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Carotid revascularization and medical management for asymptomatic carotid stenosis - Hemodynamics (CREST-H): Study design and rationale.

ABSTRACT: RATIONALE:For patients with asymptomatic high-grade carotid stenosis, clinical investigations have focused on preventing cerebral infarction, yet stenosis that reduces cerebral blood flow may independently impair cognition. Whether revascularization of a hemodynamically significant carotid stenosis can alter the course of cognitive decline has never been investigated in the context of a randomized clinical trial. HYPOTHESIS:Among patients randomized in the Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis (CREST-2) trials, the magnitude of treatment differences (revascularization versus medical management alone) with regard to cognition will differ between those with flow impairment compared to those without flow impairment. SAMPLE SIZE:We will enroll approximately 500 patients from CREST-2, of which we anticipate 100 will have hemodynamic impairment. We estimate 93% power to detect a clinically meaningful treatment difference of 0.5 SD. METHODS AND DESIGN:We will use perfusion-weighted magnetic resonance imaging to stratify by hemodynamic status. Linear regression will compare treatment differences, controlling for baseline cognitive status, age, depression, prior cerebral infarcts, silent infarction, white matter hyperintensity volume, and cerebral microbleeds. STUDY OUTCOMES:The primary outcome is change in cognition at one year. Secondary outcomes include silent infarction, change in white matter hyperintensity volume, number of cerebral microbleeds, and cortical thickness over one year. DISCUSSION:If cognitive impairment can be shown to be reversible by revascularization, then we can redefine "symptomatic carotid stenosis" to include cognitive impairment and identify a new population of patients likely to benefit from revascularization. TRIAL REGISTRATION:US National Institutes of Health (NIH) clinicaltrials.gov NCT03121209.

SUBMITTER: Marshall RS

PROVIDER: S-EPMC6384010 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Carotid revascularization and medical management for asymptomatic carotid stenosis - Hemodynamics (CREST-H): Study design and rationale.

Marshall Randolph S RS Lazar Ronald M RM Liebeskind David S DS Connolly E Sander ES Howard George G Lal Brajesh K BK Huston John J Meschia James F JF Brott Thomas G TG

International journal of stroke : official journal of the International Stroke Society 20180822 9

<h4>Rationale</h4>For patients with asymptomatic high-grade carotid stenosis, clinical investigations have focused on preventing cerebral infarction, yet stenosis that reduces cerebral blood flow may independently impair cognition. Whether revascularization of a hemodynamically significant carotid stenosis can alter the course of cognitive decline has never been investigated in the context of a randomized clinical trial.<h4>Hypothesis</h4>Among patients randomized in the Carotid Revascularizatio ...[more]

PMID: 30132751

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Project description:Rationale Trials conducted decades ago demonstrated that carotid endarterectomy by skilled surgeons reduced stroke risk in asymptomatic patients. Developments in carotid stenting and improvements in medical prevention of stroke caused by atherothrombotic disease challenge understanding of the benefits of revascularization. Aim Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2) will test whether carotid endarterectomy or carotid stenting plus contemporary intensive medical therapy is superior to intensive medical therapy alone in the primary prevention of stroke in patients with high-grade asymptomatic carotid stenosis. Methods and design CREST-2 is two multicenter randomized trials of revascularization plus intensive medical therapy versus intensive medical therapy alone. One trial randomizes patients to carotid endarterectomy plus intensive medical therapy versus intensive medical therapy alone; the other, to carotid stenting plus intensive medical therapy versus intensive medical therapy alone. The risk factor targets of centrally directed intensive medical therapy are LDL cholesterol <70?mg/dl and systolic blood pressure <140?mmHg. Study outcomes The primary outcome is the composite of stroke and death within 44 days following randomization and stroke ipsilateral to the target vessel thereafter, up to four years. Change in cognition and differences in major and minor stroke are secondary outcomes. Sample size Enrollment of 1240 patients in each trial provides 85% power to detect a treatment difference if the event rate in the intensive medical therapy alone arm is 4.8% higher or 2.8% lower than an anticipated 3.6% rate in the revascularization arm. Discussion Management of asymptomatic carotid stenosis requires contemporary randomized trials to address whether carotid endarterectomy or carotid stenting plus intensive medical therapy is superior in preventing stroke beyond intensive medical therapy alone. Whether carotid endarterectomy or carotid stenting has favorable effects on cognition will also be tested. Trial registration United States National Institutes of Health Clinicaltrials.gov NCT02089217.

Project description:Background and purposeStudies of carotid artery disease have suggested that high-grade stenosis can affect cognition, even without stroke. The presence and degree of cognitive impairment in such patients have not been reported and compared with a demographically matched population-based cohort.MethodsWe studied cognition in 1000 consecutive CREST-2 (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial) patients, a treatment trial for asymptomatic carotid disease. Cognitive assessment was after randomization but before assigned treatment. The cognitive battery was developed in the general population REGARDS Study (Reasons for Geographic and Racial Differences in Stroke), involving Word List Learning Sum, Word List Recall, and Word List fluency for animal names and the letter F. The carotid stenosis patients were >45 years old with ≥70% asymptomatic carotid stenosis and no history of prevalent stroke. The distribution of cognitive performance for the patients was standardized, accounting for age, race, and education using performance from REGARDS, and after further adjustment for hypertension, diabetes, dyslipidemia, and smoking. Using the Wald Test, we tabulated the proportion of Z scores less than the anticipated deviate for the population-based cohort for representative percentiles.ResultsThere were 786 baseline assessments. Mean age was 70 years, 58% men, and 52% right-sided stenosis. The overall Z score for patients was significantly below expected for higher percentiles (P<0.0001 for 50th, 75th, and 95th percentiles) and marginally below expected for the 25th percentile (P=0.015). Lower performance was attributed largely to Word List Recall (P<0.0001 for all percentiles) and for Word List Learning (50th, 75th, and 95th percentiles below expected, P≤0.01). The scores for left versus right carotid disease were similar.ConclusionsBaseline cognition of patients with severe carotid stenosis showed below normal cognition compared to the population-based cohort, controlling for demographic and cardiovascular risk factors. This cohort represents the largest group to date to demonstrate that poorer cognition, especially memory, in this disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02089217.

Project description:Importance:Carotid endarterectomy (CEA) among asymptomatic patients involves a trade-off between a higher short-term perioperative risk in exchange for a lower long-term risk of stroke. The clinical benefit observed in randomized clinical trials (RCTs) may not extend to real-world practice. Objective:To examine whether early intervention (CEA) was superior to initial medical therapy in real-world practice in preventing fatal and nonfatal strokes among patients with asymptomatic carotid stenosis. Design, Setting, and Participants:This comparative effectiveness study was conducted from August 28, 2018, to March 2, 2020, using the Corporate Data Warehouse, Suicide Data Repository, and other databases of the US Department of Veterans Affairs. Data analyzed were those of veterans of the US Armed Forces aged 65 years or older who received carotid imaging between January 1, 2005, and December 31, 2009. Patients without a carotid imaging report, those with carotid stenosis of less than 50% or hemodynamically insignificant stenosis, and those with a history of stroke or transient ischemic attack in the 6 months before index imaging were excluded. A cohort of patients who received initial medical therapy and a cohort of similar patients who received CEA were constructed and followed up for 5 years. The target trial method was used to compute weighted Kaplan-Meier curves and estimate the risk of fatal and nonfatal strokes in each cohort in the pragmatic sample across 5 years of follow-up. This analysis was repeated after restricting the sample to patients who met RCT inclusion criteria. Cumulative incidence functions for fatal and nonfatal strokes were estimated, accounting for nonstroke deaths as competing risks in both the pragmatic and RCT-like samples. Exposures:Receipt of CEA vs initial medical therapy. Main Outcomes and Measures:Fatal and nonfatal strokes. Results:Of the total 5221 patients, 2712 (51.9%; mean [SD] age, 73.6 [6.0] years; 2678 men [98.8%]) received CEA and 2509 (48.1%; mean [SD] age, 73.6 [6.0] years; 2479 men [98.8%]) received initial medical therapy within 1 year after the index carotid imaging. The observed rate of stroke or death (perioperative complications) within 30 days in the CEA cohort was 2.5% (95% CI, 2.0%-3.1%). The 5-year risk of fatal and nonfatal strokes was lower among patients randomized to CEA compared with patients randomized to initial medical therapy (5.6% vs 7.8%; risk difference, -2.3%; 95% CI, -4.0% to -0.3%). In an analysis that incorporated the competing risk of death, the risk difference between the 2 cohorts was lower and not statistically significant (risk difference, -0.8%; 95% CI, -2.1% to 0.5%). Among patients who met RCT inclusion criteria, the 5-year risk of fatal and nonfatal strokes was 5.5% (95% CI, 4.5%-6.5%) among patients randomized to CEA and was 7.6% (95% CI, 5.7%-9.5%) among those randomized to initial medical therapy (risk difference, -2.1%; 95% CI, -4.4% to -0.2%). Accounting for competing risks resulted in a risk difference of -0.9% (95% CI, -2.9% to 0.7%) that was not statistically significant. Conclusions and Relevance:This study found that the absolute reduction in the risk of fatal and nonfatal strokes associated with early CEA was less than half the risk difference in trials from 20 years ago and was no longer statistically significant when the competing risk of nonstroke deaths was accounted for in the analysis. Given the nonnegligible perioperative 30-day risks and the improvements in stroke prevention, medical therapy may be an acceptable therapeutic strategy.

Project description:Importance:The Carotid Revascularization Endarterectomy vs Stenting Trial (CREST) showed greater safety of carotid artery stenting (CAS) in patients younger than 70 years and carotid endarterectomy (CEA) in those older than 70 years. It is unknown how the result of CREST has influenced carotid revascularization choices in the United States. Objective:To evaluate national patterns in CAS performance in patients older than 70 years in the post-CREST (2011-2014) compared with the pre-CREST (2007-2010) era. Design, Setting, and Participants:All adults older than 70 years undergoing carotid revascularization in the United States from 2007 to 2014 were retrospectively identified from the 2007-2014 National Inpatient Sample using International Classification of Disease, Ninth Revision procedural codes. From 61 324 882 unweighted hospitalizations contained in the 2007-2014 National Inpatient Sample, 494 733 weighted carotid revascularization admissions in adults older than 70 years were identified using International Classification of Disease, Ninth Revision procedural codes. Main Outcomes and Measures:The proportion of CAS performed in all age groups over time was estimated and multivariable-adjusted models were used to compare the odds of receiving CAS in the pre-CREST with those in the post-CREST era in adults older than 70 years. Results:A total of 41.8% of all patients were women, and mean (SE) age at presentation was 78.1 (0.03) years. A total of 16.3% of CAS and 10.1% of CEA procedures were performed in patients with symptomatic stenosis. The proportion of patients older than 70 years receiving CAS increased from 11.9% in the pre-CREST to 13.8% in the post-CREST era (P = .005). In multivariable models, the odds of receiving CAS increased by 13% in all patients older than 70 years in the post-CREST compared with the pre-CREST period (odds ratio [OR], 1.13, 95% CI, 1.00-1.28, P = .04), including symptomatic women (OR, 1.31, 1.05-1.65, P = .02). Symptomatic stenosis (OR 1.39; 95% CI, 1.27-1.52; P < .001), congestive heart failure (OR, 1.48; 95% CI, 1.35-1.63; P < .001), and peripheral vascular disease (OR, 1.35; 95% CI, 1.27-1.43; P < .001) were associated with higher odds of CAS; comorbid hypertension (OR, 0.70; 95% CI, 0.66-0.74; P < .001), smoking (OR, 0.84; 95% CI, 0.78-0.91; P < .001), and weekend admission (OR, 0.77; 95% CI, 0.68-0.88; P < .001) were negatively associated with the odds of CAS. Conclusions and Relevance:Despite concerns for higher periprocedural complications with CAS in elderly patients, the odds of CAS increased in the post-CREST compared with pre-CREST era in patients older than 70 years, including symptomatic women.

Dataset Information

Carotid revascularization and medical management for asymptomatic carotid stenosis - Hemodynamics (CREST-H): Study design and rationale.

Publications

Carotid revascularization and medical management for asymptomatic carotid stenosis - Hemodynamics (CREST-H): Study design and rationale.

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