In patients with familial hypercholesterolemia, combined therapy with ezetimibe and simvastatin did not result in a significant difference in changes in intima-media thickness, as compared with simvastatin alone, despite decreases in levels of LDL cholesterol and C-reactive protein. (ClinicalTrials.gov number, NCT00552097 [ClinicalTrials.gov].).

Abstract-Large observational studies and atherosclerosis regression trials of lipid-modifying pharmacotherapy have established that intima-media thickness of the carotid and femoral arteries, as measured noninvasively by B-mode ultrasound, is a valid surrogate marker for the progression of atherosclerotic disease. To exploit fully the potential of ultrasound imaging in atherosclerosis research, standardized and strictly implemented imaging protocols should be used in both observational studies and applied clinical research. This article describes such a protocol developed at the Academic Medical Center of the University of Amsterdam, the Netherlands. Results are presented from a study that estimated atherosclerosis progression from childhood into old age by measuring intima-media thickness in subjects with familial hypercholesterolemia compared with healthy controls. Key Words: B-mode ultrasound Ⅲ familial hypercholesterolemia Ⅲ intima-media thickness Ⅲ surrogate markers A therosclerosis is a generalized disease of the arterial wall, which may progress or regress depending on a plethora of factors. [1][2][3][4][5][6] This dynamic process is characterized by arterial wall remodeling that may go unnoticed for a lifetime, but may also present as acute vascular disease and become clinically manifest. 2 Because atherosclerosis progresses over decades, epidemiological studies and intervention trials with clinical end points require long-term follow-up, participation of large populations, or both. [3][4][5][6] These requirements have to be met to provide data from which valid conclusions about the determinants of disease or the efficacy of a therapeutic intervention can be drawn. 7 As a consequence, such studies consume precious time and financial resources. 8 To overcome these challenges, surrogate markers became the focus of intense attention. 8 Such markers might be used to investigate determinants of atherosclerosis at an early stage of the process and can, subsequently, assess modifiers of atherosclerotic disease progression, such as lifestyle and pharmacological interventions.Boissel and coworkers have proposed criteria for the validity of surrogate markers as a substitute for clinical end points. 9 These investigators stipulated 3 conditions for the determination of validity. First, a surrogate marker should be more sensitive and more readily available (sensitivity and availability) than the clinical end point. Also, the surrogate marker should be easy to evaluate (convenient), preferably by noninvasive means. Second, the causal relationship between the surrogate marker and the clinical end point (proximity) should be established on the basis of epidemiological, pathophysiological, and clinical studies. It is a prerequisite that patients with and without vascular disease exhibit differences in surrogate marker measurements (specificity). Third, in intervention studies, anticipated clinical benefits (assessment of benefit) should be deducible from the observed changes in the surrogate marker. The latter argument ...

AMILIAL HYPERCHOLESTEROLemia is the paradigm of the established relationship between increased low-density lipoprotein cholesterol (LDL-C) and cardiovascular disease. 1,2 This monogenic disorder is characterized by exposure to severely elevated LDL-C levels from birth onward. 3,4 Endothelial function, measured as flow-mediated dilatation of the brachial artery, is already impaired in prepubertal children with familial hypercholesterolemia. 5 In addition to these early functional changes, accumulation of LDL-C in children with familial hypercholesterolemia leads to deterioration of the vascular morphology and gives rise to increased intimamedia thickness (IMT) of the carotid arteries. 6-9 As a sequel to these observations, myocardial ischemia and coronary artery stenoses have been documented in young adults with this disorder. 10,11 The sequence of events in untreated children proceeds from endothelial dysfunction to increased

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Imaging modalities have been developed to assess atherosclerosis in vivo in the arterial wall because large clinical end-point studies are time-consuming and costly. Historically, in-hospital angiography and Doppler ultrasonography have been used to assess atherosclerosis development. Investigations of the arterial lumen are, however, increasingly being replaced by modalities that can measure changes in the arterial wall itself-intravascular ultrasonography, MRI and multislice CT. The fact that intravascular ultrasonography is invasive, CT involves substantial radiation exposure and requires contrast agents, and that MRI is time-consuming and technically challenging all limit the widespread use of these techniques. Moreover, all modalities have high associated costs. B-mode ultrasonographic imaging of the carotid arterial walls occupies a unique position in atherosclerosis research. This method enables sensitive, reproducible and noninvasive assessment of intima-media thickness (IMT) as a continuous variable. Epidemiological and clinical trial evidence as well as digitization and standardization have made carotid IMT a validated and accepted marker for generalized atherosclerosis burden and vascular disease risk. Here we describe the application of carotid IMT measurements as a tool in risk evaluation of individuals and in studies of atherosclerosis progression and regression.

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Background: To quantify the association between effects of interventions on carotid intimamedia thickness (cIMT) progression and their effects on cardiovascular disease (CVD) risk. Methods: We systematically collated data from randomized controlled trials. cIMT was assessed as the mean value at the common-carotid-artery; if unavailable, the maximum value at the common-carotid-artery or other cIMT measures were utilized. The primary outcome was a combined CVD endpoint defined as myocardial infarction, stroke, revascularization procedures, or fatal CVD. We estimated intervention effects on cIMT progression and incident CVD for each trial, before relating the two using a Bayesian meta-regression approach. Results: We analyzed data of 119 randomized controlled trials involving 100,667 patients (mean age 62 years, 42% female). Over an average follow-up of 3.7 years, 12,038 patients developed the combined CVD endpoint. Across all interventions, each 10 μm/year reduction of cIMT progression resulted in a relative risk for CVD of 0.91 (95% credible interval 0.87-0.94), with an additional relative risk for CVD of 0.92 (0.87-0.97) being achieved independent of cIMT progression. Taken together, we estimated that interventions reducing cIMT progression by 10, 20, 30, or 40 μm/year would yield relative risks of 0.84 (0.75-0.93), 0.76 (0.67-0.85), 0.69 (0.59-0.79), or 0.63 (0.52-0.74). Results were similar when grouping trials by type of intervention, time of conduct, time to ultrasound follow-up, availability of individual-participant data, primary vs. secondary prevention trials, type of cIMT measurement, and proportion of female patients. Conclusions: The extent of intervention effects on cIMT progression predicted the degree of CVD risk reduction. This provides a missing link supporting the usefulness of cIMT progression as a surrogate marker for CVD risk in clinical trials.

Background-We previously demonstrated in a randomized placebo-controlled trial that 2-year pravastatin treatment induced a significant regression of carotid intima-media thickness (IMT) in 8-to 18-year-old children with familial hypercholesterolemia. Subsequently, we continued to follow up these children to explore the relation between the age of statin initiation and carotid IMT after follow-up on statin treatment. We also examined safety aspects of statin therapy during this long-term follow-up. Methods and Results-All 214 children who initially participated in the previous placebo-controlled study were eligible for the follow-up study. After completion of the placebo-controlled study, all children continued treatment with pravastatin 20 or 40 mg, depending on their age. Blood samples were taken on a regular basis for lipids and safety parameters, and a carotid IMT measurement was performed after an average treatment period of 4.5 years. Follow-up data for 186 children were available for the statistical analyses. Multivariate analyses revealed that age at statin initiation was an independent predictor for carotid IMT after follow-up with adjustment for carotid IMT at initiation of statin treatment, sex, and duration of treatment. Early initiation of statin treatment was associated with a subsequently smaller IMT. Furthermore, no serious laboratory adverse events were reported during follow-up, and statin treatment had no untoward effects on sexual maturation. Conclusions-These data indicate that early initiation of statin treatment delays the progression of carotid IMT in adolescents and young adults. The present study shows for the first time that early initiation of statin therapy in children with familial hypercholesterolemia might be beneficial in the prevention of atherosclerosis in adolescence. (Circulation.