Third International Stroke Trial (IST-3): response to ECASS-3 results Professor Peter Sandercock, University of Edinburgh Collaborators Meeting Vienna 26 th September 2008
Dec 13, 2015
Third International Stroke Trial (IST-3): response to
ECASS-3 results
Professor Peter Sandercock, University of Edinburgh
Collaborators MeetingVienna
26th September 2008
Outline• At a population level, between 1% and
3% of all ischaemic strokes are treated• As a result of ECASS-3 the % treated
should continue to increase, BUT• The ‘extended time’ licence will still
exclude many from treatment, and the public health benefit will be limited
• We still need IST-3 to determine if a much wider range can be treated
Estimated % of all ischaemic strokes treated with thrombolysis
• USA: 1-7%1 • Canada 3%2
• Germany 3%3
• Sweden 2.3%4
1. 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 63 130
Thrombolysis 30% 31200 47 1470*130,000 strokes per year
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
Recruitment by 31 March 2008 = 1104
0
200
400
600
800
1000
1200
May
200
0
Nov 2
000
May
200
1
Nov 2
001
May
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2
Nov 2
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3
Nov 2
003
May
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4
Nov 2
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5
Nov 2
005
May
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6
Nov 2
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May
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7
Nov 2
007
May
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8
Nov 2
008
Randomisation Date
Num
ber o
f pat
ient
s
.
Recruitment by 24.9.2008 = 1281patients
Recruitment by country in IST-3Country No. centres Pts. %
UK 39 510 40%
Poland 5 192 15%
Norway 13 146 12%
Sweden 14 131 10%
Italy 20 116 9%
Australia 10 100 8%
Belgium 3 59 5%
Austria 2 17 1%
Canada 1 7 1%
Mexico 1 3 0%
Portugal 1 0 0%
Total 109 1281
Characteristics of the 1214 patients recruited by July 2008
0%10%20%30%40%50%60%70%80%90%
100%
1st250
2nd250
3rd250
4th250
next214
> 80 years
< 80 years
Trends in type of patient recruited 2000-2008: AGE
No. patients recruited into trial
0%10%20%30%40%50%60%70%80%90%
100%
1st250
2nd250
3rd250
4th250
next214
0-3 hrs
3-6 hrs
Trends in type of patient recruited 2000-2008: Time to randomisation
No. patients recruited into trial
0%10%20%30%40%50%60%70%80%90%
100%
1st250
2nd250
3rd250
4th250
next214
POCI
LACI
PACI
TACI
No. patients recruited into trial
Trends in type of patient recruited since trial began: Infarct subtype
Overall
• Time: Median time to randomization 4.0 h
• Age: IST-3 largest randomised controlled trial in ‘older’ hyper-acute stroke – 838 patients > 70 years, – 530 patients > 80 years.
• Severity& subtype: – Wide range of severity– Subtypes not much recruited in previous trials:
153 Lacunar infarcts
77 Posterior circulation infarcts
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 63 130
Thrombolysis 30% 31200 47 1470
Letter from chairman of IST-3 Data Monitoring Committee
• Dear Peter• IST-3 DMC meeting 23rd September 2008• 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
• ECASS-3 results were positive, but apply to patients under 80 who meet the strict terms of the EU license
• IST-3 group members at the meeting agreed the ECASS-3 results would stimulate more centres to offer a thrombolysis service, which would be good.
• We would all continue to recruit eligible patients in IST3
Discussion, collaborators meeting, Vienna, 26/09/08 - 1
• There was discussion about whether or not to randomise patients aged under 80, presenting 3- 4.5 hours; if the patient otherwise met the terms of the current licence, we agreed we would generally treat such patients.
• However, we agreed that it could still be appropriate to randomise selected patients at 3-4.5 hrs, especially if – they had one of the relative contraindications specified
in the EU approval, and – treatment was considered ‘promising but unproven’ for
that individual• This shift in recruitment would not bias the trial,
since treatment groups are balanced on baseline stroke severity by the randomisation system
Discussion, collaborators meeting, Vienna, 26/09/08 - 2
Discussion, collaborators meeting, Vienna, 26/09/08 - 3
• Need to increase recruitment. IST3 should approach Boehringer to see if they can help with drug supplies in centres where trial has all approvals, but drug supply a problem.
• Suggest a statement for stroke guidelines: ‘All patients presenting within 6 hours of acute ischaemic stroke with no clear contraindications for thrombolysis should either be – Treated,
– Or, if they don’t exactly meet the terms of the licence, randomised!’
Plans for disseminating the need for IST-3 to continue
• Teleconference for National Coordinators International Advisory Board Monday 29th September.
• Slide sets on website• Webcast (provisionally set for 7th October, details to be
confirmed)• Edit and re-submit comment article to BMJ• Publish updated Cochrane review• Karolinska Stroke Update Nov 08• Collaborators meetings:
• UK stroke forum, Harrogate December 2008• Karolinska Stroke Update Stockholm Nov 17-19 2008• Swedish collaborators, Stockholm January 2009• Italian Collaborators, Florence 12-13th February 2009• Collaborators meeting; ESC Stockholm 26-29th May 2009
Summary 1• 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
Summary 2• Updated Cochrane review highlights several
questions which remain unanswered, that IST-3 will provide unique data on.
• So far, IST-3 has recruited patients that fall outside the current EU approval
• Continued recruitment in IST-3 of patients that do not meet the terms of the EU approval is – ethical – very necessary to increase knowledge