title: Selection for delayed intravenous alteplase treatment based on a prognostic score.
abstract: OBJECTIVE
  Approved use of intravenous alteplase for ischemic stroke offers net benefit. Pooled randomized controlled trial analysis suggests additional patients could benefit but others be harmed with treatment initiated beyond 4·5 h after stroke onset. We proposed prognostic scoring methods to identify a strategy for patient selection.
  
  
  METHODS
  We selected 500 patients treated by intravenous alteplase and 500 controls from Virtual International Stroke Trials Archive, matching modified Rankin score outcomes to those from pooled randomized controlled trial 4·5-6 h data. We ranked patients by prognostic score. We chose limits to optimize our sample for a net treatment benefit significant at P = 0·01 by Cochran-Mantel-Haenszel test and by ordinal regression. For validation, we had these applied to the pooled randomized controlled trial data for 4·5-6 h, testing for net benefit by Cochran-Mantel-Haenszel test, ordinal regression, and also by dichotomized outcomes: modified Rankin score 0-1, mortality and parenchymal hemorrhage type 2 bleeds. All analyses were adjusted for age and National Institutes of Health Stroke Scale.
  
  
  RESULTS
  In the training dataset, limits of 56-95 on a prognostic score retained 714 patients in whom there was net benefit significant at P = 0·01. When applied to the 1120 patients in the pooled randomized controlled trial 4·5-6 h dataset, score limits of 56-95 retained 711 patients and gave odds ratio for improved modified Rankin score distribution of 1·13, 95% confidence interval 0·87-1·47, Cochran-Mantel-Haenszel P = 0·89. More patients achieved modified Rankin score 0-1 (odds ratio 1·44, 1·02-2·05, P = 0·04) but mortality and parenchymal hemorrhage type 2 bleeds were increased: odds ratio 1·56, 1·01-2·40, P = 0·04; odds ratio 15·6, 3·7-65·8, P = 0·0002, respectively.
  
  
  CONCLUSIONS
  Selection of patients between 4·5 and 6 h based on simple clinical measures failed to deliver a population in whom the alteplase effect would be safe and effective.
authors.affiliation: Department of Medicine and Therapeutics, University of Glasgow, Glasgow, UK.
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Fulton
authors.forename: Kennedy R
authors.initials: KR
authors.lastname: Lees
authors.forename: Erich
authors.initials: E
authors.lastname: Bluhmki
authors.forename: Gabriele
authors.initials: G
authors.lastname: Biegert
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Albers
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Davis
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Donnan
authors.forename: James C
authors.initials: JC
authors.lastname: Grotta
authors.forename: Werner
authors.initials: W
authors.lastname: Hacke
authors.forename: Markku
authors.initials: M
authors.lastname: Kaste
authors.forename: Rüdiger
authors.initials: R
authors.lastname: von Kummer
authors.forename: Ashfaq
authors.initials: A
authors.lastname: Shuaib
authors.forename: Danilo
authors.initials: D
authors.lastname: Toni
mesh_terms: D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006801:Humans; D016017:Odds Ratio; D018579:Patient Selection; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D020521:Stroke / Q000188:drug therapy*; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator
keywords: analysis; clinical trials; outcomes; prognostic score; thrombolysis