1. The need for trials of i.v. thrombolysis in acute ischaemic stroke 10 th January 2008.

2. Acute stroke & TIA management Stroke & TIA = emergencies: ‘Time is brain’ Well-organised acute stroke & TIA system –Pre-hospital triage. Stroke? -> 999 ambulance –skilled clinical assessment –Re-triage in A&E -> stroke -> admit SU & ?thrombolyse, TIA -> same-day neurovascular OP 1 –immediate CT scan 2 Admit to comprehensive care Stroke Unit –acute care with physiological monitoring –protocols for management of complications –multidisciplinary rehabilitation from day 1 –care until discharge 1. Rothwell EXPRESS Lancet 2007; 2.Wardlaw, Stroke. 2004;35:2477-2483

3. Current clinical practice

4. Who should get thrombolysis with i.v. rt-PA? 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

5. Only a small, variable proportion of patients get rt-PA in USA, Germany Authorno.no. % treated hospitals patients rt-PA (range) USA Johnstone 42 1,195 4.1% (0-12%) Furlan 29 3,948 1.8% (0-10%) Reed 137 23,058 1.6% (0-5%) Germany Heuschmann 104 13,440 3.0% (0-18%)

6. 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

7. Evidence

8. Randomised trials of thrombolysis vs control in acute myocardial infarction Total no. patients by 1994!58,600 Randomised 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

9. rt-PA trials meta-analysis. Benefit declines with increasing time to treatment, but scope for benefit up to 6h? Benefit Harm 3 hours6 hours Upper and lower 95% confidence limits Line of no effect NNT 10 ‘Grey area’ NNT 10? > 30? or net harm?

10. ‘Grey areas’ of uncertainty: 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 controlled trials of i.v. thrombolysis

12. IST-3

13. Third International Stroke Trial. A large randomised trial to answer the question: can a wider variety of patients be treated? Target: up to 6000 patients from > 100 centres in 14 Countries

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 or web 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. 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

16. 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. Progress to date

18. Recruitment = 1028 patients randomised by 11.1.08.

19. Recruitment by country (07/01/08) CountryNo. centresPts.% UK34 39538% Poland517218% Norway1212713% Italy14929% Sweden Australia Belgium 14 10 3 82 78 56 7% 6% Austria Canada Mexico 111111 11 6 2 1% -

20. 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

21. Has the ‘grey area’ 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

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 scan102 (26%) Persisted (seen on 1 st & 2 nd scan) 88 (23%) Present on baseline, disappeared by 2 nd scan 64 (16%)

29. 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.

30. 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

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

32. 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

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

34. 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!