Intolerance or allergic reaction to a study medication without a suitable management alternative.
GI hemorrhage within 1 month prior to enrollment that would preclude antiplatelet therapy.
Prior major ipsilateral stroke in the past with substantial residual disability (mRS ≥ 2) that is likely to confound study outcomes.
Severe dementia.
Intracranial hemorrhage within the past 12 months.
Current neurologic illness characterized by fleeting or fixed neurologic deficits that cannot be distinguished from TIA or stroke.
Patient objects to future blood transfusions.
Platelet count <100,000/μl or history of heparin-induced thrombocytopenia.
Anticoagulation with Phenprocoumon (Marcumar®), warfarin, or a direct thrombin inhibitor, or anti-Xa agents.
Chronic atrial fibrillation.
Any episode of atrial fibrillation within the past 6 months or history of paroxysmal atrial fibrillation that is deemed to require chronic anticoagulation.
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.
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).
Left Ventricular Ejection fraction <30% or admission for heart failure in prior 6 months.
Respiratory insufficiency with life expectancy < 4 years or FEV1 <30% of predicted value.
Known malignancy other than basal cell non-melanoma skin cancer. There are two exceptions: patients with prior cancer treatment and no recurrence for >5 years are eligible, and cancer patients with life expectancy greater than 5 years are eligible for enrollment.
Any major surgery, major trauma, revascularization procedure, or acute coronary syndrome within the past 1 month.
Either the serum creatinine is ≥ 2.5 mg/dl or the estimated GFR is < 30 cc/min.Major (non-carotid) surgery/procedures planned within 3 months after enrollment.
Major (non-carotid) surgery procedure planned within 3 months after enrollment.
Currently listed or being evaluated for major organ transplantation (i.e. heart, lung, liver, kidney).
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.
Inability to understand and cooperate with study procedures or provide informed consent.
Non-atherosclerotic carotid stenosis (dissection, fibromuscular dysplasia, or stenosis following radiation therapy).
Previous ipsilateral CEA or CAS.
Ipsilateral internal or common carotid artery occlusion.
Intra-carotid floating thrombus.
Ipsilateral intracranial aneurysm > 5 mm.
WHO Class III obesity (BMI >40 kg/m2).
Coronary artery disease with two or more proximal or major diseased coronary arteries with ≥ 70% stenosis that have not, or cannot, be revascularized.
