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

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

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)

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