Abstract

Background

Thrombolytic agents, including tenecteplase, are generally used within 4.5 hours after the onset of stroke symptoms. Information on whether tenecteplase confers benefit beyond 4.5 hours is limited.

Methods

We conducted a multicenter, double-blind, randomized, placebo-controlled trial involving patients with ischemic stroke to compare tenecteplase (0.25 mg per kilogram of body weight, up to 25 mg) with placebo administered 4.5 to 24 hours after the time that the patient was last known to be well. Patients had to have evidence of occlusion of the middle cerebral artery or internal carotid artery and salvageable tissue as determined on perfusion imaging. The primary outcome was the ordinal score on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability and a score of 6 indicating death) at day 90. Safety outcomes included death and symptomatic intracranial hemorrhage.

Results

The trial enrolled 458 patients, 77.3% of whom subsequently underwent thrombectomy; 228 patients were assigned to receive tenecteplase, and 230 to receive placebo. The median time between the time the patient was last known to be well and randomization was approximately 12 hours in the tenecteplase group and approximately 13 hours in the placebo group. The median score on the modified Rankin scale at 90 days was 3 in each group. The adjusted common odds ratio for the distribution of scores on the modified Rankin scale at 90 days for tenecteplase as compared with placebo was 1.13 (95% confidence interval, 0.82 to 1.57; P=0.45). In the safety population, mortality at 90 days was 19.7% in the tenecteplase group and 18.2% in the placebo group, and the incidence of symptomatic intracranial hemorrhage was 3.2% and 2.3%, respectively.

Conclusions

Tenecteplase therapy that was initiated 4.5 to 24 hours after stroke onset in patients with occlusions of the middle cerebral artery or internal carotid artery, most of whom had undergone endovascular thrombectomy, did not result in better clinical outcomes than those with placebo. The incidence of symptomatic intracerebral hemorrhage was similar in the two groups.

Intravenous thrombolytic therapy with alteplase has generally been the standard care for eligible patients within 4.5 hours after the onset of ischemic stroke.¹ One limitation for extending the time window for thrombolysis has been an increase in the incidence of intracranial hemorrhage. In a pooled analysis of nine randomized trials that selected patients with stroke on the basis of noncontrast computed tomography (CT) of the head and compared alteplase with placebo or open control (without a placebo group) administered no more than 6 hours after stroke onset, treatment with alteplase significantly increased the odds of symptomatic intracranial hemorrhage.² Although most previous trials of thrombolytic therapy have indicated that the benefit of treatment is dependent on the earliest possible time that reperfusion can be obtained,² a meta-analysis showed a benefit of alteplase administered during the 4.5-to-9-hour time window after stroke onset in selected patients who had evidence of viable tissue on CT perfusion imaging or perfusion–diffusion magnetic resonance imaging (MRI).³ This finding suggested that, in patients with favorable imaging profiles showing salvageable brain tissue, intravenous thrombolysis in an extended window may be safe and efficacious. However, the patients in these trials did not undergo endovascular thrombectomy, which has become the preferred treatment for patients with large-vessel occlusions and imaging evidence of salvageable tissue who can be treated within 24 hours after stroke onset.

Tenecteplase is a modified form of human tissue plasminogen activator that was approved in 2000 to reduce mortality among patients with acute myocardial infarction.⁴ Several trials have shown the noninferiority of tenecteplase to alteplase when treatment is begun within 4.5 hours after stroke onset,^5-8 and the most recent American Heart Association–American Stroke Association (AHA–ASA) guidelines for acute ischemic stroke indicate that tenecteplase is a reasonable alternative to alteplase in specific patient populations.¹

Data regarding the use of tenecteplase beyond 4.5 hours after symptom onset are limited. A trial of tenecteplase in patients who had stroke symptoms when they awoke, but who were not selected on the basis of CT perfusion imaging or perfusion–diffusion MRI, showed that tenecteplase therapy was not associated with better functional outcomes than placebo; however, safety results were similar to those of thrombolytic therapy given within 4.5 hours after onset.⁹ A proof-of-concept trial showed the feasibility of treatment with tenecteplase administered no more than 24 hours after stroke onset¹⁰ in patients with evidence of salvageable tissue on CT perfusion imaging.

The Thrombolysis in Imaging Eligible, Late Window Patients to Assess the Efficacy and Safety of Tenecteplase (TIMELESS) trial was designed to test the hypothesis that intravenous tenecteplase, initiated 4.5 to 24 hours after stroke onset, would provide a benefit in patients who had a large-vessel occlusion of the internal carotid artery or the first (M1) or second (M2) segments of the middle cerebral artery and had evidence of salvageable ischemic brain tissue identified on CT perfusion or MRI perfusion–diffusion studies. (The M1 segment is the main trunk, and the M2 segment the first-order branch of the main trunk.) In this trial, patients with occlusions of the internal carotid artery or the M1 segment were anticipated to receive standard-care endovascular thrombectomy in addition to tenecteplase or placebo, whereas the use of endovascular thrombectomy in patients with an occlusion of the M2 segment was at the discretion of the treating physician.

Discussion

The TIMELESS trial did not show a significant improvement in functional outcomes at 90 days in patients with stroke who had evidence of salvageable tissue on perfusion imaging and received tenecteplase 4.5 to 24 hours after the time they were last known to be well. Most patients also underwent endovascular thrombectomy (77.3%). The incidence of recanalization at 24 hours appeared to be higher with tenecteplase than with placebo, but the incidence of reperfusion was similar in the two groups at the end of the procedure.

Given the high proportion of patients who underwent endovascular thrombectomy and had a short interval between thrombolytic administration and arterial puncture, our trial resembles various trials that compared endovascular thrombectomy with or without preceding alteplase therapy^16-22 in a time window of up to 4.5 hours after onset. The time between the administration of the intravenous thrombolytic agent and arterial puncture in these trials was longer (median, 25 minutes; interquartile range, 15 to 39) than the time between the administration of tenecteplase and arterial puncture in the current trial (15 minutes; interquartile range, 3 to 25), but the incidence of recanalization before endovascular thrombectomy was similar. A meta-analysis with the use of individual patient data that included the addition of thrombolysis to thrombectomy did not show the noninferiority of direct endovascular thrombectomy to combined treatment with an intravenous thrombolytic agent and thrombectomy.²³

In the EXTEND-IA TNK trial,⁷ treatment with tenecteplase resulted in a higher incidence of reperfusion before thrombectomy and better functional outcome than alteplase therapy among patients with ischemic stroke treated within 4.5 hours after symptom onset and before endovascular thrombectomy. The median time from the initiation of intravenous thrombolysis with tenecteplase to arterial puncture was 42 minutes in the EXTEND-IA TNK trial, as compared with 15 minutes in our trial. One possible reason for the time difference was the larger proportion of patients in the EXTEND-IA TNK trial than in our trial who received tenecteplase at a center that was not capable of providing endovascular treatment before transfer. Our trial did not enroll enough patients at such centers to provide insights into the effect of tenecteplase in this patient population.

In this trial, we found no benefit in functional outcome with tenecteplase as compared with placebo administered 4.5 to 24 hours after symptom onset in patients with ischemic stroke who had been selected on the basis of a favorable perfusion-imaging profile, most of whom subsequently underwent endovascular therapy. The incidence of brain hemorrhage was similar in the two trial groups.

Source: NEJM