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

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

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

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Content

The epidemiology of stroke and old age

Risk 1980s 2000s P value

BP (mean) 156/88 148/82 <0.0001

BP treatment 20% 47% <0.0001

AF 9.6% 16.8% 0.005

DM 10.5% 9.5% 0.69

Smokers 33% 18% <0.0001

Total Chol. 6.2mmol/L 5.4mmol/L <0.0001

Lipid treatment 0% 11% <0.0001

Risk factors in stroke patients in Oxfordshire

Rothwell et al Lancet 2004; 363: 1925-33

Framingham: Risk factors (%) amongst men at age 65 years

Risk 1950-1977 1978-1989 1990-2004 P value

BP>140/90 48 43 34 <0.001BP treatment

11 33 37 <0.001

AF 2 4 5 0.01

D.M. 7 8 12 0.04Smokers 38 24 13 <0.001

BMI 26 28 29 <0.001Total Chol. (mmol/L)

5.96 5.70 5.18 <0.001

Carandang et al JAMA 2006; 296: 2939-46

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

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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)

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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

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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

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Key Design Features

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

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Koops and Lindley BMJ 2002; 325: 415-7

Focus group and surveys amongst older people led to clear advice for IST-3

Natural History of Ischaemic Stroke Observed in IST-3

NIHSS Delay in Randomisation (hours)

Dead of Dependent at Six Months in Control Group (%)

0-5 0 to 3 42

3 to 4.5 39

4.5 to 6 23

6 to 14 0 to 3 76

3 to 4.5 72

4.5 to 6 76

15 to 24 0 to 3 94

3 to 4.5 94

4.5 to 6 100

> 25 0 to 3 100

3 to 4.5 100

4.5 to 6 100

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Patients Aged > 80 years old

IST-3 Results

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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

 <=80 177  558 683

>80 672 620 325

 All  849 1178 1008

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

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Mishra et al Thrombolysis in very elderly people BMJ 2010; 341:c6046

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

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IST-3 Results Consistent with other Common Treatments

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

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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

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Service Redesign

De Vries et al Outcome instruments to measure frailty: A systematic review Ageing Research Reviews 2011; 10: 104-114Lindley J Gerontol A Biol Sci Med Sci 2012; 67: 152-7

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

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