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High-sensitivity C-reactive protein and cardiac C-reactive protein assays: is there a need to differentiate?

Recent evidence has shown that inflammation plays a pivotal role in the inception and progression of atherosclerosis, and population studies have demonstrated a strong and independent association between baseline concentrations of inflammatory biomarkers and future coronary events. Because the majority of individuals who develop coronary events are not in a high-risk group according to the Framingham risk assessment of traditional risk factors for coronary heart disease (CHD) [6] and because one half of those who suffer myocardial infarctions have normal lipid values, measurement of inflammatory markers has been suggested as an adjunct to lipid testing to better identify individuals at increased risk (1). Of the inflammatory markers evaluated by a CDC and American Heart Association (AHA) Panel in 2002 (2,3), only C-reactive protein (CRP) met the analytical requirements for outpatient clinical use and, therefore, has been studied intensely over the past decade.

More than 25 prospective epidemiologic studies have shown that CRP is a strong and independent predictor of future myocardial infarction, ischemic stroke, peripheral arterial disease, and sudden cardiac death in apparently healthy men and women (4). Furthermore, 9 studies to date have demonstrated that CRP provides additional prognostic value to the Framingham Risk Score (4). Guidelines regarding the potential usefulness of CRP in primary and secondary prevention settings have been issued by the CDC and AHA (2). Physicians have become accustomed to use of the "high-sensitivity CRP (hsCRP)" terminology when considering measurement of CRP for vascular disease risk stratification, as opposed to the use of standard CRP assays that monitor infections and other inflammatory conditions.

To assess CHD risk, CRP must be measured by highly sensitive methods (hsCRP) that are capable of reliably measuring concentrations within the healthy reference interval. Currently, more than 30 such methods are available world-wide, many of which have been cleared by the US Food and Drug Administration (FDA). On September 22, 2005, the FDA issued new guidelines for industry and FDA staff regarding this analyte, entitled Review Criteria for Assessment of C-Reactive Protein (CRP), High Sensitivity C-Reactive Protein (hsCRP) and Cardiac C-Reactive Protein (cCRP) Assays (5). As the title of the document indicates, the FDA introduced a new category or classification for this analyte, "cardiac CRP (cCRP)".

For the reasons articulated below, we believe that such a step is unnecessary and may cause confusion.

* The expected performance criteria of hsCRP and cCRP methods are identical. Therefore, analytically, there is no valid rationale to create 2 different names for the same assay, because it may be used for more than 1 clinical application.

* The new FDA guidelines stipulate that cCRP assays should be standardized to Certified Reference Material 470, whereas the hsCRP assays, at minimum, should be traceable to Certified Reference Material 470. Fundamentally, there is no difference between standardizing an assay to a standard material and establishing traceability to a standard material; therefore, this distinction does not lead to a higher degree of accuracy for the proposed cCRP assays. This stipulation is also moot because the providers of all 28 hsCRP methods evaluated in the CDC standardization survey claim to use Certified Reference Material 470 to calibrate their methods (6).

* When hsCRP methods were first introduced, the FDA required demonstration of comparability of the new assays to a predicate device, in this case the Dade Behring assay. Such a step was absolutely necessary at the time to demonstrate the ability of the new assays to perform adequately at low CRP concentrations and to assure comparability among the high-sensitivity methods (7,8). However, according to the new guidelines, any manufacturer of an existing hsCRP reagent that seeks to have its assay labeled as cCRP must perform a "bridging study". This entails a repeat of the method-comparison study with the Dade Behring assay, for example, which is now also labeled as cCRP. According to the FDA, this action will ensure that the 2 methods are clinically comparable. It is unclear how such a step will lead to improvement of performance, considering that neither of the 2 methods has changed analytically. Furthermore, these additional studies will burden the manufacturers, and eventually the healthcare system, with unnecessary cost.

* The introduction of the term cCRP and its defined use are not only unnecessary but unclear. The regulation stipulates that hsCRP be used in "the evaluation of conditions thought to be associated with inflammation in otherwise healthy individuals", whereas cCRP is to be used "as an aid in the identification and stratification of individuals at risk for future cardiovascular disease. When used in conjunction with traditional clinical laboratory evaluation of acute coronary syndromes, cCRP may be useful as an independent marker of prognosis for recurrent events in patients with stable coronary disease or acute coronary syndrome" (5). These statements could be construed to mean that hsCRP should be used in assessing CHD risk in the primary prevention setting because atherosclerosis is a condition associated with inflammation, whereas cCRP should be used in risk stratification in the secondary prevention setting, in patients with acute coronary syndromes. Another potential interpretation of these rules is that hsCRP should be used in conditions other than cardiovascular disease, where overt infection or inflammation is absent, whereas cCRP should be used in risk assessment of heart disease. By this definition, it is unclear what the future usefulness of hsCRP might be. One can only imagine the potential confusion among clinicians over which of these 2 assays to choose for the same analyte.

* Another potentially confusing issue is the fact that the term "cardiac CRP", proposed by the FDA, is very similar to the trademarked term used by Quest Diagnostics, "cardio CRPnm", for their hsCRP assay. We believe the use of such a term by the FDA will inadvertently appear to be an endorsement by the agency of one particular assay, a stance we believe inconsistent with agency policy and one likely to further confuse the clinical community.

Although we disagree with the premise of the FDA guidelines, we applaud the agency for requesting that all CRP results, regardless of the assay used, should be reported in milligrams per liter. This recommendation is consistent with the earlier CDC/AHA guidelines (2,3).

Introducing these regulatory changes for hsCRP at this time, for no apparent gain in quality of testing, is unwarranted. It is important to note that considerable efforts have been made, on the part of the federal government and various national organizations, to educate clinicians and laboratorians about the differences between the traditional CRP and hsCRP methods and about their clinical utility. Furthermore, most publications about the utility of CRP in risk prediction of cardiovascular disease have used the term hsCRP. To our knowledge, none have used cCRP.

We hope that the FDA will reverse its action and join the other federal agencies and national scientific organizations in educating the medical and laboratory communities about the potential usefulness of hsCRP in the prediction of cardiovascular disease. The most important issue regarding hsCRP has been confusion among clinicians as to the difference between older methods of CRP evaluation and the newer hsCRP methods required for cardiovascular risk detection. We urge the FDA to help the clinical chemistry community achieve consistency in the use of these terms rather than create an even greater confusion for practicing physicians.

Christie M. Ballantyne has received grant and research support from AstraZeneca, diaDexus, Gene Logic, GlaxoSmithKline, Integrated Therapeutics, Kos, Merck, Novartis, Pfizer, Reliant, Sankyo Pharma, Schering-Plough, and Sanofi-Synthelabo. Dr. Ballantyne is also a consultant for AstraZeneca, Bayer, Merck, Novartis, Pfizer, Reliant, Schering-Plough and Sanofi-Synthelabo, and serves on the Speakers Bureau for AstraZeneca, Kos, Merck, Pfizer, Reliant, and Schering-Plough..

References

(1.) Khot UN, Khot MB, Bajzer CT, Sapp SK, Ohman EM, Brener SJ, et al. Prevalence of conventional risk factors in patients with coronary heart disease. JAMA 2003;290:898-904.

(2.) Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO III, Criqui M, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003;107:499-511.

(3.) Myers GL, Rifai N, Tracy RP, Roberts WL, Alexander RW, Biasucci LM, et al. CDC/AHA workshop on markers of inflammation and cardiovascular disease: application to clinical and public health practice: report from the laboratory science discussion group. Circulation 2004;110:e545-9.

(4.) Ridker PM, Wilson PW, Grundy SM. Should C-reactive protein be added to metabolic syndrome and to assessment of global cardiovascular risk? Circulation 2004;109:2818-25.

(5.) US Food and Drug Administration. Review criteria for assessment of C-reactive protein (CRP), high sensitivity C-reactive protein, and cardiac C-reactive protein (cCRP) assays. 2005. http://www.fda. gov/cdrh/oivd/guidance/1246.pdf (accessed November 2005).

(6.) Kimberly MM, Vesper HW, Caudill SP, Cooper GR, Rifai N, Dati F, et al. Standardization of immunoassays for measurement of high-sensitivity C-reactive protein: phase I: evaluation of secondary reference materials. Clin Chem 2003;49:611-6.

(7.) Roberts WL, Sedrick R, Moulton L, Spencer A, Rifai N. Evaluation of four automated high-sensitivity C-reactive protein methods: implications for clinical and epidemiological applications. Clin Chem 2000;46:461-8.

(8.) Roberts WL, Moulton L, Law TC, Farrow G, Cooper-Anderson M, Savory J, et al. Evaluation of nine automated high-sensitivity C-reactive protein methods: implications for clinical and epidemiological applications: part 2. Clin Chem 2001;47:418-25.

NADER RIFAI, [1] * CHRISTIE M. BALLANTYNE, [2] MARY CUSHMAN, [3] DANIEL LEVY, [4] ([dagger]) and GARY L. MYERS [5] ([dagger])

[1] Children's Hospital and Harvard Medical School, Boston, MA.

[2] Baylor College of Medicine, Houston TX.

[3] University of Vermont, Burlington, VT.

[4] Framingham Heart Study, Framingham, MA.

[5] Centers for Disease Control and Prevention, Atlanta, GA.

[6] Nonstandard abbreviations: CHD, coronary heart disease; AHA, American Heart Association; CRP, C-reactive protein; hsCRP, high-sensitivity CRP; FDA, US Food and Drug Administration; and cCRP, cardiac CRP.

* Address correspondence to this author at: Department of Laboratory Medicine, Children's Hospital, 300 Longwood Ave., Boston, MA 02115. Fax 617-730-0383; e-mail nader.rifai@childrens.harvard.edu.

([dagger]) The findings and conclusions in this report are those of the authors) and do not necessarily represent the views of the Centers for Disease Control and Prevention or the National Institutes of Health.

Received March 28, 2006; accepted April 11, 2006.

DOI: 10.1373/clinchem.2006.070904
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No portion of this article can be reproduced without the express written permission from the copyright holder.
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Title Annotation:Point
Author:Rifai, Nader; Ballantyne, Christie M.; Cushman, Mary; Levy, Daniel; Myers, Gary L.
Publication:Clinical Chemistry
Date:Jul 1, 2006
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