The role of comprehensive lipoprotein analysis in accurate heart disease risk assessment

TC – HDLc – TG/5 = LDL

Friedewald = Misclassification

As we close National Heart Month and approach the 2013 American College of Cardiology (ACC) Scientific Sessions, the role of comprehensive lipoprotein analysis will again be in the news. We’ll likely see more press that advanced lipoprotein analysis has not yet met the standard for biomarker evaluation and does not incrementally add to cardiovascular risk predicted by traditional risk factors.

Some, like Jennifer G. Robinson, M.D., M.P.H., question “What is the role of advanced lipoprotein analysis in practice?” (J Am Coll Cardiol. 2012;60(25):2607-2615. doi:10.1016/j.jacc.2012.04.067). However, what’s lost in this discussion, for the clinician, is the importance of his or her ability to make an accurate risk assessment up front — when the patient first walks through the door. If you miss the risk that’s there and fail to effectively treat it in the first place, the second part of the discussion – which treatments work best based on what information – clearly loses value.

Considering the epidemic of heart disease, stroke and diabetes that continues to negatively impact the cost and quality of health care in our nation, the validity of using a test that is 40 years old and prone to underestimation to assess and treat this problem poses considerable challenges for today’s clinician.

LDLc remains the primary target of therapy; we should be measuring it, not estimating it.

What we do know today is that estimating LDLc levels using the basic lipid panel’s Friedewald equation (TC – HDLc – TG/5 = LDL) misclassifies heart disease risk in millions of Americans each year. Triglycerides, starting at levels as low as about 150 mg/dl, can throw off the LDLc estimation: the higher the TGs, the less accurate and misleading the LDLc measurement. Therefore, what comes back in the lab report can leave the patient at risk and both physician and patient unaware of true CV risk. BLP inaccuracies also arise with low LDLc levels. When we’re trying to achieve LDLc levels below 100, or below 70 in high-risk, primarily secondary prevention patients, the BLP just wasn’t designed to be pushed that low. My colleague, Kenneth French, discusses the difficulty in estimating LDL with the BLP in this YouTube video.

Interestingly, the majority of LDL outcome studies using the Friedewald equation forced 12-hour fasting on those enrolled and excluded people with TGs over 200 mg/dl. This was necessary for accuracy at the time, and it is a good approximation when LDL is 100-200 mg/dl, but it doesn’t represent the real world challenges of clinical practice today. A direct measure of LDLc along with non-HDLc components, as provided by the VAP Lipid Panel, is more accurate— fasting or non-fasting.

I frequently refer to data presented by Seth S. Martin, M.D. at the 2012 ACC in Chicago from well-powered research involving 1.3 million patients, which demonstrated that the Friedewald formula for estimating LDLc compared to VAP Lipid Panel direct-measured LDLc cholesterol routinely misclassifies patient risk based on LDLc estimation.

While we’re waiting for the definitive outcomes study that proves which therapy modification based on which assessments reduces mortality, clinically validated accurate risk assessment and effective treatment can and must be addressed by today’s clinician.

In the clinical sample of 1.3 million adults from the Very Large Database of Lipids (VLDL) study, misclassification based on NCEP guidelines occurred in the following classes of patients:

• In patients whose LDLc was estimated <70mg/dL, if the TGs were >150mg/dL then 2/5 (40%) patients had falsely low LDLc cholesterol.
  • If TGs >200mg/dL then 3/5 (60%) had falsely low LDLc cholesterol.
  • In patients whose LDLc was estimated 70-99mg/dL, if the TGs were >150mg/dL, then 1/4 (25%) patients had falsely low LDLc cholesterol.
    • If TGs >200mg/dL then 1/2 (50%) had falsely low LDLc cholesterol.

More information on this study is available through my previous blog article, Research Underlines Need for Direct Lipid Measures.

Errors in LDL classification of 25 to 60 percent are unacceptable in today’s era of CV risk management. Dr. Martin, the lead author of the study that examined the VLDL data, also commented on the current clinical protocol to account for BLP inaccuracies from elevated triglycerides:

“While the guidelines currently address this issue by recommending non-HDLc as a secondary treatment target when triglycerides exceed 200 mg/dL, our data clearly demonstrate that this is not enough. Wider use of non-HDLc or apoB is warranted. Further, these direct measures more accurately assess total atherogenic particle burden compared with LDLc, which has important implications for risk assessment.”

Dr. Martin provides an expanded commentary on the VLDL study results in this YouTube video.

Comprehensive lipoprotein analysis with methods such as density gradient ultracentrifugation using the VAP Lipid Panel have demonstrated the ability to overcome the significant and clearly identified shortcomings of the BLP, which fails to meet current standards for risk stratification in major segments of the population.

In addition to the growing body of evidence — some of which will be presented at the upcoming ACC 2013 conference — in support of comprehensive lipid testing for select patient populations, it is important that we remember to stress the limitations of the BLP. This is important not only because of the lack of information it offers compared to comprehensive lipid assessment, but also because of the basic mathematical limitations of the BLP that affect clinician treatment decisions every day.

Being aware of the basic limitations of the BLP is important for clinical practice. These limitations are highlighted when LDLc is below 100 mg/dl and/or when TGs are over 150 mg/dl. In such cases, patients with TGs over 150 mg/dl and/or patients with LDLc targets < 100 mg/dl, directly measured LDLc is imperative along with a focus on non-HDLc and/or apoB.  With potentially large numbers of patients facing misclassification of risk, the importance of comprehensive lipid testing cannot be overstated.