Neurology · Medical Literature
IV Thrombolysis in the Extended Time Window for Acute Ischemic Stroke: An Updated Systematic Review and Meta-Analysis.
Abstract
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. 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. 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. 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. 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).
Clinical relevance
A substantial proportion of acute ischemic stroke patients present beyond the conventional 4.5-hour thrombolysis window and are therefore denied IV alteplase or tenecteplase under standard protocols. This updated systematic review and meta-analysis synthesizes the most current RCT-level evidence — including data from recent trials and individual patient data meta-analyses — to clarify whether IVT confers net benefit in this extended window. The findings are immediately relevant to emergency neurologists and stroke specialists who must make real-time treatment decisions for late-presenting or wake-up stroke patients.
Key findings
1. IVT significantly improved excellent functional outcome (mRS 0–1) at 90 days compared with BMT alone (RR 1.23; 95% CI 1.15–1.33; I² = 0%; NNT = 13), with trial sequential analysis confirming the evidence crossed the efficacy boundary, indicating a robust and conclusive treatment effect. 2. IVT improved good functional outcome (mRS 0–2) at 90 days (RR 1.15; 95% CI 1.05–1.25; I² = 59%), though the higher heterogeneity for this endpoint warrants cautious interpretation. 3. IVT reduced overall disability as measured by a ≥1-point shift across the full mRS distribution (common OR 1.26; 95% CI 1.13–1.39; I² = 0%), demonstrating a consistent ordinal benefit. 4. IVT was associated with a significantly increased risk of symptomatic intracranial hemorrhage (sICH) (RR 2.11; 95% CI 1.36–3.28; I² = 0%; NNH = 75), representing the principal safety signal. 5. Rates of any ICH and all-cause mortality at 90 days were similar between the IVT and control groups, indicating the sICH risk did not translate into excess death. 6. Prespecified subgroup analyses across thrombolytic agent, treatment window, imaging selection strategy (e.g., perfusion/DWI mismatch vs. clinical-imaging mismatch), vascular territory, and concurrent endovascular treatment revealed no significant between-subgroup differences, suggesting a broadly consistent effect.
Practice implications
Extended-window IVT (beyond 4.5 hours from last known well) should be considered in carefully selected AIS patients — particularly wake-up stroke and those with favorable penumbral imaging profiles on MRI or CT perfusion — given an NNT of 13 for excellent functional outcome and no increase in 90-day mortality. Clinicians must counsel patients and families about the approximately 2-fold elevated sICH risk (NNH = 75), and institutional protocols should incorporate advanced imaging selection criteria to optimize the benefit-risk ratio in this population. As no significant efficacy differences were detected across subgroups including thrombolytic agent and concurrent endovascular therapy, both alteplase and tenecteplase appear viable options, and IVT should not be withheld solely on the basis of planned mechanical thrombectomy in eligible large-vessel occlusion patients.