Extended-window alteplase increases functional outcomes but raises hemorrhage risk in acute ischemic stroke patients

AIM: To evaluate the efficacy, safety, and dosing of intravenous alteplase administered beyond the conventional 4.5-hour therapeutic window in adults with acute ischemic stroke. METHODS: A systematic review and meta-analysis were conducted in accordance with PRISMA guidelines. PubMed, Scopus, and Web of Science were searched through December 2025 for randomized controlled trials and observational studies assessing intravenous alteplase administered beyond 4.5 h after stroke onset, including wake-up and imaging-selected strokes. Pooled risk ratios (RRs) with 95% confidence intervals (CIs) were calculated using random-effects models. Outcomes included functional recovery, functional independence, symptomatic intracranial hemorrhage (sICH), and mortality. Sensitivity analyses and Bayesian meta-analyses were also performed. RESULTS: Ten studies comprising 2,050 patients met the inclusion criteria. Late administration of alteplase was associated with improved functional outcomes, including higher rates of favorable modified Rankin Scale scores (RR 1.34, 95% CI 1.19-1.51) and functional independence (RR 1.17, 95% CI 1.07-1.28). Treatment was associated with an increased risk of sICH (RR 4.67, 95% CI 1.85-11.76), while mortality did not differ significantly between treatment and control groups (RR 1.23, 95% CI 0.87-1.73). Bayesian analysis demonstrated consistent functional benefit with standard-dose alteplase (0.9 mg/kg), whereas reduced-dose regimens did not show consistent efficacy. CONCLUSION: Intravenous alteplase administered beyond 4.5 h after stroke onset is associated with improved functional outcomes in selected patients, despite an increased risk of symptomatic intracranial hemorrhage and no significant effect on mortality. These findings support the use of extended-window thrombolysis when guided by appropriate clinical or imaging-based selection criteria.