The third international stroke trial (IST-3) of rt-PA. Main Results II: IST3 in context of updated meta-analysis of the randomised trials. JM Wardlaw, V Murray, E Berge, G del Zoppo, PAG Sandercock, RI Lindley, G Cohen And the IST-3 Collaborative Group ESC Lisbon May 2012

Disclosures Cochrane review: United Kingdom Medical Research Council, Stroke Association, University of Edinburgh, National Health Service Health Technology Assessment Programme, Swedish Heart-Lung Fund, AFA Insurances Stockholm (Arbetsmarknadens Partners Forsakringsbolag), Karolinska Institutet, Marianne and Marcus Wallenberg Foundation, Research Council of Norway, Oslo University Hospital. The authors of the Cochrane Review have not received financial support from any pharmaceutical company to undertake the review. Individual authors serve on trial steering and adjudication committees but have no personal financial interest or otherwise competing interests with any of the material presented.

Thrombolysis Systematic Review Continuously updated since 1990 All randomised trials of thrombolysis versus control Last update 2009, for rt-PA: 11 trials, n=3977 Remaining uncertainties –Precise estimates of effects on some outcomes Death: early, late Functional outcome Haemorrhage, infarct oedema –Time windows –Age –Aspirin, stroke severity, co-morbidities Stroke 1992; CDSR st edition – 2009; Lancet 1998; Stroke 2003, 2010; Lancet Neurology 2005; BMJ 2009; and others

Methods New trials; new data from existing trials Multiple overlapping ascertainment methods –Two independent reviewers –unadjusted Peto Odds Ratios (ORs), 95% CI, fixed effects, –tests for heterogeneity between all trials and between previous trials combined and IST-3

Methods – Outcomes Outcomes : Early, <7 days –Death –Fatal intracranial haemorrhage –Death not due to intracranial haemorrhage –Symptomatic intracranial haemorrhage –Infarct swelling Late, 3 or 6 months –Deaths between early and late –Total deaths by the end of follow-up –Alive and independent (mRS 0-2) –Favourable (mRS 0-1) –Dependent (mRS 3-5) Subgroups : –Time: <3, 3-6 hours –Age <80 and  80 years, by time –Aspirin, stroke severity

12 trials in total (IST-3 is the only new trial) Previous Current Total N <3hrs hrs >80 y Follow-up 3 months 6 months New data between 2009 and 2012

Early outcomes <7days, up to 6 h

Late outcomes end of follow-up, up to 6 h

Outcomen/ %CI Early death 25 11, 39 Fatal ICH 29 23, 36 Non-ICH death SICH 58 49, 68 Total death 7 -11, 25 mRS , 66 mRS , 77 - = fewer with rt-PA Absolute effects per 1000; treated up to 6 h

Subgroups: Effect of time: <3 vs 3-6 hours

Effect of age: 80 years and time: <3 vs. 3-6 hrs

Effect of age: 80 years and time: <3, 3-6 hr Absolute effect per 1000; mRS 0-2 end of follow-up Age  80>80 yrs Time <6 hrs43 38 (16, 70)(-3, 79) <3 hrs95 96 (35, 155) (35, 157) 3-6 hrs23 -5 (-8, 54) (-61, 50) - = fewer with rt-PA;

Conclusion Effects are highly consistent across all trials despite IST-3 including a wider range of patients SICH is the single largest cause of early hazard Fewer deaths occur with rt-PA between 7 days and the end of follow-up There is no net effect of rt-PA on total death at late follow-up Benefit substantial with treatment <3 hours Benefit possible for some patients out to 6 hours Patients >80yrs have similar benefit to <80s, especially if treated <3h

Conclusion Healthcare systems should aim to treat patients as fast as possible There should be no upper age limit for rt-PA An individual patient data meta-analysis should be performed as soon as possible Trials aimed at finding ways to reduce hazard (SICH) and determine who benefits at later times should proceed as fast as possible

Acknowledgements: IST-3: 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. IST-3 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. Cochrane Funding: MRC, Stroke Association, Univ of Edinburgh, NHS HTA Programme, Norwegian Research Council, Swedish Heart-Lungfund, AFA Insurances, Karolinska Institutet, Marianne and Marcus Wallenberg Foundation. Cochrane: K. Shuler; Lisa Blackwell; Hazel Fraser; Brenda Thomas; Mei-Chiun Tseng; Take Yamaguchi; Charles Warlow; Martin Dennis; Colin Baigent; Steve Davis.

Key methodological points Central web or phone randomisation in 2 trials (IST-3, ECASS 3); rest used sequentially numbered packs Time to treatment: <3h in 2; 3-4.5h in 1; <5h in 1, 3-6h in 1, <6h in 6 Dose: 0.6 – 1.0 mg/kg (most used 0.9) Placebo: 10 identical; 2 open control Blinded follow-up: 5 trials; rest not stated Follow-up: 6m IST-3, 3m or less in the rest

Alive and independent outcome mRS 0-2, 6 hrs Absolute effect: 42/ % CI (19, 66)

Alive and favourable outcome mRS 0-1, 6 hrs Absolute effect: 55/ % CI (33, 77)

Dependency mRS 3-5 Absolute effect: -50/ % CI (-73, -27)