Protocol Summary: Version 3.10. 11th November 2015

Randomised trials have established the benefit of revascularisation by carotid endarterectomy (CEA) for moderate and severe carotid stenosis. However, a risk model derived from one of these trials and validated in another, showed that only patients with a high risk of stroke under medical therapy benefited from CEA. For a large range of patients there was neither clear benefit nor harm from CEA. Medical therapy for stroke prevention has improved since these original trials, with more widespread use of statins, more active lowering of blood pressure and more effective antiplatelet regimes. Lower optimum targets have been set for risk factor control e.g. blood pressure. Therefore CEA may not be beneficial in many patients with carotid stenosis treated by modern optimized medical therapy (OMT).

We hypothesize that in patients with carotid stenosis at low and intermediate risk for stroke, OMT alone is as effective in the long-term prevention of cerebral infarction and myocardial infarction (MI) as revascularisation and OMT combined.

ECST-2 is a multicentre, randomised, controlled, open, prospective clinical trial with blinded outcome assessment. We will use a risk model based on clinical characteristics to calculate a 5-year Carotid Artery Risk (CAR) score, which will stratify patients as at high risk (≥20%) or lower risk (<20%) of future stroke using predictive data from previous trials recalibrated to take account of the likely benefit of OMT. An interim analysis using MRI to determine the 2-year rates of cerebral infarction and haemorrhage after randomisation will be performed to assess safety and feasibility of the design and inform the design and sample size calculations for the full trial. ECST-2 will incorporate baseline imaging of carotid plaque where possible to investigate the predictive value of plaque characteristics.

A neurologist or physician with an interest in stroke; a surgeon with expertise in CEA; if available, an interventionist with expertise in CAS. Access to MRI.

Patients with symptomatic or asymptomatic atherosclerotic carotid artery stenosis (> 50%, NASCET criteria), suitable for revascularisation with CAR score indicating risk <20%.

Patients with a CAR score indicating high risk, patients refusing either treatment, unable to consent or unsuitable for revascularisation due to anatomy, ill-health or disabling stroke (current Rankin >2). Recent contralateral carotid revascularisation, cardiac or other major surgery.

Patients will be randomly allocated in equal proportions to be treated by 1) immediate carotid revascularisation with OMT or 2) OMT alone (in the latter arm, revascularisation may be performed at a later stage if it becomes more clearly indicated e.g. because of TIA during follow up). Randomisation will be stratified by centre, type of planned revascularisation, symptom status and CAR score. A web-based randomisation system will be used. We anticipate that revascularisation will be by CEA in most patients, but carotid stenting (CAS) may be used if considered more appropriate. Centres will prespecify whether a patient will receive CEA or CAS if allocated to revascularisation. Randomisation and analysis will be stratified by the pre-specified intervention. The randomisation form will include entry of data to confirm a CAR score of <20%. OMT in both arms will consist of all three of: 1) optimal antiplatelet therapy; 2) statin or other cholesterol lowering treatment with target total cholesterol of <4 mmol/l and LDL cholesterol of <2 mmol/L; 3) antihypertensive treatment, if required, with target blood pressure of 135/85 mmHg. Patients will also undergo risk factor modification e.g. advice on smoking.

The planned duration of follow up is a minimum of 5 years up to a maximum of 10 years. Recruitment and follow up will be supervised by the neurologist or stroke physician. Follow up will include ECG and troponin at 48 hours after revascularisation, with MRI at baseline and at 2 and 5 years follow up.

The planned sample size is 320 patients for the safety MRI analysis and 2000 patients for the full trial.

FFor the full trial: any stroke at any time, plus non-stroke death occurring within 30 days of revascularisation. For the safety MRI analysis: The combined 2-year rate of cerebral infarction, cerebral haemorrhage, MI or periprocedural death after randomisation as assessed by follow up MRI and screening for MI.

Ipsilateral stroke, myocardial infarction, transient ischaemic attack or any hospitalisation for vascular disease during follow up. Disabling stroke during follow up. New cerebral infarction or haemorrhage on post procedural MRI. Ipsilateral restenosis or stenosis progression. Cognitive impairment. Further treatment procedure. Adverse events attributed to medical treatment or CEA. Quality of life and economic measures.





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