CRP as a cardiovascular risk factor

• according to the Framingham study, 50% of CHD occurs in patients with below average LDL-cholesterol (LDL-C) levels. Therefore, it has been suggested that risk assessment should not rely purely on LDL-C measurements
• there is evidence that CRP had a stronger predictive value for the risk of CHD events than LDL-C in the Physicians Health Study. Furthermore, while cholesterol does not predict stroke, data would suggest that CRP does

CRP as a risk factor for cardiovascular disease

• CRP has a half-life of 18-20 hours; there is no circadian rhythm associated with CRP levels
• CRP levels are independent of age, smoking status and cholesterol levels; CRP is consistent across sex and ethnic groups
• High sensitivity CRP has been used as a means of assessing cardiovascular risk
  • low risk < 1 mg/L
  • moderate risk 1-3 mg/L
  • high risk > 3mg/L
• data suggest that the C-reactive protein level is a stronger predictor of cardiovascular events than the LDL cholesterol level and that it adds prognostic information to that conveyed by the Framingham risk score (1)
• data suggest that CRP levels may be useful in identifying apparently healthy men who are at an increased long-term risk of sudden cardiac death (2)
• many studies have reported that CRP predicts cardiovascular events, even after adjusting for traditional risk factors. In the Honolulu Heart study, CRP was predictive of events even up to 20 years later
• there is evidence that CRP has a predictive power that was additive to that of cholesterol and that both CRP and LDL-C were markers that identified two different sets of high-risk CHD patients
• CRP levels can be used to predict the development of type II diabetes in patients, even after adjustment for patient body weight. Furthermore, it has been reported that for each symptom of the metabolic syndrome present, mean CRP levels were increased

Notes:

• CRP as a screening tool
  • an epidemiological study (the third National Health and Nutrition Examination Survey) provides evidence that suggests that elevated CRP levels in the general population are in large measure attributable to traditional CHD risk factors. The study authors also conclude that "... Moreover, CRP level elevation is rare in the absence of borderline or abnormal risk factors. As such, CRP measurements may have limited clinical utility as a screening tool beyond other known CHD risk factors" (3)
  • CRP has been examined as a risk factor in the Framingham study and the authors concluded that elevated CRP level provided no further prognostic information beyond traditional office risk factor assessment to predict future major CVD and major coronary heart disease in this population sample (4)
    • a BHF fact file (5) considered the added value of including CRP as a factor with the Framingham score. The review stated that "CRP levels had little impact for patients shown to be at high (2% per annum) or low (< 1% per annum) risk of CHD by the conventional Framingham score. For those at intermediate (1- 2% per annum) risk, measuring CRP level could in theory help to stratify risk further. However, the usefulness of this approach has not yet been clearly shown.."
• statin use and reduction of CRP
  • use of intensive statin therapy leads to a lower CRP level independent of the presence of single or multiple cardiovascular risk factors (6)
  • even among patients receiving intensive statin therapy, a lower CRP level was observed in patients with the fewest coronary risk factors present, suggesting that control of multiple risk factors may be a means to further achieve lower CRP levels (6)
  • the use of rosuvastatin in the JUPITER study (7) revealed the benefits of reducing cardiovascular risk in patients with relatively low LDL but increased levels of CRP:
    • entry criterion of a low-density lipoprotein (LDL) cholesterol level of less than 130 mg per decilitre (3.4 mmol per litre) is below the currently recommended threshold for initiating pharmacologic treatment for primary prevention, although treatment at this level is indicated in patients who have clinical coronary disease or diabetes
    • in JUPITER, a high-sensitivity C-reactive protein level of 2.0 mg per litre or higher was an additional entry criterion to identify higher-risk subjects
    • trial of nearly 18,000 patients was stopped, with only 1.9 of its proposed 4 years of follow-up concluded, when the data and safety monitoring board noted a significant reduction in the primary end point among participants assigned to receive rosuvastatin (142 primary events, vs. 251 in the placebo group; hazard ratio, 0.56; 95% confidence interval [CI], 0.46 to 0.69)

Note - in patients diagnosed with cardiovascular disease, increased CRP levels independently associate with a heightened risk of both heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). (8)

Reference:

1. N Engl J Med 2002 Nov 14;347(20):1557-65
2. Circulation 2002 Jun 4;105(22):2595-9
3. Arch Intern Med. 2005 Oct 10;165(18):2063-8.
4. Arch Intern Med. 2005 Nov 28;165(21):2473-8.
5. BHF Factfile (February 2007). Novel Risk Factors and the prediction of Coronary Heart Diseas Risk
6. Ray KK et al. Relationship between uncontrolled risk factors and C-reactive protein levels in patients receiving standard or intensive statin therapy for acute coronary syndromes in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol. 2005 Oct 18;46(8):1417-24.
7. Ridker PM et al. and the JUPITER Study Group Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein NEJM 2008
8. Burger PM et al. UCC-SMART study group. C-Reactive Protein and Risk of Incident Heart Failure in Patients With Cardiovascular Disease. J Am Coll Cardiol. 2023 Aug 01;82(5):414-426.