The third international stroke trial (IST-3) main results: primary and secondary outcomes among 3035 patients The IST3 collaborative group hospitals in UK, Poland, Italy, Sweden, Norway, Australia, Portugal, Belgium, Austria, Switzerland, Canada, Mexico 23 rd May 2012 Lisbon Disclosures: Boehringer Ingelheim donated rt-PA and placebo for the first 300 patients but had no other part in the study. Available online at From today

Main features of IST - 3 Randomised, open study i.v. rt-PA vs control Target: 3100 acute ischaemic stroke < 6h Randomised by phone or internet: Key prognostic factors balanced Imaging CT or MR Oxford Handicap Scale (OHS) at 6 months Primary outcome: % ‘alive and independent’ (OHS 0-2) Secondary: ordinal ‘shift’ analysis of OHS 1 1. Analysis plan. Int J Stroke. 2012;7:186-7

Follow-up Monitor clinical state and BP for 24h hrs repeat CT/MR 7 days, death or hospital discharge - if sooner - complete CRF: 6 months: follow-up by postal questionnaire to patient or proxy / blinded telephone follow up by national coordinating centre

Adjudication, safety, monitoring International panel of experts assessed baseline and follow-up scans blind to clinical details & treatment. Clinical and scan data from patients with events / deaths < 7 days adjudicated blind to treatment allocation. Independent Data Monitoring Committee Site Monitoring Plan agreed with regulators, included targeted source data verification* *Lancet May 23 rd 2012

Eligibility and randomisation If patient fitted main eligibility/exclusion criteria clinician/patient/family discuss. If there is a: Clear INDICATION FOR rt-PA → TREAT (i.e. meets terms of current licence and patient agrees) Clear CONTRAINDICATION TO rt-PA → DON’T TREAT rt-PA ‘PROMISING BUT UNPROVEN’ → RANDOMISE

Baseline characteristics 1 (n=3035) 849 (28%) randomised < 3 hours 1617 (53%) aged > 80 years 1305 (43%) TACI syndrome 914 (30%) in AF 970 (32%) baseline NIHSS > 16 95% did not meet EU approval for rt-PA Treatment and control groups balanced on all key factors 1.Trials 2011, 12:252.

rt-PA (n=1515) Control (n=1520) n(%)n 104(7%)16(1%) Fatal & non-fatal intracranial haemorrhage < 7 days applying the ‘Cochrane’ definition, of SICH, the 7% IST-3 frequency is comparable with the 7.3% (SITS) registry of 6483 patients treated within licence in routine clinical practice 1 1. Wahlgren, Lancet 2007; 369: 275–82 P <

Deaths n rt-PA (%)n Control (%)p Within 7 days163(11%)107(7%)↑0.001 After 7 days, before 6 mo. 244(16%)300(20%)↓0.009 All deaths by 6 months. 408(27%)407(27%)0.6

Primary outcome: ‘alive and independent’ (OHS 0-2) rt-PA (n=1515) control (n=1520) n(%)n 554(37%)534(35%) Absolute difference/1000 = 14 more alive and independent (95% CI -20 to 48) NS

Ordinal analysis 6 month OHS Favourable shift; adjusted common odds ratio 1·27 (95% CI 1·10- 1·47), p=0·001 or, the odds of surviving with less disability were 27% greater for patients treated with rt-PA

Subgroups Time (hours) from stroke to randomisation 0-3h 3-4.5h 4.5-6h Age < Age> All

(interaction) Subgroups: adjusted effect on primary outcome The treatment odds ratio in each subgroup has been adjusted for the linear effects of the other key variables

At six months, for every 1000 patients treated with rt-PA All ages 0-6 hrs 14 more alive and independent (NS) 29 more ‘favourable outcome’ (p=0·018) Favourable shift in OHS(p=0.001) No difference in deaths In patients > 80 years 0-6hrs 38 more alive and independent In patients all ages < 3hrs 80 more alive and independent

Summary of evidence For the types of patient recruited in IST-3, despite the early hazards, thrombolysis within six hours improved functional outcome. Benefit did not appear to be diminished among elderly patients. Benefit was greatest among those randomised within 3 hours

Acknowledgements: The 3035 patients, the 156 hospitals in the IST-3 group, the Data Monitoring Committee, the MRC Steering Committee, Image Reading Panel, Event adjudication panel, International Advisory Board. Funding: Medical Research Council (managed by NIHR on behalf of the MRC-NIHR partnership), Stroke Association, The Health Foundation,, The Research Council of Norway, AFA Insurances (Sweden), the Swedish Heart Lung Fund, The Foundation of Marianne and Marcus Wallenberg, Stockholm County Council and Karolinska Institute Joint ALF-project grants (Sweden), the Government of Poland, the Australian Heart Foundation, Australian NHMRC, the Swiss National Research Foundation, the Swiss Heart Foundation, the Foundation for health and cardio- /neurovascular research, Basel, Switzerland and the Assessorato alla Sanita, Regione dell'Umbria. Drug and placebo for the 300 patients in the double-blind component of the start-up phase were supplied by Boehringer-Ingelheim GMBh. IST-3 acknowledges the extensive support of the NIHR Stroke Research Network, NHS Research Scotland (NRS), through the Scottish Stroke Research Network, and the National Institute for Social Care and Health Research Clinical Research Centre (NISCHR CRC). The imaging work was undertaken at the Brain Imaging Research Centre, a member of the SINAPSE collaboration, at the Division of Clinical Neurosciences, University of Edinburgh. SINAPSE is funded by the Scottish Funding Council (SFC) and the Chief Scientist Office of the Scottish Executive (CSO). Additional support was received from Chest Heart and Stroke Scotland, Desacc, University of Edinburgh, Danderyd Hospital R&D Department, Karolinska Institutet, the Dalhousie University Internal Medicine Research Fund.