Decoding the causes of ischemic stroke despite ongoing oral anticoagulation and their clinical impact: the ASPERA-R study

Abstract

BACKGROUND: Oral anticoagulants (OACs), including vitamin K antagonists and direct OACs, reduce stroke risk in atrial fibrillation (AF), yet breakthrough ischemic stroke still occurs in 1-2% of patients annually despite adequate therapy. The mechanisms underlying these events remain unclear. We aimed to identify potential causes of breakthrough ischemic stroke and assess their impact on outcomes, with a focus on drug interactions. METHODS: ASPERA-R is a multicenter retrospective study including patients with ischemic stroke despite ongoing OAC therapy for AF (February 2020-February 2025). Ongoing treatment was defined by DOAC last intake within 48 h or therapeutic INR levels for VKAs. Potential causes included interacting drugs, active cancer, and competing etiologies. Ninety-day outcomes were compared between patients with and without ≥ 1 potential cause using adjusted Cox regression. Inverse probability-weighted analyses (IPW) evaluated the impact of interacting drugs. RESULTS: Among 1649 patients (median age 80.4 years [IQR 73.2-85.6]; 860 [52.2%] female), most were on DOACs (1275; 77.3%), and 724 (43.9%) had ≥ 1 potential cause. Interacting drugs were identified in 28.4%, competing etiologies in 24.3%, and cancer in 4.4% cases. Patients with one or more potential cause had a higher risk of recurrent ischemic stroke at 90 days (HR 2.04, 95% CI 1.18-3.53) compared with those without, with no differences in other outcomes. In the IPW analyses, interacting drugs were associated with increased myocardial infarction risk (HR 3.26, 95% CI 1.30-8.17). CONCLUSIONS: Potential causes are identifiable in about half of breakthrough strokes and are associated with higher risk of recurrence compared with those without. Improved detection and management of these factors may reduce recurrence risk, warranting individualized approaches.