In this prospective study of 27,331 initially healthy women, mean baseline concentrations of fasting and nonfasting direct LDL-C were lower by ~5 to 10 mg/dL, respectively, compared with fasting Friedewald LDL-C. The direct method used in this study correlated highly with Friedewald calculation. In fasting samples, the association of direct LDL-C with incident CVD was nearly identical to LDL-C by Friedewald calculation. However, the lower LDL-C concentrations measured by this direct assay may misclassify a substantial proportion of individuals into a lower NCEP risk category. Moreover, the lack of association of nonfasting direct LDL-C with CVD questions the clinical utility of a direct assay for LDL-C measurement on a nonfasting blood sample.
Several direct methods for measuring LDL-C are currently available,(10
) but there is sparse data evaluating their predictive performance in relation to clinical events. It is believed that potential advantages of direct measurement of LDL-C may be better precision of the assay due to the single measurement, and its being relatively unaffected by the presence of increased triglyceride concentrations or a nonfasting blood draw.(5
) Some studies have shown that direct assays are generally accurate when compared to the β-quantification reference method or the Friedewald calculation.(11
) However, other studies have questioned the specificity of direct assays and their ability to meet the NCEP goal for a total error of <12%.(15
) In addition, clinical trials demonstrating the benefit of LDL-C lowering with statin therapy have used Friedewald calculation for determining LDL-C concentration,(16
) with the exception of the Heart Protection Study that used a direct assay.(17
) Our study findings demonstrate no clear advantage for using a direct assay for LDL-C compared with Friedewald calculation. Moreover, LDL-C concentration with the direct assay used in this study was ~ 5 to 10 mg/dL lower than by Friedewald calculation. While small, this systematic difference in mean LDL-C concentrations may be clinically important when assessing the need for drug intervention in a particular individual based on NCEP risk categories.
For nonfasting individuals, the direct assay has been suggested to be the preferred method for assessment of LDL-C.(1
) The findings from this study question the clinical utility of performing a direct assay for LDL-C measurement in nonfasting samples, since nonfasting LDL-C by direct assay was not associated with CVD. By contrast, nonfasting levels of apolipoprotein B100
and the ratio of apolipoprotein B100
/A-1 were associated with CVD in this group of women, although the association with CVD events was stronger in fasting samples.(18
) Importantly, the ratio of total/HDL cholesterol was associated with CVD to a similar magnitude in both fasting and nonfasting samples, and can be obtained at no additional cost.(18
) Direct assays add to healthcare costs and are more expensive than measuring triglycerides, total cholesterol, or HDL cholesterol. Future studies are needed to assess the association with CVD of direct LDL-C assays in other populations, examined according to fasting status.
There are several possible limitations of the present study. Lipid measurements were only available once at baseline and results could not be corrected for potential regression dilution bias. Although we assessed only the direct Roche method, this assay is commonly used and commercially available in the U.S. Our study included healthcare professionals who were women, mostly white, apparently healthy, and recruited from a variety of geographic locations across the US; thus, it is unclear if our results would be applicable to other ethnic populations or men. Time to last meal was self-reported, and we did not have paired samples of fasting and nonfasting measurements in the same individuals. Finally, this was a primary prevention population and further studies are needed before the data can be extended to secondary prevention populations that are frequently treated with lipid lowering medications.
Strengths of the present study include the large number of healthy women participants with simultaneous concentrations of direct and Friedewald LDL-C. Additionally, all lipid measurements were performed at a core laboratory facility that is certified for lipid testing by the National Heart, Lung, and Blood Institute/Centers for Disease Control and Prevention Lipid Standardization program. Detailed information on cardiovascular risk factors was available, allowing for analysis by the presence or absence of these factors, such as fasting status.
In summary, the direct assay used in this study correlated highly with Friedewald calculation but was generally lower by ~5 to 10 mg/dL. The lower LDL-C concentrations by direct assay may misclassify a substantial proportion of individuals into a lower NCEP risk category. While the association of LDL-C with CVD by the two methods was nearly identical in fasting samples, the lack of association of nonfasting direct LDL-C with CVD questions the clinical use of a direct assay in nonfasting blood samples.