Transcript Stroke prevention, how well are we doing? Professor

Update on IST-3 and other trials.
Or, ‘how the ECASS-3 results have
helped re-launch IST-3!’
Professor Peter Sandercock,
Co-chief investigator
IST-3 collaborator’s webcast
10th November 2008
(recruitment data updated post webcast)
Note: please feel free to use these slides in presentations and for
discussions with colleagues, but please do not cite these data in
publications without prior permission of the Trial management Group
IST-3 funding agencies
Outline
What do we know now?
• Updated Cochrane Review of all trials
• Current usage in clinical practice
• Remaining questions
IST-3
• Progress with recruitment
• Data Monitoring Committee reports
• Key messages from Steering Committee
• Publications
Cochrane Systematic Review of
Thrombolysis Trials
• All randomised controlled trials of any
thrombolytic drug versus control
• 2003 version included 18 trials (no.
patients =5675)
• Drugs: rt-PA, streptokinase, uro-kinase,
rPro-urokinase,
• Time windows:
0-3, 0-6 hrs
• Brain Imaging : CT
• Age over 80 :
42 patients
JM Wardlaw, V Murray (in preparation)
New trials included in 2008 update
•
•
•
•
•
8 new trials (n=+1477, total: n=7152)
Drugs: 3 rt-PA; 2 UK; 3 desmoteplase
Route: 2 intra-arterial, 6 intravenous
Time windows: 0-6, 3-4.5, 3-9, 0-24 hrs
Imaging pre randomisation:
– CT: 5
– MR: 3 (+1) DWI/PWI mismatch
• Age over 80: ≈42
JM Wardlaw, V Murray (in preparation)
ECASS 3
Inclusion:
• 3-4.5 hours
Age 18-80 yrs
Excluded :
• NIHSS>25 or CT infarct signs >1/3MCA
• diabetes and prior stroke
• stroke in previous 3 months,etc,etc
Outcomes:
Good functional outcome: mRS 0-1 vs 2-6
Baseline
Imbalance in age, NIHSS, prior stroke, DM
in favour of rt-PA)
(all
Death or dependency at the end of follow-up
IV urokinase
IV streptokinase
0.91 (0.64, 1.42)
0.94 (0.72, 1.24)
IV rt-PA
0.77 (0.47, 0.89)
IV streptokinase
+ aspirin
1.09 (0.49, 1.72)
IA pro-urokinase
0.55 (0.31, 1.00)
IA urokinase
0.57 (0.28, 1.14)
IV desmoteplase
0.85 (0.53, 1.38)
Total
0.82 (0.73, 0.91)
Effect of rt-PA on death or
dependency
tPA
Study or Subgroup
Mori 1992
Control
Peto Odds Ratio
Events Total Events Total Weight
Peto, Fixed, 95% CI Year
11
19
10
12
0.7%
0.32 [0.07, 1.48] 1992
ECASS 1995
171
313
185
307
16.5%
0.79 [0.58, 1.09] 1995
NINDS 1995
155
312
192
312
16.8%
0.62 [0.45, 0.85] 1995
ECASS II 1998
187
409
211
391
21.8%
0.72 [0.55, 0.95] 1998
ATLANTIS B 1999
141
307
135
306
16.5%
1.08 [0.78, 1.48] 1999
ATLANTIS A 2000
64
71
56
71
2.0%
2.35 [0.95, 5.82] 2000
Wang 2003
29
67
26
33
2.4%
0.24 [0.10, 0.56] 2003
ECASS III 2008
140
418
155
403
20.6%
0.81 [0.61, 1.07] 2008
EPITHET 2008
29
51
29
49
2.7%
0.91 [0.41, 2.01] 2008
Total (95% CI)
Total events
1967
927
1884 100.0%
Peto, Fixed, 95% CI
0.78 [0.68, 0.89]
999
Heterogeneity: Chi² = 21.09, df = 8 (P = 0.007); I² = 62%
Test for overall effect: Z = 3.79 (P = 0.0002)
Peto Odds Ratio
0.01
0.1
1
10
100
Favours tPA Favours control
rt-PA trials: 2003 versus 2008
Odds Ratios and 95% CI
SICH
(incl fatal)
Late
Death
Death or
Dependency
2003
n=2955
3.1
2.3 - 4.2
p<0.00001
1.2 *
0.9 - 1.5
p=0.14
0.8 *
0.7 - 0.9
p=0.003
2008
n=3977
3.1
2.3 - 4.0
p<0.00001
1.1
1.0 - 1.4
p=0.16
0.8 *
0.7 - 0.9
p<0.0001
* significant heterogeneity confounds interpretation
rt-PA trials: 2008. Absolute effects (no. Events
avoided /caused per 1000 treated, 95% CI)
all
0-3 hrs
3-6 hrs
SICH
60
50, 80
70
40, 100
60
50, 80
Death
10
10, 40
0
50, 50
20
0, 50
Death or
Depend.
60
100, 30
110
170, 50
40
80, 10
X = events avoided (benefit)
X = events caused (harm)
Update 2008 conclusions,
•
•
•
•
Heterogeneity still confounds interpretation
Potential for benefit to at least six hours
Limited new knowledge on latest time windows.
Almost complete lack of randomised evidence
on effects in
–
–
–
–
older patients;
concomitant antithrombotic use;
stroke severity/subtype,
diabetes
• Outcome following selection on MR mismatch not
apparently different to CT.
• No material change in main outcomes since 2003.
Estimated % of all ischaemic
strokes treated with thrombolysis
• USA:
• Canada
• Germany
• Sweden
1.
1
1-7%
2
3%
3%3
5.5%4
Cocho et al.,Qureshi et al., 2.Kapral et al,3. Heuschmann et al,
4. (http://www.riks-stroke.org).
How many stroke patients per year in UK*
might avoid being ‘dead or dependent’ with
each treatment?
% 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%
2080
63
163
Thrombolysis *130,000
30% strokes
31200 per 47
year
1470
Even if the EU approval for
thrombolysis is extended to 4.5 hrs,
this will still exclude patients who
•
•
•
•
•
•
Are aged > 80 years
Either ‘very mild stroke’ or NIHSS > 25
Prior stroke within the last 3 months
Have a history of prior stroke + Diabetes
Arrive at 4.5 to 6.0 hours
Other relative contraindications specified in
the licence (e.g. ‘extensive infarction’, which
is not defined in any way)
Stroke patients > 80 years
• Patients over 80 have
been excluded from
randomised trials and
the licence
• In the UK 30% of all
strokes are aged > 80 =
31,000 ischaemic stroke
patients each year
automatically excluded
from thrombolysis
Severe stroke (NIHSS > 25)
• This man had a large
MCA infarct
• NIHSS > 25,
• rt-PA not approved for him
• He spent many months in
hospital
• He was very disabled
• He was no longer able to
care for his wife
Mild, or rapidly improving strokes
(NIHSS < 4)
• 2 hours ago, this man
developed right
hemiparesis, now rapidly
improving.
• NIHSS < 4, so rt-PA not
approved
• Many such patients
recover without rt-PA,
• BUT 15-30% later
deteriorate suddenly ->
disabling stroke
• Should we treat them to
prevent deterioration?
Vertebro-basilar territory
ischaemic strokes
• Acute cerebellar infarct
• Excluded from previous
trials of iv rt-PA
• Time window for
treatment unclear
• Is there benefit from iv
thrombolysis for such
patients?
‘Extensive infarction’
• Does this patient
have ‘extensive
infarction?’
• Not defined in EU
approval
• Much debate about
definition
• Should this patient
be excluded from
thrombolysis?
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
IST 3 Sample size
• 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 3100 patients were recruited, the trial could
detect a 4.7% absolute difference in the
primary outcome. (remarkably close to the
4% difference seen in the updated Cochrane
review)
• 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
Randomisation Date
Nov 2008
May 2008
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
Number of patients
.
RecruitmentRecruitment
by 10.11.2008
1343 patients
by 31 March 2008 =
= 1104
1200
1000
800
600
400
200
0
n0
Ap 5
r-0
Ju 5
l- 0
Oc 5
tJa 05
n0
Ap 6
r-0
Ju 6
lOc 06
t-0
Ja 6
nA p 07
r-0
Ju 7
l- 0
Oc 7
t-0
Ja 7
n0
Ap 8
r-0
Ju 8
l- 0
Oc 8
t-0
8
Ja
Number of patients recruited per month
50
45
40
35
30
25
20
15
10
5
46 patients in past
month = increased
recruitment rate after
ECASS-3 results
released!
Randomisation date
Non UK
UK
Total
0
ECASS-3
results
.
Projected numbers of patients by mid 2011
MRC target = 3100
At 46 per month = 2806
If we can recruit an
extra 9 patients per
month, we’ll reach our
target!
Recruitment by country in IST-3
Country
No. centres
Pts.
%
UK
Poland
44
5
534
197
40%
15%
Norway
Sweden
Italy
Australia
13
14
20
10
151
137
124
107
12%
10%
9%
8%
Belgium
Austria
Canada
3
2
1
61
17
8
5%
1%
1%
Mexico
1
3
Portugal
Total
3
119
3
1343
0%
0%
Analyses of data on the 1281
patients recruited by 24.9.2008
Type of patient recruited
• Age: IST-3 largest randomised controlled
trial in ‘older’ hyper-acute stroke
– 893 patients > 70 years,
– 564 patients > 80 years.
• Severity & subtype:
– Wide range of severity
– Subtypes not much recruited in previous trials:
153 Lacunar infarcts
77 Posterior circulation infarcts
Age and time to randomisation
Age
stroke onset to
randomisation
(hrs)
< 80 years
>80 Years
0-3
89 (12%)
186 (33%)
3-4.5
323 (45%)
249 (44%)
>4.5
305 (43%)
129 (23%)
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 320 2nd 320 3rd 320 4th 322
No. patients recruited into trial
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 - 4.5 hrs
4.5 - 6 hrs
1st 320 2nd 320 3rd 320 4th322
No. patients recruited into trial
Randomisation quarter and year
4, 2008
3, 2008
2, 2008
1, 2008
4, 2007
3, 2007
2, 2007
1, 2007
4, 2006
3, 2006
2, 2006
1, 2006
4, 2005
3, 2005
2, 2005
1, 2005
Number of patients randomised
.
120
Type of patient recruited in main phase
100
80
>80, 4.5-6
>80, 3-4.5
60
>80, 0-3
<80, 4.5-6
<80, 3-4.5
40
<80, 0-3
20
0
Perfusion imaging in IST3
• The trial imaging system can store and analyse CT
and MR perfusion data from patients recruited in
IST-3
• We have been collecting these perfusion data
• If you have CT or MR perfusion and angiography
data on your IST-3 patients, please send the data
with the routine plain (non-contrast) images to the
trial office.
• IST-3 will be able to add greatly to the evidence
base on perfusion/diffusion mismatch and
response to rt-PA.
Impact of ECASS-3 on IST-3
• No evidence of a decline in IST-3 recruitment
since results released, in fact recruitment has
increased from ~30/month to 44 in the past
month!
• Recruitment of patients < 80 yrs, 3-4.5 hrs
with NIHSS < 25 is only 15% of those
recruited since ECASS-3 published
• Many centres will be assessing more patients
for thrombolysis up to 4.5 now, and so more
may be considered for entry in IST-3
Data Monitoring Committee
and MRC Steering Committee
• Data Monitoring Committee (DMC) meeting
23rd September, rapid review of ECASS3
data, updated Cochrane review, and IST3
data to inform discussions at collaborators
meeting 26th Sept, Vienna
• Full DMC meeting 30th October to consider
above data in detail
• MRC trial Steering Committee: review of
progress of trial and plans for future
Letter from IST-3 Data Monitoring
Committee 23rd September
• Dear Peter
• In preparation for the release of the ECASS-III results (and
blind to those results), the IST-3 Data Monitoring Committee
had arranged a teleconference for today (23 September
2008). Our review of the available data from IST-3 and the
other trials, including safety information from ECASS-III, does
not lead us to consider there to be any need for a change to
IST-3. We would encourage the IST-3 collaborators to
maintain the increase in the rate of recruitment. The DMC will
continue to monitor interim results from IST-3 as planned.
• Yours sincerely
• Professor Rory Collins
• Chair, IST-3 DMC
Letter from IST-3 Data Monitoring
Committee 3rd November
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
Summary
• Current EU approval is very strict and
permits treatment of only small numbers of
patients; public health impact is small
• ECASS3 results help widen the time
window a bit, but will not increase
randomised evidence of effects in older
people, or the many other categories
excluded from treatment by EU approval
• If IST-3 results confirm benefits in a wider
range, more could be treated and public
health impact greatly increased
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
IST-3 Papers in peer-reviewed journals 2007/8
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)