Transcript Where's the evidence?

IST-3, SITS MOST ECASS3 & DEFUSE
Professor Peter Sandercock
University of Edinburgh, UK
ESC May 30th 2007
Glasgow
Competing interests:
Outline
Current knowledge
SITS MOST: Current use of rt-PA ‘in licence’
Selecting patients for thrombolysis
Plain CT
Perfusion MR or CT
DEFUSE
Current trials of iv thrombolysis
DIAS-2
ECASS-3
IST-3
Randomised trials of thrombolysis vs
control in acute myocardial infarction
Total no. patients by 1994!
58,600
Randomised trials trials of thrombolysis vs
control 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!
Variation in use of rt-PA for acute ischaemic
stroke ‘within licence’ in Europe recorded in
SITS-MOST registry 2007
rt-PA for stroke per million pop'n
250
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
200
150
100
50
0
SITS register November 2005
SITS-MOST 29/1/2007
rt-PA trials meta-analysis. Benefit declines
with increasing time to treatment, but scope
for benefit up to 6h (Lancet 2004; 363: 768–74)
Benefit
Upper and lower 95% confidence limits
Harm
Line of no effect
3 hours
6 hours
What is known from randomised
controlled trials (RCT) about i.v.
rt-PA for acute ischaemic stroke
• Very limited RCT data on effects patients
aged > 80 years
• ‘Time is brain’; early treatment is best
• EMEA approval for use < 3hrs in patients
aged less than 80 years
• Application of treatment in routine practice
varies from < 1 to 200 per million people.
• Potential for benefit in selected patients up
to 6hrs; can the licence be extended?
Selecting patients by presence/absence of
‘Early ischaemia’ signs on CT: effect on
response to rt-PA
• Observational studies show1 extent of early
ischaemic change (ASPECTS score) influences
prognosis after stroke
• But data from two randomised trials, (1,926
patients ), provide no evidence that presence of
‘early infarct change’ significantly modifies
treatment effect of thrombolysis2
• But analysis has insufficient statistical power –
need larger RCTs
1. Hill CMAJ 2005;172(10):1307-12. . 2. Wardlaw et al, Radiology 2005: 235: 444
Selecting patients by MR or CT
perfusion
• Concept: perfusion-diffusion ‘mismatch’ on MR or
CT identifies patients with acute ischaemic tissue
likely to be ‘salvaged’ by reperfusion therapy
• Several methods are available to measure the
perfusion lesion with MR (PWI) & CT
• No consensus over which method is best
• Prospective study to assess 10 currently
available methods: does the method affect the %
of patients with ‘mismatch’?1
1. Kane, Wardlaw, Carpenter. Stroke 2007 (in press)
Review of observational studies of
mismatch and outcome: infarct growth
occurs in patients without mismatch
Kane et al, JNNP 2007;78;485-491
Results: 10 perfusion parameters for one patient
Proportion with mismatch varies enormously
with method (3-72%): need an internationally
agreed standard!
% No PWI lesion
% Mismatch
80
70
50
40
30
20
10
BV
qC
BF
qC
TT
qM
rC
BF
ax
C
m
TT
rM
TT
P
FW
H
M
PT
F
F
0
AT
Percentage
60
Where are we with ‘mismatch’ after
DEFUSE and before EPITHET?
• DEFUSE:1 observational study of MRA,
PWI/DWI in 74 patients treated off label with
rt-PA 3-6 hours (6 unsuccessful PWI); 37/68
(54%) had mismatch
• Early reperfusion was more often associated
with favourable clinical response in patients
with a perfusion/diffusion mismatch (p =0.04)
• EPITHET: RCT of rt-PA vs control in patients
3-6 hours. All have DWI/PWI. Will provide
randomised evidence on whether mismatch
modifies response to rt-PA.
1. Albers et al. Ann Neurol 2006; 60 (5): 508–517.
Current randomised controlled trials of i.v.
thrombolysis
Trial
Thrombolytic
agent
Patient selection
trial size & time window
EPITHET
rt-PA
DIAS -2
Desmoteplase
Clinical, CT (+ DWI/PWI MRI)
3-6 hours
100 patients
Results 2008
DWI/PWI or CT perfusion
3-9 hours
186 patients
ECASS III
rt-PA
Clinical and CT; Hemispheric
Stroke 3-4.5 hours
800 patients (n=491 Oct. 06)
Results 2008
Third International Stroke Trial. A large
randomised trial to answer the question: can a
wider variety of patients be treated?
Target: 6000 patients from 300 centres in
36 Countries
Main features of IST - 3
• International, multi-centre, Prospective,
Randomised, Open, Blinded Endpoints study
of i.v. rt-PA vs control. Independent.
Investigator-led
• Primary outcome: the proportion of patients
alive and independent at six months
(Modified Rankin 0,1 or 2)
• Randomisation by telephone or internet with
on-line minimisation to balance key
prognostic factors.
• Blinded central review of all scans
Recruitment & randomisation
If you consider your patient:
• Has a clear indication for thrombolysis (i.e.
meets terms of licence):
Treat with rt-PA.
• Has a clear contraindication to thrombolysis:
DO NOT treat with rt-PA.
• Thrombolysis is ‘promising but unproven,’
consider RANDOMISING the patient in IST-3.
Randomisation Date
Recruitment at 25.05.2007 = 808:
Nov 2007
May 2007
Nov 2006
May 2006
Nov 2005
May 2005
Nov 2004
May 2004
Nov 2003
May 2003
Nov 2002
May 2002
1000
Nov 2001
May 2001
600
Nov 2000
May 2000
.
700
Number of patients
IST3: Cumulative number of patients randomised
Recruitment
900
800
500
400
300
200
100
0
Recruitment by country
Country
No. centres
Pts.
%
UK
22
300
38%
Poland
5
158
20%
Norway
9
111
14%
Italy
12
71
9%
Belgium
2
50
6%
Australia
9
53
6%
Sweden
9
49
6%
Austria
Canada
1
1
8
5
1%
1%
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 no. hours from onset to
randomisation
1st 197 2nd 198 3rd 197 4th 198
patients patients patients patients
< 3h
24%
17%
16%
21%
>3 h
76%
83%
84%
79%
3.9
4.2
4.2
4.0
median hrs
Age at randomisation. 280 patients aged > 80 =
increased
world
evidence base 7 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
OCSP subtype
LACI
12%
POCI
6%
PACI
36%
TACI
45%
Report of the IST 3 Data
Monitoring Committee
We reviewed analyses based on 597 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
www.ist3.com
Lots of new features on the website!
We need further large trials to:
• Determine reliably:
– whether there are patients outside strict criteria of current
approval who benefit < 3hrs
– which type of patients benefit 3-6 hours
– Balance of risk and benefit in older patients
– New centres welcome to join IST£ and ECASS-3
• Contribute further evidence to:
– persuade doubting clinicians to change practice
– reduce inequalities in patient access to treatment
– persuade health authorities to fund:
• cost of drug treatment
• a well-organised acute stroke service in every acute hospital