Review

Continuing Medical EducationNature Clinical Practice Cardiovascular Medicine (2008) 5, 621-635
doi:10.1038/ncpcardio1322  
Received 14 January 2008 | Accepted 24 June 2008 | Published online: 19 August 2008

The use of high-sensitivity assays for C-reactive protein in clinical practice

Kiran Musunuru*, Brian G Kral, Roger S Blumenthal, Valentin Fuster, Catherine Y Campbell, Ty J Gluckman, Richard A Lange, Eric J Topol, James T Willerson, Milind Y Desai, Michael H Davidson and Samia Mora  About the authors

Correspondence *Johns Hopkins Ciccarone Preventive Cardiology Center, 600 North Wolfe Street/Blalock 524C, Baltimore, MD 21287, USA

Email kmusunu1@jhmi.edu

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Learning objectives

Upon completion of this activity, participants should be able to:

  1. Differentiate between low-, high-, and intermediate cardiac-risk patients.
  2. Identify ideal patients for testing with the high-sensitivity C-reactive protein (hsCRP) assay.
  3. Describe the role of hsCRP testing in stroke, diabetes, and the metabolic syndrome.
  4. Discuss how therapies, such as statins, influence CRP levels.

Competing interests

K Musunuru has served as a consultant for Alnylam Pharmaceuticals within the last year. TJ Gluckman has received honoraria from Sanofi-Aventis and Pfizer and has served as a consultant for Merck within the last year. MH Davidson has received honoraria from and served as a consultant for diaDexus within the last year. They declare no conflicts of interest pertaining to this topic. The other authors and the Journal Editor H Camm declared no competing interests. The CME questions author CP Vega declared an association with Novartis, Inc., the other CME questions author A Del Negro declared no competing interests.

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Summary

High-sensitivity assays that accurately measure levels of the inflammatory biomarker C-reactive protein have been proposed for use in assessments of risk for cardiovascular disease (CVD). A growing body of evidence supports recommendations for these tests in selected asymptomatic individuals deemed to be at intermediate risk of CVD according to traditional risk-factor assessments and who do not already warrant chronic treatment with aspirin and statin therapy. Data suggests that these high-sensitivity assays should be used in combination with measurements of LDL-cholesterol levels to assist risk stratification of selected patients for prevention of CVD.

Review criteria

We identified English-language, peer-reviewed publications through searches of MEDLINE and the Cochrane Database from January 1990 through December 2007 using the search term "C-reactive protein", in combination with one of the following: "heart disease", "stroke", "hypertension", "metabolic syndrome" or "stroke". Bibliographies from these references were also reviewed. We selected papers on the clinical risk prediction of cardiovascular disease or diabetes mellitus that used multivariate adjustment for at least four traditional risk factors. We excluded studies in which the populations had significant prevalence of comorbidities. If data was separated for each sex we considered them as separate populations.

Keywords:

coronary disease, diabetes mellitus, prevention, risk factors, stroke

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Introduction

More than 800,000 individuals have a myocardial infarction annually in the US, and another 700,000 experience a stroke.1 Nearly half of these events occur in patients with no overt evidence of hyperlipidemia and 15% to 20% occur in patients with none of the major traditional risk factors.2, 3 At the opposite end of the spectrum, a disproportionate number of events occur in individuals with a history of myocardial infarction, which indicates that these patients have a high level of risk for recurrent events.

Although half of women and two-thirds of men in the US are affected by cardiovascular disease (CVD) after the age of 40 years,1, 4 only a small proportion of asymptomatic adults (<1% of women and approximately 5% of men) are classified as being at high risk for CVD by contemporary risk scores. This discrepancy has been termed the 'detection gap'.5 In the US, 10% of asymptomatic women (approx7 million) and 40% of asymptomatic men (approx26 million) are considered to be at intermediate risk.5, 6 As the level of risk determines the intensity of preventive interventions, a clear need exists for improved risk assessment in asymptomatic individuals, particularly those at intermediate risk.

The National Cholesterol Education Program Adult Treatment Panel (NCEP-ATP) III guidelines7 provide a global risk score for 'hard' coronary heart disease (CHD) events (myocardial infarction and death caused by coronary heart disease), and the 1998 Framingham risk-score equation estimates total CHD events (myocardial infarction, cardiac death, coronary insufficiency);8, 9 a 10-year absolute risk of a hard coronary event of below 10% is considered low risk, while 10–20% represents intermediate risk, and greater than 20% represents high risk.7 Some study groups have proposed that the intermediate-risk category should be extended to include individuals whose 10-year absolute risk is between 5% and 20%. Proponents of this change argue that this alternative cut-off identifies a group of individuals, especially women, who could gain more benefit from aspirin, intensive lipid-lowering therapy and lifestyle modification than individuals with a 10-year absolute risk of less than 5% could.5, 10 Increasingly, therefore, the intermediate-risk category is being divided into 'low' and 'high' subgroups (i.e. 5% to <10%, and greater than or equal to10% to <20%).

Numerous biomarkers have been proposed to improve predictions of CVD risk. A biomarker is useful if it meets the following criteria: its measurement adds to clinical knowledge and provides risk information that is independent of established predictors; it is easy to measure and test results are easy to interpret in a primary-care setting; an accurate, reproducible and internationally standardized assay is available; and measurement of the biomarker has a favorable cost:benefit ratio.11 Biomarkers used for screening purposes should also improve patient management, particularly through improved accuracy of risk classification and guidance in choice of therapy.11

C-reactive protein (CRP) is an easily measured and widely investigated biomarker of inflammation. The link between inflammation and atherosclerosis is well established; inflammation is a key element of the atherosclerotic process, and contributes to all of its stages (plaque initiation, growth, and rupture).12, 13, 14 Thus, serum levels of inflammatory markers such as CRP might be expected to improve predictions of CHD and stroke risk in at least some patient populations.

Although a number of articles related to the high-sensitivity CRP (hsCRP) test have been published, no review has comprehensively addressed the relevance of hsCRP test results in a variety of scenarios encountered in clinical practice—primary prevention of CVD, stroke, and diabetes mellitus, and secondary prevention of CVD. We summarize the available data and assess whether they support proposed guidelines for clinical use of hsCRP tests. We consider CRP levels to be a means to improve risk stratification and to enable therapy to be closely matched to level of risk, not as a therapeutic target in its own right. Data are lacking as to whether reductions in CRP levels per se reduce cardiovascular risk independently of other modifiable risk factors.

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Published data

Primary prevention

In 2003, the Centers for Disease Control and Prevention and the AHA issued recommendations for the use of inflammatory biomarkers in CVD detection, prevention and treatment.15 At that time, the body of evidence in support of the clinical use of hsCRP tests was modest, and most recommendations were given an ACC/AHA class II level of support, which indicated that the weight of evidence was favorable but more data were needed before general consensus could be reached.

Since 2003, considerable data have been published on the use of hsCRP tests to improve assessments of cardiovascular risk for patients in primary-prevention programs. We found at least 20 prospective studies of distinct cohorts, which demonstrated that elevated levels of CRP are associated with an elevated risk of future coronary events after adjustment for at least four traditional risk factors, including Framingham risk factors and/or diabetes and obesity (Table 1).16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 This association applied both to men and women across a wide age range (e.g. from middle-aged to elderly). Some studies stratified groups of patients by their hsCRP test results—CRP levels of less than 1 mg/l, 1–3 mg/l, and greater than 3 mg/l—and showed that these cutoffs correspond with low-risk, moderate-risk and high-risk groups, respectively, although actual levels of risk were fairly linear across a wide range of CRP levels.

Table 1 Association of C-reactive protein with coronary heart disease in primary prevention populations: studies that show a significant association after multivariate adjustment (P <0.05).
Table 1 - Association of C-reactive protein with coronary heart disease in primary prevention populations: studies that show a significant association after multivariate adjustment (P <0.05).
Full tableFigures & Tables indexDownload PowerPoint slide (480K)

A small number of studies reported a positive association between hsCRP test results and coronary event rate but none of these correlations reached statistical significance after adjustment for at least four other risk factors (Table 2).25, 27, 36, 37, 38, 39, 40, 42, 43, 44 Initial analysis of data from the Framingham Study found that CRP levels did not provide clear incremental value over the Framingham risk score;36 however, the test used to measure CRP was not a high-sensitivity assay. When the analysis was repeated using a high-sensitivity assay, there was a positive correlation between CRP and CVD; after multivariate adjustment, CRP levels greater than 3 mg/l on hsCRP assay were significantly associated with increased incident CVD (Table 1 and 2).23

Table 2 Association of C-reactive protein with coronary heart disease in primary prevention populations: studies that do not show a significant association after multivariate adjustment (P >0.05).
Table 2 - Association of C-reactive protein with coronary heart disease in primary prevention populations: studies that do not show a significant association after multivariate adjustment (P >0.05).
Full tableFigures & Tables indexDownload PowerPoint slide (333K)

Although informative, individual studies are subject to variation and interpreting risk data can be difficult. To date one formal meta-analysis has been performed, but a clear need remains for further pooled investigations such as that from the Emerging Risk Factors Collaboration. A meta-analysis of 22 prospective studies found that after adjustment for traditional risk factors individuals whose CRP levels were in the top tertile on hsCRP assay (>3 mg/l) have a odds ratio of 1.45 for major cardiac events (95% CI 1.25–1.68) compared with those in the lowest tertile (CRP levels of <1 mg/l on hsCRP assay).31 This meta-analysis incorporated studies that individually demonstrated a statistically significant association between hsCRP test results and cardiac events (including many of the studies listed in Table 1) as well as a number of studies that did not show a statistically significant association (some of which are listed in Table 2). Inclusion of both types of study suggests that the overall conclusion of the meta-analysis was not confounded by publication bias.

C-reactive protein levels vs traditional risk factors: do these measurements add incremental value?

Interestingly, in studies in which traditional risk factors underwent rigorous multivariate analysis to assess the strength of their associations with CVD risk, the magnitude of the association between incident CVD and hsCRP test results was comparable with that between CVD and LDL-cholesterol level, systolic blood pressure, or smoking behavior (Table 3). However, even if the association between elevated CRP levels on hsCRP assay and increased CVD risk is similar to that of individual traditional risk factors, the burden lies on proponents of hsCRP tests to demonstrate that the addition of hsCRP test results to CVD risk-prediction strategies has a clinical benefit, even if only in limited patient populations. Data from the Women's Health Study suggest that the addition of CRP level to the NCEP-ATP III global risk score improves the accuracy of CVD risk assessment in some asymptomatic individuals. In this large, prospective, cohort study of asymptomatic middle-aged women, the addition of hsCRP test results to the NCEP-ATP III global risk score reclassified many intermediate-risk individuals as high-risk or low-risk; following hsCRP assessment, 32% of women with an absolute 10-year risk of severe coronary events of between 5% and 10%, and 42% of women with a 10-year absolute risk of between 10% and 20% were reclassified into a low-risk or high-risk group.45

Table 3 Magnitude of association between C-reactive protein and coronary heart disease compared with traditional risk factors in primary prevention studies that reported these comparisons.
Table 3 - Magnitude of association between C-reactive protein and coronary heart disease compared with traditional risk factors in primary prevention studies that reported these comparisons.
Full tableFigures & Tables indexDownload PowerPoint slide (322K)

In 2007, a study conducted in the same cohort of women analyzed 35 cardiovascular risk factors, and found that hsCRP test results provided the best prediction of incident CVD events (myocardial infarction, stroke, revascularization, and CVD-related death) when used along with traditional risk factors (age, cholesterol, blood pressure, smoking and diabetes) and parental history of myocardial infarction before age 60 years.46 When this expanded risk algorithm (the Reynolds Risk Score) was validated in a separate group of 8,158 women who were followed up for 10 years, it provided a more accurate risk assessment than did the smaller set of traditional risk factors; 44.2% of women in the intermediate-risk categories (10-year risks of between 5% and 10%, or between 10% and 20%) were reclassified into higher risk (26.6%) or lower risk (17.6%) categories.46 Whether the Reynolds Risk Score will yield similar results in more diverse populations than that in the Women's Health Study remains to be seen. In a cohort of middle-aged, asymptomatic men, Koenig et al. showed that hsCRP results provided incremental information on risk beyond that obtained using the Framingham risk score, particularly in those at intermediate risk.47 Additional studies show that hsCRP results provide risk information incremental to that of the Framingham risk score in elderly men at intermediate risk and elderly women at high risk of CVD events.20, 23

The c-statistic

The reclassification of intermediate-risk individuals to a different risk category could have important implications for preventive pharmacotherapy in these patients. However, whether such reclassification improves patient outcomes remains to be seen. In the absence of long-term, prospective studies, statistical criteria are being used to evaluate the incremental utility of hsCRP test results. In a 2006 publication from the Framingham Offspring Study, elevated baseline levels of CRP assessed by hsCRP assay were associated with increased overall mortality during 7 years of follow-up.48 Despite this increased mortality, the c-statistic (a measure of test validity derived from the receiver-operator curve, whereby a value of 0.5 signifies a test of no utility and a value of 1.0 signifies a test with perfect discrimination) of the risk-prediction model did not change with the addition of hsCRP test results. Indeed, most studies have found that the inclusion of hsCRP results in models does not increase the c-statistic significantly.

Whether the c-statistic is more suited to analyses of data from retrospective case–control studies than for assessments of risk-prediction models generated from prospective studies, and whether criteria other than the c-statistic could be more appropriate to assess such risk models is under debate.49, 50, 51 Although an improved c-statistic value is one criterion by which a biomarker can be judged to be useful, relying solely on the c-statistic could give misleading results and force the exclusion of clearly useful risk factors—for example, the individual addition or subtraction of blood pressure and lipid profile from a model based on Framingham risk factors does not significantly change the c-statistic.51 As more risk factors are incorporated into a model, it becomes increasingly difficult for additional risk factors to increase the c-statistic, even if that risk factor carries as strong an association with the disease in question as the other risk factors.

The optimal set of parameters by which to judge the additive value of a biomarker to risk-prediction algorithms is a subject of active investigation. A summary quantitative measure of model fit—the net reclassification index—identifies the proportion of individuals who move up or down the risk categories with the use of additional biomarkers.52 This index has been used to assess whether hsCRP test results add information to traditional risk factors. In the Women's Health Study, the net reclassification index when hsCRP results were included was 6%,34 whereas in the Framingham study, the net reclassification index when hsCRP results were included was 9%.23

Even if one accepts that the c-statistic is the gold standard by which to assess the utility of hsCRP testing, most analyses of hsCRP data have considered whether the c-statistic changes when this test is applied to a whole population, rather than just to intermediate-risk patients. In a cohort of middle-aged, asymptomatic men, addition of hsCRP results to the Framingham risk model improved the c-statistic from 0.735 to 0.750 when calculated for the whole study population—a modest change that could be interpreted as being of little clinical importance. By contrast, when calculated for just intermediate-risk individuals who had a 10-year CVD risk of 11–14%, the c-statistic increased from 0.725 to 0.776, and increased from 0.695 to 0.751 for patients with a 10-year risk of 15–19%—considerable improvements that support the use of hsCRP tests in these subgroups.47 More analyses of this kind in different cohorts could help determine the appropriateness of the c-statistic as a tool to establish the value of a biomarker.

In summary, hsCRP assessment in asymptomatic individuals seems to be most useful for those classified as intermediate risk on the basis of traditional risk factors (e.g. an NCEP-ATP III global risk score between 5% and 20%) and who do not already warrant chronic treatment with aspirin and a statin. In individuals at very low risk, even a doubling or tripling of risk (e.g. from 1% to 3%) would not change their risk classification, and so should not greatly change the physician's or patient's behavior as the patient's absolute CVD risk remains low. Conversely, high-risk individuals are candidates for chronic aspirin and lipid-lowering therapy regardless of their hsCRP test results. Among individuals at intermediate risk, however, reclassification to a higher or lower CVD risk category on the basis of hsCRP test results could influence the decision whether to use more-aggressive or less-aggressive preventive strategies.

Substantially more data now support the use of hsCRP tests in selected asymptomatic patients than were available in 2003, when the Centers for Disease Control and Prevention and AHA guidelines were published. Nevertheless, more data are needed to establish the utility of hsCRP test results in the creation of improved risk-prediction strategies—such as the Reynolds Risk Score—and validation of those strategies in intermediate-risk individuals in numerous cohorts.

Stroke and hypertension

In many prospective studies, elevated CRP levels measured by hsCRP assay have correlated with an increased risk of stroke, even after adjustment for multiple traditional risk factors (Table 4).21, 24, 30, 34, 53, 54, 55, 56, 57 However, as with CVD events, some studies failed to demonstrate a statistically significant association.38, 55, 58, 59, 60 When these studies are considered together, the relative risk associated with elevated CRP levels on hsCRP tests is comparable to the relative risk of other established risk factors for stroke, with an up to threefold increase in risk in individuals with high CRP levels, compared to those with low CRP levels. As a result of this strong association, physicians involved in the primary prevention of stroke could consider the use of hsCRP assays to differentiate between individuals with other (non-CRP) risk factors for stroke who would not otherwise receive preventive therapy. Data are, however, lacking on what proportion of individuals would be appropriately reclassified as being at higher or lower risk for stroke following incorporation of hsCRP testing.

Table 4 Association of C-reactive protein with stroke in primary prevention populations.
Table 4 - Association of C-reactive protein with stroke in primary prevention populations.
Full tableFigures & Tables indexDownload PowerPoint slide (404K)

Among individuals with blood pressure above the desired goals specified by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) guidelines, the concomitant finding of elevated levels of CRP on hsCRP testing should encourage the use of antihypertensive therapy and intensified lifestyle modification. However, reason suggests that all patients with hypertension and other risk factors for stroke should be counseled to undertake lifestyle modification. In conclusion, specific data do not yet exist to support the use of hsCRP tests in addition to traditional risk-prediction strategies for stroke.

The metabolic syndrome and diabetes mellitus

In individuals with the metabolic syndrome, elevated CRP levels on hsCRP tests correlated with an increased risk of developing non-insulin-dependent diabetes, and with the development of both diabetes and CVD.41, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76 Multiple prospective cohort studies have confirmed that hsCRP assay results are associated with incident non-insulin-dependent diabetes, independently of other risk factors such as obesity, particularly in women (Table 5).41, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72 In addition, CRP levels are associated with CVD risk among those with the metabolic syndrome and seem to differentiate individuals at high risk for both incident diabetes mellitus and CVD events from those at low risk.

Table 5 Association of C-reactive protein with diabetes mellitus in primary prevention populations.
Table 5 - Association of C-reactive protein with diabetes mellitus in primary prevention populations.
Full tableFigures & Tables indexDownload PowerPoint slide (398K)

Among individuals already diagnosed with diabetes, hsCRP test results can further stratify their cardiovascular risk,71, 73, 74 which underscores the pathophysiologic link between insulin resistance, inflammation and CVD.66, 75, 76 As noted for stroke risk factors, physicians should recommend intensive lifestyle modification to all individuals who meet criteria for the metabolic syndrome, regardless of whether they have elevated CRP levels.

Lifestyle interventions

Weight reduction, smoking cessation and exercise are recommended for patients at risk for CVD or diabetes, and these interventions have been shown to lower CRP levels on hsCRP assay.77, 78, 79, 80, 81, 82, 83 Of note, however, data are lacking as to whether a decrease in CRP levels detected on hsCRP testing per se reduces cardiovascular risk independently of other modifiable risk factors. Lifestyle interventions should emphasize both increased physical activity and dietary interventions that help the patient obtain and maintain an ideal body weight. In a large study of asymptomatic, adult women, after adjustment for cardiovascular risk factors, the relative risks associated with a CRP level of greater than 3 mg/l on hsCRP testing were 1.3 for inactive, normal-weight women, 2.7 for active, overweight women, 3.1 for inactive, overweight women, 8.3 for active, obese women, and 9.9 for those who were inactive and obese.80 In a comprehensive review of 40 observational studies and 12 randomized clinical trials, most of which were conducted in healthy individuals, both reduced fitness and increased fatness contributed to increased inflammation and elevated CRP levels on hsCRP tests. Baseline hsCRP test results could be important in the overall changes observed with intervention studies. The greatest changes in outcome are seen in those individuals with high baseline hsCRP test results; in some studies, no changes were seen in individuals who had low baseline hsCRP test results.84

Statin therapy

Many studies have shown that statin therapy lowers CRP levels, as measured by hsCRP tests, although relatively little correlation exists between the degree of LDL-cholesterol reduction and the decline in hsCRP test results in individual patients.85, 86, 87, 88 These data are consistent with laboratory studies that demonstrated statins to have anti-inflammatory as well as lipid-lowering effects.89, 90, 91 As statins seem to be somewhat unique among lipid-lowering agents in this regard, statins should be used preferentially over other lipid-lowering agents in the hypercholesterolemic patient with elevated CRP levels on hsCRP testing. A greater degree of CVD event reduction with statin therapy occurs in hypercholesterolemic patients who have elevated CRP levels on hsCRP testing than occurs in those who have similar elevations in cholesterol levels but low CRP levels on hsCRP assay;16, 87, 88, 92 however, whether CRP is raised or not, all hypercholesterolemic patients should receive lipid-lowering therapy. Whether statins prevent CVD events in individuals who have elevated CRP levels on hsCRP testing but who do not have hyperlipidemia was the subject of a large-scale clinical trial (Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin [JUPITER]). The JUPITER study was stopped early, in March 2008, owing to overwhelming evidence of a benefit of rosuvastatin therapy versus placebo in reducing adverse clinical outcomes.93 Until the results of JUPITER are published, statin therapy cannot be routinely recommended to patients with low levels of LDL cholesterol and high levels of CRP on hsCRP testing; however, encouragement of substantial lifestyle changes (i.e. exercise, weight loss and complete smoking cessation) is a reasonable approach if these measures have not already been undertaken. Of note, other agents, including metformin, thiazolidinediones, insulin, angiotensin-receptor blockers, and combinations of agents, such as ezetimibe and statin combination therapy, are known to lower CRP levels as measured by hsCRP assay, but their optimum roles in primary prevention remain to be determined.

Secondary prevention

A number of studies have demonstrated the prognostic utility of hsCRP testing in patients with acute coronary syndromes,94, 95, 96, 97, 98, 99 even when troponin is undetectable.98 When such high-risk patients receive statin therapy, the best long-term clinical outcomes occur among those who achieve very low levels of LDL cholesterol (<1.8 mmol/l) and CRP (hsCRP test results <2 mg/l). In the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT–TIMI 22)88 and Aggrastat to Zocor (A to Z) trials,97 in terms of reduction in coronary event rate and improvement in survival, achievement of low CRP levels was as important as attainment of low LDL-cholesterol levels. Furthermore, better outcomes were seen in individuals with both low LDL-cholesterol and low CRP levels than in those with low LDL-cholesterol and high CRP levels, as measured by hsCRP assay.

Similar results have also been found in individuals with stable coronary artery disease; those who achieve low CRP levels measured by hsCRP assay while on statin therapy have a reduced risk of stroke100 and regression of atherosclerosis on intravascular ultrasonography.87 These data indicate that achieving low CRP levels on hsCRP testing after initiation of statin therapy could be an important therapeutic goal along with very low levels of LDL cholesterol. A reasonable approach is to consider use of hsCRP tests in patients with a history of CVD who have achieved LDL-cholesterol goals on low-dose or moderate-dose statin therapy—the finding of a high CRP level on hsCRP assay could help guide the decision whether to further intensify statin therapy, although this strategy remains to be formally validated in a prospective trial.

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Practical considerations

High-sensitivity C-reactive protein assays

CRP cutoffs of less than 1 mg/l, 1–3 mg/l, and greater than 3 mg/l are commonly used for cardiovascular risk discrimination, and correspond to approximate tertile risk values in white populations of European origin.85 These same values also discriminate between levels of risk for incident diabetes and vascular events among those with the metabolic syndrome.

Limited information is available on the utility of these tertile levels in hsCRP testing of minority populations,85 although evidence indicates that CRP levels on hsCRP testing are often higher in African Americans than in individuals of white European origin and Asian Americans.101, 102 Of note, rates of CVD are also raised in African Americans compared with white Americans.1 The effect of different treatment strategies across different ethnic groups on the basis of risk stratification according to hsCRP test results is currently unknown.

The relationship between hsCRP test results and CVD risk is linear across the full range of CRP levels. An alternative system that divides hsCRP test results into five CRP categories (<0.5 mg/l, 0.5–1.0 mg/l, 1.0–3.0 mg/l, 3.0–5.0 mg/l, and >5.0 mg/l) could provide further discrimination,101 much in the same manner that five categories are currently recommended for stratification of blood pressure measurements and lipid levels.103 The division of hsCRP test results into tertiles for risk-stratification purposes is consistent with methods of risk discrimination used in major population studies but could lead to confusion and inconvenience if applied in clinical practice. For primary prevention, therefore, a conservative recommendation is that high CRP levels on hsCRP testing are defined as 3 mg/l or greater. This threshold readily identifies a group of individuals who have substantially increased CVD risk compared with individuals who have hsCRP test results below 1 mg/l. For secondary prevention, levels of 2 mg/l or greater are consistent with the increased CVD risk of patients with established coronary disease who also receive ongoing treatment with statins.104

Individuals with CRP levels that are consistently greater than 10 mg/l are at particularly high risk for developing CVD.101, 103 CRP levels greater than 10 mg/l should not be viewed, therefore, as uninformative; patients whose CRP level assessed by hsCRP assay lies in this range should undergo repeat assessment at a later date to see if the level remains elevated. A sustained CRP elevation indicates increased long-term vascular risk and perhaps warrants treatment.101, 103, 104, 105

Whereas most epidemiologic studies have relied on single measurements of CRP assessed by hsCRP assay per patient, in practice the clinical value of the hsCRP assay could be improved if individuals with an initially high value undergo repeat assessment at least 1 month later. As hsCRP test results are not affected by intraindividual circadian variation or recent food ingestion, a blood sample for hsCRP assay can be obtained at any time of day, and a fasting sample is not required.73 Variation in hsCRP test results is comparable to that seen in cholesterol measurements.73 Whether significant seasonal variation exists in hsCRP test results and how this variation might affect vascular risk remains unclear.106, 107 As patients in the midst of an acute-phase response can have transiently elevated CRP levels on hsCRP assay, repeat testing is recommended for all values in excess of 5 mg/l. If the second blood sample yields a lower hsCRP test result than the first, the second value should be used in assessments of CVD risk. When persistently high hsCRP test results are obtained, vascular risk seems to be high regardless of the cause of the underlying inflammation.101, 103, 104, 105

Although conventional assays are capable of detecting high levels of CRP during the acute-phase response, these assays are not sensitive enough to detect the low levels of inflammation needed for vascular risk prediction. As many hospital-based and outpatient laboratories offer conventional CRP testing to assess the presence of systemic inflammatory states (i.e. collagen vascular disease, rheumatologic conditions, endocarditis) and hsCRP testing for cardiovascular evaluation, physicians must specify an 'hsCRP' test when they seek information on vascular risk.

Multiple commercial hsCRP assays are available that have been standardized to provide consistent clinical information in inpatient and outpatient settings.73 A comprehensive program for standardization of commercial hsCRP assays was completed in 2003, so that all hsCRP test results are now reported in mg/l.

Specificity for cardiovascular disease

CRP is an important marker of general inflammation and, therefore, could highlight the presence of chronic inflammatory conditions other than atherosclerosis. Case–control and retrospective studies have found associations between cancer and elevated CRP levels on hsCRP testing, however, prospective studies have not confirmed this association.108 Elevated levels of CRP on hsCRP testing in cancer patients most likely reflect prevalent disease rather than being a marker of future CVD risk.108 Of note, hsCRP test results were shown to predict all-cause mortality in two studies published in 2008.109, 110 In both studies, CVD was the most common cause of death underlying all-cause mortality, as it is in the general population, where CVD accounts for more than 60% of adult deaths. Even in light of the possibility that elevations in CRP are not specific to vascular mortality but might also predict nonvascular mortality, in intermediate-risk patients with multiple CVD risk factors, elevated CRP levels should be regarded as a clear marker of increased CVD risk that can indicate a need for therapy specifically intended to reduce vascular mortality (e.g. statins).

Cost-effectiveness

Cost-effectiveness is an important consideration when new biomarkers are assessed for use in screening. Markers used to screen all patients have severe cost implications. A 2003 cost-effectiveness analysis examined the incremental cost-effectiveness of hsCRP screening followed by targeted statin therapy for individuals with elevated CRP levels, compared with dietary counseling alone, for the primary prevention of cardiovascular events among patients with low or normal LDL-cholesterol levels.111 The investigators found that using hsCRP screening to identify individuals without overt hyperlipidemia who would nonetheless benefit from statin therapy for the primary prevention of CVD was a cost-effective option—the potential incremental cost-effectiveness ratio was US$48,100 per quality-adjusted life-year for 58-year-old men and $94,400 per quality-adjusted life-year for 58-year-old women. In some scenarios, hsCRP screening was even cost-saving. The cost-effectiveness of this screening strategy varied by patients' level of baseline cardiovascular risk and the cost and efficacy of statin therapy in patients found to have high CRP levels on hsCRP screening. In light of the early termination of the JUPITER trial, the efficacy of statins might be much higher in asymptomatic individuals than originally expected.

In the primary-prevention setting, a screening strategy that always requires lipids to be measured before hsCRP evaluation would probably not be cost-effective. In a patient known to have a Framingham risk estimate of between 5% and 20% on the basis of prior evaluations (i.e. intermediate risk) and who is not receiving aspirin and/or statin therapy, a concomitant hsCRP test at the time of lipid assessment could be appropriate. As the cost of hsCRP testing is low, this approach might be more efficient and more cost-effective than scheduling a second physician visit and additional phlebotomy after lipid results have been obtained.

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Conclusions

CRP levels as assessed by hsCRP assay are associated with CVD in multiple patient groups and add predictive power to traditional risk scores for some intermediate-risk individuals. CRP data could also assist with the identification of patients who would benefit from lifestyle modification and pharmacologic preventive therapies. The available data support selective use of hsCRP assays to improve risk prediction in the primary-prevention setting in individuals at intermediate CVD risk according to traditional risk scores and who do not already warrant chronic aspirin and statin therapy. Data that support the selective use of hsCRP assay results to guide treatment in secondary prevention patients who are not already on maximal statin therapy are currently limited. In both contexts, further validation studies will be needed before these strategies are universally endorsed.

Key points

  • In asymptomatic individuals, C-reactive protein (CRP) levels are associated with risk of cardiovascular disease, including both coronary events and stroke, independent of traditional risk factors
  • High-sensitivity CRP assay results add predictive power to current coronary risk scores for some intermediate-risk individuals and, in some individuals, could highlight a need for treatment with chronic aspirin and statin therapy if not already on therapy
  • CRP levels are associated with clinical outcomes in high-risk individuals treated with statin therapy and, in some individuals, measurement of CRP in conjunction with LDL cholesterol could be useful
  • CRP levels are associated with incident diabetes mellitus and cardiovascular disease outcomes in individuals with the metabolic syndrome

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Acknowledgments

Charles P Vega, University of California, Irvine, CA, and A Del Negro, Medscape Cardiology, New York, NY, are the authors of and are solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

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References

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Competing interests

K Musunuru has served as a consultant for Alnylam Pharmaceuticals within the last year. TJ Gluckman has received honoraria from Sanofi-Aventis and Pfizer and has served as a consultant for Merck within the last year. MH Davidson has received honoraria from and served as a consultant for diaDexus within the last year. They declare no conflicts of interest pertaining to this topic. The other authors declared no competing interests.

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Subject areas under which this article appears: Disease markers