The third international stroke trial (IST-3)
main results: primary and secondary
outcomes among 3035 patients
The IST3 collaborative group - 156 hospitals in UK, Poland,
Italy, Sweden, Norway, Australia, Portugal, Belgium, Austria,
Switzerland, Canada, Mexico
Disclosures: Boehringer Ingelheim donated rt-PA and placebo for the first 300
patients but had no other part in the study.
23rd May 2012
Lisbon
Available online at
www.thelancet.com
From 12.00 today
Main features of IST - 3
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Randomised, open study i.v. rt-PA vs control
Target: 3100 acute ischaemic stroke < 6h
Randomised by phone or internet:
Key prognostic factors balanced
Imaging CT or MR
Oxford Handicap Scale (OHS) at 6 months
Primary outcome: % ‘alive and independent’
(OHS 0-2)
• Secondary: ordinal ‘shift’ analysis of OHS1
1. Analysis plan. Int J Stroke. 2012;7:186-7
Follow-up
• Monitor clinical state and BP for 24h
• 24-48 hrs repeat CT/MR
• 7 days, death or hospital discharge - if
sooner - complete CRF:
• 6 months: follow-up by postal
questionnaire to patient or proxy /
blinded telephone follow up by national
coordinating centre
Adjudication, safety, monitoring
• International panel of experts assessed
baseline and follow-up scans blind to clinical
details & treatment.
• Clinical and scan data from patients with
events / deaths < 7 days adjudicated blind to
treatment allocation.
• Independent Data Monitoring Committee
• Site Monitoring Plan agreed with regulators,
included targeted source data verification*
*Lancet May 23rd 2012
Eligibility and randomisation
If patient fitted main eligibility/exclusion criteria
clinician/patient/family discuss. If there is a:
• 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
Baseline characteristics1 (n=3035)
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849 (28%) randomised < 3 hours
1617 (53%) aged > 80 years
1305 (43%) TACI syndrome
914 (30%) in AF
970 (32%) baseline NIHSS > 16
95% did not meet EU approval for rt-PA
Treatment and control groups balanced on
all key factors
1.Trials 2011, 12:252. http://www.trialsjournal.com/content/12/1/252
Fatal & non-fatal intracranial
haemorrhage < 7 days
rt-PA
(n=1515)
n
(%)
104 (7%)
Control
(n=1520)
n
(%)
16
(1%)
P < 0.0001
applying the ‘Cochrane’ definition, of SICH, the 7% IST-3
frequency is comparable with the 7.3% (SITS) registry of 6483
patients treated within licence in routine clinical practice1
1. Wahlgren, Lancet 2007; 369: 275–82
Deaths
n
rt-PA
(%)
n
Control
(%)
p
Within 7 days
163
(11%) 107
(7%)
↑0.001
After 7 days,
before 6 mo.
244
(16%) 300 (20%)
↓0.009
All deaths by 6
months.
408
(27%) 407 (27%)
0.6
Primary outcome: ‘alive and
independent’ (OHS 0-2)
rt-PA
(n=1515)
n
(%)
554 (37%)
control
(n=1520)
n
(%)
534 (35%)
Absolute difference/1000
= 14 more alive and independent
(95% CI -20 to 48) NS
Ordinal analysis 6 month OHS
Favourable shift; adjusted common odds ratio
1·27 (95% CI 1·10- 1·47), p=0·001
or, the odds of surviving with less disability were
27% greater for patients treated with rt-PA
Subgroups
Time (hours) from stroke
to randomisation
0-3h 3-4.5h
4.5-6h
Age <80
177
558
683
Age >80
672
620
325
849
1178
1008
All
Subgroups: adjusted effect on primary
outcome
(interaction)
The treatment odds ratio in each subgroup has
been adjusted for the linear effects of the other
key variables
At six months, for every 1000
patients treated with rt-PA
All ages 0-6 hrs
14 more alive and independent (NS)
29 more ‘favourable outcome’ (p=0·018)
Favourable shift in OHS (p=0.001)
No difference in deaths
In patients > 80 years 0-6hrs
38 more alive and independent
In patients all ages < 3hrs
80 more alive and independent
Summary of evidence
• For the types of patient recruited in
IST-3, despite the early hazards,
thrombolysis within six hours
improved functional outcome.
• Benefit did not appear to be
diminished among elderly patients.
• Benefit was greatest among those
randomised within 3 hours
Acknowledgements:
The 3035 patients, the 156 hospitals in the IST-3 group, the Data
Monitoring Committee, the MRC Steering Committee, Image Reading Panel,
Event adjudication panel, International Advisory Board.
Funding: Medical Research Council (managed by NIHR on behalf of the MRC-NIHR partnership),
Stroke Association, The Health Foundation,, The Research Council of Norway, AFA Insurances
(Sweden), the Swedish Heart Lung Fund, The Foundation of Marianne and Marcus Wallenberg,
Stockholm County Council and Karolinska Institute Joint ALF-project grants (Sweden), the
Government of Poland, the Australian Heart Foundation, Australian NHMRC, the Swiss National
Research Foundation, the Swiss Heart Foundation, the Foundation for health and cardio/neurovascular research, Basel, Switzerland and the Assessorato alla Sanita, Regione dell'Umbria.
Drug and placebo for the 300 patients in the double-blind component of the start-up phase were
supplied by Boehringer-Ingelheim GMBh. IST-3 acknowledges the extensive support of the NIHR
Stroke Research Network , NHS Research Scotland (NRS), through the Scottish Stroke Research
Network, and the National Institute for Social Care and Health Research Clinical Research Centre
(NISCHR CRC). The imaging work was undertaken at the Brain Imaging Research Centre, a
member of the SINAPSE collaboration, at the Division of Clinical Neurosciences, University of
Edinburgh. SINAPSE is funded by the Scottish Funding Council (SFC) and the Chief Scientist Office
of the Scottish Executive (CSO). Additional support was received from Chest Heart and Stroke
Scotland, Desacc, University of Edinburgh, Danderyd Hospital R&D Department, Karolinska
Institutet, the Dalhousie University Internal Medicine Research Fund.