Efficacy and Safety of Intravenous Thrombolytics in Ischemic Stroke Beyond the 4.5-Hour Time Window: A Systematic Review and Meta-Analysis

Abstract

Background: Stroke significantly impacts global health, and IV thrombolytics such as tenecteplase and alteplase are time sensitive. While they show promise beyond 4.5 h, evidence is inconclusive. This meta-analysis assesses IVT's efficacy and safety past 4.5 h. Methods: PubMed, Cochrane Central, and ScienceDirect were searched till August 2025. The risk ratios (RR) were pooled along with 95% confidence intervals under the random effect model using the Review Manager version 5.4.1. Results: Thirteen randomized trials involving 3602 patients were analyzed. Compared to the control group, IVT significantly improved the rates of excellent (RR = 1.22; 95%CI: [1.13, 1.31];p < 0.00001; I2 = 0%) and good (RR = 1.11; 95%CI: [1.06, 1.18];p < 0.0001; I2 = 0%) functional outcomes. However, the risk of symptomatic (RR = 2.28; 95%CI:[1.35, 3.85];p = 0.002; I2 = 0%) and any (RR = 1.22; 95%CI:[1.01, 1.46];p = 0.04; I2 = 13%) intracranial hemorrhage (ICH) was also higher with IVT; mortality rates, however, showed no significant difference (RR = 1.10; 95%CI:[0.89, 1.36];p = 0.35). TNK at 0.25 mg/kg did not improve functional outcomes or increase the risk of ICH. Similarly, low-dose 0.60 mg/kg alteplase did not significantly enhance functional outcomes or raise the risk of ICH, while alteplase at 0.90 mg/kg showed results consistent with the overall IVT group. Conclusion: IVT administered beyond the 4.5-h window in acute ischemic stroke significantly improved excellent and good functional outcomes. Although the use of IVT was associated with a higher risk of symptomatic and any ICH, the mortality rates remained comparable. Further high-quality randomized trials are necessary to confirm and reinforce these results.