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; Rustam Al-Shahi Salman; Stephanie Lewis

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, Rustam Al-Shahi Salman (Member of Group Organisation), Stephanie Lewis (Member of Group Organisation)

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

Abstract / Description of output

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.

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 - Jun 2012

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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
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IST3 (Supplement to R39189) - Third International Stroke Trial (Formerlly MRC G0400069)
Sandercock, P., Dennis, M. & Wardlaw, J.
Other, UK-based charities
1/04/10 → 30/09/13
Project: Research
Imaging perfusion deficits and thrombolysis safety and efficacy in acute ischaemic stroke. The Third International Stroke Trial (IST-3)
Wardlaw, J. & Sandercock, P.
Other
1/09/09 → 31/12/12
Project: Research

The third International Stroke Trial (IST-3)
Sandercock, P. (Creator), Wardlaw, J. (Creator), Lindley, R. (Creator), Cohen, G. (Creator) & Whiteley, W. (Creator), Edinburgh DataShare, 25 Jan 2021
DOI: 10.7488/ds/1350
Dataset

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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., ... Lewis, S. (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

@article{299243f6f8604350bd87438c8cd43a9f,

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 = "BackgroundThrombolysis 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.MethodsIn 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.Findings3035 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).InterpretationFor 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.",

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 {Al-Shahi Salman}, Rustam and Stephanie Lewis",

year = "2012",

month = jun,

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

language = "English",

volume = "379",

pages = "2352--2363",

journal = "The Lancet",

issn = "0140-6736",

publisher = "Elsevier",

number = "9834",

}

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, Al-Shahi Salman, R & Lewis, S 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

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, 06.2012, p. 2352-2363.

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

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]): 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

A2 - Al-Shahi Salman, Rustam

A2 - Lewis, Stephanie

PY - 2012/6

Y1 - 2012/6

N2 - BackgroundThrombolysis 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.MethodsIn 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.Findings3035 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).InterpretationFor 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.

AB - BackgroundThrombolysis 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.MethodsIn 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.Findings3035 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).InterpretationFor 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.

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 -

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 / Description of output

Access to Document

Fingerprint

Projects

IST3 (Supplement to R39189) - Third International Stroke Trial (Formerlly MRC G0400069)

Imaging perfusion deficits and thrombolysis safety and efficacy in acute ischaemic stroke. The Third International Stroke Trial (IST-3)

Datasets

The third International Stroke Trial (IST-3)

Cite this