C-Reactive Protein Hits the Big Time

Abstract & Commentary

Synopsis: Elevated CRP levels are associated with inducible ischemia in patients with stable coronary disease, particularly among those not treated with beta-blockers or statins.

Source: Beattie MS, et al. Circulation. 2003;107:245-250.

There has been a drum roll of reports over the past several years regarding high-sensitivity c-reactive protein (hs-CRP) in the evaluation of primary and secondary cardiovascular prevention. Driven by the remarkable output of reports from Paul Ridker, MD, of the Brigham and Women’s Hospital at Harvard, many data indicate that measurement of this stable protein should be of use in the risk assessment of patients with and without coronary artery disease (CAD). Many studies have indicated that hs-CRP levels are independently predictive of CAD events in diverse patient populations and in apparently healthy individuals. The robust hs-CRP data have been highly consistent in relating an elevated level to subsequent cardiovascular events.

A recent report from Circulation correlates the elevation with exercise-induced ischemia. In the same issue, there is a study suggesting that statins reduce cardiovascular deaths in those with high CRPs and positive serology for cytomegalic virus.1 Two important studies from Ridker’s group include a long-term evaluation of women with metabolic syndrome, where CRP measurement "adds clinically important prognostic information," indicating an interaction between inflammatory markers and outcome in individuals who meet the criteria for this high-risk condition.2 In another important observation, a study of 28,000 healthy subjects in the Women’s Health Study with a mean 8-year follow-up, CRP levels were predictive of vascular events, even more so than LDL cholesterol.3 Furthermore, the data suggest that women who had a below-median LDL level and an elevated CRP (> 3 mg/L) had a greater hazard than an elevated LDL without an elevation of CRP. The combination of a high CRP and high LDL had the worst outcome, whereas a low LDL and low CRP (< 1 mg/L) had the best prognosis.

In Ridker’s expert opinion mini-review, he concludes that CRP levels should be part and parcel of everyday practice. In healthy populations, "the primary use of CRP should be at the time of cholesterol screening . . . as an adjunct of global risk assessment."4 He suggests that low and intermediate levels of LDL cholesterol and an elevated CRP increase the long-term risk of healthy individuals, and this should influence the aggressiveness of risk factor interventions, including lifestyle changes, as well as pharmacotherapy. He suggests an alternative approach to only measure CRP in individuals felt to be at an intermediate risk (eg, 5-20% cardiac event 10-year Framingham Risk Score). He reports on increasing use of CRP measurements in the emergency room setting in individuals with chest pain syndromes and negative troponin, citing literature evidence that an elevated CRP in such an environment is associated with an increased risk of events.

In the same issue of Circulation, an important Task Force report from the AHA/CDC workshop on Inflammatory Markers and Cardiovascular Disease—Applications to Clinical and Public Health Practice was published.5 This workshop was held almost 1 year ago, focusing on inflammatory markers and cardiovascular disease and dealing with a wide variety of issues in this emerging area. The new document reports the major findings and conclusions of the workshop with more information coming in future publications. A writing group of the workshop members reviewed the evidence that inflammation is a key pathophysiologic phenomenon in atherosclerosis, and they reviewed the vascular aspects of this process, which involves activation of cytokines and other bioactive substances related to inflammation at all levels of the atherogenic process. While there are a wide variety of pro-inflammatory risk factors that can be measured, the Task Force concluded that hs-CRP is "far and away the best and the most reliable substance that can be used outside of the research laboratory." They go on to ask whether CRP is a risk marker or risk factor; they reach no conclusion. However, it seems clear from data in the literature that an elevated CRP is an active factor increasing vascular events. The Task Force concludes that there is a risk increase of 2-fold in individuals for major coronary events in populations that are at the highest tertile of CRP levels (> 3 mg/L).

They cite a "dose-response relationship between the level of hs-CRP and the risk of incident heart disease," and emphasize that there are data that suggest a relationship between the inflammatory marker and sudden death and peripheral arterial disease and that hs-CRP levels are predictive in men and women, in the elderly as well as the young. It should be pointed out that ethnic minorities, particularly blacks, are not well represented in the overall CRP database, and more research needs to be done in these individuals. The Task Force lists a variety of CVD events and death that are associated with elevated CRP, including unstable angina and acute myocardial infarction. A high CRP may be a marker for restenosis following PCI and may predict stroke. Increased body weight and the metabolic syndrome are associated with an increased CRP, as are some of the classic CAD risk factors, including hypertension, cigarette smoking, metabolic syndrome, diabetes, female hormonal state, and chronic infections and inflammatory processes. There is ample evidence to recommend obtaining a hs-CRP as a marker of risk in individuals at intermediate risk by global assessment (ie, 10-20% risk of CAD over a 10-year period). This approach has been given a IIa rating. The group report recommends that individuals with stable or unstable coronary syndromes might benefit from measurements of hs-CRP as an "independent marker of prognosis for recurrent events, including death and MI, and restenosis after PCI." Last, they stress that the CRP measurements in patients with established vascular disease may not have significant clinical value in terms of choice of therapy, other than by perhaps underscoring a more aggressive approach to risk factor modification.

The Task Force recommends obtaining 2 CRP measurements, similar to cholesterol guidelines, to make sure that individuals do not have a systemic inflammatory condition, trauma, or active infection. They stress that levels > 10 mg/L should be disregarded and to look for nonvascular infection or inflammation in such individuals. In clinical practice, CRP should be best used to assist risk assessment in individuals being considered for lipid-lowering, antiplatelet, or other drug therapies, as well as recommendations for an enhanced emphasis on lifestyle modifications. Several studies suggest that patients with elevated hs-CRP vs normal levels may enjoy a greater actual risk reduction from targeted pharmacotherapy, including aspirin and statins. "The writing group endorses the optional use of hs-CRP to identify patients without known CVD who may be at higher absolute risk than estimated by major risk factors, specifically, those with an intermediate 10-20% 10-year CAD risk." They emphasize that traditional cardiovascular risk factors must be assessed prior to hs-CRP determination, which they accept as "an independent predictor of increased coronary risk." Also, the writing group concurs with Ridker that the use of CRP testing in individuals with established vascular disease is uncertain and at the present time does not seem to be of obvious benefit. Finally, the writing group cites the "striking lack of level A evidence" related to randomized clinical trials supporting CRP data.

Comment by Jonathan Abrams, MD

While many questions remain, it appears that CRP has finally broken through the prevention community barrier against recommending this test for screening. However, the writing group "recommends against screening of the entire adult population," rather using the assay "as an adjunct to the major risk factors to further assess absolute risk for coronary disease primary prevention." Tightening of pharmacotherapy and enhancement of motivation are clearly major benefits derived from defining an individual at a high risk because of a CRP > 3 mg/L. The Task Force recommends the use of hs-CRP testing, albeit with a number of stipulations. Physicians should be certain that their hospital or laboratory uses one of the accredited devices; the cost, however, should be low, and the stability of the measurements are quite good, with relatively modest intra-individual variation over time. Finally, it behooves the physician to remember that what is being measured is one of a variety of inflammatory markers and to keep in mind that a low CRP value indicates little to no inflammation, whereas a high value (ie, > 3 mg/L) clearly indicates an ongoing inflammatory process, whether it be in the coronary arterial circulation, aorta, or elsewhere. Such observations should trigger extremely aggressive and sustained risk modification approachs to such individuals.

References

1. Horne BD, et al. Circulation. 2003;107:258-263.

2. Ridker PM, et al. Circulation. 2003;107:391-397.

3. Ridker PM, et al. N Engl J Med. 2002;347:1557-1565.

4. Ridker PM. Circulation. 2003;107:363-369.

5. Pearson TA, et al. Circulation. 2003;107:499-511.

Recommended Reading

1. Libby P. Atherosclerosis: The New View. Scientific American. 2002;286:46.

Dr. Abrams is Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque, NM.