Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: A meta-analysis of individual patient data from randomised trials

Jonathan Emberson, Kennedy R. Lees, Patrick Lyden, Lisa Blackwell, Gregory Albers, Erich Bluhmki, Thomas G Brott, Geoff Cohen, Stephen Davis, Geoffrey Donnan, James Grotta, George Howard, Markku Kaste, Masatoshi Koga, Ruediger Von Kummer, Maarten Lansberg, Richard I. Lindley, Gordon Murray, Jean Marc Olivot, Mark ParsonsBarbara Tilley, Danilo Toni, Kazunori Toyoda, Nils Wahlgren, Joanna Wardlaw, William Whiteley, Gregory J. Del Zoppo, Colin Baigent, Peter Sandercock, Werner Hacke

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Abstract

Background Alteplase is effective for treatment of acute ischaemic stroke but debate continues about its use after longer times since stroke onset, in older patients, and among patients who have had the least or most severe strokes. We assessed the role of these factors in affecting good stroke outcome in patients given alteplase. Methods We did a pre-specified meta-analysis of individual patient data from 6756 patients in nine randomised trials comparing alteplase with placebo or open control. We included all completed randomised phase 3 trials of intravenous alteplase for treatment of acute ischaemic stroke for which data were available. Retrospective checks confirmed that no eligible trials had been omitted. We defined a good stroke outcome as no significant disability at 3-6 months, defined by a modified Rankin Score of 0 or 1. Additional outcomes included symptomatic intracranial haemorrhage (defined by type 2 parenchymal haemorrhage within 7 days and, separately, by the SITS-MOST definition of parenchymal type 2 haemorrhage within 36 h), fatal intracranial haemorrhage within 7 days, and 90-day mortality. Findings Alteplase increased the odds of a good stroke outcome, with earlier treatment associated with bigger proportional benefit. Treatment within 3·0 h resulted in a good outcome for 259 (32·9%) of 787 patients who received alteplase versus 176 (23·1%) of 762 who received control (OR 1·75, 95% CI 1·35-2·27); delay of greater than 3·0 h, up to 4·5 h, resulted in good outcome for 485 (35·3%) of 1375 versus 432 (30·1%) of 1437 (OR 1·26, 95% CI 1·05-1·51); and delay of more than 4·5 h resulted in good outcome for 401 (32·6%) of 1229 versus 357 (30·6%) of 1166 (OR 1·15, 95% CI 0·95-1·40). Proportional treatment benefits were similar irrespective of age or stroke severity. Alteplase significantly increased the odds of symptomatic intracranial haemorrhage (type 2 parenchymal haemorrhage definition 231 [6·8%] of 3391 vs 44 [1·3%] of 3365, OR 5·55, 95% CI 4·01-7·70, p<0·0001; SITS-MOST definition 124 [3·7%] vs 19 [0·6%], OR 6·67, 95% CI 4·11-10·84, p<0·0001) and of fatal intracranial haemorrhage within 7 days (91 [2·7%] vs 13 [0·4%]; OR 7·14, 95% CI 3·98-12·79, p<0·0001). The relative increase in fatal intracranial haemorrhage from alteplase was similar irrespective of treatment delay, age, or stroke severity, but the absolute excess risk attributable to alteplase was bigger among patients who had more severe strokes. There was no excess in other early causes of death and no significant effect on later causes of death. Consequently, mortality at 90 days was 608 (17·9%) in the alteplase group versus 556 (16·5%) in the control group (hazard ratio 1·11, 95% CI 0·99-1·25, p=0·07). Taken together, therefore, despite an average absolute increased risk of early death from intracranial haemorrhage of about 2%, by 3-6 months this risk was offset by an average absolute increase in disability-free survival of about 10% for patients treated within 3·0 h and about 5% for patients treated after 3·0 h, up to 4·5 h. Interpretation Irrespective of age or stroke severity, and despite an increased risk of fatal intracranial haemorrhage during the first few days after treatment, alteplase significantly improves the overall odds of a good stroke outcome when delivered within 4·5 h of stroke onset, with earlier treatment associated with bigger proportional benefits. Funding UK Medical Research Council, British Heart Foundation, University of Glasgow, University of Edinburgh.

Original languageEnglish (US)
Pages (from-to)1929-1935
Number of pages7
JournalThe Lancet
Volume384
Issue number9958
DOIs
StatePublished - Nov 29 2014

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Tissue Plasminogen Activator
Meta-Analysis
Stroke
Intracranial Hemorrhages
Therapeutics
4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid
Hemorrhage
Cause of Death
Mortality
Biomedical Research
Placebos

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  • Medicine(all)

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Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke : A meta-analysis of individual patient data from randomised trials. / Emberson, Jonathan; Lees, Kennedy R.; Lyden, Patrick; Blackwell, Lisa; Albers, Gregory; Bluhmki, Erich; Brott, Thomas G; Cohen, Geoff; Davis, Stephen; Donnan, Geoffrey; Grotta, James; Howard, George; Kaste, Markku; Koga, Masatoshi; Von Kummer, Ruediger; Lansberg, Maarten; Lindley, Richard I.; Murray, Gordon; Olivot, Jean Marc; Parsons, Mark; Tilley, Barbara; Toni, Danilo; Toyoda, Kazunori; Wahlgren, Nils; Wardlaw, Joanna; Whiteley, William; Del Zoppo, Gregory J.; Baigent, Colin; Sandercock, Peter; Hacke, Werner.

In: The Lancet, Vol. 384, No. 9958, 29.11.2014, p. 1929-1935.

Research output: Contribution to journalArticle

Emberson, J, Lees, KR, Lyden, P, Blackwell, L, Albers, G, Bluhmki, E, Brott, TG, Cohen, G, Davis, S, Donnan, G, Grotta, J, Howard, G, Kaste, M, Koga, M, Von Kummer, R, Lansberg, M, Lindley, RI, Murray, G, Olivot, JM, Parsons, M, Tilley, B, Toni, D, Toyoda, K, Wahlgren, N, Wardlaw, J, Whiteley, W, Del Zoppo, GJ, Baigent, C, Sandercock, P & Hacke, W 2014, 'Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: A meta-analysis of individual patient data from randomised trials', The Lancet, vol. 384, no. 9958, pp. 1929-1935. https://doi.org/10.1016/S0140-6736(14)60584-5
Emberson, Jonathan ; Lees, Kennedy R. ; Lyden, Patrick ; Blackwell, Lisa ; Albers, Gregory ; Bluhmki, Erich ; Brott, Thomas G ; Cohen, Geoff ; Davis, Stephen ; Donnan, Geoffrey ; Grotta, James ; Howard, George ; Kaste, Markku ; Koga, Masatoshi ; Von Kummer, Ruediger ; Lansberg, Maarten ; Lindley, Richard I. ; Murray, Gordon ; Olivot, Jean Marc ; Parsons, Mark ; Tilley, Barbara ; Toni, Danilo ; Toyoda, Kazunori ; Wahlgren, Nils ; Wardlaw, Joanna ; Whiteley, William ; Del Zoppo, Gregory J. ; Baigent, Colin ; Sandercock, Peter ; Hacke, Werner. / Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke : A meta-analysis of individual patient data from randomised trials. In: The Lancet. 2014 ; Vol. 384, No. 9958. pp. 1929-1935.
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abstract = "Background Alteplase is effective for treatment of acute ischaemic stroke but debate continues about its use after longer times since stroke onset, in older patients, and among patients who have had the least or most severe strokes. We assessed the role of these factors in affecting good stroke outcome in patients given alteplase. Methods We did a pre-specified meta-analysis of individual patient data from 6756 patients in nine randomised trials comparing alteplase with placebo or open control. We included all completed randomised phase 3 trials of intravenous alteplase for treatment of acute ischaemic stroke for which data were available. Retrospective checks confirmed that no eligible trials had been omitted. We defined a good stroke outcome as no significant disability at 3-6 months, defined by a modified Rankin Score of 0 or 1. Additional outcomes included symptomatic intracranial haemorrhage (defined by type 2 parenchymal haemorrhage within 7 days and, separately, by the SITS-MOST definition of parenchymal type 2 haemorrhage within 36 h), fatal intracranial haemorrhage within 7 days, and 90-day mortality. Findings Alteplase increased the odds of a good stroke outcome, with earlier treatment associated with bigger proportional benefit. Treatment within 3·0 h resulted in a good outcome for 259 (32·9{\%}) of 787 patients who received alteplase versus 176 (23·1{\%}) of 762 who received control (OR 1·75, 95{\%} CI 1·35-2·27); delay of greater than 3·0 h, up to 4·5 h, resulted in good outcome for 485 (35·3{\%}) of 1375 versus 432 (30·1{\%}) of 1437 (OR 1·26, 95{\%} CI 1·05-1·51); and delay of more than 4·5 h resulted in good outcome for 401 (32·6{\%}) of 1229 versus 357 (30·6{\%}) of 1166 (OR 1·15, 95{\%} CI 0·95-1·40). Proportional treatment benefits were similar irrespective of age or stroke severity. Alteplase significantly increased the odds of symptomatic intracranial haemorrhage (type 2 parenchymal haemorrhage definition 231 [6·8{\%}] of 3391 vs 44 [1·3{\%}] of 3365, OR 5·55, 95{\%} CI 4·01-7·70, p<0·0001; SITS-MOST definition 124 [3·7{\%}] vs 19 [0·6{\%}], OR 6·67, 95{\%} CI 4·11-10·84, p<0·0001) and of fatal intracranial haemorrhage within 7 days (91 [2·7{\%}] vs 13 [0·4{\%}]; OR 7·14, 95{\%} CI 3·98-12·79, p<0·0001). The relative increase in fatal intracranial haemorrhage from alteplase was similar irrespective of treatment delay, age, or stroke severity, but the absolute excess risk attributable to alteplase was bigger among patients who had more severe strokes. There was no excess in other early causes of death and no significant effect on later causes of death. Consequently, mortality at 90 days was 608 (17·9{\%}) in the alteplase group versus 556 (16·5{\%}) in the control group (hazard ratio 1·11, 95{\%} CI 0·99-1·25, p=0·07). Taken together, therefore, despite an average absolute increased risk of early death from intracranial haemorrhage of about 2{\%}, by 3-6 months this risk was offset by an average absolute increase in disability-free survival of about 10{\%} for patients treated within 3·0 h and about 5{\%} for patients treated after 3·0 h, up to 4·5 h. Interpretation Irrespective of age or stroke severity, and despite an increased risk of fatal intracranial haemorrhage during the first few days after treatment, alteplase significantly improves the overall odds of a good stroke outcome when delivered within 4·5 h of stroke onset, with earlier treatment associated with bigger proportional benefits. Funding UK Medical Research Council, British Heart Foundation, University of Glasgow, University of Edinburgh.",
author = "Jonathan Emberson and Lees, {Kennedy R.} and Patrick Lyden and Lisa Blackwell and Gregory Albers and Erich Bluhmki and Brott, {Thomas G} and Geoff Cohen and Stephen Davis and Geoffrey Donnan and James Grotta and George Howard and Markku Kaste and Masatoshi Koga and {Von Kummer}, Ruediger and Maarten Lansberg and Lindley, {Richard I.} and Gordon Murray and Olivot, {Jean Marc} and Mark Parsons and Barbara Tilley and Danilo Toni and Kazunori Toyoda and Nils Wahlgren and Joanna Wardlaw and William Whiteley and {Del Zoppo}, {Gregory J.} and Colin Baigent and Peter Sandercock and Werner Hacke",
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TY - JOUR

T1 - Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke

T2 - A meta-analysis of individual patient data from randomised trials

AU - Emberson, Jonathan

AU - Lees, Kennedy R.

AU - Lyden, Patrick

AU - Blackwell, Lisa

AU - Albers, Gregory

AU - Bluhmki, Erich

AU - Brott, Thomas G

AU - Cohen, Geoff

AU - Davis, Stephen

AU - Donnan, Geoffrey

AU - Grotta, James

AU - Howard, George

AU - Kaste, Markku

AU - Koga, Masatoshi

AU - Von Kummer, Ruediger

AU - Lansberg, Maarten

AU - Lindley, Richard I.

AU - Murray, Gordon

AU - Olivot, Jean Marc

AU - Parsons, Mark

AU - Tilley, Barbara

AU - Toni, Danilo

AU - Toyoda, Kazunori

AU - Wahlgren, Nils

AU - Wardlaw, Joanna

AU - Whiteley, William

AU - Del Zoppo, Gregory J.

AU - Baigent, Colin

AU - Sandercock, Peter

AU - Hacke, Werner

PY - 2014/11/29

Y1 - 2014/11/29

N2 - Background Alteplase is effective for treatment of acute ischaemic stroke but debate continues about its use after longer times since stroke onset, in older patients, and among patients who have had the least or most severe strokes. We assessed the role of these factors in affecting good stroke outcome in patients given alteplase. Methods We did a pre-specified meta-analysis of individual patient data from 6756 patients in nine randomised trials comparing alteplase with placebo or open control. We included all completed randomised phase 3 trials of intravenous alteplase for treatment of acute ischaemic stroke for which data were available. Retrospective checks confirmed that no eligible trials had been omitted. We defined a good stroke outcome as no significant disability at 3-6 months, defined by a modified Rankin Score of 0 or 1. Additional outcomes included symptomatic intracranial haemorrhage (defined by type 2 parenchymal haemorrhage within 7 days and, separately, by the SITS-MOST definition of parenchymal type 2 haemorrhage within 36 h), fatal intracranial haemorrhage within 7 days, and 90-day mortality. Findings Alteplase increased the odds of a good stroke outcome, with earlier treatment associated with bigger proportional benefit. Treatment within 3·0 h resulted in a good outcome for 259 (32·9%) of 787 patients who received alteplase versus 176 (23·1%) of 762 who received control (OR 1·75, 95% CI 1·35-2·27); delay of greater than 3·0 h, up to 4·5 h, resulted in good outcome for 485 (35·3%) of 1375 versus 432 (30·1%) of 1437 (OR 1·26, 95% CI 1·05-1·51); and delay of more than 4·5 h resulted in good outcome for 401 (32·6%) of 1229 versus 357 (30·6%) of 1166 (OR 1·15, 95% CI 0·95-1·40). Proportional treatment benefits were similar irrespective of age or stroke severity. Alteplase significantly increased the odds of symptomatic intracranial haemorrhage (type 2 parenchymal haemorrhage definition 231 [6·8%] of 3391 vs 44 [1·3%] of 3365, OR 5·55, 95% CI 4·01-7·70, p<0·0001; SITS-MOST definition 124 [3·7%] vs 19 [0·6%], OR 6·67, 95% CI 4·11-10·84, p<0·0001) and of fatal intracranial haemorrhage within 7 days (91 [2·7%] vs 13 [0·4%]; OR 7·14, 95% CI 3·98-12·79, p<0·0001). The relative increase in fatal intracranial haemorrhage from alteplase was similar irrespective of treatment delay, age, or stroke severity, but the absolute excess risk attributable to alteplase was bigger among patients who had more severe strokes. There was no excess in other early causes of death and no significant effect on later causes of death. Consequently, mortality at 90 days was 608 (17·9%) in the alteplase group versus 556 (16·5%) in the control group (hazard ratio 1·11, 95% CI 0·99-1·25, p=0·07). Taken together, therefore, despite an average absolute increased risk of early death from intracranial haemorrhage of about 2%, by 3-6 months this risk was offset by an average absolute increase in disability-free survival of about 10% for patients treated within 3·0 h and about 5% for patients treated after 3·0 h, up to 4·5 h. Interpretation Irrespective of age or stroke severity, and despite an increased risk of fatal intracranial haemorrhage during the first few days after treatment, alteplase significantly improves the overall odds of a good stroke outcome when delivered within 4·5 h of stroke onset, with earlier treatment associated with bigger proportional benefits. Funding UK Medical Research Council, British Heart Foundation, University of Glasgow, University of Edinburgh.

AB - Background Alteplase is effective for treatment of acute ischaemic stroke but debate continues about its use after longer times since stroke onset, in older patients, and among patients who have had the least or most severe strokes. We assessed the role of these factors in affecting good stroke outcome in patients given alteplase. Methods We did a pre-specified meta-analysis of individual patient data from 6756 patients in nine randomised trials comparing alteplase with placebo or open control. We included all completed randomised phase 3 trials of intravenous alteplase for treatment of acute ischaemic stroke for which data were available. Retrospective checks confirmed that no eligible trials had been omitted. We defined a good stroke outcome as no significant disability at 3-6 months, defined by a modified Rankin Score of 0 or 1. Additional outcomes included symptomatic intracranial haemorrhage (defined by type 2 parenchymal haemorrhage within 7 days and, separately, by the SITS-MOST definition of parenchymal type 2 haemorrhage within 36 h), fatal intracranial haemorrhage within 7 days, and 90-day mortality. Findings Alteplase increased the odds of a good stroke outcome, with earlier treatment associated with bigger proportional benefit. Treatment within 3·0 h resulted in a good outcome for 259 (32·9%) of 787 patients who received alteplase versus 176 (23·1%) of 762 who received control (OR 1·75, 95% CI 1·35-2·27); delay of greater than 3·0 h, up to 4·5 h, resulted in good outcome for 485 (35·3%) of 1375 versus 432 (30·1%) of 1437 (OR 1·26, 95% CI 1·05-1·51); and delay of more than 4·5 h resulted in good outcome for 401 (32·6%) of 1229 versus 357 (30·6%) of 1166 (OR 1·15, 95% CI 0·95-1·40). Proportional treatment benefits were similar irrespective of age or stroke severity. Alteplase significantly increased the odds of symptomatic intracranial haemorrhage (type 2 parenchymal haemorrhage definition 231 [6·8%] of 3391 vs 44 [1·3%] of 3365, OR 5·55, 95% CI 4·01-7·70, p<0·0001; SITS-MOST definition 124 [3·7%] vs 19 [0·6%], OR 6·67, 95% CI 4·11-10·84, p<0·0001) and of fatal intracranial haemorrhage within 7 days (91 [2·7%] vs 13 [0·4%]; OR 7·14, 95% CI 3·98-12·79, p<0·0001). The relative increase in fatal intracranial haemorrhage from alteplase was similar irrespective of treatment delay, age, or stroke severity, but the absolute excess risk attributable to alteplase was bigger among patients who had more severe strokes. There was no excess in other early causes of death and no significant effect on later causes of death. Consequently, mortality at 90 days was 608 (17·9%) in the alteplase group versus 556 (16·5%) in the control group (hazard ratio 1·11, 95% CI 0·99-1·25, p=0·07). Taken together, therefore, despite an average absolute increased risk of early death from intracranial haemorrhage of about 2%, by 3-6 months this risk was offset by an average absolute increase in disability-free survival of about 10% for patients treated within 3·0 h and about 5% for patients treated after 3·0 h, up to 4·5 h. Interpretation Irrespective of age or stroke severity, and despite an increased risk of fatal intracranial haemorrhage during the first few days after treatment, alteplase significantly improves the overall odds of a good stroke outcome when delivered within 4·5 h of stroke onset, with earlier treatment associated with bigger proportional benefits. Funding UK Medical Research Council, British Heart Foundation, University of Glasgow, University of Edinburgh.

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