Dose-Specific Intra-Arterial Thrombolysis After Endovascular Thrombectomy for Large-Vessel Occlusion Stroke: A Network Meta-Analysis of Randomized Trials

BACKGROUND: Randomized trials evaluating adjunctive intra-arterial (IA) thrombolysis after endovascular thrombectomy (EVT) for large-vessel occlusion acute ischemic stroke have recently emerged, and the optimal agent and dose remain uncertain. We compared the efficacy and safety of dose-specific IA thrombolysis regimens following successful EVT. METHODS: We systematically searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials from inception to October 30, 2025, for randomized controlled trials enrolling adults with large-vessel occlusion acute ischemic stroke who achieved angiographic reperfusion after EVT and were randomized to adjunctive IA alteplase, tenecteplase, or urokinase versus EVT alone. We performed a frequentist random-effects network meta-analysis and estimated odds ratios with 95% CIs. Treatments were ranked using P-scores. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool, and certainty of evidence was evaluated using Grading of Recommendations, Assessment, Development and Evaluation adapted for network meta-analysis. RESULTS: Seven randomized controlled trials comprising 2126 patients (median age ≈69 years; ≈40% women; predominantly anterior circulation stroke) formed a coherent 6-node treatment network. For excellent functional recovery (modified Rankin Scale score, 0–1 at 90 days), IA alteplase 0.225 mg/kg showed higher odds versus control (odds ratio, 1.94 95% CI, 1.31–2.87), followed by tenecteplase 0.125 mg/kg (odds ratio, 1.90 95% CI, 1.12–3.23). Lower-dose tenecteplase regimens (0.0625 and 0.03125 mg/kg) and urokinase showed attenuated or uncertain effects. No regimen demonstrated a statistically significant difference in symptomatic intracranial hemorrhage or 90-day mortality compared with control, and safety estimates were imprecise. Global heterogeneity and inconsistency were low across outcomes. CONCLUSIONS: In this dose-specific network meta-analysis of randomized controlled trials, IA alteplase 0.225 mg/kg and tenecteplase 0.125 mg/kg showed a signal consistent with improved excellent functional recovery after successful EVT for large-vessel occlusion acute ischemic stroke. Effects on broader functional outcomes were attenuated, and safety estimates were imprecise. These findings are hypothesis-generating and should inform the design of future dose-specific randomized controlled trials rather than guide current clinical practice.