Tenecteplase versus standard of care for minor ischaemic stroke with proven occlusion (TEMPO-2): a randomised, open label, phase 3 superiority trial

TEMPO-2 investigators

doi:10.1016/S0140-6736(24)00921-8

Tenecteplase versus standard of care for minor ischaemic stroke with proven occlusion (TEMPO-2): a randomised, open label, phase 3 superiority trial

TEMPO-2 investigators

Information Studies

University of Calgary
King's College London
Queen's University Kingston
Hospital Clínico Universitario de Valladolid
University of Valladolid
Foothills Medical Centre
Alberta Children's Hospital
Griffith University
Universidade Estadual Paulista Júlio de Mesquita Filho
University of Alberta
University of New South Wales
Université Laval
University of Melbourne
University Health Network–Toronto Western Hospital
Population Health Research Institute, Ontario
Countess of Chester Hospital NHS Foundation Trust
Box Hill Hospital
Monash University
St George's University Hospitals NHS Foundation Trust
University of Ottawa
St John's of God Hospital Vienna
University of British Columbia
University of Western Australia
Medical University of Vienna
Imperial College Healthcare Trust
University of Saskatchewan
Red Deer Regional Hospital Centre
University College Dublin
University of Oxford
Royal Adelaide Hospital
University of Adelaide
Queen's Medical Centre
Hospital Geral De Fortaleza
Western University
Hospital Moinhos de Vento
Hospital Vall d'Hebron
McGill University
University of Glasgow
Victoria General Hospital
Universidade de São Paulo
Keele University
Fundació Institut d'Investigació Biomèdica de Girona Dr Josep Trueta
University College Hospitals London
University of Manitoba
University of Newcastle
John Hunter Hospital
Helsinki University Hospital
National Neuroscience Institute of Singapore
Royal Victoria Hospital Belfast
Royal College of Surgeons in Ireland
University Hospitals Birmingham NHS Trust
Christchurch Hospital New Zealand
Sunnybrook Health Sciences Centre
Cambridge University Hospitals NHS Trust
University of Toronto
Städtisches Klinikum Dresden

Research output: Contribution to journal › Article › peer-review

107 Scopus citations

Abstract

BACKGROUND: Individuals with minor ischaemic stroke and intracranial occlusion are at increased risk of poor outcomes. Intravenous thrombolysis with tenecteplase might improve outcomes in this population. We aimed to test the superiority of intravenous tenecteplase over non-thrombolytic standard of care in patients with minor ischaemic stroke and intracranial occlusion or focal perfusion abnormality.

METHODS: In this multicentre, prospective, parallel group, open label with blinded outcome assessment, randomised controlled trial, adult patients (aged ≥18 years) were included at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the UK. Eligible patients with minor acute ischaemic stroke (National Institutes of Health Stroke Scale score 0-5) and intracranial occlusion or focal perfusion abnormality were enrolled within 12 h from stroke onset. Participants were randomly assigned (1:1), using a minimal sufficient balance algorithm to intravenous tenecteplase (0·25 mg/kg) or non-thrombolytic standard of care (control). Primary outcome was a return to baseline functioning on pre-morbid modified Rankin Scale score in the intention-to-treat (ITT) population (all patients randomly assigned to a treatment group and who did not withdraw consent to participate) assessed at 90 days. Safety outcomes were reported in the ITT population and included symptomatic intracranial haemorrhage and death. This trial is registered with ClinicalTrials.gov, NCT02398656, and is closed to accrual.

FINDINGS: The trial was stopped early for futility. Between April 27, 2015, and Jan 19, 2024, 886 patients were enrolled; 369 (42%) were female and 517 (58%) were male. 454 (51%) were assigned to control and 432 (49%) to intravenous tenecteplase. The primary outcome occurred in 338 (75%) of 452 patients in the control group and 309 (72%) of 432 in the tenecteplase group (risk ratio [RR] 0·96, 95% CI 0·88-1·04, p=0·29). More patients died in the tenecteplase group (20 deaths [5%]) than in the control group (five deaths [1%]; adjusted hazard ratio 3·8; 95% CI 1·4-10·2, p=0·0085). There were eight (2%) symptomatic intracranial haemorrhages in the tenecteplase group versus two (<1%) in the control group (RR 4·2; 95% CI 0·9-19·7, p=0·059).

INTERPRETATION: There was no benefit and possible harm from treatment with intravenous tenecteplase. Patients with minor stroke and intracranial occlusion should not be routinely treated with intravenous thrombolysis.

FUNDING: Heart and Stroke Foundation of Canada, Canadian Institutes of Health Research, and the British Heart Foundation.

Original language	English
Pages (from-to)	2597-2605
Number of pages	9
Journal	The Lancet
Volume	403
Issue number	10444
DOIs	https://doi.org/10.1016/S0140-6736(24)00921-8
State	Published - Jun 15 2024

Keywords

Aged
Female
Fibrinolytic Agents/therapeutic use
Humans
Ischemic Stroke/drug therapy
Male
Middle Aged
Prospective Studies
Standard of Care
Tenecteplase/therapeutic use
Thrombolytic Therapy/methods
Tissue Plasminogen Activator/therapeutic use
Treatment Outcome

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10.1016/S0140-6736(24)00921-8

Cite this

@article{f44e92d7c22a4ef7914c80c3b47093d3,

title = "Tenecteplase versus standard of care for minor ischaemic stroke with proven occlusion (TEMPO-2): a randomised, open label, phase 3 superiority trial",

abstract = "BACKGROUND: Individuals with minor ischaemic stroke and intracranial occlusion are at increased risk of poor outcomes. Intravenous thrombolysis with tenecteplase might improve outcomes in this population. We aimed to test the superiority of intravenous tenecteplase over non-thrombolytic standard of care in patients with minor ischaemic stroke and intracranial occlusion or focal perfusion abnormality.METHODS: In this multicentre, prospective, parallel group, open label with blinded outcome assessment, randomised controlled trial, adult patients (aged ≥18 years) were included at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the UK. Eligible patients with minor acute ischaemic stroke (National Institutes of Health Stroke Scale score 0-5) and intracranial occlusion or focal perfusion abnormality were enrolled within 12 h from stroke onset. Participants were randomly assigned (1:1), using a minimal sufficient balance algorithm to intravenous tenecteplase (0·25 mg/kg) or non-thrombolytic standard of care (control). Primary outcome was a return to baseline functioning on pre-morbid modified Rankin Scale score in the intention-to-treat (ITT) population (all patients randomly assigned to a treatment group and who did not withdraw consent to participate) assessed at 90 days. Safety outcomes were reported in the ITT population and included symptomatic intracranial haemorrhage and death. This trial is registered with ClinicalTrials.gov, NCT02398656, and is closed to accrual.FINDINGS: The trial was stopped early for futility. Between April 27, 2015, and Jan 19, 2024, 886 patients were enrolled; 369 (42\%) were female and 517 (58\%) were male. 454 (51\%) were assigned to control and 432 (49\%) to intravenous tenecteplase. The primary outcome occurred in 338 (75\%) of 452 patients in the control group and 309 (72\%) of 432 in the tenecteplase group (risk ratio [RR] 0·96, 95\% CI 0·88-1·04, p=0·29). More patients died in the tenecteplase group (20 deaths [5\%]) than in the control group (five deaths [1\%]; adjusted hazard ratio 3·8; 95\% CI 1·4-10·2, p=0·0085). There were eight (2\%) symptomatic intracranial haemorrhages in the tenecteplase group versus two (<1\%) in the control group (RR 4·2; 95\% CI 0·9-19·7, p=0·059).INTERPRETATION: There was no benefit and possible harm from treatment with intravenous tenecteplase. Patients with minor stroke and intracranial occlusion should not be routinely treated with intravenous thrombolysis.FUNDING: Heart and Stroke Foundation of Canada, Canadian Institutes of Health Research, and the British Heart Foundation.",

keywords = "Aged, Female, Fibrinolytic Agents/therapeutic use, Humans, Ischemic Stroke/drug therapy, Male, Middle Aged, Prospective Studies, Standard of Care, Tenecteplase/therapeutic use, Thrombolytic Therapy/methods, Tissue Plasminogen Activator/therapeutic use, Treatment Outcome",

author = "\{TEMPO-2 investigators\} and Coutts, \{Shelagh B.\} and Sandeep Ankolekar and Ramana Appireddy and Arenillas, \{Juan F.\} and Zarina Assis and Peter Bailey and Barber, \{Philip A.\} and Rodrigo Bazan and Buck, \{Brian H.\} and Butcher, \{Ken S.\} and Camden, \{Marie Christine\} and Campbell, \{Bruce C.V.\} and Casaubon, \{Leanne K.\} and Luciana Catanese and Kausik Chatterjee and Choi, \{Philip M.C.\} and Brian Clarke and Dar Dowlatshahi and Julia Ferrari and Field, \{Thalia S.\} and Aravind Ganesh and Darshan Ghia and Mayank Goyal and Stefan Greisenegger and Omid Halse and Mackenzie Horn and Gary Hunter and Oje Imoukhuede and Kelly, \{Peter J.\} and James Kennedy and Carol Kenney and Kleinig, \{Timothy J.\} and Kailash Krishnan and Fabricio Lima and Mandzia, \{Jennifer L.\} and Martha Marko and Martins, \{Sheila O.\} and George Medvedev and Menon, \{Bijoy K.\} and Mishra, \{Sachin M.\} and Carlos Molina and Aimen Moussaddy and Muir, \{Keith W.\} and Parsons, \{Mark W.\} and Penn, \{Andrew M.W.\} and Arthur Pille and Pontes-Neto, \{Oct{\'a}vio M.\} and Christine Roffe and Joaquin Serena and L. Smith",

year = "2024",

month = jun,

day = "15",

doi = "10.1016/S0140-6736(24)00921-8",

language = "English",

volume = "403",

pages = "2597--2605",

journal = "The Lancet",

issn = "0140-6736",

publisher = "Elsevier B.V.",

number = "10444",

}

TY - JOUR

T1 - Tenecteplase versus standard of care for minor ischaemic stroke with proven occlusion (TEMPO-2)

T2 - a randomised, open label, phase 3 superiority trial

AU - TEMPO-2 investigators

AU - Coutts, Shelagh B.

AU - Ankolekar, Sandeep

AU - Appireddy, Ramana

AU - Arenillas, Juan F.

AU - Assis, Zarina

AU - Bailey, Peter

AU - Barber, Philip A.

AU - Bazan, Rodrigo

AU - Buck, Brian H.

AU - Butcher, Ken S.

AU - Camden, Marie Christine

AU - Campbell, Bruce C.V.

AU - Casaubon, Leanne K.

AU - Catanese, Luciana

AU - Chatterjee, Kausik

AU - Choi, Philip M.C.

AU - Clarke, Brian

AU - Dowlatshahi, Dar

AU - Ferrari, Julia

AU - Field, Thalia S.

AU - Ganesh, Aravind

AU - Ghia, Darshan

AU - Goyal, Mayank

AU - Greisenegger, Stefan

AU - Halse, Omid

AU - Horn, Mackenzie

AU - Hunter, Gary

AU - Imoukhuede, Oje

AU - Kelly, Peter J.

AU - Kennedy, James

AU - Kenney, Carol

AU - Kleinig, Timothy J.

AU - Krishnan, Kailash

AU - Lima, Fabricio

AU - Mandzia, Jennifer L.

AU - Marko, Martha

AU - Martins, Sheila O.

AU - Medvedev, George

AU - Menon, Bijoy K.

AU - Mishra, Sachin M.

AU - Molina, Carlos

AU - Moussaddy, Aimen

AU - Muir, Keith W.

AU - Parsons, Mark W.

AU - Penn, Andrew M.W.

AU - Pille, Arthur

AU - Pontes-Neto, Octávio M.

AU - Roffe, Christine

AU - Serena, Joaquin

AU - Smith, L.

PY - 2024/6/15

Y1 - 2024/6/15

N2 - BACKGROUND: Individuals with minor ischaemic stroke and intracranial occlusion are at increased risk of poor outcomes. Intravenous thrombolysis with tenecteplase might improve outcomes in this population. We aimed to test the superiority of intravenous tenecteplase over non-thrombolytic standard of care in patients with minor ischaemic stroke and intracranial occlusion or focal perfusion abnormality.METHODS: In this multicentre, prospective, parallel group, open label with blinded outcome assessment, randomised controlled trial, adult patients (aged ≥18 years) were included at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the UK. Eligible patients with minor acute ischaemic stroke (National Institutes of Health Stroke Scale score 0-5) and intracranial occlusion or focal perfusion abnormality were enrolled within 12 h from stroke onset. Participants were randomly assigned (1:1), using a minimal sufficient balance algorithm to intravenous tenecteplase (0·25 mg/kg) or non-thrombolytic standard of care (control). Primary outcome was a return to baseline functioning on pre-morbid modified Rankin Scale score in the intention-to-treat (ITT) population (all patients randomly assigned to a treatment group and who did not withdraw consent to participate) assessed at 90 days. Safety outcomes were reported in the ITT population and included symptomatic intracranial haemorrhage and death. This trial is registered with ClinicalTrials.gov, NCT02398656, and is closed to accrual.FINDINGS: The trial was stopped early for futility. Between April 27, 2015, and Jan 19, 2024, 886 patients were enrolled; 369 (42%) were female and 517 (58%) were male. 454 (51%) were assigned to control and 432 (49%) to intravenous tenecteplase. The primary outcome occurred in 338 (75%) of 452 patients in the control group and 309 (72%) of 432 in the tenecteplase group (risk ratio [RR] 0·96, 95% CI 0·88-1·04, p=0·29). More patients died in the tenecteplase group (20 deaths [5%]) than in the control group (five deaths [1%]; adjusted hazard ratio 3·8; 95% CI 1·4-10·2, p=0·0085). There were eight (2%) symptomatic intracranial haemorrhages in the tenecteplase group versus two (<1%) in the control group (RR 4·2; 95% CI 0·9-19·7, p=0·059).INTERPRETATION: There was no benefit and possible harm from treatment with intravenous tenecteplase. Patients with minor stroke and intracranial occlusion should not be routinely treated with intravenous thrombolysis.FUNDING: Heart and Stroke Foundation of Canada, Canadian Institutes of Health Research, and the British Heart Foundation.

AB - BACKGROUND: Individuals with minor ischaemic stroke and intracranial occlusion are at increased risk of poor outcomes. Intravenous thrombolysis with tenecteplase might improve outcomes in this population. We aimed to test the superiority of intravenous tenecteplase over non-thrombolytic standard of care in patients with minor ischaemic stroke and intracranial occlusion or focal perfusion abnormality.METHODS: In this multicentre, prospective, parallel group, open label with blinded outcome assessment, randomised controlled trial, adult patients (aged ≥18 years) were included at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the UK. Eligible patients with minor acute ischaemic stroke (National Institutes of Health Stroke Scale score 0-5) and intracranial occlusion or focal perfusion abnormality were enrolled within 12 h from stroke onset. Participants were randomly assigned (1:1), using a minimal sufficient balance algorithm to intravenous tenecteplase (0·25 mg/kg) or non-thrombolytic standard of care (control). Primary outcome was a return to baseline functioning on pre-morbid modified Rankin Scale score in the intention-to-treat (ITT) population (all patients randomly assigned to a treatment group and who did not withdraw consent to participate) assessed at 90 days. Safety outcomes were reported in the ITT population and included symptomatic intracranial haemorrhage and death. This trial is registered with ClinicalTrials.gov, NCT02398656, and is closed to accrual.FINDINGS: The trial was stopped early for futility. Between April 27, 2015, and Jan 19, 2024, 886 patients were enrolled; 369 (42%) were female and 517 (58%) were male. 454 (51%) were assigned to control and 432 (49%) to intravenous tenecteplase. The primary outcome occurred in 338 (75%) of 452 patients in the control group and 309 (72%) of 432 in the tenecteplase group (risk ratio [RR] 0·96, 95% CI 0·88-1·04, p=0·29). More patients died in the tenecteplase group (20 deaths [5%]) than in the control group (five deaths [1%]; adjusted hazard ratio 3·8; 95% CI 1·4-10·2, p=0·0085). There were eight (2%) symptomatic intracranial haemorrhages in the tenecteplase group versus two (<1%) in the control group (RR 4·2; 95% CI 0·9-19·7, p=0·059).INTERPRETATION: There was no benefit and possible harm from treatment with intravenous tenecteplase. Patients with minor stroke and intracranial occlusion should not be routinely treated with intravenous thrombolysis.FUNDING: Heart and Stroke Foundation of Canada, Canadian Institutes of Health Research, and the British Heart Foundation.

KW - Aged

KW - Female

KW - Fibrinolytic Agents/therapeutic use

KW - Humans

KW - Ischemic Stroke/drug therapy

KW - Male

KW - Middle Aged

KW - Prospective Studies

KW - Standard of Care

KW - Tenecteplase/therapeutic use

KW - Thrombolytic Therapy/methods

KW - Tissue Plasminogen Activator/therapeutic use

KW - Treatment Outcome

UR - https://www.scopus.com/pages/publications/85194580885

U2 - 10.1016/S0140-6736(24)00921-8

DO - 10.1016/S0140-6736(24)00921-8

M3 - Article

C2 - 38768626

AN - SCOPUS:85194580885

SN - 0140-6736

VL - 403

SP - 2597

EP - 2605

JO - The Lancet

JF - The Lancet

IS - 10444

ER -

Tenecteplase versus standard of care for minor ischaemic stroke with proven occlusion (TEMPO-2): a randomised, open label, phase 3 superiority trial

Abstract

Keywords

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