Thrombolysis in the Delayed Treatment Window for Acute Ischemic Stroke: Updated Systematic Review and Meta-Analysis

BACKGROUND: Intravenous thrombolysis is a standard treatment for acute ischemic stroke but has traditionally been limited to 4.5 hours after symptom onset. This time-based restriction may exclude patients with salvageable brain tissue, especially those with wake-up or unknown-onset strokes. Multimodal imaging allows for the identification of viable penumbra beyond traditional treatment windows. This study compiles randomized evidence evaluating intravenous thrombolysis in imaging-selected patients treated after 4.5 hours. METHODS: We conducted a systematic review and meta-analysis in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, Embase, and Cochrane Central were searched through February 2026 for randomized trials comparing intravenous thrombolysis (alteplase or tenecteplase) with best medical therapy in patients presenting beyond 4.5 hours or with wake-up/unknown-onset stroke selected by imaging. The primary outcome was excellent functional outcome at 90 days (modified Rankin Scale score 0-1). Secondary outcomes included functional independence (modified Rankin Scale score 0-2), symptomatic intracranial hemorrhage, and 90-day mortality. RESULTS: Fourteen trials involving 4192 participants were analyzed. Intravenous thrombolysis improved excellent functional outcomes (modified Rankin Scale score 0-1; risk ratio, 1.22 [95% CI, 1.16-1.29]) and functional independence (modified Rankin Scale score 0-2; risk ratio, 1.12 [95% CI, 1.06-1.18]). Both alteplase and tenecteplase contributed to these benefits. Thrombolysis increased the risk of symptomatic intracranial hemorrhage (risk ratio, 2.58 [95% CI, 1.58-4.22]) but did not significantly affect 90-day mortality (risk ratio, 1.15 [95% CI, 0.97-1.35]). CONCLUSIONS: In patients selected using advanced imaging, intravenous thrombolysis performed after 4.5 hours improves functional outcomes without increasing mortality, supporting a tissue-based rather than strictly time-based approach to treating acute ischemic stroke.