EXTEND-IA TNK: Increased tenecteplase dose does not improve stroke outcomes
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A 0.4 mg/kg dose of tenecteplase administered before endovascular thrombectomy in patients with large vessel occlusion ischemic stroke did not significantly improve cerebral reperfusion compared with a 0.25 mg/kg dose, according to data from the EXTEND-IA TNK Part 2 trial presented at the International Stroke Conference.
Results from this study were simultaneously published in JAMA.
The first part of the EXTEND-IA TNK trial was presented in 2018. As Healio previously reported, treatment with tenecteplase (TNKase, Genentech), compared with alteplase (Activase, Genentech), yielded more frequent reperfusion and improved clinical outcomes among patients with acute ischemic stroke who were selected for thrombectomy.
Trial enrollment
Researchers analyzed data from 300 patients with ischemic stroke within 4.5 hours of the onset of stroke from 27 hospitals in Australia and one in New Zealand between December 2017 and July 2019.
“Our recruitment was quite rapid,” Bruce C.V. Campbell, MBBS, BMedSc, PhD, head of stroke at the Royal Melbourne Hospital and professorial fellow at the University of Melbourne in Parkville, Australia, said during the presentation. “We had 300 patients recruited over 18 months. ... It’s a tribute to the rapid uptake of endovascular therapy in Australia and around the world.”
Patients were assigned 0.4 mg/kg (n = 150; mean age, 72 years; 51% men) or 0.25 mg/kg tenecteplase (n = 150; mean age, 74 years; 55% men) given as a bolus before endovascular thrombectomy.
“Tenecteplase is a genetically modified alteplase that has greater fibrin specificity, greater resistance to inhibitors and a longer half-life that permits a convenient, single bolus administration,” Campbell said during the presentation. “This eliminates the bolus-infusion gap that often occurs with alteplase and ensures the entire lytic dose is given without infusion interruption. Tenecteplase is also less expensive than alteplase in many countries and is the standard lytic for ST-elevation myocardial infarction.”
Follow-up was conducted at day 3 in the hospital and at 90 days by phone to assess the modified Rankin Scale score. The primary outcome was substantial reperfusion, defined as blood flow restoration to greater than 50% of the involved territory or the absence of retrievable intracranial thrombus. Several prespecified secondary outcomes were assessed related to the modified Rankin Scale score, symptomatic intracranial hemorrhage within 36 hours, substantial neurological improvement at 3 days and all-cause death.
The primary outcome occurred in 19.3% in the group assigned 0.4 mg/kg tenecteplase and in the group assigned 0.25 mg/kg of tenecteplase (difference = 0%; 95% CI, –8.9 to 8.9; adjusted RR = 1.03; 95% CI, 0.66-1.61).
There were no significant differences between the 0.4 mg/kg group and the 0.25 mg/kg group for the six secondary outcomes regarding the four functional outcomes, all-cause death (17% vs. 15%, respectively; unadjusted risk difference = 2.7%; 95% CI, –5.6 to 11) or symptomatic intracranial hemorrhage (4.7% vs. 1.3%, respectively; unadjusted risk difference = 3.3%; 95% CI, –0.5 to 7.2).
Dose comparisons
“There was no advantage of increasing the dose to 0.4 mg/kg,” Campbell said during the presentation. “However, these data are reassuring that there’s a window of safety. We are generally estimating the weight in patients, and if we inadvertently overestimate the weight, this would suggest there is a window of safety from the 0.25 [mg/kg] to the 0.4 mg/kg dose. I would argue that the 0.25 mg/kg dose is likely the most appropriate for stroke.” – by Darlene Dobkowski
References:
Campbell BCV, et al. LB1. Presented at: International Stroke Conference; Feb. 19-21, 2020; Los Angeles.
Campbell BCV, et al. JAMA. 2020;doi:10.1001/jama.2020.1511.
Disclosures: Campbell reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.
Editor’s Note: This article was updated on Feb. 25, 2020 to correct a typo in the range of difference in the primary outcome. The Editors regret the error.
Perspective
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Philip B. Gorelick, MD, MPH
In 300 acute ischemic stroke patients with large artery occlusions randomized to treatment with tenecteplase 0.25 mg/kg vs. 0.4 mg/kg, there were no statistically significant differences between the two doses for the outcome endpoints substantial reperfusion, modified Rankin Scale, early improvement or death. There were slightly more symptomatic intracranial hemorrhages in the higher-dose treatment group; however, a number of these might be explained away by thrombectomy-related wire perforations.
Tenecteplase is more fibrin specific, cheaper and easier to administer (given by intravenous bolus) compared with alteplase. This study shows that in patients with large artery occlusion and acute ischemic stroke, the lower dose of tenecteplase (0.25 mg/kg) is sufficient and provides a window of safety if the dose is overestimated.
There remains debate about the proper dose of tenecteplase in patients with acute ischemic stroke and who do not have large artery occlusion, though based on the current study, some have argued that the lower dose should be sufficient.
The 2019 management of acute ischemic stroke guidance statement from the American Heart Association (Powers WJ, et al. Stroke. 2019;doi:10.1161/STR.0000000000000211) mentions use of tenecteplase in acute stroke treatment, and readers are advised to review the guideline.
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