Resumen
Background: Intravenous recombinant tissue plasminogen activator (rtPA) is approved in Europe for use in patients with acute ischaemic stroke who meet strictly defined criteria. IST-3 sought to improve the external validity and precision of the estimates of the overall treatment effects (efficacy and safety) of rtPA in acute ischaemic stroke, and to determine whether a wider range of patients might benefit.Design: International, multi-centre, prospective, randomized, open, blinded endpoint (PROBE) trial of intravenous rtPA in acute ischaemic stroke. Suitable patients had to be assessed and able to start treatment within 6 hours of developing symptoms, and brain imaging must have excluded intracranial haemorrhage and stroke mimics.Results: The initial pilot phase was double blind and then, on 01/08/2003, changed to an open design. Recruitment began on 05/05/2000 and closed on 31/07/2011, by which time 3035 patients had been included, only 61 (2%) of whom met the criteria for the 2003 European approval for thrombolysis. 1617 patients were aged over 80 years at trial entry. The analysis plan will be finalised, without reference to the unblinded data, and published before the trial data are unblinded in early 2012. The main trial results will be presented at the European Stroke Conference in Lisbon in May 2012 with the aim to publish simultaneously in a peer-reviewed journal. The trial result will be presented in the context of an updated Cochrane systematic review. We also intend to include the trial data in an individual patient data meta-analysis of all the relevant randomised trials.Conclusion: The data from the trial will: improve the external validity and precision of the estimates of the overall treatment effects (efficacy and safety) of iv rtPA in acute ischaemic stroke; provide: new evidence on the balance of risk and benefit of intravenous rtPA among types of patients who do not clearly meet the terms of the current EU approval; and, provide the first large-scale randomised evidence on effects in patients over 80, an age group which had largely been excluded from previous acute stroke trials.Trial registration: ISRCTN25765518.
| Idioma original | English |
|---|---|
| Número de artículo | 252 |
| Publicación | Trials |
| Volumen | 12 |
| DOI | |
| Estado | Published - nov. 30 2011 |
| Publicado de forma externa | Sí |
Nota bibliográfica
Funding Information:The IST-3 collaborative group wishes chiefly to acknowledge the support of 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 co-sponsors. 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: UK MRC 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, the Australian Heart Foundation, Australian NHMRC, the National Heart Foundation Australia, the Swiss National Research Foundation, the Swiss Heart Foundation, Foundation for health and cardio-/ neurovascular research, Basel, Switzerland and the Assessorato alla Sanita, Regione dell’Umbria. Drug and placebo for the 300 patients in the double-blind component of the start-up phase were supplied by Boehringer-Ingelheim GMBh. IST-3 acknowledges the extensive support of the NIHR Stroke Research Network, NHS Research Scotland (NRS), through the Scottish Stroke Research Network, and the National Institute for Social Care and Health Research Clinical Research Centre (NISCHR CRC). The imaging work was undertaken at the Brain Imaging Research Centre http://www.bric.ed.ac. uk, a member of the SINAPSE collaboration http://www.sinapse.ac.uk, at the Division of Clinical Neurosciences, University of Edinburgh. SINAPSE is funded by the Scottish Funding Council (SFC) and the Chief Scientist Office of the Scottish Executive (CSO). Additional support was received from Chest Heart and Stroke Scotland, Desacc, University of Edinburgh, Danderyd Hospital R&D Department, Karolinska Institutet, the Dalhousie University Internal Medicine Research Fund. The study was designed, conducted, analysed and reported independently of all of the sponsors and funding agencies. Trial Steering Committee Independent Chairman, Professor Colin Baigent (university of Oxford), Professor David Chadwick, (Former Chairman, Retired)): University of Liverpool; Independent members: Dr Pippa Tyrrell (Manchester University), Professor Gordon Lowe (Glasgow University); Co-principal Investigators: Professor Peter Sandercock (Edinburgh University); Professor Richard Lindley (Professor of Geriatric Medicine, University of Sydney); Chief Investigator for Neuroradiology: Professor Joanna Wardlaw (Edinburgh University) Statistician: Geoff Cohen; Trial Manager: Ms Karen Innes. Heather Goodare: lay representative CT reading panel Joanna Wardlaw, Andrew Farrall, Rüdiger von Kummer, Lesley Cala, Anders von Heijne, Zoe Morris, Alessandro Adami, Andre Peeters, Gillian Potter, Nick Brady. Data Monitoring Committee Professor Rory Collins, Oxford University, UK (Chairman), Professor Philip Bath (Nottingham University), Professor Jan van Gijn (former member, now retired) (University of Utrecht, The Netherlands), Professor Richard Gray (University of Oxford), Professor Robert Hart (McMaster University, Canada), Professor Salim Yusuf (McMaster University, Canada). Event Adjudication Committee Keith Muir, Peter Sandercock, Richard Lindley National Co-ordinators and Associate National Co-ordinators Australia: Richard Lindley, Graeme J. Hankey. Austria: Karl Matz, Michael Brainin. Belgium: Andre Peeters. Canada: Gord Gubitz, Stephen Phillips. Italy: Stefano Ricci. Mexico: Antonio Arauz. Norway: Eivind Berge, Karsten Bruins Slot. Poland: Anna Czlonkowska, Adam Kobayashi. Portugal: Manuel Correia. Switzerland: Phillippe Lyrer. Sweden: Veronica Murray, Andreas Terent, Bo Norrving, Per Wester: UK: Graham Venables Trial Coordinating Centre, Edinburgh Karen Innes, Alison Clark, David Perry, Vera Soosay, David Buchanan, Sheila Grant, Eleni Sakka, Jonathan Drever, Pauli Hanley, Indee Herath, Ann Leigh Brown, Paul Chmielnik, Christopher Armit, Andrea Walton, Mischa Hautvast, Steff Lewis, Graeme Heron, Sylvia Odusanya, Pam Linksted, Ingrid Kane, Will Whiteley, Robin Sellar, Philip White, Peter Keston, Andrew Farrell, Zoe Morris, Hector Miranda. National Co-ordinating centres: Italy (up to September 2008) Maria Grazia Celani, Enrico Righetti (after September 2008) Silvia Cenciarelli, Tatiana Mazzoli Central Follow up for Italy: Teresa Anna Cantisani. Poland Jan Bembenek Sweden Eva Isaakson. Norway Eivind Berge, Karsten Bruins Slot. Centres and countries The list of participating centres and the collaborators at each site are listed in additional file 2.
Funding Information:
Reimbursement for reading CT scans for ECASS III from Boehringer Ingelheim; funding to department. Is the contact reviewer for the Cochrane systematic reviews of thrombolytic treatment for acute stroke. Is director of the Brain Research Imaging Centre for Scotland. This is located within the Department of Clinical Neurosciences at the University of Edinburgh. The Centre houses a research magnetic resonance 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, GE and BI. These commercial sources contributed to the purchase of the scanner, but not the running costs or any individual studies. Has attended meetings held by Boehringer Ingelheim during the licencing of rtPA. She attended as an unpaid independent external adviser 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. She is not on any speaker panels or panels of experts nor does she have any paid consultancies with pharmaceutical or imaging manufacturing companies.
ASJC Scopus Subject Areas
- Medicine (miscellaneous)
- Pharmacology (medical)