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TNK 4.5-24h Meta-Analysis

Tenecteplase for Acute Ischemic Stroke at 4.5 to 24 Hours: A Meta-Analysis of Randomized Controlled Trials

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Year of Publication: 2026

Authors: Zixin Wang, Jiamin Li, Xinyi Wang, ..., Qingfeng Ma

Journal: Stroke

Citation: Stroke. 2026;57:00–00. DOI: 10.1161/STROKEAHA.125.053256

Link: https://www.ahajournals.org/doi/10.1161/STROKEAHA.125.053256

PDF: https://www.ahajournals.org/doi/epub/10....EAHA.124.050117

Clinical Question

Does tenecteplase (TNK) benefit patients with acute ischemic stroke treated within 4.5 to 24 hours, and does the benefit differ based on whether endovascular thrombectomy (EVT) is available?

Bottom Line

TNK improves excellent functional outcomes and recanalization in patients with acute ischemic stroke treated within 4.5 to 24 hours without increasing risks of symptomatic ICH or mortality. Extended-window TNK provides greater additional benefits when EVT is inaccessible, establishing its role as an alternative reperfusion strategy in resource-limited settings.

Major Points

  • Systematic review and meta-analysis of 4 RCTs (ROSE-TNK, TIMELESS, TRACE-III, CHABLIS-T II) including 1278 patients
  • First meta-analysis to perform EVT-stratified subgroup analysis (non-EVT vs EVT-permitted)
  • Overall: TNK significantly improved excellent functional outcome (mRS 0-1: OR 1.34, 95% CI 1.06-1.71, P=0.02) and recanalization (OR 3.30, 95% CI 1.59-6.84, P=0.001)
  • Non-EVT subgroup (596 patients): TNK improved excellent outcome (OR 1.46, P=0.04), good outcome (OR 1.50, P=0.02), recanalization (OR 6.17, P<0.00001), and ENI (OR 3.21, P<0.0001)
  • EVT-permitted subgroup (682 patients): TNK only improved recanalization (OR 2.36, P=0.003), with no significant effect on functional outcomes
  • No significant differences in sICH (OR 1.68, P=0.17), PH2 (OR 2.03, P=0.06), or 90-day mortality (OR 1.04, P=0.81)
  • DWI-FLAIR mismatch subgroup showed significant ENI benefit (OR 4.68, P=0.03)
  • MRI/CT perfusion subgroup showed excellent outcome benefit (OR 1.36, P=0.01)
  • All 4 included trials showed low risk of bias or some concerns, with no high-risk studies

Design

Study Type: Systematic review and meta-analysis of randomized controlled trials

Randomization: 1

Blinding: Variable across included trials: ROSE-TNK and TRACE-III were open-label; TIMELESS was placebo-controlled and blinded; CHABLIS-T II was open-label with some concerns for deviations from intended interventions

Enrollment Period: 2019 to 2023 across included trials

Follow-up Duration: 90 days

Centers: 203

Countries: China, United States, Canada

Sample Size: 1278

Analysis: Random-effects meta-analysis using Review Manager 5.4.1. Dichotomous outcomes presented as odds ratios with 95% CIs. Heterogeneity assessed using Cochran Q test (P<0.1 significant) and I² statistic (>75% high heterogeneity). Prespecified subgroup analyses by EVT availability (non-EVT vs EVT-permitted), neuroimaging modality (DWI-FLAIR mismatch vs MRI/CT perfusion), and geographic region (China vs US/Canada). Subgroup effects compared using χ²-based interaction tests. GRADE approach used to assess certainty of evidence.

Inclusion Criteria

  • Randomized controlled trials
  • Adult patients with acute ischemic stroke
  • Presentation within 4.5 to 24 hours after symptom onset or last known well
  • Eligible for intravenous thrombolysis based on imaging selection
  • Intervention: TNK 0.25 mg/kg intravenously
  • Comparator: Standard medical treatment or placebo
  • Primary outcome included excellent functional outcome (mRS 0-1) at 90 days

Exclusion Criteria

  • Non-randomized trials
  • Treatment initiation within 4.5 hours only
  • Studies focused solely on wake-up strokes
  • Studies restricted to 4.5-6 hour window only
  • Incomplete studies
  • Wrong population

Baseline Characteristics

CharacteristicTNK group (overall)Control group (overall)
Sample size643635
Age range62.7-72 years median62.8-73 years median
Sex - Male46.5-77.5%46.5-70.8%
NIHSS score median7.5-127-12
Baseline infarct core volume0.32-16.4 mL0.40-14.9 mL
EVT performedVariable: 0% (ROSE-TNK, TRACE-III), 53.2% (CHABLIS-T II), 77.2% (TIMELESS)Variable: 0% (ROSE-TNK, TRACE-III), 56.6% (CHABLIS-T II), 77.4% (TIMELESS)

Arms

FieldTenecteplase (TNK)Control
InterventionIntravenous tenecteplase at 0.25 mg/kg administered within 4.5 to 24 hours of acute ischemic stroke onset. Patients selected based on neuroimaging criteria: DWI-FLAIR mismatch (ROSE-TNK) or CT/MRI perfusion-based salvageable tissue confirmation with or without large vessel occlusion screening (TIMELESS, TRACE-III, CHABLIS-T II). Eligible patients had NIHSS scores ≥5-6 and prestroke mRS 0-2.Standard medical treatment (ROSE-TNK, TRACE-III, CHABLIS-T II) or placebo (TIMELESS) administered within 4.5 to 24 hours. Same imaging selection criteria and eligibility requirements as TNK group.
DurationSingle bolus administrationPer protocol

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Excellent functional outcome defined as modified Rankin Scale (mRS) score of 0-1 at 90 daysPrimary183/634 (28.9%)225/641 (35.1%)6.24%0.02
Good functional outcome (mRS 0-2) at 90 daysSecondary271/634 (42.7%)301/641 (47.0%)OR 1.16 (0.84-1.60)0.38
ReperfusionSecondary132/411 (32.1%)147/413 (35.6%)OR 1.33 (0.69-2.54)0.39
RecanalizationSecondary154/543 (28.4%)256/549 (46.6%)OR 3.30 (1.59-6.84)0.001
Early neurological improvement (ENI)Secondary44/401 (11.0%)75/400 (18.8%)OR 2.12 (0.81-5.55)0.13
Non-EVT subgroup - Excellent functional outcomeSecondary81/292 (27.7%)108/304 (35.5%)OR 1.46 (1.02-2.08)0.04
Non-EVT subgroup - Good functional outcomeSecondary108/292 (37.0%)141/304 (46.4%)OR 1.50 (1.07-2.09)0.02
Non-EVT subgroup - RecanalizationSecondary14/237 (5.9%)69/247 (27.9%)OR 6.17 (3.36-11.33)<0.00001
Non-EVT subgroup - ENISecondary18/289 (6.2%)51/290 (17.6%)OR 3.21 (1.82-5.66)<0.0001
EVT-permitted subgroup - Excellent functional outcomeSecondary102/342 (29.8%)117/337 (34.7%)OR 1.25 (0.91-1.73)0.17
EVT-permitted subgroup - Good functional outcomeSecondary163/342 (47.7%)160/337 (47.5%)OR 0.95 (0.61-1.50)0.84
EVT-permitted subgroup - RecanalizationSecondary140/306 (45.8%)187/302 (61.9%)OR 2.36 (1.34-4.17)0.003
Symptomatic intracerebral hemorrhage (sICH)Adverse12/619 (1.9%)21/633 (3.3%)OR 1.68 (0.80-3.52)0.17
Parenchymal hematoma type 1Adverse2/506 (0.4%)9/522 (1.7%)OR 3.60 (0.87-14.95)0.08
Parenchymal hematoma type 2Adverse11/619 (1.8%)23/633 (3.6%)OR 2.03 (0.98-4.22)0.06
Poor functional outcome (mRS 5-6) at 90 daysAdverse129/634 (20.3%)131/641 (20.4%)OR 1.00 (0.73-1.36)0.99
Death within 90 daysAdverse89/634 (14.0%)94/641 (14.7%)OR 1.04 (0.76-1.43)0.81
Non-EVT subgroup - sICHAdverse2/292 (0.7%)8/304 (2.6%)OR 3.91 (0.82-18.58)0.09
Non-EVT subgroup - Death within 90 daysAdverse33/292 (11.3%)38/304 (12.5%)OR 1.57 (0.31-8.01)0.58
EVT-permitted subgroup - sICHAdverse10/327 (3.1%)13/329 (4.0%)OR 1.31 (0.57-3.04)0.53
EVT-permitted subgroup - Death within 90 daysAdverse56/342 (16.4%)56/337 (16.6%)OR 1.02 (0.68-1.53)0.93

Subgroup Analysis

Prespecified subgroup analyses performed by: (1) EVT availability (non-EVT vs EVT-permitted) - showed significant interaction with TNK providing greater benefits when EVT unavailable; (2) Neuroimaging modality (DWI-FLAIR mismatch vs MRI/CT perfusion) - DWI-FLAIR group showed ENI benefit (OR 4.68, P=0.03), perfusion group showed excellent outcome benefit (OR 1.36, P=0.01); (3) Geographic region (China vs US/Canada) - China trials showed benefits in excellent outcome (OR 1.36, P=0.04), reperfusion (OR 1.88, P=0.02), and recanalization (OR 4.61, P<0.00001), while US/Canada (TIMELESS only) showed recanalization benefit (OR 1.86, P=0.006). No significant subgroup differences in safety outcomes across any subgroup analyses.

Criticisms

  • Only 4 RCTs included, resulting in relatively small sample size that may reduce robustness of conclusions, particularly in subgroup analyses
  • Within non-EVT subgroup, TRACE-III patients accounted for 86.6% of total, potentially dominating pooled treatment effects
  • TIMELESS and CHABLIS-T II enrolled patients who underwent EVT, but did not report outcomes stratified by EVT status, limiting ability to isolate TNK-specific effects
  • Heterogeneity observed across trials in neuroimaging selection criteria (DWI-FLAIR mismatch vs CT/MRI perfusion), EVT utilization rates (0-77.4%), and outcome definitions
  • Included trials predominantly from China (3 of 4 studies), limiting generalizability to other populations
  • Unable to formally assess publication bias due to limited number of studies (<10 trials)
  • EVT-permitted subgroup analysis limited to comparison between trials rather than individual patient-level data
  • Different control interventions across trials (standard care vs placebo) may introduce heterogeneity
  • Moderate heterogeneity observed in some outcomes (I²=45-77% for good functional outcome, reperfusion, recanalization, ENI)
  • No assessment of optimal patient selection criteria beyond imaging-based inclusion
  • Unable to evaluate dose-response relationships or optimal timing within 4.5-24 hour window

Funding

Noncommunicable Chronic Diseases-National Science and Technology Major Project (grants 2024ZD0527600 and 2024ZD0527603) and the National Key Research and Development Program of China (grant 2023YFC2506504)

Based on: TNK 4.5-24h Meta-Analysis (Stroke, 2026)

Authors: Zixin Wang, Jiamin Li, Xinyi Wang, ..., Qingfeng Ma

Citation: Stroke. 2026;57:00–00. DOI: 10.1161/STROKEAHA.125.053256

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