Biomarkers and primary prevention screening Tue, 15 May 2001 20:00:00


Boston, MA - A head-to-head comparison of potential biomarkers for subclinical atherosclerosis in the Physicians' Health Study suggests that C-reactive protein (CRP) and the total cholesterol (TC)/HDL-C ratio are the strongest predictors of PAD and could be used in combination for improved primary prevention screening. The analysis, conducted by Dr Paul Ridker (Center for Cardiovascular Disease Prevention, Harvard Medical School) and colleagues, is published in the May 16, 2001 issue of Journal of the American Medical Association, alongside the latest NCEP guidelines.

"It's a tad humorous," notes Ridker in a heartwire interview, "This issue of JAMA has in it our manuscript saying you must move beyond cholesterol to understand how to predict risk, and...the exact same issue has the new guidelines which of course take into account none of the new biology."

The new biology, according to Ridker, is that atherosclerosis is an inflammatory disorder, not just a lipid disorder, and that a good inflammatory marker can help identify individuals at risk in a primary prevention setting. "This is the fourth or fifth major paper to say that CRP really does add to the predictive value of lipids," Ridker says, "This has been shown for heart attacks and stroke previously for men and women, and this paper shows it also to be true for PAD."

In this present paper, Ridker et al report a case-controlled analysis from the Physicians' Health Study, in which they examine the ability of 11 biomarkers to predict the development of PAD. The researchers measured the biomarkers in baseline plasma samples from 140 participants who developed PAD over the average 9-year study follow-up, and from 140 age- and smoking status- matched controls who remained free of vascular disease.
Adjusted relative risk of PAD associated with 4th quartile biomarker levels

Biomarker	RR* (95% CI)	p value
	3.1 (1.6-6.5)	<0.001
	2.3 (1.1-4.7)	0.003
	0.6 (0.2-0.9)	0.03
	2.8 (1.3-5.9)	0.003
	3.9 (1.7-8.6)	<0.001
	0.6 (0.3-1.1)	0.1
	2.9 (1.6-6.3)	<0.001
	1.1 (0.6-2.2)	0.6
	1.1 (0.5-2.1)	0.7
	2.2 (1.1-4.7)	0.02
	2.8 (1.3-5.9)	0.01

*Risk of PAD for patients with 4th quartile biomarker levels as compared to 1st quartile levels


The authors found that the majority of the biomarkers were significant independent predictors of PAD in this general healthy population. The ratio TC/HDL-C was the strongest predictor among the lipid biomarkers, and CRP was the strongest nonlipid predictor.

Notably, when the researchers looked to see which of the 11 biomarkers would improve current primary prevention screening, they found that the inflammatory parameters added significantly to the predictive power of standard lipid measures (TC or TC/HDL-C). hsCRP had a greater additive value than fibrinogen. The predictive values of LDL-C, Apo A-1, and Apo B-100 were redundant to TC and TC/HDL-C - not surprising given the intercorrelation between these lipid measures. For the same reason, the authors found testing for both CRP and fibrinogen was not more informative than screening for one alone.

"These CRP levels are very potent predictors of risk even when the cholesterol levels are low. So you can't just rely on the cholesterol - that's the point," Ridker concludes, " The facts are that half of all heart attacks and strokes occur among people in the United States with normal cholesterol."

In the JAMA article, Ridker and colleagues recommend, "the strongly positive findings in this study...merit careful consideration among clinicians interested in programs in general population-based screening to improve the detection of subclinical atherosclerosis." For more information on how to use CRP in screening, Ridker points to a recent review article he authored, in which he has laid out how to take the lipid levels and CRP level, and compute a patient's risk.