Radiology Section - Ultrasonic Measurement of Carotid Intimal-Medial Thickness as an Assessment of Subclinical Atherosclerosis

IMPORTANT REMINDER

Regence Medical Policies are developed to provide guidance for members and providers regarding coverage in accordance with contract terms. Benefit determinations are based in all cases on the applicable contract language. To the extent there may be any conflict between the Medical Policy and contract language, the contract language takes precedence.

PLEASE NOTE: Contracts exclude from coverage, among other things, services or procedures that are considered investigational or cosmetic. Providers may bill members for services or procedures that are considered investigational or cosmetic. Providers are encouraged to inform members before rendering such services that the members are likely to be financially responsible for the cost of these services.

Description

Established major risk factors for coronary artery disease (CHD) have been identified by the National Cholesterol Education Program (NCEP) Expert Panel. (2) These risk factors include elevated serum levels of low-density lipoprotein (LDL) cholesterol and total cholesterol, and low serum levels of high-density lipoprotein (HDL) cholesterol. Other risk factors include a history of cigarette smoking, hypertension, family history of premature CHD, and age. The third report of the NCEP Adult Treatment Panel (ATP III) establishes various treatment strategies to modify the risk of CHD, based in part on target goals of LDL cholesterol. Pathology studies have demonstrated that levels of traditional risk factors are associated with the extent and severity of atherosclerosis. However, at every level of risk factor exposure, there is substantial variation in the amount of atherosclerosis, presumably related to genetic susceptibility and the influence of other risk factors. Therefore, there has been interest in identifying a technique that can measure and monitor atherosclerosis that reflects the pathological endpoint of CHD risk factors. The carotid arteries can be well visualized by ultrasonography, and ultrasonographic measurements of the thickness of the carotid intimal-medial wall (IMT) have been investigated as a technique to identify and monitor subclinical atherosclerosis. B-mode ultrasound is most commonly used, and the intimal-medial thickness is measured and averaged over six sites in each carotid artery.

A limitation of carotid artery IMT as a surrogate for coronary artery disease is that it does not accurately assess the total atherosclerotic burden and therefore cannot predict the severity of coronary artery disease or distinguish patients with one-vessel, two-vessel, or more coronary artery disease. Given these limitations, more recent research has used the combined carotid artery IMT and femoral artery IMT measurements to more accurately determine atherosclerotic burden of the coronary arteries.

Policy/Criteria

1. Ultrasound of the carotid and/or femoral artery intimal-medial wall thickness for screening and monitoring for coronary artery disease in clinically asymptomatic individuals is considered investigational.
2. Carotid artery ultrasound for the evaluation of a cerebrovascular condition suspected on the basis of abnormal symptoms may be considered medically necessary.

Scientific Background

A literature search identified multiple observational studies correlating measurements of carotid intimal-medial wall (IMT) with either established risk factors for CHD or the incidence of cardiovascular events. For example, in the Atherosclerosis Risk in Communities (ARIC) study, the authors evaluated risk factors associated with increased carotid IMT in 15,800 subjects. (2) Carotid IMT had a graded relationship with increasing quartiles of plasma total cholesterol, LDL cholesterol, and triglycerides. Carotid IMT was then also correlated with the incidence of coronary heart disease in a subgroup of patients enrolled in the trial after 4 to 7 years of follow-up. (3) Among the 12,841 subjects studied, there were 290 incident events. The hazard ratio rate for men and women, adjusted for age and sex, comparing extreme carotid IMT (i.e., >/= 0.1mm) to non-extreme IMT (i.e., < 0.1mm) 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 carotid IMT. The authors concluded that mean carotid IMT is a noninvasive predictor of future 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 over. The main objective of the Rotterdam Study was to investigate the prevalence and incidence of risk factors for chronic diseases in the elderly, including cardiovascular disease. One aspect of the study sought to determine whether progression of atherosclerosis in asymptomatic elderly subjects is a prelude to cardiovascular events. Measurements of carotid IMT were used to assess the progression of atherosclerosis. Increasing carotid IMT was associated with increasing risks of stroke and MI. (4) O'Leary and colleagues performed carotid IMT in 4,476 asymptomatic subjects aged 65 years or older without clinical cardiovascular disease. (4) The incidence of cardiovascular events correlated with measurements of carotid IMT thickness; this association remained significant after adjustment for traditional risk factors. The authors conclude that increases in the thickness of carotid IMT are directly associated with an increased risk of myocardial infarction and stroke in older adults without a history of cardiovascular disease. (5) Hodis and colleagues studied 146 men aged 40 to 59 years old who previously had coronary artery bypass surgery. (6) Subjects underwent measurements of carotid IMT every 6 months and underwent coronary angiography at baseline and every 2 years. Average follow-up was 8.8 years. For each 0.03-mm increase in carotid IMT, the relative risk for nonfatal myocardial infarction or coronary death was 2.2, and the relative risk for any coronary event was 3.1. Absolute thickness and progression in thickness predicted risk for coronary events beyond that predicted by coronary arterial measures of atherosclerosis and lipid measurements. The authors remark that ultrasonographic monitoring carotid IMT may be a useful surrogate endpoint for clinical coronary events.

Several other studies have, in fact, used carotid IMT measurements as outcome measures. In this setting, serial measurements of carotid IMT 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 (a 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. (7, 8) A total of 919 asymptomatic men and women were randomized to receive various combinations of lovastatin, warfarin, and placebo over a 3-year period. The principal outcome measurement was the progression of carotid IMT, tested at 6 sites in both carotid arteries. Lovastatin treatment was associated with a reduction in the progression of mean maximum carotid IMT. The Monitored Atherosclerosis Regression Study also included measurements of carotid IMT every 6 months for 4 years in a subset of enrolled subjects. (9) The authors concluded that lipid-lowering therapy resulted in a regression of carotid IMT.

It is evident from a literature search that ultrasonographic measurement of carotid IMT has emerged as a research tool for the assessment of subclinical atherosclerosis, which has been incorporated into clinical trials as an outcome measure. However, it is unclear how this measurement can be used to benefit patient management. One proposal is to use carotid IMT as an additional risk factor to further categorize those patients who would be classified as at an "intermediate risk" for CHD on the basis of established CHD risk factors, such as total cholesterol, LDL cholesterol, and HDL cholesterol levels. Identification of additional independent risk factors might then be able to identify those intermediate risk patients who might benefit from more aggressive risk reduction. As noted in the Discussion section, there is substantial variation in the extent and severity of atherosclerosis among patients considered to be at similar risk based on traditional risk factors. Therefore, measurements of carotid IMT could be used to provide incremental information to traditional risk factor assessment. In the National Cholesterol Expert Panel (NCEP) Adult Treatment Panel III (ATP III) report, carotid intimal thickness was identified as an "emerging non-lipid risk factor” and offered the following comments (10):

"One test in this category [tests for atherosclerotic plaque burden] is carotid sonography used to measure intimal-medial thickness (IMT) of the carotid arteries. The extent of carotid atherosclerosis correlates positively with the severity of coronary atherosclerosis. Furthermore, recent studies show that severity of IMT independently correlates with risk for major coronary events. Thus, measurement of carotid IMT theoretically could be used as an adjunct in CHD risk assessment. For instance, the finding of an elevated carotid IMT (e.g., >/= 75th percentile for age and sex) could elevate a person with multiple risk factors to a higher risk category. However, its expense, lack of availability, and difficulties with standardization preclude a current recommendation for its use in routine risk assessment for the purpose of modifying intensity of LDL lowering therapy. Even so, if carried out under proper conditions, carotid IMT could be used to identify person at higher risk than that revealed by the major risk factors alone."

However, at the present time there appears to be no scientific literature that directly and experimentally test the hypothesis that measurement of carotid IMT results in improved patient outcomes, and no specific guidance on how measurements of carotid IMT should be incorporated into risk assessment and risk management.  The U.S Preventative Services Task Force does not comment on this testing in their recommendations. (14) Studies continue to report a relationship between carotid intimal-medial wall thickness and early myocardial disease. (15-20) However, the role of this information in improving clinical outcomes has not yet been demonstrated in clinical trials.

A literature search through February 10, 2008 failed to return any published clinical studies that alter the policy criteria.

References

1. BlueCross and BlueShield Association Medical Policy Reference Manual, Policy No. 2.02.16
2. Dobs AS, Nieto FJ, Szklo M et al. Risk factors for popliteal and carotid wall thickness in the Atherosclerosis Risk in Communities (ARIC) study. Am J Epidemiol 1999;150(10):1055-67
3. Chambless LE, Heiss G, Folsom AR et al. Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the Atherosclerosis Risk in Communities (ARIC) study, 1987-1993. Am J Epidemiol 1997;146(6):483-94
4. Bots MI, Hoes AW, Koudstaal PJ et al. Common carotid intima-media thickness and risk of stroke and myocardial infarction: the Rotterdam Study. Circulation 1997;96(5):1432-7
5. O'Leary DH, Polak JF, Kronmal RA et al. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med 1999;340(1):14-22
6. Hodis H, Mack W, et al. The role of carotid-arterial intima-media thickness in predicting clinical coronary events. Annals of Internal Medicine 1998;128:262-269
7. Probstfield JL, Margitic SE, Byington RP et al. Results of the primary outcome measure and clinical events from the Asymptomatic Carotid Progression Study. Am J Cardiol 1995;76(9):47C-53C
8. Byington RP, Evans GW, Espeland MA et al. Effects of lovastatin and warfarin on early carotid atherosclerosis: sex-specific analyses. Asymptomatic Carotid Artery Progression Study (ACAPS) Research Group. Circulation 1999;100(3):e14-7
9. Hodis HN, Mack WJ, LaBree L et al. Reduction in carotid arterial wall thickness using lovastatin and dietary therapy: a randomized controlled clinical trial. Ann Intern Med 1996;124(6):548-56
10. National Cholesterol Education Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.  www.nhlbi.nih.gov/guidelines/cholesterol/atp3xsum.pdf (Verified 2/11/08)
11. Anand SS, Yi Q, Gerstein H et al. Relationship of metabolic syndrome and fibrinolytic dysfunction to cardiovascular disease. Circulation 2003;108(4):420-5
12. Wagenknecht LE, Zaccaro D, Espeland MA et al. Diabetes and progression of carotid atherosclerosis; the insulin resistance atherosclerosis study. Arterioscler Thromb Vasc Biol 2003;23(6):1035-41
13. Singh TP, Groehn H, Kazmers A. Vascular function and carotid intimal medial thickness in children with insulin-dependent diabetes mellitus. J Am Coll Cardiol 2003;41(4):661-5
14. U.S. Preventive Services Task Force. Screening for Coronary Heart Disease: Recommendation Statement. February 2004. Agency for Healthcare Research and Quality, Rockville, MD. Accessible at: www.ahrq.gov/clinic/3rduspstf/chd/chdrs.htm  (Verified 2/11/08)
15. Fernandes VR, Polak JF, Edvardsen Tet al. Subclinical atherosclerosis and incipient regional myocardial dysfunction in asymptomatic individuals: the Multi-Ethnic Study of Atherosclerosis (MESA). J Am Coll Cardiol 2006; 47(12):2420-8
16. Gepner AD, Keevil JG, Wyman RA et al. Use of carotid intima-media thickness and vascular age to modify cardiovascular risk prediction. J Am Soc Echocardiogr 2006; 19: 1170-4
17. Lorenz MW, Markus HS, Bots ML et al. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation 2007;115(4):459-67.
18. Roman MJ, Moeller E, Davis A et al. Preclinical carotid atherosclerosis in patients with rheumatoid arthritis. Ann Intern Med 2006;144(4):249-56
19. Manolio TA, Arnold AM, Post W et al. Ethnic differences in the relationship of carotid atherosclerosis to coronary calcification: the Multi-Ethnic Study of Atherosclerosis. Atherosclerosis 2007 Apr 3; Epub ahead of print.
20. Kanwar M, Rosman HS, Fozo PK et al. Usefulness of carotid ultrasound to improve the ability of stress testing to predict coronary artery disease. Am J Cardiol 2007;99(9):1196-200.

Cross References

Computed Tomography to Detect Coronary Artery Calcifications, Regence Medical Policy Manual, Radiology, Policy No. 6

Contrast-Enhanced Computed Tomographic Angiography (CTA) for Coronary Artery Evaluation, Regence Medical Policy Manual, Radiology, Policy No. 46

Computed Tomography for Pulmonary Indications, Regence Medical Policy Manual, Radiology, Policy No. 32

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