C-Reactive Protein Testing Not for Everyone

The upbeat cardiac news last month involved a protein in the blood called C-reactive protein, or CRP. High levels are a sign of inflammation within the artery walls, which some researchers see as an important predictor of heart disease. All they lacked was the proof that reducing a high CRP level would also reduce the risk. As the story played out in the media, two studies that appeared in the same issue of The New England Journal of Medicine have produced the strongest evidence to date. They purportedly showed that lowering CRP levels with statin-drug therapy can lower the rate of heart attacks in people with severe heart disease.

The findings are likely to encourage widespread use of the CRP test. And this, in turn, will greatly expand the market for statins, a drug class that includes Lipitor, Mevacor, Zocor, Pravachol and Crestor. Both studies deserve scrutiny because they are destined to lead to a broader use of statins by people for whom the drugs may cause more harm than good. Both were funded by companies that make statin drugs, and the lead authors of each study, like most cardiovascular research physicians, have strong financial ties to the cardiac drug industry.

First of all, the participants in both studies had severe heart disease. And the CRP test has yet to be proven useful to people in the early stages of heart disease or to healthy people who are at risk for developing heart disease. The lead author of one study, Paul Ridker, MD, of Brigham and Women's Hospital in Boston , was quoted extensively in the media with variations on his comment to The New York Times: “What we now have is hard clinical evidence that reducing CRP is as least as important as lowering cholesterol.” Keep in mind that half of all heart attacks occur in people with normal cholesterol levels.

In both studies the participants had been randomly assigned to take either daily high-dose Lipitor (80 mg) or a lower dose of Pravachol (40 mg). Both measured the effect of reducing CRP levels. In the study headed by Dr. Ridker, there was a higher reduction in heart attacks and strokes among people taking high-dose Lipitor. In the other study led by Steven Nissen, MD, of the Cleveland Clinic, the participants on high-dose Lipitor showed (on ultrasound) greater reductions in the rate of atherosclerosis progression.

There are several reasons to be skeptical about Dr. Ridker's study, according to John Abramson, MD, author of Overdosed America and a clinical instructor at Harvard Medical School . After careful review of this study, Dr. Abramson said that he remains unconvinced that the researchers proved that reduced CRP levels account for the reduced incidence of heart attack and stroke.

High CRP levels may merely be an indicator that a person is at higher risk for another heart attack or stroke, he explained in a telephone interview. What's more, Dr. Abramson drew attention to the high percentage of the study participants who smoked. “36% of these people were smokers—if the goal is really to reduce heart disease, then it doesn't make sense to focus attention exclusively on CRP without addressing smoking cessation and other lifestyle modifications like exercise that are at least as effective as statin therapy,” he said. “Not only does current smoking raise the CRP levels, but the risk remains elevated for 10 to 14 years after people stop smoking.” The Ridker study did not identify how many of the participants were former smokers. Ironically, the relationship between high CRP levels and smoking had already been established in an earlier study conducted by the same research team, according to Dr. Abramson, who added, “CRP might simply be a measure of smoking status.”

Statin drugs work when given appropriately, explained Dr. Abramson, referring to the fact that all the study participants had recently been hospitalized either for a heart attack or unstable angina. “After these people had been treated with statins for a month, however, those whose CRP levels remained high appeared to be at higher risk of having another heart attack or stroke, but we don't have evidence that additional treatment—with even more drugs—will further reduce their risk.”

Whether it is appropriate to prescribe statins to women is another unknown. Heart disease trials now include women, but they are underrepresented, reaching no more than one-third of all participants (the new studies are no exception). What's more, most clinical trials have not separated the findings that apply to women. This makes it difficult to know one way or another whether statins are safe and effective for half the human race. At least one researcher is paying attention, Beatrice Golomb, MD, PhD, assistant professor of medicine, University of California at San Diego . “No study that has released gender-specific information has shown a survival benefit to statin use in women,” said Dr. Golomb in a telephone interview, making it clear that she was referring to all the major statin trials that included women with and without heart disease. And there is no conclusive evidence that statins spare women without heart disease a non-fatal heart attack or stroke.

“Another group that should also be careful about taking high-dose Lipitor on the basis of the new findings includes everyone over the age of 65 years,” observed Dr. Abramson. “It is important to remember that the earlier version of this study [published last year] showed no difference -- whether the participants in this age group took high-dose Lipitor or lower dose Pravachol.”

High doses of statins used in the new studies should be a concern for everyone, according to Dr. Golomb, who has been documenting the serious adverse reactions to this drug class. “There is reason to be concerned about 80 mg. because the benefit of statins is dose dependent, and so are the harms,” she said, “There is more potential for serious adverse reactions.” Dr. Golomb is also the principal investigator of the University of California San Diego Statin Study . People typically take statins for life; yet the statin trials lasted no more than five years.

“What matters is not just whether the person has a heart attack or not,” she continued, “What matters is the over-all complications and over-all mortality, yet in most cases, the drug companies have not released the non-cardiac data.” Dr. Golomb explained that the few statin trials that have done so, either showed the benefits and harms of the drug were even or there was “a trend toward harm”—that is, more women died in the statin group then in the placebo group, but this was not statistically significant.

All government-funded trials, Dr. Golomb continued, are obligated to make their serious adverse events data available to the public. This includes hospitalizations, prolonged hospitalizations and deaths from all causes. “But the reality is that all the major statin trials are funded by drug companies, and there is no obligation to release this critical information,” Dr. Golomb said, adding that she wrote each drug company that has failed to release its data and was turned down. “They [the drug companies] claim it's irrelevant.”

To Dr. Abramson, lifestyle changes are the forgotten element in the rush to drug therapy: “We know that people over 65, who don't smoke, eat a Mediterranean-style diet, exercise regularly, drink moderately, have a death rate reduced by two-thirds that of people the same age who don't maintain these healthy habits.”