lancet-header

Preprints with The Lancet is a collaboration between The Lancet Group of journals and SSRN to facilitate the open sharing of preprints for early engagement, community comment, and collaboration. Preprints available here are not Lancet publications or necessarily under review with a Lancet journal. These preprints are early-stage research papers that have not been peer-reviewed. The usual SSRN checks and a Lancet-specific check for appropriateness and transparency have been applied. The findings should not be used for clinical or public health decision-making or presented without highlighting these facts. For more information, please see the FAQs.

Randomised Trial of Tenectplase Versus Alteplase for Acute Stroke within 4.5h of Onset: The Second Alteplase-Tenecteplase Trial Evaluation for Stroke Thrombolysis (ATTEST-2)

23 Pages Posted: 20 May 2024

See all articles by Keith Muir

Keith Muir

University of Glasgow - Institute of Neuroscience and Psychology

Gary Ford

Government of the United Kingdom - Oxford University Hospitals NHS Foundation Trust

Ian Ford

University of Glasgow

Joanna Wardlaw

University of Edinburgh - Centre for Clinical Brain Sciences; UK Dementia Research Institute - Edinburgh Dementia Research Centre; University of Edinburgh - Edinburgh Imaging

Alex McConnachie

University of Glasgow - Robertson Institute of Biostatistics and Clinical Trials Unit

Nicola Greenlaw

University of Glasgow

Grant Mair

University of Edinburgh - Centre for Clinical Brain Sciences

Nikola Sprigg

University of Nottingham

Christopher I. Price

University of Newcastle

Mary J. Macleod

University of Aberdeen - Medical Sciences and Nutrition

Sofia Dima

Royal Victoria Infirmary

Marius Venter

Imperial College London - Charing Cross Hospital

Liqun Zhang

NHS Foundation Trust - St. Georges University Hospitals

Eoin O’Brien

NHS Foundation Trust - Addenbrooke's Hospital

Ranjan Sanyal

Government of the United Kingdom - University Hospitals of North Midlands

John Reid

Aberdeen Royal Infirmary

Laszlo Sztriha

King’s College Hospital NHS Foundation Trust

Syed Haider

Countess of Chester NHS Foundation Trust

William N. Whiteley

University of Edinburgh

James Kennedy

University of Oxford

Richard Perry

University College London

Sekaran Lakshmanan

Government of the United Kingdom - Luton and Dunstable University Hospital

Annie Chakrabarti

Norfolk and Norwich University Hospital

Ahamad Hassan

Leeds General Infirmary - Department of Neurology

Richard Marigold

University of Southampton - Southampton General Hospital

Senthil Raghunathan

Nottingham University Hospitals NHS Trust

Don Sims

The Queen Elizabeth Hospital

Mohit Bhandari

Watford General Hospital

Ivan Wiggam

Royal Victoria Hospital

Khalid Rashed

Taunton & Somerset NHS Foundation Trust

Chris Douglass

Manchester Centre for Clinical Neurosciences

ATTEST-2 Investigators

Independent

More...

Abstract

Background: Tenecteplase has potential benefits over alteplase, the standard agent for intravenous thrombolysis in acute ischaemic stroke, because it is administered as a single bolus and might have superior efficacy. ATTEST-2 investigated whether tenecteplase 0.25mg/kg was non-inferior or superior to alteplase 0.9mg/kg within 4.5h of onset.

Methods: We undertook a prospective, multicentre, randomised parallel group open label trial with blinded end-point evaluation in previously independent adults eligible for intravenous thrombolysis <4.5h from symptom onset. Participants were randomised 1:1 to alteplase or tenecteplase. The primary endpoint was the distribution of the day 90 modified Rankin Scale (mRS). Secondary endpoints included excellent (mRS 0-1) and independent (mRS 0-2) recovery, major early neurological improvement, health-related quality of life and whether endovascular thrombectomy was required. We tested the primary outcome for non-inferiority (odds ratio for tenecteplase versus alteplase non-inferiority limit of 0.75), and for superiority if non-inferiority was confirmed. Safety outcomes were mortality, symptomatic intracranial haemorrhage (SICH), radiological intracranial haemorrhage and major extracranial bleeding.

Findings: Between Jan 2017 and May 2023, 1,858 patients were randomised at 39 UK centres.  1,777 patients received study drug;  885 were allocated tenecteplase and 892 alteplase. At randomisation, mean age was 70 years, median NIHSS was 7. Large vessel occlusion was present in 18.7% and 12.4% underwent thrombectomy. Tenecteplase was non-inferior to alteplase for both mRS distribution (odds ratio [95% Confidence Interval] 1.07 [0.90, 1.27], pnoninferiority<0.0001; absolute increase in mRS 0-1, 2.0% [-2.7, 6.8], p=0.002). Tenecteplase was not superior on the primary or any secondary outcome. Death occurred in 68 (7.7%) tenecteplase-treated compared to 75 (8.4%) alteplase-treated patients (OR 0.96, 95% Cis 0.69, 1.33, p=0.79) and SICH in 20 (2.3%) tenecteplase versus 15 (1.7%) alteplase-treated patients (OR 1.37, 95% Cis 0.69, 2.70, p=0.36).

Interpretation: Tenecteplase 0.25mg/kg was non-inferior to 0.9 mg/kg alteplase within 4.5h of symptom onset in acute ischaemic stroke.

Trial Registration: Registered on clinicaltrials.gov (NCT02814409).

Funding: The Stroke Association and British Heart Foundation.

Declaration of Interest: Keith W Muir – Lecture fees, Advisory Board fees from Boehringer Ingelheim; lecture fees from Brainomix, IschemaView; Consultancy fees Abbvie, Biogen, Hyperfine, Lumosa, Woolsey Pharma. Gary A Ford – Personal remuneration for advisory board/steering committee activity from CSLBehring, educational activities from Bayer His employer has received remuneration for consultancy with AstraZeneca. Ian Ford – Research grants to University from The Stroke Association and British Heart Foundation Joanna M Wardlaw – academic research grants but no industry, advisory or speaker fees or stock interests.. Alex McConnachie - Research grants to the University from The Stroke Association and British Heart Foundation. Nicola Greenlaw – Research grants to the University from The Stroke Association and British Heart Foundation. Grant Mair – Personal remuneration for consultancy with Canon Medical Research Europe Ltd. Nikola Sprigg – none. Christopher I. Price – none. Mary Joan MacLeod – Advisory board and educational meeting remuneration from Astra Zeneca. Sofia Dima – none. Marius Venter – none. Liqun Zhang – none. Eoin O’Brien – none. Ranjan Sanyal - none. John Reid – none. Laslo Sztriha – none. Syed Haider - none. Will Whiteley - ESOC guideline for thrombolysis; DMC for TEMPO-2. James Kennedy – none. Richard Perry – none. Sekaran Lakshmanan – none. Annie Chakrabarti – none. Ahamad Hassan – Clinical Advisor to Peninsula Technology Assessment Group, University of Exeter Medical School (External Advisory Group NICE Technology Appraisal of Tenecteplase for treating acute ischaemic stroke, ID6306)- Unpaid. Richard Marigold – none. Senthil Raghunathan – none. Don Sims - none. Mohit Bhandari -Research meeting remuneration for LIBREXIA from Janssen & Bristol Myers Squibb. Ivan Wiggam - none. Khalid Rashed - none. Chris Douglass - none.

Ethical Approval: The trial was approved by Scotland A Research Ethics Committee (ref 16/SS/0137).

Keywords: stroke, treatment, thrombolysis, tenecteplase, alteplase, randomised controlled trial, clinical trial, acute treatment, reperfusion, ischaemic stroke

Suggested Citation

Muir, Keith and Ford, Gary and Ford, Ian and Wardlaw, Joanna and McConnachie, Alex and Greenlaw, Nicola and Mair, Grant and Sprigg, Nikola and Price, Christopher I. and Macleod, Mary J. and Dima, Sofia and Venter, Marius and Zhang, Liqun and O’Brien, Eoin and Sanyal, Ranjan and Reid, John and Sztriha, Laszlo and Haider, Syed and Whiteley, William N. and Kennedy, James and Perry, Richard and Lakshmanan, Sekaran and Chakrabarti, Annie and Hassan, Ahamad and Marigold, Richard and Raghunathan, Senthil and Sims, Don and Bhandari, Mohit and Wiggam, Ivan and Rashed, Khalid and Douglass, Chris and Investigators, ATTEST-2, Randomised Trial of Tenectplase Versus Alteplase for Acute Stroke within 4.5h of Onset: The Second Alteplase-Tenecteplase Trial Evaluation for Stroke Thrombolysis (ATTEST-2). Available at SSRN: https://ssrn.com/abstract=4831843 or http://dx.doi.org/10.2139/ssrn.4831843

Keith Muir (Contact Author)

University of Glasgow - Institute of Neuroscience and Psychology ( email )

Gary Ford

Government of the United Kingdom - Oxford University Hospitals NHS Foundation Trust ( email )

Ian Ford

University of Glasgow ( email )

Adam Smith Business School
Glasgow, G12 8LE
United Kingdom

Joanna Wardlaw

University of Edinburgh - Centre for Clinical Brain Sciences ( email )

Old College
South Bridge
Edinburgh, Scotland EH8 9JY
United Kingdom

UK Dementia Research Institute - Edinburgh Dementia Research Centre

United Kingdom

University of Edinburgh - Edinburgh Imaging

Edinburgh
United Kingdom

Alex McConnachie

University of Glasgow - Robertson Institute of Biostatistics and Clinical Trials Unit ( email )

Nicola Greenlaw

University of Glasgow ( email )

Adam Smith Business School
Glasgow, G12 8LE
United Kingdom

Grant Mair

University of Edinburgh - Centre for Clinical Brain Sciences ( email )

Nikola Sprigg

University of Nottingham ( email )

Christopher I. Price

University of Newcastle ( email )

Mary J. Macleod

University of Aberdeen - Medical Sciences and Nutrition ( email )

Aberdeen
United Kingdom

Sofia Dima

Royal Victoria Infirmary ( email )

Marius Venter

Imperial College London - Charing Cross Hospital ( email )

London
United Kingdom

Liqun Zhang

NHS Foundation Trust - St. Georges University Hospitals ( email )

Eoin O’Brien

NHS Foundation Trust - Addenbrooke's Hospital ( email )

Ranjan Sanyal

Government of the United Kingdom - University Hospitals of North Midlands ( email )

John Reid

Aberdeen Royal Infirmary ( email )

Aberdeen
United Kingdom

Laszlo Sztriha

King’s College Hospital NHS Foundation Trust ( email )

Syed Haider

Countess of Chester NHS Foundation Trust ( email )

William N. Whiteley

University of Edinburgh

Old College
South Bridge
Edinburgh, EH8 9JY
United Kingdom

James Kennedy

University of Oxford ( email )

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Richard Perry

University College London ( email )

Sekaran Lakshmanan

Government of the United Kingdom - Luton and Dunstable University Hospital ( email )

Luton
United Kingdom

Annie Chakrabarti

Norfolk and Norwich University Hospital ( email )

Ahamad Hassan

Leeds General Infirmary - Department of Neurology ( email )

Richard Marigold

University of Southampton - Southampton General Hospital ( email )

University Rd.
Southampton SO17 1BJ, SO17 1LP
United Kingdom

Senthil Raghunathan

Nottingham University Hospitals NHS Trust ( email )

Nottingham
United Kingdom

Don Sims

The Queen Elizabeth Hospital ( email )

Mohit Bhandari

Watford General Hospital ( email )

United Kingdom

Ivan Wiggam

Royal Victoria Hospital ( email )

Belfast
Ireland

Khalid Rashed

Taunton & Somerset NHS Foundation Trust ( email )

Chris Douglass

Manchester Centre for Clinical Neurosciences ( email )