Abstract Body (Do not enter title and authors here): Background: Guidelines recommend intravenous thrombolysis (IVT) within 4.5 hours for acute ischemic stroke (AIS). Imaging-selected patients may benefit from IVT beyond this window.

Methods: PubMed, Scopus, and Cochrane Library were searched through February 2025 for randomized controlled trials (RCTs) comparing IVT beyond 4.5 hours from symptom onset or last known well (LKW) with standard care (without IVT) in AIS patients with salvageable brain tissue. Primary outcomes were excellent functional outcome at 3 months (modified Rankin Scale [mRS] 0–1), good functional outcome (mRS 0–2), and symptomatic intracranial hemorrhage (sICH). Secondary outcomes included early neurological improvement (ENI), recanalization, reperfusion, type II parenchymal hemorrhage (type II PH), systemic hemorrhage, and 3-month mortality. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Subgroup analysis compared alteplase and tenecteplase (TNK).

Results: Eleven RCTs with 3,425 patients (mean age 69.5 years; 58.9% male) were included, with 1,737 receiving IVT and 1,688 on standard care. The mean baseline National Institutes of Health Stroke Scale (NIHSS) score was 8.3; IVT was given at a mean of 8.46 hours post-onset; 2.93% had endovascular thrombectomy. In the extended time window, IVT was linked to increased odds of achieving excellent functional outcome at 3 months (OR = 1.42; 95% CI, 1.20–1.67), good functional outcome at 3 months (OR = 1.28; 95% CI, 1.11–1.46), ENI (OR = 3.25; 95% CI, 2.10–5.03), and successful recanalization (OR = 3.67; 95% CI, 2.26–5.97); However, the rate of reperfusion did not differ significantly between the groups (OR = 1.38; 95% CI, 0.54–3.55). sICH occurred more frequently in the IVT group compared to the standard treatment group (OR = 3.23; 95% CI, 1.51–6.93). The risks of type II PH (OR = 2.84; 95% CI, 0.98–8.21), systemic hemorrhage (OR = 2.29; 95% CI, 0.73–7.14), and 3-month mortality (OR = 1.27; 95% CI, 0.92–1.74) were comparable between groups. Subgroup analysis showed comparable efficacy between alteplase and TNK, with TNK showing a nonsignificant trend toward lower sICH risk (OR = 2.59; 95% CI, 0.99–6.75) compared to alteplase (OR = 4.73; 95% CI, 1.35–16.63).

Conclusion: In AIS patients treated 4.5–24 hours post-LKW, IVT improved functional outcomes compared to standard care despite higher sICH risk. TNK appeared non-inferior to alteplase. Further RCTs are needed to refine late-window thrombolysis.