Update on the third international stroke trial (IST-3) of thrombolysis for acute ischaemic stroke and baseline features of the 3035 patients recruited

Peter Sandercock; Richard Lindley; Joanna Wardlaw; Martin Dennis; Karen Innes; Geoff Cohen; Will Whiteley; David Perry; Vera Soosay; David Buchanan; Graham Venables; Anna Czlonkowska; Adam Kobayashi; Eivind Berge; Karsten Bruins Slot; Veronica Murray; Andre Peeters; Graeme J Hankey; Karl Matz; Michael Brainin; Stefano Ricci; Teresa A Cantisani; Gordon Gubitz; Stephen J Phillips; Arauz Antonio; Manuel Correia; Phillippe Lyrer; Ingrid Kane; Erik Lundstrom; IST-3 Collaborative Group; Phyo Kyaw Myint

doi:10.1186/1745-6215-12-252

Update on the third international stroke trial (IST-3) of thrombolysis for acute ischaemic stroke and baseline features of the 3035 patients recruited

Peter Sandercock, Richard Lindley, Joanna Wardlaw, Martin Dennis, Karen Innes, Geoff Cohen, Will Whiteley, David Perry, Vera Soosay, David Buchanan, Graham Venables, Anna Czlonkowska, Adam Kobayashi, Eivind Berge, Karsten Bruins Slot, Veronica Murray, Andre Peeters, Graeme J Hankey, Karl Matz, Michael BraininStefano Ricci, Teresa A Cantisani, Gordon Gubitz, Stephen J Phillips, Arauz Antonio, Manuel Correia, Phillippe Lyrer, Ingrid Kane, Erik Lundstrom, IST-3 Collaborative Group, Phyo Kyaw Myint

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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: ISRCTN25765518.

Original language	English
Article number	252
Number of pages	10
Journal	Trials
Volume	12
DOIs	https://doi.org/10.1186/1745-6215-12-252
Publication status	Published - 30 Nov 2011

Keywords

acute disease
brain ischemia
double-blind method
fibrinolytic agents
humans
prospective studies
sample size
stroke
thrombolytic therapy
tissue plasminogen activator

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10.1186/1745-6215-12-252

1745-6215-12-252
© 2011 Sandercock et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Sandercock, P., Lindley, R., Wardlaw, J., Dennis, M., Innes, K., Cohen, G., Whiteley, W., Perry, D., Soosay, V., Buchanan, D., Venables, G., Czlonkowska, A., Kobayashi, A., Berge, E., Slot, K. B., Murray, V., Peeters, A., Hankey, G. J., Matz, K., ... Myint, P. K. (2011). Update on the third international stroke trial (IST-3) of thrombolysis for acute ischaemic stroke and baseline features of the 3035 patients recruited. Trials, 12, Article 252. https://doi.org/10.1186/1745-6215-12-252

Sandercock, P, Lindley, R, Wardlaw, J, Dennis, M, Innes, K, Cohen, G, Whiteley, W, Perry, D, Soosay, V, Buchanan, D, Venables, G, Czlonkowska, A, Kobayashi, A, Berge, E, Slot, KB, Murray, V, Peeters, A, Hankey, GJ, Matz, K, Brainin, M, Ricci, S, Cantisani, TA, Gubitz, G, Phillips, SJ, Antonio, A, Correia, M, Lyrer, P, Kane, I, Lundstrom, E, IST-3 Collaborative Group & Myint, PK 2011, 'Update on the third international stroke trial (IST-3) of thrombolysis for acute ischaemic stroke and baseline features of the 3035 patients recruited', Trials, vol. 12, 252. https://doi.org/10.1186/1745-6215-12-252

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title = "Update on the third international stroke trial (IST-3) of thrombolysis for acute ischaemic stroke and baseline features of the 3035 patients recruited",

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: ISRCTN25765518.",

keywords = "acute disease, brain ischemia, double-blind method, fibrinolytic agents, humans, prospective studies, sample size, stroke, thrombolytic therapy, tissue plasminogen activator",

author = "Peter Sandercock and Richard Lindley and Joanna Wardlaw and Martin Dennis and Karen Innes and Geoff Cohen and Will Whiteley and David Perry and Vera Soosay and David Buchanan and Graham Venables and Anna Czlonkowska and Adam Kobayashi and Eivind Berge and Slot, {Karsten Bruins} and Veronica Murray and Andre Peeters and Hankey, {Graeme J} and Karl Matz and Michael Brainin and Stefano Ricci and Cantisani, {Teresa A} and Gordon Gubitz and Phillips, {Stephen J} and Arauz Antonio and Manuel Correia and Phillippe Lyrer and Ingrid Kane and Erik Lundstrom and {IST-3 Collaborative Group} and Myint, {Phyo Kyaw}",

year = "2011",

month = nov,

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doi = "10.1186/1745-6215-12-252",

language = "English",

volume = "12",

journal = "Trials",

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TY - JOUR

T1 - Update on the third international stroke trial (IST-3) of thrombolysis for acute ischaemic stroke and baseline features of the 3035 patients recruited

AU - Sandercock, Peter

AU - Lindley, Richard

AU - Wardlaw, Joanna

AU - Dennis, Martin

AU - Innes, Karen

AU - Cohen, Geoff

AU - Whiteley, Will

AU - Perry, David

AU - Soosay, Vera

AU - Buchanan, David

AU - Venables, Graham

AU - Czlonkowska, Anna

AU - Kobayashi, Adam

AU - Berge, Eivind

AU - Slot, Karsten Bruins

AU - Murray, Veronica

AU - Peeters, Andre

AU - Hankey, Graeme J

AU - Matz, Karl

AU - Brainin, Michael

AU - Ricci, Stefano

AU - Cantisani, Teresa A

AU - Gubitz, Gordon

AU - Phillips, Stephen J

AU - Antonio, Arauz

AU - Correia, Manuel

AU - Lyrer, Phillippe

AU - Kane, Ingrid

AU - Lundstrom, Erik

AU - IST-3 Collaborative Group

AU - Myint, Phyo Kyaw

PY - 2011/11/30

Y1 - 2011/11/30

N2 - 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.

AB - 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.

KW - acute disease

KW - brain ischemia

KW - double-blind method

KW - fibrinolytic agents

KW - humans

KW - prospective studies

KW - sample size

KW - stroke

KW - thrombolytic therapy

KW - tissue plasminogen activator

U2 - 10.1186/1745-6215-12-252

DO - 10.1186/1745-6215-12-252

M3 - Article

C2 - 22129158

SN - 1745-6215

VL - 12

JO - Trials

JF - Trials

M1 - 252

ER -

Update on the third international stroke trial (IST-3) of thrombolysis for acute ischaemic stroke and baseline features of the 3035 patients recruited

Abstract

Keywords

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