Comparative efficacy and safety of different doses of intravenous thrombolytics in acute ischemic stroke: a GRADE-assessed network meta-analysis of randomized controlled trials.

To compare the efficacy and safety of different doses of intravenous thrombolytic agents in patients with acute ischemic stroke (AIS) and guide optimal dose selection. We searched PubMed, Scopus, Web of Science, and Cochrane CENTRAL until March 2025 to identify randomized controlled trials (RCTs) evaluating alteplase (tPA), tenecteplase (TNK), reteplase, and recombinant human prourokinase (rhPro-UK) at any dose in patients with AIS. Analysis was performed using R software, and risk ratios (RRs) with 95% confidence intervals (CIs) were pooled. Primary outcomes included symptomatic intracranial hemorrhage (sICH), 90-day mortality, excellent functional outcome (defined as modified Rankin Scale [mRS] score 0-1), and functional independence (defined as mRS 0-2). We included 21 RCTs (16,643 patients). Compared to tPA (0.9 mg/kg), tPA (0.6 mg/kg) was associated with a significantly lower risk of sICH (RR = 0.48, 95% CI: 0.27-0.86), while TNK (0.4 mg/kg) showed a higher risk (RR = 1.88, 95% CI: 1.06-3.35). No significant differences were observed in 90-day mortality, functional independence, or serious adverse events across interventions. Reteplase (18 + 18 mg) (RR = 1.13, 95% CI: 1.05-1.21) and TNK (0.25 mg/kg) (RR = 1.05, 95% CI: 1.01-1.10) significantly improved 90-day excellent functional recovery compared to tPA (0.9 mg/kg). TNK (0.32 mg/kg) showed the lowest risk probability for any ICH and parenchymal hemorrhage. Some safety outcomes showed dose-dependent effects: lower-dose tPA and intermediate-dose TNK reduced ICH risk compared to higher doses, while mortality and functional independence remained comparable across doses.