title: Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke.
abstract: BACKGROUND
  Intravenous thrombolysis with alteplase is the only approved treatment for acute ischemic stroke, but its efficacy and safety when administered more than 3 hours after the onset of symptoms have not been established. We tested the efficacy and safety of alteplase administered between 3 and 4.5 hours after the onset of a stroke.
  
  
  METHODS
  After exclusion of patients with a brain hemorrhage or major infarction, as detected on a computed tomographic scan, we randomly assigned patients with acute ischemic stroke in a 1:1 double-blind fashion to receive treatment with intravenous alteplase (0.9 mg per kilogram of body weight) or placebo. The primary end point was disability at 90 days, dichotomized as a favorable outcome (a score of 0 or 1 on the modified Rankin scale, which has a range of 0 to 6, with 0 indicating no symptoms at all and 6 indicating death) or an unfavorable outcome (a score of 2 to 6 on the modified Rankin scale). The secondary end point was a global outcome analysis of four neurologic and disability scores combined. Safety end points included death, symptomatic intracranial hemorrhage, and other serious adverse events.
  
  
  RESULTS
  We enrolled a total of 821 patients in the study and randomly assigned 418 to the alteplase group and 403 to the placebo group. The median time for the administration of alteplase was 3 hours 59 minutes. More patients had a favorable outcome with alteplase than with placebo (52.4% vs. 45.2%; odds ratio, 1.34; 95% confidence interval [CI], 1.02 to 1.76; P=0.04). In the global analysis, the outcome was also improved with alteplase as compared with placebo (odds ratio, 1.28; 95% CI, 1.00 to 1.65; P<0.05). The incidence of intracranial hemorrhage was higher with alteplase than with placebo (for any intracranial hemorrhage, 27.0% vs. 17.6%; P=0.001; for symptomatic intracranial hemorrhage, 2.4% vs. 0.2%; P=0.008). Mortality did not differ significantly between the alteplase and placebo groups (7.7% and 8.4%, respectively; P=0.68). There was no significant difference in the rate of other serious adverse events.
  
  
  CONCLUSIONS
  As compared with placebo, intravenous alteplase administered between 3 and 4.5 hours after the onset of symptoms significantly improved clinical outcomes in patients with acute ischemic stroke; alteplase was more frequently associated with symptomatic intracranial hemorrhage. (ClinicalTrials.gov number, NCT00153036.)
authors.affiliation: Department of Neurology, Universität Heidelberg, Heidelberg, Germany. werner.hacke@med.uni-heidelberg.de
authors.forename: Werner
authors.initials: W
authors.lastname: Hacke
authors.forename: Markku
authors.initials: M
authors.lastname: Kaste
authors.forename: Erich
authors.initials: E
authors.lastname: Bluhmki
authors.forename: Miroslav
authors.initials: M
authors.lastname: Brozman
authors.forename: Antoni
authors.initials: A
authors.lastname: Dávalos
authors.forename: Donata
authors.initials: D
authors.lastname: Guidetti
authors.forename: Vincent
authors.initials: V
authors.lastname: Larrue
authors.forename: Kennedy R
authors.initials: KR
authors.lastname: Lees
authors.forename: Zakaria
authors.initials: Z
authors.lastname: Medeghri
authors.forename: Thomas
authors.initials: T
authors.lastname: Machnig
authors.forename: Dietmar
authors.initials: D
authors.lastname: Schneider
authors.forename: Rüdiger
authors.initials: R
authors.lastname: von Kummer
authors.forename: Nils
authors.initials: N
authors.lastname: Wahlgren
authors.forename: Danilo
authors.initials: D
authors.lastname: Toni
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D002545:Brain Ischemia / Q000188:drug therapy; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D007262:Infusions, Intravenous; D020300:Intracranial Hemorrhages / Q000139:chemically induced; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020521:Stroke / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator