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Title: 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.
Austin Authors: Emberson, Jonathan;Lees, Kennedy R;Lyden, Patrick;Blackwell, Lisa;Albers, Gregory W;Bluhmki, Erich;Brott, Thomas;Cohen, Geoff;Davis, Stephen M;Donnan, Geoffrey A ;Grotta, James;Howard, George;Kaste, Markku;Koga, Masatoshi;von Kummer, Ruediger;Lansberg, Maarten;Lindley, Richard I;Murray, Gordon;Olivot, Jean Marc;Parsons, Mark W;Tilley, Barbara;Toni, Danilo;Toyoda, Kazunori;Wahlgren, Nils;Wardlaw, Joanna;Whiteley, William;del Zoppo, Gregory J;Baigent, Colin;Sandercock, Peter;Hacke, Werner
Institutional Author: Stroke Thrombolysis Trialists' Collaborative Group
Affiliation: Department of Neurology, Cedars-Sinai, Los Angeles, CA, USA
University of Newcastle, Newcastle, NSW, Australia
University of Texas Health Science Center, Houston, TX, USA
The George Institute for Global Health, University of Sydney, Sydney, NSW, Australia
The Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia
University of Washington, Seattle, WA, USA
University of Alabama, Birmingham, AL, USA
Mayo Clinic, Jacksonville, FL, USA
Stanford University, Stanford, CA, USA
University of Melbourne, Melbourne, Victoria, Australia
University of Edinburgh, Edinburgh, UK
University of Glasgow, Glasgow, UK
Clinical Trial Service Unit & Epidemiological Studies Unit, University of Oxford, Oxford, UK
Boehringer Ingelheim, Ingelheim, Germany.
Helsinki University Central Hospital, Helsinki, Finland.
Technische University, Dresden, Germany.
Sapienza University, Rome, Italy.
National Cerebral and Cardiovascular Centre, Suita, Japan.
Karolinska Institutet, Clinical Neuroscience, Stockholm, Sweden.
University of Heidelberg, Heidelberg, Germany.
Issue Date: 5-Aug-2014
Publication information: Lancet (london, England) 2014; 384(9958): 1929-35
Abstract: 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.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.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.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.UK Medical Research Council, British Heart Foundation, University of Glasgow, University of Edinburgh.
Gov't Doc #: 25106063
DOI: 10.1016/S0140-6736(14)60584-5
Type: Journal Article
Subjects: Acute Disease
Age Factors
Aged, 80 and over
Clinical Trials, Phase III as Topic
Fibrinolytic Agents.administration & dosage.adverse effects
Infusions, Intravenous
Intracranial Hemorrhages.chemically induced.mortality
Middle Aged
Randomized Controlled Trials as Topic
Stroke.drug therapy.mortality
Tissue Plasminogen Activator.administration & dosage.adverse effects
Treatment Outcome
Appears in Collections:Journal articles

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