Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial

Study Overview
=================
Brief Summary
-----------------
Carotid revascularization for primary prevention of stroke (CREST-2) is two independent multicenter, randomized controlled trials of carotid revascularization and intensive medical management versus medical management alone in patients with asymptomatic high-grade carotid stenosis. One trial will randomize patients in a 1:1 ratio to endarterectomy versus no endarterectomy and another will randomize patients in a 1:1 ratio to carotid stenting with embolic protection versus no stenting. Medical management will be uniform for all randomized treatment groups and will be centrally directed.

Detailed Description
-----------------
Prevention of stroke involves managing and treating risk factors. Most strokes are caused when blood flow to a portion of the brain is blocked. One place this often happens is in the carotid artery. This blockage is called atherosclerosis or hardening of the arteries. The purpose of this trial is to determine the best way to prevent strokes in people who have a high amount of blockage of their carotid artery but no stroke symptoms related to that blockage. Each eligible participant will be evaluated to determine which procedure(s) is best for him/her. All participants will receive intensive medical treatment. In addition, participants will be randomized to receive the selected procedure or not. The trial will be conducted in the United States and Canada by physicians carefully selected on their ability to perform the procedures at low risk. Another key component of the trial is that important stroke risk factors, including hypertension, diabetes, high cholesterol, cigarette smoking, physical activity, and diet will be managed intensively. Participants will remain in the study for 4 years.

Official Title
-----------------
Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial

Conditions
-----------------
Carotid Stenosis

Intervention / Treatment
-----------------
* Procedure: Carotid endarterectomy (CEA)
* Device: Carotid Stenting (CAS)
* Other: Intensive Medical Management - no CEA
* Other: Intensive Medical Management - no CAS


Participation Criteria
=================
Eligibility Criteria
-----------------
General Inclusion Criteria Patients ≥35 years old. Carotid stenosis defined as: Stenosis ≥70% by catheter angiography (NASCET Criteria); OR by DUS with ≥70% stenosis defined by a peak systolic velocity of at least 230 cm/s plus at least one of the following: an end diastolic velocity ≥100 cm/s, or internal carotid/common carotid artery peak systolic velocity ratio ≥4.0, or CTA with ≥ 70% stenosis, or MRA with ≥ 70% stenosis. No medical history of stroke or TIA ipsilateral to the stenosis within 180 days of randomization. Life-long asymptomatic patients will be defined as having no medical history of stroke or transient ischemic attack and negative responses to all of the symptom items on the Questionnaire for Verifying Stroke-free Status (QVSS).18 Patients must have a modified Rankin Scale score of 0 or 1 at the time of informed consent. Women must not be of childbearing potential or, if of childbearing potential, have a negative pregnancy test prior to randomization. Patients must agree to comply with all protocol-specified follow-up appointments. Patients must sign a consent form that has been approved by the local governing Institutional Review Board (IRB)/Medical Ethics Committee (MEC) of the respective clinical site. Randomization to treatment group will apply to only one carotid artery for patients with bilateral carotid stenosis. Management of the non-randomized stenosis may be done in accordance with local PI recommendation. Treatment of the non-study internal carotid artery must take place at least 30 days prior to randomization, or greater than 44 days after randomization and 30 days after the study procedure is completed (whichever is longer). Carotid stenosis must be treatable with CEA, CAS, or either procedure. General Exclusion Criteria Intolerance or allergic reaction to a study medication without a suitable management alternative. GI hemorrhage within 1 month prior to enrollment that would preclude antiplatelet therapy. Prior major ipsilateral stroke in the past with substantial residual disability (mRS ≥ 2) that is likely to confound study outcomes. Severe dementia. History of major symptomatic intracranial hemorrhage within 12 months that was not related to anticoagulation. Prior Intracranial hemorrhage that the investigator believes represents a contraindication to the perioperative or periprocedural antithrombotic and antiplatelet treatments necessary to complete endarterectomy or stenting per protocol. Current neurologic illness characterized by fleeting or fixed neurologic deficits that cannot be distinguished from TIA or stroke. Patient objects to future blood transfusions. Platelet count <100,000/microliter or history of heparin-induced thrombocytopenia. Anticoagulation with Phenprocoumon (Marcumar®), warfarin, or a direct thrombin inhibitor, or anti-Xa agents. Chronic atrial fibrillation. Any episode of atrial fibrillation within the past 6 months or history of paroxysmal atrial fibrillation that is deemed to require chronic anticoagulation. Other high-risk cardiac sources of emboli, including left ventricular aneurysm, severe cardiomyopathy, aortic or mitral mechanical heart valve, severe calcific aortic stenosis (valve area < 1.0 cm2), endocarditis, moderate to severe mitral stenosis, left atrial thrombus, or any intracardiac mass, or known unrepaired PFO with prior paradoxical embolism. Unstable angina defined as rest angina with ECG changes that is not amenable to revascularization (patients should undergo planned coronary revascularization at least 30 days before randomization). Left Ventricular Ejection fraction <30% or admission for heart failure in prior 6 months. Respiratory insufficiency with life expectancy < 4 years or FEV1 <30% of predicted value. Known malignancy other than basal cell non-melanoma skin cancer. There are two exceptions to this rule: patients with prior cancer treatment and no recurrence for >5 years are eligible for enrollment and cancer patients with life expectancy of greater than 5 years are eligible for enrollment. Any major surgery, major trauma, revascularization procedure, or acute coronary syndrome within the past 1 month. Either the serum creatinine is ≥ 2.5 mg/dl or the estimated GFR is < 30 cc/min. Major (non-carotid) surgery/procedures planned within 3 months after enrollment. Currently listed or being evaluated for major organ transplantation (i.e. heart, lung, liver, kidney). Actively participating in another drug or aortic arch or cerebrovascular device trial for which participation in CREST-2 would be compromised with regard to follow-up assessment of outcomes or continuation in CREST-2. Inability to understand and cooperate with study procedures or provide informed consent. Non-atherosclerotic carotid stenosis (dissection, fibromuscular dysplasia, or stenosis following radiation therapy). Previous ipsilateral CEA or CAS. Ipsilateral internal or common carotid artery occlusion. Intra-carotid floating thrombus. Ipsilateral intracranial aneurysm > 5 mm. Extreme morbid obesity that would compromise patient safety during the procedure or would compromise patient safety during the periprocedural period. Coronary artery disease with two or more proximal or major diseased coronary arteries with 70% stenosis that have not, or cannot, be revascularized. Specific carotid endarterectomy exclusion criteria Patients who are being considered for revascularization by CEA must not have any of the following criteria: Serious adverse reaction to anesthesia not able to be overcome by pre-medication. Distal/intracranial stenosis greater than index lesion. Any of the following anatomical: radical neck dissection; surgically inaccessible lesions (e.g. above cervical spine level 2 (C2)); adverse neck anatomy that limits surgical exposure (e.g. spinal immobility - inability to flex neck beyond neutral or kyphotic deformity, or short obese neck); presence of tracheostomy stoma; laryngeal nerve palsy contralateral to target vessel; or previous extracranial-intracranial or subclavian bypass procedure ipsilateral to the target vessel. Specific Carotid Artery Stenting Exclusion Criteria Patients who are being considered for revascularization by CAS must not have any of the following criteria: Allergy to intravascular contrast dye not amenable to pre-medication. Type III, aortic arch anatomy. Angulation or tortuosity (≥ 90 degree) of the innominate and common carotid artery that precludes safe, expeditious sheath placement or that will transmit a severe loop to the internal carotid after sheath placement. Severe angulation or tortuosity of the internal carotid artery (including calyceal origin from the carotid bifurcation) that precludes safe deployment of embolic protection device or stent. Severe tortuosity is defined as 2 or more ≥ 90 degree angles within 4 cm of the target stenosis. Proximal/ostial CCA, innominate stenosis or distal/intracranial stenosis greater than index lesion. Excessive circumferential calcification of the stenotic lesion defined as >3mm thickness of calcification seen in orthogonal views on fluoroscopy.(Note: Anatomic considerations such as tortuosity, arch anatomy, and calcification must be evaluated even more carefully in elderly subjects (≥ 70 years).) Target ICA vessel reference diameter <4.0 mm or >9.0 mm. Target ICA measurements may be made from angiography of the contralateral artery. The reference diameter must be appropriate for the devices to be used. Inability to deploy or utilize an FDA-approved Embolic Protection Device (EPD). Non-contiguous lesions and long lesions (>3 cm). Qualitative characteristics of stenosis and stenosis-length of the carotid bifurcation (common carotid) and/or ipsilateral external carotid artery, that preclude safe sheath placement. Occlusive or critical ilio-femoral disease including severe tortuosity or stenosis that necessitates additional endovascular procedures to facilitate access to the aortic arch or that prevents safe and expeditious femoral access to the aortic arch. String sign of the ipsilateral common or internal carotid artery. Angiographic, CT, MR or ultrasound evidence of severe atherosclerosis of the aortic arch or origin of the innominate or common carotid arteries that would preclude safe passage of the sheath and other endovascular devices to the target artery as needed for carotid stenting.

Ages Eligible for Study
-----------------
Minimum Age: 35 Years
Maximum Age: 100 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: CREST-2 is two parallel multi-center randomized, observer-blinded endpoint clinical trials.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Carotid Endarterectomy (CEA)<br>Carotid Endarterectomy | Procedure: Carotid endarterectomy (CEA)<br>* Carotid endarterectomy<br>|
| Active Comparator: Carotid Stenting (CAS)<br>Carotid Stenting | Device: Carotid Stenting (CAS)<br>* Carotid stenting<br>|
| Experimental: Intensive Medical Management - no CEA<br>Intensive Medical Management alone - no CEA | Other: Intensive Medical Management - no CEA<br>* Intensive Medical Management alone - no CEA<br>|
| Experimental: Intensive Medical Management - no CAS<br>Intensive Medical Management alone - no CAS | Other: Intensive Medical Management - no CAS<br>* Intensive Medical Management alone - no CAS<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stroke and death | The primary outcome is the composite of stroke plus death within 44 days after randomization and ipsilateral stroke thereafter up to 4 years. | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cognitive Function | The assess if MEDICAL management differs from CAS, and differs from CEA, to maintain the level of cognitive function at the 4-year assessment. | 4 years | 
| Major Stroke | if there are treatment differences in the incidence of major stroke at 4-years among all arms of the study | 4 years | 
| Effect modification | Potential effect modification of the CAS or CEA versus MEDICAL differences, based on patient age, sex, severity of carotid stenosis, restenosis, risk factor level, and duration of asymptomatic period. | 4 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
asymptomatic, carotid, stent, endarterectomy, embolic protection, medical management, hypertension, hyperlipidemia, cognition, risk factor control