This meta-analysis aims to evaluate the efficacy and safety of intravenous thrombolytics (IVTs) in ischemic stroke beyond the 4.5-hour window.

Stroke significantly affects global health, and IVTs like tenecteplase and alteplase are highly time-dependent. Although they show potential beyond 4.5 hours, the evidence remains inconclusive.

PubMed, Cochrane Central, and ScienceDirect were searched through August 2025. The risk ratios (RRs) were pooled with 95% confidence intervals under the random effects model using Review Manager version 5.4.1. The quality assessment was done using the Cochrane Risk of Bias (RoB) 2.0 tool. An excellent functional outcome is defined as a modified Rankin Scale (mRS) score of 0-1. A good functional outcome is defined as an mRS of 0-2.   

Thirteen randomized controlled trials involving a total of 3,602 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). Tenecteplase 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.

IVT significantly improved the functional outcomes (excellent and good) but increased the risk of ICH (symptomatic and any) with comparable mortality, primarily in the alteplase 0.90 mg/kg subgroup. However, the 0.25 mg/kg tenecteplase and 0.60 mg/kg low-dose alteplase showed no increase in functional or hemorrhagic outcomes.