Blue Cross and Blue Shield of Montan (BCBSMT) considers high density lipoprotein (HDL) subclass testing experimental, investigational and unproven for the diagnosis and management of cardiovascular disease.
This policy was originally developed in 2003 and has been updated with searches of scientific literature through April 2013. This section of the current policy has been substantially revised. The following is a summary of the key literature to date.
High density lipoprotein (HDL) subclass as a predictor of cardiovascular risk
A large number of prospective observational studies have examined the relationship between HDL subclass and cardiovascular risk. A representative sample of some of the most salient studies is discussed below.
In the Kuopio Ischemic Heart Disease Risk Factor Study, both total HDL-C and levels of HDL-2 had significant independent associations with risk of acute myocardial infarction (MI). (3) The Quebec Cardiovascular Study investigated the association of HDL-2 and HDL-3 subclasses with ischemic heart disease in a subsample of 944 French-Canadian men participating in the larger trial. (1) During the 10-year follow-up, levels of HDL-2 were statistically significant as independent predictors of CAD events, but the difference in predictive value with and without HDL subclasses was not considered clinically significant.
In contrast, some studies have not reported HDL subclassification to be an independent predictor of coronary artery disease (CAD). The Atherosclerosis Risk in Communities (ARIC) study, a large prospective cohort study, followed 12,000 middle-aged individuals free of CAD at baseline for 10 years. (2) In this study, prediction of CAD was not improved by the addition of either apo A-I levels or HDL density. Similarly, in the Physicians’ Health Study (4) and the Caerphilly and Speedwell Collaborative Heart Disease Studies, (5) both of which were studies of middle-aged men, risk prediction based on HDL-C was also not improved by HDL subclassification.
Measurement of HDL Particle Size and Concentration by NMR
The relationship between HDL particle size and the risk of coronary heart disease was examined in the European Prospective Investigation of Cancer (EPIC)- -Norfolk cohort study using a nested case-control design. (6) In the EPIC-Norfolk study, healthy individuals between the ages of 45-79 years were enrolled and followed for the development of coronary disease. The nested case control study matched 1,035 individuals who developed coronary disease with 1,920 controls who did not develop coronary disease. Small particle size was associated with an adverse cardiometabolic risk profile, and an increased risk of coronary disease in men (odds ratio [OR]: 1.43; 95% confidence interval (CI): 1.01-2.03) but not in women (OR: 0.84; 95% CI: 0.52-1.35).
In a post-hoc analysis from the EPIC-Norfolk study, El Harchaoui et al. (7) measured HDL particle size and number using NMR spectroscopy and gradient gel electrophoresis. The authors reported numerous multivariate regression models, controlling for various combinations of other lipid measures. HDL particle number was an independent predictor of CAD risk in all of the models reported. HDL particle size was an independent predictor in some models, but significance was lost when apo B was included as a covariate.
Numerous measures have been used in HDL subclass testing. The current evidence generally supports the contention that HDL subclass testing may add independent predictive information to standard lipid measurements. To improve outcomes, clinicians must have the tools to translate this information into clinical practice. The tools for linking HDL subclasses to clinical decision making (both in risk assessment and treatment response) are currently not available. HDL subclassification has not been incorporated into quantitative risk assessment models or treatment guidelines that can be used in clinical practice, such as the Adult Treatment Panel (ATP) III. The ATP III practice guidelines continue to tie clinical decision making to conventional lipid measures, such as total cholesterol, Low density lipoprotein cholesterol (LDL-C), and high density lipoprotein cholesterol (HDL-C). Therefore, it is not yet possible to conclude that these measures improve outcomes or that they should be adopted in routine clinical care.
None of the available evidence is sufficient to demonstrate impact on clinical outcomes or to prompt reconsideration of the current policy statement, which remains unchanged.
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