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)

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).