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Background and purposeIntravenous 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.MethodsWe 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.ResultsPrediction 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.ConclusionsThere 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.Clinical trial registration url Unique identifier: ISRCTN25765518.

Original publication




Journal article



Publication Date





1000 - 1006


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.).


IST-3 Collaborative Group, Humans, Intracranial Hemorrhages, Acute Disease, Tissue Plasminogen Activator, Recombinant Proteins, Fibrinolytic Agents, Treatment Outcome, Logistic Models, Risk Factors, Predictive Value of Tests, ROC Curve, Recovery of Function, Aged, Aged, 80 and over, Female, Male, Stroke