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
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
N1 - Funding Information:
This collaboration is coordinated by the Clinical Trial Service Unit & Epidemiological Studies Unit at the University of Oxford, UK. The Unit receives core funding from the UK Medical Research Council and the British Heart Foundation. This work also received support from the University of Glasgow and University of Edinburgh.
Funding Information:
CB, LB, and JE have not accepted fees, honoraria, or paid consultancies but are involved in clinical trials of lipid-modifying treatment funded by Merck to the University of Oxford, with the University the trial sponsor in all cases. KRL has received speaker fees from and has served on the data monitoring committee of trials for Boehringer Ingelheim; his department has received research grant support from Genentech. GA has received research grant support from Lundbeck, fees for consultancy and advisory board membership from Lundbeck, Covidien, Codman, and Genentech, fees for acting as an expert witness, and owns stock in iSchemaView. EB is employed by Boehringer Ingelheim. SD has received honoraria from Boehringer Ingelheim, EVER Pharma, and Sanofi and has received fees for consultancy and advisory board membership from Boehringer Ingelheim and Sanofi. GD has received research grant support from the NHMRC (Australia) and honoraria from Pfizer and Bristol-Myers Squibb. JG has received fees for consultancy and advisory board membership from Lundbeck. RvK has received speaker fees and honoraria from Penumbra and Lundbeck. RIL has received honoraria from Boehringer Ingelheim. JMO has received speaker fees from Boehringer Ingelheim. MP has received travel support from Boehringer Ingelheim. BT has received honoraria from Pfizer. DT has received speaker fees and fees for consultancy and advisory board membership from Boehringer Ingelheim and Bayer. KT has received research grant support from the Ministry of Health, Labour, and Welfare of Japan, and speaker fees from Mitsubishi Tanabe Pharma. JW has received research grant support from the UK Medical Research Council and from Boehringer Ingelheim to the University of Edinburgh for a research scanner bought more than 10 years ago. WW has received research grant support from the UK Medical Research Council. PS has received honoraria for lectures which were paid to the department from Boehringer Ingelheim. WH has received research grant support from Boehringer Ingelheim, and speaker fees and fees for consultancy and advisory board membership from Boehringer Ingelheim. PL, TB, GC, GH, MKa, MKo, ML, GM, NW, and GJdZ declare no competing interests.
Publisher Copyright:
© 2014 Emberson et al. Open Access article distributed under the terms of CC BY.
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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U2 - 10.1016/S0140-6736(14)60584-5
DO - 10.1016/S0140-6736(14)60584-5
M3 - Article
C2 - 25106063
AN - SCOPUS:84919432580
VL - 384
SP - 1929
EP - 1935
JO - The Lancet
JF - The Lancet
SN - 0140-6736
IS - 9958
ER -