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TRACEIII

Tenecteplase Reperfusion Therapy in Acute Ischemic Cerebrovascular Events-III (TRACE-III) trial

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Year of Publication: 2024

Authors: Yunyun Xiong, Bruce C.V. Campbell, Lee H. Schwamm, ..., Yongjun Wang

Journal: The New England Journal of Medicine

Citation: N Engl J Med 2024;391:203-12.

Link: https://www.nejm.org/doi/full/10.1056/NEJMoa2402980

PDF: https://www.researchgate.net/publication...mxpY2F0aW9uIn19

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?

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 were not eligible for 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 care.
Tenecteplase improved 90-day mRS 0–1 rates: 33.0% vs. 24.2% (RR 1.37; 95% CI, 1.04–1.81; P=0.03).
Functional independence (mRS ≤2) was 43.6% with tenecteplase vs. 33.3% with standard care.
Symptomatic ICH occurred in 3.0% vs. 0.8% (RR 3.82; 95% CI, 0.82–17.87).
Complete recanalization at 24h: 27.9% vs. 5.9%.
Mortality was similar (13.3% vs. 13.1%).

      

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
Prestroke mRS 0–1
NIHSS 6–25
Large-vessel occlusion (ICA or M1/M2) on CTA/MRA
Salvageable brain tissue on perfusion imaging: ischemic core <70 ml, mismatch ratio ≥1.8, mismatch volume ≥15 ml

Exclusion Criteria

Planned endovascular thrombectomy at randomization
Guideline-based contraindications to thrombolytics
Unrecognized infarction >1/3 MCA territory

Baseline Characteristics

Characteristic	Control	Active
Median age (IQR) - yr	68 (59–76)	67 (58–75)
Male sex no. (%)	167 (66.3%)	183 (69.3%)
Hypertension- no. (%)	180 (71.4%)	177 (67.0%)
Diabetes mellitus no. (%)	71 (28.2%)	69 (26.1%)
Atrial fibrillation - no. (%)	48 (19.0%)	49 (18.6%)
Modified Rankin scale score before stroke - 0 no. (%)	216 (85.7%)	230 (87.1%)
Modified Rankin scale score before stroke - 1 no. (%)	36 (14.3%)	34 (12.9%)
Median NIHSS score at randomization (IQR)	10 (7–14)	11 (7–15)
Category of onset of stroke - Known onset time - no. (%)	149 (59.1%)	143 (54.2%)
Category of onset of stroke - Unwitnessed onset - no. (%)	19 (7.5%)	20 (7.6%)
Category of onset of stroke - Stroke on awakening - no. (%)	84 (33.3%)	101 (38.3%)
Median volume of irreversibly injured ischemic core at initial imaging (IQR) - ml	14.9 (6.0–29.3)	16.4 (5.7–28.4)
Median volume of perfusion lesion at initial imaging (IQR) -ml	123.2 (74.6–180.1)	119.1 (79.8–177.2)

Arms

Field	Tenecteplase	Control
Intervention	Intravenous tenecteplase 0.25 mg/kg (max 25 mg) 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, sex, NIHSS (<10 vs ≥10), time from last known well, occlusion site. Post hoc: age (<65 vs ≥65), EVT (yes vs no), ischemic core volume. No significant heterogeneity found.

Criticisms

Open-label design despite blinded outcome assessment
Exclusion of patients eligible for thrombectomy limits generalizability
Study population entirely in China, where stroke mechanisms differ
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 large infarcts had symptomatic ICH

Funding

National Natural Science Foundation of China, Beijing Municipal Science and Technology Commission and Zhongguancun Science Park Administrative Committee, China Shijiazhuang Pharmaceutical Company Recomgen Pharmaceutical

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.

Content summarized and formatted by NeuroTrials.ai.

TRACEIII

(2024)

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.

Inclusion Criteria

Ischemic stroke with LVO (ICA, M1, M2), 4.5-24 hours from last known well, mRS 0-1, NIHSS 6-25, core < 70ml, penumbra > 15ml, penumbra/core ratio > 1.8.

Study Design

Arms: Tenecteplase (TNK) vs. No Thrombolysis (Standard Medical Treatment)

Patients per Arm: TNK: 262, No Thrombolysis: 252

Outcome

• 90d mRS 0-1: TNK 33%, No Thrombolysis 24.2%. • 90d mRS 0-2: TNK 43.6%, No Thrombolysis 33.3%. • Major improvement in 72h: TNK 16%, No Thrombolysis 6%. • sICH: TNK 3%, No Thrombolysis 0.8%. • Death within 90 days: TNK 13%, No Thrombolysis 13%. • Any serious adverse events: TNK 20.1%, No Thrombolysis 17.1%..

Bottom Line

Major Points

516 patients were randomized: 264 to tenecteplase and 252 to standard care.
Tenecteplase improved 90-day mRS 0–1 rates: 33.0% vs. 24.2% (RR 1.37; 95% CI, 1.04–1.81; P=0.03).
Functional independence (mRS ≤2) was 43.6% with tenecteplase vs. 33.3% with standard care.
Symptomatic ICH occurred in 3.0% vs. 0.8% (RR 3.82; 95% CI, 0.82–17.87).
Complete recanalization at 24h: 27.9% vs. 5.9%.
Mortality was similar (13.3% vs. 13.1%).

Study Design

Study Type: Phase 3, multicenter, prospective, open-label, randomized, blinded-outcome-assessment trial
Randomization: Yes
Blinding: Blinded outcome assessments by certified clinicians and adjudication committee
Sample Size: 516
Follow-up: 90 days
Centers: 58
Countries: China

Primary Outcome

Definition: mRS 0–1 at 90 days (absence of disability)

Control	Intervention	HR/OR	P-value
61 (24.2%)	87 (33.0%)	1.37 (1.04 to 1.81)	0.03

Limitations & Criticisms

Open-label design despite blinded outcome assessment
Exclusion of patients eligible for thrombectomy limits generalizability
Study population entirely in China, where stroke mechanisms differ
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 large infarcts had symptomatic ICH

Citation

N Engl J Med 2024;391:203-12.

View Original Publication →

TRACEIII

Tenecteplase Reperfusion Therapy in Acute Ischemic Cerebrovascular Events-III (TRACE-III) trial

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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