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Editroial
NEJM

Volume 347:1615-1617 November 14, 2002 Number 20

C-Reactive Protein � To Screen or Not to Screen?
Prediction is very difficult, especially about the future.
� Niels Bohr

More than 20 years ago, 246 risk factors for coronary heart disease (CHD) had already been identified, and the number continues to grow.1 Advances in genomics and proteomics will provide even more candidate markers to consider for routine assessment in practice. Risk stratification is important because information about the probability of a cardiovascular event in the future can help target therapy and resources to those most likely to benefit. Of the several hundred known correlates of CHD, only a handful have had the staying power to be recommended for routine screening. The question of which new risk factors, if any, should be added to conventional risk assessment with regard to CHD is important for clinicians and policymakers, especially because the disease continues to be a major public health problem.

The impetus to pursue new predictors of CHD arises from the discovery that traditional risk factors do not fully account for the occurrence of disease. For example, only about half of patients with CHD have hypercholesterolemia.2 This finding may indicate that average levels of cholesterol in the population are not normal from a pathobiologic perspective, but it also underscores the multifactorial pathogenesis of CHD.

Important advances in understanding the pathophysiology of atherosclerosis have been made in recent years, and inflammatory mechanisms are now believed to play a central part in the origins and complications of CHD.3 C-reactive protein is an acute-phase reactant that markedly increases during an inflammatory response. C-reactive protein levels have been helpful for decades in monitoring many diseases. A new use for this old test has gained momentum in recent years as a result of observations that minor elevations of C-reactive protein are predictive of cardiovascular events in patients with CHD.4 High-sensitivity tests for C-reactive protein now make possible the measurement of C-reactive protein levels within the normal range.5 C-reactive protein not only may be a marker of low-grade chronic systemic inflammation but also may be directly involved in atherosclerosis; it can amplify the inflammatory response through complement activation, tissue damage, and activation of endothelial cells.6 The possibility that the high-sensitivity assay for C-reactive protein may enhance our prognostic and therapeutic capabilities is of considerable interest, but its value has not been fully established.

In this issue of the Journal, Ridker et al. add to the growing body of evidence that C-reactive protein is an independent predictor of cardiovascular disease.7 The authors previously used data from the Women's Health Study to conduct a small case�control analysis with three years of follow-up. The results showed that C-reactive protein levels predicted the risk of cardiovascular disease.8 The current study, which extends the previous results, includes data from the entire study cohort of nearly 28,000 women with data on base-line levels of C-reactive protein, who were followed for a mean of eight years, and uses a composite cardiovascular end point.

The crude data showed that C-reactive protein levels predicted subsequent cardiovascular disease more strongly than did the levels of low-density lipoprotein (LDL) cholesterol. When adjusted for a variety of traditional risk factors, C-reactive protein and LDL cholesterol were equivalent in their ability to discriminate women who later had an event from those who did not, on the basis of the area under the receiver-operating-characteristic curve, but C-reactive protein was found to be a better predictor when a likelihood test was performed. Statistical significance can be inflated with large sample sizes, of course, whereas the clinical importance of a difference may be minimal. This fact should be taken into consideration as statistics are translated into clinical strategy. In the study by Ridker et al., the association between C-reactive protein and cardiovascular disease was independent of traditional risk factors, but no information is provided from a formal test to determine whether there was added value over the information provided by the global Framingham risk score. The data lend support to the inflammatory hypothesis of the pathogenesis of coronary heart disease and also raise a number of important issues about statistical predictors of coronary heart disease and their clinical relevance. The findings of Ridker et al. from this study of healthy women are consistent with published reports in diverse populations.9 These data raise the question of whether it is time to begin more widespread assessment of C-reactive protein.

In 1968, Wilson and Jungner outlined criteria for screening programs and suggested that if there is no generally accepted treatment, it is premature to embark on routine screening.10 The landscape of prevention has changed dramatically since that time, and there is growing recognition that levels of one risk factor can modify treatment plans aimed at ameliorating another risk factor. A more contemporary set of questions to consider before implementing routine screening for newly identified risk factors is shown in Table 1. The answers to many of the questions remain unknown with respect to C-reactive protein.


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 		 Table 1. Ten Questions to Consider before Screening for Novel Risk Factors in Clinical Practice.

 
 
C-reactive protein has been associated with mortality from all causes in the elderly, suggesting that it is a nonspecific marker of clinical outcomes.11 Moreover, multiple markers of inflammation have been identified (although most have not been as extensively studied as C-reactive protein), and in the future, inflammatory markers more specific to the progression of atherosclerosis may be identified. C-reactive protein is correlated with central adiposity and insulin resistance.12 The association of C-reactive protein with metabolic risk factors may account for some of its predictive value and does not clarify treatment strategies. Primary- and secondary-prevention trials have shown that treatment with statins reduces levels of C-reactive protein and rates of cardiovascular disease, with the beneficial effects of treatment greatest among those with elevated base-line levels of C-reactive protein.13,14 These data are promising, but they come from a post hoc analysis and need to be confirmed in prospective trials. Several other pharmacotherapies have been shown to reduce levels of C-reactive protein, but data on a possible correlation between a reduction in inflammation and a reduction in clinical events are limited.6

Is there a downside to beginning widespread screening for C-reactive protein before definitive data become available? Historically, beta carotene provides an example. Plasma levels of carotenoids are predictive of coronary heart disease and are also a marker of other risk factors.15 Substantial data from basic-science and epidemiologic studies lent support to the oxidation hypothesis of coronary heart disease, yet in randomized trials, beta carotene therapy did not prove beneficial and was, surprisingly, associated with an elevated risk of cancer.15 Even if the inflammation hypothesis proves to be correct, the cost effectiveness of altering management on the basis of the results of screening for C-reactive protein needs to be determined.

Evidence supports an association of higher levels of C-reactive protein with an increased risk of cardiovascular disease, but the predictive power of this association is markedly diminished when adjusted for other risk factors. Any clinical significance of the added value of C-reactive protein over conventional markers of coronary heart disease is debatable. The relative contributions of C-reactive protein as a marker, a causative agent, or a consequence of coronary heart disease are unclear. This uncertainty does not preclude C-reactive protein from playing an important part in prognostication and the tailoring of therapy; however, whether its value will be confirmed in randomized trials is unknown. Such research will provide vital information to confirm or refute the inflammatory hypothesis of atherosclerosis. Before these data become available, it may be premature to adopt widespread assessment of C-reactive protein. In the interim, it is prudent to focus effort and resources on screening for and treatment of major conventional risk factors, levels of which are suboptimal worldwide. Scientists and policymakers should develop a systematic approach to testing and adopting screening guidelines for emerging risk factors. A major criterion in the process of developing evidence-based screening guidelines should be that routine assessment of a new biologic marker has been demonstrated to enhance patient care and reduce the burden of cardiovascular disease.


Lori Mosca, M.D., M.P.H., Ph.D.
Columbia University
New York, NY 10032

References

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