Key result
Potential causes of breakthrough stroke linked to ~104% higher 90-day recurrent ischemic stroke risk.
Why the study?
Breakthrough ischemic stroke occurs in 1-2% of atrial fibrillation patients annually despite oral anticoagulation, but the underlying mechanisms remain unclear.
Does the presence of potential causes of oral anticoagulant failure increase the risk of recurrent ischemic stroke in patients with atrial fibrillation experiencing a breakthrough stroke?
Observational (n=1,649)
Yes
Does the presence of potential causes of oral anticoagulant failure increase the risk of recurrent ischemic stroke in patients with atrial fibrillation experiencing a breakthrough stroke?
Hazard Ratio: 2.04 (95% CI 1.18–3.53)
Absolute Event Rate: 4.8% vs 2.4%
p-value: p=0.011
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“Our results challenge the empirical practice of switching anticoagulants after a breakthrough stroke. Continuation seems to be a safer and simpler strategy.”
“This sobering reality underscores the need for better strategies in secondary prevention.”
In patients with atrial fibrillation experiencing breakthrough ischemic stroke on oral anticoagulation, identifiable potential causes are present in nearly half of cases and are associated with a twofold increased risk of 90-day recurrent stroke.
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 an observational in Ischemic stroke despite ongoing oral anticoagulation for atrial fibrillation (n=1,649). Presence of ≥ 1 potential cause of breakthrough stroke (interacting drugs, competing etiologies, active cancer) vs. No potential cause was evaluated on 90-day occurrence of a new ischemic stroke (HR 2.04, 95% CI 1.18-3.53, p=0.011). The presence of one or more potential causes of breakthrough stroke, such as interacting drugs or competing etiologies, increased the risk of recurrent ischemic stroke at 90 days (HR 2.04).
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