Adjunctive Intra-Arterial Thrombolysis After Successful Endovascular Thrombectomy for Acute Ischemic Stroke: A Systematic Review, Meta-Analysis, and Trial Sequential Analysis

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Abstract
Background: Successful endovascular thrombectomy does not always result in optimal neurological recovery in patients with acute ischemic stroke, likely because macrovascular recanalization may not fully restore distal or microvascular perfusion. Adjunctive intra-arterial thrombolysis (IAT) has emerged as a potential strategy to enhance reperfusion after thrombectomy, but its efficacy and safety remain uncertain. Methods: We conducted a systematic review and meta-analysis of randomized controlled trials comparing adjunctive intra-arterial thrombolysis after successful endovascular reperfusion versus standard care or placebo in acute ischemic stroke. We searched PubMed, Scopus, Web of Science, and Embase from inception to August 2026. Meta-analysis was performed using Review Manager (RevMan 5.4). Outcomes included excellent functional outcome (modified Rankin Scale [mRS] 0–1), functional independence (mRS 0–2), mortality, Barthel Index, EuroQol five-dimension (EQ-5D) scores, intracranial hemorrhage (ICH), symptomatic ICH, and systemic bleeding. Subgroup analyses were conducted according to thrombolytic agent and circulation territory. Exploratory trial sequential analysis (TSA) assessed the accumulating evidence for selected outcomes under specified assumptions. Results: Nine trials contributed data on 2810 patients. Adjunctive intra-arterial thrombolysis increased the likelihood of excellent functional outcome at 90 days compared with control (risk ratio [RR] 1.23, 95% confidence interval [CI] 1.13–1.35; p < 0.00001), with low statistical heterogeneity (I2 = 17%). TSA supported this finding under the specified assumptions, with the required information size of 1321 patients exceeded. Functional independence did not differ significantly (RR 1.03, 95% CI 0.96–1.10); its TSA remained inconclusive, with 2805 patients representing 8.2% of the required information size of 34,407. Mortality (RR 1.05, 95% CI 0.90–1.23), symptomatic ICH (RR 1.19, 95% CI 0.83–1.71), and systemic bleeding did not differ significantly; these findings do not exclude clinically important harm. Any ICH was more frequent with IAT (RR 1.17, 95% CI 1.03–1.32; p = 0.02), but TSA was inconclusive. EQ-5D scores did not differ significantly. Subgroup findings were exploratory. Conclusions: Adjunctive IAT after successful thrombectomy was associated with a higher likelihood of excellent functional recovery at 90 days. TSA supported this benefit under the stated assumptions but did not establish that future evidence cannot change the estimate. IAT was associated with a modest increase in any ICH that was not confirmed by TSA. Evidence for functional independence and symptomatic hemorrhage remains inconclusive, and nonsignificant safety comparisons should not be interpreted as equivalence. Further trials should evaluate efficacy, patient selection, agent and dose, circulation territory, and adequately powered safety outcomes.

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