Moy, Claudia S.

Introduction: Small vessel disease is associated with decreased cognitive function, possibly differential by race. Age-related central arterial stiffening increases pulsatility resulting in hypoperfusion, microvascular damage and remodeling in the brain, potentially impairing cognition. We examined if arterial stiffness and pressure amplification are associated with lacunar infarcts and greater volumes of white matter hyperintensities (WMH) in a sample of Caucasian and African American (AA) older adults. Methods: We analyzed a cross-sectional sample of ARIC participants aged 67-90 years (n=1486) from visit 5 (2011-2013), with brain magnetic resonance imaging (MRI). The Omron VP-1000 Plus was used to measure aortic stiffness (carotid-femoral pulse wave velocity [cfPWV]) and pressure amplification measures (pulse pressure amplification [PPA], central pulse pressure [cPP], and estimated central systolic blood pressure [cSBP]). Aortic stiffness and pressure amplification were dichotomized at race-specific 25th percentile cut points. Brain MRI using 3D-1.5T equipment quantified the presence of lacunar infarcts and volumes of WMH following a standardized protocol. Logistic regression, adjusted for age, sex, education, ApoE4, heart rate, smoking and body mass index, was used to quantify the odds of lacunar infarcts in participants with high vs. low cfPWV, cPP, cSBP, and low vs. high PPA. Linear regression models, additionally adjusted for intracranial volume, estimated the difference in log-transformed volumes of WMH among participants with high vs. low cfPWV, cPP, cSBP, and low vs. high PPA. Probability sampling weights for an MRI were included to allow for generalizability to the full visit 5 cohort. Results: Among the 1486 participants with a brain MRI (mean age: 76, 41% male, 26% AA), measures of aortic stiffness and pressure amplification were associated with lacunar infarcts in Caucasians, but not in AAs. Caucasian participants with a high cfPWV had greater odds of lacunar infarcts (Odds Ratio [OR] =2.02, 95% confidence interval [CI]: 1.23, 2.20). Caucasians with high cSBP had higher odds of lacunar infarcts (OR=1.72, 95% CI: 1.10, 2.69). In Caucasians, high cfPWV was associated with a 21% (95% CI: 6, 38) greater volume of WMH as compared to a low cfPWV; high cSBP was associated with a 28% (95% CI: 14, 45) greater volume of WMH compared to a low cSBP. In AAs, high cfPWV was associated with a 32% (95% CI: 7, 62) greater volume of WMH as compared to low cfPWV. Cerebral microvascular imaging markers did not differ quantitatively with measures of PPA and cPP. Conclusions: Central arterial stiffening and pressure amplification are plausible microvascular contributors to cognitive aging, providing new information on modifiable pathways for previously observed associations between cardiovascular disease risk factors and the rates of cognitive decline and dementia among older adults.

Background: Presence of atherosclerotic disease in more than one vascular bed (polyvascular disease) is associated with an increased risk of long-term vascular events. In the setting of asymptomatic carotid stenosis, the predictors of disease in other vascular beds is not well delineated. Objective: To identify the frequency and predictors of disease in other vascular beds the CREST 2 randomized trial population with hemodynamically significant stenosis. Methods: Recorded baseline characteristics among CREST 2 participants included: demographics, past medical history, lifestyle factors, and laboratory studies. Each variable was tested against three potential definitions of disease in other beds (cardiac, peripheral arterial disease (PAD) or disease in cardiac + PAD). Statistical analysis was done with Chi square and t tests as appropriate. Results: Data from 1447 patients were available for analysis. In these subjects with carotid disease, 51% also had cardiac disease, 24% also had PAD, and 16% had disease in in both cardiac and PAD. There was no relationship between age or race and presence of disease in other beds. Those with cardiac disease were more likely to be male. Diabetes, hypertension, hypercholesterolemia, and former history of smoking were all more common in those with either cardiac and PAD (TABLE). Elevated triglyceride and low HDL levels were also associated with all three definitions of disease in other beds. Those with either PAD or cardiac + PAD were more likely to be current smokers. Conclusions: Among CREST 2 participants, several medical conditions and lifestyle factors were associated with an increased frequency of disease in other vascular beds. Smoking, in particular, appears to be more common in those with PAD. Future analyses will address whether those with disease in other beds have higher rates of stroke or death.

Baseline Differences in Risk Factor Control and Medication Use Between 2 Trials Employing Intensive Medical Management (SAMMPRIS & CREST2) Background: The CREST2 trial Intensive Medical Management (IMM) protocol was adapted from the SAMMPRIS trial. However, since the 2011 publication of initial results of SAMMPRIS, there has been a greater appreciation for the importance of risk factor control in patients at risk of stroke associated with atherosclerosis. Therefore, we sought to determine differences in baseline risk factor control and medication use between SAMMPRIS and CREST2. Methods: Baseline risk factor and medication use data from 451 patients enrolled in SAMMPRIS (2008-2011) with severe symptomatic intracranial atherosclerosis and 1473 patients enrolled in CREST2 (2014-2019) with severe asymptomatic carotid stenosis were compared using the Chi-square test and t-test. Results: The Table shows baseline risk factor values and medications. SAMMPRIS patients were younger but had significantly worse risk factor control than CREST2 patients for all measures. There was no significant difference in statin use at baseline, but the mean SAMMPRIS subjects’ LDL was 16.1 mg/dL higher than in CREST2. CREST2 patients had higher rates of use of angiotensin receptor blockers (ARB), calcium channel blockers (CCB), and thiazides, but lower rates of use of angiotensin converting enzyme (ACE) inhibitors. Conclusions: Despite being older, CREST2 patients have significantly better baseline risk factor profiles than SAMMPRIS patients. This could be due to greater appreciation of the importance of risk factor control and healthy lifestyle habits for stroke prevention or more aggressive treatment targets in guideline recommendations. Although risk factor control appears to be improving since SAMMPRIS, many CREST2 patients are still not meeting recommended risk factor goals at baseline and may benefit from IMM protocols.

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.

Introduction: Accurately balancing risks of interventional treatment and intracranial hemorrhage (ICH) in the untreated course of unruptured brain arteriovenous malformation (uBAVM) patients is critical for optimal management. Observational studies of uBAVM afford an opportunity to address important gaps and previous criticisms of randomized data to help guide treatment decisions and assess long-term risk/benefit ratio. We previously published an individual patient data meta-analysis (IPDMA) in 4 MARS cohorts and identified ICH presentation and increasing age as significant predictors of ICH during follow-up, but was not powered to detect predictors in those with uBAVM. Thus, the goals of this project are to identify risk factors for ICH in uBAVMs, to estimate the risk with precision, and to create personalized, risk-prediction models. Methods: MARS is an international, multi-center study of 11 cohorts with target enrollment of 4,500 uBAVM patients ascertained through population-based or referral-based studies. We are harmonizing both retrospective and prospective data, including clinical, lifestyle, imaging, and angiographic factors. Treatments, complications, and functional outcomes (physician and patient-reported) will be updated annually between 2018-2022. We propose to: 1) identify predictors of outcome in uBAVMs using IPDMA; 2) test whether long-term outcomes differ by treatment using statistical approaches for causal inference and unbiased estimates; 3) compare treatment outcomes in randomized and non-randomized data to address generalizability; and 4) validate models and provide a novel tool for calculating individualized risks. Eligible sites have: a) prior BAVM publications; b) data from a minimum of 100 uBAVM patients; c) agree to random outcome adjudication; and d) agree to MARS data sharing policy. Discussion: The NIH-funded MARS consortium will provide important and comprehensive characterization of the untreated and treated course of uBAVMs, using large observational datasets and sophisticated epidemiological approaches. The data and models generated will be a useful resource for decision-making. We welcome participation from eligible sites with longitudinal data on uBAVM patients

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.

Background: In CREST2, intensive medical management of subjects’ vascular risk factors is overseen by the site Principal Investigator (PI) and implemented by a designated Medical Management Physician (MMP) and coordinator. These physicians have different specialties and experience with risk factor management. We sought to determine the relationship between risk factor control and PI and MMP specialty. Methods: Data on 613 patients with at least 1 follow-up visit from 105 CREST2 sites were used for these analyses. CREST2 sites were categorized based on both PI specialty and MMP specialty. Specialty of the site-designated primary MMP was used for sites with more than one MMP. We compared the percentage of patients in target at last follow-up visit for the primary risk factors, LDL < 70 mg/dL and SBP <140 mm Hg, among PI specialties and MMP specialties, using the chi-square test. Results: The table shows the number of patients by PI and MMP specialty, as well as their control of SBP and LDL. There were no significant differences in control of SBP or LDL by PI specialty. There was a trend toward an association between LDL control and MMP specialty, with higher rates of LDL control at sites with Internal Medicine MMP specialists and lower rates of control with Vascular Surgery MMPs. SBP control rates were not significantly different across MMP specialties. Conclusions: In this early analysis of risk factor control in the CREST2 study, site PI and MMP specialty did not have a significant effect on LDL and SBP during follow-up. This suggests that protocol care pathways are generalizable to diverse physicians.

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