Endarterectomy Combined With Optimal Medical Therapy (OMT) vs OMT Alone in Patients With Asymptomatic Severe Atherosclerotic Carotid Artery Stenosis at Higher-than-average Risk of Ipsilateral Stroke 

Study Overview
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Brief Summary
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The purpose of this study is to determine whether carotid surgery combined with optimal medical therapy improves long-term survival free of ipsilateral stroke in patients with asymptomatic carotid stenosis at higher-than-average risk of ipsilateral stroke when compared with optimal medical therapy alone.

Detailed Description
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Carotid artery stenosis >= 50% affects about 3% of subjects >= 60 years and accounts for up to 15% of all ischemic strokes. Overall, patients with asymptomatic carotid stenosis have a low risk of ipsilateral stroke on modern medical therapy. It is therefore uncertain whether the benefit of carotid surgery still justifies the perioperative risk of stroke or death, and whether revascularisation is good value for money considering competing demands on health services. Several imaging techniques have been developed to identify patients with asymptomatic carotid stenosis at higher-than-average risk of ipsilateral stroke. Specifically, the presence of transcranial Doppler (TCD)-detected embolic signals, intraplaque haemorrhage on magnetic resonance imaging, TCD-measured impaired cerebral vasomotor reserve or rapid stenosis progression have all been shown to involve an at least 3-fold higher risk of ipsilateral stroke. However, before recommendations for clinical practice can be made regarding the use of these tools, their utility must be demonstrated in a formal randomised clinical trial. Our hypothesis is that the use of these predictors can identify a subset of patients with asymptomatic carotid stenosis who could benefit from prophylactic endarterectomy. Carotid endarterectomy The procedure will be carried out with the technique routinely used by each surgeon. Operative reports and perioperative complications will be collected. CEA will have to be performed as soon as possible, within 60 days after randomization. Optimal medical therapy OMT will be applied to all patients and started immediately after randomisation. OMT will be defined by the adhoc committee and follow relevant guidelines. It will include: Antiplatelet therapy. If the patient requires anticoagulation for any reason (e.g. atrial fibrillation), the patient should be treated with an appropriate anticoagulant according to the practice at the centre as an alternative to antiplatelet therapy. Antihypertensive treatment, if required, to achieve a target blood pressure < 140/90 mmHg (higher targets may be defined by the OMT committee for selected conditions, e.g. contralateral carotid occlusion) Application of structured programs, such as stepped-care approach using ranking of antihypertensive drugs will be used. High-dose statin treatment (target LDL < 0.7 g/l). A stepped-care approach with raking of lipid-lowering drugs will also be used. Patients smoking at the time of randomisation will be encouraged to stop and join a smoking cessation and support program. Other lifestyle modification: reduction of alcohol consumption, choosing healthy food, increasing regular physical activity, reduction of body weight if relevant. OMT may be modified during the course of the trial to take account revised guidelines or new evidence.

Official Title
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 Endarterectomy Combined With Optimal Medical Therapy Versus Optimal Medical Therapy Alone in Patients With Asymptomatic Severe Atherosclerotic Carotid Artery Stenosis at Higher-than-average Risk of Ipsilateral Stroke 

Conditions
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Asymptomatic Carotid Artery Stenosis

Intervention / Treatment
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* Other: Carotid endarterectomy (CEA) combined with optimal medical therapy (OMT)
* Drug: Optimal medical therapy alone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 50 years or over No ipsilateral stroke or TIA within 180 days of randomization Atherosclerotic carotid stenosis between 70 and 99% (NASCET method) At least one of the following markers of ipsilateral stroke risk: Silent brain infarction on MRI, DWi, consistent with embolism from or hemodynamic consequences of the qualifyiing stenosis History of contralateral TIA or ischemic stroke due to atherosclerotic carotid disease Predominantly echolucent plaque on ultrasound Rapid (within 1 year) carotid stenosis progresion TCD-detected microembolic signals Impairment of TCD-measured cerebral vasomotor reserve Intraplaque haemorrhage on magnetic resonance imaging Rapid and severe stenosis progression Patient is able and willing to give informed consent Exclusion Criteria: Previous revascularization procedure in the artery to be randomised Patients not suitable for endarterectomy due to anatomical factors Carotid stenosis caused by non-atherosclerotic disease e.g. neck radiotherapy or fibromuscular disease Patients who have had contralateral carotid artery or vertebral artery or intracranial artery revascularisation within 6 weeks prior to randomisation Patients with planned revascularisation of the contralateral carotid artery or a vertebral artery or an intracranial artery within 6 weeks after randomisation or the date of CEA Patients who have had coronary artery bypass grafting within 3 months prior to randomisation or other major surgery within 6 weeks prior to randomisation Patients with planned coronary artery bypass grafting or other major surgery within 6 weeks after CEA of the artery considered for treatment in the trial Patients with pre-existing disability (modified Rankin score greater than 2) Patients who have a low 5-year life expectancy (see appendix for definition) Patients intolerant or allergic to all of the medications available for OMT Patients in clinical trials of investigational medicinal products or who have been in clinical trials within the last 4 months will not be enrolled unless otherwise agreed Patients who are known to be pregnant Patients unwilling or unable to participate in follow-up

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carotid endarterectomy combined with optimal medical therapy<br>Carotid endarterectomy (CEA) combined with optimal medical therapy (OMT) | Other: Carotid endarterectomy (CEA) combined with optimal medical therapy (OMT)<br>* Carotid endarterectomy (CEA) combined with optimal medical therapy (OMT) (Surgery and Drug)<br>|
| Active Comparator: Optimal medical therapy (OMT)<br>Optimal medical therapy (OMT) | Drug: Optimal medical therapy alone<br>* Optimal medical therapy alone<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ipsilateral stroke or procedural stroke or death | Any ipsilateral stroke within 6 years after randomization or procedural (within 30 days after revascularization) stroke or death | M1, M6, M12, M18, M24, M30, M36, M42, M48, M54, M60, M66, M72 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Any stroke or procedural death | Any stroke within 6 years after randomization or procedural death (within 30 days after revascularization) | M1, M6, M12, M18, M24, M30, M36, M42, M48, M54, M60, M66, M72 | 
| Any disabling or fatal stroke or procedural death | Any disabling or fatal stroke within 6 years after randomization or procedural death (within 30 days after revascularization) | M1, M6, M12, M18, M24, M30, M36, M42, M48, M54, M60, M66, M72 | 
| Any stroke or TIA or procedural death | Any stroke or TIA within 6 years after randomization or procedural death within 6 years after randomization | M1, M6, M12, M18, M24, M30, M36, M42, M48, M54, M60, M66, M72 | 
| Any stroke or death | Any stroke or death within 6 years after randomization | M1, M6, M12, M18, M24, M30, M36, M42, M48, M54, M60, M66, M72 | 
| Myocardial infarction | Myocardial infarction within 6 years after randomization | M1, M6, M12, M18, M24, M30, M36, M42, M48, M54, M60, M66, M72 | 
| Any death | Any death within 6 years after randomization | M1, M6, M12, M18, M24, M30, M36, M42, M48, M54, M60, M66, M72 | 
| Cardiovascular death | Cardiovascular death within 6 years after randomization | M1, M6, M12, M18, M24, M30, M36, M42, M48, M54, M60, M66, M72 | 
| Any hospitalisation for vascular disease | Any hospitalisation for vascular disease within 6 years after randomization | M1, M6, M12, M18, M24, M30, M36, M42, M48, M54, M60, M66, M72 | 
| Cranial nerve palsy attributed to revascularisation | Cranial nerve palsy attributed to revascularisation within 30 days after revascularization | M1 | 
| Haematoma caused by treatment requiring surgery, transfusion or prolonging hospital stay | Haematoma caused by treatment requiring surgery, transfusion or prolonging hospital stay within 30 days after revascularization | M1 | 
| Further revascularisation of the randomised artery after the initial attempt. | Further revascularisation of the randomised artery after the initial attempt. | M1, M6, M12, M18, M24, M30, M36, M42, M48, M54, M60, M66, M72 | 
| Carotid revascularisation | Carotid revascularisation during follow-up other than that allocated at randomisation | M1, M6, M12, M18, M24, M30, M36, M42, M48, M54, M60, M66, M72 | 
| New cerebral infarction or haemorrhage | New cerebral infarction or haemorrhage on MRI at 2 years | M24 | 
| Increase in white-matter changes | Increase in white-matter changes on MRI at 2 years. | M0, M24 | 
| Cognitive impairment | Cognitive impairment assessed by the Montreal Cognitive Assessment (MoCA) with adjustment for demographic factors. | M0, M24 | 
| Depression | Depression measured by the Centre for Epidemiologic Studies Depression (CES-D) Scale. | M0, M24 | 
| Health-related quality of life | Health-related quality of life measured using the European Quality Of Life (EQ-5D). | M0, M24 | 
| Disability | Disability measured by the modified Rankin scale with structured interview | M0, M24 | 
| Achievement of goals for each of the components of optimal medical treatment | Achievement of goals for each of the components of optimal medical treatment | M1, M6, M12, M18, M24, M30, M36, M42, M48, M54, M60, M66, M72 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Carotid stenosis,stroke,endarterectomy,medical therapy