January 27, 2005
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In This Issue . . .

CRP Watch: Pondering Predictability
A look at current controversies surrounding hs-CRP testing.


CRP Watch: Pondering Predictability

While research on the prognostic power of C-reactive protein (CRP) continues to grow, several clinical lab professionals are sounding alarm bells, warning that the test’s nonspecificity hampers its potential benefits. In addition, those criticizing calls for widespread testing insist that there’s still no solid evidence showing that lowering CRP levels actually lowers the risk of a coronary event. This month, Strategies examines some of the questions surrounding the clinical value of CRP testing.

In recent years, CRP has emerged as a key biomarker for cardiovascular disease risk; one that is particularly helpful for evaluating patients who do not exhibit tell-tale signs of coronary heart disease (CHD) such as hypertension, obesity, smoking, and high cholesterol. Using high-sensitivity assays to measure CRP at levels < 10 mg/L provides a window into the patient’s inflammatory state, since the level of this protein rises as inflammation increases, indicating plaque build-up along the arterial walls. These accumulating plaques can rupture, leading to a heart attack or stroke.

“For many years atherosclerosis has been thought of as just a disease of lipids and a blockage of arteries,” said Nader Rifai, PhD, Professor of Pathology at Harvard Medical School and Director of the Clinical Chemistry Laboratory at Children's Hospital in Boston, Mass. “But this did not really explain why certain people who have small plaques remain stable in comparison to others with bigger plaques. The plaque stability is related to the inflammatory state of the area, and being an inflammatory marker, CRP is a good indicator of the likelihood of a plaque rupturing and causing a clinical event.”

But there are other possible explanations for elevated CRP levels, which according to Stanley Levinson, PhD, Professor of Pathology and Laboratory Medicine at the University of Louisville, Ky., make the test non-specific for heart disease. Acute infections, chronic diseases, hormone replacement therapy (HRT), age, obesity, and atrial arrhythmias can all cause increased CRP levels. While many of these factors—including HRT—can bump up the risk of heart disease, most are treatable, insisted Levinson. “Diabetes by control of blood sugar, obesity by weight reduction, smoking by cessation, and lipids by lipid-altering drugs,” he explained. “Whether or not identifying elevated CRP levels…will yield an effective way to determine who should be treated is unclear and can only be determined by randomized prospective studies.”

What are the Right Intervals?

In addition to the question of specificity, the interval algorithms for CRP used in different studies to evaluate CHD risk have also been questioned. Patients’ CRP levels are currently assessed according to three risk categories: low (<1.0 mg/L), moderate (1.0–3.0 mg/L) and high (>3.0 mg/L), based on guidelines from the American Heart Association and the Centers for Disease Control and Prevention (CDC). More recently, however, Rifai and Paul Ridker, MD, MPH, of Boston’s Center for Cardiovascular Disease Prevention looked at CHD risk in women and their CRP levels in 10 intervals (Circulation 2004; 109: 1955–9). In an opinion piece published last year in Clinical Chemistry, Levinson, et al., took issue with Ridker and Rifai’s study, in part because their results showed no practical difference between CRP concentrations of 0.64 (low risk) and 7.73 mg/L (high risk). These ranges translate into risk ratios of 1.7 and 1.9, respectively, and are therefore not different from a clinical perspective.

Another study published last year in Clinical Chemistry also looked at CRP concentrations among U.S. women (Clin Chem 2004; 50: 574–581). Data in this study—headed by Earl S. Ford, MD, MPH, of the CDC’s Division of Adult and Community Health—indicated that 40% of the women between the ages of 30 and 39 included had CRP concentrations greater than 3.3 mg/L. However, the risk for women in this age group of having a coronary event is very low, further underscoring the poor predictive value of CRP, said Levinson. “Since about 60% of the apparently healthy women between the ages of 30 and 49 fall into this CRP range, discrimination for CHD by this test is very poor, and it is unlikely that randomized studies will show it to be a useful test for screening in the general population,” said Levinson.

Another reason for a randomized study would be to determine the cost-effectiveness of widespread use of this testing. “Surely one would have to do a randomized study to see if there are enough people, with absolutely no other risk factors except elevated CRP levels, that wouldn’t [otherwise] be treated,” said Levinson. “It would be hard to imagine that it would be cost-effective to screen everyone with no risk factors.”

Another outspoken critic of CRP level assessments is James O. Westgard, PhD, FACB, a pathology and laboratory medicine professor at the University of Wisconsin-Madison Medical School and co-founder of Westgard QC, Inc. (Madison, Wis.). In an essay posted on his Web site (http://www.westgard.com/quest15.htm), Westgard takes aim at intra-individual biological variations when CRP is assessed and relative risk evaluated when levels are broken up into quintiles (see Figure 1), based on results of a 1997 study conducted on 26 individuals (Clin Chem 1997;43: 52–58). Many of the subjects in the study would have been classified into different quintiles of risk if their CRP levels were measured over time, Westgard indicated. “Two individuals in this group of 26 would actually have been classified as ‘lowest risk’ at one time and ‘highest risk’ at another time,” he wrote. “If that holds true for the general population, that means that 8% of the population may change in classification from lowest to highest risk, or vice versa, depending on when they happen to be measured.”
Reprinted with permission from James O. Westgard, Ph.D., Westgard QC, Inc. 

Counterpoint

In response to Levinson’s opinion article in Clinical Chemistry, Rifai rejected the criticisms and pointed to the 22 prospective epidemiological studies that have been performed in Europe and the U.S. “CRP is not a poor predictor,” he insisted. “Coronary heart disease is the leading cause of death in the Western world. Almost 50% of those who have coronary heart disease have normal lipid levels. CRP helps identify a great percentage of those people.”

Rifai also reiterated the importance of looking at the patients’ comprehensive health profile, rather than relying on one factor—such as CRP levels—to assess risk. “When you look at a patient, you look at the entire risk profile, so when you do the global risk assessment of the patient, you look if the patient is obese, if the patient is a smoker, the patient’s age, if the patient has hypertension,” he explained. “You will also look at cholesterol and CRP and put all this information in context when you make a clinical decision, but you do not treat a single factor.”

CRP’s Future as a Functional Marker?

Rather than analyzing CRP levels in individuals without apparent CHD risk factors, researchers might want to look at levels in people who already have the disease, since levels decrease significantly with lipid lowering therapy, such as statin drugs. “New guidelines recommend optional LDL cholesterol (LDL-C) goals of less than 70 mg/dL, as compared to the old target of less than 100 mg/dL for very high-risk persons. That therapy should be aimed to reduce LDL-C 30-40% below baseline,” said Levinson. In addition, CRP also has potential as a functional marker for plaque and risk regression, but again, Levinson insisted that more randomized studies are necessary to pursue this application. Statin therapy and CRP levels were the focus of two studies recently published in the January 6th issue of the New England Journal of Medicine (see Current CRP Developments).

Refocusing on Conventional Risks

Given the lack of a solid, evidence-based link between CRP levels and adverse coronary events, Levinson advised that clinical laboratory directors and supervisors discourage the use of the hs-CRP test in favor of focusing on conventional and treatable risk factors, including obesity and elevated LDL levels. Of course, lipid lowering drugs such as statins have been shown to lower CRP levels, but Levinson insisted this relationship needs further investigation, noting that if someone goes on a cholesterol lowering drug and their CRP level decreases, it still doesn’t mean they are at a lower risk for a heart attack.

However, with increased attention in the public media on the potential benefits of CRP testing, more patients may be asking their physicians for the test. Physicians in turn may seek the advice of clinical lab directors in choosing a test for their patients. “I suggest that clinicians stick to guidelines well defined by the NCEP [National Cholesterol Education Program]. Overweight persons should reduce [their weight], smokers should cease [smoking], and all people should exercise at least a half hour per day,” said Levinson. “I don't see any need for hs-CRP [testing] in making the great majority of these decisions.”

Current CRP Developments:

  • Recent CRP Research in NEJM. CRP levels and statin therapy were the subject of two studies in the Jan. 6th issue of the New England Journal of Medicine. Ridker et.al. evaluated data from the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trials. This study looked at LDL and CRP levels and the risk of recurrent adverse coronary events among CHD patients in two treatment groups; those receiving intensive treatment of 80 mg of atorvastatin daily, and those receiving moderate treatment of 40 mg of pravastatin daily. Results showed that while both LDL and CRP levels decreased, patients who had low CRP levels after statin therapy had better clinical outcomes than those with higher CRP levels, regardless of their resulting LDL level. The second study, known as the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial, also looked at this same population in relation to the progression of atherosclerosis. Preliminary findings from REVERSAL’s investigators indicate that a reduced rate of progression is associated with intensive, as compared with moderate, statin treatment and is also related to greater reductions in both CRP and atherogenic lipoprotein levels. To read the studies, go to http://content.nejm.org/content/vol352/issue1/index.shtml. A subscription is required to read the entire text.
  • JUPITER Trial: Recruitment is currently underway for the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, which is being led by Ridker. Investigators will follow approximately 15,000 participants at 500 clinics in the U.S. and Canada over a three- to four-year period to determine if statin drugs can prevent cardiovascular disease among individuals who have normal LDL levels but increased CRP levels. Eligible participants are men aged 55 years and older and women aged 65 years and older with no history of heart attack, stroke, or other serious cardiovascular event. LDL levels must be less than 130 mg/dL and CRP levels must be 2 mg/L or greater. For more information, visit www.JUPITERstudy.com.
  • Standards Development. An article in the October 2004 issue of Clinical Laboratory News examined current efforts toward standardizing measurement for cardiovascular disease risk and developing reference standards and proficiency testing.
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