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; Stephen J Phillips; Antonio Arauz; IST-3 Collaborative Group; Phyo Kyaw Myint

doi:10.1016/S0140-6736(12)60768-5

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 GubitzStephen J Phillips, Antonio Arauz, IST-3 Collaborative Group, Phyo Kyaw Myint

Research output: Contribution to journal › Article › peer-review

978 Citations (Scopus)

Abstract

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 patients were enrolled by 156 hospitals in 12 countries. All of these patients were included in the analyses (1515 in the rt-PA group vs 1520 in the control group), of whom 1617 (53%) were older than 80 years of age. At 6 months, 554 (37%) patients in the rt-PA group versus 534 (35%) in the control group were alive and independent (OHS 0-2; adjusted odds ratio [OR] 1·13, 95% CI 0·95-1·35, p=0·181; a non-significant absolute increase of 14/1000, 95% CI -20 to 48). An ordinal analysis showed a significant shift in OHS scores; common OR 1·27 (95% CI 1·10-1·47, p=0·001). Fatal or non-fatal symptomatic intracranial haemorrhage within 7 days occurred in 104 (7%) patients in the rt-PA group versus 16 (1%) in the control group (adjusted OR 6·94, 95% CI 4·07-11·8; absolute excess 58/1000, 95% CI 44-72). More deaths occurred within 7 days in the rt-PA group (163 [11%]) than in the control group (107 [7%], adjusted OR 1·60, 95% CI 1·22-2·08, p=0·001; absolute increase 37/1000, 95% CI 17-57), but between 7 days and 6 months there were fewer deaths in the rt-PA group than in the control group, so that by 6 months, similar numbers, in total, had died (408 [27%] in the rt-PA group vs 407 [27%] in the control group).

INTERPRETATION: For the types of patient recruited in IST-3, despite the early hazards, thrombolysis within 6 h improved functional outcome. Benefit did not seem to be diminished in elderly patients.

FUNDING: 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.

Original language	English
Pages (from-to)	2352-2363
Number of pages	12
Journal	The Lancet
Volume	379
Issue number	9834
DOIs	https://doi.org/10.1016/S0140-6736(12)60768-5
Publication status	Published - 23 Jun 2012

Bibliographical note

Copyright © 2012 Elsevier Ltd. All rights reserved.

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

Keywords

adolescent
adult
age distribution
aged
aged, 80 and over
brain ischemia
double-blind method
drug administration schedule
female
fibrinolytic agents
humans
infusions, intravenous
male
middle aged
recombinant proteins
secondary prevention
severity of illness index
stroke
thrombolytic therapy
tissue plasminogen activator
treatment outcome
young adult

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Sandercock, P., Wardlaw, J. M., Lindley, R. I., Dennis, M., Cohen, G., Murray, G., Innes, K., Venables, G., Czlonkowska, A., Kobayashi, A., Ricci, S., Murray, V., Berge, E., Slot, K. B., Hankey, G. J., Correia, M., Peeters, A., Matz, K., Lyrer, P., ... Myint, P. K. (2012). 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. The Lancet, 379(9834), 2352-2363. https://doi.org/10.1016/S0140-6736(12)60768-5

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. / Sandercock, Peter; Wardlaw, Joanna M; Lindley, Richard I et al.
In: The Lancet, Vol. 379, No. 9834, 23.06.2012, p. 2352-2363.

Research output: Contribution to journal › Article › peer-review

Sandercock, P, Wardlaw, JM, Lindley, RI, Dennis, M, Cohen, G, Murray, G, Innes, K, Venables, G, Czlonkowska, A, Kobayashi, A, Ricci, S, Murray, V, Berge, E, Slot, KB, Hankey, GJ, Correia, M, Peeters, A, Matz, K, Lyrer, P, Gubitz, G, Phillips, SJ, Arauz, A, IST-3 Collaborative Group & Myint, PK 2012, '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', The Lancet, vol. 379, no. 9834, pp. 2352-2363. https://doi.org/10.1016/S0140-6736(12)60768-5

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title = "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",

abstract = "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 patients were enrolled by 156 hospitals in 12 countries. All of these patients were included in the analyses (1515 in the rt-PA group vs 1520 in the control group), of whom 1617 (53%) were older than 80 years of age. At 6 months, 554 (37%) patients in the rt-PA group versus 534 (35%) in the control group were alive and independent (OHS 0-2; adjusted odds ratio [OR] 1·13, 95% CI 0·95-1·35, p=0·181; a non-significant absolute increase of 14/1000, 95% CI -20 to 48). An ordinal analysis showed a significant shift in OHS scores; common OR 1·27 (95% CI 1·10-1·47, p=0·001). Fatal or non-fatal symptomatic intracranial haemorrhage within 7 days occurred in 104 (7%) patients in the rt-PA group versus 16 (1%) in the control group (adjusted OR 6·94, 95% CI 4·07-11·8; absolute excess 58/1000, 95% CI 44-72). More deaths occurred within 7 days in the rt-PA group (163 [11%]) than in the control group (107 [7%], adjusted OR 1·60, 95% CI 1·22-2·08, p=0·001; absolute increase 37/1000, 95% CI 17-57), but between 7 days and 6 months there were fewer deaths in the rt-PA group than in the control group, so that by 6 months, similar numbers, in total, had died (408 [27%] in the rt-PA group vs 407 [27%] in the control group).INTERPRETATION: For the types of patient recruited in IST-3, despite the early hazards, thrombolysis within 6 h improved functional outcome. Benefit did not seem to be diminished in elderly patients.FUNDING: 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.",

keywords = "adolescent, adult, age distribution, aged, aged, 80 and over, brain ischemia, double-blind method, drug administration schedule, female, fibrinolytic agents, humans, infusions, intravenous, male, middle aged, recombinant proteins, secondary prevention, severity of illness index, stroke, thrombolytic therapy, tissue plasminogen activator, treatment outcome, young adult",

author = "Peter Sandercock and Wardlaw, {Joanna M} and Lindley, {Richard I} and Martin Dennis and Geoff Cohen and Gordon Murray and Karen Innes and Graham Venables and Anna Czlonkowska and Adam Kobayashi and Stefano Ricci and Veronica Murray and Eivind Berge and Slot, {Karsten Bruins} and Hankey, {Graeme J} and Manuel Correia and Andre Peeters and Karl Matz and Phillippe Lyrer and Gord Gubitz and Phillips, {Stephen J} and Antonio Arauz and {IST-3 Collaborative Group} and Myint, {Phyo Kyaw}",

note = "Copyright {\textcopyright} 2012 Elsevier Ltd. All rights reserved. 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",

year = "2012",

month = jun,

day = "23",

doi = "10.1016/S0140-6736(12)60768-5",

language = "English",

volume = "379",

pages = "2352--2363",

journal = "The Lancet",

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number = "9834",

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TY - JOUR

T1 - 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])

T2 - a randomised controlled trial

AU - Sandercock, Peter

AU - Wardlaw, Joanna M

AU - Lindley, Richard I

AU - Dennis, Martin

AU - Cohen, Geoff

AU - Murray, Gordon

AU - Innes, Karen

AU - Venables, Graham

AU - Czlonkowska, Anna

AU - Kobayashi, Adam

AU - Ricci, Stefano

AU - Murray, Veronica

AU - Berge, Eivind

AU - Slot, Karsten Bruins

AU - Hankey, Graeme J

AU - Correia, Manuel

AU - Peeters, Andre

AU - Matz, Karl

AU - Lyrer, Phillippe

AU - Gubitz, Gord

AU - Phillips, Stephen J

AU - Arauz, Antonio

AU - IST-3 Collaborative Group

AU - Myint, Phyo Kyaw

N1 - Copyright © 2012 Elsevier Ltd. All rights reserved. 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

PY - 2012/6/23

Y1 - 2012/6/23

N2 - 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 patients were enrolled by 156 hospitals in 12 countries. All of these patients were included in the analyses (1515 in the rt-PA group vs 1520 in the control group), of whom 1617 (53%) were older than 80 years of age. At 6 months, 554 (37%) patients in the rt-PA group versus 534 (35%) in the control group were alive and independent (OHS 0-2; adjusted odds ratio [OR] 1·13, 95% CI 0·95-1·35, p=0·181; a non-significant absolute increase of 14/1000, 95% CI -20 to 48). An ordinal analysis showed a significant shift in OHS scores; common OR 1·27 (95% CI 1·10-1·47, p=0·001). Fatal or non-fatal symptomatic intracranial haemorrhage within 7 days occurred in 104 (7%) patients in the rt-PA group versus 16 (1%) in the control group (adjusted OR 6·94, 95% CI 4·07-11·8; absolute excess 58/1000, 95% CI 44-72). More deaths occurred within 7 days in the rt-PA group (163 [11%]) than in the control group (107 [7%], adjusted OR 1·60, 95% CI 1·22-2·08, p=0·001; absolute increase 37/1000, 95% CI 17-57), but between 7 days and 6 months there were fewer deaths in the rt-PA group than in the control group, so that by 6 months, similar numbers, in total, had died (408 [27%] in the rt-PA group vs 407 [27%] in the control group).INTERPRETATION: For the types of patient recruited in IST-3, despite the early hazards, thrombolysis within 6 h improved functional outcome. Benefit did not seem to be diminished in elderly patients.FUNDING: 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.

AB - 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 patients were enrolled by 156 hospitals in 12 countries. All of these patients were included in the analyses (1515 in the rt-PA group vs 1520 in the control group), of whom 1617 (53%) were older than 80 years of age. At 6 months, 554 (37%) patients in the rt-PA group versus 534 (35%) in the control group were alive and independent (OHS 0-2; adjusted odds ratio [OR] 1·13, 95% CI 0·95-1·35, p=0·181; a non-significant absolute increase of 14/1000, 95% CI -20 to 48). An ordinal analysis showed a significant shift in OHS scores; common OR 1·27 (95% CI 1·10-1·47, p=0·001). Fatal or non-fatal symptomatic intracranial haemorrhage within 7 days occurred in 104 (7%) patients in the rt-PA group versus 16 (1%) in the control group (adjusted OR 6·94, 95% CI 4·07-11·8; absolute excess 58/1000, 95% CI 44-72). More deaths occurred within 7 days in the rt-PA group (163 [11%]) than in the control group (107 [7%], adjusted OR 1·60, 95% CI 1·22-2·08, p=0·001; absolute increase 37/1000, 95% CI 17-57), but between 7 days and 6 months there were fewer deaths in the rt-PA group than in the control group, so that by 6 months, similar numbers, in total, had died (408 [27%] in the rt-PA group vs 407 [27%] in the control group).INTERPRETATION: For the types of patient recruited in IST-3, despite the early hazards, thrombolysis within 6 h improved functional outcome. Benefit did not seem to be diminished in elderly patients.FUNDING: 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.

KW - adolescent

KW - adult

KW - age distribution

KW - aged

KW - aged, 80 and over

KW - brain ischemia

KW - double-blind method

KW - drug administration schedule

KW - female

KW - fibrinolytic agents

KW - humans

KW - infusions, intravenous

KW - male

KW - middle aged

KW - recombinant proteins

KW - secondary prevention

KW - severity of illness index

KW - stroke

KW - thrombolytic therapy

KW - tissue plasminogen activator

KW - treatment outcome

KW - young adult

U2 - 10.1016/S0140-6736(12)60768-5

DO - 10.1016/S0140-6736(12)60768-5

M3 - Article

C2 - 22632908

SN - 0140-6736

VL - 379

SP - 2352

EP - 2363

JO - The Lancet

JF - The Lancet

IS - 9834

ER -