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Rationale: Why do we still need a large trial?
IST-3 The Third International Stroke Trial:
National Coordinators’ Meeting
25 May 2005, Bologna
Professor Richard Lindley, Co-Principal Investigator
Outline
• Why large trials?
• Why do we need more randomised
evidence?
– Small evidence base
– Variation in clinical practice
• Areas of uncertainty
• Current trials
• IST3 design
Rationale for large trials
• Acute ischaemic stroke treatment currently
unsatisfactory
• Aspirin effective but has only modest benefit
(approximately 1% absolute benefit) BUT currently
has a greater public health impact than thrombolysis
(large number of patients treated with a modestly
effective treatment)
• Thrombolysis proven to be effective for only highly
selected patients (10-15% absolute benefit) BUT few
treated and minimal public health benefit (small
number of patients treated with a powerful treatment)
History of acute stroke trials
• Modern era dependent on wide-spread
availability of CT (and MRI) scanners,
therefore a short history
• Only two “mega-trials” IST and CAST
• Industry dominated acute stroke trials all
seriously underpowered (in comparison to
secondary prevention stroke trials)
Lubeluzole
• N = 3510 patients, confidence interval
for death or dependency at the end of
follow-up 0.91 to 1.19
• Trials only powered to detect a 10-15%
absolute benefit
Gavestinel (GAIN trials)
• GAIN Americas, 90% power to detect a 10%
absolute benefit (n = 1646), 2% absolute
benefit observed for independent survival
BUT 4% more dead
• GAIN International, 90% power to detect a 6-
10% absolute benefit (n=1800), - 0.8%
absolute benefit observed for independent
survival and 1.6% more dead (95% CI for
odds ratio for worse outcome 0.81 to 1.26)
Trials in acute stroke are far
too small
“It is still not sufficiently widely appreciated just how
large clinical trials need to be to detect reliably the
sort of moderate, but important, differences in major
outcomes that might exist (especially if effects in
different subgroups are to be assessed reliably).”
Collins and MacMahon Lancet 2001; 357: 373-380
Neuroprotectors unlikely to have a
major treatment benefit
You need to OPEN occluded
arteries
With trials of about 20,000
subjects, the pharmaceutical
industry can be reassured
that they have not missed an
important new treatment for
acute stroke
Worthwhile reductions in
stroke death and disability
60% dead or disabled at six months in control group
58% dead or disabled at six months in treatment group
Sample size Power
5000 50%
9000 80%
13000 90%
16000 95%
Lessons from cardiology
ISIS-2 Mortality in placebo group 13%
Trial Mortality in best treatment arm
ISIS-2 8%
ISIS-4 7%
GUSTO 6%
Message: Moderate cumulative treatment effects
halved MI mortality over a 10 year period
Lessons from stroke medicine
IST Death/dependency in control group 64%
Trial Death/dependency in best treatment
arm
IST 63% (aspirin)
Stroke units 58%
rt-PA 58% (i.e. current negligible impact)
Message: Moderate cumulative treatment effects
have potential impact in stroke
Lessons from cardiology
ISIS-1 1986 16,000 patients
ISIS-2 1988 17,000 patients
ISIS-3 1992 40,000 patients
GUSTO 1993 41,000 patients
ISIS-4 1995 60,000 patients
Thrombolytic Time Window: Acute MI
60,000 patients from “mega-trials”
Fibrinolytic Therapy Trialists’ Group. Lancet 1994;343:311-322
Thrombolysis for acute
ischaemic stroke
• Standard accepted treatment for MI
• Slow acceptance for acute stroke
NINDS Trial Published in 1995
• 624 patients • Major treatment effect
• Clinical inclusion 120-160 more
criteria independent survivors
• CT scan to exclude per 1,000 treatment
a bleed or mimic (no • Independent re-
other exclusions) analysis 2003 confirms
• Treatment to begin results
within 3 hours of • 10 years later
stroke treatment not widely
• i.v. rt-PA 0.9mg/kg implemented
over 1 hour
ECASS II Published in 1998
• 800 patients 18 to 80 • Non-significant
years modest benefit 37
• Clinical inclusion criteria more independent
• CT scan to exclude a survivors per 1,000
bleed, mimic and > 1/3 treatment
MCA ischaemia)
• Treatment to begin • 7 years later
within 6 hours of stroke treatment not
• i.v. rt-PA 0.9mg/kg over implemented for 3-6
1 hour hour time window
ECASS II Published in 1998
• Powered to detect • Detected a 3.7%
a 10% absolute absolute
difference with difference
80% power
ECASS III Currently recruiting
• Aged 18 to 80 years
• 800 patients recruited 3-4 hours post
stroke
• Still powered to detect a 10%
absolute difference, this time with
90% power
Evidence
Randomised trials of thrombolysis vs
control in acute myocardial infarction
Total no. patients 1994 58,600
Randomised trials trials of thrombolysis vs
control in acute ischaemic stroke
Total (all agents) 2005 5,675
rt-PA 2005 2,700
rt-PA < 3hrs 2005 930
rt-PA aged > 80 years 42
i.v. rt-PA benefit <6 hours:
reduction in ‘death or dependency’
20% reduction with rt-PA (95% CI 7-23%)
BUT the significant between- trial
heterogeneity (I2=62%) makes result unreliable
Unacceptable variation in usage
in clinical practice
Only a small, variable proportion of
patients get rt-PA in USA, Germany
Author no. no. % treated
hospitals patients rt-PA (range)
USA
Johnstone 42 1,195 4.1% (0-12%)
Furlan 29 3,948 1.8% (0-10%)
Reed 137 23,058 1.6% (0-5%)
Germany
Heuschmann 104 13,440 3.0% (0-18%)
Effect of hospital, age and presence of
neurologist on likelihood of receiving
thrombolysis for acute ischaemic stroke among
23,058 acute stroke patients from 137
community hospitals in USA
• In 35% of hospitals, no patients at all
given rt-PA.
• Strong trends to less rt-PA use:
– with increasing age,
– if no neurologist available
Reed et al. Stroke 2001: 32; 1832-44
Variation in use of rt-PA for acute ischaemic
stroke ‘within licence’ in Europe
60
Finland
Austria
rt-PA for stroke per million pop'n
50 Sweden
Norway
40 Belgium
Spain
Germany
30
Netherlands
Denmark
20 Italy
UK
10 Greece
France
Portugal
0
SITS register (2003-5) March 2005
‘Grey areas’ of uncertainty: i.v.
rt-PA promising but unproven
for patients who:
• Present < 3hrs & do not exactly meet NINDS
criteria
• All patients 3-6hours
• Older patients (>75 years)
• Severe stroke, mild stroke…...
• Have subtle, early ischaemic change on CT
• Etc etc …
Sample size required to answer these
questions about iv rt-PA reliably
0-1.5 1.5-3.0 3.0-4.5 4.5-6.0
hours
rt-PA study group. Lancet 2004; 363: 768–74
Current trials
Current randomised trials of i.v.
thrombolysis
Trial Thrombolytic Patient selection
agent trial size & time window
EPITHET rt-PA Clinical, CT (+ DWI/PWI MRI)
3-6 hours
100 patients
DIAS -2 Desmoteplase DWI/PWI or CT perfusion
3-9 hours
186 patients
ECASS III rt-PA Clinical and CT
3-4 hours
800 patients
Small (n< 300) trials of other interventions
IA thrombolysis Mechanical
MELT MR-RESCUE
SYNTHESIS
GP IIb/IIIA Ultrasound +/- rt-PA
AbESTT2 (n=1800) CLOTBUST-2?
CLEAR MUST
ROSIE
SETIS
SATIS
None of these trials will
reliably answer the main
questions
Main features of IST - 3
• International, multi-centre, Prospective,
Randomised, Open, Blinded Endpoints study of i.v.
rt-PA vs control.
• Target 6000 patients
• Primary outcome: the proportion of patients alive
and independent at six months (Modified Rankin
0,1 or 2)
• Central telephone randomisation with on-line
minimisation to balance key prognostic factors.
• Web-based blinded detailed central review of all
scans (ASPECTS, 1/3 MCA rule, dense MCA etc)
• Conducted to EU GCP standards.
IST - 3 Protocol
IST-3 Sample size: 6,000 patients
• 1500 patients randomised within 3
hours will give >95% power (alpha 0.05)
to detect a 10% increase in the
proportion of patients alive and
independent at 6 months (40% to 50%).
• 4500 patients randomised from 3 to 6
hours will give >90% power (alpha 0.05)
to detect a 5% increase in the
proportion of patients alive and
independent at 6 months (40% to 45%).
IST - 3 Protocol
IST-3 main eligibility criteria
• Symptoms and signs of clinically
definite acute stroke
• Time of onset of stroke is known and
treatment can be started within 6
hours of this onset
• CT or MRI has reliably excluded both
intracranial haemorrhage and
structural brain lesions which can
mimic stroke
• Fuller details at: www.ist3.com
IST-3 main exclusion
criteria
• Major surgery, trauma,GI or urinary
tract haemorrhage within previous 21
days
• Arterial puncture at a non-compressible
site within the previous 7 days
• Any known coagulation defect
• Hypo- or hyperglycaemia sufficient to
account for neurological symptoms
Early infarct signs on CT
Hypodensity : loss of grey/white differentiation,
loss of the lentiform nucleus
Swelling : effacement of sulci, squashing the ventricle
4 hours 24 hours
IST-3: Training to read CT scans
web-based CT reading and feedback system:
• Log on to www.neuroimage.co.uk
• Register
• Do first 20 scans (2 batches)
- get 1 CPD credit what you, the reference standard,
-get feedback five experts and all other
specialties said about that scan,
and a follow-up scan to see where
the infarct appeared
•Do all six batches
- get 5 CPD credits
IST-3 Imaging: Training materials to read scans
IST-3 Imaging: Training materials to read scans
IST-3 trial: randomisation
If patient fits main eligibility/exclusion criteria,
Clinician/patient/family discuss. If:
• 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
Conclusion. Need to
• Implement existing knowledge: redesign services to
increase equity of access to thrombolysis within
licence
• Increase the evidence base; worldwide effort to
randomise sufficient patients to in IST-3 (and other
trials) to provide reliable evidence on current
questions
• Be aware of benefits of participating in IST-3:
– It helps address a ‘real world’ intervention
– You will get education on acute stroke care/CT scanning
– If the trial result is positive, active trial centres more likely
to be able to adopt new treatment quickly
New UK centres needed: please
encourage other centres to join the trial
register at www.ist3.com
Can we get 10-20% of ischaemic
stroke treated with rt-PA?
999
Within 6 Hrs
Nurse led Stroke
Management
process -
Evaluation and
Triage
To achieve this we need
seriously reliable data on:
• Treatment effect to 6 hours (and maybe
beyond)
• Treatment effects by age, stroke
subtype, severity, presence of aspirin
and early ischaemic change on CT etc
Such change requires a convincing trial! Impact of
megatrials in cardiology on thrombolysis for MI
IST-3: The window of opportunity
• In 1998 acute stroke services were too
under-developed for a thrombolysis
“mega-trial”
• Stroke services world-wide are being
developed and maturing
• rt-PA has a track record in an “effective
but not useful” time window
• It is now the most promising treatment
to evaluate
IST-3: Streamlined design
• Methodology of large simple stroke trial
developed over 15 years
• IST-3 designed with consumers and
collaborative group
• Central organisation and delegated
responsibilities share as much of the
work as possible
• Evidence based trial monitoring!
AbESTT-2 IST-3
IST-3 is simple & streamlined! Compare the paperwork
needed for AbESTT-2 trial vs IST-3
So we need hospital teams to be treating
stroke as an emergency…
…and not lounging around drinking coffee!
