Combo Therapy Stroke Trial Ends One Debate

The long-awaited findings of the TIMELESS trial, published earlier this year in the New England Journal of Medicine, answered one important question concerning the use of tenecteplase (TNK) in late-window patients experiencing acute ischemic stroke (AIS).

“This study was the first to show that the clot-dissolving drug does not increase the risk of intracerebral hemorrhage in patients with large-vessel occlusion when given up to 24 hours after symptom onset,” says Amre Nouh, MD, MBA, FAHA, Regional Chair of Neurology for Cleveland Clinic in Florida, and a member of the Scientific Advisory Committee that helped design the trial.

Why it matters

Right now the time window for thrombolysis is limited to within 4.5 hours after a patient was last known to be well, while endovascular thrombectomy can be performed within a longer time frame, in some cases up to 24 hours.

According to a unified database of confirmed stroke centers published in 2022, less than half of U.S. emergency departments are in hospitals equipped to care for patients presenting with acute stroke. And only a few hundred are certified to perform endovascular thrombectomy, the preferred treatment for patients with large-vessel occlusion (LVO) and salvageable ischemic brain tissue.

“Of the two major recanalization strategies for ischemic stroke, thrombolytic therapy is the most widely accessible,” says Dr. Nouh. “If we can extend the treatment window, we can potentially improve outcomes, especially for patients in small, community hospital settings and rural areas.”

Novel design

TIMELESS is a multicenter, double-blind, randomized, placebo-controlled trial that looked at the efficacy and safety of tenecteplase in late-window patients with AIS. The study enrolled 458 patients across 112 centers in the U.S. and Canada, including Cleveland Clinic in Ohio. These individuals had a LVO of the internal carotid artery or the first (M1) or second (M2) segments of the middle cerebral artery and evidence of salvageable ischemic brain tissue.

As reported in the NEJM, 228 patients received tenecteplase (0.25 mg per kilogram of body weight, up to 25 mg) and 230 received placebo. The median time from when the patient was last known to be well to randomization was approximately 12 hours in the TNK group and approximately 13 hours in the placebo group. Most patients (77.3%) underwent thrombectomy, with a median of 16 minutes between IV bolus with TNK or placebo and arterial puncture for thrombectomy.

“TIMELESS is one of the largest trials of its kind and was years in the making,” describes Dr. Nouh, whose research focus is on LVO stroke. “We used a novel recruitment paradigm in an attempt to enroll patients in spoke sites prior to arrival at a stroke center.”

Safety and efficacy

Although the combination of TNK and endovascular thrombectomy was found to be safe, with similar incidence of brain hemorrhage and comparable 90 day mortality rates, TNK did not impart better clinical outcomes than placebo. The median score on the Rankin scale at 90 days was 3 in each group. This scale is an indicator of disability and ranges from 0 to 6, with the highest score indicating death.

“Our findings are bittersweet,” admits Dr. Nouh. “A major limit of the study was that many patients were enrolled in larger centers and were treated quickly, so that the drug did not have enough time to work prior to thrombectomy.”

He notes dwell-time, or the duration a drug remains active within the bloodstream, is an important factor in the efficacy of TNK and one of its advantages over alteplase, the only FDA-approved thrombolytic for acute ischemic stroke.

“Ultimately, the TIMELESS trial demonstrated that TNK has a good safety profile with no increased risk of bleeding complications when combined with thrombectomy in late-window patients, putting an end to one debate,” says Dr. Nouh. “But more research will be needed to determine if certain subgroups may benefit more from TNK, such as patients with occlusion of the M1 segment, as suggested by this trial.”

Early adopter of TNK

First FDA-approved in 2000 to reduce mortality in acute myocardial infarction, TNK has been proven to have noninferior safety and efficacy compared with alteplase in acute ischemic stroke. “Tenecteplase is also easier to administer and more cost-effective,” notes Dr. Nouh.

According to findings from the EXTEND-IA TNK trial, the bioengineered tissue plasminogen activator also has a potential advantage in early recanalization. Due to these findings and other studies, the American Heart Association/American Stroke Association guidelines were updated in 2019 to include TNK as an alternative therapy.

Cleveland Clinic was an early adopter of TNK, and in January 2022 made an enterprise-wide switch from alteplase to tenecteplase for thrombolysis for AIS. This includes Cleveland Clinic in Florida, which is home to two comprehensive stroke centers, one thrombectomy-capable center, and two primary stroke centers.

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