Abstract
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
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Details
1 Western General Hospital, The IST-3 Co-ordinating Centre, Neurosciences Trial Unit, Edinburgh, UK (GRID:grid.417068.c) (ISNI:0000000406249907)
2 Sydney Medical School - Westmead and The George Institute for Global Health, University of Sydney, Discipline of Medicine, Australia (GRID:grid.1013.3) (ISNI:000000041936834X)
3 Royal Hallamshire Hospital, Neurology Department, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK (GRID:grid.416126.6) (ISNI:0000000406416031)
4 Institute of Psychiatry and Neurology, Medical University of Warsaw, 2nd Department of Neurology, Department of Experimental and Clinical Pharmacology, Warsaw, Poland (GRID:grid.416126.6)
5 Oslo University Hospital, Department of Internal Medicine, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000000403898485)
6 Karolinska Institutet, Danderyd Hospital, Department of Clinical Sciences, Stockholm, Sweden (GRID:grid.55325.34)
7 Cliniques universitaires Saint-Luc, Service de neurologie, Bruxelles, Belgium (GRID:grid.48769.34) (ISNI:0000000404616320)
8 Royal Perth Hospital, Department of Neurology, Perth, Australia (GRID:grid.416195.e) (ISNI:0000000404533875)
9 Landesklinikum Donauregion Tulln, Neurologische Abteilung, Tulln, Austria (GRID:grid.416195.e)
10 UO Neurologia, Citta' di Castello, Italy (GRID:grid.416195.e)
11 Azienda Ospedaliera di, S C di Neurofisiopatologia, Perugia, Italy (GRID:grid.417287.f) (ISNI:0000000417603158)
12 Dalhousie University and Queen Elizabeth II Health Sciences Centre, Halifax Infirmary, Division of Neurology, Halifax, Canada (GRID:grid.55602.34) (ISNI:0000000419368200)
13 Instituto Nacional de Neurologia, Mexico, Mexico (GRID:grid.419204.a) (ISNI:0000000086375954)
14 Hospital Geral de Santo Antonio, Neurology Department, Porto, Portugal (GRID:grid.413438.9) (ISNI:0000000405745247)
15 University Hospital Basel, Department of Neurology, Basel, Switzerland (GRID:grid.410567.1)
16 Royal Sussex County Hospital, Stroke Unit, Brighton, UK (GRID:grid.416225.6) (ISNI:0000000086107239)
17 Uppsala University Hospital, Neurology, Institute of Neuroscience, Uppsala, Sweden (GRID:grid.412354.5) (ISNI:0000000123513333)