IMPORTANCE: Intravenous thrombolysis (IVT) is an established therapy for acute ischemic stroke when administered within 4.5 hours of symptom onset. However, many patients present beyond this window or with unknown onset, and recent randomized clinical trials (RCTs) have evaluated whether imaging-selected patients may benefit from thrombolysis in the extended window.
OBJECTIVE: To evaluate the functional and safety outcomes associated with IVT administered 4.5 hours or more after stroke onset.
DATA SOURCES: PubMed, Embase, and Cochrane Central Register of Controlled Trials were systematically searched from database inception through March 3, 2026.
STUDY SELECTION: RCTs enrolling adults with acute ischemic stroke treated with IVT 4.5 hours or more after symptom onset were included. Trials comparing thrombolysis with placebo or standard medical care and reporting functional or safety outcomes were eligible.
DATA EXTRACTION AND SYNTHESIS: Data were extracted independently by 2 reviewers following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Risk ratios (RRs) and mean differences with 95% CIs were pooled using random-effects models. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool.
MAIN OUTCOMES AND MEASURES: Primary outcomes were excellent functional outcome (modified Rankin scale scores of 0-1 at 90 days), good functional outcome (modified Rankin scale scores of 0-2 at 90 days), all-cause 90-day mortality, and symptomatic intracerebral hemorrhage (ICH).
RESULTS: Fourteen RCTs including 4174 patients (2102 in the thrombolysis group and 2072 in the control group) were analyzed, 9 of which were published within the past 5 years. IVT was associated with a higher likelihood of excellent functional outcome (RR, 1.22; 95% CI, 1.14-1.31) and good functional outcome (RR, 1.12; 95% CI, 1.06-1.18) at 90 days. Mortality did not differ between groups (RR, 1.13; 95% CI, 0.93-1.38), but thrombolysis was associated with an increased the risk of symptomatic ICH (RR, 2.44; 95% CI, 1.45-4.09). Absolute treatment effects corresponded to a number needed to treat of 12 to 16 for an additional favorable outcome and a number needed to harm of 62 for symptomatic ICH.
CONCLUSIONS AND RELEVANCE: In this systematic review and meta-analysis of 14 RCTs, IVT administered beyond 4.5 hours after stroke onset was associated with improved functional outcomes despite an increased risk of symptomatic ICH, supporting extension of thrombolytic therapy beyond the conventional treatment window in appropriately imaging-selected patients.
| Discipline Area | Score |
|---|---|
| Hospital Doctor/Hospitalists |  |
| Internal Medicine | |
| Emergency Medicine | |
| Neurology |  |
Most useful for hospital physicians taking care of strokes, but primary care should know so we can direct those for care even if past the 4.5-hour window up to 24 hours.
As a U.S. hospitalist, management of acute stroke is critical and is one of the most challenging things we deal with. As “time is brain,” decisions on IV thrombolysis versus EVT and appropriate timing are critical controversies. In this study, carefully selected patients with brains at risk received IV thrombolysis beyond the 4.5-hour window and showed better functional outcomes at 90 days (NNT 18) but more bleeds (NNH 64). If it is my brain, I will take the dichotomous choice of "much better" or "much worse" any day. Take-aways: Use TNK; use advanced imaging to carefully select the patients outside 4.5 hours who have significant brain at risk and significant benefit from the late intervention.
Well done meta-analysis that confirms what recent trials have shown: imaging selection of patients in the extended time window identifies those who can benefit from thrombolysis. The estimate of the overall NNT and NNH in this population is useful to practitioners. Clarity on optimal selection criteria remains to be established.
This quality meta-analysis of RCTs shows benefit of thrombolysis beyond 4.5 hours with little heterogeneity between the various trials and with most studies showing a low-bias risk. Note, though, that patients in these studies were carefully selected, which is a point the authors are careful to emphasize.
