1. Thrombolysis for patients > 80 – a different view Peter Sandercock On behalf of the IST3 collaborative Group UKSF Glasgow 1 st December 2009

2. Some questions 1.Why does age > 80 matter? 2.Are people >80 years getting rt-PA? 3.For people aged > 80 vs < 80 yrs -Are the benefits different? -Are the risks (intracranial haemorrhage) different? 4. Is there a role for specialist brain imaging to sort out which older patients should receive thrombolysis? 5. Do we need more trials in the over 80s?

3. Why does it matter? It’s a big problem Every year in the UK ~ 30,000 people aged > 80 have an acute ischaemic stroke EU approval for thrombolysis excludes > 80 year olds Ageism in rt-PA usage

4. Ageism: the older you are, the less likely you are to get rt-PA for stroke: Germany Förch. Stroke 2009;40:1900-2 Age

5. Randomised trial evidence for rt- PA in the over 80’s? Wardlaw J et al, Cochrane Database Systematic Reviews 2009 11 randomised trials of rt-PA for stroke 3977 patients Only 42 patients aged > 80 years!

6. In patients aged < 80: effect on death OR 1.14 (0.95-1.38) Wardlaw J, Cochrane Database Systematic Reviews 2009 Non-significant 14% increase in odds of death (95% CI, 5% reduction to 38% increase)

7. Non-randomised cohort studies. Outcome after iv thrombolysis for stroke > 80 versus <80 years of age: 6 cohort studies included 2,244 patients 477 aged ≥80 years Potential for bias - can’t adjust for baseline differences in those 80 years Engelter. Age and Ageing 2006; 35: 572–580

8. Non-randomised cohorts: Death Engelter. Age and Ageing 2006; 35: 572–580 People aged > 80 more likely to die with rt-PA

9. Non- randomised cohorts: good outcome in survivors (mRS 0-1) Engelter. Age and Ageing 2006; 35: 572–580 People aged > 80 less likely to survive with a good outcome after rt-PA

10. Summary of non-random studies Imbalances in baseline variables; hard to assess balance of risk and benefit Need reliable randomised evidence on the balance of risk and benefit For stroke patients aged ≥80 years, it is safe and reasonable to include such patients in randomised placebo- controlled trials. Engelter. Age and Ageing 2006; 35: 572–580

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

12. 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

13. Randomised trials with IST-3 design (to include > 80’s) applauded … will inevitably include patients with comorbidities, but we need to embrace frailty… … must be flexible and use creative strategies to facilitate participation of older individuals in clinical trials. … endpoints that are relevant to older individuals should be assessed: … physical handicap, … quality of life.’ Lancet Neurology. Editorial 2009

14. Number of patients recruited per quarter year in each age and time stratum Age time(h) ECASS-3 published

15. Imaging for selection??? Structural –CT WM lesions, atrophy, old strokes –MR Microbleeds, white matter lesions, atrophy Angiography –CT –MR Perfusion –CT –MR No reliable RCT evidence!

16. Ongoing randomised trials IST-3 all ages < 6hrs. target = 3100 patients Predicted 1000 patients > 80 years To date IST-3 has recruited more than 800 patients > 80 years: –300/800 (37%) recruited 0 - 3 hrs –640/800 (79%) recruited 0 - 4.5 hrs More UK centres welcome TESPI 600 patients > 80 years < 3hrs To date recruited 36 patients

17. Summary: rt-PA for the over 80’s Why does it matter? In the UK 30,000 people/yr aged > 80 have an acute stroke! Are they getting rt-PA? Very few, and variably! For people aged > 80 vs < 80 yrs: Are the benefits different? Don’t know! Are the risks different? Don’t know! Specialist brain imaging to select? Don’t know! Need more RCT evidence in over 80s? YES

19. Main features of IST - 3 International, multi-centre, Prospective, Randomised, Open, Blinded Endpoints (PROBE) design study of i.v. rt-PA vs control. Independent. Investigator-led Primary outcome: the proportion of patients alive and independent at six months (Modified Rankin 0,1 or 2) Randomisation by telephone or internet with on- line minimisation to balance key prognostic factors. Blinded central review of all scans Recruitment ends mid 2011, results early 2012

20. USA: Increasing age reduces odds of treatment with rt-PA: Reduction (compared with age < 60) p Age 60-69*30%0.07 Age 70-79*30% 0.003 Age 80-89*60% < 0.001 Age 90 +*80% < 0.001 Survey of 23,058 ischemic strokes in 137 US hospitals. Reed et al, Stroke 2001; 32: 1832-1840 *

21. Neurology in the elderly: more trials urgently needed 1 the average age of participants in the NINDS trial of alteplase for acute stroke was 67 years 1 patients aged 80 years and older were specifically excluded from the post-registration studies; 1 consequently, alteplase is not licensed for use in patients older than 80 years. 1 ‘…the International Stroke Trial (IST-3), which is including substantial numbers of patients in this age-group, will definitively assess the effectiveness of alteplase for the very elderly’ 2 1. Editorial Lancet Neurology 2009. 2.Sanossian. Lancet Neurology 2009

22. Patient selection from thrombolysis – does CTA, CTP, MRA or MRP add anything (or just delay the start of treatment)? DIAS 1& 2 RCTs – ‘we know the answer already’ - MR DWI PWI ‘mismatch’ must be present: trials negative EPITHET – RCT, but too small to say whether presence or absence of mismatch is helpful DEFUSE – no control group!!!! DIAS-3&4 – ‘we know the answer already’ - need to show a blocked artery to benefit EXTEND – no, you need ‘penumbral mismatch’ to select IST-3 aiming to collect pre-randomisation data on perfusion, angiography or both in 100-300 patients

23. Stroke thrombolysis > 80 years Patients over 80 have been excluded from randomised trials and hence from the licence 2 randomised trials are recruiting patients > 80 –IST-3 will recruit > 1000 patients > 80yr (800 already) –Italian trial (TESPI) recruiting patients > 80yr < 3hrs. (36 to date)

24. Effect of IV rt-PA < on ‘death or dependency’: age < 80 Heterogeneity (Chi 2 p=0.007) I 2 = 62% Test for overall effect p=0.0001 Wardlaw J et al, Cochrane Database Systematic Reviews 2009 926 999

25. Symptomatic ICH Engelter. Age and Ageing 2006; 35: 572–580