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Safety Concerns Halt High-dose Tenecteplase Stroke Study

A study investigating a high dose (0.4 mg/kg) of the bolus thrombolytic tenecteplase in the treatment of patients with moderate to severe acute ischemic stroke was stopped prematurely because of increased rates of intracranial hemorrhage (ICH) and mortality with the agent, compared with the standard-of-care thrombolytic, alteplase.

“We are not continuing studies with the 0.4 mg/kg dose of tenecteplase, and I don’t think anyone will advocate using this dose now after these results,” study author Annette Fromm, MD, consultant neurologist at Haukeland University Hospital, Bergen, Norway, told | Medscape Cardiology.

Fromm presented results of the NOR-TEST 2, Part A trial on May 4 at the European Stroke Organisation Conference (ESOC) 2022, held in Lyon, France, and also accessible virtually. It was also simultaneously published online in the Lancet Neurology.

Two other studies of tenecteplase used at a lower dose (0.25 mg/kg) were presented during the same session of the ESOC meeting (ACT and TASTE-A), and both showed encouraging results for the new bolus agent, compared with alteplase, with no additional safety concerns.

The different results in these studies are most probably explained by the different doses of tenecteplase used, experts said.

Commenting on the study, Joanna Wardlaw, MD, professor of applied neuroimaging at the University of Edinburgh, United Kingdom, and chair of the ESOC Planning Group, said: “The likely explanation for the increased harm shown in NOR-TEST 2A is the higher dose of tenecteplase, and that the study was conducted in more severe stroke patients who have a higher risk of bleeding and other complications, although there was also an imbalance with older and more prestroke dependency in the tenecteplase group.”

Fromm explained that tenecteplase is a modified version of alteplase with several potential advantages, such as a longer half-life and higher fibrin specificity, which allows it to be given as a single bolus dose rather than a bolus followed by a 1-hour infusion required for alteplase.

“The rapid administration method of tenecteplase is a considerable advantage in the setting of acute ischemic stroke, compared with the 1-hour infusion of alteplase, which might be prone to interruptions and complicate the logistics for patients who need transportation,” the NOR-TEST authors note. However, large-scale studies to identify the optimum dose need to be conducted.

The Norwegian group conducted a previous study — NOR-TEST 1 — which compared the 0.4 mg/kg dose of tenecteplase with alteplase in a population of patients with mainly mild stroke (median National Institutes of Health Stroke Scale [NIHSS] score 4). That study failed to show superiority of the 0.4 mg/kg dose of tenecteplase over alteplase. Although the study was not powered for noninferiority, the two drugs showed similar outcomes in terms of efficacy and bleeding.

“We wanted to do another study with this dose of tenecteplase but in patients with moderate to severe strokes. This was the NOR-TEST 2A study,” Fromm said.

The aim of NOR-TEST 2A was to establish the noninferiority of tenecteplase 0.4 mg/kg to alteplase 0.9 mg/kg for patients with moderate or severe ischemic stroke (NIHSS score of 6 or more).

The study planned to include more than 1000 such patients who were eligible for thrombolysis and admitted within 4.5 hours of symptom onset who were to be randomized to intravenous tenecteplase (0.4 mg/kg) or standard dose alteplase (0.9 mg/kg).

The study was stopped after 216 patients had been enrolled when a safety review showed an imbalance in the rates of symptomatic ICH between the treatment groups.

Of the 204 patients entered into the modified intention-to-treat analysis, 100 were randomly allocated tenecteplase and 104 were allocated alteplase.

Results showed that the primary outcome — a favorable functional outcome defined as a modified Rankin Scale (mRS) score of 0 to 1 at 3 months — was reported less frequently in patients receiving tenecteplase than alteplase (32% vs 51%; unadjusted odds ratio [OR], 0.45; P = .0064).

Any intracranial hemorrhage was significantly more frequent with tenecteplase than with alteplase (21% vs 7%; unadjusted OR, 3.68; P = .0031).

Mortality at 3 months was also significantly higher with tenecteplase than with alteplase (16% vs 5%; unadjusted OR, 3.56; = .013).

Numerically, more cases of symptomatic intracranial hemorrhage were reported with tenecteplase than with alteplase (6% vs 1%); unadjusted OR, 6.57; P = .061).

Fromm pointed out that the two groups in NOR-TEST 2A were not as well balanced as they were in NOR-TEST 1 in terms of baseline characteristics.

“In NOR-TEST 2A, the tenecteplase group had more older patients with higher prestroke disability and more patients who had had a previous stroke. The alteplase group were younger and less prestroke disability and there were also more stroke mimics in this group, so this may have led to a lower bleeding risk the alteplase group,” she suggested. “In addition, the alteplase group showed a lower-than-expected ICH rate of about 1 in 100.”  

The researchers performed an analysis to try to account for these factors, but this did not make much difference to the results, with the tenecteplase group still showing a higher ICH rate.

“This suggests that other factors contribute to this difference, the most likely being the dose of tenecteplase used,” Fromm said.

“The 0.4 mg/kg dose has not been studied extensively. We used the 0.4 mg/kg dose in the NOR-TEST 1 study and that did not show an increase in ICH versus alteplase, but that study was conducted in patients with milder strokes who have a lower bleeding risk,” she noted.

“Other trials are testing a dose of 0.25 mg/kg, which seems to show better safety results,” she added.  

The Norwegian researchers are now planning a new trial — NOR-TEST 2B —comparing tenecteplase 0.25 mg/kg with alteplase in patients with moderate to severe stroke.

In an editorial accompanying publication of the NOR-TEST 2A study, Shelagh Coutts, MD, University of Calgary, Canada, and Amy Yu, MD, University of Toronto, note that before NOR-TEST 2 started, the optimum dose of tenecteplase for stroke had been up for debate, with doses ranging from 0.1 mg/kg to 0.5 mg/kg having been studied.

The editorialists say the magnitude of harm in NOR-TEST 2 is surprising, and although it could be simply due to chance, it is similar to that seen in a previous pilot dose-escalation safety.

“We will never know if the magnitude of harm seen in NOR-TEST 2 was seen by chance, because results from this study mean that 0.4 mg/kg will not be used in acute stroke trials again,” they conclude.

The NOR-TEST 2A study was funded by a grant from the Norwegian National Programme for Clinical Therapy Research. Fromm reports no disclosures.

European Stroke Organisation Conference (ESOC) 2022. Presented May 4, 2022.  

Lancet Neurol. Published online May 4, 2022. Abstract, Editorial

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