Cardiovascular Biomarkers Have Little Clinical Utility

BY MARY ANN MOON

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Both conventional and novel cardiovascular biomarkers are of little value in the clinical management of patients who have or may develop cardiovascular disease, according to two unrelated studies published in JAMA.

The first study was designed to determine whether C-reactive protein plays a causal role in coronary heart disease--a topic that remains hotly debated because of the conflicting results of many studies of the issue. The researchers in this study found that CRP does not likely cause CHD, said Dr. Paul Elliott of Imperial College London and his associates.

MEASURING BIOMARKERS MINIMALLY IMPROVED THE ACCURACY OF RISK PREDICTION MODELS BASED ON CONVENTIONAL CV FACTORS.

The researchers first performed a genome-wide association analysis involving nearly 18,000 subjects participating in five large cohort studies and a replication study involving more than 13,000 subjects with the goal of identifying the genetic loci associated with CRP levels in different populations. The findings confirmed that CRP levels correspond with known common genetic variants at several loci.

Dr. Elliott and his colleagues then compiled data on CRP levels from 35 observational studies involving 28,112 patients with CHD (cases) and 100,823 subjects without CHD (controls), and performed a Mendelian randomization study.

The researchers found no association between variants in the CRP locus and CHD, "arguing against a causal role for CRP in atherosclerosis" (JAMA 2009;302:37-48).

Previous observational studies that have linked CRP levels with CHD "may be confounded by association with other CHD risk factors, or reflect a secondary inflammatory response associated with atherosclerosis (reverse causation), rather than indicate a causal relationship," according to Dr. Elliott and his associates.

The researchers added that therapies aimed at reducing CRP levels probably will not be effective against CHD.

The second biomarkers study examined the clinical usefulness of measuring two conventional cardiovascular biomarkers--CRP and B-natriuretic peptide (BNP)--and four novel biomarkers--cystatin C, lipoprotein-associated phospholipase 2 (Lp-PLA2), midregional proadrenomedullin (MR-proADM) and midregional proatrial natriuretic peptide (MR-proANP).

The researchers assessed these biomarkers in a population-based cohort of 5,067 middle-aged men and women (mean age 58 years) who did not have cardiovascular disease.

There were 418 cardiovascular and 230 cardiac events during a median follow-up of 13 years.

Both individually and in combination, measuring these biomarkers "minimally improved the accuracy of risk prediction models over and above conventional CV risk factors," said Dr. Olle Melander of Lund University, Malmö, Sweden, and associates.

"With use of biomarkers, it is possible to define groups with twofold differences in cardiovascular risk. Nonetheless, the translation of this benefit to individual risk prediction appears minimal," they noted (JAMA 2009;302:49-57).

In particular, adding these biomarkers to standard risk assessment usually would not "result in reclassification of individuals to new, clinically meaningful risk categories," and would lead to changes in therapy for only an estimated 1% of patients.

Neither Dr. Elliott nor Dr. Melander reported any financial conflicts of interest related to their research.

When asked to comment on this article, Dr. M. Craig Donaldson, chairman of the department of surgery, atMetroWest Medical Center, Framingham, Mass., stated: "These two recent studies suggest reduced clinical utility of biomarkers of cardiovascular disease. The first study adds evidence that CRP is not causative of atherosclerosis and that therapies directed at CRP are, therefore, not likely to stop atherogenesis.

"Nonetheless, CRP may be a useful way of tracking efficacy of therapies that target both causes of atherogenesis and associated elevations of CRP. The second study found little added value of a panel of novel markers beyond traditional risk factors in predicting incidence of cardiovascular disease over time.

"Stay tuned for further episodes in the search for a useful 'blood test' for disease of the pipes being constantly washed by traveling blood," he concluded.

Dr. Donaldson is an associate medical editor for VASCULAR SPECIALIST.

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