Carotid intimal-media thickness as a surrogate for cardiovascular disease events in trials of HMG-CoA reductase inhibitors

BACKGROUND: Surrogate measures for cardiovascular disease events have the potential to increase greatly the efficiency of clinical trials. A leading candidate for such a surrogate is the progression of intima-media thickness (IMT) of the carotid artery; much experience has been gained with this endpoint in trials of HMG-CoA reductase inhibitors (statins). METHODS AND RESULTS: We examine two separate systems of criteria that have been proposed to define surrogate endpoints, based on clinical and statistical arguments. We use published results and a formal meta-analysis to evaluate whether progression of carotid IMT meets these criteria for HMG-CoA reductase inhibitors (statins). IMT meets clinical-based criteria to serve as a surrogate endpoint for cardiovascular events in statin trials, based on relative efficiency, linkage to endpoints, and congruency of effects. Results from a meta-analysis and post-trial follow-up from a single published study suggest that IMT meets established statistical criteria by accounting for intervention effects in regression models. CONCLUSION: Carotid IMT progression meets accepted definitions of a surrogate for cardiovascular disease endpoints in statin trials. This does not, however, establish that it may serve universally as a surrogate marker in trials of other agents

Coronary age as a risk factor in the modified Framingham risk score

BACKGROUND: Clinical guidelines emphasize risk assessment as vital to patient selection for medical primary intervention. However, risk assessment methods are restricted in their ability to predict further coronary events. The most widely accepted tool in the United States is the Framingham risk score. In these equations age is a powerful risk factor. Although the extent of coronary atherosclerosis increases with age, there is large inter-individual variability in the rate of development and progression of this disease. This fact limits the utility of Framingham scoring when applied to individuals. Electron beam tomography (EBT), which measures coronary calcium, provides a non-invasive method for assessing coronary plaque burden, thus offering the possibility of providing a more accurate estimate of an individual's "arterial age" than from chronological age alone. METHODS: In this paper we discuss a new and simple method for incorporating the coronary calcium score (CCS) to modify the Framingham Risk Assessment (FRA). Using this method, a coronary artery calcium (CAC) age equivalent is generated that replaces chronological age in Framingham scoring. RESULTS AND DISCUSSION: Using a percentile table of CCS scores by age group and sex, individuals are matched to the age group whose calcium score most closely approximates their own individual score. The original 10-year absolute risk score of a 65-year old man with a CCS of 6 based on chronological age is 10%, whereas the modified absolute risk score based on CAC age equivalents is 2%. CONCLUSION: Our approach of replacing chronological age with CAC age equivalents in the Framingham equations possesses simplicity of application combined with precision. Physicians can easily derive adjusted Framingham risk scores and prescribe intervention methods based on patients' ten-year risks. The adjusted ten-year risks are likely to be more accurate than unadjusted risks since they are based on coronary calcium score information. The modified FRA approach not only may increase the predicted risk for some patients, but also may decrease the predicted risk for others, making it a more precise adjustment than other methods

Differences in carotid arterial morphology and composition between individuals with and without obstructive coronary artery disease: A cardiovascular magnetic resonance study

Objective: We sought to determine differences with cardiovascular magnetic resonance (CMR) in the morphology and composition of the carotid arteries between individuals with angiographically-defined obstructive coronary artery disease (CAD, = 50% stenosis, cases) and those with angiographically normal coronaries (no lumen irregularities, controls). Methods and results: 191 participants (50.3% female; 50.8% CAD cases) were imaged with a multi-sequence, carotid CMR protocol at 1.5T. For each segment of the carotid, lumen area, wall area, total vessel area (lumen area + wall area), mean wall thickness and the presence or absence of calcification and lipid-rich necrotic core were recorded bilaterally. In male CAD cases compared to male controls, the distal bulb had a significantly smaller lumen area (60.0 [plus or minus] 3.1 vs. 79.7 [plus or minus] 3.2 mm[super]2, p less than 0.001) and total vessel area (99.6 [plus or minus] 4.0 vs. 119.8 [plus or minus] 4.1 mm[super]2; p less than 0.001), and larger mean wall thickness (1.25 [plus or minus] 0.03 vs. 1.11 [plus or minus] 0.03 mm; p = 0.002). Similarly, the internal carotid had a smaller lumen area (37.5 [plus or minus] 1.8 vs. 44.6 [plus or minus] 1.8 mm[super]2; p = 0.006) and smaller total vessel area (64.0 [plus or minus] 2.3 vs. 70.9 [plus or minus] 2.4 mm[super]2; p = 0.04). These metrics were not significantly different between female groups in the distal bulb and internal carotid or for either gender in the common carotid. Male CAD cases had an increased prevalence of lipid-rich necrotic core (49.0% vs. 19.6%; p = 0.003), while calcification was more prevalent in both male (46.9% vs. 17.4%; p = 0.002) and female (33.3% vs. 14.6%; p = 0.031) CAD cases compared to controls. Conclusion: Males with obstructive CAD compared to male controls had carotid bulbs and internal carotid arteries with smaller total vessel and lumen areas, and an increased prevalence of lipid-rich necrotic core. Carotid calcification was related to CAD status in both males and females. Carotid CMR identifies distinct morphological and compositional differences in the carotid arteries between individuals with and without angiographically-defined obstructive CAD.Carotid Atherosclerosis (MRI) Progression Study (CAMPS, HL076378) and Cardiovascular Research Training Program (T-32, HL07838); and the General Clinical Research Center at the Wake Forest University School of Medicine (M01 RR-07122)

Carotid intima-medial thickness measured on multiple ultrasound frames: evaluation of a DICOM-based software system

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Utility of Atherosclerosis Imaging in the Evaluation of High-Density Lipoprotein–Raising Therapies

Decreased level of high density-lipoprotein cholesterol (HDL-C) is a rigorous predictor for future cardiovascular events. Much effort is being made to develop HDL-C–raising pharmacotherapies in the attempt to avert the pandemic of atherosclerotic disease. Important properties by which HDL-C–raising compounds are effective involve improvement of cholesterol uptake from macrophages in plaque for transport back to the liver, improvement of endothelial function, and anti-inflammatory effects. Vascular imaging can aid in the determination which HDL-C–raising compounds are effective. Ultrasound and MRI have proved suitable for assessment of structural changes of the vessel wall. Ultrasound can also be used or assessment of endothelial function. 18F-fluordeoxyglucose positron emission tomography has opened up the possibility to assess vessel wall inflammation. In this article we discuss these various imaging techniques and how they can assess efficacy as well as provide pathophysiologic information on the mechanism of action of novel HDL-C–raising drugs

Using Basic Science to Design a Clinical Trial: Baseline Characteristics of Women Enrolled in the Kronos Early Estrogen Prevention Study (KEEPS)

Observational and epidemiological studies suggest that menopausal hormone therapy (MHT) reduces cardiovascular disease (CVD) risk. However, results from prospective trials showed neutral or adverse effects most likely due to differences in participant demographics, such as age, timing of initiation of treatment, and preexisting cardiovascular disease, which reflected in part the lack of basic science information on mechanisms of action of hormones on the vasculature at the time clinical trials were designed. The Kronos Early Estrogen Replacement Study (KEEPS) is a prospective, randomized, controlled trial designed, using findings from basic science studies, to test the hypothesis that MHT when initiated early in menopause reduces progression of atherosclerosis. KEEPS participants are younger, healthier, and within 3 years of menopause thus matching more closely demographics of women in prior observational and epidemiological studies than women in the Women’s Health Initiative hormone trials. KEEPS will provide information relevant to the critical timing hypothesis for MHT use in reducing risk for CVD