Stroke Etiologies With Intravenous Thrombolysis before Thrombectomy and Functional Outcomes in Anterior Circulation Large Vessel Occlusion

OBJECTIVE: The benefit of intravenous thrombolysis (IVT) before endovascular treatment (EVT) in patients with acute ischemic stroke due to large vessel occlusion (LVO) who present directly to EVT-capable centers remains uncertain, and the effect may differ according to underlying stroke etiology. We assessed whether the benefit of IVT plus EVT versus EVT alone varied by stroke etiologies (large-artery atherosclerosis, cardioembolism, or other/undetermined). METHODS: We performed an individual participant data meta-analysis of 6 randomized controlled trials (RCTs) that compared IVT plus EVT to EVT alone in patients with LVO within 4.5 hours of stroke onset or time last known well. The heterogeneity of treatment effect was assessed using ordinal logistic regression models with interaction terms for stroke etiology and treatment in the intention-to-treat population, followed by subsequent mixed-effects meta-analysis. An additional analysis was performed to assess whether the treatment effect of IVT plus EVT differed by atrial fibrillation status. RESULTS: Among 2,313 eligible patients from 6 RCTs, 1,160 were randomized to the IVT plus EVT group and 1,153 to the EVT alone group. Median age was 71 years (interquartile range [IQR] = 62-78 years), and 44.3% of patients were women. Stroke etiology was classified as cardioembolism in 977 of 2,313 patients (42%), large artery atherosclerosis in 430 (19%), and other or unknown/undetermined in 906 (39%). No evidence of treatment effect modification by stroke etiologies on the association between IVT and 90-day functional outcome was observed (P for interaction = 0.60). For patients with other/undetermined stroke etiology, IVT plus EVT was associated with better 90-day functional prognosis (adjusted common odds ratio for a lower level of disability = 1.34, 95% confidence interval [CI] = 1.05-1.69). No treatment effect modification by stroke etiology was found for safety outcomes. No treatment effect heterogeneity by atrial fibrillation was found for all outcomes. INTERPRETATION: Among patients with LVO presenting directly to EVT-capable centers, stroke etiologies do not modify the overall efficacy or safety of IVT before EVT. The isolated benefit observed in the other/undetermined subgroup requires confirmation. ANN NEUROL 2026 ANN NEUROL 2026.