Neurology. 2026 Aug 11;107(3):e218294. doi: 10.1212/WNL.0000000000218294. Epub 2026 Jul 23.
ABSTRACT
BACKGROUND AND OBJECTIVES: IV thrombolysis (IVT) is the standard treatment for acute ischemic stroke (AIS) within 4.5 hours of symptom onset, yet many patients present beyond this window. Recent randomized-controlled clinical trials (RCTs) and updated guidelines suggest potential benefit of IVT in selected patients treated in the extended time window, but the overall evidence remains evolving. We aimed to evaluate the efficacy and safety of IVT beyond 4.5 hours from last known well.
METHODS: We systematically searched MEDLINE, Scopus, and ClinicalTrials.gov for RCTs and individual patient data meta-analyses of RCTs comparing IVT plus best medical therapy (BMT) with BMT alone in patients with AIS presenting more than 4.5 hours after last known well. The primary efficacy outcome was excellent functional outcome at 90 days (modified Rankin Scale [mRS] score 0-1). Secondary efficacy outcomes included good functional outcome (mRS 0-2) and reduced disability (≥1-point shift across the mRS). The primary safety outcome was symptomatic intracranial hemorrhage (sICH); secondary safety outcomes were any ICH and all-cause mortality at 90 days. Prespecified subgroup analyses were performed according to thrombolytic agent, treatment window, imaging selection strategy, vascular territory, and administration of endovascular treatment. Trial sequential analysis was conducted for the primary outcome to evaluate the robustness of the cumulative evidence.
RESULTS: Thirteen studies were included, comprising 2,456 patients in the IVT group (mean age = 68.2 years; 37% female, mean baseline NIH Stroke Scale [NIHSS] score = 11.5) and 2,411 patients in the control group (mean age = 68.6 years; 38% female, mean baseline NIHSS score = 11.0). IVT significantly improved excellent functional outcome (risk ratio [RR] 1.23; 95% CI 1.15-1.33; I2 = 0%; NNT = 13), good functional outcome (RR 1.15; 95% CI 1.05-1.25; I2 = 59%), and reduced disability (common odds ratio 1.26; 95% CI 1.13-1.39; I2 = 0%). IVT was associated with increased risk of sICH (RR 2.11; 95% CI 1.36-3.28; I2 = 0%; NNH = 75). The rates of any ICH and all-cause mortality were similar between the 2 groups. No significant subgroup differences were documented across different subgroups. Trial sequential analysis confirmed that the cumulative evidence for the primary outcome crossed the efficacy boundary, supporting a robust treatment effect.
DISCUSSION: IVT in the extended time window was associated with improved functional outcomes without increased mortality, supporting its use in selected patients despite a higher rate of sICH.
TRIAL REGISTRATION INFORMATION: The prespecified protocol of the present systematic review and meta-analysis has been registered in the International Prospective Register of Ongoing Systematic Reviews (registration ID: CRD420261330511).
PMID:42492020 | DOI:10.1212/WNL.0000000000218294