Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial

General Inclusion Criteria

   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 Exclusion Criteria

   1. 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 exclusion criteria

Patients who are being considered for revascularization by CEA must not have any of the
following criteria:

   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 Exclusion Criteria

Patients who are being considered for revascularization by CAS must not have any of the
following criteria:

   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.