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Linking Biologic, Epidemiologic, and Trial Data: What is the relationship of CRP to CVD?
Phil Greenland

Narrative Review: Assessment of C-Reactive Protein in Risk Prediction for Cardiovascular Disease
Donald M. Lloyd-Jones, MD, ScM; Kiang Liu, PhD; Lu Tian, ScD; and Philip Greenland, MD
Ann Intern Med, 2006 Jul 4;145(1):35-42

Some experts propose C-reactive protein (CRP) as a screening tool for prediction of cardiovascular disease (CVD). Many epidemiologic studies show positive associations between elevated CRP levels and incident CVD. Assessment of the value of new prognostic tests, however, must rely on understanding of test characteristics rather than on associations measured by relative risks. In the case of CRP, test characteristics must be judged in the context of currently available CVD risk prediction algorithms. In this review of literature published before January 2006, the authors describe what is known about the additional utility of CRP in risk prediction. They find no definitive evidence that, for most individuals, CRP adds substantial predictive value above that provided by risk estimation using traditional risk factors for CVD. Use of CRP may add to risk estimation in a limited subset of individuals who are at intermediate predicted risk according to the Framingham risk score. The authors propose that many questions still must be addressed before CRP is incorporated into risk prediction algorithms and before universal screening with CRP can be recommended.

Conclusions

Inflammation is a major mechanism in the process of atherogenesis and in triggering of clinical CVD events. Some experts propose that CRP, a nonspecific marker of inflammation, is a new tool that improves CVD risk estimation and that it should be used as a routine clinical risk assessment test (6). However, as with almost all novel risk factors that have been described for cardiovascular risk, CRP, when examined critically, does not improve risk discrimination enough to recommend its routine adoption for population screening.

In 2003, the Centers for Disease Control and Prevention and the American Heart Association published a scientific statement on the applications of screening with markers of inflammation (5). The panel made the following class IIa recommendation: "Measurement of hs[high-sensitivity]-CRP ... in those judged at intermediate risk by global risk assessment (10 to 20% risk for CHD per 10 years), at the discretion of the physician, may help direct further evaluation and therapy in the primary prevention of CVD. The benefits of such therapy based on this strategy remain uncertain." The panel also concluded that "the entire adult population should not be screened for hs-CRP for purposes of cardiovascular risk assessment."

Three years later, we agree with the panel's recommendation. Specific individuals may benefit from knowledge of their CRP level, but many questions still must be answered before we accept it as a standard CVD risk factor, incorporate it into risk prediction algorithms, and use it for universal screening. Until we understand whether and how we should incorporate CRP into clinical practice, it should remain, at most, a "tiebreaker" test, measured selectively in individuals at intermediate risk for CVD when the merits of beginning drug therapy for other risk factors are unclear. Future evaluations of CRP should focus not on measurement of associations but on test characteristics such as likelihood ratios and the additional utility of CRP over and above traditional risk factor measurement.

References

  1. Greenland P, O'Malley PG. When is a new prediction marker useful? A consideration of lipoprotein-associated phospholipase A2 and C-reactive protein for stroke risk. Arch Intern Med. 2005 Nov 28;165(21):2454-6.
  2. Greenland P, Gaziano JM. Selecting asymptomatic patients for coronary computed tomography or electrocardiographic exercise testing. N Engl J Med. 2003 Jul 31;349(5):465-73.
  3. Greenland P, Smith SC Jr, Grundy SM. Improving coronary heart disease risk assessment in asymptomatic people: role of traditional risk factors and noninvasive cardiovascular tests. Circulation. 2001 Oct 9;104(15):1863-7.
  4. Danesh J, Wheeler JG, Hirschfield GM, Eda S, Eiriksdottir G, Rumley A, Lowe GD, Pepys MB, Gudnason V. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med. 2004 Apr 1;350(14):1387-97.
  5. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002 Nov 14;347(20):1557-65.
  6. Cook NR, Buring JE, Ridker PM. The Effect of Including C-Reactive Protein in Cardiovascular Risk Prediction Models for Women. Ann Intern Med. 2006 Jun 5; [Epub ahead of print]
  7. Lloyd-Jones DM, Liu K, Tian L, Greenland P. Narrative Review: Assessment of C-Reactive Protein in Risk Prediction for Cardiovascular Disease. Ann Intern Med. 2006 Jun 5; [Epub ahead of print]
  8. Smith GD, Timpson N, Lawlor DA. C-Reactive Protein and Cardiovascular Disease Risk: Still an Unknown Quantity? Ann Intern Med. 2006 Jun 5; [Epub ahead of print]
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