Transcript Stroke prevention, how well are we doing? Professor

Thrombolysis for acute ischaemic
stroke 1: why do we still need to
do randomised trials & IST3?
Professor Peter Sandercock
On behalf of IST-3 Collaborative Group
and for Gruppo Italiano IST-3
University of Edinburgh
Who SHOULD get thrombolysis with i.v.
rt-PA ‘within licence’?
• Patient MUST be
– able to be treated within 3 hours
– aged under 80
– not have a history of prior stroke + Diabetes
– not have any of the standard exclusions
– NIHSS < 25
– No extensive infarction on CT
• There must be a discussion of risk/consent
Who ACTUALLY gets rt-PA for acute
ischaemic stroke ‘within licence’ in Europe?
rt-PA for stroke per million pop'n
250
200
150
100
50
0
Finland
Sweden
Austria
Norway
Czech Republic
Slovenia
Belgium
Denmark
Spain
Iceland
Germany
Portugal
Italy
Slovakia
Australia
Netherlands
United Kingdom
Lithuania
Poland
France
Greece
Croatia
Hungary
Russia
SITS-MOST 29/1/2007
Why so much variability in
clinical practice?
•
•
•
•
•
Insufficient evidence base
Licence does not apply to older people
What to do after 3 hours?
How to balance risk and benefit?
No consensus on imaging
– Which method: CT or MR?
– How should CT or MR appearance influence
decision about thrombolysis?
Compare evidence base! Number of pts in
randomised trials of thrombolysis vs control
in acute myocardial infarction
Total no. patients by 1994!
58,600
in acute ischaemic stroke
Total (all agents)
5,675
rt-PA
2,700
rt-PA < 3hrs
rt-PA aged > 80 years
930
42
Number of older patients
with acute stroke per year
in UK
87,000 patients aged > 70 years
47,000 patients aged > 80 years
= A big problem for acute medical
services!
rt-PA trials meta-analysis. Benefit declines
with increasing time to treatment, but scope
for benefit up to 6h?
Benefit
Upper and lower 95% confidence limits
NNT 10
Harm
‘Grey area’
NNT 10? > 30? or net
harm?
Line of no effect
3 hours
6 hours
Risk of treatment: fatal
haemorrhage 3%
Risk of NOT treating with rt-PA? Fatal deterioration
due to swelling in large infarcts.
CT at 5hrs
Early ischaemic change
CT at 72 hrs
Swelling and midline shift
‘Area Grigia’ di incertezza:
i.v. rt-PA promising but
unproven for patients who:
• Present < 3hrs & do not exactly meet NINDS
criteria
• All patients 3-6hours
• Older patients (>75 years)
• Severe stroke, mild stroke…...
• Have subtle, early ischaemic change on CT
• Etc etc …
Current randomised trials of i.v.
thrombolysis vs control
Trial
Thrombolytic
agent
EPITHET
rt-PA
ECASS III
rt-PA
IST-3
rt-PA
Patient selection
trial size & time window
Clinical, CT (+ DWI/PWI MRI)
3-6 hours
100 patients
Results 2008
Clinical and CT; Age < 80
Stroke onset 3-4.5 hours
800 patients
Results mid 2008
Clinical and CT;
Ischaemic stroke 0-6 hours
Up to 6000 patients
Thrombolysis for acute ischaemic
stroke 2: progress with the trial.
Where are we now, what is our
target?
Professor Peter Sandercock
On behalf of IST-3 Collaborative Group
and for Gruppo Italiano IST-3
University of Edinburgh
Main features of IST - 3
• International, multi-centre, Prospective,
Randomised, Open, Blinded Endpoints study of i.v.
rt-PA vs control.
• Primary outcome: the proportion of patients alive
and independent at six months
• Simple central telephone randomisation with online minimisation to balance key prognostic factors.
• Web-based blinded detailed central review of all
scans (ASPECTS, 1/3 MCA rule, dense MCA etc)
• Conducted to EU GCP standards.
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
Recruitment by country: coppa del mondo
Country
No. centres
Pts.
%
UK
34
377
38%
Poland
5
172
18%
Norway
12
125
13%
Italy
14
91
9%
Sweden
Australia
Belgium
Austria
Canada
Mexico
14
10
3
1
1
1
73
69
56
8
5
1
7%
7%
6%
1%
1%
-
Gruppo Italiano IST-3 : 2006
Serie A (>5 patients)
Milano
Citta Della Pieve
Aosta
Serie B (<5 patients)
Citta di Castello
Perugia, Silvestrini
Gubbio
Foligno
Negrar
Vittoria
Ciccone
Ricci
Botacchi
Cenciarelli
Agnelli
Bigaroni
Brustengi
Adami
Iemolo
23
17
6
2
1
1
0
0
0
Gruppo Italiano IST-3 : 2007
*recruited a patient within last 30 days
Serie A (>5 patients)
Citta Della Pieve*
Niguarda, Milano
Aosta
Citta di Castello
Vibo Valentia*
27
25
13
5
5
Serie B (<5 patients)
Foligno
4
Sacro Cuore Negrar Verona
Vittoria
Spoleto
Perugia, Silvestrini
4
3
2
1
Gubbio
Piacenza
1
1
Centri che stanno per partire
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•
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•
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•
•
Genova
Modena
Foggia
Legnango
Peschiera
Verona
Bologna
Reggio Emilia
Bari
Has the ‘area grigia’ changed
since IST-3 began?
Characteristics of patients at
baseline
Number of patients
.
Delay between stroke onset and randomisation
(Median = 4.1 hours)
300
250
200
150
100
50
0
1 or less
1 to 2
2 to 3
3 to 4
4 to 5
Hours between stroke onset and randomisation
>5
Trends in type of patient recruited since trial
began: Time to randomisation
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
0-3 hrs
3.1-6 hrs
1st 224 2nd 224 3rd 224 4th 224
No. patients recruited into trial
Age at randomisation > 330 patients aged > 80 =
increased
world
evidence base 8 x!
Age
at randomisation
.
300
Number of patients
250
200
150
100
50
0
50 or
under
51-60
61-70
71-80
81-90
91-100
Age in years at randomisation
Over
100
Trends in type of patient recruited since trial
began: age
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
> 80 years
< 80 years
1st 224
2nd 224`
3rd 224
4th 224
No. patients recruited into trial
Trends in type of patient recruited since trial
began: Infarct subtype
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
POCI
LACI
PACI
TACI
1st 224
2nd 224` 3rd 224
4th 224
No. patients recruited into trial
Expert’s opinion of
randomisation CT*
• Acute ischaemic change
• Periventricular lucencies
• Normal
64%
44%
6%
*scans may show more than one abnormality
Frequency of hyperdense artery
on baseline and follow-up CT
Present on baseline scan
152 (39%)
Present on follow-up scan
102 (26%)
Persisted (seen on 1st & 2nd scan)
88 (23%)
Present on baseline,
disappeared by 2nd scan
64 (16%)
Has the ‘area grigia’ changed
since IST- began?
NO
2007 report of the IST 3 Data
Monitoring Committee
We reviewed analyses based on 896 randomised
patients. We should like to commend the
investigators for the high quality and completeness
of the data, as well as the exemplary conduct of the
trial.
The DMC did not consider it necessary to
recommend any change to the study protocol…
we would encourage the investigators to make
every effort to recruit all eligible patients so that
reliable evidence emerges as rapidly as possible.
Professor Rory Collins, Chairman
Recruitment strategy: the future
• Focus efforts on countries already
in trial
• Increase number of centres in
these countries
• Work with existing centres to
maintain or increase recruitment.
Recruitment strategy: the future.
In Italy this means:
• Can your centre recruit enough so
you move up (or you can join)
Serie A in Gruppo Italiano IST-3?
• Can Italy move up in the coppa del
mondo IST-3?
Projected total number of centres, and
number of active centres
160
31 Dec 08: total centres
.
140
100
31 Dec 08: active centres
1 Oct 07: total centres
80
60
1 Oct 07: active centres
40
20
Randomisation date
May 08
May 07
May 06
May 05
May 04
May 03
May 02
May 01
0
May 00
Number of centres
120
Sample size (MRC Protocol)
• with 1000 patients we could detect a 7%
absolute difference in the primary outcome,
which is consistent with the effect size
among patients randomised within 3 hours of
stroke in the Cochrane review.
• If 3500 patients were recruited, the trial could
detect a 4% absolute difference in the
primary outcome.
• With 6000 patients, mostly treated between 3
& 6 hours of onset, the trial could detect a
3% absolute difference in the primary
outcome
Protocol version 1.92 September 2005
Recruitment = 982 patients randomised
st target!
Recruitment
by 30.11.07.
Almost
reached
1
IST3: Cumulative number of patients randomised
1000
900
.
700
Number of patients
800
600
500
400
300
200
100
Randomisation Date
Nov 2007
May 2007
Nov 2006
May 2006
Nov 2005
May 2005
Nov 2004
May 2004
Nov 2003
May 2003
Nov 2002
May 2002
Nov 2001
May 2001
Nov 2000
May 2000
0
Hot news!
• We applied to MRC to extend trial to reach
one of our targets
• UK Medical Research Council
– Recognised the importance of the trial
– agreed to this plan
– given extra funds (~ €500,000),
• IST-3 can continue recruitment to mid
2011and report trial in 2012 if needed
Sample size (MRC Protocol)
• with 1000 patients we could detect a 7%
absolute difference in the primary outcome,
which is consistent with the effect size
among patients randomised within 3 hours of
stroke in the Cochrane review.
• If 3500 patients were recruited, the trial could
detect a 4% absolute difference in the
primary outcome.
• With 6000 patients, mostly treated between 3
& 6 hours of onset, the trial could detect a
3% absolute difference in the primary
outcome
Protocol version 1.92 September 2005
New plan: recruit 3,100 by 2011
With 3100, we could
detect a 4.7%
benefit. NNT 21
Third International Stroke Trial. A large
randomised trial to answer the question:
can a wider variety of patients be treated?
Target: 3100 patients or more from ~ 100
centres in 14 Countries by 2011
Conclusions
• IST-3 asks very important questions
– Who benefits?
– By how much?
– How to make best use of CT to select patients?
• It is the LAST CHANCE to get these data
• We MUST go on
• The approval by MRC = recognition of the
scientific importance of our work
• Our data will influence clinical practice in the
REAL world!