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Multiple biomarker index useful only in asymptomatic patients with mild atherosclerosis

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A multiple biomarker index, one that includes markers of inflammation, is only modestly associated with increased risks of coronary heart disease and cardiovascular disease in asymptomatic patients, according to the results of a new study [1]. The increased risk of events for patients with a biomarker score above the median occurs mainly in those with a mild amount of existing atherosclerosis, according to investigators.

“Our purpose was to use both subclinical disease screening and the biomarker index to see if this combined approach helped improve risk stratification in asymptomatic patients,” lead investigator Dr Nathan Wong (University of California, Irvine) told heartwire. “I don’t think it’s entirely obvious, but the biomarkers might add to risk prediction in certain patients. We have a limited sample with a limited number of events showing that maybe the biomarkers work in people with intermediate levels of atherosclerosis. I do think, however, the results need further validation.”

Presenting the results of the study here at the World Congress of Cardiology, Wong said there is a lot of interest in the potential role of new biomarkers and the concept of a multibiomarker approach, where clinicians would be able to calculate risk scores based on various different pathologies. Research in the past few years, however, has provided mixed results with regard to the clinical utility of most biomarkers for the improvement of risk assessment.

One analysis of the Framingham Heart Study failed to show an improvement in the prediction of cardiovascular events when adding 10 common contemporary biomarkers to standard risk factors. An analysis of elderly men with and without cardiovascular disease in the Uppsala Longitudinal Study of Adult Men (ULSAM), however, showed that the addition of several biomarkers of cardiovascular and renal dysfunction significantly improved risk stratification for death from cardiovascular causes. Both of these recent studies were reported by heartwire.

Biomarkers with nonredundant pathobiology

In this newest study, Wong said that his group was interested in possibly identifying certain subgroups where the addition of biomarkers might result in an improvement in risk prediction.

“The concept here was to see if we could use different biomarkers that have nonredundant pathobiology and perhaps combine these with subclinical disease testing with coronary calcium as a way of assessing atherosclerotic burden,” he said. “The way this might work would be in an intermediate-risk population, where a patient might have a nominal LDL cholesterol cut point of 100 or 130 [mg/dL]. If you found patients with elevated biomarkers and an increased coronary artery calcium score, we might bump that person to a higher-risk stratum, thereby treating them more aggressively.”

The group studied 1302 asymptomatic patients, mean age 59 years old, who received coronary artery calcium (CAC) scanning as part of the Early Identification of Subclinical Atherosclerosis by Noninvasive Imaging Research (EISNER) study. Calcium scores were classified as none/minimal (CAC 0-9), mild (10-99), and moderate/significant (>100). The biomarker index, consisting of high-sensitivity C-reactive protein (CRP), interleukin-6 (IL-6), brain natriuretic peptide (BNP), myeloperoxidase (MPO), plasminogen activator inhibitor-1 (PAI-1), and angiotensinogen, was calculated by assigning points to each biomarker depending on its measurement, with zero points if the measure were in the first quartile or three points if it were in the highest quartile.

After an average follow-up of four years, regardless of the biomarker index, coronary heart disease and cardiovascular disease event rates were similar in patients with low CAC scores and in those with high CAC scores. Among those with intermediate CAC scores—those considered to have mild atherosclerosis disease burden—coronary heart disease and cardiovascular disease event rates differed significantly among those who fell above or below the median biomarker index score.

Incidence of events by combined CAC-biomarker category

Cohort CHD events (%) CVD events (%)
CAC 09, biomarker index <8.0 (median) 0.5 0.7
CAC 09, biomarker index >8.0 0.3 0.3
CAC 1099, biomarker index <8.0 0.7 2.7
CAC 1099, biomarker index >8.0 4.6 4.6
CAC >100, biomarker index <8.0 9.5 10.2
CAC >100, biomarker index >8.0 9.7 11.1

In a Cox proportional hazards model that adjusted for standard risk factors, including age, gender, total- and HDL-cholesterol levels, diabetes, smoking, and blood pressure, Wong and colleagues showed that the difference in risk was most pronounced among those with mild levels of atherosclerosis.

Risk-factor-adjusted Cox proportional hazards model

Cohort Coronary heart disease events (95% CI) Cardiovascular disease events (95% CI)
CAC 09, biomarker index <8.0 (median) 1.0 (reference) 1.0 (reference)
CAC 09, biomarker index >8.0 1.0 1.0
CAC 1099, biomarker index <8.0 1.3 (0.1-13.0) 3.8 (0.9-15)
CAC 1099, biomarker index >8.0 9.2 (2.2-38) 6.2 (1.7-23)
CAC >100, biomarker index <8.0 19.3 (5.2-71) 13.8 (4.3-44)
CAC >100, biomarker index >8.0 20.1 (5.4-75) 14.9 (4.7-48)

“From a multivariable analysis, the result is consistent with other studies showing that a high biomarker index is associated with higher risk, but what this study has shown is that the relationship seems to be limited to patients with an intermediate level of atherosclerotic disease measured by coronary calcium.”

To heartwire, Wong said further follow-up is still needed to better define the combined impact of multiple biomarkers and subclinical atherosclerosis. The findings, however, suggest the clinical significance of a multiple biomarker index will remain controversial.

“I think the future is likely going to reside in some sort of combined approach,” he said. “We know that there are patients who aren’t picked up by the traditional risk scores, such as Framingham or the European risk score. There are people who are considered low risk but who have a significant risk of disease and end up having events. Different imaging technologies might be useful—coronary calcium scanning is useful in predicting long-term risk—but we also need a method of predicting short-term risk.”

Source: heartwire