Howard, Virginia J

The recently published SPACE-2 trial (Stent-Supported Percutaneous Angioplasty of the Carotid Artery Versus Endarterectomy-2) compared 3 treatments to prevent stroke in patients with asymptomatic carotid stenosis ≥70%: (1) carotid endarterectomy plus best medical treatment (BMT), (2) transfemoral carotid artery stenting plus BMT, or (3) BMT alone. Because of low enrollment, the findings of similar safety and efficacy for carotid endarterectomy, carotid artery stenting, or BMT alone were inconclusive. Publication of the CREST (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial)-2 results should provide level A evidence that has been lacking for 2 to 3 decades, to guide treatment of asymptomatic patients with severe carotid stenosis. For symptomatic patients with ≥70% stenosis, no trials are underway to update the degree of benefit reported for carotid endarterectomy by NASCET (North American Carotid Endarterectomy Trial) and ECST (European Carotid Surgery Trial), published in 1991. Subsequently, the use of cigarettes has plummeted, and major improvements in medical treatments and in carotid revascularization have emerged. These advances have coincided with abrupt decline in the clinical end points necessary for treatment comparisons in procedural trials. One of the advances in the invasive management of carotid disease has been transcarotid artery revascularization, already with limited approval by the US Food and Drug Administration. Establishing safety and efficacy of transcarotid artery revascularization compared with carotid endarterectomy, carotid artery stenting, or BMT alone may be challenging because of enrollment, regulatory, and funding barriers to design and complete an adequately powered randomized trial.

Background and Purpose: Studies 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. Methods: We 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. Results: There 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. Conclusions: Baseline 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.

Background and Purpose: CREST (Carotid Revascularization Endarterectomy Versus Stenting Trial) reported a higher periprocedural risk for any stroke, death, or myocardial infarction for women randomized to carotid artery stenting (CAS) compared with women randomized to carotid endarterectomy (CEA). No difference in risk by treatment was detected for women relative to men in the 4-year primary outcome. We aimed to conduct a pooled analysis among symptomatic patients in large randomized trials to provide more precise estimates of sex differences in the CAS-to-CEA risk for any stroke or death during the 120-day periprocedural period and ipsilateral stroke thereafter. Methods: Data from the Carotid Stenosis Trialists’ Collaboration included outcomes from symptomatic patients in EVA-3S (Endarterectomy Versus Angioplasty in Patients With Symptomatic Severe Carotid Stenosis), SPACE (Stent-Protected Angioplasty Versus Carotid Endarterectomy in Symptomatic Patients), ICSS (International Carotid Stenting Study), and CREST. The primary outcome was any stroke or death within 120 days after randomization and ipsilateral stroke thereafter. Event rates and relative risks were estimated using Poisson regression; effect modification by sex was assessed with a sex-by-treatment-by-trial interaction term, with significant interaction defined a priori as P ≤0.10. Results: Over a median 2.7 years of follow-up, 433 outcomes occurred in 3317 men and 1437 women. The CAS-to-CEA relative risk of the primary outcome was significantly lower for women compared with men in 1 trial, nominally lower in another, and nominally higher in the other two. The sex-by-treatment-by-trial interaction term was significant ( P =0.065), indicating heterogeneity among trials. Contributors to this heterogeneity are primarily differences in periprocedural period. When the trials are nevertheless pooled, there were no significant sex differences in risk in any follow-up period. Conclusions: There were significant differences between trials in the magnitude of sex differences in treatment effect (CAS-to-CEA relative risk), indicating pooling data from these trials to estimate sex differences might not be valid. Whether sex is acting as an effect modifier of the CAS-to-CEA treatment effect in symptomatic patients remains uncertain. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00190398 (EVA-3S) and NCT00004732 (CREST). URL: https://www.isrctn.com ; Unique identifier: ISRCTN57874028 (SPACE) and ISRCTN25337470 (ICSS).

OBJECTIVE Given temporal changes in diabetes prevalence and stroke incidence, this study investigated age, race, and sex differences in the diabetes–stroke association in a contemporary prospective cohort, the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study. RESEARCH DESIGN AND METHODS We included 23,002 non-Hispanic black and white U.S. adults aged ≥45 years without prevalent stroke at baseline (2003–2007). Diabetes was defined as fasting glucose ≥126 mg/dL, random glucose ≥200 mg/dL, or use of glucose-lowering medication. Incident stroke events were expert adjudicated and available through September 2017. RESULTS The prevalence of diabetes was 19.1% at baseline. During follow-up, 1,018 stroke events occurred. Among adults aged &lt;65 years, comparing those with diabetes to those without diabetes, the risk of stroke was increased for white women (hazard ratio [HR] 3.72 [95% CI 2.10–6.57]), black women (HR 1.88 [95% CI 1.22–2.90]), and white men (HR 2.01 [95% CI 1.27–3.27]) but not black men (HR 1.27 [95% CI 0.77–2.10]) after multivariable adjustment. Among those aged ≥65 years, diabetes increased the risk of stroke for white women and black men, but not black women (HR 1.05 [95% CI 0.74–1.48]) or white men (HR 0.86 [95% CI 0.62–1.21]). CONCLUSIONS In this contemporary cohort, the diabetes–stroke association varied by age, race, and sex together, with a more pronounced effect observed among adults aged &lt;65 years. With the recent increase in the burden of diabetes complications at younger ages in the U.S., additional efforts are needed earlier in life for stroke prevention among adults with diabetes.

Background and Purpose— Multicenter clinical trials attempt to select sites that can move rapidly to randomization and enroll sufficient numbers of patients. However, there are few assessments of the success of site selection. Methods— In the CREST-2 (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trials), we assess factors associated with the time between site selection and authorization to randomize, the time between authorization to randomize and the first randomization, and the average number of randomizations per site per month. Potential factors included characteristics of the site, specialty of the principal investigator, and site type. Results— For 147 sites, the median time between site selection to authorization to randomize was 9.9 months (interquartile range, 7.7, 12.4), and factors associated with early site activation were not identified. The median time between authorization to randomize and a randomization was 4.6 months (interquartile range, 2.6, 10.5). Sites with authorization to randomize in only the carotid endarterectomy study were slower to randomize, and other factors examined were not significantly associated with time-to-randomization. The recruitment rate was 0.26 (95% confidence interval, 0.23–0.28) patients per site per month. By univariate analysis, factors associated with faster recruitment were authorization to randomize in both trials, principal investigator specialties of interventional radiology and cardiology, pre-trial reported performance >50 carotid angioplasty and stenting procedures per year, status in the top half of recruitment in the CREST trial, and classification as a private health facility. Participation in StrokeNet was associated with slower recruitment as compared with the non-StrokeNet sites. Conclusions— Overall, selection of sites with high enrollment rates will likely require customization to align the sites selected to the factor under study in the trial. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT02089217.