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.