplete data on anticoagulation quality limit interpretation. The findings suggest that identifying coexisting stroke mechanisms may support individualized secondary prevention strategies.