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.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  UK Medical Research Council, British Heart Foundation, University of Glasgow, University of Edinburgh.
authors.affiliation: Clinical Trial Service Unit & Epidemiological Studies Unit, University of Oxford, Oxford, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Emberson
authors.affiliation: University of Glasgow, Glasgow, UK.
authors.forename: Kennedy R
authors.initials: KR
authors.lastname: Lees
authors.affiliation: Department of Neurology, Cedars-Sinai, Los Angeles, CA, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Lyden
authors.affiliation: Clinical Trial Service Unit & Epidemiological Studies Unit, University of Oxford, Oxford, UK.
authors.forename: Lisa
authors.initials: L
authors.lastname: Blackwell
authors.affiliation: Stanford University, Stanford, CA, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Albers
authors.affiliation: Boehringer Ingelheim, Ingelheim, Germany.
authors.forename: Erich
authors.initials: E
authors.lastname: Bluhmki
authors.affiliation: Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Brott
authors.affiliation: University of Edinburgh, Edinburgh, UK.
authors.forename: Geoff
authors.initials: G
authors.lastname: Cohen
authors.affiliation: University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Davis
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Donnan
authors.affiliation: University of Texas Health Science Center, Houston, TX, USA.
authors.forename: James
authors.initials: J
authors.lastname: Grotta
authors.affiliation: University of Alabama, Birmingham, AL, USA.
authors.forename: George
authors.initials: G
authors.lastname: Howard
authors.affiliation: Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Kaste
authors.affiliation: National Cerebral and Cardiovascular Centre, Suita, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Koga
authors.affiliation: Technische University, Dresden, Germany.
authors.forename: Ruediger
authors.initials: R
authors.lastname: von Kummer
authors.affiliation: Stanford University, Stanford, CA, USA.
authors.forename: Maarten
authors.initials: M
authors.lastname: Lansberg
authors.affiliation: The George Institute for Global Health, University of Sydney, Sydney, NSW, Australia.
authors.forename: Richard I
authors.initials: RI
authors.lastname: Lindley
authors.affiliation: University of Edinburgh, Edinburgh, UK.
authors.forename: Gordon
authors.initials: G
authors.lastname: Murray
authors.affiliation: Stanford University, Stanford, CA, USA.
authors.forename: Jean Marc
authors.initials: JM
authors.lastname: Olivot
authors.affiliation: University of Newcastle, Newcastle, NSW, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Parsons
authors.affiliation: University of Texas Health Science Center, Houston, TX, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Tilley
authors.affiliation: Sapienza University, Rome, Italy.
authors.forename: Danilo
authors.initials: D
authors.lastname: Toni
authors.affiliation: National Cerebral and Cardiovascular Centre, Suita, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Toyoda
authors.affiliation: Karolinska Institutet, Clinical Neuroscience, Stockholm, Sweden.
authors.forename: Nils
authors.initials: N
authors.lastname: Wahlgren
authors.affiliation: University of Edinburgh, Edinburgh, UK.
authors.forename: Joanna
authors.initials: J
authors.lastname: Wardlaw
authors.affiliation: University of Edinburgh, Edinburgh, UK.
authors.forename: William
authors.initials: W
authors.lastname: Whiteley
authors.affiliation: University of Washington, Seattle, WA, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: del Zoppo
authors.affiliation: Clinical Trial Service Unit & Epidemiological Studies Unit, University of Oxford, Oxford, UK. Electronic address: colin.baigent@ctsu.ox.ac.uk.
authors.forename: Colin
authors.initials: C
authors.lastname: Baigent
authors.affiliation: University of Edinburgh, Edinburgh, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Sandercock
authors.affiliation: University of Heidelberg, Heidelberg, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Hacke
mesh_terms: D000208:Acute Disease; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D017326:Clinical Trials, Phase III as Topic; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D007262:Infusions, Intravenous; D020300:Intracranial Hemorrhages / Q000139:chemically induced / Q000401:mortality; D008297:Male; D008875:Middle Aged; D016032:Randomized Controlled Trials as Topic; D020521:Stroke / Q000188:drug therapy* / Q000401:mortality; D061665:Time-to-Treatment; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator
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