Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial

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.

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.

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 ≥

   1. 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 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).)

10. Target ICA vessel reference diameter 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.

11. Inability to deploy or utilize an FDA-approved Embolic Protection Device (EPD).

12. Non-contiguous lesions and long lesions (>3 cm).

13. Qualitative characteristics of stenosis and stenosis-length of the carotid bifurcation (common carotid) and/or ipsilateral external carotid artery, that preclude safe sheath placement.

14. 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.

1. 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.