1. SYDNEY MEDICAL SCHOOL What do the IST-3 results mean for the elderly patient with acute stroke? Westmead Hospital Clinical School | George Institute for Global Health Richard I Lindley | Professor

2. Potential Financial Conflicts of Interest ›I have received payment from Boehringer Ingelheim in my role as member of the Scientific Committee, and speaker for the Australian “Hearts and Minds” meeting ›I am on no Advisory Boards ›I have no shares in medical or pharmaceutical companies

3. Treatment of the Elderly Patient with Acute Stroke The epidemiology of stroke and old age Treatment effects seen in IST-3 Treatment effects in elderly people Implications for stroke services 3 Content

4. The epidemiology of stroke and old age Risk1980s2000sP value BP (mean)156/88148/82<0.0001 BP treatment20%47%<0.0001 AF9.6%16.8%0.005 DM10.5%9.5%0.69 Smokers33%18%<0.0001 Total Chol.6.2mmol/L5.4mmol/L<0.0001 Lipid treatment0%11%<0.0001 Risk factors in stroke patients in Oxfordshire Rothwell et al Lancet 2004; 363: 1925-33

5. Framingham: Risk factors (%) amongst men at age 65 years Risk 1950-19771978-19891990-2004P value BP>140/90 484334<0.001 BP treatment 113337<0.001 AF2450.01 D.M.78120.04 Smokers 382413<0.001 BMI262829<0.001 Total Chol. (mmol/L) 5.965.705.18<0.001 Carandang et al JAMA 2006; 296: 2939-46

6. Observed changes in stroke incidence in Oxford ›Up to a 40% reduction in the age-specific incidence of stroke ›Likely due to major reductions in population blood pressure, cholesterol and smoking 6

7. Implications for future stroke incidence ›Stroke will increasingly occur in frail people ›Stroke subtypes will change reflecting the changing underlying population risks, the most important being AF ›AF causes severe stroke (TACI and PACI ischaemic stroke subtypes) 7

8. Some Recent Australian Data ›Population of 148,000 -318 Stroke events (258 ischaemic) -109 cardioembolic (92 AF) ›Third of ischaemic stroke largely preventable Leyden et al Stroke Society of Australasia International Journal of Stroke 2011; 6 (Suppl 1): 21 Incidence study from Western Suburbs of Adelaide 8

9. IST-3 ›No upper age limit ›Patients were functionally independent prior to stroke ›Common co-morbidities were not contraindications therefore patients with prior stroke and diabetes were included (provided they were independent) ›CT/MRI required to exclude intracranial haemorrhage ›Randomisation and treatment to commence < 6 hours from stroke onset ›Treatment considered promising but unproven ›Informed consent obtained 9 Key Design Features

10. Consumer involvement in IST-3: Consent issues ›Most (98%) older people would accept a risk of death if a disabling stroke could be avoided using thrombolysis treatment ›“At my age I’d rather take a risk in the hope of retaining my independence” ›Consumers advised us to quote the natural history of stroke such as “half of all survivors are disabled and many die from the stroke” ›Consumers wanted to know the hard facts about potential risks such as the possible 4% (or 1 in 25) risk of fatal intracranial haemorrhage due to rt-PA 10 Koops and Lindley BMJ 2002; 325: 415-7 Focus group and surveys amongst older people led to clear advice for IST-3

11. Natural History of Ischaemic Stroke Observed in IST-3 NIHSSDelay in Randomisation (hours) Dead of Dependent at Six Months in Control Group (%) 0-50 to 342 3 to 4.539 4.5 to 623 6 to 140 to 376 3 to 4.572 4.5 to 676 15 to 240 to 394 3 to 4.594 4.5 to 6100 > 250 to 3100 3 to 4.5100 4.5 to 6100 11 Patients Aged > 80 years old

12. IST-3 Results 12

13. Baseline characteristics: number of patients aged > 80 in each time window Delay (hours) from stroke to randomisation Age 0-3 3-4.5 4.5-6 <=80177 558683 >80672620325 All 84911781008

14. IST-3 Consistent with Observational Data ›Retrospective analysis of patients undergoing thrombolysis and registered in the Safe Implementation of Treatment in Stroke – International Stroke Thrombolysis Registry (SITS-ISTR) and controls who had not had thrombolysis within the Virtual International Stroke Trials Archive (VISTA) ›Odds of favourable outcome: -< 80 years 1.6 (1.5 to 1.7), n = 25 789 -> 80 years 1.4 (1.3 to 1.6), n = 3439 14 Mishra et al Thrombolysis in very elderly people BMJ 2010; 341:c6046

15. Treatment effects in old age ›Treatment directions rarely change direction with increasing age i.e. treatments that are beneficial in younger people are generally beneficial in older people ›Relative risk reductions with effective treatments generally attenuate with increasing age and frailty as other comorbidities increase risks and reduce benefits ›Absolute risk reductions can increase in old age as older people are at greater risks of poor outcome than younger people 15 IST-3 Results Consistent with other Common Treatments

16. Proportional effects of fibrinolytic therapy for MI on mortality during days 0-35 subdivided by age 16

17. Implications for Stroke Services and Research ›Upper age limits for stroke thrombolysis should be removed ›Poor prognosis of severe stroke (particularly AF related large vessel occlusion) without acute intervention should be considered ›Consent discussion should include potential benefits and risks ›Continued efforts need to be made to decrease onset to needle time, particularly for older people ›Future trial design should consider more detailed estimation of premorbid functional abilities and frailty rather than impose an arbitrary upper age limit 17 Service Redesign De Vries et al Outcome instruments to measure frailty: A systematic review Ageing Research Reviews 2011; 10: 104-114 Lindley J Gerontol A Biol Sci Med Sci 2012; 67: 152-7

18. Conclusions ›IST-3 should lead to wider implementation of thrombolysis for older people ›Health service redesign will be required to implement results in many countries ›IST-3 and associated studies will help provide essential information to guide acute stroke physicians in appropriate selection and consent discussions with older people and their families ›Future research should avoid upper age limits 18