This policy was originally created in 2012; this section of the current policy has been substantially revised, and has been updated with searches of the MEDLINE database through December 2011. Following is a summary of the key literature to date.
Evaluation of a diagnostic technology typically focuses on the following three parameters:
- Technical performance.
- Diagnostic parameters (sensitivity, specificity, positive and negative predictive value); and
- Demonstration of clinical utility; the diagnostic information can be used to improve patient outcomes.
In the Atherosclerosis Risk in Communities (ARIC) study, the authors evaluated risk factors associated with increased carotid intima-medial thickness (CIMT) in 15,800 subjects. CIMT had a graded relationship with increasing quartiles of plasma total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides. IMT was then also correlated with the incidence of CHD in a subgroup of patients enrolled in the trial after four to seven years of follow-up. Among the 12,841 subjects studied, there were 290 incident events. The hazard ratio (HR) rate for men and women, adjusted for age and gender, comparing extreme (CIMT) (i.e., ≤ 1 mm) to non-extreme CIMT (i.e., <1 mm) was 5.07 for women and 1.85 for men. The strength of the relationship was reduced by including major CHD risk factors but remained elevated for higher measurements of CIMT. The authors concluded that mean CIMT is a noninvasive predictor of future coronary heart disease (CHD) incidence.
The Rotterdam study was a prospective cohort study that started in 1989 and recruited 7,983 men and women aged 55 years and older. The main objective of the Rotterdam study was to investigate the prevalence and incidence of risk factors for chronic diseases, including cardiovascular disease, in elderly individuals. One aspect of the study sought to determine whether progression of atherosclerosis in asymptomatic elderly subjects is a prelude to cardiovascular events. Measurements of CIMT were used to assess the progression of atherosclerosis. Increasing CIMT was associated with increasing risks of stroke and myocardial infarction (MI). O'Leary and colleagues performed CIMT in 4,476 asymptomatic subjects aged 65 years or older without clinical cardiovascular disease. The incidence of cardiovascular events correlated with measurements of CIMT; this association remained significant after adjustment for traditional risk factors. The authors concluded that increases in CIMT are directly associated with an increased risk of MI and stroke in older adults without a history of cardiovascular disease.
The Carotid Atherosclerosis Progression Study (CAPS) was a longitudinal study of 4,904 subjects. All subjects received a baseline CIMT measurement, as well as traditional risk factor analysis, and were followed over a 10-year period (mean follow-up 8.5 years, range 7.1-10.0 years). Adverse outcome events were MI in 73 patients (1.5%), angina or MI in 271 patients (5.5%), and death in 72 subjects (1.5%). Lorenz et al. have recently published a retrospective review of the data from CAPS. The authors modeled the predictive value of CIMT on the cardiovascular adverse events within that decade. Because the thresholds of CIMT measurements that would lead to reclassification of risk are unknown, the authors used 24 different models of reclassification and five statistical tests. Each model compares the predictive value of traditional risk factors alone with those risk factors with the addition of CIMT. The authors were unable to find significance in the reclassification models with the addition of CIMT measurements. They concluded that this retrospective analysis does not support the use of CIMT as a clinically useful risk classification tool when used in conjunction with traditional risk factor analysis.
Several other studies have, in fact, used CIMT measurements as outcome measures. In this setting, serial measurements of CIMT are performed, as opposed to a single measure. For example, the Asymptomatic Carotid Artery Progression Study (ACAPS) was designed to evaluate the role of lovastatin (an HMG-CoA reductase inhibitor, i.e., a statin drug) in patients asymptomatic for cardiovascular disease and with LDL cholesterol levels at or below the limits established by the National Cholesterol Education Program. A total of 919 asymptomatic men and women were randomly assigned to receive various combinations of lovastatin, warfarin, and placebo over a three-year period. The principal outcome measurement was the progression of CIMT, tested at six sites in both carotid arteries. Lovastatin treatment was associated with a reduction in the progression of mean maximum CIMT. The Monitored Atherosclerosis Regression Study also included measurements of CIMT every six months for four years in a subset of enrolled subjects. The authors concluded that lipid-lowering therapy resulted in a regression of CIMT.
CIMT is frequently being used in the research setting but application or widespread use is uncertain. In the Multi-Ethnic Study of Atherosclerosis (MESA) trial, an ongoing cohort study of atherosclerosis, CIMT was found to be a modestly better predictor of stroke but a worse predictor of CHD than coronary artery calcium score at a median follow-up of 3.9 years among 6,698 adults asymptomatic at baseline. In a 2010 article from MESA, CIMT results in 4,792 healthy, nondiabetic adults who were not on lipid-lowering medications were compared in six different lipid groups, including normolipemia and several types of common dyslipidemias. The mean CIMT values were increased only for the combined hyperlipidemia (defined as any HDL-C level, LDL-cholesterol [C] >160 and triglyceride >150) and simple hypercholesterolemia (defined as any HDL-C level, LDL-C >160 and triglyceride <150) groups. In another MESA report, in 2011, on 6,760 patients with elevated high-sensitivity C-reactive protein (hsCRP) as defined by the JUPITER study, CIMT increases correlated with obesity but only mildly with hsCRP. In the Bogalusa Heart Study of 991 subjects, obesity along with overweight and elevated metabolic risk was also associated with increased CIMT. In this study population, 41% of patients were found to have increased CHD risk. In the CARDIA study, clotting factor VII was associated with increases in CIMT in 1,254 subjects. CIMT is also used as a surrogate outcome measure in atherosclerosis treatment research studies.
In 2010, Raiko et al. compared cardiovascular disease risk scoring tools for identification of CHD risk to CIMT results in 2,204 healthy adults, aged 24-39 years, from the Cardiovascular Risk in Young Finns study. The cardiovascular disease risk scoring tools evaluated included the Framingham, Reynolds Risk Score, Systematic Coronary Risk Evaluation (SCORE), PROCAM, and Finrisk cardiovascular risk scores. In this population-based follow-up study, the authors found all of the cardiovascular disease risk scores performed equally in being able to predict subclinical atherosclerosis as measured by high CIMT six years later.
Mookadam and colleagues conducted a systematic review of the role of CIMT in predicting individual cardiovascular event risk and as a tool in assessing therapeutic interventions. The authors concluded that CIMT is an independent risk factor for cardiovascular events and may be useful in determining treatment when there is uncertainty regarding the approach or patient reluctance. However, further studies are needed to identify the best approaches to screening and interventions to prevent progression of atherosclerosis.
A search of the online site clinicaltrials.gov database in June 2011 identified three open, prospective, randomized trials. Trials NCT00613158 and NCT00734123 will stratify subjects to treatment arms based on CIMT. The end point in the first trial will be the course of atherosclerosis measured by both CIMT and carotid artery calcium score at two years and the incidence of cardiovascular disease at five years of follow-up. The second study will follow the progression of atherosclerosis and cardiovascular disease in a treatment versus placebo trial. At present, published intervention trials using this technology in clinical care are lacking.
In the third trial, the IMPRESS Study (NCT01330602) will randomly stratify 1,310 subjects with intermediate risk of cardiovascular events and family history of premature atherosclerosis to either a disease management program with intensive pharmacologic and behavioral interventions for primary prevention or usual health care management. The study will evaluate whether the disease management program is effective and whether changes in CIMT over three years can determine atherosclerotic status and future cardiovascular events.
Practice Guidelines and Position Statements
In October 2009, the U.S. Preventive Services Task Force (USPSTF) published a systematic review of CIMT within the scope of a larger recommendation statement entitled “Using Nontraditional Risk Factors in Coronary Heart Disease Risk Assessment”. On the basis of fair- and good-quality studies, the USPSTF states that CIMT, independently of Framingham risk factors, predicts coronary heart disease (CHD) in asymptomatic patients. These studies were longitudinal, population-based studies conducted in the U.S. and the Netherlands. USPSTF reviewed the Atherosclerosis Risk in Communities (ARIC) study and concluded that CIMT measurement can result in risk prediction that is modestly improved, particularly in adult men. However, the review cautions that the studies that did show an association were all done in a research setting, and therefore one cannot draw conclusions on the applicability of CIMT to the intermediate-risk population at large.
The Summary of Recommendation specific to CIMT is stated as: “The U.S. Preventive Services Task Force (USPSTF) concludes that the current evidence is insufficient to assess the balance of benefits and harms of using...[CIMT]…to screen asymptomatic men and women with no history of CHD to prevent CHD events.” The USPSTF identifies the following research need: “The predictive value…of carotid IMT…should be examined in conjunction with traditional Framingham risk factors for predicting CHD events and death.”
The 2010 American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines indicates: “Measurement of carotid artery IMT is reasonable for cardiovascular risk assessment in asymptomatic adults at intermediate risk.” The guidelines note an increased CIMT reading may be used as a guide in determining clinical treatment, but evidence has not demonstrated improvements in outcomes when incorporating CIMT measurement into treatment decision making. Additionally, the Guidelines state: “Clinical tools integrating carotid IMT within global risk scoring systems are not available. The incremental value of carotid IMT and cost effectiveness beyond that available from standard risk assessments to improve overall patient outcomes is not established.” Furthermore, “serial scanning of carotid IMT is challenging in individual patients across brief time horizons due to variability in measurement in relation to the rate of disease progression and is therefore not recommended in clinical settings.”
The American Society of Echocardiography Consensus Statement (2008) endorsed by the Society for Vascular Medicine, states that CIMT is a feature of arterial wall aging “that is not synonymous with atherosclerosis, particularly in the absence of plaque.” The statement recommends measurement of both CIMT and carotid plaque by ultrasound “for refining CVD risk assessment in patients at intermediate cardiovascular disease risk (Framingham Risk Score 6–20%) without established CHD, peripheral arterial disease, cerebrovascular disease, diabetes mellitus, or abdominal aortic aneurysm.” However, the authors acknowledge that, “More research is needed to determine whether improved risk prediction observed with CIMT or carotid plaque imaging translates into improved patient outcomes.”
The ATP III does not recommend using “emerging risk factors” in the assessment of persons for primary prevention. It does state that “emerging risk factors” may be useful in certain patient-centered circumstances.
The existing data are insufficient to determine the impact of this technology on net health outcome. At the present time, there appears to be no scientific literature that directly and experimentally tests the hypothesis that measurement of CIMT results in improved patient outcomes and no specific guidance on how measurements of CIMT should be incorporated into risk assessment and risk management. Recent studies correlate increased CIMT with many other commonly used markers for risk of CHD but do not define how its use in clinical practice improves outcomes.
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