Exploring Between-Study Heterogeneity in Extended-Window IV Thrombolysis for Acute Ischemic Stroke: A Meta-Analysis of 18 Randomized Controlled Trials.

Abstract (English)

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 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; <i>p</i> < 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; <i>p</i> < 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; <i>p</i> = 0.004). IVT increased the risk of sICH (3.2% vs 1.4%; RR 1.90; 95% CI 1.28-2.84; <i>p</i> = 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; <i>p</i> = 0.53). Meta-regression showed that thrombectomy (&#x3b2; = -0.275, <i>p</i> = 0.012 for mRS shift; &#x3b2; = -0.186, <i>p</i> = 0.032 for mRS 0-2) is the primary driver of between-study heterogeneity, explaining 66%-100% of intertrial variance. DISCUSSION: 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. CLASSIFICATION OF EVIDENCE: 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.