Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2)

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.

General Inclusion Criteria

1. Patients ≥ 35 years old.
2. Carotid stenosis defined as: stenosis ≥ 70% by angiography (NASCET Criteria); or by DUS with ≥ 70% stenosis defined by a peak systolic velocity of at least 230 cm/s and an end diastolic velocity ≥ 100 cm/s, or internal carotid/ common carotid artery peak systolic velocity ratio ≥ 4.0, or by a peak systolic velocity on DUS ≥ 230 cm/s plus CTA or MRA confirmation.
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).
4. Patients must have a modified Rankin 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 at least 30 days after the study procedure is completed.
9. Carotid stenosis must be treatable with CEA, CAS, or either procedures.

General Exclusion Criteria

1. Intolerance or allergic reaction to a study medication without a suitable alternative.
2. GI hemorrhage within 1 month prior to enrollment that would preclude antiplatelet therapy.
3. Major ipsilateral stroke in the past with substantial residual disability (mRS ≥ 2) that is likely to confound study outcomes.
4. Severe dementia.
5. Intracranial hemorrhage within the past 12 months.
6. Neurologic illness characterized by fleeting or fixed neurologic deficits that cannot be distinguished from TIA or stroke.
7. Patient objects to future blood transfusions.
8. Platelet count < 100,000/microliter, uncorrected INR > 1.5, bleeding time > 1 minute beyond upper limit normal (at screening), or history of heparin-induced thrombocytopenia.
9. Anticoagulation with Phenprocoumon, warfarin, or a direct thrombin inhibitor.
10. Chronic atrial fibrillation.
11. Any episode of atrial fibrillation within the past 6 months or history of paroxysmal atrial fibrillation that is deemed to require chronic anticoagulation.
12. 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.
13. 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).
14. Ejection fraction < 30% or admission for heart failure in prior 6 months.
15. Respiratory insufficiency with life expectancy < 4 years or FEV1< 30% of predicted value (example, diagnosed malignancy).
16. Any major surgery, major trauma, revascularization procedure, or acute coronary syndrome within the past 3 months.
17. Serum creatinine ≥ 2.5 mg/dl or estimated GFR ≤ 50cc/min (at screening).
18. Major (non-carotid) surgery/procedures planned within 3 months after enrollment.
19. Currently listed or being evaluated for major organ transplantation (i.e. heart, lung, liver, kidney).
20. Actively participating in another drug or device trial that has not completed follow-up.
21. Inability to understand and cooperate with study procedures or provide informed consent.
22. Non-atherosclerotic carotid stenosis (dissection, fibromuscular dysplasia, or stenosis following radiation therapy).
23. Previous ipsilateral CEA or CAS.
24. Ipsilateral internal or common carotid artery occlusion.
25. Intra-carotid floating thrombus.
26. Ipsilateral intracranial aneurysm > 5mm.
27. WHO Class III obesity (BMI > 40 kg/m2).
28. Contra-lateral common or internal carotid artery occlusion.

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. Coronary artery disease with two or more proximal or major diseased coronary arteries with greater than or equal to 70% stenosis that have not, or cannot, be revascularized prior to CEA.
3. Any of the following anatomical exclusions for CEA: 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.
4. Known allergy to heparin or bivalirudin.
5. For age < 50 years, CAS is the favored procedure. However, the CREST results for asymptomatic patients showed wide confidence intervals about the point estimates comparing CAS and CEA. Accordingly, choice of CEA or CAS cannot be mandated; individual patient characteristics and preferences may supersede guidelines based upon patient age. (See Section 8.1.3 for more details)

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. 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.
3. Angiographic, CT, MR or ultrasound evidence of severe atherosclerosis of the aortic arch or origin of the innominate or common carotid arteries.
4. Type III, calcified aortic arch anatomy.
5. Qualitative characteristics of stenosis and stenosis-length of the carotid bifurcation (common carotid) and/or ipsilateral external carotid artery, in combination with elements of the exclusions # 3 and 4 that preclude safe sheath placement.
6. 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.
7. 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.
8. Excessive circumferential calcification of the stenotic lesion defined as > 3mm thickness of calcification seen in orthogonal views on fluoroscopy.
9. Anatomic considerations such as tortuosity, arch anatomy, and calcification must be evaluated even more carefully in elderly subjects (≥ 70 years).
10. "String sign" of the ipsilateral common or internal carotid artery.
11. Lesions > 20 mm in length.
12. 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.
13. Inability to deploy or utilize an FDA-approved Embolic Protection Device (EPD).
14. For age > 74 years, CEA is the favored procedure. However, the CREST results for asymptomatic patients showed wide confidence intervals about the point estimates comparing CAS and CEA. Accordingly, choice of CEA or CAS cannot be mandated; individual patient characteristics and preferences may supersede guidelines based upon patient age)