title: Systematic review of evidence on thrombolytic therapy for acute ischaemic stroke.
abstract: BACKGROUND
  Recent trials of thrombolytic therapy in acute ischaemic stroke have given apparently conflicting results. Only one trial, the National Institute of Neurological Disorders and Stroke trial of tissue plasminogen activator (tPA), suggested that thrombolysis was definitely beneficial. To make sense of these results, we have done a systematic review of all available randomised trials of thrombolysis in acute ischaemic stroke.
  
  
  METHODS
  From all available completed randomised trials of thrombolytic therapy compared with control in acute ischaemic stroke (with prerandomisation CT), we checked tabular data on deaths during roughly the first 2 weeks, deaths from all causes and functional outcome (disability) at the end of the trial follow-up period, and early symptomatic and fatal intracranial haemorrhages.
  
  
  RESULTS
  12 trials included 3435 patients, of whom 694 (20%) were dead and 1001 (39%) of 2567 were functionally dependent at the end of follow-up (duration of follow-up varied between trials, but the longest was 6 months). 214 (6%) of the 3435 patients had early symptomatic or fatal intracranial haemorrhages. Thrombolytic therapy was associated with a significant excess of early deaths (91 per 1000 patients treated [95% CI 54-134]), and total deaths (37 per 1000 [20-83]), but there was nevertheless a significant reduction in the number of patients in the combined outcome of dead or dependent (65 fewer per 1000 patients treated [28-107]). There was a substantial and significant excess of symptomatic and fatal intracranial haemorrhages with thrombolysis-which was similar in all recent trials-of about 70 extra symptomatic intracranial haemorrhages per 1000 patients treated (of which 51 per 1000 were fatal). In the cohort of patients randomised within 3 h of stroke, there was a significant reduction in the number of patients who were dead or dependent at the end of follow-up (141 fewer dead or dependent per 1000 patients treated [75-206] and a non-significant increase in the number dead (nine per 1000 treated [-39 to 70]). There was significant heterogeneity between the trials for total deaths at the end of follow-up, which may be partly explained by differences in the use of antithrombotic drugs within the first 24 h of thrombolysis; the variation in severity of strokes included: the time window to thrombolytic treatment; and the dose of thrombolytic drug used. There were no direct comparisons of tPA with streptokinase or urokinase: much of the poor outcome in the streptokinase-treated patients might be explained by the inclusion of more severe strokes, greater use of antithrombotic drugs, higher doses, and the longer time to treatment compared with the trials that used tPA.
  
  
  CONCLUSIONS
  Thrombolysis requires further testing in large randomised trials because the risks seem substantial, and the benefit uncertain. The time window for effective treatment remains unclear. There is no objective evidence to suggest that tPA is safer than streptokinase; the apparent hazards and benefits may be similar when differences in trial design and baseline variables are accounted for.
authors.affiliation: Department of Clinical Neurosciences, University of Edinburgh, UK. JMW@skull.dcn.ed.ac.uk
authors.forename: J M
authors.initials: JM
authors.lastname: Wardlaw
authors.forename: C P
authors.initials: CP
authors.lastname: Warlow
authors.forename: C
authors.initials: C
authors.lastname: Counsell
mesh_terms: D002545:Brain Ischemia / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D016017:Odds Ratio; D010960:Plasminogen Activators / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D013300:Streptokinase / Q000627:therapeutic use; D016019:Survival Analysis; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use; D016896:Treatment Outcome; D014568:Urokinase-Type Plasminogen Activator / Q000627:therapeutic use
chemical_list: D013300:Streptokinase; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator