IST-3: What are the
implications for rt-PA therapy?
Peter Sandercock
University of Edinburgh
on behalf of the IST-3 collaborative group
ESC Lisbon
23rd May 2012
Disclaimer & disclosures
• I will present relevant data from current research
and there may be data or statements not covered
by current regulatory approval. This presentation
does not suggest clinical use beyond regulatory
approval.
• Please always check the most current prescribing
information as approved for your country.
• IST-3 was conducted completely independently.
BI donated drug and placebo for the first 300
patients in IST-3 and thereafter made no financial
contribution, & had no role in data collection,
analysis, reporting or the decision to publish.
• IST-3 disclosures in full in Lancet publication
Baseline characteristics1 (n=3035)
• 849 (28%) randomised < 3 hours
• 1617 (53%) aged > 80 years
• 1305 (43%) TACI syndrome
• 970 (32%) baseline NIHSS > 16
• 914 (30%) in AF
• 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
Time to randomisation and age
1400
1200
Number
1000
800
<80 yrs
>80 yrs
600
400
200
0
0-3
3-4.5
4.5-6
Time to randomisation (hrs)
Number
Stroke severity: 970 (32%) NIHSS > 16
900
800
700
600
500
400
300
200
100
0
0 to 5
6 to 10 11 to 15 16 to 20 21 to 35
NIHSS
Safety: 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
Overall - all patients 0-6 hrs:
‘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
Overall: 6 month OHS
Favourable shift; adjusted common odds ratio
1·27 (95% CI 1·10- 1·47), p=0·001
Ordinal will be more statistically efficient than
primary outcome for subgroup analysis
Focus on early treatment
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: ‘alive and independent’
(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
One thing that the IST-3 results
cannot do is reaffirm or refute
prior trials of thrombolytic
therapy…
Stroke 2012; 43; May 3 (online)
Effect on ‘alive and independent’
(OHS/mRS 0-2) among patients < 3hrs
IST-3 does affirm the benefits of
Early treatment < 3hrs
Implications for practice.
IST-3 enables clinicians to:
• Consider thrombolytic treatment for a wider
variety of patients,
– Particularly those aged over 80 years
– With more severe strokes
• Reinforce their efforts to increase the
proportion of ischaemic strokes treated < 3
hours
• Have greater confidence that mortality is not
increased by treatment
Implications for research
• The data strengthen the rationale for the
ongoing trials of thrombolysis among
patients presenting more than 4.5 hours
after onset
• Need for the planned STTC individual
patient data meta-analysis to determine
which characteristics (other than age &
time) identify who is most likely to benefit
• The imposition of upper age limits on future
trials in acute stroke will become harder to
justify.
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.
Follow-up at 6 months
rt-PA
(n=1515)
Placebo
(n=1520)
11
13
Alive, disability imputed
31
41
Known disability status
1473
1466
No· for analysis
(OHS known or imputed)
1515
1520
Status at six months
Not known dead/alive
Vital status known for
3011/3035 = 99.2%
Kaplan-Meier survival
rt-PA
Control