Reactive Protein

Key Points

• CRP can be measured in patients with a 10-year Framingham risk score of 10% to 20%.

• CRP helps further stratify patients into low-, moderate-, and high-risk groups.

• CRP should not be measured in low-risk or high-risk groups because it is unlikely to alter management.

Elevations in serum levels of C-reactive protein (CRP) have emerged as an important marker of systemic inflammation and increased risk for cardiovascular disease (Ridker, 2001; Ridker et al., 2002). CRP is a pentraxin molecule that, like other acute-phase reactants, is produced by the liver in response to increased levels of IL-6. Approximately one half of all strokes and acute MIs occur in people with normal cholesterol levels (Braunwald, 1997). Consequently, traditional risk factor evaluation does not always accurately identify patients at risk for acute cardiovascular events. Serum CRP levels measured with a high-sensitivity assay (hsCRP) add significant prognostic information when evaluating global cardiovascular risk factor burden at all levels of the calculated Framingham risk score and with all levels of severity of the metabolic syndrome.

Although not yet a therapeutic target, accumulating evidence suggests that CRP may play a direct role in athero-genesis (Ridker et al., 2003; Toth, 2005). CRP stimulates the expression of endothelial CAMs, monocyte chemoattractant protein-1, angiotensin type-1 receptors, endothelin-1 and promotes LDL oxidation. When bound to oxidized LDL, CRP can activate, complement, and promote formation of the cytotoxic membrane attack complex (Bhakdi et al., 1999; Torzewski et al., 1998). CRP induces endothelial cell dysfunction (Venugopal et al., 2002; Verma et al., 2002) and promotes the scavenging of LDL particles by macrophages. CRP is expressed by the cellular constituents of atheroma-tous plaque, further implicating its role in atherogenesis (Yasojima et al., 2001).

A number of studies have demonstrated a strong relationship between hsCRP and risk for cardiovascular disease. In the Physicians' Health Study, men in the highest quartile of CRP had a threefold higher risk for MI over 8 years of follow-up compared to men in the lowest quartile (Ridker et al., 1997). Similarly, the European Monitoring Trends and Determinants in Cardiovascular Disease (MONICA) study demonstrated a 2.6-fold increased risk for an acute cardiovascular event among men in the highest versus lowest quartiles of CRP over 8 years of follow-up (Koenig et al., 1999). CRP measurements also portend risk in women. Among women enrolled in the Women's Health Study, elevated CRP portends risk for cardiovascular disease and emerged as a better predictor of risk than serum LDL-C (Ridker et al., 2000, 2002). Elevated CRP levels are also associated with increased risk for stroke, metabolic syndrome, and new-onset DM (Pradhan et al., 2001; Ridker et al., 2003; Rost et al., 2001). Among patients with established CAD, a high CRP is associated with increased risk for recurrent ACS (Blake et al., 2003).

The AHA and CDC issued guidelines on the use of CRP for stratifying patients at risk for cardiovascular disease

(Pearson et al., 2003). High-sensitivity assays for this ana-lyte are highly reproducible and accurate. Although other inflammatory markers have demonstrated predictive value (e.g., VCAM-1, lipoprotein associated phospholipase A2), at present, CRP is the only such marker recommended for risk-screening purposes. Patients at low (10-yr risk <5%) and high (CAD, CAD risk equivalent, or 10-yr risk >20%) risk should not be screened for CRP. In the primary prevention setting, the target population consists of patients at moderate risk (10-yr risk 5%-20%). CRP levels less than 1.0, 1.0 to 3.0, and greater than 3.0 mg/L portend low, intermediate, and high risk, respectively, for cardiovascular disease. CRP should be measured twice over 2 weeks and the results averaged; hsCRP values that exceed 10 mg/L suggest acute inflammation and should not be used. The test should be repeated when acute infection or inflammation has resolved. Patients in the high-risk group should institute lifestyle modification. Weight loss, exercise, and smoking cessation reduce CRP significantly. Pharmacologic intervention should be instituted for dyslipidemia, hypertension, and impaired glycemic control as indicated. AHA and CDC do not recommend CRP screening in patients with established cardiovascular disease. These patients should already be receiving aggressive lifestyle and pharmacologic intervention to reduce risk for secondary events.

The Justification for the Use of Statin in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial was a primary prevention trial performed in 26 countries (Ridker et al., 2008). The primary objective was to determine if statin therapy would reduce risk for first-time events in men and women at risk for CVD secondary to elevated hsCRP (>2.0 ng/L) but did not meet criteria for lipid-lowering statin therapy because of a low to normal LDL-C of less than 130 mg/dL, as set by the National Cholesterol Education Program. Men older than 50 and women over 60 were enrolled, had no evidence of atherosclerotic disease, and could not be diabetic. The combined primary end point included stroke, MI, cardiovascular mortality, need for revascularization, and hospitalization for unstable angina. Analysis was by intention to treat. The median age of subjects was 66.0 years. The median baseline lipid profile included: LDL-C of 108 mg/ dL, TGs of 118 mg/dL, and HDL-C of 49 mg/dL. The median attained lipid values after 4 years of rosuvastatin therapy included LDL-C of 55 mg/dL, triglyceride of 99 mg/dL, and HDL-C of 50 mg/dL. The median achieved serum CRP level after 1 and 4 years of rosuvastatin therapy was 2.2 and 1.8 mg/L, respectively. Rosuvastatin therapy reduced the relative risk for the primary composite end point by 44% compared to placebo. Significant relative risk reductions with rosuvas-tatin were also achieved in multiple secondary end points, including nonfatal MI (65%), nonfatal stroke (48%), arterial revascularization (46%), and all-cause mortality (20%). The composite end points of MI, stroke, or hospitalization for unstable angina and MI, stroke, or cardiovascular death were both reduced by 47%. All prespecified subgroups (male/ female, age >65 or <65, with or without hypertension, ±met-abolic syndrome, smoking status, Framingham risk score >10% or <10%) derived significant benefit from rosuvastatin therapy. JUPITER is the first primary prevention trial with a statin to demonstrate statistically significant reductions in cardiovascular events for women (46%), elderly patients (>70 yr; 39%), and African American and Hispanic patients

(37%). Projected over 5 years, the number needed to treat (NNT) to prevent one vascular event is estimated at 25, a favorable figure for a primary prevention trial. In JUPITER, rosuvastatin therapy was also associated with reduced risk for thromboembolic phenomena.

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