Background: For patients presenting with acute ischemic stroke in the late therapeutic window (>4.5 hours), the optimal treatment strategy remains debated. We conducted a network meta-analysis comparing endovascular thrombectomy, thrombolysis with alteplase or tenecteplase, and best medical therapy in patients with salvageable tissue, focusing on both efficacy and safety outcomes. Methods: We systematically searched MEDLINE, EMBASE, Scopus, Cochrane Library through July 2025, identifying RCTs enrolling adults with anterior circulation large vessel occlusion in the late window based on CT/MR perfusion imaging. A random-effects network meta-analysis compared EVT, alteplase, tenecteplase, and best medical therapy. Primary outcome was functional independence; secondary outcomes included severe disability/death, mortality, and symptomatic intracranial hemorrhage. Results: Fifteen trials enrolling 4,497 patients were included. Time-to-treatment across studies was 10.05 ± 4.78 hours. EVT was associated with significantly reduced 90-day mortality compared to alteplase (OR 0.41; 95% CI 0.19–0.89) and better functional outcomes (mRS 0–2 OR 2.12; 95% CI 0.75–5.98). EVT also reduced the odds of mRS 5–6 (OR 0.42; 95% CI 0.18–1.00) and showed a numerically favorable safety profile over alteplase in sICH risk (OR 0.39; 95% CI 0.08–1.91). Compared with tenecteplase, EVT lowered mortality (OR 0.61; 95% CI 0.38–0.98) with comparable efficacy. Tenecteplase had a lower sICH risk than alteplase (OR 0.27; 95% CI 0.05–1.57). Rankograms showed EVT consistently ranked highest for efficacy and safety. Conclusion: In patients with salvageable tissue presenting in the late window, EVT provides superior efficacy and safety compared to thrombolysis or medical therapy alone. Tenecteplase may offer safety advantages over alteplase. These findings support prioritizing EVT access and rapid imaging in late-presenting stroke.
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