Clinical use of C-reactive protein for cardiovascular disease.

Abstract: Recent evidence supports an association between elevation of inflammatory markers, such as C-reactive protein, and subsequent cardiovascular disease risk. The American Heart Association released guidelines in 2003 to help clinicians know when to use such markers. Because inflammatory markers are associated with diabetes, obesity, and hypertension, knowledge of the role of such markers is extremely important for prevention and chronic disease management. Newer studies published after the guidelines, and another recent review provide further documentation of the growing role of inflammation in cardiovascular risk. Based on the available literature, this article reviews the new guidelines, more recent evidence since the guidelines, and forms recommendations for primary care clinical practice.

Key Words: C-reactive protein, cardiovascular risk, inflammatory markers

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Although researchers have published much evidence to support an association between certain inflammatory markers and subsequent cardiovascular disease risk, guidelines on how and when to use such markers have been missing until recently. In late January of 2003, the American Heart Association (AHA) and the Centers for Disease Control (CDC) issued a joint statement regarding the application and use of clinical inflammatory markers in clinical and public health practice. (1) The evidence cited in that review and another recent review (2) provide new guidelines for clinicians. Based on the available literature, this article reviews the new guidelines, more recent evidence since the guidelines, and forms recommendations for primary care clinical practice.

Evidence for the Inflammation-Cardiovascular Disease Link

Pathophysiology 

Research in the last several years has established that inflammation plays a role in the atherosclerotic process. Endothelial injury and plaque rupture are considered to be inflammatory processes that may be provoked by many factors, including smoking and hyperglycemia. (3-6) Further atherogenic processes involving the production of leukocyte soluble adhesion molecules, transformation and migration of macrophages, oxidation, and thrombosis contribute to a process characterized by inflammation at almost every step. Several inflammatory proteins are produced in the above process and are potentially useful for measurement of the process in clinical practice. However, many of the markers are elevated in many types of systemic inflammation, thus measurement of them may not be specific for cardiovascular inflammation. Furthermore, many of the molecules are unstable or are assayed using techniques with limited availability, such as intracellular adhesion molecule-1 or interleukin-6. White blood cell count, fibrinogen, and serum amyloid A, while available widely, are less specific or not well studied. The most available, specific, and clinically useful measure is highly sensitive C-reactive protein (hsCRP). (1)

Clinical predictors of elevated C-reactive protein

No specific physical findings except obesity have been correlated with C-reactive protein (CRP) levels. However, several patient conditions and characteristics are associated with increased or decreased levels of hsCRP, including hyperglycemia. (6-10) These factors are shown in Table 1.

Clinical evidence of CRP as a predictor of cardiovascular disease

Recent studies have focused on the measurement of high sensitivity CRP as a predictor of subsequent cardiovascular outcomes. The prognostic value of CRP has been tested in a variety of clinical settings. In patients with symptomatic coronary artery disease (CAD), elevated CRP has been shown to be associated with increased cardiovascular risk, including myocardial infarction. Furthermore, cohort studies have demonstrated increased cardiovascular risk even in apparently healthy individuals with elevated CRP. (11) Elevated CRP also has been associated with worse prognosis and recurrent events in patients with stroke (1, 12) and peripheral arterial disease (13) in prospective cohort studies. In addition, CRP has been reported to correlate with a variety of other cardiovascular risk factors and conditions, including hyperglycemia, (6) hypertension, (14) diabetes, (15) and congestive heart failure. (16)

Types and strength of research evidence for CRP as a cardiovascular disease risk factor

Several studies have reported an increased occurrence of CAD in patients who had significantly elevated CRP in the upper percentiles for the study group. Two separate meta-analyses of prospective population based cohort studies observed a relative odds ratio of 2.0 for major coronary events between subjects who were in the upper percentiles for CRP when compared with those individuals who were in a lower percentile. (17) Also, other population based cohort studies such as the MONICA (monitoring trends and determinants in cardiovascular disease) Augsberg Center in Germany, the Atherosclerosis Risk in Communities Study, the Women's Health Study, and the Honolulu Heart Study, have shown a positive correlation between CRP and the occurrence of CAD, with higher levels of CRP corresponding to a greater risk of CAD. (18-20) In other population-based cohort studies, even when adjusted by stratification or multivariable statistical analysis for such traditional CAD factors as age, smoking, elevated cholesterol, obesity, family history, and diabetes, CRP remains an independent risk factor for CAD. (11,21)

Several studies have also shown that CRP, when combined with lipid profiles, is a better predictor of future CAD than lipid profile alone. For example, a recent prospective cohort study in the New England Journal of Medicine (7) followed over 27,000 apparently healthy American women who had baseline CRP and cholesterol panels drawn. They were followed for 8 years for the development of myocardial infarction, CAD, stroke, need for revascularization, or death from cardiovascular cause. This study showed that elevated baseline CRP was actually a better predictor of future CAD events than low-density lipoprotein (LDL) alone; however, the combination of LDL and CRP was a better prognostic factor than either alone. (11)

CRP has not thus far been found to be strongly correlated with the extent of atherosclerotic disease. One cross-sectional family-based study did not show any correlation between CRP and extent of atherosclerotic disease of the carotids as determined by Doppler ultrasound. (22) Other studies have found no association between CRP and coronary calcium as determined by electron beam computerized tomography. (23)

In addition to being a predictor of events in low-risk patients, (11) CRP is also useful in predicting outcomes in patients presenting with known coronary artery disease, including angina. In one prospective cohort study of patients with unstable angina, CRP levels over 3 mg/L have predicted increased rates of recurrent ischemic events, higher rates of progression to myocardial infarction, and revascularization when compared with those with lower levels of CRP. (24) In another study of 825 patients with known coronary disease, CRP was found to independently predict cardiovascular events at one year. (25)

The above studies indicate the usefulness of CRP as an indicator of long-term risk. However, CRP also has been investigated in the more acute setting of acute chest pain and acute myocardial infarction. For example, in one prospective cohort study, an elevated CRP in the setting of unstable angina was associated with a poorer in-hospital outcome, including a higher mortality rate, and higher rate of myocardial infarction and need for revascularization. (26) Others have found an association between elevated CRP and a greater likelihood of left ventricle thrombus formation after anterior myocardial infarction. (27)

Evidence for the Use of CRP in Clinical Practice

Risk factor assessment

Of the available inflammatory measures, CRP appears to hold the most promise as a possible screening tool for cardiovascular disease. According to the AHA statement, CRP may be most useful as a means to augment risk assessment in persons already identified at some risk due to other factors such as hyperlipidemia. Further clinical trials will be needed to ascertain whether elevated CRP itself needs to be screened for and treated when present in isolation. CRP levels do not correlate well with the level of atherosclerosis, thus they have limited usefulness in selecting people who need angioplasty or coronary bypass procedures. A better potential use may be to consider elevated CRP as an additional risk factor to provide support for drug treatment or more dramatic lifestyle changes in individuals with borderline results from basic risk assessment. (1) Posthoc analyses from two randomized trials suggest that persons with elevated hsCRP have higher absolute-risk cardiovascular reduction when treated with either lovastatin or aspirin. This evidence supports the use of CRP measurements to target patients for medical therapy for primary prevention.

Monitoring

Another use of CRP that has been considered is to monitor the effects of therapy with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins). However, while statins reduce CRP levels, the response is not consistent from individual to individual, with some hyperresponders and some nonresponders. Furthermore, it is not currently known whether the responders with lower CRP levels have a greater reduction in risk than the nonresponders. Thus, monitoring response with CRP levels is not indicated on the basis of current evidence.

Screening apparently healthy individuals

The 2003 AHA/CDC statement does not recommend screening asymptomatic persons with minimal or no cardiovascular risk. The panel had several questions regarding the characteristics of a useful cardiovascular screening test that have remained unanswered in relation to CRP. For example: "Does the marker predict cardiovascular disease endpoints in the short, medium, or long term?"; and "Does measurement of the marker indicate efficacy of therapy or changing prognosis?" In regard to CRP, the question remains as to whether CRP is a risk marker or a separate and independent cause of further atherogenesis. Since there are no completed trials demonstrating lower cardiovascular disease after therapy to lower CRP, the question of a clinical trial-based estimate of cardiovascular benefit remains unanswered.

The AHA panel also asked whether screening for elevated CRP is cost-effective. In a paper published soon after the AHA guidelines were released, Blake et al (28) addressed this question. In the decision analysis, the authors used a Markov model to estimate the benefits, costs, and incremental cost-effectiveness of CRP screening followed by targeted statin therapy, for primary prevention of cardiovascular disease in persons without elevated LDL levels. They found that the incremental cost-effectiveness ratio for screening plus statin therapy compared with no screening or therapy was $48,100 per quality-adjusted life year. They used clinical trial and cohort data to estimate benefit, and current statin and treatment costs. Sensitivity analysis, based on the near-future possibility of lower-cost generic statins being available, revealed that if statin therapy were to cost $1 per day, that the cost-effectiveness ratio for screening would be reduced to $4,900 per quality-adjusted life year for men and $19,600 for women, which compares favorably with other commonly used therapies.

Conclusion

Current evidence and the recommendations of the American Heart Association support CRP as the marker of choice among inflammatory markers, and high sensitivity CRP methods should be used. The measurement of other markers of inflammation is not recommended at this time for use in assessing cardiovascular risk.

For CRP, the AHA cutpoints of low risk (<1.0 mg/L), average risk (1.0-3.0 mg/L), and high risk (>3.0 mg/L) correspond to approximate thirds in the adult population, such that about one third of adults in the US population are contained in each risk category. Individuals at high risk levels of CRP are at an approximately two-fold greater risk of cardiovascular disease than the low-risk persons.

CRP is recommended as an adjunct in risk assessment for people at intermediate risk (eg, 10-20% risk of CVD over the next 10 years). (29) Several online tools are available for performing this 10-year CVD risk assessment, among them the web site for the National Cholesterol Education Program. (30) On the basis of current evidence, screening of the entire adult low-risk population for elevated CRP is not recommended. Individuals already at high risk should already be targeted for medication and lifestyle interventions (including using aspirin and statins) for the primary prevention of cardiovascular disease, thus additional screening with CRP is unwarranted.

No clinical trials have been completed in which a population has been randomly allocated to screening for elevated CRP compared with no screening and then followed for cardiovascular disease events, and therefore definitive statements cannot be made regarding the utility of treating elevated CRP. Clinicians should follow the emerging field of inflammatory markers and keep abreast of research regarding CRP and cardiovascular disease to be able to offer the best strategies for CVD prevention in their patients.

Table 1. Patient factors associated with increased or decreased levels
of C-reactive protein (a,b)

Higher C-reactive protein
  Elevated blood pressure
  Body mass index
  Cigarette smoking
  Metabolic syndrome
  Hyperglycemia
  Low HDL/high TG
  Estrogen/progesterone use
  Chronic infection
  Rheumatoid arthritis
Lower C-reactive protein
  Alcohol consumption
  Increased exercise/physical activity
  Weight loss
  Medications (statins, fibrates, niacin)

(a) HDL, high-density lipoproteins; TG, triglycerides.
(b) Adapted from Pearson. (1)

Accepted June 4, 2004.

References

1. Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice. A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003;107:499-511.

2. Rosenson RS, Koenig W. Utility of inflammatory markers in the management of coronary artery disease. Am J Cardiol 2003;92(supp):10i-18i.

3. Ross R. Atherosclerosis: an inflammatory disease. N Eng J Med 1999;340:115-126.

4. Bazzano LA, He J, Muntner P, et al. Relationship between cigarette smoking and novel risk factors for cardiovascular disease in the United States. Ann Intern Med 2003;138:891-897.

5. Plutzky J. Inflammatory pathways in atherosclerosis and acute coronary syndromes. Am J Cardiol 2001;88(suppl):10K-15K.

6. King DE, Mainous AG III, Buchanan TA, et al. C-reactive protein and glycemic control in adults with diabetes. Diabetes Care 2003;26:1535-1539.

7. Stewart SH, Mainous AG III, Gilbert G. Relation between alcohol consumption and C-reactive protein levels in the adult US population. J Am Board Fam Pract 2002;15:437-442.

8. Mainous AG, Pearson WS. Aspirin and ibuprofen: potential mediators of the cardiovascular risk due to smoking? Fam Med 2003;35:112-118.

9. King DE, Egan BM, Geesey ME. Relation of dietary fat and fiber to elevation of C-reactive protein. Am J Cardiol 2003;92:1335-1339.

10. King DE, Carek PJ, Mainous AG III et al. Inflammatory markers and exercise: differences related to exercise type. Med Sci Sports Exer 2003;35:575-581.

11. Ridker PM, Rifai N, Rose L, et al. Comparison of C-reactive and low density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 2002;347:1557-1565.

12. Arenillas JF, Alvarez-Sabin J, Molina CA, et al. C-reactive protein predicts further ischemic events in first-ever transient ischemic attack or stroke patients with intracranial large-artery occlusive disease. Stroke 2003;34:2463-2468.

13. McDermott MM, Greenland P, Green D, et al. D-dimer, inflammatory markers, and lower extremity functioning in patients with and without peripheral arterial disease. Circulation 2003;107:3191-3198.

14. Sesso HD, Buring JE, Rifai N, et al. C-reactive protein and the risk of developing hypertension. JAMA 2003;290:2945-2951.

15. Pradhan AD, Manson JE, Rifai N, et al. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 2001;286:327-334.

16. Vasan RS, Sullivan LM, Roubenoff R, et al. Framingham Heart Study. Inflammatory markers and risk of heart failure in elderly subjects without prior myocardial infarction: the Framingham Heart Study. Circulation 2003;107:1486-1491.

17. Danesh J, Whincup P, Walker M, et al. Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. BMJ 2000;321:199-204.

18. 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 MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circulation 1999;99:237-242.

19. Folsom AR, Aleksic N, Catellier D, et al. C-reactive protein and incident coronary heart disease in the Atherosclerosis Risk In Communities (ARIC) study. Am Heart J 2002;144:233-238.

20. Sakkinen P, Abbott RD, Curb JD, et al. C-reactive protein and myocardial infarction. J Clin Epidemiol 2002;55:445-451.

21. Ridker PM. High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation 2001;103:1813-1818.

22. Folsom AR, Pankow JS, Tracy RP, et al. Association of C-reactive protein with markers of prevalent atherosclerotic disease. Am J Cardiol 2001;88:112-117.

23. Redberg RF, Rifai N. Gee L, et al. Lack of association of C-reactive protein and coronary calcium by electron beam computed tomography in postmenopausal women: implications for coronary artery disease screening. J Am Coll Cardiol 2000;36:39-43.

24. Liuzzo G, Buffon A, Biasucci LM, et al. Enhanced inflammatory response to coronary angioplasty in patients with severe unstable angina. Circulation 1998;98:2370-2376.

25. Arroyo-Espliguero R, Avanzas P, Cosin-Sales J, et al. C-reactive protein elevation and disease activity in patients with coronary artery disease. Eur Heart J 2004;25:401-408.

26. Verheggen PE, de Maat MP, Cats VM, et al. Inflammatory status as a main determinant of outcome in patients with unstable angina, independent of coagulation activation and endothelial cell function. Eur Heart J 1999;20:567-574.

27. Anzai T, Yoshikawa T, Kaneko H, et al. Association between serum C-reactive protein elevation and left ventricular thrombus formation after first anterior myocardial infarction. Chest 2004;125:384-389.

28. Blake GJ, Ridker PM, Kuntz KM. Potential cost-effectiveness of C-reactive protein screening followed by targeted statin therapy for the primary prevention of cardiovascular disease among patients without overt hyperlipidemia. Am J Med 2003;114:485-494.

29. Wilson PW, Culleton BF. Epidemiology of cardiovascular disease in the United States. Am J Kidney Dis 1998;32(5 Suppl 3):S56-S65.

30. National Cholesterol Education Program web site. Available at http://hin.nhlbi.nih.gov/atpiii/calculator.asp. Accessed May 6, 2004.

RELATED ARTICLE: Key Points

* C-reactive protein (CRP) is the most clinically useful cardiovascular inflammatory marker, and is highly correlated with future cardiovascular risk.

* Highly sensitive CRP levels correlate with subsequent cardiovascular risk as follows: low risk (<1.0 mg/L), average risk (1.0-3.0 mg/L), and high risk (>3.0 mg/L). Individuals at high risk are at approximately two-fold greater risk of cardiovascular disease than low-risk persons.

* Screening of the entire adult low-risk population is not recommended. CRP screening is recommended as an adjunct for risk assessment for people at intermediate risk (eg, 10-20% risk of cardiovascular disease over the next 10 years).

Dana E. King, MD, Arch G. Mainous III, PHD, and Marcia L. Taylor, MD

From the Department of Family Medicine, Medical University of South Carolina, Charleston, SC.

Reprint requests to Dana E. King, MD, Department of Family Medicine, Medical University of South Carolina, 295 Calhoun Street, Charleston, SC 29464. Email: [e-mail]