Tenecteplase

Tenecteplase for Stroke at 4.5 to 24 Hours with Perfusion-Imaging Selection

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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 therapy16-22 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

Intravenous tenecteplase compared with alteplase for acute ischaemic stroke in Canada (AcT): a pragmatic, multicentre, open-label, registry-linked, randomised, controlled, non-inferiority trial.

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BACKGROUND: Intravenous thrombolysis with alteplase bolus followed by infusion is a global standard of care for patients with acute ischaemic stroke. We aimed to determine whether tenecteplase given as a single bolus might increase reperfusion compared with this standard of care.

METHODS: In this multicentre, open-label, parallel-group, registry-linked, randomised, controlled trial (AcT), patients were enrolled from 22 primary and comprehensive stroke centres across Canada. Patients were eligible for inclusion if they were aged 18 years or older, with a diagnosis of ischaemic stroke causing disabling neurological deficit, presenting within 4·5 h of symptom onset, and eligible for thrombolysis per Canadian guidelines. Eligible patients were randomly assigned (1:1), using a previously validated minimal sufficient balance algorithm to balance allocation by site and a secure real-time web-based server, to either intravenous tenecteplase (0·25 mg/kg to a maximum of 25 mg) or alteplase (0·9 mg/kg to a maximum of 90mg; 0·09 mg/kg as a bolus and then a 60 min infusion of the remaining 0·81 mg/kg). The primary outcome was the proportion of patients who had a modified Rankin Scale (mRS) score of 0-1 at 90-120 days after treatment, assessed via blinded review in the intention-to-treat (ITT) population (ie, all patients randomly assigned to treatment who did not withdraw consent). Non-inferiority was met if the lower 95% CI of the difference in the proportion of patients who met the primary outcome between the tenecteplase and alteplase groups was more than -5%. Safety was assessed in all patients who received any of either thrombolytic agent and who were reported as treated. The trial is registered with ClinicalTrials.gov, NCT03889249, and is closed to accrual.

FINDINGS: Between Dec 10, 2019, and Jan 25, 2022, 1600 patients were enrolled and randomly assigned to tenecteplase (n=816) or alteplase (n=784), of whom 1577 were included in the ITT population (n=806 tenecteplase; n=771 alteplase). The median age was 74 years (IQR 63-83), 755 (47·9%) of 1577 patients were female and 822 (52·1%) were male. As of data cutoff (Jan 21, 2022), 296 (36·9%) of 802 patients in the tenecteplase group and 266 (34·8%) of 765 in the alteplase group had an mRS score of 0-1 at 90-120 days (unadjusted risk difference 2·1% [95% CI – 2·6 to 6·9], meeting the prespecified non-inferiority threshold). In safety analyses, 27 (3·4%) of 800 patients in the tenecteplase group and 24 (3·2%) of 763 in the alteplase group had 24 h symptomatic intracerebral haemorrhage and 122 (15·3%) of 796 and 117 (15·4%) of 763 died within 90 days of starting treatment

INTERPRETATION: Intravenous tenecteplase (0·25 mg/kg) is a reasonable alternative to alteplase for all patients presenting with acute ischaemic stroke who meet standard criteria for thrombolysis.

Newer clot-busting medication may someday increase time for stroke treatment

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Research Highlights:

  • In a Phase 2a clinical trial in China, the clot busting medication tenecteplase was effective in restoring blood flow to the brain without symptomatic brain bleeding.
  • Blood flow was safely restored to a small group of ischemic stroke patients with large vessel occlusion, at 4.5 to 24 hours from time of last-seen-well using tenecteplase, therefore, larger direct comparison, clinical trials to validate this approach are needed.
  • Researchers say their findings indicate tenecteplase may someday extend the window for stroke treatment from 4.5 to 24 hours.

Embargoed until 11:28 a.m. CT/12:28 p.m. ET Thursday, Feb. 10, 2022

NEW ORLEANS, Feb. 10, 2022 — If patients with clot-caused strokes obtain medical care more than 4½ hours after their symptoms are noticed, it is too late to receive the standard clot-busting medication alteplase. However, in this study from China, tenecteplase appears to lengthen the window for additional stroke treatment to up to 24 hours, according to preliminary, late-breaking science presented today at the American Stroke Association’s International Stroke Conference 2022, a world premier meeting for researchers and clinicians dedicated to the science of stroke and brain health being held in person in New Orleans and virtually, Feb. 9-11, 2022.

A one-hour infusion of alteplase is the standard treatment for a clot-caused (ischemic) stroke, administered within 4.5 hours of first stroke symptoms. Alteplase dissolves blood clots that are blocking arteries supplying oxygen-rich blood to the lungs or brain and has been FDA-approved for the immediate treatment of ischemic stroke since 1996.

A newer medication, tenecteplase, is also a clot-busting medication and is a bioengineered variant of alteplase, and there are ongoing studies to determine its safety, efficacy and treatment parameters for ischemic stroke. Previous studies of Tenecteplase to treat acute ischemic stroke patients found it may be non-inferior to alteplase and may be superior for treating large-vessel strokes.

“The stroke burden continues to grow across the world, and particularly in China where stroke is the leading cause of death,” said Xin Cheng, M.D., Ph.D., lead author of the study and associate professor of neurology at the Huashan Hospital of Fudan University and the National Center for Neurological Disorders in Shanghai, China. “There are two major limitations in thrombolysis [treatment to dissolve dangerous clots and restore blood flow] with alteplase: the restricted time window of 4.5 hours, and a low rate of success in re-opening arteries and restoring blood flow when a large brain vessel is blocked.”

To evaluate the potential of using tenecteplase to treat patients with large-vessel strokes, Cheng and colleagues studied 86 patients with ischemic strokes, treated at 13 different hospitals in China. The patients had brain imaging between 4.5 and 24 hours after they were last known to be free of stroke symptoms. On imaging, all study participants were found to have large, affected brain areas that could potentially be salvaged if blood flow was re-established and a few small areas that were unlikely to benefit from treatment (called a penumbral mismatch).

Study participants were randomly assigned to two groups:

  • 43 patients (average age of 68 years; 58.1% male) received a lower (0.25 mg/kg) dose of tenecteplase; and
  • 43 patients (average age of 67 years; 72.1% male) received a higher (0.32 mg/kg) dose of tenecteplase.

The researchers had determined a pre-established, combined, positive outcome of effectiveness and safety if there was major restoration of blood flow without symptomatic brain bleeding 24-48 hours after treatment. If more than 7 of 43 patients met the positive outcome criteria, that intervention dose of tenecteplase would be deemed of sufficient promise to warrant further study. In addition to tenecteplase, some patients underwent endovascular therapy (thrombectomy) to mechanically remove a clot, at the discretion of the treating physician.

The researchers found:

  • At the lower dose of tenecteplase, 14 of 43 patients (32.6%) achieved the designated positive outcome criteria.
  • At the higher dose of tenecteplase, 10 of 43 patients (23.3%) achieved the designated positive outcome criteria.
  • Among all study participants evaluated 3 months after treatment, more than half (53.5%) of the patients were no more than slightly disabled, not able to carry out all previous activities but did not require daily assistance, and 38.4% of the participants either had no significant symptoms of residual neurological deficits or had mild symptoms but were able to return to pre-stroke activities of daily living.

“Tenecteplase appears to be safe and potent in reestablishing blood flow through blocked, large brain vessels, thereby preventing damage to brain tissue at risk of dying. Using perfusion imaging [to measure blood flow throughout the blood vessels] to assess patients with larger areas of potentially salvageable brain tissue and smaller areas that have already been lost to the stroke, it seems feasible that with tenecteplase we may be able to extend the time window for treatment to 24 hours after the time the patient was last known to be well. However, we still need more data from randomized controlled trials before practice changes to routinely include tenecteplase,” Cheng said.

In the subset of patients who received tenecteplase and underwent endovascular therapy (also known as thrombectomy or mechanical clot removal), fewer patients (3 of 34, or 8.8%) reached the primary outcome measure of restoring blood flow without symptomatic brain bleeding, compared to those who received only tenecteplase (21 of 52, or 40.4%).

“In our study, tenecteplase seems to be quite effective and safe in patients who do not need endovascular therapy. More research is needed to understand why tenecteplase was less effective in restoring blood flow and more likely to result in symptomatic brain bleeding among those who had endovascular therapy,” Cheng said.

As a Phase 2a trial, the focus of this research was to evaluate whether a treatment is safe and effective enough to proceed to a larger clinical trial with more study participants and to determine the potential medication doses appropriate for further research. Based on the results of this trial, the lower dose of tenecteplase is being evaluated in a larger, nationwide, Phase 2b study in China to compare the effectiveness and safety of tenecteplase versus standard treatment.

The study’s limitations include being a phase 2a clinical trial without a control group and these results from China may not be generalizable to other non-Chinese populations.

“Strokes involving large arteries in the brain due to plaque build-up are much more common among people of Chinese or Asian ethnicity compared with people of Caucasian descent. These types of strokes usually have more sustained blood flow through collateral vessels than embolic strokes, which are caused by a blood clot that forms elsewhere in the body and travels to the brain. The optimal strategy to restore blood flow in patients with large-artery plaque build-up is unknown, and there is a question of whether endovascular treatment [thrombectomy] is appropriate and effective in this type of stroke. With a huge stroke burden and limited access to centers capable of endovascular treatment in China, a potent intravenous thrombolytic like tenecteplase may be more meaningful,” Cheng said.

The latest ischemic stroke treatment guidelines from the American Heart Association recommend it may be reasonable to consider tenecteplase to treat ischemic stroke among select patients. Several recent clinical trials focused on ischemic stroke have directly compared alteplase and tenecteplase, however, large, Phase 3 trials are still ongoing.

Study co-authors are Lan Hong, M.D.; Leonid Churilov, Ph.D.; Jin Zhang, M.D.; Jianhong Yang, M.D.; Yu Geng, M.D.; Yifeng Ling, M.D.; Lumeng Yang, M.D.; Longting Lin, Ph.D.; Mark Parsons, M.D., Ph.D., and Qiang Dong, M.D., Ph.D. The list of authors’ disclosures is available in the abstract.

The study authors reported funding from the National Key R&D Program of China.

Statements and conclusions of studies that are presented at the American Stroke Association and American Heart Association’s scientific meetings are solely those of the study authors and do not necessarily reflect the Association’s policy or position. The Association makes no representation or guarantee as to their accuracy or reliability. Abstracts presented at the Association’s scientific meetings are not peer-reviewed, rather, they are curated by independent review panels and are considered based on the potential to add to the diversity of scientific issues and views discussed at the meeting. The findings are considered preliminary until published as a full manuscript in a peer-reviewed scientific journal.

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A randomized trial of tenecteplase versus alteplase for acute ischemic stroke.

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Intravenous alteplase is the only approved treatment for acute ischemic stroke. Tenecteplase, a genetically engineered mutant tissue plasminogen activator, is an alternative thrombolytic agent.
METHODS: In this phase 2B trial, we randomly assigned 75 patients to receive alteplase (0.9 mg per kilogram of body weight) or tenecteplase (0.1 mg per kilogram or 0.25 mg per kilogram) less than 6 hours after the onset of ischemic stroke. To favor the selection of patients most likely to benefit from thrombolytic therapy, the eligibility criteria were a perfusion lesion at least 20% greater than the infarct core on computed tomographic (CT) perfusion imaging at baseline and an associated vessel occlusion on CT angiography. The coprimary end points were the proportion of the perfusion lesion that was reperfused at 24 hours on perfusion-weighted magnetic resonance imaging and the extent of clinical improvement at 24 hours as assessed on the National Institutes of Health Stroke Scale (NIHSS, a 42-point scale on which higher scores indicate more severe neurologic deficits).
RESULTS: The three treatment groups each comprised 25 patients. The mean (+/-SD) NIHSS score at baseline for all patients was 14.4+/-2.6, and the time to treatment was 2.9+/-0.8 hours. Together, the two tenecteplase groups had greater reperfusion (P=0.004) and clinical improvement (P<0.001) at 24 hours than the alteplase group. There were no significant between-group differences in intracranial bleeding or other serious adverse events. The higher dose of tenecteplase (0.25 mg per kilogram) was superior to the lower dose and to alteplase for all efficacy outcomes, including absence of serious disability at 90 days (in 72% of patients, vs. 40% with alteplase; P=0.02).
CONCLUSIONS: Tenecteplase was associated with significantly better reperfusion and clinical outcomes than alteplase in patients with stroke who were selected on the basis of CT perfusion imaging.

Source:NEJM

 

Tenecteplase for Acute Stroke?

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An investigational drug shows promise in a phase IIB study.

For more than a decade, intravenous tissue plasminogen activator (TPA) has been the only approved pharmacological treatment for acute ischemic stroke. Tenecteplase, an investigational drug, is a modified version of TPA with greater fibrin specificity and a longer half-life. Researchers conducted this randomized, phase IIB trial to compare standard TPA with two doses of tenecteplase (0.1 mg/kg or 0.25 mg/kg) for patients seen at one of three centers within 6 hours of stroke onset. Inclusion criteria were standard clinical criteria, a computed tomography (CT) perfusion deficit at least 20% greater than the infarct core, and CT angiography evidence of occlusion in the anterior, middle, or posterior cerebral arteries. The two primary endpoints were radiologic evidence of reperfusion at 24 hours and improvement on the NIH Stroke Scale (NIHSS) from before treatment to 24 hours after treatment. The two tenecteplase groups were pooled for analysis of the primary results.

Of 2768 patients screened, 75 met both clinical and CT criteria. The 75 participants were enrolled at a mean of 2.9 hours after stroke onset and had a mean NIHSS score of 14.4. Tenecteplase was significantly better than TPA with regard to radiologic reperfusion (79% vs. 55%) and with regard to clinical improvement (8-point vs. 3-point improvement on the NIHSS). At 3 months, 72% of the higher-dose tenecteplase patients had an excellent outcome, compared with 40% of the TPA group, a significant difference. The rates of hemorrhagic complications did not differ significantly between the TPA and tenecteplase groups.

Comment: This trial showed better short-term radiologic and clinical outcomes with tenecteplase than with TPA for acute ischemic stroke. The trial was not powered to assess 3-month outcomes, but the higher-dose tenecteplase patients had better 3-month outcomes than the TPA patients. A previous dose-ranging study of tenecteplase was inconclusive; the trial was terminated because of slow enrollment (Stroke 2010; 41:707).

This innovative study required additional radiologic criteria for thrombolysis treatment (CT perfusion and CT angiography), in addition to the standard clinical criteria. These criteria make pathophysiological sense, but they also restricted enrollment. A larger phase III study of tenecteplase should be considered, but the authors should also consider altering the enrollment criteria (e.g., by removing some of the exclusion criteria used in the current study) to make the treatment more broadly applicable to the acute ischemic stroke population. Until these further studies are complete, tenecteplase should not be used to treat ischemic stroke.

Source:Journal Watch Neurology