Journal article

The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial

Peter Sandercock, Joanna M Wardlaw, Richard I Lindley, Martin Dennis, Geoff Cohen, Gordon Murray, Karen Innes, Graham Venables, Anna Czlonkowska, Adam Kobayashi, Stefano Ricci, Veronica Murray, Eivind Berge, Karsten Bruins Slot, Graeme J Hankey, Manuel Correia, Andre Peeters, Karl Matz, Phillippe Lyrer, Gord Gubitz Show all



BACKGROUND: Thrombolysis is of net benefit in patients with acute ischaemic stroke, who are younger than 80 years of age and are treated within 4·5 h of onset. The third International Stroke Trial (IST-3) sought to determine whether a wider range of patients might benefit up to 6 h from stroke onset. METHODS: In this international, multicentre, randomised, open-treatment trial, patients were allocated to 0·9 mg/kg intravenous recombinant tissue plasminogen activator (rt-PA) or to control. The primary analysis was of the proportion of patients alive and independent, as defined by an Oxford Handicap Score (OHS) of 0-2 at 6 months. The study is registered, ISRCTN25765518. FINDINGS: 3035 patient..

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Awarded by UK MRC

Awarded by Government of Poland

Awarded by Australian Heart Foundation

Awarded by Australian NHMRC

Awarded by Medical Research Council

Funding Acknowledgements

UK Medical Research Council, Health Foundation UK, Stroke Association UK, Research Council of Norway, Arbetsmarknadens Partners Forsakringsbolag (AFA) Insurances Sweden, Swedish Heart Lung Fund, The Foundation of Marianne and Marcus Wallenberg, Polish Ministry of Science and Education, the Australian Heart Foundation, Australian National Health and Medical Research Council (NHMRC), Swiss National Research Foundation, Swiss Heart Foundation, Assessorato alla Sanita, Regione dell'Umbria, Italy, and Danube University.r EB has received honoraria for lectures at meetings arranged by Boehringer Ingelheim, and reimbursement for costs for attending these meetings. AC has received lecture fees and conference travel costs from Boehringer Ingelheim. GB has received honoraria and speaker fees from Boehringer Ingelheim, Sanofi Synthlabo Aventis, Hoffman La Roche, and Novo Nordisk. AK has received lecture fees and conference travel costs from Boehringer Ingelheim. RIL has received payment in his role as conference scientific committee member and for occasional lectures from Boehringer Ingelheim; has attended national stroke meetings organised and funded by Boehringer Ingelheim; and is not a member of any industry advisory boards. PS has received lecture fees (paid to the Division of Clinical Neurosciences, University of Edinburgh) and travel expenses from Boehringer Ingelheim for occasional lectures given at international conferences; and was a member of the Independent Data and Safety Monitoring Board (DSMB) of the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial funded by Boehringer Ingelheim and received attendance fees and travel expenses for attending DSMB meetings (paid to the Division of Clinical Neurosciences, University of Edinburgh). KBS has received an honorarium for a lecture from Boehringer Ingelheim and had costs for participating in scientific meetings reimbursed; is a member of the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) and the Cardiovascular Working Party. The views expressed in this article are the personal views of KBS and should not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency or one of its committees or working parties. VM has received an unrestricted educational grant for a meeting on thrombolysis in stroke at which IST-3 was discussed. JMW received reimbursement for reading CT scans for European Cooperative Acute Stroke Study III (ECASS III) from Boehringer Ingelheim in the form of funding to her department, the Division of Clinical Neurosciences, University of Edinburgh; is the contact reviewer for the Cochrane systematic reviews of thrombolytic treatment for acute stroke; has attended meetings held by Boehringer Ingelheim as an unpaid independent external adviser during the licensing of rt-PA, but was refunded her travel expenses and the time away from work; has attended and spoken at national and international stroke meetings organised and funded by Boehringer Ingelheim for which she received honoraria and travel expenses; and is director of the Brain Research Imaging Centre for Scotland, which is located within the Department of Clinical Neurosciences at the University of Edinburgh, Edinburgh, Scotland and houses a research MRI scanner, which was funded by the UK Research Councils Joint Research Equipment Initiative, supplemented by grants and donations from various other sources including Novartis, Schering, General Electric, and Boehringer Ingelheim.These commercial sources contributed to the purchase of the scanner, but not the running costs or any individual studies. All other members of the writing committee declare that they have no conflicts of interest.r The IST-3 collaborative group thanks all the patients who participated in the study, and the many individuals not specifically mentioned in the paper who have supported the study. IST-3 is an investigator led trial. The University of Edinburgh and the Lothian Health Board are cosponsors. The start-up phase was supported by a grant from the Stroke Association, UK. The expansion phase was funded by The Health Foundation UK. The main phase of the trial is funded by the following organisations: UK MRC (grant numbers G0400069 and EME 09-800-15) and managed by NIHR on behalf of the MRC-NIHR partnership; The Research Council of Norway; AFA Insurances (Sweden); the Swedish Heart Lung Fund; The Foundation of Marianne and Marcus Wallenberg; Stockholm County Council and Karolinska Institute Joint ALF-project grants (Sweden); the Government of Poland (grant number 2PO5B10928); the Australian Heart Foundation (grant number G 04S 1638); Australian NHMRC (grant number 457343); the Swiss National Research Foundation; the Swiss Heart Foundation; Foundation for health and cardio-/neurovascular research, Basel, Switzerland; the Assessorato alla Sanita, Regione dell'Umbria; Danube University, Krems, Austria. Drug and placebo for the 300 patients in the double-blind component of the start-up phase were supplied by Boehringer Ingelheim. We thank the NIHR Stroke Research Network, NHS Research Scotland, through the Scottish Stroke Research Network, and the National Institute for Social Care and Health Research Clinical Research Centre for their support. The imaging work was undertaken at the Brain Imaging Research Centre, a member of the SINAPSE collaboration, at the Division of Clinical Neurosciences, University of Edinburgh. SINAPSE is funded by the Scottish Funding Council and the Chief Scientist Office of the Scottish Executive. Additional support was received from Chest Heart and Stroke Scotland, DesAcc, University of Edinburgh, Danderyd Hospital R&D Department, Karolinska Institutet, Oslo University Hospital, and the Dalhousie University Internal Medicine Research Fund. This report presents independent research supported by the NIHR through the UK Stroke Research Network. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health.