The Reasons and Uses for C-Reactive Protein (CRP)
I've been reading a lot about how CRP is supposed to yield important information about cardiovascular risk in my patients. What exactly is CRP? How do I measure it and what does that measurement tell me? When should I consider measuring it? And finally, should I be measuring CRP to monitor patients with coronary artery disease?
Response from Christopher P. Cannon, MD
C-reactive protein (CRP) is actually an old marker that has undergone a renaissance in recent years as a window into the world of inflammation in cardiovascular disease. Hundreds of studies over the past decade have established vascular inflammation as a central part of the pathogenesis of coronary artery disease (CAD). Although multiple markers of inflammation have been evaluated -- including fibrinogen, serum amyloid A, and other novel markers -- the high-sensitivity assay for CRP has proven to provide the most reliable data that can be correlated with clinical outcomes.
CRP is an acute-phase protein produced by the liver in response to various cytokines, including interleukin (IL)-6, IL-1 and tumor necrosis factor (TNF)-alpha during acute injury, infections, inflammatory stimuli, and malignant disease. The studies investigating the role of CRP as a risk factor for CAD have made use of a high-sensitivity CRP (hsCRP) assay that detects levels of CRP that had been considered normal in the past, but may indicate chronic low levels of inflammation.
The hsCRP assay is widely available in almost any commercial or hospital laboratory. There are several different manufacturers of the test, but, basically, any of the hsCRP assays are reliable and have been approved by the US Food and Drug Administration.
Numerous prospective epidemiologic studies have shown that hsCRP is a predictor of cardiovascular risk, independent of whatever other parameter you are measuring. Furthermore, when hsCRP levels are added to the results of calculating plasma lipid levels and the Framingham Risk Score, the accuracy of the prediction increases.
The most recent American Heart Association (AHA) consensus statement recommended that hsCRP be used as an emerging risk factor to further stratify patients who are at intermediate risk according to the Framingham global risk stratification tool -- meaning they are calculated to have a 10% to 20% 10-year risk of having a cardiovascular event. The panel suggested the following cutpoints for CRP levels:
However, the same guidelines stated that they did not have evidence, as of January 2003, for recommending measurement of hsCRP in the entire population.
Thus, if your patient falls in the "intermediate-risk" category according to the Framingham risk score and the CRP is > 3 mg/L, he or she can be judged have to a higher level of risk -- and this means, I believe, that the patient would qualify for more aggressive treatment.
"More aggressive treatment" begins, of course, with seriously urging patients to achieve aggressive diet, exercise, and lifestyle changes. Unfortunately, we all know that in real practice this is difficult to achieve in almost any patient who presents with this level of CAD risk.
Thus, it is good that statins have been shown to lower levels of hsCRP, and, of course, these patients should almost certainly be on a statin even before their CRP levels are considered. Of interest, a primary prevention clinical outcomes trial is under way to examine the benefits of statin therapy for patients with elevated hsCRP, but average or normal levels of low-density lipoprotein (LDL) cholesterol, who would not currently meet the criteria of the third report of the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP III) for treatment with LDL-lowering medications.
Another intriguing use of the hsCRP assay is for potentially monitoring patients' response to risk factor modification. In the Pravastatin or Atorvastatin Evaluation and Infection Therapy -- Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial, we found that for post-acute coronary syndrome patients who were uncontrolled on medication, the more risk factors they had, the higher their level of CRP (Figure). As a result we suggested the CRP could be seen as a global barometer of risk. This leads to the intriguing possibility that one could monitor CRP in patients and increase the intensity of their risk factor management if the CRP were not fully controlled.
(Enlarge Image)
Achieved CRP on statin therapy vs number of uncontrolled risk factors. BMI = body mass index; BP = blood pressure; CRP = C-reactive protein; HDL = high-density lipoprotein; LDL = low-density lipoprotein; TG = triglyceride
I am just starting to do this in selected patients. Further data are needed to evaluate this new paradigm of treatment monitoring, of course, and at best this would only aim to complement all of our standard risk factor management - but, nevertheless, this might be an additional tool to ensure we are getting the best possible treatment for our patients.
I've been reading a lot about how CRP is supposed to yield important information about cardiovascular risk in my patients. What exactly is CRP? How do I measure it and what does that measurement tell me? When should I consider measuring it? And finally, should I be measuring CRP to monitor patients with coronary artery disease?
Response from Christopher P. Cannon, MD
C-reactive protein (CRP) is actually an old marker that has undergone a renaissance in recent years as a window into the world of inflammation in cardiovascular disease. Hundreds of studies over the past decade have established vascular inflammation as a central part of the pathogenesis of coronary artery disease (CAD). Although multiple markers of inflammation have been evaluated -- including fibrinogen, serum amyloid A, and other novel markers -- the high-sensitivity assay for CRP has proven to provide the most reliable data that can be correlated with clinical outcomes.
CRP is an acute-phase protein produced by the liver in response to various cytokines, including interleukin (IL)-6, IL-1 and tumor necrosis factor (TNF)-alpha during acute injury, infections, inflammatory stimuli, and malignant disease. The studies investigating the role of CRP as a risk factor for CAD have made use of a high-sensitivity CRP (hsCRP) assay that detects levels of CRP that had been considered normal in the past, but may indicate chronic low levels of inflammation.
The hsCRP assay is widely available in almost any commercial or hospital laboratory. There are several different manufacturers of the test, but, basically, any of the hsCRP assays are reliable and have been approved by the US Food and Drug Administration.
Numerous prospective epidemiologic studies have shown that hsCRP is a predictor of cardiovascular risk, independent of whatever other parameter you are measuring. Furthermore, when hsCRP levels are added to the results of calculating plasma lipid levels and the Framingham Risk Score, the accuracy of the prediction increases.
The most recent American Heart Association (AHA) consensus statement recommended that hsCRP be used as an emerging risk factor to further stratify patients who are at intermediate risk according to the Framingham global risk stratification tool -- meaning they are calculated to have a 10% to 20% 10-year risk of having a cardiovascular event. The panel suggested the following cutpoints for CRP levels:
low risk (< 1.0 mg/L)
average risk (1.0-3.0 mg/L)
high risk (> 3.0 mg/L)
However, the same guidelines stated that they did not have evidence, as of January 2003, for recommending measurement of hsCRP in the entire population.
Thus, if your patient falls in the "intermediate-risk" category according to the Framingham risk score and the CRP is > 3 mg/L, he or she can be judged have to a higher level of risk -- and this means, I believe, that the patient would qualify for more aggressive treatment.
"More aggressive treatment" begins, of course, with seriously urging patients to achieve aggressive diet, exercise, and lifestyle changes. Unfortunately, we all know that in real practice this is difficult to achieve in almost any patient who presents with this level of CAD risk.
Thus, it is good that statins have been shown to lower levels of hsCRP, and, of course, these patients should almost certainly be on a statin even before their CRP levels are considered. Of interest, a primary prevention clinical outcomes trial is under way to examine the benefits of statin therapy for patients with elevated hsCRP, but average or normal levels of low-density lipoprotein (LDL) cholesterol, who would not currently meet the criteria of the third report of the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP III) for treatment with LDL-lowering medications.
Another intriguing use of the hsCRP assay is for potentially monitoring patients' response to risk factor modification. In the Pravastatin or Atorvastatin Evaluation and Infection Therapy -- Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial, we found that for post-acute coronary syndrome patients who were uncontrolled on medication, the more risk factors they had, the higher their level of CRP (Figure). As a result we suggested the CRP could be seen as a global barometer of risk. This leads to the intriguing possibility that one could monitor CRP in patients and increase the intensity of their risk factor management if the CRP were not fully controlled.
(Enlarge Image)
Achieved CRP on statin therapy vs number of uncontrolled risk factors. BMI = body mass index; BP = blood pressure; CRP = C-reactive protein; HDL = high-density lipoprotein; LDL = low-density lipoprotein; TG = triglyceride
I am just starting to do this in selected patients. Further data are needed to evaluate this new paradigm of treatment monitoring, of course, and at best this would only aim to complement all of our standard risk factor management - but, nevertheless, this might be an additional tool to ensure we are getting the best possible treatment for our patients.
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