Intravenous thrombolysis for acute ischemic stroke in the extended time window of 4.5-24 h: a systematic review and network meta-analysis of randomized controlled trials.

OBJECTIVE

This study aims to systematically evaluate the efficacy and safety of different intravenous thrombolytic agents in patients with acute ischemic stroke (IS) who present between 4.5 and 24 h after symptom onset. A network meta-analysis was conducted to compare the available treatments and provide evidence to support clinical decision-making and inform updates to clinical guidelines.

METHODS

A systematic search was conducted in PubMed, Embase, the Cochrane Library, and Web of Science, covering the period from the inception of each database to February 1, 2026. Randomized controlled trials (RCTs) comparing different intravenous thrombolytic regimens within the extended time window were included. Primary outcomes included a modified Rankin Scale score of 0-1 at 90 days, mRS 0-2 at 90 days, improvement in the National Institutes of Health Stroke Scale at 24 h, reperfusion at 24 h, symptomatic intracranial hemorrhage at 36 h, and mortality at 90 days. A network meta-analysis using a frequentist random-effects model was conducted to report relative risks and 95% confidence intervals. Interventions were ranked using the cumulative ranked area under the curve, and the certainty of the evidence was assessed using the GRADE/CINeMA framework.

RESULTS

A total of 10 RCTs (2,409 patients) were included, involving five interventions: alteplase (rt-PA), tenaplase (TNK), JX10, standard of care (SoC), and placebo (PBO). For the primary outcome of 90-day mRS 0-2, compared with SoC, rt-PA significantly increased the proportion of functionally independent patients (RR = 1.21, 95% CI 1.06-1.38, low certainty), JX10 (RR = 1.50, 95% CI 0.87-2.58, very low certainty) and TNK (RR = 1.07, 95% CI 0.93-1.23, low certainty) showed a trend toward improvement but did not reach statistical significance. The SUCRA ranking showed that JX10 (87.7%) and rt-PA (77.0%) ranked first and second, respectively. Regarding the early surrogate endpoint of 24-h reperfusion, rt-PA (RR = 2.65, 95% CI 1.57-4.46, low certainty) was superior to SoC and ranked first in the SUCRA ranking (99.9%). Regarding safety, rt-PA significantly increased the risk of 36-h SICH compared with SoC (RR = 5.82, 95% CI 1.47-22.95, low certainty), while JX10 had the highest risk of bleeding (SUCRA 82.1%). There were no statistically significant differences in 90-day mortality rates among the interventions. The certainty of the evidence was predominantly low to very low, primarily limited by risk of bias, imprecision, and indirectness.

CONCLUSION

In patients with acute IS within 4.5-24 h of onset, rt-PA significantly improves functional independence at 90 days and 24-h reperfusion, but increases the risk of symptomatic intracranial hemorrhage. The ranking analysis suggested JX10 might have a favorable functional outcome profile, but this finding is derived from a single, small-sample, dose-exploratory study n = 90 with no direct comparative data against other thrombolytics. Consequently, the evidence for JX10 is considered hypothesis-generating only, and its clinical efficacy and safety remain unestablished. Given the high risk of hemorrhage, its clinical application is not yet supported. The therapeutic advantages of TNK have not been fully demonstrated, though its safety profile is relatively superior. Clinical decision-making requires individualized consideration based on imaging screening, bleeding risk assessment, and patient preference. There is an urgent need for larger-scale, rigorously designed head-to-head RCTs to provide higher-quality evidence for expanding the time window for thrombolytic therapy.

SYSTEMATIC TRIAL REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/view/CRD420261350208, identifier: CRD420261350208.