Thrombolysis for acute ischaemic stroke 1: why do we still need to do randomised trials & IST3?

1. Thrombolysis for acute ischaemic stroke 1: why do we still need to do randomised trials & IST3? Professor Peter Sandercock On behalf of IST-3 Collaborative Group and for Gruppo Italiano IST-3 University of Edinburgh

2. Who SHOULD get thrombolysis with i.v. rt-PA ‘within licence’? • Patient MUST be • able to be treated within 3 hours • aged under 80 • not have a history of prior stroke + Diabetes • not have any of the standard exclusions • NIHSS < 25 • No extensive infarction on CT • There must be a discussion of risk/consent

3. Who ACTUALLY gets rt-PA for acute ischaemic stroke ‘within licence’ in Europe? SITS-MOST 29/1/2007

4. Why so much variability in clinical practice? • Insufficient evidence base • Licence does not apply to older people • What to do after 3 hours? • How to balance risk and benefit? • No consensus on imaging • Which method: CT or MR? • How should CT or MR appearance influence decision about thrombolysis?

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

6. 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!

7. rt-PA trials meta-analysis. Benefit declines with increasing time to treatment, but scope for benefit up to 6h? Benefit Upper and lower 95% confidence limits NNT 10 ‘Grey area’ NNT 10? > 30? or net harm? Line of no effect Harm 3 hours 6 hours

8. Risk of treatment: fatal haemorrhage 3%

9. Risk of NOT treating with rt-PA? Fatal deterioration due to swelling in large infarcts. CT at 5hrs CT at 72 hrs Early ischaemic change Swelling and midline shift

10. ‘Area Grigia’ di incertezza: i.v. rt-PA promising but unproven for patients who: • Present < 3hrs & do not exactly meet NINDS criteria • All patients 3-6hours • Older patients (>75 years) • Severe stroke, mild stroke…... • Have subtle, early ischaemic change on CT • Etc etc …

11. Current randomised trials of i.v. thrombolysis vs control

13. Thrombolysis for acute ischaemic stroke 2: progress with the trial. Where are we now, what is our target? Professor Peter Sandercock On behalf of IST-3 Collaborative Group and for Gruppo Italiano IST-3 University of Edinburgh

14. Main features of IST - 3 • International, multi-centre, Prospective, Randomised, Open, Blinded Endpoints study of i.v. rt-PA vs control. • Primary outcome: the proportion of patients alive and independent at six months • Simple central telephone randomisation with on-line minimisation to balance key prognostic factors. • Web-based blinded detailed central review of all scans (ASPECTS, 1/3 MCA rule, dense MCA etc) • Conducted to EU GCP standards.

15. IST-3 trial: randomisation If patient fits main eligibility/exclusion criteria, Clinician/patient/family discuss. If: • 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

17. Recruitment by country: coppa del mondo

18. Gruppo Italiano IST-3 : 2006

19. Gruppo Italiano IST-3 : 2007 *recruited a patient within last 30 days

20. Centri che stanno per partire • Genova • Modena • Foggia • Legnango • Peschiera • Verona • Bologna • Reggio Emilia • Bari

21. Has the ‘area grigia’ changed since IST-3 began?Characteristics of patients at baseline

22. (Median = 4.1 hours)

23. Trends in type of patient recruited since trial began: Time to randomisation No. patients recruited into trial

24. Age at randomisation > 330 patients aged > 80 = increased world evidence base 8 x!

25. Trends in type of patient recruited since trial began: age No. patients recruited into trial

26. Trends in type of patient recruited since trial began: Infarct subtype No. patients recruited into trial

27. Expert’s opinion of randomisation CT* • Acute ischaemic change 64% • Periventricular lucencies 44% • Normal 6% *scans may show more than one abnormality

28. Frequency of hyperdense artery on baseline and follow-up CT Present on baseline scan 152 (39%) Present on follow-up scan 102 (26%) Persisted (seen on 1st & 2nd scan) 88 (23%) Present on baseline, disappeared by 2nd scan 64 (16%)

29. Has the ‘area grigia’ changed since IST- began?NO

30. 2007 report of the IST 3 Data Monitoring Committee We reviewed analyses based on 896 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

31. Recruitment strategy: the future • Focus efforts on countries already in trial • Increase number of centres in these countries • Work with existing centres to maintain or increase recruitment.

32. Recruitment strategy: the future. In Italy this means: • Can your centre recruit enough so you move up (or you can join) Serie A in Gruppo Italiano IST-3? • Can Italy move up in the coppa del mondo IST-3?

33. Projected total number of centres, and number of active centres

34. Sample size (MRC Protocol) • with 1000 patients we could detect a 7% absolute difference in the primary outcome, which is consistent with the effect size among patients randomised within 3 hours of stroke in the Cochrane review. • If 3500 patients were recruited, the trial could detect a 4% absolute difference in the primary outcome. • With 6000 patients, mostly treated between 3 & 6 hours of onset, the trial could detect a 3% absolute difference in the primary outcome Protocol version 1.92 September 2005

35. Recruitment = 982 patients randomised by 30.11.07. Almost reached 1st target! Recruitment

36. Hot news! • We applied to MRC to extend trial to reach one of our targets • UK Medical Research Council • Recognised the importance of the trial • agreed to this plan • given extra funds (~ €500,000), • IST-3 can continue recruitment to mid 2011and report trial in 2012 if needed

37. Sample size (MRC Protocol) • with 1000 patients we could detect a 7% absolute difference in the primary outcome, which is consistent with the effect size among patients randomised within 3 hours of stroke in the Cochrane review. • If 3500 patients were recruited, the trial could detect a 4% absolute difference in the primary outcome. • With 6000 patients, mostly treated between 3 & 6 hours of onset, the trial could detect a 3% absolute difference in the primary outcome Protocol version 1.92 September 2005

38. New plan: recruit 3,100 by 2011 With 3100, we could detect a 4.7% benefit. NNT 21

39. Third International Stroke Trial. A large randomised trial to answer the question: can a wider variety of patients be treated? Target: 3100 patients or more from ~ 100 centres in 14 Countries by 2011

40. Conclusions • IST-3 asks very important questions • Who benefits? • By how much? • How to make best use of CT to select patients? • It is the LAST CHANCE to get these data • We MUST go on • The approval by MRC = recognition of the scientific importance of our work • Our data will influence clinical practice in the REAL world!