Intravenous Thrombolysis Beyond the Conventional Time Window for Acute Ischemic Stroke: A Systematic Review and Meta-Analysis
In imaging-selected acute ischemic stroke, intravenous clot-busting therapy after 4.5 hours improved 90-day function but increased symptomatic brain bleeding.
*Systematic review and meta-analysis of randomized trials; Level 1a.
Citation
Patel S, Nischal SA, Kale KM, Gooch MR, Tjoumakaris SI, Jabbour PM. Intravenous Thrombolysis Beyond the Conventional Time Window for Acute Ischemic Stroke. JAMA Network Open. 2026;9(8):e2626990. doi:10.1001/jamanetworkopen.2026.26990
Background
Clot-busting treatment is proven within 4.5 hours of ischemic stroke, but many patients arrive later or wake with symptoms. Imaging can identify patients who may still have brain tissue that can be saved.
Patients
Adults with acute ischemic stroke treated at least 4.5 hours after last known well. Trials generally excluded large completed strokes or very severe deficits.
Intervention
Intravenous alteplase or tenecteplase, often guided by advanced brain imaging.
Control
Placebo or standard medical care.
Outcome
Excellent function, good function, death, and symptomatic brain bleeding. Function used the modified Rankin scale (0=no symptoms, 6=death).
Follow-up Period
90 days.
Results
| Outcome | Relative effect | Absolute impact |
|---|---|---|
| Excellent function at 90 days (primary) | Risk ratio 1.22 (95% CI 1.14 to 1.31) | 1 extra excellent outcome per 12 treated |
| Good function at 90 days (primary) | Risk ratio 1.12 (95% CI 1.06 to 1.18) | 1 extra good outcome per 16 treated |
| Symptomatic brain bleeding (primary safety) | Risk ratio 2.44 (95% CI 1.45 to 4.09) | 1 extra harm per 62 treated |
| Death by 90 days (primary) | NS | — |
The review included 14 randomized trials and 4174 patients. Evidence certainty was rated high for primary outcomes.
Limitations
Patients were highly selected, usually by imaging, so results should not be applied to all late-presenting strokes. Study-level data limited patient-specific analysis. Imaging methods, treatment windows, and use of clot removal procedures varied across trials.
Funding
No funding reported; consultant conflicts outside study.
Clinical Application
Consider late intravenous thrombolysis only when imaging shows salvageable brain tissue; possible indication creep beyond selected patients.
Discussion
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In this systematic review/meta-analysis of 14 RCTs, IVT beyond 4.5 hours improved 90-day excellent functional outcome (RR 1.22; NNT≈12) but increased symptomatic ICH (RR 2.44; NNH≈62). Are the trials’ imaging-selected populations valid and applicable enough to change your thrombolysis practice? In this meta-analysis, IVT beyond 4.5 hours had a symptomatic intracerebral hemorrhage RR of 2.44, but the reported NNH was 62. Which statement best explains the difference between these measures?