Reteplase and non-immunogenic staphylokinase show superior functional outcomes vs alteplase in AIS within 4.5h

BackgroundAlthough several newer thrombolytic agents for acute ischemic stroke (AIS) within 4.5 h of onset have been developed, their relative efficacy, safety, and optimal dosing remain unclear. A comprehensive comparison across all available agents is therefore needed.MethodsWe systematically searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science for English-language reports of randomized controlled trials (RCTs) published up to December 12, 2025. Eligible trials enrolled adult AIS patients treated with intravenous thrombolysis. Primary outcomes were 90-day excellent (modified Rankin Scale [mRS] score 0–1) and good (mRS 0–2) functional outcomes. Safety outcomes were symptomatic intracranial hemorrhage (sICH), and all-cause mortality. A frequentist network meta-analysis using a fixed-effect consistency model was conducted to estimate odds ratios (ORs) with 95% confidence intervals (CIs).ResultsA total of 21 RCTs involving 16,837 patients were included. For achieving mRS 0–1, reteplase (18 + 18 mg) showed a statistically significant advantage over alteplase (0.9 mg/kg) (OR 1.60; 95% CI, 1.27–2.02), and non-immunogenic recombinant staphylokinase (10 mg) demonstrated a statistically significant benefit (OR 2.23; 95% CI, 1.43–3.48). Reteplase (18 + 18 mg) also improved the likelihood of mRS 0–2 compared with alteplase (OR 1.41; 95% CI, 1.08–1.84). For safety, non-immunogenic recombinant staphylokinase significantly reduced sICH risk compared with tenecteplase 0.25 mg/kg (OR 0.31; 95% CI, 0.11–0.94). No significant differences in 90-day mortality were observed among treatments.ConclusionWithin the 4.5-h treatment window, reteplase (18 + 18 mg) and non-immunogenic recombinant staphylokinase (10 mg) were associated with the highest probabilities of improved functional outcomes.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/view/CRD420251152754.