Menon BK, Buck BH, Singh N, et al. Intravenous tenecteplase compared with alteplase for acute ischaemic stroke in Canada (AcT): a pragmatic, multicentre, open-label, registry-linked, randomised, controlled, non-inferiority trial. Lancet. 2022 Jul 16;400(10347):161-169. doi: 10.1016/S0140-6736(22)01054-6. Epub 2022 Jun 29. (Original study)

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.

FUNDING: Canadian Institutes of Health Research, Alberta Strategy for Patient Oriented Research Support Unit.

Discipline Area Score
Emergency Medicine 6 / 7
Neurology 6 / 7
Hemostasis and Thrombosis 6 / 7
Hospital Doctor/Hospitalists 5 / 7
Internal Medicine 5 / 7
Comments from MORE raters

Emergency Medicine rater

While it is 'useful' to be able to quote the result of an RCT that shows that intravenous tenecteplase compared with alteplase for acute ischaemic stroke is not inferior with regard to outcome and side effects, this does not matter to most practicing emergency physicians. These days, acute stroke treatment is subject to institution-specific protocols. Few emergency physicians are able to change the institutional protocol at their discretion. Therefore, these study results probably don't have direct relevance to EM care.

Emergency Medicine rater

This large trial comparing tenecteplase to alteplase for acute stroke found no differences in clinical outcomes, bleeding, or other complications. This is consistent with the other large completed phase 3 trial, NOR-TEST. Tenecteplase may be easier to administer and cost less, but the authors conclusion that this provides "compelling rationale" to change protocols to tenecteplase from alteplase is overstated. This is especially so since at least one other phase 3 trial (NOR-TEST2) was stopped early for harm in the tenecteplase arm, and there are no compelling trial results suggesting superior outcomes with tenecteplase. A placebo arm would be beneficial in future trials as there are still many more negative alteplase studies in acute stroke than positive ones, and there remains reason to be skeptical that any thrombolytic provides true net benefit in acute stroke.

Emergency Medicine rater

This well done RCT compared alteplase and tenectaplase for stroke given within 4.5 hours of symptom onset. The trial was done over about 2 years in 22 Canadian centers enrolling 1600 patients, of whom 1577 were included in the intention-to-treat analysis. The end point of a modified Rankin score of 0-1 was reached by 36·9% of patients in the tenecteplase group compared with 34·8% in the alteplase group. The difference was less than the prestudy non-inferiority 5%, so the conclusion was no difference between the two treatments. There was no statistically significant difference between the two treatments in terms of intracranial hemorrhage or mortality.

Internal Medicine rater

Nice trial. Not a big surprise, though, that tenectplase works just as well as alteplase as a thrombolysis agent in acute ischemic stroke. I have one serious critical point. The authors' aim according to the abstract was to "determine whether tenecteplase given as a single bolus might increase reperfusion compared with this standard of care." If this is true, it seems irrational to focus on the non-inferiority-analysis.

Neurology rater

This large pragmatic trial of tenecteplase versus alteplase in acute ischemic stroke showed that tenecteplase at a dose of .25 mg/kg was non-inferior to alteplase in excellent outcomes (modified Rankin Scale of 0 to 1). Because it is more convenient to give a bolus rather than an infusion, tenecteplase will likely be the thrombolytic of choice for acute ischemic stroke in the future.
Comments from EvidenceAlerts subscribers

Dr. paul ransom (7/9/2022 5:57 AM)

The elephant in the room is that neither intervention, tenecteplase or alteplase, has a successful track record over the past 30 years. A long and inglorious history of failed trials, large amounts of drug company money, and wishful thinking attest tothe failure of trying to make thrombolysis for acute stroke follow the paradigm of thrombolysis for acute MI. Brain tissue is not heart muscle. Clots in coronary arteries are not the same as most clots in brain arteries. This trial should have added in a non-intervention group that, based on the evidence conducted by a truly impartial assessor of the functional score, would have done at least as well as either of these groups, or probably better.