Key result
Identified breakthrough stroke causes are linked to ~2-fold higher 90-day recurrent ischemic stroke risk.
Why the study?
Breakthrough ischemic stroke occurs in 1–2% of AF patients annually despite adequate oral anticoagulation, but the underlying mechanisms remain unclear.
Does the presence of potential causes (such as interacting drugs, cancer, or competing etiologies) increase the risk of recurrent ischemic stroke at 90 days in patients with atrial fibrillation and breakthrough stroke on oral anticoagulation?
Cohort (n=1,649)
Yes
Does the presence of potential causes (such as interacting drugs, cancer, or competing etiologies) increase the risk of recurrent ischemic stroke at 90 days in patients with atrial fibrillation and breakthrough stroke on oral anticoagulation?
Hazard Ratio: 2.04 (95% CI 1.18–3.53)
In patients with atrial fibrillation experiencing breakthrough ischemic stroke on oral anticoagulation, identifying potential causes like drug interactions or competing etiologies is associated with a doubled risk of recurrent stroke at 90 days, highlighting the need for individualized management.
Multiple etiologies associated with higher recurrent stroke risk; hypothesis-generating for tailored prevention trials, should not change practice.
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.
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Santis et al. (2026) conducted a cohort in Ischemic stroke despite ongoing oral anticoagulation for atrial fibrillation (n=1,649). Presence of ≥1 potential cause for breakthrough stroke (e.g., interacting drugs, active cancer, competing etiologies) vs. No potential cause identified was evaluated on Recurrent ischemic stroke at 90 days (HR 2.04, 95% CI 1.18-3.53). The presence of ≥1 potential cause (e.g., interacting drugs) was associated with an increased 90-day risk of recurrent ischemic stroke compared to no identified cause (HR 2.04; 95% CI 1.18-3.53).
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