David I. Buckley, MD, MPH; Rongwei Fu, PhD; Michele Freeman, MPH; Kevin Rogers, MD; Mark Helfand, MD, MPH
C-reactive protein (CRP) may help to refine global risk assessment for coronary heart disease (CHD), particularly among persons who are at intermediate risk on the basis of traditional risk factors alone.
To assist the U.S. Preventive Services Task Force (USPSTF) in determining whether CRP should be incorporated into guidelines for CHD risk assessment.
MEDLINE search of English-language articles (1966 to November 2007), supplemented by reference lists of reviews, pertinent studies, editorials, and Web sites and by expert suggestions.
Prospective cohort, caseâ€“cohort, and nested caseâ€“control studies relevant to the independent predictive ability of CRP when used in intermediate-risk persons.
Included studies were reviewed according to predefined criteria, and the quality of each study was rated.
The validity of the body of evidence and the net benefit or harm of using CRP for CHD risk assessment were evaluated. The combined magnitude of effect was determined by meta-analysis. The body of evidence is of good quality, consistency, and applicability. For good studies that adjusted for all Framingham risk variables, the summary estimate of relative risk for incident CHD was 1.58 (95% CI, 1.37 to 1.83) for CRP levels greater than 3.0 mg/L compared with levels less than 1.0 mg/L. Analyses from 4 large cohorts were consistent in finding evidence that including CRP improves risk stratification among initially intermediate-risk persons. C-reactive protein has desirable test characteristics, and good data exist on the prevalence of elevated CRP levels in intermediate-risk persons. Limited evidence links changes in CRP level to primary prevention of CHD events.
Study methods for measuring Framingham risk variables and other covariates varied. Ethnic and racial minority populations were poorly represented in most studies, limiting generalizability. Few studies directly assessed the effect of CRP on risk reclassification in intermediate-risk persons.
Strong evidence indicates that CRP is associated with CHD events. Moderate, consistent evidence suggests that adding CRP to risk prediction models among initially intermediate-risk persons improves risk stratification. However, sufficient evidence that reducing CRP levels prevents CHD events is lacking.
FRS = Framingham risk score.
* Number of participants included in the analysis.
CHD = coronary heart disease; CRP = C-reactive protein; CVD = cardiovascular disease.
* Number of cohorts included in the analysis.
† Framingham risk factors are based on reference 2.
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Nancy R. Cook
Brigham and Women's Hospital, Harvard Medical School, Boston, MA
October 17, 2009
Biomarker evaluation "“ the case for CRP
In their review Buckley et al (1) state that the utility of measuring CRP is uncertain and conclude that routine screening of CRP cannot be recommended. The reasoning behind this conclusion, however, appears flawed. First, since the literature review in 2007, additional papers have been published, particularly ones featuring risk reclassification including the Reynolds Risk Score for men (2) and the analysis of high- sensitivity CRP in the Framingham cohort (3). The latter work should replace the cited negative study from Framingham which did not use the high-sensitivity assay.
Second, the authors cite a lack of evidence that change in CRP directly links to prevention. Whether CRP is causal or not does not limit its use as a predictive marker. The same criterion has not been applied to other risk factors such as high-density lipoprotein (HDL) cholesterol, which has been well-accepted as a risk marker for decades. There is a notable lack of randomized trial data showing that raising HDL directly leads to the prevention of cardiovascular events (4).
Third, while the focus on risk reclassification is appreciated, this is not the most meaningful measure of a marker's value as stated. JUPITER presents stronger evidence, showing that those above and below a Framingham risk of 10% but with high CRP both experienced the same sizeable reduction in risk. Given these results, whether these individuals would be reclassified into a higher risk group seems moot for clinical utility and only relevant for cost-effectiveness analyses.
The authors should take note of a recent statement from the AHA regarding the evaluation of novel markers (5). This proposes phases, including case-control studies, prospective evaluation, and incremental value, all of which the USPSTF agrees are fulfilled by CRP. Additional phases are clinical utility, evaluating whether a novel marker changes predicted risk enough to change therapy. Risk reclassification suggests that this is true for CRP, comparable to well-accepted markers. A stronger criterion is whether use of the marker improves clinical outcomes, especially in randomized trials. JUPITER used CRP to identify individuals who would not otherwise be treated, and found a substantial reduction in cardiovascular events. A final question is whether the additional costs of testing and treatment are justified. The low cost of the test and the dramatic results of treatment should make this simple test worthwhile in avoiding cardiovascular events and perhaps saving lives.
1. Buckley DI, Fu R, Freeman M, Rogers K, Helfand M. C-reactive protein as a risk factor for coronary heart disease: A systematic review and meta-analyses for the U.S. Preventive Services Task Force. Ann Intern Med. 2009;151:483-95.
2. Ridker PM, Paynter NP, Rifai N, Gaziano JM, Cook NR. C-reactive protein and parental history improve global cardiovascular risk prediction: the Reynolds Risk Score for men. Circulation. 2008;118:2243- 51.
3. Wilson PWF, Pencina M, Jacques P, Selhub J, D'Agostino Sr R, O'Donnell CJ. C-reactive protein and reclassification of cardiovascular risk in the Framingham Heart Study. Circ Cardiovasc Qual Outcomes. 2008;1:92-97.
4. Pfeffer MA, Sacks FM. Leapfrogging data: No shortcuts for safety or efficacy information. Circulation. 2008;118:2491-4.
5. Hlatky MA, Greenland P, Arnett DK, et al. Criteria for evaluation of novel markers of cardiovascular risk: a scientific statement from the American Heart Association. Circulation. 2009;119:2408-16.
David I. Buckley
Oregon Evidence-based Practice Center; Oregon Health & Science University
January 11, 2010
The Authors Respond
Dr. Cook asserts that, in our systematic review and assessment of the body of evidence (1), we conclude that "routine screening of CRP cannot be recommended." This is incorrect. We made no recommendations about routine screening. Rather, we presented our findings to the US Preventive Services Task Force (USPSTF), which is solely responsible for USPSTF recommendations.
We found that CRP is associated with CHD events and adding CRP level to a global risk score among initially intermediate-risk persons reclassifies some patients. However, we found that the benefit of reclassifying patients in this manner is uncertain (1).
We agree that direct causality is not an essential criterion. We also agree that a marker's ability to improve clinical outcomes is better evidence of usefulness than its ability to improve risk classification; but we disagree about whether or not CRP meets this criterion. Reclassification means that CRP identifies some patients for more intensive treatment, and not others. Is it really a better way of selecting patients for more intensive treatment than alternatives? For example, would randomly selected intermediate-risk patients benefit as much from intensive statin therapy? A trial that compares CRP testing to no CRP testing, or one that compares treatment in patients with high CRP levels to patients with intermediate or low CRP, could answer this question.
JUPITER, a trial of high-dose statin treatment, did neither (2). It found that high-dose statin treatment improved CVD outcomes in subjects with an elevated CRP, but did not test the hypothesis that use of CRP improves outcomes compared with the alternative of intensifying therapy without a CRP test. JUPITER did not determine whether reclassification based on CRP might identify intermediate risk patients who are most likely to benefit from high dose statin therapy in addition to therapeutic lifestyle changes. For example, JUPITER excluded intermediate risk patients with LDL levels above 130 mg/dL, a group that might also be considered for intensifying therapy.
Cook suggests that we take note of the AHA statement regarding the evaluation of novel markers (3). While it uses different terminology, the AHA statement is consistent with the criteria we proposed to the USPSTF, in 2005, to assess CRP and other markers (4). In AHA terms, our review found that CRP meets the criteria at several evaluation phases, including "prospective validation, and incremental value." We also found it likely that CRP meets the next criterion, "corresponding to reclassification in our system." The AHA then calls for randomized trials of whether use of the marker improves clinical outcomes. As discussed above, CRP has not met this criterion. Finally, the AHA considers cost-effectiveness, which we did not evaluate in our review.
2. Hlatky MA. Expanding the orbit of primary prevention--moving beyond JUPITER. New England Journal of Medicine. 2008;359(21):2280-2.
3. Hlatky MA, Greenland P, Arnett DK, et al. Criteria for evaluation of novel markers of cardiovascular risk: a scientific statement from the American Heart Association. Circulation. 2009;119:2408-16.
4. Helfand M, Buckley DI, Freeman M, Fu R, Rogers K, Fleming C, Humphrey LL. Emerging risk factors for coronary heart disease: a summary of systematic reviews conducted for the U.S. Preventive Services Task Force. Ann Intern Med. 2009;151:496-507.
Buckley DI, Fu R, Freeman M, et al. C-Reactive Protein as a Risk Factor for Coronary Heart Disease: A Systematic Review and Meta-analyses for the U.S. Preventive Services Task Force. Ann Intern Med. 2009;151:483–495. doi: https://doi.org/10.7326/0003-4819-151-7-200910060-00009
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Published: Ann Intern Med. 2009;151(7):483-495.
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