1. Third International Stroke Trial (IST-3): response to ECASS-3 results Professor Peter Sandercock, University of Edinburgh Collaborators Meeting Vienna 26 th 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 Canada 3% 2 Germany 3% 3 Sweden 2.3% 4 1.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? % treated with this intervention Number treated per year Benefit per 1000 treated Number who avoid death or dependency Aspirin80%104000131350 Stroke Unit60%78000564370 Thrombolysis2%208063130 Thrombolysis30%31200471470 *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 CountryNo. centresPts.% UK3951040% Poland519215% Norway1314612% Sweden1413110% Italy201169% Australia101008% Belgium3595% Austria2171% Canada171% Mexico130% Portugal10 0% Total1091281

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

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? % treated with this intervention Number treated per year Benefit per 1000 treated Number who avoid death or dependency Aspirin80%104000131350 Stroke Unit60%78000564370 Thrombolysis2%208063130 Thrombolysis30%31200471470

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. 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 Discussion, collaborators meeting, Vienna, 26/09/08 - 1

23. 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 Discussion, collaborators meeting, Vienna, 26/09/08 - 2

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 29 th 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