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A Comparison of C-Reactive Protein, Fibrinogen, Homocysteine, Lipoprotein(a), and Standard Cholesterol Screening as Predictors of Peripheral Arterial Disease

Paul M. Ridker, MD,MPH; Meir J. Stampfer, MD; Nader Rifai, PhD

JAMA. 2001;285:2481-2485.

Context  Several novel risk factors for atherosclerosis have recently been proposed, but few comparative data exist to guide clinical use of these emerging biomarkers.

Objective  To compare the predictive value of 11 lipid and nonlipid biomarkers as risk factors for development of symptomatic peripheral arterial disease (PAD).

Design, Setting, and Participants  Nested case-control study using plasma samples collected at baseline from a prospective cohort of 14 916 initially healthy US male physicians aged 40 to 84 years, of whom 140 subsequently developed symptomatic PAD (cases); 140 age- and smoking status–matched men who remained free of vascular disease during an average 9-year follow-up period were randomly selected as controls.

Main Outcome Measure  Incident PAD, as determined by baseline total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol–HDL-C ratio, triglycerides, homocysteine, C-reactive protein (CRP), lipoprotein(a), fibrinogen, and apolipoproteins (apo) A-I and B-100.

Results  In univariate analyses, plasma levels of total cholesterol (P<.001), LDL-C (P = .001), triglycerides (P = .001), apo B-100 (P = .001), fibrinogen (P = .02), CRP (P = .006), and the total cholesterol–HDL-C ratio (P<.001) were all significantly higher at baseline among men who subsequently developed PAD compared with those who did not, while levels of HDL-C (P = .009) and apo A-I (P = .05) were lower. Nonsignificant baseline elevations of lipoprotein(a) (P = .40) and homocysteine (P = .90) were observed. In multivariable analyses, the total cholesterol–HDL-C ratio was the strongest lipid predictor of risk (relative risk [RR] for those in the highest vs lowest quartile, 3.9; 95% confidence interval [CI], 1.7-8.6), while CRP was the strongest nonlipid predictor (RR for the highest vs lowest quartile, 2.8; 95% CI, 1.3-5.9). In assessing joint effects, addition of CRP to standard lipid screening significantly improved risk prediction models based on lipid screening alone (P<.001).

Conclusions  Of 11 atherothrombotic biomarkers assessed at baseline, the total cholesterol–HDL-C ratio and CRP were the strongest independent predictors of development of peripheral arterial disease. C-reactive protein provided additive prognostic information over standard lipid measures.

Author Affiliations: Center for Cardiovascular Disease Prevention (Drs Ridker and Rifai), Channing Laboratory (Dr Stampfer), and Leducq Center for Molecular and Genetic Epidemiology of Cardiovascular Disorders (Dr Ridker), Brigham and Women's Hospital, Harvard Medical School; Department of Epidemiology, Harvard School of Public Health (Dr Stampfer); and the Departments of Laboratory Medicine and Pathology, Children's Hospital Medical Center, Harvard Medical School (Dr Rifai), Boston, Mass.

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