Sex Differences in Outcomes After Breakthrough Ischemic Stroke on Oral Anticoagulants for Atrial Fibrillation: An ASPERA‐R Inverse Probability Weighted Analysis

Background Sex‐specific outcomes after breakthrough ischemic stroke on oral anticoagulation (OAC) are unexplored. We compared 90‐day outcomes by sex and explored modifiers. Methods ASPERA‐R (Advancing Knowledge in Ischemic Stroke Patients on Oral Anticoagulants retrospective cohort; NCT06823466) was an international, multicenter, retrospective study enrolling adults (aged >18 years) with breakthrough ischemic stroke on OAC for atrial fibrillation. Primary outcome was 90‐day return to baseline neurologic function (modified Rankin Scale mRS score 0–1 maintained if prestroke 0–1; or same/lower mRS score if prestroke ≥2). Secondary outcomes were 90‐day mRS shift, recurrent ischemic stroke/transient ischemic attack, myocardial infarction, and all‐cause and vascular death. Safety outcomes included 90‐day moderate‐to‐severe bleeding, intracranial hemorrhage, 24‐hour hemorrhagic transformation, and 24‐hour symptomatic intracranial hemorrhage. We applied inverse probability weighting and regression models to compare outcomes. Prespecified subgroup analysis tested sex‐specific interactions. Results We included 1649 patients (women, 52.2%; mean±SD age, 78.0±10.7 years). Women were older (80.2±9.6 versus 76.3±10.8 years; unweighted standardized mean difference=0.376), had higher baseline National Institutes of Health Stroke Scale score (13 interquartile range, 9–19 versus 9 interquartile range, 4–17; unweighted standardized mean difference=0.227), and worse prestroke mRS score (unweighted standardized mean difference=0.237). After weighting, women were less likely to return to baseline neurologic function (35.2% versus 42.7%; adjusted risk ratio, 0.82 95% CI, 0.71–0.96; P =0.015), had worse mRS distribution (adjusted odds ratio, 1.17 95% CI, 1.01–1.37; P =0.043), and had higher recurrent ischemic stroke/transient ischemic attack (4.8% versus 2.8%; adjusted hazard ratio HR, 1.70 95% CI, 1.01–2.86; P =0.045). Women showed a trend toward more moderate‐to‐severe bleeding (4.6% versus 2.8%; adjusted HR, 1.63 95% CI, 0.96–2.72; P =0.070). Subgroup analyses revealed significant sex interactions for OAC type, competing cause, endovascular treatment, and OAC restart. Conclusions Women had worse 90‐day outcomes than men after breakthrough ischemic stroke on OAC for atrial fibrillation, highlighting the need for sex‐aware management.