Third International Stroke Trial (IST-3): response to ECASS-3 results

1. Third International Stroke Trial (IST-3): response to ECASS-3 results Professor Peter Sandercock, University of Edinburgh Collaborators Meeting Vienna 26th September 2008

2. Outline • At a population level, between 1% and 3% of all ischaemic strokes are treated • As a result of ECASS-3 the % treated should continue to increase, BUT • The ‘extended time’ licence will still exclude many from treatment, and the public health benefit will be limited • We still need IST-3 to determine if a much wider range can be treated

3. Estimated % of all ischaemic strokes treated with thrombolysis • USA: 1-7%1 • Canada3%2 • Germany3%3 • Sweden 2.3%4 • Cocho et al.,Qureshi et al., 2.Kapral et al,3.Heuschmann et al, • 4. (http://www.riks-stroke.org).

4. How many stroke patients per year in UK* might avoid being ‘dead or dependent’ with each treatment? *130,000 strokes per year

5. Even if the EU approval for thrombolysis is extended to 4.5 hrs, this will still exclude patients who • Are aged > 80 years • Either ‘very mild stroke’ or NIHSS > 25 • Prior stroke within the last 3 months • Have a history of prior stroke + Diabetes • Arrive at 4.5 to 6.0 hours • Other relative contraindications specified in the licence (e.g. ‘extensive infarction’, which is not defined in any way)

6. Stroke patients > 80 years • Patients over 80 have been excluded from randomised trials and the licence • In the UK 30% of all strokes are aged > 80 = 31,000 ischaemic stroke patients each year automatically excluded from thrombolysis

7. Severe stroke (NIHSS > 25) • This man had a large MCA infarct • NIHSS > 25, • rt-PA not approved for him • He spent many months in hospital • He was very disabled • He was no longer able to care for his wife

8. Mild, or rapidly improving strokes (NIHSS < 4) • 2 hours ago, this man developed right hemiparesis, now rapidly improving. • NIHSS < 4, so rt-PA not approved • Many such patients recover without rt-PA, • BUT 15-30% later deteriorate suddenly -> disabling stroke • Should we treat them to prevent deterioration?

9. Vertebro-basilar territory ischaemic strokes • Acute cerebellar infarct • Excluded from previous trials of iv rt-PA • Time window for treatment unclear • Is there benefit from iv thrombolysis for such patients?

10. ‘Extensive infarction’ • Does this patient have ‘extensive infarction?’ • Not defined in EU approval • Much debate about definition • Should this patient be excluded from thrombolysis?

11. Third International Stroke Trial. A large randomised trial to answer the question: can a wider variety of patients be treated? Target: up to 3100 patients from > 100 centres in 12 Countries by mid 2011

12. IST 3 Sample size • 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 3100 patients were recruited, the trial could detect a 4.7% absolute difference in the primary outcome. (remarkably close to the 4% difference seen in the updated Cochrane review) • 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

13. Recruitment by 24.9.2008 = 1281patients

14. Recruitment by country in IST-3

15. Characteristics of the 1214 patients recruited by July 2008

16. Trends in type of patient recruited 2000-2008: AGE No. patients recruited into trial

17. Trends in type of patient recruited 2000-2008: Time to randomisation No. patients recruited into trial

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

19. Overall • Time: Median time to randomization 4.0 h • Age: IST-3 largest randomised controlled trial in ‘older’ hyper-acute stroke • 838 patients > 70 years, • 530 patients > 80 years. • Severity& subtype: • Wide range of severity • Subtypes not much recruited in previous trials: 153 Lacunar infarcts 77 Posterior circulation infarcts

20. How many stroke patients per year in UK* might avoid being ‘dead or dependent’ with each treatment?

21. Letter from chairman of IST-3 Data Monitoring Committee • Dear Peter • IST-3 DMC meeting 23rd September 2008 • In preparation for the release of the ECASS-III results (and blind to those results), the IST-3 Data Monitoring Committee had arranged a teleconference for today (23 September 2008). Our review of the available data from IST-3 and the other trials, including safety information from ECASS-III, does not lead us to consider there to be any need for a change to IST-3. We would encourage the IST-3 collaborators to maintain the increase in the rate of recruitment. The DMC will continue to monitor interim results from IST-3 as planned. • Yours sincerely • Professor Rory Collins • Chair, IST-3 DMC

22. Discussion, collaborators meeting, Vienna, 26/09/08 - 1 • ECASS-3 results were positive, but apply to patients under 80 who meet the strict terms of the EU license • IST-3 group members at the meeting agreed the ECASS-3 results would stimulate more centres to offer a thrombolysis service, which would be good. • We would all continue to recruit eligible patients in IST3

23. Discussion, collaborators meeting, Vienna, 26/09/08 - 2 • There was discussion about whether or not to randomise patients aged under 80, presenting 3- 4.5 hours; if the patient otherwise met the terms of the current licence, we agreed we would generally treat such patients. • However, we agreed that it could still be appropriate to randomise selected patients at 3-4.5 hrs, especially if • they had one of the relative contraindications specified in the EU approval, and • treatment was considered ‘promising but unproven’ for that individual • This shift in recruitment would not bias the trial, since treatment groups are balanced on baseline stroke severity by the randomisation system

24. Discussion, collaborators meeting, Vienna, 26/09/08 - 3 • Need to increase recruitment. IST3 should approach Boehringer to see if they can help with drug supplies in centres where trial has all approvals, but drug supply a problem. • Suggest a statement for stroke guidelines: ‘All patients presenting within 6 hours of acute ischaemic stroke with no clear contraindications for thrombolysis should either be • Treated, • Or, if they don’t exactly meet the terms of the licence, randomised!’

25. Plans for disseminating the need for IST-3 to continue • Teleconference for National Coordinators International Advisory Board Monday 29th September. • Slide sets on website • Webcast (provisionally set for 7th October, details to be confirmed) • Edit and re-submit comment article to BMJ • Publish updated Cochrane review • Karolinska Stroke Update Nov 08 • Collaborators meetings: • UK stroke forum, Harrogate December 2008 • Karolinska Stroke Update Stockholm Nov 17-19 2008 • Swedish collaborators, Stockholm January 2009 • Italian Collaborators, Florence 12-13th February 2009 • Collaborators meeting; ESC Stockholm 26-29th May 2009

26. Summary 1 • Current EU approval is very strict and permits treatment of only small numbers of patients; public health impact is small • ECASS3 results help widen the time window a bit, but will not increase randomised evidence of effects in older people, or the many other categories excluded from treatment by EU approval • If IST-3 results confirm benefits in a wider range, more could be treated and public health impact greatly increased

27. Summary 2 • Updated Cochrane review highlights several questions which remain unanswered, that IST-3 will provide unique data on. • So far, IST-3 has recruited patients that fall outside the current EU approval • Continued recruitment in IST-3 of patients that do not meet the terms of the EU approval is • ethical • very necessary to increase knowledge