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Late-Window Tenecteplase for Stroke Works When Thrombectomy's Out of the Question
TRACE-III trial finds benefit for lytic given up to 24 hours after stroke onset
For stroke patients, late administration of tenecteplase improved clinical outcomes in situations in which thrombectomy was not available immediately, according to the Chinese TRACE-III trial.
Patients with ischemic stroke due to large vessel occlusion (LVO) and proof of salvageable brain tissue were more likely to have no disability (modified Rankin scale scores 0-1) at 90 days if they had been given tenecteplase instead of standard therapy alone (33% vs 24.2%, relative rate [RR] 1.37, 95% CI 1.04-1.81), reported Yongjun Wang, MD, PhD, of Beijing Tiantan Hospital and Capital Medical University, and colleagues in the New England Journal of Medicine.
The study included 516 patients who had presented within 4.5 to 24 hours after they were last known to be well, including those who had wake-up strokes and unwitnessed strokes. The vast majority did not undergo endovascular thrombectomy, a therapy known to be beneficial but hard to access for many people.
"In developed countries, most patients present first to hospitals in which endovascular thrombectomy is unavailable and are then transferred to a thrombectomy-capable center. The TRACE-III trial provides evidence that these patients, who may no longer be eligible for thrombectomy by the time they arrive at the thrombectomy center, can benefit from intravenous tenecteplase therapy at the primary stroke center," the authors wrote.
The trial's findings were also presented at the Chinese Stroke Association & Tiantan International Stroke Conference.
Tenecteplase is an established thrombolytic agent for people in the 4.5-hour window of stroke onset, and the agent has been shown to be noninferior to alteplase. It is currently gaining traction over alteplase, given its administration as a single bolus instead of an infusion.
In an accompanying editorial, Vivien Lee, MD, of Ohio State University Wexner Medical Center in Columbus, highlighted the "far-reaching global clinical implications" of using tenecteplase in an extended time window.
"In geographic regions that lack resources to develop thrombectomy programs, the administration of tenecteplase in the 24-hour window after stroke onset may be a practical treatment alternative that could improve functional outcomes in patients with [LVO] on an international scale," she wrote.
Even in the U.S., she added, "only one third of the population has direct access to thrombectomy within 30 minutes from their present location," and most people would only get a delayed thrombectomy with interhospital transfer.
In TRACE-III, the safety outcome of mortality was a similar 13.3% and 13.1% of patients in the tenecteplase and control groups, respectively. However, symptomatic intracranial hemorrhage (sICH) within 36 hours occurred in significant excess for the tenecteplase group (3% vs 0.8%, RR 3.82, 95% CI 0.82-17.87).
Wang's team urged careful evaluation for areas of hypodensity on noncontrast CT -- associated with sICH in five out of nine patients who turned out to have these protocol violations on central imaging review -- when considering the use of late-window thrombolytic agents.
"This approach does require perfusion-imaging capability at these smaller hospitals, but the TRACE-III trial and other trials provide evidence for the feasibility of this approach with the use of CT-based methods and automated software," they wrote.
Previously, the TIMELESS investigators had tried and failed to show a clinical benefit to tenecteplase beyond the first few hours of LVO stroke onset. This older trial was limited by participation of comprehensive stroke centers that could provide immediate access to thrombectomy, Lee said.
"This difference in trial design allowed the TRACE-III trial to accomplish what the TIMELESS trial could not: a longer duration of exposure to tenecteplase, which resulted in a beneficial outcome relative to no thrombolytic therapy," she noted.
TRACE-III was a phase III trial conducted at 58 centers in China from 2022 to 2023. Eligible patients were adults with LVO of the middle cerebral artery or internal carotid artery, based on CT or MRI angiography, who did not have access to endovascular thrombectomy. They had to have salvageable brain tissue as identified on perfusion imaging (CT perfusion or perfusion-diffusion MRI) using iStroke software and a score of 6 to 25 on the NIH Stroke Scale (NIHSS).
Out of 1,469 screened patients, 516 were randomly assigned to tenecteplase (0.25 mg/kg up to 25 mg) or standard treatment (e.g., antiplatelets). Median age was 67 years, and 68% were men. Median NIHSS was 10.
A median 12.3 hours passed between stroke onset and randomization. The median door-to-needle time was 139 minutes. Fewer than 2% of the patients in both groups underwent rescue endovascular thrombectomy, which was allowed at the discretion of the treating clinician.
The trial's open-label design was a major limitation, Wang and colleagues acknowledged.
"The use of tenecteplase in the extended time window in conjunction with a model of transfer to another facility for planned thrombectomy was not well represented in either the TIMELESS or TRACE-III trial and continues to remain a gap in knowledge that warrants further trials," Lee wrote.
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Disclosures
TRACE III was funded by the National Natural Science Foundation of China, the Beijing Municipal Science and Technology Commission and Zhongguancun Science Park Administrative Committee, and the China Shijiazhuang Pharmaceutical Company Recomgen Pharmaceutical.
Wang had no disclosures.
Lee had no disclosures.
Primary Source
New England Journal of Medicine
Source Reference: Xiong Y, et al "Tenecteplase for ischemic stroke at 4.5 to 24 hours without thrombectomy" N Engl J Med 2024; DOI: 10.1056/NEJMoa2402980.
Secondary Source
New England Journal of Medicine
Source Reference:Lee VH "Small step or giant leap? Expanding the acute stroke thrombolysis window to 24 hours" N Engl J Med 2024; DOI: 10.1056/NEJMe2405846.
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