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

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; I 2 = 0%) and good (RR = 1.11; 95%CI: [1.06, 1.18];p < 0.0001; I 2 = 0%) functional outcomes. However, the risk of symptomatic (RR = 2.28; 95%CI:[1.35, 3.85];p = 0.002; I 2 = 0%) and any (RR = 1.22; 95%CI:[1.01, 1.46];p = 0.04; I 2 = 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.