TY - JOUR KW - Female KW - Humans KW - Aged KW - Male KW - Treatment Outcome KW - Middle Aged KW - Age Factors KW - Aged, 80 and over KW - Randomized Controlled Trials as Topic KW - Acute Disease KW - Clinical Trials, Phase III as Topic KW - Fibrinolytic Agents/ administration & dosage/adverse effects KW - Infusions, Intravenous KW - Intracranial Hemorrhages/chemically induced/mortality KW - Stroke/ drug therapy/mortality KW - Time-to-Treatment KW - Tissue Plasminogen Activator/ administration & dosage/adverse effects AU - Lindley Richard AU - Lees K. AU - Grotta J. AU - Sandercock P. AU - Cohen G. AU - Murray G. AU - Wardlaw J. AU - Whiteley W. AU - Baigent C. AU - Lyden P. AU - Emberson J. AU - Donnan G. AU - Blackwell L. AU - Koga M. AU - Toyoda K. AU - von Kummer R. AU - Albers G. AU - Bluhmki E. AU - Brott T. AU - Davis S. AU - Howard G. AU - Kaste M. AU - Lansberg M. AU - Olivot J. AU - Parsons M. AU - Tilley B. AU - Toni D. AU - Wahlgren N. AU - del Zoppo G. AU - Hacke W. 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.

AD - Clinical Trial Service Unit & Epidemiological Studies Unit, University of Oxford, Oxford, UK.
University of Glasgow, Glasgow, UK.
Department of Neurology, Cedars-Sinai, Los Angeles, CA, USA.
Stanford University, Stanford, CA, USA.
Boehringer Ingelheim, Ingelheim, Germany.
Mayo Clinic, Jacksonville, FL, USA.
University of Edinburgh, Edinburgh, UK.
University of Melbourne, Melbourne, VIC, Australia.
The Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia.
University of Texas Health Science Center, Houston, TX, USA.
University of Alabama, Birmingham, AL, USA.
Helsinki University Central Hospital, Helsinki, Finland.
National Cerebral and Cardiovascular Centre, Suita, Japan.
Technische University, Dresden, Germany.
The George Institute for Global Health, University of Sydney, Sydney, NSW, Australia.
University of Newcastle, Newcastle, NSW, Australia.
Sapienza University, Rome, Italy.
Karolinska Institutet, Clinical Neuroscience, Stockholm, Sweden.
University of Washington, Seattle, WA, USA.
Clinical Trial Service Unit & Epidemiological Studies Unit, University of Oxford, Oxford, UK. Electronic address: colin.baigent@ctsu.ox.ac.uk.
University of Heidelberg, Heidelberg, Germany. AN - 25106063 BT - Lancet DP - NLM ET - 2014/08/12 LA - eng LB - PROF M1 - 9958 N1 - Emberson, Jonathan
Lees, Kennedy R
Lyden, Patrick
Blackwell, Lisa
Albers, Gregory
Bluhmki, Erich
Brott, Thomas
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
Stroke Thrombolysis Trialists' Collaborative Group
G0400069/Medical Research Council/United Kingdom
G0902303/Medical Research Council/United Kingdom
MR/K026992/1/Medical Research Council/United Kingdom
British Heart Foundation/United Kingdom
Medical Research Council/United Kingdom
Meta-Analysis
Research Support, Non-U.S. Gov't
Review
England
Lancet. 2014 Nov 29;384(9958):1929-35. doi: 10.1016/S0140-6736(14)60584-5. Epub 2014 Aug 5. 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.

PY - 2014 SN - 1474-547X (Electronic)
0140-6736 (Linking) SP - 1929 EP - 35 T2 - Lancet TI - 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 VL - 384 ER -