PDF: Extended-Window IVT Meta-Analysis
(2026)Objective
In adults with acute ischemic stroke presenting >4.5 hours from last known well, does IV thrombolysis (alteplase or tenecteplase) added to best medical therapy improve 90-day functional outcomes and safety compared with best medical therapy alone?
Study Summary
• mRS 0–2 at 90 d: 1,334/2,439 (54.7%) vs 1,151/2,400 (48.0%); RR 1.15 (95% CI 1.05–1.25; p=0.002).
• Symptomatic ICH: 76/2,429 (3.1%) IVT vs 29/2,367 (1.2%) BMT; RR 2.11 (95% CI 1.36–3.28; p<0.001); NNH=75.
Intervention
IV thrombolysis (alteplase 0.6 or 0.9 mg/kg, or tenecteplase 0.25 mg/kg) plus best medical therapy vs best medical therapy alone; some trials permitted concomitant endovascular treatment.
Inclusion Criteria
Adults with acute ischemic stroke presenting >4.5 hours from last known well (including wake-up/unknown-onset strokes), enrolled in RCTs comparing IVT + BMT vs BMT alone (with or without placebo); anterior, posterior, or both circulations; imaging selection ranged from noncontrast CT to advanced perfusion/DWI-FLAIR mismatch.
Study Design
Arms: IVT + BMT (n=2,456) vs BMT alone (n=2,411)
Patients per Arm: 2,456 IVT vs 2,411 BMT (N=4,867 across 12 RCTs + 1 IPDM)
Outcome
• Secondary efficacy — mRS 0–2: RR 1.15 (1.05–1.25); disability shift cOR 1.26 (1.13–1.39).
• Primary safety — sICH: 3.1% vs 1.2% (RR 2.11, 95% CI 1.36–3.28; NNH=75).
• Secondary safety — any ICH RR 1.32 (1.00–1.74, p=0.051); mortality RR 1.03 (0.89–1.18, p=0.72).
• No subgroup interaction for efficacy by agent, window (4.5–9 h, 4.5–24 h, >4.5 h), imaging (advanced vs standard), circulation, or EVT; sICH interaction for EVT (RR 1.52 with EVT vs RR 5.03 without).
• GRADE: Moderate for functional outcomes; High for sICH; Low for any ICH and mortality.
Bottom Line
Across 12 RCTs and 1 IPDM (4,867 patients), IVT beyond 4.5 hours significantly improved excellent functional outcome at 90 days (mRS 0–1: 40.2% vs 32.5%; RR 1.23, 95% CI 1.15–1.33; NNT=13) with a consistent shift toward less disability, at the cost of a higher symptomatic ICH rate (3.1% vs 1.2%; RR 2.11; NNH=75) but no increase in 90-day mortality. Benefit was consistent across thrombolytic agents (alteplase and tenecteplase), time windows (4.5–9 h, 4.5–24 h, wake-up), imaging strategies, vascular territories, and with or without EVT.
Major Points
- 13 studies pooled: 12 RCTs plus 1 individual patient data meta-analysis (Campbell 2019 pooling EXTEND, ECASS4-EXTEND, EPITHET); IVT arm n=2,456 (mean age 68.2, 37% female, mean NIHSS 11.5) vs BMT n=2,411 (68.6 y, 38% female, NIHSS 11.0); mean time from last known well ~10.7–11.1 hours; 16% received EVT in each arm.
- Included trials span alteplase (0.6–0.9 mg/kg) and tenecteplase (0.25 mg/kg): ATTENTION LATE, Campbell IPDM (EXTEND / ECASS4-EXTEND / EPITHET), EXPECTS, HOPE, OPTION, ROSE-TNK, THAWS, TIMELESS, TNK PLUS, TRACE III, TRACE 5, TWIST, WAKE-UP.
- Primary efficacy — excellent functional outcome (mRS 0–1 at 90 d): 40.2% (980/2,439) IVT vs 32.5% (780/2,400) BMT; RR 1.23 (95% CI 1.15–1.33; PI 1.14–1.34; I²=0%; p<0.01); NNT=13 (95% CI 9–21); no subgroup differences by agent, time window, imaging, territory, or EVT.
- Secondary efficacy — mRS 0–2: 54.7% vs 48.0%; RR 1.15 (1.05–1.25; I²=59%; p=0.002). Disability shift (≥1-point mRS reduction): common OR 1.26 (1.13–1.39; I²=0%; p<0.001).
- Primary safety — sICH: 3.1% (76/2,429) IVT vs 1.2% (29/2,367) BMT; RR 2.11 (1.36–3.28; I²=0%; p<0.001); NNH=75 (95% CI 37–231); sICH RR 1.52 (0.75–3.08) in EVT trials vs 5.03 (2.35–10.77) in non-EVT trials (subgroup p=0.02).
- Secondary safety — any ICH: 12.5% (105/841) vs 9.4% (79/839); RR 1.32 (1.00–1.74; p=0.051; 4 studies). All-cause mortality at 90 d: 13.2% (321/2,438) vs 12.6% (300/2,387); RR 1.03 (0.89–1.18; p=0.72).
- Post hoc subgroup within advanced imaging (perfusion CTP/MRP vs DWI-FLAIR mismatch): no significant differences across any outcome, with consistent direction of effect.
- Trial sequential analysis: cumulative Z-curve crossed both the conventional (Z=1.96) and O'Brien-Fleming sequential monitoring boundaries for the primary outcome — evidence deemed conclusive for the assumed 3% absolute risk difference.
- GRADE certainty: Moderate for mRS 0–1, mRS 0–2, and disability shift; High for sICH (upgraded 1 grade for RR>2); Low for any ICH and 90-day mortality (imprecision).
- Small study effects: Egger p=0.01 for sICH suggested some small-study bias; no other outcomes showed asymmetry; leave-one-out sensitivity confirmed robustness of all outcomes except any ICH (borderline).
Study Design
- Study Type
- Aggregate-data systematic review and meta-analysis of RCTs (PRISMA 2020) with trial sequential analysis and GRADE evidence rating
- Randomization
- Yes
- Blinding
- Included trials: WAKE-UP, TIMELESS, and the 3 IPDM component trials were placebo-controlled; others were open-label or open-label with blinded outcome adjudication
- Sample Size
- 4867
- Follow-up
- 90 days for all primary and secondary outcomes
- Countries
- China, USA, Australia, New Zealand, Canada, Japan, Belgium, UK, Germany, France, Taiwan, Finland, Norway, Sweden, Denmark, Italy, Greece, Multiple international sites
Primary Outcome
Definition: Excellent functional outcome at 90 days, defined as modified Rankin Scale score 0–1
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 780/2,400 (32.5%) | 980/2,439 (40.2%) | - (1.15-1.33) | <0.01 |
Limitations & Criticisms
- Aggregate study-level data only — no individual patient data; cannot precisely define optimal patient selection subgroups.
- Substantial clinical heterogeneity across trials in inclusion criteria (time window 4.5–9 h to 24 h to wake-up), imaging paradigms (CT alone vs perfusion vs DWI-FLAIR), core-volume/mismatch thresholds, and vascular territory.
- Egger regression p=0.01 for sICH suggests small-study effects for the primary safety outcome.
- sICH definitions differ across trials; a formal harmonized definition was not applied.
- Standard-imaging trials disproportionately enrolled posterior circulation strokes and cannot be directly generalized to unselected anterior circulation patients.
- 3 trials (ATTENTION LATE, TNK PLUS, TRACE-5) were only presented at the 2026 International Stroke Conference — not yet peer-reviewed at time of publication.
- Any-ICH outcome relied on only 4 trials, was borderline significant, and was sensitive to leave-one-out.
- Concomitant EVT in ~16% of patients complicates isolation of IVT's independent pharmacologic effect.
Citation
Neurology 2026;107(3):e218294. DOI: 10.1212/WNL.0000000000218294