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
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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 plan
Primary 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: questions
Compared 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):
• Primary outcome mRS at 90 days
• Sample size ~5000
• 100+ sites, with emphasis on Asia
?
China
20 centres
?
?
Europe (UK, France,,
Belgium, Germany, Austria,
Italy, Portugal, Spain,
Norway, Sweden, Finland
Korea
10-15 centres
~30 centres
Taiwan
10-15 centres
India
15 centres
SE Asia (Vietnam,
South America
(Chile, Brazil,
Colombia, Peru)
Thailand, Malaysia, Singapore)
10-15 centres
?
~20 centres
Australia
14 centres
IA/interventional
• IMS-III
• SYNTHESIS
• EXTEND-IA
• MR RESCUE
• PISTE
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
Recruitment and Active Sites N =
631 (22/02/12)
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
Synthesis Investigators
SYNTHESIS (n=362)
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
<6h
< 4.5 h

CT scan on day 4 (± 2)

Monitoring for 7 days-Adverse events

90 days blind efficacy evaluation-Telephone modified Rankin scale
When?
• STTC analyses – 2013/2014
• SYNTHESIS and IMS – III – 2013
• The rest – it’s up to you to support
these trials!
Acknowledgements:
thanks to Jo Broderick, Alfonso Ciccone and
Craig Anderson for slides