DESCRIPTION (provided by applicant): The broad, long-term objective of this application is to advance primary prevention of stroke in patients at risk for stroke due to atherosclerosis of the carotid artery. Four to eight percent of adults have asymptomatic carotid stenosis exceeding 50%. Carotid stenosis is often managed either by endarterectomy or stenting. About 100,000 carotid endarterectomies and 40,000 carotid stenting procedures are done each year in the US. Up to 90% of these procedures are done on asymptomatic patients. Medical therapy has improved. The ACST trial demonstrated that medical management of hyperlipidemia can attenuate the benefits of revascularization in patients with asymptomatic stenosis. Further advances in managing atherosclerotic risk factors may negate benefit that might otherwise be realized through revascularization, making the morbidity of the procedures unjustifiable. Endarterectomy and stenting have also improved. The results for endarterectomy in CREST showed a periprocedural stroke and death rate of 1.4%. For stenting, the rate was the lowest yet reported in a randomized controlled trial, 2.5%, and that rate was improving in the last tertil of enrollment. We will conduct two parallel randomized, multicenter non-inferiority trials (CREST-2). The primary specific aims will be to compare the effectiveness of intensive medical management to carotid endarterectomy (n=1050) and also to compare the effectiveness of intensive medical management to stenting (n=1050) for patients with high-grade asymptomatic carotid artery stenosis. The primary endpoint will be a composite of any stroke or death within 30 days of randomization plus ipsilateral stroke up to 4 years of follow-up. Vascular risk factors, including hypertension, diabetes mellitus, cigarette smoking and hyperlipidemia, will be managed centrally using modern aggressive targets. Should intensive medical management be declared non-inferior to endarterectomy, stenting or both, up to 5,000 periprocedural strokes may be prevented.