IST-3, SITS MOST ECASS-3 & DEFUSE

1. IST-3, SITS MOST ECASS-3 & DEFUSE Professor Peter Sandercock University of Edinburgh, UK ESC May 30th 2007 Glasgow Competing interests:

2. Outline Current knowledge SITS MOST: Current use of rt-PA ‘in licence’ Selecting patients for thrombolysis Plain CT Perfusion MR or CT DEFUSE Current trials of iv thrombolysis DIAS-2 ECASS-3 IST-3

3. Randomised trials of thrombolysis vs control in acute myocardial infarction Total no. patients by 1994! 58,600 Randomised trials trials of thrombolysis vs control in acute ischaemic stroke Total (all agents) 5,675 rt-PA 2,700 rt-PA < 3hrs 930 rt-PA aged > 80 years 42

4. Number of older patients with acute stroke per year in UK 87,000 patients aged > 70 years 47,000 patients aged > 80 years = A big problem for acute medical services!

5. Variation in use of rt-PA for acute ischaemic stroke ‘within licence’ in Europe recorded in SITS-MOST registry 2007 SITS register November 2005 SITS-MOST 29/1/2007

6. rt-PA trials meta-analysis. Benefit declines with increasing time to treatment, but scope for benefit up to 6h (Lancet 2004; 363: 768–74) Benefit Upper and lower 95% confidence limits Line of no effect Harm 3 hours 6 hours

7. What is known from randomised controlled trials (RCT) about i.v. rt-PA for acute ischaemic stroke • Very limited RCT data on effects patients aged > 80 years • ‘Time is brain’; early treatment is best • EMEA approval for use < 3hrs in patients aged less than 80 years • Application of treatment in routine practice varies from < 1 to 200 per million people. • Potential for benefit in selected patients up to 6hrs; can the licence be extended?

8. Selecting patients by presence/absence of ‘Early ischaemia’ signs on CT: effect on response to rt-PA • Observational studies show1 extent of early ischaemic change (ASPECTS score) influences prognosis after stroke • But data from two randomised trials, (1,926 patients ), provide no evidence that presence of ‘early infarct change’ significantly modifies treatment effect of thrombolysis2 • But analysis has insufficient statistical power – need larger RCTs 1. Hill CMAJ 2005;172(10):1307-12. . 2. Wardlaw et al, Radiology 2005: 235: 444

9. Selecting patients by MR or CT perfusion • Concept: perfusion-diffusion ‘mismatch’ on MR or CT identifies patients with acute ischaemic tissue likely to be ‘salvaged’ by reperfusion therapy • Several methods are available to measure the perfusion lesion with MR (PWI) & CT • No consensus over which method is best • Prospective study to assess 10 currently available methods: does the method affect the % of patients with ‘mismatch’?1 1. Kane, Wardlaw, Carpenter. Stroke 2007 (in press)

10. Review of observational studies of mismatch and outcome: infarct growth occurs in patients without mismatch Kane et al, JNNP 2007;78;485-491

11. Results: 10 perfusion parameters for one patient

12. Proportion with mismatch varies enormously with method (3-72%): need an internationally agreed standard!

13. Where are we with ‘mismatch’ after DEFUSE and before EPITHET? • DEFUSE:1 observational study of MRA, PWI/DWI in 74 patients treated off label with rt-PA 3-6 hours (6 unsuccessful PWI); 37/68 (54%) had mismatch • Early reperfusion was more often associated with favourable clinical response in patients with a perfusion/diffusion mismatch (p =0.04) • EPITHET: RCT of rt-PA vs control in patients 3-6 hours. All have DWI/PWI. Will provide randomised evidence on whether mismatch modifies response to rt-PA. 1. Albers et al. Ann Neurol 2006; 60 (5): 508–517.

14. Current randomised controlled trials of i.v. thrombolysis

15. Third International Stroke Trial. A large randomised trial to answer the question: can a wider variety of patients be treated? Target: 6000 patients from 300 centres in 36 Countries

16. Main features of IST - 3 • International, multi-centre, Prospective, Randomised, Open, Blinded Endpoints study of i.v. rt-PA vs control. Independent. Investigator-led • Primary outcome: the proportion of patients alive and independent at six months (Modified Rankin 0,1 or 2) • Randomisation by telephone or internet with on-line minimisation to balance key prognostic factors. • Blinded central review of all scans

17. Recruitment & randomisation If you consider your patient: • Has a clear indication for thrombolysis (i.e. meets terms of licence): Treat with rt-PA. • Has a clear contraindication to thrombolysis: DO NOT treat with rt-PA. • Thrombolysis is ‘promising but unproven,’ consider RANDOMISINGthe patient in IST-3.

18. Recruitment Recruitment at 25.05.2007 = 808:

19. Recruitment by country

20. (Median = 4.1 hours)

21. Trends in no. hours from onset to randomisation

22. Age at randomisation. 280 patients aged > 80 = increased world evidence base 7 x!

23. OCSP subtype

24. Report of the IST 3 Data Monitoring Committee We reviewed analyses based on 597 randomised patients. We should like to commend the investigators for the high quality and completeness of the data, as well as the exemplary conduct of the trial. The DMC did not consider it necessary to recommend any change to the study protocol… we would encourage the investigators to make every effort to recruit all eligible patients so that reliable evidence emerges as rapidly as possible. Professor Rory Collins, Chairman

25. www.ist3.com Lots of new features on the website!

26. We need further large trials to: • Determine reliably: • whether there are patients outside strict criteria of current approval who benefit < 3hrs • which type of patients benefit 3-6 hours • Balance of risk and benefit in older patients • New centres welcome to join IST£ and ECASS-3 • Contribute further evidence to: • persuade doubting clinicians to change practice • reduce inequalities in patient access to treatment • persuade health authorities to fund: • cost of drug treatment • a well-organised acute stroke service in every acute hospital