title: Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials.
abstract: BACKGROUND
  Early administration of intravenous recombinant tissue plasminogen activator (rt-PA) after ischaemic stroke improves outcome. Previous analysis of combined data from individual patients suggested potential benefit beyond 3 h from stroke onset. We re-examined the effect of time to treatment with intravenous rt-PA (alteplase) on therapeutic benefit and clinical risk by adding recent trial data to the analysis.
  
  
  METHODS
  We added data from ECASS III (821 patients) and EPITHET (100 patients) to a pool of common data elements from six other trials of alteplase for acute stroke (2775 patients). We used multivariate logistic regression to assess the relation of stroke onset to start of treatment (OTT) with treatment on favourable 3-month outcome (defined as modified Rankin score 0-1), mortality, and occurrence and outcome of clinically relevant parenchymal haemorrhage. The presence of an arterial occlusion was inferred from the patient's symptoms and absence of haemorrhage or other causes of ischaemic stroke. Vascular imaging was not a requirement in the trials. All patients with confirmed OTT within 360 min were included in the analysis.
  
  
  RESULTS
  Treatment was started within 360 min of stroke onset in 3670 patients randomly allocated to alteplase (n=1850) or to placebo (n=1820). Odds of a favourable 3-month outcome increased as OTT decreased (p=0.0269) and no benefit of alteplase treatment was seen after around 270 min. Adjusted odds of a favourable 3-month outcome were 2.55 (95% CI 1.44-4.52) for 0-90 min, 1.64 (1.12-2.40) for 91-180 min, 1.34 (1.06-1.68) for 181-270 min, and 1.22 (0.92-1.61) for 271-360 min in favour of the alteplase group. Large parenchymal haemorrhage was seen in 96 (5.2%) of 1850 patients assigned to alteplase and 18 (1.0%) of 1820 controls, with no clear relation to OTT (p=0.4140). Adjusted odds of mortality increased with OTT (p=0.0444) and were 0.78 (0.41-1.48) for 0-90 min, 1.13 (0.70-1.82) for 91-180 min, 1.22 (0.87-1.71) for 181-270 min, and 1.49 (1.00-2.21) for 271-360 min.
  
  
  CONCLUSIONS
  Patients with ischaemic stroke selected by clinical symptoms and CT benefit from intravenous alteplase when treated up to 4.5 h. To increase benefit to a maximum, every effort should be taken to shorten delay in initiation of treatment. Beyond 4.5 h, risk might outweigh benefit.
  
  
  BACKGROUND
  None.
authors.affiliation: Department of Medicine and Therapeutics, Faculty of Medicine, University of Glasgow, Western Infirmary, Glasgow, UK. k.r.lees@clinmed.gla.ac.uk
authors.forename: Kennedy R
authors.initials: KR
authors.lastname: Lees
authors.forename: Erich
authors.initials: E
authors.lastname: Bluhmki
authors.forename: Rüdiger
authors.initials: R
authors.lastname: von Kummer
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Brott
authors.forename: Danilo
authors.initials: D
authors.lastname: Toni
authors.forename: James C
authors.initials: JC
authors.lastname: Grotta
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Albers
authors.forename: Markku
authors.initials: M
authors.lastname: Kaste
authors.forename: John R
authors.initials: JR
authors.lastname: Marler
authors.forename: Scott A
authors.initials: SA
authors.lastname: Hamilton
authors.forename: Barbara C
authors.initials: BC
authors.lastname: Tilley
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Davis
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Donnan
authors.forename: Werner
authors.initials: W
authors.lastname: Hacke
authors.forename: Kathryn
authors.initials: K
authors.lastname: Allen
authors.forename: Jochen
authors.initials: J
authors.lastname: Mau
authors.forename: Dieter
authors.initials: D
authors.lastname: Meier
authors.forename: Gregory
authors.initials: G
authors.lastname: del Zoppo
authors.forename: D A
authors.initials: DA
authors.lastname: De Silva
authors.forename: K S
authors.initials: KS
authors.lastname: Butcher
authors.forename: M W
authors.initials: MW
authors.lastname: Parsons
authors.forename: P A
authors.initials: PA
authors.lastname: Barber
authors.forename: C
authors.initials: C
authors.lastname: Levi
authors.forename: C
authors.initials: C
authors.lastname: Bladin
authors.forename: G
authors.initials: G
authors.lastname: Byrnes
mesh_terms: D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D020300:Intracranial Hemorrhages / Q000139:chemically induced; D016032:Randomized Controlled Trials as Topic; D011994:Recombinant Proteins / Q000008:administration & dosage; D020521:Stroke / Q000188:drug therapy*; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D005343:Fibrinolytic Agents; D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator