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. One to two percent of adults in the U.S. have asymptomatic atherosclerotic stenosis of the carotid artery exceeding 50% luminal narrowing. 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. The findings of trials assessing the efficacy of revascularization begun in the 1980’s and 1990’s that showed efficacy of revascularization are now in question because of improvements in medical therapy to prevent atherosclerosis and atherothrombosis and concurrent improvements in revascularization by endarterectomy and by carotid stenting. To address the question of how best to treat patients with ≥70% carotid bifurcation stenosis to prevent stroke, we are currently completing the first funding cycle for the CREST-2 trials. CREST-2 is a pair of parallel randomized, multicenter trials with the primary aims: 1) to compare the effectiveness of intensive medical management (IMM) vs. carotid endarterectomy plus IMM (n=1240), and 2) to compare the effectiveness of IMM vs. carotid stenting plus IMM (n=1240). The primary endpoint is a composite of any stroke or death within 44 days of randomization (periprocedural risk) plus ipsilateral stroke up to 4 years of follow-up. An important secondary endpoint is cognitive function, assessed periodically and by a centralized, standardized computer- aided telephone interview. Endpoints are assessed in a manner blinded to treatment assignment. IMM involves central management of vascular risk factors, including hypertension, diabetes mellitus, cigarette smoking and hyperlipidemia. Primary risk factor therapeutic targets are systolic blood pressure <130 mmHg and a low- density lipoprotein (LDL) cholesterol level of <70 mg/dL. IMM also includes telephone-delivered periodic lifestyle coaching. Preliminary data show that the IMM has significantly favorably improved vascular risk factors across treatment arms. As of October 26, 2020, a total of 70% (1734/2480) of the required patients have been randomized across the US, Canada, and Spain. All procedures are performed only by rigorously credentialed surgeons and interventionists. IMM and revascularization procedures are being successfully delivered. Cross- overs and withdrawal from the study are within design assumptions, and the quality of the data is high. CREST-2 supports a companion ancillary study known as CREST-H (NCT03121209) that tests the cognitive implications of revascularization in patients with hemispheric hypoperfusion. We are requesting support to complete recruitment, complete follow-up of the cohort (2-years after recruitment of last patient), and report study results.