Bijoy K Menon1, Brian H Buck2, Nishita Singh3, Yan Deschaintre4, Mohammed A Almekhlafi5, Shelagh B Coutts5, Sibi Thirunavukkarasu2, Houman Khosravani6, Ramana Appireddy7, Francois Moreau8, Gord Gubitz9, Aleksander Tkach10, Luciana Catanese11, Dar Dowlatshahi12, George Medvedev13, Jennifer Mandzia14, Aleksandra Pikula15, Jai Shankar16, Heather Williams17, Thalia S Field18, Alejandro Manosalva19, Muzaffar Siddiqui20, Atif Zafar21, Oje Imoukhuede22, Gary Hunter23, Andrew M Demchuk5, Sachin Mishra2, Laura C Gioia4, Shirin Jalini7, Caroline Cayer24, Stephen Phillips9, Elsadig Elamin10, Ashkan Shoamanesh11, Suresh Subramaniam3, Mahesh Kate2, Gregory Jacquin4, Marie-Christine Camden25, Faysal Benali3, Ibrahim Alhabli3, Fouzi Bala3, MacKenzie Horn3, Grant Stotts12, Michael D Hill5, David J Gladstone6, Alexandre Poppe4, Arshia Sehgal3, Qiao Zhang3, Brendan Cord Lethebe26, Craig Doram3, Ayoola Ademola27, Michel Shamy12, Carol Kenney3, Tolulope T Sajobi27, Richard H Swartz6. 1. Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada; Department of Radiology, University of Calgary, Calgary, AB, Canada; Cumming School of Medicine and Department of Community Health Sciences, University of Calgary, Calgary, AB, Canada; Hotchkiss Brain Institute, Calgary, Canada. Electronic address: bkmmenon@ucalgary.ca. 2. Division of Neurology, Department of Medicine, University of Alberta, Edmonton, AB, Canada. 3. Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada. 4. Department of Neurosciences, Université de Montréal, Montreal, QC, Canada; Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, QC, Canada. 5. Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada; Department of Radiology, University of Calgary, Calgary, AB, Canada; Cumming School of Medicine and Department of Community Health Sciences, University of Calgary, Calgary, AB, Canada; Hotchkiss Brain Institute, Calgary, Canada. 6. Department of Medicine (Division of Neurology), Hurvitz Brain Sciences Program, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada. 7. Division of Neurology, Department of Medicine, Queen's University, Kingston, ON, Canada. 8. Université de Sherbrooke, Sherbrooke, QC, Canada. 9. Queen Elizabeth Health Sciences Centre, Halifax, NS, Canada. 10. Kelowna General Hospital, Kelowna, BC, Canada. 11. Hamilton Health Sciences Centre and McMaster University, Hamilton, ON, Canada. 12. Department of Medicine, University of Ottawa and the Ottawa Heart Research Institute, Ottawa, ON, Canada. 13. University of British Columbia and the Fraser Health Authority, New Westminster, BC, Canada. 14. London Health Sciences Centre and Western University, London, ON, Canada. 15. Toronto Western Hospital and the University of Toronto, Toronto, ON, Canada. 16. University of Manitoba, Winnipeg, MB, Canada. 17. Queen Elizabeth Hospital, Charlottetown, PE, Canada. 18. Vancouver Stroke Program and the Division of Neurology, University of British Columbia, Vancouver, BC, Canada. 19. Medicine Hat Regional Hospital, Medicine Hat, AB, Canada. 20. Grey Nuns Community Hospital, Edmonton, AB, Canada. 21. St Michael's Hospital, Toronto, ON, Canada. 22. Red Deer Regional Hospital, Red Deer, AB, Canada. 23. University of Saskatchewan, Saskatoon, SK, Canada. 24. Centre de recherche du CHUS, Centre intégré Universitaire de Santé et des Services Sociaux de l'Estrie, Sherbrooke, QC, Canada. 25. Enfant-Jésus Hospital, Centre Hospitalier Universitaire de Québec, Laval University, Québec City, QC, Canada. 26. Cumming School of Medicine and Department of Community Health Sciences, University of Calgary, Calgary, AB, Canada. 27. Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada; Cumming School of Medicine and Department of Community Health Sciences, University of Calgary, Calgary, AB, Canada.
Abstract
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.
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.