TRACEIII
Tenecteplase Reperfusion Therapy in Acute Ischemic Cerebrovascular Events-III (TRACE-III) trial
Clinical Question
In patients with ischemic stroke due to large-vessel occlusion and salvageable brain tissue, who do not have access to endovascular thrombectomy, does tenecteplase administered 4.5 to 24 hours after stroke onset reduce disability compared to standard medical treatment?
Study Overview
Objective
To evaluate the effectiveness of TNK in patients with large vessel occlusion (LVO) who did not undergo thrombectomy within an extended time window of 4.5-24 hours.
Study Summary
In patients with LVO who did not undergo thrombectomy, treatment with TNK in an extended window of 4.5-24 hours was associated with less disability..
Intervention
Tenecteplase (TNK) versus standard medical treatment.
Patients per Arm
TNK: 262, No Thrombolysis: 252
Bottom Line
Tenecteplase administered 4.5 to 24 hours after stroke onset improved disability outcomes in patients with large-vessel occlusion and salvageable brain tissue who did not have access to endovascular thrombectomy, though with a numerically higher risk of symptomatic intracranial hemorrhage.
Major Points
- 516 patients were randomized: 264 to tenecteplase and 252 to standard medical treatment. Rescue endovascular thrombectomy was performed in 4 tenecteplase and 5 standard-care patients (<2% overall).
- Tenecteplase improved 90-day mRS 0-1 rates: 33.0% vs. 24.2% (relative rate 1.37; 95% CI, 1.04-1.81; P=0.03).
- Functional independence (mRS ≤2) at 90 days was 43.6% with tenecteplase vs. 33.3% with standard care (relative rate 1.31; 95% CI, 1.05-1.63).
- Symptomatic ICH within 36 hours occurred in 3.0% vs. 0.8% (relative rate 3.82; 95% CI, 0.82-17.87).
- Complete recanalization at 24 hours: 27.9% vs. 5.9%.
- Mortality at 90 days was similar (13.3% vs. 13.1%; relative rate 1.01; 95% CI, 0.65-1.58).
Design
Study Type: Phase 3, multicenter, prospective, open-label, randomized, blinded-outcome-assessment trial
Randomization: 1
Blinding: Blinded outcome assessments by certified clinicians and adjudication committee
Enrollment Period: January 2022 through November 2023
Follow-up Duration: 90 days
Centers: 58
Countries: China
Sample Size: 516
Analysis: Intention-to-treat analysis; log-binomial regression for primary outcome; ordinal logistic regression for mRS distribution; generalized linear mixed models for NIHSS change; subgroup analyses with logistic regression
Inclusion Criteria
- Age ≥18 years
- Stroke onset or last known well 4.5 to 24 hours prior (including stroke on awakening and unwitnessed stroke)
- Prestroke mRS 0-1
- NIHSS 6-25
- Large-vessel occlusion (intracranial ICA or M1/M2 segment of MCA) on CTA/MRA
- Salvageable brain tissue on perfusion imaging: ischemic core <70 ml, mismatch (perfusion-core difference) volume ≥15 ml, mismatch ratio ≥1.8
Exclusion Criteria
- Planned endovascular thrombectomy at randomization
- Guideline-based contraindications to thrombolytics
- Unrecognized infarction >1/3 MCA territory
Arms
| Field | Tenecteplase | Control |
|---|---|---|
| Intervention | Intravenous tenecteplase 0.25 mg/kg (max 25 mg) as a bolus over 5-10 seconds immediately after randomization | Antiplatelet therapy per investigator discretion, per 2018 Chinese AIS guidelines |
| Duration | Single dose; follow-up to 90 days | Per clinical care; follow-up to 90 days |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| mRS 0-1 at 90 days (absence of disability) | Primary | 61 (24.2%) | 87 (33.0%) | 1.37 | 0.03 |
| Ordinal mRS distribution at 90 days | Secondary | 1.33 | |||
| Functional independence (mRS ≤2) at 90 days | Secondary | 84 (33.3%) | 115 (43.6%) | 1.31 | |
| Major neurologic improvement at 72 hours | Secondary | 15/249 (6.0%) | 40/250 (16.0%) | 2.66 | |
| Reperfusion at 24 hours | Secondary | 27/229 (11.8%) | 48/239 (20.1%) | 1.7 | |
| NIHSS change from baseline at 7 days | Secondary | -2 (-5 to 0) | -4 (-6 to -1) | -1.47 | |
| Complete recanalization at 24 hours | Secondary | 14 (5.9%) | 69 (27.9%) | ||
| Symptomatic intracranial hemorrhage within 36 hours after randomization | Adverse | 2 (0.8%) | 8 (3.0%) | 3.82 | |
| Death within 90 days | Adverse | 33 (13.1%) | 35 (13.3%) | 1.01 | |
| Moderate or severe systemic bleeding within 90 days (GUSTO criteria) | Adverse | 2 (0.8%) | 5 (1.9%) | 2.36 | |
| Any adverse event | Adverse | 129 (51.2%) | 134 (50.8%) | 0.99 | |
| Any serious adverse event | Adverse | 43 (17.1%) | 53 (20.1%) | 1.18 | |
| Parenchymal hematoma type 2 | Adverse | 1 (0.4%) | 4 (1.5%) |
Subgroup Analysis
Prespecified subgroups: age (<80 vs ≥80), sex, NIHSS (<10 vs ≥10), time from last known well (>4.5-9.0 h vs >9.0-24.0 h vs stroke on awakening), occlusion site (ICA vs M1 vs M2). Post hoc: age (<65 vs ≥65), EVT (yes vs no), ischemic core volume (<20 vs 20-<50 vs ≥50 ml). No significant heterogeneity found.
Criticisms
- Open-label design despite blinded outcome assessment
- Exclusion of patients with access to thrombectomy limits generalizability to comprehensive stroke centers
- Study population entirely in China, where intracranial atherosclerosis is more prevalent and atrial fibrillation is less prevalent than in Western populations
- Effect size smaller than with thrombectomy
- Median ischemic core volume and NIHSS score lower than prior late-window studies
- Five of nine protocol-violation patients with extensive hypodensity on noncontrast CT developed symptomatic ICH
Funding
National Natural Science Foundation of China (grant 82171272); Beijing Municipal Science and Technology Commission and Zhongguancun Science Park Administrative Committee (grant Z211100003521019); China Shijiazhuang Pharmaceutical Company Recomgen Pharmaceutical (provided tenecteplase and unrestricted infrastructure grant).
Based on: TRACEIII (The New England Journal of Medicine, 2024)
Authors: Yunyun Xiong, Bruce C.V. Campbell, Lee H. Schwamm, ..., Yongjun Wang
Citation: N Engl J Med 2024;391:203-12.
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