Statins, CRP test get boost from high-profile study

Results of a large-scale study offered significant evidence that statin drugs reduced cardiovascular disease risks for patients with normal cholesterol but high levels of an inflammatory marker. As a result, physicians now face the challenge of incorporating this promising, albeit incomplete, data into everyday preventive care.

For instance, testing for the inflammatory marker, high-sensitivity C-reactive protein, hasn't been a big part of the practice of Bob Gramling, MD, DSc, a family physician in Rochester, N.Y. But he expects that to change in the very near future.

"I will be asked to do it more," said Dr. Gramling, an assistant professor in family medicine as well as community and preventive medicine at the University of Rochester. "I'm going to be thinking about it more."

This point of view is gaining momentum because results from that heavily publicized trial -- the first to use hs-CRP to guide cardiovascular prevention rather than only assess risk -- were released Nov. 9 at the American Heart Assn.'s scientific sessions in New Orleans. They also were published in the Nov. 20 New England Journal of Medicine and attracted widespread media attention.

Researchers with the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin, or JUPITER, tracked 17,802 participants for just short of two years. They found that patients with high levels of hs-CRP but otherwise healthy cholesterol profiles who took 20 mg of this drug daily dramatically reduced their risks of cardiovascular events and death when compared with those who were taking placebos. Another pair of papers presented at the AHA meeting reinforced hs-CRP's potential for cardiovascular disease risk stratification.

"These findings suggest that adding hs-CRP levels to traditional risk factors could identify millions more adults for whom treatment with statins appears to lower the risk of heart attack," said Elizabeth G. Nabel, MD, director of the National Heart, Lung, and Blood Institute.

Most physicians concur that JUPITER is a significant study. But a great deal of disagreement still exists about how widespread hs-CRP testing should become and how often a prescription for statins is needed.

"It's a very important study. It was well done. The people who did it are to be congratulated," said Mark Hlatky, MD, a cardiologist and professor at California's Stanford University School of Medicine. He wrote the accompanying NEJM editorial. "But how do we generalize the results?"

What will be JUPITER's impact?

Whether to test for hs-CRP and how to respond to the numbers has been controversial for years. Physicians increasingly are using this marker to determine strategies for those at intermediate risk for cardiovascular disease. Several studies have suggested that it is an effective strategy, and the Reynolds Risk Score includes it. This risk assessment tool was designed by Paul Ridker, MD, the principal investigator of JUPITER. He also is one of the patent holders for the hs-CRP assay.

This biomarker, however, is not a part of the more widely used Framingham Risk Score. AHA guidelines say its role in directing prevention strategies is unclear, and several papers comparing it with other risk factor measures have not found that it adds much to an overall assessment.

The response to this latest development varied widely. For some physicians, this trial gave them the evidence for which they were waiting.

"I think it's very important and very significant," said Lawrence K. Monahan, MD, an internist in Roanoke, Va., and clinical professor at the University of Virginia School of Medicine and the Virginia College of Osteopathic Medicine. He added that he would "without a doubt" be testing for hs-CRP more often.

Others are more hesitant. The relative risk reduction was significant, but questions remain about how clinically meaningful it would be to apply cholesterol-lowering treatment to those whose baseline risk may not be that high. "What we have not seen is what were the absolute levels of risk, and how far did they go down," said Dr. Hlatky.

Another necessary step is to identify the characteristics that make some patients benefit more than others from this statin use.

Concerns also stem from the potential long-term implications of more people taking statins at even younger ages for an even longer portion of their lives -- issues not answered by this project. The study, which was originally planned to follow patients for five years, was halted after an average of 1.9 years because the immediate benefits were so significant.

"We could find after 15 to 20 years of statin use higher rates of some other life-threatening condition. We have the potential to create a fair amount of harm," Dr. Gramling said.

Others worry about the cost associated with hs-CRP testing and treating patients who have high levels of this marker but normal cholesterol, especially if they are prescribed rosuvastatin. This drug is one of the more expensive in its class, although several physicians said they would likely opt for a generic. But it's not clear if JUPITER's results can be generalized in this manner.

"My own personal belief is that for the same degree of lipid lowering, it doesn't matter much which statin you're on," Dr. Hlatky said.

In addition, some physicians were skeptical about the possible role the study's funder may have played in the results. AstraZeneca Pharmaceuticals, the manufacturer of rosuvastatin, paid for the research.

"This immediately makes me suspicious," said Elizabeth Gabay, MD, an internist at Interfaith Community Health Center in Bellingham, Wash. "I would like to see a study not paid for by a maker of a statin. Then I would be more inclined to believe the results." The study authors noted in the published report, though, that AstraZeneca had no access to the data before the paper was submitted for publication and played no part in data analyses or drafting the paper.

The company now plans to file an application with the Food and Drug Administration for an expanded indication for this drug, according to an AstraZeneca statement. Rosuvastatin currently has FDA approval as an add-on to dietary efforts to lower cholesterol. It is marketed by AstraZeneca as Crestor.