C-REACTIVE PROTEIN, FIBRINOGEN, AND CARDIOVASCULAR DISEASE PREDICTION By Patrick Whitledge PA-S2 South University Physician Assistant Program

Funding Funding for this research project was provided by the British Heart Foundation, The UK Medical Research Council and GlaxoSmithKline

Background Currently there is a debate among the medical community about the value of assessing levels of c-reactive protein and other biomarkers of inflammation for the prediction of first cardiovascular events.

Current ATP III Risk Factors

Physiology C-reactive protein is not normally found in the blood of healthy people. It appears after an injury, infection, or inflammation and disappears when the injury heals or the infection or inflammation goes away. The amount of CRP produced by the body varies from person to person, and this difference is affected by an individual's genetic makeup and lifestyle. Higher CRP levels tend to be found in individuals who smoke, have high blood pressure, are overweight and do not exercise. Atherosclerosis is considered in many ways an inflammatory disorder of the blood vessels resulting in the release of CRP from the liver.

Methods Data was analyzed from 52 prospective studies, which included 246,669 participants without a known history of cardiovascular disease, to see if adding CRP or fibrinogen levels to conventional risk factors could better predict cardiovascular risk.

Methods Inclusion Criteria for prospective studies: No history of cardiovascular disease in participants A baseline CRP, fibrinogen, or both had been obtained prior to the start of the study. Complete information on participants age, sex, smoking status, history of diabetes, total and HDL cholesterol levels must have been collected.

Statistical Analysis For all analyses, values of CRP were log-transformed. The main outcome was a first cardiovascular event, defined as a MI, fatal CAD, or stroke. Prognostic models were compared with use of measures of discrimination. (They used a c-index and a d-measure, both of which quantify the degree to which a model can predict the order of disease events.)

Characteristics of the Study Participants The mean age was 61 +/- 9yrs 56% of participants were male 57% of participants were from Western Europe 34% were from North America CRP levels were available for 166,596 participants Among that 166,596 participants, 13,568 experienced a cardiovascular event.

Characteristics of the Study Participants Fibrinogen levels were available for 185,892 participants among who there were 12,021 first cardiovascular event. Info of both CRP and Fibrinogen levels were available for 95,733 participants.

Results When information on a biomarker of inflammation was used has a prognostic indicator the C-index was increased by with CRP levels and with fibrinogen levels yielding a net reclassification improvement of 1.52% and 0.83%, respectively for the predicted 10 year risk categories of low ( 20%). It was also observed that use of information on CRP and fibrinogen improved cardiovascular risk discrimination in men but not women. CRP was also found to have a greater predictive value in current smokers then nonsmokers.

Potential for Disease Prevention The researchers modeled a population of 100,000 adults age 40 and up and with similar characteristics of the population found in the 52 cohort studies. Of the 100,000 people, 15,025 people would be classified as being in the intermediate risk category for having a cardiovascular event in the next 10 years when using current risk factors.

Potential for Disease Prevention According to current treatment guidelines of the 15,025 adults 13,199 would not be eligible for statin treatment. Adding assessment of CRP levels in these remaining 13,199 patients would cause 690 of them to be eligible for statin therapy and of that 690, 151 pts would have a cardiovascular event in the next 10 years. Thus, in accordance with the ATP III criteria, such targeted assessment of CRP could help prevent about 30 additional cardiovascular events over a 10yr period.

Final Argument Assessment of CRP in people with a intermediate risk for cardiovascular event could help prevent one additional event for every 440 people screened. However a exploratory analysis suggested that these biomarkers only improved risk analysis for men.