A research investigating a excessive dose (0.4 mg/kg) of the bolus thrombolytic tenecteplase within the remedy of sufferers with reasonable to extreme acute ischemic stroke was stopped prematurely due to elevated charges of intracranial hemorrhage (ICH) and mortality with the agent, in contrast with the standard-of-care thrombolytic, alteplase.
“We’re not persevering with research with the 0.4 mg/kg dose of tenecteplase, and I do not assume anybody will advocate utilizing this dose now after these outcomes,” research creator Annette Fromm, MD, advisor neurologist at Haukeland College Hospital, Bergen, Norway, advised theheart.org | Medscape Cardiology.
Fromm offered outcomes of the NOR-TEST 2, Half A trial on Could 4 on the European Stroke Organisation Convention (ESOC) 2022, held in Lyon, France, and likewise accessible just about. It was additionally concurrently printed on-line within the Lancet Neurology.
Two different research of tenecteplase used at a decrease dose (0.25 mg/kg) had been offered throughout the identical session of the ESOC assembly (ACT and TASTE-A), and each confirmed encouraging outcomes for the brand new bolus agent, in contrast with alteplase, with no extra security issues.
The completely different leads to these research are likely defined by the completely different doses of tenecteplase used, specialists mentioned.
Commenting on the research, Joanna Wardlaw, MD, professor of utilized neuroimaging on the College of Edinburgh, United Kingdom, and chair of the ESOC Planning Group, mentioned: “The probably clarification for the elevated hurt proven in NOR-TEST 2A is the upper dose of tenecteplase, and that the research was carried out in additional extreme stroke sufferers who’ve a better danger of bleeding and different problems, though there was additionally an imbalance with older and extra prestroke dependency within the tenecteplase group.”
Fromm defined that tenecteplase is a modified model of alteplase with a number of potential benefits, similar to an extended half-life and better fibrin specificity, which permits it to be given as a single bolus dose reasonably than a bolus adopted by a 1-hour infusion required for alteplase.
“The speedy administration methodology of tenecteplase is a substantial benefit within the setting of acute ischemic stroke, in contrast with the 1-hour infusion of alteplase, which could be susceptible to interruptions and complicate the logistics for sufferers who want transportation,” the NOR-TEST authors notice. Nonetheless, large-scale research to determine the optimum dose must be carried out.
The Norwegian group carried out a earlier research — NOR-TEST 1 — which in contrast the 0.4 mg/kg dose of tenecteplase with alteplase in a inhabitants of sufferers with primarily gentle stroke (median Nationwide Institutes of Well being Stroke Scale [NIHSS] rating 4). That research failed to indicate superiority of the 0.4 mg/kg dose of tenecteplase over alteplase. Though the research was not powered for noninferiority, the 2 medicine confirmed comparable outcomes when it comes to efficacy and bleeding.
“We wished to do one other research with this dose of tenecteplase however in sufferers with reasonable to extreme strokes. This was the NOR-TEST 2A research,” Fromm mentioned.
The purpose of NOR-TEST 2A was to ascertain the noninferiority of tenecteplase 0.4 mg/kg to alteplase 0.9 mg/kg for sufferers with reasonable or extreme ischemic stroke (NIHSS rating of 6 or extra).
The research deliberate to incorporate greater than 1000 such sufferers who had been eligible for thrombolysis and admitted inside 4.5 hours of symptom onset who had been to be randomized to intravenous tenecteplase (0.4 mg/kg) or commonplace dose alteplase (0.9 mg/kg).
The research was stopped after 216 sufferers had been enrolled when a security assessment confirmed an imbalance within the charges of symptomatic ICH between the remedy teams.
Of the 204 sufferers entered into the modified intention-to-treat evaluation, 100 had been randomly allotted tenecteplase and 104 had been allotted alteplase.
Outcomes confirmed that the first final result — a positive purposeful final result outlined as a modified Rankin Scale (mRS) rating of 0 to 1 at 3 months — was reported much less ceaselessly in sufferers receiving tenecteplase than alteplase (32% vs 51%; unadjusted odds ratio [OR], 0.45; P = .0064).
Any intracranial hemorrhage was considerably extra frequent with tenecteplase than with alteplase (21% vs 7%; unadjusted OR, 3.68; P = .0031).
Mortality at 3 months was additionally considerably greater with tenecteplase than with alteplase (16% vs 5%; unadjusted OR, 3.56; P = .013).
Numerically, extra instances of symptomatic intracranial hemorrhage had been reported with tenecteplase than with alteplase (6% vs 1%); unadjusted OR, 6.57; P = .061).
Fromm identified that the 2 teams in NOR-TEST 2A weren’t as nicely balanced as they had been in NOR-TEST 1 when it comes to baseline traits.
“In NOR-TEST 2A, the tenecteplase group had extra older sufferers with greater prestroke incapacity and extra sufferers who had had a earlier stroke. The alteplase group had been youthful and fewer prestroke incapacity and there have been additionally extra stroke mimics on this group, so this will likely have led to a decrease bleeding danger the alteplase group,” she prompt. “As well as, the alteplase group confirmed a lower-than-expected ICH charge of about 1 in 100.”
The researchers carried out an evaluation to attempt to account for these elements, however this didn’t make a lot distinction to the outcomes, with the tenecteplase group nonetheless displaying a better ICH charge.
“This implies that different elements contribute to this distinction, the more than likely being the dose of tenecteplase used,” Fromm mentioned.
“The 0.4 mg/kg dose has not been studied extensively. We used the 0.4 mg/kg dose within the NOR-TEST 1 research and that didn’t present a rise in ICH versus alteplase, however that research was carried out in sufferers with milder strokes who’ve a decrease bleeding danger,” she famous.
“Different trials are testing a dose of 0.25 mg/kg, which appears to indicate higher security outcomes,” she added.
The Norwegian researchers are actually planning a brand new trial — NOR-TEST 2B —evaluating tenecteplase 0.25 mg/kg with alteplase in sufferers with reasonable to extreme stroke.
In an editorial accompanying publication of the NOR-TEST 2A research, Shelagh Coutts, MD, College of Calgary, Canada, and Amy Yu, MD, College of Toronto, notice that earlier than NOR-TEST 2 began, the optimum dose of tenecteplase for stroke had been up for debate, with doses starting from 0.1 mg/kg to 0.5 mg/kg having been studied.
The editorialists say the magnitude of hurt in NOR-TEST 2 is shocking, and though it may very well be merely on account of probability, it’s much like that seen in a earlier pilot dose-escalation security.
“We are going to by no means know if the magnitude of hurt seen in NOR-TEST 2 was seen by probability, as a result of outcomes from this research imply that 0.4 mg/kg won’t be utilized in acute stroke trials once more,” they conclude.
The NOR-TEST 2A research was funded by a grant from the Norwegian Nationwide Programme for Medical Remedy Analysis. Fromm experiences no disclosures.
European Stroke Organisation Convention (ESOC) 2022. Introduced Could 4, 2022.
Lancet Neurol. Printed on-line Could 4, 2022. Summary, Editorial