Abstract / Summary
Background/Objectives: Adjunctive intra-arterial thrombolysis (IAT) after successful endovascular thrombectomy has been associated with a higher probability of excellent functional recovery in previous randomized-trial meta-analyses. Since those syntheses, the evidence base has expanded to include IAT-TOP, restricted to basilar artery occlusion, and CHOICE-2, in which 90-day mortality was 12.1% with adjunctive alteplase and 6.4% with thrombectomy alone. We therefore examined how the efficacy and mortality profiles changed as randomized evidence accumulated. Methods: This PRISMA 2020-compliant systematic review and meta-analysis was prospectively registered in PROSPERO (CRD420251006577). Eligible studies were randomized controlled trials (RCTs) comparing adjunctive intra-arterial fibrinolytic therapy administered after trial-defined successful or near-successful post-thrombectomy reperfusion with no adjunctive intra-arterial fibrinolysis. PubMed/MEDLINE, Embase, and CENTRAL were searched through 15 August 2026, with ClinicalTrials.gov searched separately. Nine RCTs comprising 2828 randomized participants were included at the systematic-review level. Event counts were re-extracted from primary trial publications and pooled as risk ratios (RRs) using random-effects models with restricted maximum likelihood estimation and Hartung–Knapp confidence intervals (CIs). Cumulative meta-analysis tracked how the efficacy and mortality estimates changed as evidence accumulated, while fragility analyses assessed the stability of the corresponding statistical inferences. This research received no external funding. Results: Adjunctive IAT increased excellent functional recovery (modified Rankin Scale [mRS] 0–1; 8 RCTs; RR 1.266, 95% CI 1.135–1.412; I2 = 0.0%), with a 95% prediction interval of 1.047–1.530 and a meta-analytic Fragility Index of 15. Ninety-day all-cause mortality did not differ significantly between groups (8 RCTs; RR 1.036, 95% CI 0.817–1.314); immediately before CHOICE-2 entered the cumulative synthesis, the corresponding estimate was RR 0.984 (95% CI 0.801–1.209). In the bidirectional reverse-fragility analysis, the earliest significance transition identified by the search occurred after 24 one-patient event-status modifications and was in the direction of increased mortality with adjunctive IAT (RR 1.174, 95% CI 1.002–1.377; p = 0.048). No transition toward reduced mortality was identified through the same modification depth. No trial was judged to be at high risk of bias using RoB 2. GRADE certainty was moderate for excellent functional recovery, 90-day mortality, and functional independence and low for hemorrhagic outcomes. Conclusions: The efficacy and mortality components of the benefit–risk profile of adjunctive IAT have not evolved in parallel. The improvement in excellent functional recovery persisted as randomized evidence accumulated and remained comparatively stable to perturbation of the observed event data, whereas mortality remains unresolved. The cumulative and reverse-fragility findings do not establish a treatment-related mortality excess; however, the absence of statistical significance should not be interpreted as affirmative evidence of mortality neutrality. The current randomized evidence therefore supports a reproducible functional benefit while preserving clinically relevant uncertainty regarding survival.