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What’s on the horizon? Peter Sandercock ESC Lisbon 23rd May 2012.
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Transcript of What’s on the horizon? Peter Sandercock ESC Lisbon 23rd May 2012.
Outline
• What are the key questions now?• What RANDOMISED trials are
addressing them?• When will we see the results?• Focus on larger phase III trials
Key questions
• Clinical patient selection?• Advanced imaging selection?• Any other IV drug clearly better
than rt-PA?• Do lower dose IV treatments have
a better risk/benefit ratio?• Is IA drug +/- clot pulling really
better than IV?
Simple clinical selection criteria
• Time from onset
• Age
• Clinical severity NIHSS, SSS, OCSP
• Pre-treatment brain scan
• BP
• Glucose
• Background anti-platelet/anticoagulant
• Etc…
Must combine baseline characteristics
• Patients who present early have higher NIHSS
• Patients presenting later are more likely to show ischaemic change on CT or MR
IST-3 update. Trials 2012
Stroke Thrombolysis Trialists Collaboration (STTC)
• Individual patient data meta-analysis of all i.v. rt-PA RCT’s, update of 2010 pooled analysis
• Protocol and analysis plan in final draft
• Meeting of Steering Group 24th May 2012
• Plan to meet mid 2013 to review preliminary analyses
STTC analyses - draft planPrimary analyses• after what treatment delay is benefit lost or does
harm begin, • do age or stroke severity modify the proportional
effect of rt-PA on stroke outcome?
Secondary• Effect of treatment allocation on: death within 90
days, SICH, Symptomatic ischaemic brain oedema
• Effect modification by baseline characteristics
Ongoing Phase 3 trials iv thrombolysis vs control
rt-PA• TESPI (> 80 years < 3hrs) 162/600• *EXTEND, MR mismatch criteria 3 – 9h• *ECASS 4, MR mismatch criteria 3 – 9h
Desmoteplase• *DIAS 4. Vessel occlusion / stenosis on MRI
or CTA 3-9 hrs
*advanced imaging selection
ENCHANTED: questionsCompared to standard (0.9 mg/kg) rtPA,is low-dose (0.6 mg/kg) i.v. rtPA:
– at least equivalent in clinical outcomes?– safer in terms of a lower risk of symptomatic
intracerebral haemorrhage (sICH)?Compared to guideline BP control, does intensive BP control*
– provide superior clinical outcomes– have a lower risk of sICH?
*(<180-185 mmHg systolic target before initiation of rtPA), vs rapid intensive BP lowering (140-150 mmHg systolic target):
Australia14 centres
India 15
centres
South America(Chile, Brazil,
Colombia, Peru)
~20 centres
China20
centres
Taiwan10-15 centres
Korea10-15 centres
Europe (UK, France,, Belgium,
Germany, Austria, Italy, Portugal, Spain, Norway,
Sweden, Finland
~30 centres
SE Asia (Vietnam, Thailand, Malaysia,
Singapore) 10-15 centres
?
?
?
?
• Primary outcome mRS at 90 days
• Sample size ~5000
• 100+ sites, with emphasis on Asia
IMS-3 Design• Randomised trial of combined IV/IA approach vs standard IV t-PA
• 900 subjects < 3hrs• NIHSS >/= 10, or NIHSS 8-9 with
CTA evidence of ICA, M1 or basilar occlusion prior to initiation of IV rtPA
• IA therapy includes choice of catheter/devices and IA t-PA
Update• stopped by the NINDS because of crossing a
futility boundary at a predetermined DSMB review that included 587 patients.
• the study had a very low likelihood of demonstrating the pre-specified, clinically significant difference in benefit between the treatment arms of the study.
• The DSMB’s decision was based upon the primary outcome in the study, the Modified Rankin Score at 3 months, meeting the threshold for futility.
• While enrollment was stopped because of futility, no serious safety concerns were identified
Acute stroke
Medical history-Physical Examination-NIHSS score
Laboratory-ECG
CT scan
Verify neuroradiologist's availability
Informed consent
Randomization(0-4.5 h)
Angio & IA rt-PA&devices IV rt-PA < 6 h < 4.5 h
CT scan on day 4 (± 2)
Monitoring for 7 days-Adverse events
90 days blind efficacy evaluation-Telephone modified Rankin scale
SYNTHESIS (n=362)SYNTHESIS (n=362)