Exploring Between-Study Heterogeneity in Extended-Window IV Thrombolysis for Acute Ischemic Stroke: A Meta-Analysis of 18 Randomized Controlled Trials
Abstract
BACKGROUND AND OBJECTIVES
IV thrombolysis (IVT) is the standard-of-care evidence-based treatment of eligible patients with acute ischemic stroke (AIS) within 4.5 hours of symptom onset. Emerging evidence supports its use beyond this time window, leading to expanded recommendations for selected patients presenting between 4.5 and 24 hours. We performed a systematic review and meta-analysis to evaluate IVT in the 4.5- to 24-hour window and to explore sources of between-study heterogeneity.
METHODS
We searched MEDLINE, Cochrane Library, and ClinicalTrials.gov from inception through February 2026. Eligible studies were randomized controlled trials (RCTs) or individual patient-data meta-analyses of RCTs comparing IVT with control in patients with AIS presenting beyond 4.5 hours from last known well. The primary outcome was excellent functional recovery, defined as a modified Rankin Scale (mRS) of 0-1 at 90 days. Secondary outcomes included functional independence (mRS of 0-2 at 90 days); change in mRS disability, quantified as the common odds ratio (OR) for a 1-point improvement across the full ordinal mRS distribution (ordinal analysis); and safety measures such as 90-day mortality and symptomatic intracranial hemorrhage (sICH). Risk ratios (RRs) with 95% CIs were pooled. Multivariable meta-regression simultaneously modeled thrombolytic agent, endovascular thrombectomy context, and territory to disentangle confounded predictors.
RESULTS
Fifteen studies representing 18 RCTs and…
How strong is the evidence?
Evidence Hub reads this as a meta-analysis, done in people. Its evidence level is 1 of 5 (Highest · pooled evidence). Pooled evidence from several studies sits at the top of the evidence pyramid. Reported size: 5,168 participants or records.
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