PHOENIX — Selected stroke patients did not benefit clinically from having the window of tenecteplase therapy extended beyond the first few hours of stroke onset, the randomized TIMELESS trial found.

In patients with large-vessel occlusions (LVOs) and evidence of salvageable tissue on perfusion imaging — most who also received endovascular thrombectomy — functional outcomes at day 90 were about the same whether patients were randomized to tenecteplase or placebo 4.5 to 24 hours after stroke onset (median modified Rankin scale score 3 in both groups; adjusted common OR 1.13, 95% CI 0.82-1.57), reported Gregory Albers, MD, of Stanford Stroke Center in Palo Alto, California, at the American Stroke Association’s International Stroke Conference.

Safety data did not significantly favor either the tenecteplase or placebo group in this late window, with similar rates of 90-day mortality (19.7% vs 18.2%) and symptomatic intracranial hemorrhage (3.2% vs 2.3%), Albers noted of the results, which were published simultaneously in the New England Journal of Medicine.

There was a greater incidence of complete recanalization at 24 hours with tenecteplase (76.7% vs 63.9%; adjusted OR 1.89, 95% CI 1.21-2.95), but angiographic reperfusion was no different between groups at the end of the procedure (89.1% vs 85.4%).

Amid the disappointing results for tenecteplase, there did appear to be a hypothesis-generating signal that people with occlusions in the M1 segment had particularly good outcomes with the thrombolytic, based on a subgroup analysis.

“Taken together, the trial results tentatively suggest that pretreatment with tenecteplase before thrombectomy may be beneficial in patients with occlusions in the M1 segment when administered in the 4.5-to-24-hour window, but they also suggest that tenecteplase is probably unlikely to help patients who present with large-vessel occlusions and do not undergo thrombectomy,” wrote Dana Leifer, MD, of Weill Cornell Medical College in New York City, in an accompanying editorial.

A notable 77.3% of patients underwent thrombectomy in TIMELESS. The trial was therefore underpowered to make conclusions about tenecteplase’s effects on the minority of people who did not receive endovascular therapy, Albers and colleagues acknowledged.

What’s more, stroke patients who did not have LVOs were wholly excluded from the trial, Leifer pointed out.

Therefore, the door may not be closed on an extended window of tenecteplase stroke treatment.

After all, tenecteplase is faster and more powerful than alteplase (Activase or tPA), leading to it being increasingly used off-label for stroke despite alteplase being the only thrombolytic currently FDA approved to treat ischemic stroke.

“Tenecteplase is a genetically modified variant of alteplase that has a higher specificity for fibrin and a longer half-life,” Leifer wrote. “Because studies suggest that tenecteplase is as safe and effective as alteplase and can be administered rapidly rather than requiring infusion over a period of 1 hour as alteplase does, tenecteplase is increasingly being used instead of alteplase.”

Previously, a phase II trial had shown that tenecteplase looked feasible for thrombolysis in stroke patients presenting up to 24 hours after symptom onset.

Ongoing trials including the ETERNAL-LVO trial are comparing tenecteplase against standard of care in patients presenting up to 24 hours after time last known to be well.

TIMELESS was a multicenter trial that enrolled patients with ischemic stroke at 112 centers in the U.S. and Canada. Eligible patients had to have evidence of occlusion of the middle cerebral artery (M1 segment or M2 branches) or internal carotid artery and salvageable tissue on CT perfusion imaging or perfusion-diffusion MRI of the head.

Investigators randomly split the 458 study participants into groups receiving tenecteplase (0.25 mg/kg, up to 25 mg) or placebo, with the assigned treatment administered 4.5 to 24 hours after the patient was last known to be well.

Median age was 72 years, and 53.5% of participants were women. Median NIH Stroke Scale score was 12, and the occlusion site was the M1 or M2 segment in the bulk of patients.

While the study dictated that tenecteplase or placebo be given as soon as possible, ideally before the arterial puncture for a planned endovascular thrombectomy, a median 12 hours passed between the time the patient was last known to be well and randomization to tenecteplase (1 hour longer for those randomized to placebo).

Please enable JavaScript to view the

comments powered by Disqus.