IST-3: Progress, continuing uncertainties in thrombolysis and challenges

1. IST-3: Progress, continuing uncertainties in thrombolysis and challenges Peter Sandercock & Richard Lindley Co-chief investigators, IST-3 IST-3 Collaborators Meeting, Glasgow 30th May 2007

2. Recruitment Recruitment = 809 patients from 83 centres in 9 countries

3. Patient no 801 Dr Eric Lindstrom and team Uppsala, Sweden

4. Recruitment by country Dr Kneale Metcalf, Norfolk and Norwich Hospital 300th UK patient

5. (Median = 4.1 hours) 152 patients < 3 hours

6. 6 month outcome

7. Joanna Wardlaw, Imaging CI

8. Sending images to Edinburgh Eleni • We have re-organised office to reduce work for collaborators & to reduce errors • We are keen to help you find the easiest way to send your scans • If you have problems sending scans, contact Eleni.Sakka@ed.ac.uk • Options for sending scans • Web upload • FTP • CD ROM • Cut film

9. Sending images to Edinburgh • Sometimes the date and time of the scan is altered during the process of transferring it electronically (to the date and time it was copied, not the time it was performed) • So, to reduce problems in scan handling, we now ask you please to complete an image transfer form for EVERY scan you send (even if you send the scan electronically by email/web upload, CD etc). This includes the date and time it was performed • If you’re sending scans, please let us know which ones are perfusion scans

10. Sending images: scan transfer form • Please send an image transfer form with EVERY scan • On the scan transfer form, tell us if the scan is • pre-randomisation • a routine post-randomisation scan at 24-48h • an extra scan • If you send the scan electronically, please tell us if the file includes a perfusion study

11. Expert’s opinion of randomisation CT

12. 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

13. Thank you! You are now participants in the largest ever trial of stroke thrombolysis! And now ... A reminder of the areas of uncertainty & How do we meet the challenge to make IST-3 even larger?

14. 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

15. Thrombolysis use in USA Matchar et al. Stroke 2007; 38: 459

16. Determinants of Treatment • 15% relative increase in treatment between 2002 and 2004 • 16-fold increase in the likelihood of treatment if in a Stroke Centre (www.strokecenter.org) • Larger hospital size, teaching centre and urban location were weaker predictors of treatment

17. Challenges: can we get > 20% of ischaemic stroke patients treated with rt-PA? Within 6 Hrs Stroke team Evaluation and Triage

18. ‘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 …

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

20. Philosophy of IST-3 group • Realistic treatment protocol for typical hospitals: • Reasonable clinical assessment1 • CT based imaging • Intravenous treatment • Stroke unit based care • Standard of care increasingly feasible • Recruit patients in whom treatment is promising but unproven 1 Hand et al Stroke 2007

21. NIHSS at randomisation (median = 11)

22. Age at randomisation. 292 patients aged > 80 = increased world evidence base 7 x!

23. IST-3 trends in no. hours from onset to randomisation

24. Ideal Recruitment

26. Recruitment drive • Please help to increase recruitment by: • Presentations in your centre • Publicity and presentations in your country • Helping to recruit new centres in your country • Approach Stroke Networks in your country for support • Co-ordinating office in Edinburgh working hard to help new countries and centres to join (Portugal, Hungary, Brazil, India)

27. Third International Stroke Trial: an international collaboration to address the world-wide problem of stroke

28. Publications so far • Over 40 published abstracts • Peer reviewed publications (links to publications on IST-3 website) on: • Methods of consent (Cerebrovasc Dis 2006) • Protocol (Int J Stroke 2006) • Protocol Summary (Lancet website 2006) • Submitted • Validation of prognostic model at baseline (Submitted to JNNP) • Correlation between OCSP clinical syndrome and baseline CT on first 500 patients (in revision)

30. Imaging update

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

32. 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)

33. Results: 10 perfusion parameters for one patient

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

35. Imaging update: publications on imaging methods • Magnetic resonance perfusion-diffusion mismatch and thrombolysis in acute ischaemic stroke: a systematic review. Kane, Sandercock, Wardlaw. J. Neurol. Neurosurg. Psychiatry 007;78;485-491. • Comparison of ten different Magnetic Resonance perfusion imaging processing methods in acute ischemic stroke. Effect on lesion size, proportion of patients with diffusion/perfusion mismatch, clinical scores and radiological outcomes. Kane, Carpenter, Chappell, Rivers, Armitage, Sandercock, Wardlaw. Stroke (in press) • The NeuroGrid stroke exemplar clinical trial protocol. Wardlaw, Bath, Sandercock, Perry, Palmer,Watson, Lloyd, Geddes, Farrall. Int J Stroke 2007: Vol 2, February 2007, 63–69

36. Extra slides

37. OCSP subtype by country

38. OCSP subtype About 100 lacunar and 50 Posterior circulation infarcts

39. Uptake of thrombolysis for stroke requires a large convincing trial!

40. Main features of IST - 3 • International, multi-centre, Prospective, Randomised, Open, Blinded Endpoints study of i.v. rt-PA vs control. • Target 6000 patients • Primary outcome: the proportion of patients alive and independent at six months (Modified Rankin 0,1 or 2) • 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.

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