Lal, Brajesh K.

Introduction: Careful selection and timely activation of clinical sites in multicenter clinical trials is critical for successful enrollment, subject safety, and generalizability of results. Methods: In the Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2), a multidisciplinary Site Selection Committee evaluated applicants referred via participation in CREST, CREST principal investigators (PIs) and other investigators, StrokeNet and industry partners. Data for consideration included performance metrics in CREST and other carotid trials and a site selection questionnaire containing information on the investigators as well as quantitative data on carotid procedures performed. Any FDA warning letters were reviewed. Results: The Committee met bi-weekly for 36 months (n=64 meetings). Applications from 176 sites between March 2014 and July 2016 were evaluated: 153 were approved, 7 are under Committee review, 5 were approved but withdrew, 5 were placed on a waiting list, and 6 were rejected. One-hundred-four sites have completed the regulatory and training requirements to randomize: 51 (49%) academic medical centers, 31 (30%) private hospital-based centers, 16 (15%) private office-based practices, and 6 (6%) Veterans Administration medical centers. The mean times from application-to- approval was 5.2 weeks (interquartile range, 1.9, 6.2), and from approval-to-randomization status was 46.7 weeks (interquartile range, 35.4, 51.7). Specialties of the 104 site PIs are vascular surgery for 35 (33.7%), cardiology for 30 (28.8%), neurology for 25 (24%), neurosurgery for 8 (7.7%), interventional radiology for 4 (3.8%), and interventional neuroradiology for 2 (1.9%). Conclusions: Careful site selection is time-consuming for prospective sites and for trial leadership. Times from application-to-site-approval were modest (mean = 5.2 weeks), in contrast to the times for completing regulatory and training requirements (mean = 46.7 weeks). However, subject enrollment by teams from a wide range of medical centers led by a multi-disciplinary cohort of PIs will promote the generalizability of trial results.

Introduction: Outcomes from endovascular procedures are highly dependent on the experience and skill of the operating physician. The multi-disciplinary CREST-2 Interventional Management Committee (IMC) was charged with credentialing a cohort of skilled interventionists with adequate contemporary case volumes. Methods: Applicants were required to submit 25 consecutive cases completed within 5 years as primary operator out of a required total experience of ≥ 50 cases (≥ 20 for operators completing training). Interventionists not approved on initial review were asked to submit additional cases (with procedural angiograms), the number depending on quality and recent-quantity of the cases. Results: The IMC has had 102 meetings, and 283 interventionists have been evaluated: 104 (37%) interventionists were cardiologists, 64 (23%) vascular surgeons, 42 (15%) neurosurgeons, 32 (11%) neuroradiologists, 26 (9%) neurologists, 9 (3%) interventional radiologists, and 6 (2%) other. The mean total experience among the 226 interventionists with available information was 220±263 carotid stent cases (median 135; range 10-2500). A total of 7037 cases have been reviewed by the IMC, dating from August 2001 to April 2016, with 3366 symptomatic, 3541 asymptomatic and 130 undetermined. The range of cases reviewed per interventionist was 5 to 50. Of the 251 interventionists with sufficient periprocedural follow-up data, no stroke events were reported by 152 (60.5%), and at least one or more stroke events were reported by 99 (39.5%). The IMC has approved 115 interventionists, 29 at the first review and 86 subsequently, based upon submission and review of 631 additional contemporary cases (mean=7 cases per interventionist); 122 have approval pending submission of additional cases; 33 have been denied; 8 have been deferred; 4 have been approved for the CREST-2 Companion Registry only; and 1 is pending decision. Discussion: Rigorous evaluation and credentialing of carotid stenters in CREST-2 has been demanding, for the candidates and for the evaluators. Yet the cohort of interventionists so selected should be able to provide the high-quality stenting outcomes necessary for acceptance of the trial results.

Background and Purpose: Despite a higher incidence of stroke and a more adverse cardiovascular risk factor profile in Blacks and Hispanics compared with Whites, carotid artery revascularization is performed less frequently among these subpopulations. We assessed racial differences in high-grade (≥70% diameter-reducing) carotid stenosis. Methods: Consecutive clients in a Nationwide Life Line for-Profit Service to screen for vascular disease, 2005 to 2019 were evaluated in a cross-sectional study. The prevalence of high-grade stenosis, defined by a carotid ultrasound peak systolic velocity of ≥230 cm/s, was assessed. Participants self-identified as White, Black, Hispanic, Asian, Native American, or other. Race/ethnic differences were assessed using Poisson regression. The number of individuals in the United States with high-grade stenosis was estimated by applying prevalence estimates to 2015 US Census population estimates. Results: The prevalence of high-grade carotid stenosis was estimated in 6 130 481 individuals. The prevalence of high-grade stenosis was higher with increasing age in all race-sex strata. Generally, Blacks and Hispanics had a lower prevalence of high-grade stenosis compared with Whites, while Native Americans had a higher prevalence. For example, for men aged 55 to 65, the relative risk of stenosis compared with Whites was 0.40 (95% CI, 0.29–0.55) and 0.61 (95% CI, 0.46–0.81) for Blacks and Hispanics, respectively; and 1.53 (95% CI, 1.12–2.10) for Native Americans. When these prevalence estimates were applied to the Census estimates of the US population, an estimated 327 721 individuals have high-grade stenosis, of whom 7% are Black, 7% Hispanic, and 43% women. Conclusions: Despite their having a more adverse cardiovascular risk profile, there was a lower prevalence of high-grade carotid artery stenosis for both the Black and Hispanic relative to the White clients. This lower prevalence of high-grade stenosis is a potential contributor to the lower use of carotid revascularization procedures in these minority populations.

Background: Data from the CDC show that approximately one-quarter of adults have elevated triglyceride (TG) levels. Recent trials have demonstrated that pharmacologic treatment of high TG levels, in patients already on statin therapy, reduces the rate of major vascular events such as myocardial infarction and stroke (REDUCE-IT trial). We sought to assess how often patients with asymptomatic carotid stenosis (CS) have elevated TG levels and factors associated with high TG values. Methods: Patients enrolled in the Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST 2) were analyzed. Baseline lipid profiles were evaluated to determine high TG treatment eligibility as per the REDUCE-IT trial. We also evaluated baseline use of pharmacologic treatment for high TG levels. Demographic factors and baseline medical conditions were studied in relation to high (>150 mg/dl) TG values. Chi square and t tests were used to assess baseline factors and abnormal TG values. Results: As of August 10, 2020, 1655 of 1689 randomized patients (mean age 69.7 years, 61% men) had baseline lipid profiles suitable for analysis. Treatment eligibility according to REDUCE-IT (LDL 41-100 mg/dl, TG>150 mg/dl) was present in 21% (345) of subjects. In these patients, the median TG value was 205 (IQR 93) mg/dl. Fibrate medications were used at baseline in 4.5% of patients. Analysis of demographic and medical history factors and TG values greater than 150 mg/dl is found in the Table. There was significant positive correlation between baseline hemoglobin A1C and triglyceride values (p<0.0001) Conclusions: One in five patients in CREST 2 has TG values that potentially justify pharmacologic treatment. Elevated TG levels are most correlated with diabetes, hypertension, obesity, decreased physical activity, and heart disease. Clinicians should investigate treatment of elevated TG levels as a component of intensive medical therapy for stroke prevention.

The American Venous Forum (AVF) and the Society for Vascular Surgery set forth these guidelines for the management of endothermal heat-induced thrombosis (EHIT). The guidelines serve to compile the body of literature on EHIT and to put forth evidence-based recommendations. The guidelines are divided into the following categories: classification of EHIT, risk factors and prevention, and treatment of EHIT. One major feature is to standardize the reporting under one classification system. The Kabnick and Lawrence classification systems are now combined into the AVF EHIT classification system. The novel classification system affords standardization in reporting but also allows continued combined evaluation with the current body of literature. Recommendations codify the use of duplex ultrasound for the diagnosis of EHIT. Risk factor assessments and methods of prevention including mechanical prophylaxis, chemical prophylaxis, and ablation distance are discussed. Treatment guidelines are tailored to the AVF EHIT class (ie, I, II, III, IV). Reference is made to the use of surveillance, antiplatelet therapy, and anticoagulants as deemed indicated, and the recommendations incorporate the use of the novel direct oral anticoagulants. Last, EHIT management as it relates to the great and small saphenous veins is discussed.

Background and Purpose: The CREST2 trial (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis) is comparing intensive medical management (IMM) alone to IMM plus revascularization with carotid endarterectomy or transfemoral carotid artery stenting for preventing stroke or death within 44 days after randomization or ipsilateral ischemic stroke thereafter. There are extensive clinical trial data on outcomes after revascularization of asymptomatic carotid stenosis, but not for IMM. As such, the experimental treatment in CREST2 is IMM, which is described in this article. Methods: IMM consists of aspirin 325 mg/day and intensive risk factor management, primarily targeting systolic blood pressure <130 mm Hg (initially systolic blood pressure <140 mm Hg) and LDL (low-density lipoprotein) cholesterol <70 mg/dL. Secondary risk factor targets focus on tobacco smoking, non-HDL (high-density lipoprotein), HbA1c (hemoglobin A1c), physical activity, and weight. Risk factor management is performed by site personnel and a lifestyle coaching program delivered by telephone. We report interim risk factor data on 1618 patients at baseline and last follow-up through 24 months. Results: The mean baseline LDL of 80.5 mg/dL improved to 66.7 mg/dL. The mean baseline systolic blood pressure of 139.7 mm Hg improved to 130.3 mm Hg. The proportion of patients in-target improved from 43% to 61% for systolic blood pressure <130 mm Hg and from 45% to 67% for LDL<70 mg/dL (both changes P <0.001). Conclusions: The rigorous multimodal approach to intensive stroke risk factor management in CREST2 has resulted in significant improvements in risk factor control that will enable a comparison of cutting-edge medical care to revascularization in patients with asymptomatic carotid stenosis. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02089217.

The coronavirus disease 2019 (COVID-19) global pandemic has resulted in diversion of healthcare resources to the management of patients infected with SARS-CoV-2 virus. Elective interventions and surgical procedures in most countries have been postponed and operating room resources have been diverted to manage the pandemic. The Venous and Lymphatic Triage and Acuity Scale was developed to provide an international standard to rationalise and harmonise the management of patients with venous and lymphatic disorders or vascular anomalies. Triage urgency was determined based on clinical assessment of urgency with which a patient would require medical treatment or surgical intervention. Clinical conditions were classified into six categories of: (1) venous thromboembolism (VTE), (2) chronic venous disease, (3) vascular anomalies, (4) venous trauma, (5) venous compression and (6) lymphatic disease. Triage urgency was categorised into four groups and individual conditions were allocated to each class of triage. These included (1) medical emergencies (requiring immediate attendance), example massive pulmonary embolism; (2) urgent (to be seen as soon as possible), example deep vein thrombosis; (3) semi-urgent (to be attended to within 30–90 days), example highly symptomatic chronic venous disease, and (4) discretionary/non-urgent- (to be seen within 6–12 months), example chronic lymphoedema. Venous and Lymphatic Triage and Acuity Scale aims to standardise the triage of patients with venous and lymphatic disease or vascular anomalies by providing an international consensus-based classification of clinical categories and triage urgency. The scale may be used during pandemics such as the current COVID-19 crisis but may also be used as a general framework to classify urgency of the listed conditions.

Background: The importance of physical activity in preventing major vascular events has received increased attention in the past decade. Due to the inclusion of the INTERVENT lifestyle modification program, the CREST2 trial provides a unique opportunity to study physical activity profiles in patients with severe asymptomatic extracranial carotid stenosis. Hypothesis: Based on data from a trial of intracranial stenosis patients, we aimed to evaluate the hypothesis that <40% of carotid stenosis subjects will have optimal physical activity levels. We also assessed key subgroups to determine patterns of physical activity. Methods: We analyzed 1087 CREST2 participants with baseline data on physical activity. The Physician-based Assessment and Counseling for Exercise (PACE) score is recorded for each patient and dichotomized as “in target” (4-8 points) or “out of target” (<4 points). A PACE score of <4 indicates a subject who does not engage in regular exercise. Results are analyzed for the entire trial. Chi square testing and t-tests were performed for evaluation of subgroup differences. Results: The mean age of the study population is 69.5±7.8 years (60% male). The median PACE score at baseline is 4.0 (mean 3.8±2.1; IQR 2 to 6). The Table shows baseline characteristics of patients by mean PACE score. Being male, not having diabetes mellitus, having a body mass index <30kg/m2, being a non-smoker, and not having a history of peripheral arterial disease were associated with significantly higher mean PACE scores (P<0.01). Conclusions: We have defined several patient groups with asymptomatic carotid stenosis that have suboptimal physical activity. These results provide opportunities for targeted efforts to improve primary stroke prevention. These baseline data will also allow investigators to determine if trial involvement and the INTERVENT program leads to improvement in the level of physical activity.

Objectives: Assessment of carotid disease is most commonly performed with duplex ultrasonography (DUS). Measures of plaque area and tissue composition from DUS images may identify patients at risk for future neurologic events, and may assess the effects of vascular risk-factor modification (by measuring change in plaque area and/or tissue constituents). We quantified plaque area and tissue constituents from DUS images of CREST-2 participants at baseline and correlated them with their baseline vascular risk factors. Methods: CREST-2 consists of two multicenter, randomized trials in patients with asymptomatic ≥70% carotid stenosis comparing intensive medical management (IMM) plus endarterectomy or stenting vs IMM alone. Baseline B-mode DUS images from 500 patients underwent manual plaque outlining and automatic pixel brightness assessment. Plaque area, grayscale median (GSM), Gray-Weale score for heterogeneity, and areas for intraplaque hemorrhage and lipid were the output parameters. We computed the parameter estimates (95% confidence intervals) for baseline patient characteristics (age, sex, race, diabetes, smoking, BMI, blood pressure and LDL levels) versus plaque characteristics. Results: High-risk plaque features (larger plaque area, lower GSM , lower Gray-Weale scores, or larger areas of hemorrhage and lipid) were present in older patients, males, and those with elevated diastolic blood pressure and LDL levels (Table). Conclusions: In a randomized trial of asymptomatic patients with high-grade carotid stenosis, DUS-based computation of plaque geometry and tissue composition is feasible. Elevated diastolic blood pressure and LDL levels at baseline are associated with high-risk plaque characteristics. These novel findings identify potentially modifiable targets for aggressive treatment to reduce stroke-risk in patients with carotid stenosis.