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].).

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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 ...