Comparison of intravenous thrombolysis agents for acute ischemic stroke: a systematic review and network meta-analysis

Background Intravenous thrombolysis (IVT) is the most important treatment for acute ischemic stroke (AIS) patients within 4.5 h of symptom onset, but the lack of head-to-head trials prevents comparisons of the IVT agents’ efficacy and safety, posing challenges for the selection of the best IVT agent. We aimed to evaluate all IVT agents’ effectiveness and safety in AIS treatment within 4.5 h of symptom onset. Methods We conducted a frequentist random-effects network meta-analysis to calculate relative risks (RRs) along with 95% confidence intervals (95% CI) using Stata. Between-study clinical and methodological heterogeneity was evaluated through pre-specified subgroup and sensitivity analyses; because the evidence formed a star-shaped network centered on alteplase (rt-PA) without closed loops, a consistency model was fitted. The primary efficacy outcome was excellent functional outcome (modified Rankin Scale [mRS] 0–1 at 90 days), and the primary safety outcome was symptomatic intracranial hemorrhage (SICH, ECASS III criteria) within 24–48 h. Secondary functional and safety outcomes were also evaluated. The risk of bias and the quality of evidence were assessed with the Cochrane Risk of Bias tool and the Confidence in Network Meta-Analysis tool. Results Nineteen RCTs involving 14,464 patients evaluated five IVT agents (rt-PA, tenecteplase [TNK], reteplase [rPA], recombinant human prourokinase [rhPro-UK], and staphylokinase [SAK]) and placebo. For primary efficacy outcome (mRS 0–1 at 90 days): SUCRA ranking was SAK (91.3%), rPA (83.8%), rhPro-UK (51.2%), TNK (50.5%), and rt-PA (23.2%). Compared with rt-PA, rPA significantly increased the likelihood of excellent recovery (RR 1.13, 95% CI: 1.06–1.19; high certainty), outperforming TNK (RR 1.09, 95% CI: 1.01–1.16; high certainty) and rhPro-UK (RR 1.08, 95% CI: 1.00–1.17; high certainty). TNK was also associated with a higher likelihood of excellent recovery compared with rt-PA (RR 1.04, 95% CI: 1.00–1.08; moderate certainty). For primary safety outcome (24–48 h SICH): SUCRA ranking for reducing bleeding risk was rhPro-UK (97.4%), rt-PA (56.5%), rPA (29.3%), and TNK (16.9%). rhPro-UK conferred a significantly lower risk of SICH compared with TNK (RR 0.23, 95% CI: 0.06–0.87; moderate certainty). No significant differences in SICH risk were detected among rPA, TNK, and rt-PA. No significant differences were observed across agents for 90-day all-cause mortality or any intracranial hemorrhage. Conclusion The rPA and TNK were associated with improved functional recovery compared with standard rt-PA, while rhPro-UK demonstrated potential in minimizing sICH risk, and direct head-to-head randomized trials remain needed. Systematic review registration PROSPERO, CRD42024615928.