Late-Window Tenecteplase for Stroke Works When Thrombectomy’s Out of the Question

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.