Shifting Cardiovascular Guidelines Focus Attention On Lab’s Role, Emerging Tests

While results from laboratory testing continue to play a pivotal role in risk assessment and management of cardiovascular disease, some experts feel that new guidelines published by the leading associations do not go far enough in incorporating newer markers of cardiovascular risk. The American College of Cardiology and American Heart Association (ACC-AHA) in July published the final version of the 2013 Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Risk in Adults and the 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk. Those involved in the drafting of the guidelines defend the rigorous systematic review of randomized controlled trials with arteriosclerotic cardiovascular disease (ASCVD) outcomes utilized and say the resulting guidelines are not merely reaffirmation of previous recommendations. The guidelines include the development of new risk prediction equations and a new cholesterol guideline framework that is not simply an extension of previous Adult Treatment Panel III (ATP III) guidelines. From the laboratory perspective, the fasting lipid panel remains the cornerstone of testing mentioned in the guidelines. The ACC-AHA panel recommends a fasting lipid panel prior to the initiation of statin therapy comprising total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), and (calculated) high-density lipoprotein cholesterol (HDL-C), followed by a second lipid panel four weeks to 12 weeks after initiation of therapy to determine a patient’s adherence. Additional lipid panels, as clinically indicated, should be performed every three months to 12 months. Unlike the ATP III recommendations, the ACC-AHA cholesterol guidelines represent a “dramatic departure” from previously recommended risk-dependent LDL-C targets and rely upon the percent reduction of LDL-C. While the recommendations call for calculation of LDL-C using the Friedewald equation, research shows that the Friedewald equation might not be reliable in patients who have triglycerides more than 200 mg/dL and an LDL-C less than 70 mg/dL. “In these patients, laboratories might need to reflex to either a direct method or to an ultracentrifugation method to quantify LDL-C,” according to a piece on the laboratory’s role in adoption of the new guidelines, written by Ishwarlal Jialal, M.D., Ph.D., from the University of California at Davis, in the American Journal of Clinical Pathology. “Also, laboratories should adhere to standardized protocols to minimize preanalytic variation such as the patient fasting at least 10 to 12 hours.” Should Additional Tests Have Been Considered? Several aspects of the guidelines have been controversial, with one of the criticisms being that the ACC-AHA guidelines did not go far enough in endorsing alternative markers of ASCVD. Jialal cites apolipoprotein B and LDL particles as alternate measures of LDL and estimated glomerular filtration rate and albuminuria (measures of chronic kidney disease) as additional risk markers for cardiovascular disease as some of the tests not included. In an editorial in the September issue of Mayo Clinic Proceedings, Jennifer Robinson, M.D., vice chair of the ACC-AHA cholesterol guideline development committee, says the group did review the epidemiologic evidence for apolipoprotein B, creatinine and glomerular filtration rate, and microalbuminuria but found a lack of evidence to determine whether they improved risk prediction using the new 5 percent and 7.5 percent 10-year risk of nonfatal and fatal stroke or myocardial infarction. She writes that while this is a direction for future research, there is not presently “compelling evidence” for the general use of these tests. The ACC-AHA found the strongest predictors of the 10-year risk of ASCVD events (first occurrence of nonfatal myocardial infarction, coronary heart disease death, or fatal or nonfatal stroke) were age, sex, race, total cholesterol, HDL-C, systolic blood pressure, blood pressure treatment status, diabetes, and current smoking status. But a task force of Mayo Clinic experts feels adjunctive measures should also be considered for risk stratification, including genetic determinants of ASCVD, according to a special article published in the September issue of the Mayo Clinic Proceedings. To refine risk, the group, led by Iftikhar Kullo, M.D., also recommends a blood test to measure lipoprotein(a), or Lp(a), a type of LDL cholesterol (reimbursed $17 by Medicare). The Lp(a) level is determined by genes, and high levels are associated with increased cardiovascular risk. Unlike hs-CRP, which the authors say is a marker of risk, the genetic variants associated with high Lp(a) levels are a causal risk factor. They say elevated levels of Lp(a) would reclassify 4.1 percent of intermediate-risk individuals to higher risk. “A one-time measurement of Lp(a) should be considered when there is uncertainty in the estimates of 10-year ASCVD risk, particularly in those with a family history of ASCVD,” write Kullo and colleagues. Mayo researchers are pushing ahead on improving the understanding of genomic information to further refine cardiovascular risk with a pilot trial called the Myocardial Infarction Genes (MI-GENES) study. “The suboptimal performance of available ASCVD risk algorithms needs to be acknowledged, and research efforts to improve risk assessment in asymptomatic adults should be intensified,” Kullo writes. “Although the variants have modest effect sizes, most are not associated with conventional risk factors and therefore provide an orthogonal means of risk assessment, in contrast to several existing biomarkers such as hs-CRP whose incremental predictive utility is diminished because of its correlation with factors such as obesity, diabetes, and hypertension.” To Fast or Not? One additional criticism of the ACC-AHA guidelines is the issue of fasting. The guidelines, while recommending fasting lipids, do not specify the length of time for fasting. Researchers of several recent studies are calling on national and international professional organizations to re-examine the necessity of fasting for LDL-C based in part on the argument that nonfasting lipids may actually be superior in predicting cardiovascular outcomes because the nonfasting state may more accurately reflect the body’s exposure to circulating lipids. The latest study to question the benefits of fasting was published online July 11 in Circulation. The researchers from New York University (New York) found that over 14 years of follow-up in a national cohort of National Health and Nutrition Examination Survey III participants (1988 to 1994), mortality (all-cause and cardiovascular) was similar between 4,299 pairs of adults undergoing fasting (eight hours or more) and nonfasting lipid panels (less than eight hours). Fasting did not improve the prognostic value of LDL-C values, and the authors urge a reassessment of the fasting necessity, which they say can become a practical issue standing in the way of hyperlipidemia detection. Takeaway: The assessment of cardiovascular risk is an evolving area of clinical care that will likely incorporate adjunct tests into more traditional assessments. While recent guidelines have generated some controversy, laboratory test results will continue to play an important role in informing clinical discussions.