Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial

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 ≥
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.