Patient description: A 46-year-old man presents with dizziness and frequent headaches. He has a family history of CAD, but no other cardiovascular risk factors such as smoking, high blood pressure, and diabetes mellitus and is physically active. The patient's LDL-C and HDL-C levels were 545 and 53 mg/dL, respectively. His fasting glucose and triglyceride levels (85 and 158 mg/dL, resp.) were within normal limits. The patient reported no use of lipid-lowering medications. Neck auscultation revealed a systolic murmur 3+/6+ in the neck, radiating to the skull. Ultrasonography of the carotid arteries, revealed severe stenosis in the left internal carotid artery (LICA), as well as moderate stenosis in the right internal carotid artery (RICA) estimated between 40% and 50%. For the LICA, the peak-systolic (PSV) and end-diastolic velocity (EDV) cutoff values were 208.5 cm/s and 54.5 cm/s, respectively; RICA PSV was 91.72 cm/s and RICA EDV was 37.37 cm/s. Plaque was observed in the anterior and posterior walls of the internal carotid artery and common carotid artery, which were characterized as bulky plates extending to the middle third of the internal coronary arteries (ICAs) and as predominantly echogenic and hyperechoic, with less than 50% of the area being echolucent with uneven surfaces.

Clinical trial eligibility criteria: eligible ages (years): 35.0-999.0,  Carotid Stenosis General 1. Patients ≥35 years old. 2. 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: 1. an end diastolic velocity ≥100 cm/s, or 2. internal carotid/common carotid artery peak systolic velocity ratio ≥4.0, or 3. CTA with ≥ 70% stenosis, or 4. MRA with ≥ 70% stenosis. 3. 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 4. Patients must have a modified Rankin Scale score of 0 or 1 at the time of informed consent. 5. Women must not be of childbearing potential or, if of childbearing potential, have a negative pregnancy test prior to randomization. 6. Patients must agree to comply with all protocol-specified follow-up appointments. 7. 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. 8. 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). 9. Carotid stenosis must be treatable with CEA, CAS, or either procedure. General  Intolerance or allergic reaction to a study medication without a suitable management alternative. 2. GI hemorrhage within 1 month prior to enrollment that would preclude antiplatelet therapy. 3. Prior major ipsilateral stroke in the past with substantial residual disability (mRS ≥ 2) that is likely to confound study outcomes. 4. Severe dementia. 5. History of major symptomatic intracranial hemorrhage within 12 months that was not related to anticoagulation. 6. 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. 7. Current neurologic illness characterized by fleeting or fixed neurologic deficits that cannot be distinguished from TIA or stroke. 8. Patient objects to future blood transfusions. 9. Platelet count <100,000/microliter or history of heparin-induced thrombocytopenia. 10. Anticoagulation with Phenprocoumon (Marcumar®), warfarin, or a direct thrombin inhibitor, or anti-Xa agents. 11. Chronic atrial fibrillation. 12. Any episode of atrial fibrillation within the past 6 months or history of paroxysmal atrial fibrillation that is deemed to require chronic anticoagulation. 13. 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. 14. 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). 15. Left Ventricular Ejection fraction <30% or admission for heart failure in prior 6 months. 16. Respiratory insufficiency with life expectancy < 4 years or FEV1 <30% of predicted value. 17. 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. 18. Any major surgery, major trauma, revascularization procedure, or acute coronary syndrome within the past 1 month. 19. Either the serum creatinine is ≥ 2.5 mg/dl or the estimated GFR is < 30 cc/min. 20. Major (non-carotid) surgery/procedures planned within 3 months after enrollment. 21. Currently listed or being evaluated for major organ transplantation (i.e. heart, lung, liver, kidney). 22. 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. 23. Inability to understand and cooperate with study procedures or provide informed consent. 24. Non-atherosclerotic carotid stenosis (dissection, fibromuscular dysplasia, or stenosis following radiation therapy). 25. Previous ipsilateral CEA or CAS. 26. Ipsilateral internal or common carotid artery occlusion. 27. Intra-carotid floating thrombus. 28. Ipsilateral intracranial aneurysm > 5 mm. 29. Extreme morbid obesity that would compromise patient safety during the procedure or would compromise patient safety during the periprocedural period. 30. 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 Patients who are being considered for revascularization by CEA must not have any of the following 1. Serious adverse reaction to anesthesia not able to be overcome by pre-medication. 2. Distal/intracranial stenosis greater than index lesion. 3. 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 Patients who are being considered for revascularization by CAS must not have any of the following 1. Allergy to intravascular contrast dye not amenable to pre-medication. 2. Type III, aortic arch anatomy. 3. 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. 4. 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. 5. 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).) 6. 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. 7. Inability to deploy or utilize an FDA-approved Embolic Protection Device (EPD). 8. Non-contiguous lesions and long lesions (>3 cm). 9. Qualitative characteristics of stenosis and stenosis-length of the carotid bifurcation (common carotid) and/or ipsilateral external carotid artery, that preclude safe sheath placement. 10. 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. 11. 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