C-reactive protein, fibrinogen, and cardiovascular disease prediction

Abstract

Background: There is debate about the value of assessing levels of C-reactive protein (CRP) and other biomarkers of inflammation for the prediction of first cardiovascular events.

Methods: We analyzed data from 52 prospective studies that included 246,669 participants without a history of cardiovascular disease to investigate the value of adding CRP or fibrinogen levels to conventional risk factors for the prediction of cardiovascular risk. We calculated measures of discrimination and reclassification during follow-up and modeled the clinical implications of initiation of statin therapy after the assessment of CRP or fibrinogen.

Results: The addition of information on high-density lipoprotein cholesterol to a prognostic model for cardiovascular disease that included age, sex, smoking status, blood pressure, history of diabetes, and total cholesterol level increased the C-index, a measure of risk discrimination, by 0.0050. The further addition to this model of information on CRP or fibrinogen increased the C-index by 0.0039 and 0.0027, respectively (P<0.001), and yielded a net reclassification improvement of 1.52% and 0.83%, respectively, for the predicted 10-year risk categories of "low" (<10%), "intermediate" (10% to <20%), and "high" (≥20%) (P<0.02 for both comparisons). We estimated that among 100,000 adults 40 years of age or older, 15,025 persons would initially be classified as being at intermediate risk for a cardiovascular event if conventional risk factors alone were used to calculate risk. Assuming that statin therapy would be initiated in accordance with Adult Treatment Panel III guidelines (i.e., for persons with a predicted risk of ≥20% and for those with certain other risk factors, such as diabetes, irrespective of their 10-year predicted risk), additional targeted assessment of CRP or fibrinogen levels in the 13,199 remaining participants at intermediate risk could help prevent approximately 30 additional cardiovascular events over the course of 10 years.

Conclusions: In a study of people without known cardiovascular disease, we estimated that under current treatment guidelines, assessment of the CRP or fibrinogen level in people at intermediate risk for a cardiovascular event could help prevent one additional event over a period of 10 years for every 400 to 500 people screened. (Funded by the British Heart Foundation and others.).

Figure 1. Changes in the C-Index after the Addition of Information on Lipid Markers and C-Reactive Protein or Fibrinogen to a Non–Lipid-Based Model

The nonlipid model denotes a risk score that includes information on age, systolic blood pressure, smoking status, and diabetes status, stratified according to sex. CI denotes confidence interval, CRP C-reactive protein, and HDL high-density lipoprotein.

Figure 2. Changes in the C-Index with the Addition of Information on C-Reactive Protein or Fibrinogen to a Model with Conventional Risk Factors, According to Subgroup

P values are for differences in the C-index changes across subgroups. Error bars indicate 95% confidence intervals. For each comparison, only studies with information on all subgroup levels were used (hence, subgroup total numbers do not always equal overall total numbers). Since not all the contributing studies had complete information across all subgroup levels, comparisons across subgroups (e.g., men vs. smokers) may not be reliable owing to between-study differences. “Predicted 10-year CVD risk” refers to the predicted 10-year risk of cardiovascular disease events calculated on the basis of the 2008 version of the Framingham risk score.

Figure 3. Modeling of Reclassification per 100,000 Persons Initially Screened for Conventional Risk Factors Only and Then Screened for C-Reactive Protein or Fibrinogen

Reclassification was based on observed data from participants with complete information on conventional risk factors and CRP levels (72,574 participants in 22 studies) or fibrinogen levels (83,061 participants in 27 studies). Adult Treatment Panel (ATP) III guidelines recommend treatment in only 1826 of these people (e.g., persons with diabetes) in the intermediate risk group, leaving 13,199 people in this group currently ineligible for treatment with statins. Details of the modeling are available in the Supplementary Appendix. CVD denotes cardiovascular disease.