Tenecteplase in the Extended 4.5-24-Hour Window for Acute Ischemic Stroke: An Updated Meta-Analysis of RCTs with EVT-Stratified Subgroup Analysis.

Background: The efficacy of tenecteplase for acute ischemic stroke (AIS) beyond 4.5 h remains uncertain, particularly across care pathways with and without endovascular thrombectomy (EVT). We performed an updated systematic review and meta-analysis using an EVT-stratified framework. Methods: PubMed, Embase, Scopus, and the Cochrane Library were searched through February 2026 for randomized controlled trials comparing tenecteplase with control in imaging-selected patients with AIS presenting 4.5-24 h from last known well. The primary outcome was excellent functional outcome (mRS 0-1) at 90 days. Secondary outcomes were good functional outcome (mRS 0-2), recanalization, early neurological improvement, symptomatic intracranial hemorrhage, and 90-day mortality. Random-effects models with Hartung-Knapp adjustment were used. Subgroup analyses by EVT availability were interpreted as exploratory because of the limited number of trials. Results: Five trials including 1844 patients were analyzed. Tenecteplase improved excellent functional outcome (RR 1.25, 95% CI 1.10-1.42; p = 0.0005) with no heterogeneity (I2 = 0%) and no interaction by EVT status (p-interaction = 0.961). Good functional outcome was not significantly different overall (RR 1.10, 95% CI 0.97-1.24; p = 0.135). Significant subgroup interactions were observed for recanalization (p-interaction = 0.004) and early neurological improvement (p-interaction = 0.002), with benefits concentrated in non-EVT settings. However, the larger effect on recanalization did not translate proportionally into functional recovery, supporting separation of vessel-opening outcomes from patient-centered outcomes. Symptomatic intracranial hemorrhage showed a nonsignificant increase in four estimable studies (RR 1.88, 95% CI 0.94-3.78; p = 0.074), whereas 90-day mortality did not differ significantly (RR 1.11, 95% CI 0.85-1.43; p = 0.43). Conclusions: In imaging-selected AIS presenting 4.5-24 h after onset, tenecteplase improved excellent functional outcome irrespective of EVT availability, while benefits for recanalization and early neurological improvement were largely confined to non-EVT settings. Because recanalization is an intermediate endpoint, these findings should not be interpreted as proof of a proportional clinical benefit. Future extended-window trials should specify EVT status.