title: Effects of alteplase on survival after ischaemic stroke (IST-3): 3 year follow-up of a randomised, controlled, open-label trial.
abstract: BACKGROUND
  The effect of alteplase on patient survival after ischaemic stroke is the subject of debate. We report the effect of intravenous alteplase on long-term survival after ischaemic stroke of participants in the Third International Stroke Trial (IST-3).
  
  
  METHODS
  In IST-3, done at 156 hospitals in 12 countries (Australia, Europe, and the UK), participants (aged >18 years) were randomly assigned with a telephone voice-activated or web-based system in a 1:1 ratio to treatment with intravenous 0·9 mg/kg alteplase plus standard care or standard care alone within 6 h of ischaemic stroke. We followed up participants in the UK and Scandinavia (Sweden and Norway) for survival up to 3 years after randomisation using data from national registries and compared survival in the two groups with proportional hazards survival analysis, adjusting for key prognostic variables. IST-3 is registered with the ISRCTN registry, number ISRCTN25765518.
  
  
  RESULTS
  Between May 5, 2000, and July 27, 2011, 3035 participants were enrolled in IST-3. Of these, 1948 (64%) of 3035 participants were scheduled for analysis of 3 year survival, and 1946 (>99%) of these were included in the analysis (967 [50%] in the alteplase plus standard care group and 979 [50%] in the standard care alone group). By 3 years after randomisation, 453 (47%) of 967 participants in the alteplase plus standard care group and 494 (50%) of 979 in the standard care alone group had died (risk difference 3·6% [95% CI -0·8 to 8·1]). Participants allocated to alteplase had a significantly higher hazard of death during the first 7 days (99 [10%] of 967 died in the alteplase plus standard care group vs 65 [7%] of 979 in the standard care alone group; hazard ratio 1·52 [95% CI 1·11-2·08]; p=0·004) and a significantly lower hazard of death between 8 days and 3 years (354 [41%] of 868 vs 429 [47%] of 914; 0·78 [0·68-0·90]; p=0·007).
  
  
  CONCLUSIONS
  Alteplase treatment within 6 h after ischaemic stroke was associated with a small, non-significant reduction in risk of death at 3 years, but among individuals who survived the acute phase, treatment was associated with a significant increase in long-term survival. These results are reassuring for clinicians who have expressed concerns about the effect of alteplase on survival.
  
  
  BACKGROUND
  Heart and Stroke Scotland, UK Medical Research Council, Health Foundation UK, Stroke Association UK, Research Council of Norway, AFA Insurance, Swedish Heart Lung Fund, Foundation of Marianne and Marcus Wallenberg, Polish Ministry of Science and Education, Australian Heart Foundation, Australian National Health and Medical Research Council, Swiss National Research Foundation, Swiss Heart Foundation, Assessorato alla Sanita (Regione dell'Umbria), and Danube University.
authors.affiliation: Department of Internal Medicine, Oslo University Hospital, Oslo, Norway. Electronic address: eivind.berge@medisin.uio.no.
authors.forename: Eivind
authors.initials: E
authors.lastname: Berge
authors.affiliation: Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Cohen
authors.affiliation: Department of Neurology, University Hospital of North Norway, Tromsø, Norway; Institute of Clinical Medicine, University of Tromsø, Tromsø, Norway.
authors.forename: Melinda B
authors.initials: MB
authors.lastname: Roaldsen
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Lundström
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Isaksson
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
authors.forename: Ann-Sofie
authors.initials: AS
authors.lastname: Rudberg
authors.affiliation: Department of Internal Medicine, Oslo University Hospital, Oslo, Norway.
authors.forename: Karsten Bruins
authors.initials: KB
authors.lastname: Slot
authors.affiliation: Health Research Institute, University of Limerick, Limerick, Ireland.
authors.forename: John
authors.initials: J
authors.lastname: Forbes
authors.affiliation: Health Economics Research Centre, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
authors.forename: Joel
authors.initials: J
authors.lastname: Smith
authors.affiliation: Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Drever
authors.affiliation: Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Wardlaw
authors.affiliation: George Institute for Global Health, University of Sydney, Sydney, NSW, Australia; Discipline of Medicine, University of Sydney, Sydney, NSW, Australia.
authors.forename: Richard I
authors.initials: RI
authors.lastname: Lindley
authors.affiliation: Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Peter A G
authors.initials: PA
authors.lastname: Sandercock
authors.affiliation: Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: William N
authors.initials: WN
authors.lastname: Whiteley
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002545:Brain Ischemia / Q000188:drug therapy* / Q000401:mortality*; D005260:Female; D005343:Fibrinolytic Agents / Q000009:adverse effects / Q000494:pharmacology*; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D017063:Outcome Assessment, Health Care; D020521:Stroke / Q000188:drug therapy* / Q000401:mortality*; D016019:Survival Analysis; D010959:Tissue Plasminogen Activator / Q000009:adverse effects / Q000494:pharmacology*
chemical_list: D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator