Competing Stroke Etiologies and Outcomes After Breakthrough Ischemic Stroke on Oral Anticoagulants in Patients With Atrial Fibrillation

BACKGROUND AND OBJECTIVES: Patients with atrial fibrillation (AF) who experience an ischemic stroke despite oral anticoagulation (OAC) face a high risk of recurrence and bleeding. We aimed to compare 90-day outcomes between patients with and without competing stroke etiologies after a breakthrough ischemic stroke while on OAC for AF. METHODS: ASPERA-R retrospectively enrolled adults (>18 years) with AF who experienced a breakthrough ischemic stroke, defined as either first or recurrent event, occurring on continuous OAC (last intake ≤48 hours), across 35 centers from February 2020 to February 2025. Patients' eligibility required imaging-confirmed ischemic stroke, baseline vessel imaging, and a standardized 90-day follow-up. Patients with inadequate anticoagulant dosing or poor adherence were excluded. Competing etiologies were defined as any additional mechanism coexisting with cardioembolism and plausibly contributing to the index stroke. The primary outcome was 90-day recurrent ischemic stroke; secondary outcomes included modified Rankin Scale shift, myocardial infarction, and vascular and all-cause death. Bleedings were also evaluated. We performed inverse probability weighting to balance baseline covariates and applied Cox or regression models to compare outcomes. RESULTS: Among 1,649 patients (mean age 78 years, 47.8% male), 24.3% had competing etiologies, most commonly large artery atherosclerosis (59.9%). Considering the weighted population, 90-day recurrent ischemic stroke occurred more often in those with competing etiologies (6.0% vs 2.7%; adjusted hazard ratio [aHR] 2.62, 95% CI 2.01-3.42; p < 0.001). Risk was greatest for large artery atherosclerosis and other determined causes. Competing etiologies also had worse disability distribution (adjusted odds ratio 1.30, 95% CI 1.08-1.55; p = 0.005) and higher all-cause mortality (aHR 1.58, 95% CI 1.18-2.12; p = 0.002). Moderate-to-severe bleeding was higher with competing etiologies (aHR 1.82, 95% CI 1.08-3.09; p = 0.026), whereas 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. DISCUSSION: One in 4 patients with AF and breakthrough ischemic stroke on OAC had competing etiologies, most often large artery atherosclerosis. These patients showed higher risk of recurrent stroke, functional dependence, mortality, and bleeding, highlighting the need for development of individualized secondary prevention. Main study limitations include observational retrospective design and incomplete data on on-treatment anticoagulation quality. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT06823466.