C-Reactive Protein in the Prediction of Cardiovascular Disease

N Engl J Med 2000; 343:512-513August 17, 2000

Article

To the Editor:

Ridker et al. provided a stimulating article on inflammatory markers and cardiovascular disease in women (March 23 issue).1 Not surprisingly, the popular press picked up on the article and gave their findings prominent coverage. It is not clear that Ridker et al. wanted this to happen. Their findings are cast in terms of relative risk only, not in terms of traditional predictive value; it is the latter that is more relevant to the practicing physician.2 That is, we learn that subjects in the highest quartile for high-sensitivity C-reactive protein (hs-CRP), relative to those in the lowest quartile, had a 4.4-fold risk of cardiovascular events. However, the overall risk was just 0.4 percent (122 events in 28,263 subjects over a period of three years). We suspect that the positive predictive value (the proportion of all subjects with “elevated” levels of hs-CRP who had cardiac events) in this population was low.

We were unable to calculate the conventional predictive values from the data supplied in the article. It would be instructive if the authors provided the predictive values so that readers could determine whether this new test is genuinely ready for “prime-time” screening.

Even though this test performed better than measurements of conventional lipid markers such as low-density lipoprotein (LDL) cholesterol in this population (at least in terms of relative risk), there are other relevant data about LDL cholesterol that are lacking for hs-CRP. For example, we know that lowering LDL cholesterol levels has beneficial effects,3 we have effective methods to lower LDL cholesterol levels, and we have data on the cost effectiveness of such strategies.4

Gary L. Horowitz, M.D.
Bruce A. Beckwith, M.D.
Beth Israel Deaconess Medical Center, Boston, MA 02215

4 References

1
Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000;342:836-843
Full Text | Web of Science | Medline

2
Galen RS, Gambino SR. Beyond normality: the predictive value and efficacy of medical diagnoses. New York: John Wiley, 1975.

3
National Cholesterol Education Program. Second report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Circulation 1994;89:1329-1445
Web of Science

4
Hamilton VH, Racicot F-E, Zowall H, Coupal L, Grover SA. The cost-effectiveness of HMG-CoA reductase inhibitors to prevent coronary heart disease: estimating the benefits of increasing HDL-C. JAMA 1995;273:1032-1038
CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: In our study of inflammatory and lipid markers we used a matched, nested case–control analysis that allowed direct comparison of the magnitude of risk associated with various cardiovascular risk factors after age and smoking status were taken into account. Of the 12 factors evaluated — which included LDL cholesterol, high-density lipoprotein (HDL) cholesterol, Lp(a) lipoprotein, and homocysteine — hs-CRP was the strongest predictor of future cardiovascular events. Moreover, hs-CRP levels were predictive of the risk of cardiovascular events among study participants with low levels of LDL cholesterol; these data underscore the importance of the inflammatory process in atherothrombosis.

Our matched, nested case–control study was designed to maximize biologic validity. It is not, however, conducive to calculating absolute risks. We thus concur with Horowitz and Beckwith that generalizing our results to other populations must be done with caution and that studies addressing absolute risks are needed. We further concur that the reduction of lipid levels remains a fundamentally important method to reduce cardiovascular risk. At the same time, since half of all heart attacks and strokes occur among apparently healthy men and women without overt hyperlipidemia, we believe it important for clinicians to consider emerging biologic data that go beyond the use of cholesterol screening as the sole method of assessing cardiovascular risk. With regard to hs-CRP, several large-scale studies in the United States1-3 and Europe4,5 have now demonstrated the potential importance of this inflammatory marker in the detection of cardiovascular risk.

Finally, we wish to correct an error in the last sentence of the Results section of our abstract. As described in the text and in Table 4 of our article, our multivariate analysis was performed on a per-quartile basis. Thus, this sentence should read, “In multivariate analyses, the only plasma markers that independently predicted risk were hs-CRP (increase in relative risk per quartile, 1.5; 95 percent confidence interval, 1.1 to 2.1) and the ratio of total cholesterol to HDL cholesterol (increase in relative risk per quartile, 1.4; 95 percent confidence interval, 1.1 to 1.9).”

Paul M. Ridker, M.D.
Julie E. Buring, Sc.D.
Nader Rifai, Ph.D.
Brigham and Women's Hospital, Boston, MA 02115

5 References

1
Kuller LH, Tracy RP, Shaten J, Meilahn EN. Relationship of C-reactive protein and coronary heart disease in the MRFIT nested case-control study: Multiple Risk Factor Intervention Trial. Am J Epidemiol 1996;144:537-547
Web of Science | Medline

2
Tracy RP, Lemaitre RN, Psaty BM, et al. Relationship of C-reactive protein to risk of cardiovascular disease in the elderly: results from the Cardiovascular Health Study and the Rural Health Promotion Project. Arterioscler Thromb Vasc Biol 1997;17:1121-1127
CrossRef | Web of Science | Medline

3
Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973-979[Erratum, N Engl J Med 1997;337:356.]
Full Text | Web of Science | Medline

4
Koenig W, Sund M, Frohlich M, et al. C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsberg Cohort Study, 1984 to 1992. Circulation 1999;99:237-242
Web of Science | Medline

5
Haverkate F, Thompson SG, Pyke SDM, Gallimore JR, Pepys MB. Production of C-reactive protein and risk of coronary events in stable and unstable angina. Lancet 1997;349:462-466
CrossRef | Web of Science | Medline

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Xiaoshan Zhu, Dayue Duan, Nelson G. Publicover. (2010) Magnetic bead based assay for C-reactive protein using quantum-dot fluorescence labeling and immunoaffinity separation. The Analyst 135:2, 381
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Jerzy Krupinski, Marta M. Turu, Mark Slevin, José Martínez-González. (2008) Carotid plaque, stroke pathogenesis, and CRP: Treatment of ischemic stroke. Current Cardiology Reports 10:1, 25-30
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Jerzy Krupinski, Marta M. Turu, Mark Slevin, José Martínez-González. (2007) Carotid plaque, stroke pathogenesis, and CRP: Treatment of ischemic stroke. Current Treatment Options in Cardiovascular Medicine 9:3, 229-235
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Mario Napoli, Francesca Papa. (2005) Inflammation, blood pressure, and stroke: an opportunity to target primary prevention?. Current Hypertension Reports 7:1, 44-51
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Mario Di Napoli, Francesca Papa. (2004) Clinical application of C-reactive protein in stroke prevention: bright and dark sides of the moon. Expert Review of Neurotherapeutics 4:4, 613-622
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