Transcript UNIS Template

What do the IST-3 results mean for
the elderly patient with acute stroke?
SYDNEY MEDICAL SCHOOL
Richard I Lindley | Professor
Westmead Hospital Clinical School | George Institute for Global Health
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
Content
• 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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The epidemiology of stroke and old age
Risk factors in stroke patients in Oxfordshire
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
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
11
43
33
34
37
<0.001
<0.001
2
7
38
26
5.96
4
8
24
28
5.70
5
12
13
29
5.18
0.01
0.04
<0.001
<0.001
<0.001
BP
treatment
AF
D.M.
Smokers
BMI
Total Chol.
(mmol/L)
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
Incidence study from Western Suburbs of Adelaide
› 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
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IST-3
Key Design Features
› 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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Consumer involvement in IST-3: Consent issues
Focus group and surveys amongst older people led to clear advice for IST-3
› 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”
Koops and Lindley BMJ 2002; 325: 415-7
› 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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Natural History of Ischaemic Stroke Observed in IST-3
Patients Aged > 80 years old
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
0 to 3
76
3 to 4.5
72
4.5 to 6
76
0 to 3
94
3 to 4.5
94
4.5 to 6
100
0 to 3
100
3 to 4.5
100
4.5 to 6
100
6 to 14
15 to 24
> 25
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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
Mishra et al Thrombolysis in very elderly people BMJ 2010; 341:c6046
› 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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Treatment effects in old age
IST-3 Results Consistent with other Common Treatments
› 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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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
Service Redesign
› 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
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
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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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