Value of C-reactive protein testing questioned by many

When assessing heart disease risk, physicians are increasingly opting to include a test for C-reactive protein, a marker of inflammation. Some already consider it routine, although most use it mainly as a tie-breaker to determine strategies for middle-risk patients.

But is the test useful? Whether CRP testing provides insights is a question clinicians and scientists have been struggling to answer.

The question was hotly debated at last month's annual meeting of the Clinical Ligand Assay Society in Chicago. The subject also has been the focus of numerous studies. The conclusions vary.

For instance, according to a paper published in an April issue of the New England Journal of Medicine, CRP levels are only a so-so heart disease predictor, offering specificity and sensitivity comparable with a blood pressure check. Cholesterol and smoking status were the most significant risk indicators. CRP levels seemed to add little to the profile and did not change prevention strategies.

"The extra predictive information above and beyond the established risk factors is rather limited," said Dr. John Danesh, lead author and professor of epidemiology and medicine at Cambridge University in the United Kingdom. "There's no compelling reason to measure C-reactive protein at the present time, although it remains a question requiring further evaluation."

But on the other side, a study of 27,000 healthy American women published in the Nov. 14, 2002, NEJM amplified what many smaller studies had concluded for years -- that CRP could be used to identify many more people who were at risk for cardiovascular events.

"We have a simple, inexpensive way to do a better job of identifying high-risk patients," said Paul M. Ridker, MD, MPH, lead author of that paper and director of the center for cardiovascular disease prevention at Brigham and Women's Hospital in Boston.

Still, clinical guidelines have not embraced it. Guidelines that were issued by the American Heart Assn. and the Centers for Disease Control and Prevention in January 2003 recommended against populationwide CRP testing but did say it might be useful for those at moderate risk of an event within the next decade.

So, back to the question: Should doctors test or not?

Reasons against

According to the authors of the April NEJM study, CRP testing should be used only in a research setting. Doctors who have decided against incorporating it into their practices often argue that it adds little beyond cost to the well-established battery of tests.

"Exactly what more are we going to learn by one more test?" asked Barbara Yawn, MD, a family physician in Rochester, Minn. "We have so many risk factors that are modifiable, and we're not paying as much attention to those as we should," added Dr. Yawn, also director of research at Olmsted Medical Center. She is not affiliated with the NEJM study.

Heart disease experts also expressed concern because the test has not been standardized in the lab to the extent that cholesterol testing has. They also suspect that most physicians are not using it correctly. This could mislead patients and doctors.

"It should be performed twice, two weeks apart," said Peter W.F. Wilson, MD, program director of general clinical research in the Dept. of Endocrinology, Diabetes and Medical Genetics at the Medical University of South Carolina. He was a presenter at the CLAS meeting. "Most clinicians are not doing that," Dr. Wilson said.

Other common diseases such as arthritis or cancer also can cause CRP to spike, triggering complaints that the marker is not specific enough.

"It's a pretty useless test," said Stanley S. Levinson, PhD, director of clinical chemistry at the Dept. of Veterans Affairs medical center in Louisville, Ky., during the CLAS meeting. "Suppose a person has cancer, but we treat him for heart disease. Then they die of the tumor."

And while CRP might be a cardiac risk factor, studies have yet to confirm if lowering it reduces risk. There also are no specific medications for CRP, although statins and lifestyle alterations that affect cholesterol levels seem to have the same impact on CRP.

"We don't have a specific treatment for it," said Ken Mukamal, MD, MPH, an internist and assistant professor of medicine at Harvard University. "It's the risk factor without much to do about it."

But the test does have its fans. Many physicians view it as a determinant that can move a patient who is straddling the low-risk and high-risk categories firmly into one box or the other. It also can act as an extra factor to compel a patient to initiate primary prevention.

"If the cholesterol is all perfectly normal, they are string beans, exercising every day, eating a healthy diet, the blood pressure is normal, they don't have a strong family history, they don't have diabetes and yet they still have some evidence of possible hardening of the arteries, then it might be the tie-breaker at the end of the line," said Larry Monahan, MD, an internist in Roanoke, Va.

Only a minority of physicians are using it routinely, but even those most in favor of CRP testing agree that this is not ready for wide-scale use. There are many physicians, however, who believe it has a great deal of potential.

"I can see where this test is going to be standard," said Raymond Christensen, MD, a family physician in Duluth, Minn., and assistant dean for rural health at the University of Minnesota School of Medicine. "Patients are starting to ask for it, and I do use it sometimes, although I don't use it routinely at this point."