Transcript Stroke prevention, how well are we doing? Professor

IST-3: progress with the trial
internationally and plans for
the future
Peter Sandercock
Riunione Gruppo Italiano IST-3
Firenze
13th February 2009
Gruppo Italiano IST-3
Capo
Riunione Gruppo 2007
Outline
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Rationale
Progress with recruitment
Characteristics of patients in trial
Outcomes assessed in IST-3
Long-term effects of small benefits
Data Monitoring Committee reports
Publications
Future plans
How many stroke patients per year might
avoid being ‘dead or dependent’ with each
treatment in UK? (130,000 strokes/year)
% treated
with this
intervention
Number
treated per
year
Benefit per
1000
treated
Number who
avoid death or
dependency
Aspirin
80%
104000
13
1350
Stroke Unit
60%
78000
56
4370
Thrombolysis
2%*
2500
63
150
Thrombolysis
30%**
31200
47
1470
*USA population average
**If IST-3 overall positive?
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
Even if, post- ECASS-3, the EU approval for
thrombolysis extends time window to 4.5
hrs, this will still exclude patients who:
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Are aged > 80 years
Have ‘very mild stroke’ or NIHSS > 25
Had prior stroke within the last 3 months
Have a history of prior stroke + Diabetes
Arrive at 4.5 to 6.0 hours
Have other relative contraindications
specified in the licence (e.g. ‘extensive
infarction’, which is not defined in any way)
Projected recruitment
At current rate of 57 per month, final n = 3157
MRC target n = 3100
12th Feb 2009, n= 1477
ECASS-3 Results
published
2000
July 2011
Recruitment by country in IST-3
Country
No. centres
Pts.
%
UK
Poland
44
5
591
213
40%
14%
Sweden
Norway
Italy
Australia
15
13
20
10
158
156
134
119
11%
11%
9%
8%
Belgium
Austria
Canada
3
2
1
63
19
8
4%
1%
1%
Mexico
1
3
Portugal
Switzerland
4
1
6
1
0%
0%
0%
Characteristics of patients
Age
>70 =1130
>80 = 791
Time:
Mean onset to randomisation = 3.95
hours
NIHSS
Mean =12.3
Trends in type of patient recruited 2000-2008:
AGE
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
> 80 years
< 80 years
1st
250
2nd
250
3rd
250
4th
250
No. patients recruited into trial
next
214
OCSP subtype
97
177
POCI
LACI
669
TACI
PACI
580
NIHSS at baseline
391
290
311
288
196
0 to 5
6 to 10 11 to 15 16 to 20 over 20
450
400
350
300
250
200
150
100
50
0
At the end of the trial, IST-3 will
have recruited about
• Older age:
– 2200 patients > 70 years, of whom
– 1000 patients > 80 years.
• Severity of stroke:
– Severe: 300 with NIHSS > 24
– Mild: 600 with NIHSS < 5
• Subtypes not much recruited in previous trials:
– 800 with AF (cardioembolic infarct)
– 370 with lacunar infarcts
– 200 with posterior circulation infarcts
Long-term outcomes in stroke trials
• Randomized controlled trials (RCTs)
should reflect the effect of treatments
on long-term outcomes.1
• BUT, the follow-up period of RCTs
tends to be relatively short.
• Model:2 Treatments that produce even
relatively small reductions in disability
after ischemic stroke are likely to be
cost-effective, even if they have a high
price.
1. US National panel on cost-effectiveness. 2.Samsa et al J CLIN EPIDEMIOL 1999 52;3:259–271
Samsa’s model predictions
Samsa et al J CLIN EPIDEMIOL 52;3:259–271, 1999.
Model validation: Impact of functional status at six months
on long term survival in 7710 patients with ischaemic
stroke in 3 prospective cohort studies (OCSP).
Bruins slot, Sandercock et al BMJ 2008 doi:10.1136/bmj.39456.688333.BE
Validation: Impact of functional status at six months on
long term survival in 7710 patients with ischaemic stroke
in 3 prospective cohort studies
• Functional status of patients six months after onset
of an ischaemic stroke has a significant and
substantial effect on long term survival
• A difference of one Rankin grade has a large effect
• Less than half those alive with severe disability at
six months will survive five years; a survival statistic
comparable with that of several malignancies.
• This validates Samsa’s hypothesis and model
estimates with empirical data
• Treatments with even modest effects could prove
very cost-effective
Bruins slot, Sandercock et al BMJ 2008 doi:10.1136/bmj.39456.688333.BE
Outcomes in IST-3
Primary:
• The proportion of patients alive and independent (mRS
0-2) at 6 months
Secondary:
• Early (events < 7 days): Deaths, Symptomatic
intracranial haemorrhage. Recurrent ischaemic stroke,
Neurological deterioration attributed to swelling of the
initial ischaemic stroke, Neurological deterioration not
attributable to swelling of the initial ischaemic stroke or
haemorrhage.
• 6 months: mRS, EQ-5D (EuroQol), place of residence,
• 18 months: as at 6 months
• > 18 mo (UK+ Nordic): mortality follow-up via National
Registers of Deaths
IST-3 Italy coordinator’s local support
team (+visitors) hard at work…..
Letter from IST-3 Data Monitoring
Committee 3rd November 2009
The IST-3 Data Monitoring Committee held its
scheduled interim review of the unblinded data from
IST-3 on 30 October 2008. Based on our review of
these data, as well as the safety and efficacy data
from the other trials of tPA in acute stroke (including
recently reported ECASS-III among patients treated
3 and 4.5 hours after symptom onset), the DMC
concluded there was no need for any change to IST3. We would encourage the IST-3 collaborators to
maintain the increase in the rate of recruitment,
and in particular, to consider all eligible patients
for randomisation (irrespective of the presenting
time from symptom onset).
Professor Rory Collins Chair, IST-3 DMC
IST-3 Papers in peer-reviewed journals 2007-9
1. Wardlaw JM, Bath P, Sandercock P, Perry D, Palmer J,
Watson G, Lloyd S, Geddes J, Farrall A. The NeuroGrid
stroke exemplar clinical trial protocol. International Journal of
Stroke. 2007;2:63-9
2. Sandercock P, Lindley R, Wardlaw J, Dennis M, Lewis S,
Venables G, et al. The Third International Stroke Trial (IST)
of thrombolysis for acute ischaemic stroke.. Trials 2008;9(37)
http://www.trialsjournal.com/content/9/1/37
3. SCOPE (Stroke Complications and Outcomes Prediction
Engine) Collaborations and IST. Predicting outcome in hyperacute stroke: validation of a prognostic model in the Third
International Stroke Trial (IST3).. Journal of Neurology
Neurosurgery and Psychiatry 2008;79:397-400
4. Adam Kobayashi, et al, on behalf of the IST-3 Collaborative
Group. Oxfordshire Community Stroke Project clinical stroke
syndrome and appearances of tissue and vascular lesions
on pre-treatment CT in hyperacute ischaemic stroke among
the first 510 patients in the Third International Stroke Trial
(IST-3). Stroke (in Press)
Key Messages from Professor Colin Baigent,
Chairman of IST-3 Steering Committee
• There are encouraging signs that recruitment
in IST-3 is continuing to accelerate, reflecting
encouragement from the results of ECASS-3
• This increased rate is likely to be maintained,
since new centres continue to join the trial
• The revised target of 3100 by mid 2011 now
appears eminently feasible
• The Steering Committee was reassured and
encouraged by the very positive report from
the DMC
Plans for 2009 & beyond
• 2009 Presentations
– Plenary: AHA stroke conference San Diego (17th February)
• 2009 Collaborators meetings
– Italy (14th February)
– International: ESC, Stockholm (27/28th May)
– UK: UKSF (3rd-5th December)
• 2010 Application for funding for
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Individual patient data meta-analysis (all rt-PA trials)
Long-term survival follow-up
Image analyses
‘Making the data publicly available’
• Mid 2011 recruitment ends
• Results reported early 2012
Summary: IST-3 will provide evidence
on the effects of rt-PA :
In patients ‘outside’ the current EU approval in:
• Age (>80 years)
• People with other relative contraindications
• In variety of clinical subgroups not studied in large
numbers (cardio-embolic, lacunar, posterior
circulation)
• When given in a wide variety of hospitals
On other outcomes:
• < 7 days (inc massive oedema)
• long-term: survival, QoL, cost-effectiveness
Summary. IST-3 Italy
• Italy continues to make a significant
contribution to IST-3
• New centres will be welcome join if they can
start randomising before 31st Dec 2010.
• The more patients we can recruit, the more
reliable the estimates of effect will be
• IST-3 will provide valuable randomised
evidence on clinical, CT and MR factors
relevant to use of thrombolysis in everyday
practice