title: Targeting recombinant tissue-type plasminogen activator in acute ischemic stroke based on risk of intracranial hemorrhage or poor functional outcome: an analysis of the third international stroke trial.
abstract: OBJECTIVE
  Intravenous recombinant tissue-type plasminogen activator (r-tPA), despite a risk of early symptomatic intracranial hemorrhage (sICH), is of net clinical benefit to acute stroke patients. We tested if predictive models could identify patients least likely to be harmed by sICH or those who gained no net benefit.
  
  
  METHODS
  We used the Third International Stroke Trial (IST-3) trial data set, an international, multicenter, open treatment randomized trial of 0.9 mg/kg r-tPA versus control in 3035 patients with acute ischemic stroke. We compared the discrimination and calibration of previously developed predictive models for ICH and poststroke poor outcome and developed a new model using variables selected by systematic review. We calculated the absolute and relative risk reduction of death or dependency with r-tPA in patients at a low, medium, or high predicted risk of sICH or poor functional outcome.
  
  
  RESULTS
  Prediction models for sICH or poor outcome (Hemorrhage After Thrombolysis [HAT]; Sugar, Early Infarct Signs, Dense Artery, Age, National Institutes of Health (NIH) Stroke Score (SEDAN); Glucose Race Age Sex Pressure Stroke Severity [GRASPS]; Stroke Thrombolytic Predictive Instrument; Dense Artery, Rankin Score, Age, Glucose, Onset to Treatment Time, NIHSS [DRAGON]; Totaled Health Risks in Vascular Events [THRIVE]; our new model; and a model with National Institutes of Health Stroke Scale and age) had similar area under receiver operator characteristic curves (AUROCC) to predict sICH (P for difference >0.05). The simplest model (with covariates National Institutes of Health Stroke Scale and age) predicted both sICH (AUROCC, 0.63; 95% CI, 0.58-0.68) and poststroke poor functional outcome (AUROCC, 0.80; 95% CI, 0.77-0.82) similarly to complex models. There was no evidence that the effect of r-tPA in patients at high predicted risk of sICH or poor functional outcome after stroke was less than in those at lower risk.
  
  
  CONCLUSIONS
  There is a clinically relevant net positive effect of r-tPA in patients with acute stroke at a high predicted risk of sICH or poor functional outcome.
  
  
  BACKGROUND
  http://www.controlled-trials.com. Unique identifier: ISRCTN25765518.
authors.affiliation: From the Divisions of Clinical Neurosciences (W.N.W., G.C., P.S.) and Neuroimaging Sciences (J.W.), University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom; Edinburgh MRC Hub for Trials Methodology Research, Centre for Population Health Sciences, University of Edinburgh, Edinburgh, United Kingdom (D.T., G.M.); and Neurological and Mental Health Division, The George Institute for Global Health, University of Sydney, Sydney, Australia (R.I.L.).
authors.forename: William N
authors.initials: WN
authors.lastname: Whiteley
authors.forename: Douglas
authors.initials: D
authors.lastname: Thompson
authors.forename: Gordon
authors.initials: G
authors.lastname: Murray
authors.forename: Geoff
authors.initials: G
authors.lastname: Cohen
authors.forename: Richard I
authors.initials: RI
authors.lastname: Lindley
authors.forename: Joanna
authors.initials: J
authors.lastname: Wardlaw
authors.forename: Peter
authors.initials: P
authors.lastname: Sandercock
mesh_terms: D000208:Acute Disease; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D020300:Intracranial Hemorrhages / Q000139:chemically induced* / Q000453:epidemiology*; D016015:Logistic Models; D008297:Male; D011237:Predictive Value of Tests; D012372:ROC Curve; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D020127:Recovery of Function / Q000187:drug effects; D012307:Risk Factors; D020521:Stroke / Q000188:drug therapy* / Q000453:epidemiology*; 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
keywords: prognosis; randomized controlled trial; stroke; thrombolytic therapy