title: Thrombolysis (different doses, routes of administration and agents) for acute ischaemic stroke.
abstract: BACKGROUND
  Stroke is a leading cause of death and disability world wide. Thrombolysis with recombinant tissue plasminogen activator (rt-PA) is licensed for treatment of acute ischaemic stroke in the early hours after symptom onset. It has been shown in randomised controlled trials (RCTs) and the 2009 Cochrane review of thrombolysis for acute ischaemic stroke to reduce dependency but at the increased risk of intracranial haemorrhage. Methods to reduce the risk of haemorrhage while retaining or enhancing the benefit could increase the use of thrombolytic treatment. While most available information comes from RCTs of intravenous rt-PA at 0.9 mg/kg, it is possible that other doses, drugs and other routes of administration might increase benefit and reduce the hazard.
  
  
  OBJECTIVE
  To assess the risks and benefits of different thrombolytic agents, doses and routes of administration for the treatment of acute ischaemic stroke.
  
  
  METHODS
  We searched the Cochrane Stroke Group Trials Register (May 2012), MEDLINE (1966 to May 2012) and EMBASE (1980 to May 2012). We handsearched journals and conference proceedings, searched ongoing trials registers and contacted pharmaceutical companies and researchers.
  
  
  METHODS
  Unconfounded randomised and quasi-randomised trials of different doses of a thrombolytic agent, or different agents, or the same agent given by different routes, in people with confirmed acute ischaemic stroke.
  
  
  METHODS
  Two review authors independently assessed trial eligibility and quality, and extracted the data using a structured proforma. We cross-checked and resolved discrepancies by discussion to reach consensus. We obtained translations and additional information from study authors where required.
  
  
  RESULTS
  We included 20 trials involving 2527 patients. Concealment of allocation was poorly described. Different doses (of tissue plasminogen activator, urokinase, desmoteplase or tenecteplase) were compared in 13 trials (N = 1433 patients). Different agents (tissue plasminogen activator versus urokinase, tissue-cultured urokinase versus conventional urokinase, tenecteplase versus tissue plasminogen activator) were compared in five trials (N = 875 patients). Five trials (N = 485) compared different routes of administration. As some trials compared different agents and different doses, some patients contributed to two analyses. There was an approximately three-fold increase in fatal intracranial haemorrhages in patients allocated to higher than to lower doses of the same thrombolytic drug (odds ratio (OR) 2.71, 95% confidence interval (CI) 1.22 to 6.04). There was no difference in the number of patients who were dead or dependent at the end of follow-up between those allocated higher or lower doses of thrombolytic drug (OR 0.86, 95% CI 0.62 to 1.19). Higher versus lower doses of desmoteplase were associated with more deaths at the end of follow-up (OR 3.21, 95% CI 1.23 to 8.39). There was no evidence of any benefit for intra-arterial over intravenous treatment.
  
  
  CONCLUSIONS
  These limited data suggest that higher doses of thrombolytic agents may lead to higher rates of bleeding. However, the evidence is inadequate to conclude whether lower doses of thrombolytic agents are more effective than higher doses, or whether one agent is better than another, or which route of administration is the best, for acute ischaemic stroke. At present, intravenous rt-PA at 0.9mg/kg as licensed in many countries appears to represent best practice and other drugs, doses or routes of administration should only be used in randomised controlled trials.
authors.affiliation: Division of Clinical Neurosciences, University of Edinburgh, Edinburgh, UK. joanna.wardlaw@ed.ac.uk.
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Wardlaw
authors.forename: Panos
authors.initials: P
authors.lastname: Koumellis
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
mesh_terms: D000208:Acute Disease; D002545:Brain Ischemia / Q000188:drug therapy*; D002543:Cerebral Hemorrhage / Q000139:chemically induced* / Q000453:epidemiology; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D020521:Stroke / Q000188:drug therapy*; D000077785:Tenecteplase; D015912:Thrombolytic Therapy / Q000009:adverse effects; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000009:adverse effects; D014568:Urokinase-Type Plasminogen Activator / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; D000077785:Tenecteplase