Transcript Stroke prevention, how well are we doing? Professor

The third international stroke trial (IST-3) of
rt-PA.
Main Results II: IST3 in context of updated
meta-analysis of the randomised trials.
JM Wardlaw, V Murray, E Berge, G del Zoppo,
PAG Sandercock, RI Lindley, G Cohen
And the IST-3 Collaborative Group
ESC
Lisbon
May 2012
Disclosures
Cochrane review:
United Kingdom Medical Research Council, Stroke
Association, University of Edinburgh, National Health
Service Health Technology Assessment Programme,
Swedish Heart-Lung Fund, AFA Insurances Stockholm
(Arbetsmarknadens Partners Forsakringsbolag),
Karolinska Institutet, Marianne and Marcus Wallenberg
Foundation,
Research Council of Norway, Oslo University Hospital.
The authors of the Cochrane Review have not received
financial support from any pharmaceutical company to
undertake the review.
Individual authors serve on trial steering and adjudication
committees but have no personal financial interest or
otherwise competing interests with any of the material
presented.
Thrombolysis Systematic Review
• Continuously updated since 1990
• All randomised trials of thrombolysis versus
control
• Last update 2009, for rt-PA: 11 trials, n=3977
• Remaining uncertainties
– Precise estimates of effects on some outcomes
• Death: early, late
• Functional outcome
• Haemorrhage, infarct oedema
– Time windows
– Age
– Aspirin, stroke severity, co-morbidities
Stroke 1992; CDSR 1994 1st edition – 2009; Lancet 1998; Stroke 2003, 2010; Lancet
Neurology 2005; BMJ 2009; and others
Methods
• New trials; new data from existing trials
• Multiple overlapping ascertainment
methods
– Two independent reviewers
– unadjusted Peto Odds Ratios (ORs), 95%
CI, fixed effects,
– tests for heterogeneity between all trials
and between previous trials combined and
IST-3
Methods – Outcomes
Outcomes :
Early, <7 days
–
–
–
–
–
Death
Fatal intracranial haemorrhage
Death not due to intracranial haemorrhage
Symptomatic intracranial haemorrhage
Infarct swelling
Late, 3 or 6 months
–
–
–
–
–
Deaths between early and late
Total deaths by the end of follow-up
Alive and independent (mRS 0-2)
Favourable (mRS 0-1)
Dependent (mRS 3-5)
Subgroups :
– Time: <3, 3-6 hours
– Age <80 and  80 years, by time
– Aspirin, stroke severity
New data between 2009 and 2012
12 trials in total (IST-3 is the only new trial)
Total N
<3hrs
3-6hrs
>80 y
Follow-up
Previous
3977
957
2743
94
3 months
Current
7012
1806
4927
1711
6 months
Early outcomes <7days, up to 6 h
Late outcomes end of follow-up, up to 6 h
Absolute effects per 1000; treated up to 6 h
Outcome
n/1000
95%CI
Early death
Fatal ICH
Non-ICH death
SICH
25
29
-4
58
11, 39
23, 36
-16 8
49, 68
Total death
mRS 0-2
mRS 0-1
7
42
55
-11, 25
19, 66
33, 77
- = fewer with rt-PA
Subgroups: Effect of time: <3 vs 3-6 hours
Effect of age: <80 vs. > 80 years
and time: <3 vs. 3-6 hrs
Effect of age: <80 vs. > 80 years
and time: <3, 3-6 hr
Absolute effect per 1000; mRS 0-2 end of follow-up
80
>80 yrs
43
(16, 70)
38
(-3, 79)
<3 hrs
95
(35, 155)
96
(35, 157)
3-6 hrs
23
(-8, 54)
-5
(-61, 50)
Age
Time
<6 hrs
- = fewer with rt-PA;
Conclusion
• Effects are highly consistent across all trials despite IST-3
including a wider range of patients
• SICH is the single largest cause of early hazard
• Fewer deaths occur with rt-PA between 7 days
and the end of follow-up
• There is no net effect of rt-PA on total death at late follow-up
• Benefit substantial with treatment <3 hours
• Benefit possible for some patients out to 6 hours
• Patients >80yrs have similar benefit to <80s,
especially if treated <3h
Conclusion
• Healthcare systems should aim to treat patients
as fast as possible
• There should be no upper age limit for rt-PA
• An individual patient data meta-analysis should be
performed as soon as possible
• Trials aimed at finding ways to reduce hazard
(SICH) and determine who benefits at later times
should proceed as fast as possible
Acknowledgements:
Cochrane: K. Shuler; Lisa Blackwell; Hazel Fraser; Brenda Thomas; Mei-Chiun Tseng; Take
Yamaguchi; Charles Warlow; Martin Dennis; Colin Baigent; Steve Davis.
Cochrane Funding: MRC, Stroke Association, Univ of Edinburgh, NHS HTA Programme,
Norwegian Research Council, Swedish Heart-Lungfund, AFA Insurances, Karolinska
Institutet, Marianne and Marcus Wallenberg Foundation.
IST-3: 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.
IST-3 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.
Key methodological points
• Central web or phone randomisation in 2
trials (IST-3, ECASS 3); rest used
sequentially numbered packs
• Time to treatment: <3h in 2; 3-4.5h in 1; <5h
in 1, 3-6h in 1, <6h in 6
• Dose: 0.6 – 1.0 mg/kg (most used 0.9)
• Placebo: 10 identical; 2 open control
• Blinded follow-up: 5 trials; rest not stated
• Follow-up: 6m IST-3, 3m or less in the rest
Alive and independent
outcome mRS 0-2, 6 hrs
Absolute effect: 42/1000 95% CI (19, 66)
Alive and favourable outcome
mRS 0-1, 6 hrs
Absolute effect: 55/1000 95% CI (33, 77)
Dependency mRS 3-5
Absolute effect: -50/1000 95% CI (-73, -27)