Neurology · Medical Literature
Exploring Between-Study Heterogeneity in Extended-Window IV Thrombolysis for Acute Ischemic Stroke: A Meta-Analysis of 18 Randomized Controlled Trials.
Abstract
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. 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. Fifteen studies representing 18 RCTs and encompassing 5,168 patients were included in the primary analysis. Of the 18 included RCTs, 11 required advanced perfusion imaging (CTP or MRP mismatch) or diffusion-weighted imaging/fluid-attenuated inversion recovery mismatch to confirm salvageable tissue; the remaining 7 permitted noncontrast CT/CT angiography-based selection. IVT significantly improved excellent functional outcome at 90 days (mRS 0-1; 40.3% vs 33.2%, RR 1.21; 95% CI 1.13-1.30; p < 0.001; number needed to treat [NNT] = 14) and good functional outcome (mRS 0-2; 54.5% vs 50.1%, RR 1.09; 95% CI 1.04-1.15; p < 0.001; NNT = 23). IVT was associated with significantly greater odds of reduced disability across the full mRS spectrum (common OR 1.18; 95% CI 1.07-1.32; p = 0.004). IVT increased the risk of sICH (3.2% vs 1.4%; RR 1.90; 95% CI 1.28-2.84; p = 0.002; number needed to harm = 57) but did not increase 90-day mortality (13.7% vs 13.0% RR 1.04; 95% CI 0.92-1.18; p = 0.53). Meta-regression showed that thrombectomy (β = -0.275, p = 0.012 for mRS shift; β = -0.186, p = 0.032 for mRS 0-2) is the primary driver of between-study heterogeneity, explaining 66%-100% of intertrial variance. Extended-window IVT improves functional outcomes across a wider spectrum of stroke subgroups than previously recognized. The benefit seems greatest for patients with more severe strokes in settings where thrombectomy is unavailable, providing the evidence base for offering a critical reperfusion strategy for the substantial proportion of patients worldwide who lack timely access to thrombectomy. This study provides American Academy of Neurology Class I evidence that IVT administered 4.5-24 hours after moderate-to-severe AIS onset in patients with salvageable tissue, where thrombectomy is not readily available, improves functional outcome at 90 days without increasing mortality.
Clinical relevance
This meta-analysis addresses a critical evidence gap regarding the efficacy and safety of IV thrombolysis (IVT) beyond the established 4.5-hour window, directly impacting the substantial global population of AIS patients who present in delayed or wake-up stroke fashion. With expanded guidelines now permitting IVT up to 24 hours in selected patients, clinicians urgently need high-quality, pooled RCT data to guide patient selection and shared decision-making. The findings are particularly consequential for resource-limited settings and low-to-middle-income countries where mechanical thrombectomy infrastructure remains inaccessible to the majority of stroke patients.
Key findings
1. Extended-window IVT (4.5–24 hours) significantly improved excellent functional outcome (mRS 0–1 at 90 days): 40.3% vs. 33.2% (RR 1.21; 95% CI 1.13–1.30; p < 0.001; NNT = 14). 2. IVT significantly improved functional independence (mRS 0–2 at 90 days): 54.5% vs. 50.1% (RR 1.09; 95% CI 1.04–1.15; p < 0.001; NNT = 23). 3. IVT produced significantly greater odds of ordinal mRS improvement across the full disability spectrum (common OR 1.18; 95% CI 1.07–1.32; p = 0.004), confirming benefit beyond dichotomized outcomes. 4. IVT significantly increased symptomatic intracranial hemorrhage (sICH): 3.2% vs. 1.4% (RR 1.90; 95% CI 1.28–2.84; p = 0.002; NNH = 57), representing a meaningful but manageable safety signal. 5. IVT did not increase 90-day all-cause mortality: 13.7% vs. 13.0% (RR 1.04; 95% CI 0.92–1.18; p = 0.53), confirming an acceptable overall risk-benefit profile. 6. Multivariable meta-regression identified concurrent thrombectomy eligibility as the primary driver of between-study heterogeneity (β = −0.275, p = 0.012 for mRS shift; β = −0.186, p = 0.032 for mRS 0–2), explaining 66–100% of intertrial variance; benefit from IVT was attenuated in thrombectomy-eligible trial populations.
Practice implications
Clinicians should consider offering IVT to AIS patients presenting 4.5–24 hours from last known well who demonstrate salvageable tissue on advanced perfusion imaging (CTP/MRP mismatch) or DWI-FLAIR mismatch, particularly those with moderate-to-severe deficits in settings where timely mechanical thrombectomy is unavailable — this trial-level evidence (AAN Class I) supports broadening real-world utilization in thrombectomy-inaccessible environments. The favorable NNT of 14 for excellent outcome versus NNH of 57 for sICH provides a compelling risk-benefit ratio to guide shared decision-making and institutional protocol development, while reinforcing that imaging-based patient selection is essential to maximize benefit and minimize hemorrhagic risk. In centers where thrombectomy is available, the attenuated IVT effect in that context warrants further prospective study to define whether bridging IVT adds incremental benefit, and clinicians should continue to prioritize door-to-puncture efficiency over routine bridging in thrombectomy-capable settings.