The problem of hypoperfusion despite recanalization: A systematic review and meta-analysis of randomized clinical trials of intra-arterial thrombolysis as an adjunct to successful recanalization

Abstract BACKGROUND: The efficacy of intra-arterial (IA) thrombolysis following successful endovascular thrombectomy (EVT) in acute ischemic stroke remains controversial, with conflicting evidence. METHODS: We systematically searched PubMed, Embase, Cochrane Library, Web of Science, ClinicalTrials.gov, and International Stroke Conference proceedings through July 18, 2025, for randomized controlled trials (RCTs) comparing IA thrombolysis versus placebo/no treatment after successful EVT. Statistical pooling with random effects was undertaken to calculate risk ratios of functional outcome (modified Rankin Scale [mRS]) at 90 days, changes in National Institutes of Health Stroke Scale score, health-related quality of life measured with the European Quality of Life 5-Dimension 5-Level scores, and safety measures. Additional subgroup analyses were performed according to key clinical and treatment characteristics. RESULTS: Six RCTs involving 1,923 patients (979 receiving IA thrombolysis, 944 controls) were included. IA thrombolysis was associated with higher rates of excellent functional outcome (risk ratio [RR] 1.24, 95% confidence interval [CI] 1. 10–1.39, P = 0.0001, I² = 15%). Subgroup analysis revealed significant benefit in patients with eTICI 2b (RR: 1.51, 95% CI: 1.02–2.24) but not eTICI 2c/3 (RR: 1.22, 95% CI: 0.99–1.50). While functional independence (mRS 0–2) showed no significant difference (RR: 1.05, 95% CI: 0.97–1 .14 ), the ordinal analysis demonstrated a favorable mRS shift (common odds ratio: 1.22, 95% CI: 1.04–1.43). No significant differences were observed in mortality at 90 days, or symptomatic intracerebral hemorrhage. CONCLUSIONS: IA thrombolysis following successful EVT recanalization may improve excellent functional outcomes at 90 days, particularly in patients with eTICI 2b reperfusion, without raising safety concerns.