Wider Benefit Seen From Cholesterol Drugs

By PAM BELLUCK

10 nov 2008--A large new study suggests that millions more people could benefit from taking the cholesterol-lowering drugs known as statins, even if they have low cholesterol, because the drugs can significantly lower their risk of heart attacks, strokes and death.

The study, involving nearly 18,000 people worldwide, tested statin treatment in men 50 and older and in women 60 and older who did not have high cholesterol or histories of heart disease. What they did have was high levels of a protein called high-sensitivity C-reactive protein, or CRP, which indicates inflammation in the body.

The study, presented Sunday at an American Heart Association convention in New Orleans and published online in The New England Journal of Medicine, found that the risk of heart attack was more than cut in half for people who took statins.

Those people were also almost 50 percent less likely to suffer a stroke or need angioplasty or bypass surgery, and they were 20 percent less likely to die. The statin was considered so beneficial that an independent safety monitoring board stopped what was supposed to be a five-year trial last March after less than two years.

Scientists said the research could provide clues on how to address a long-confounding statistic: that half of heart attacks and strokes occur in people without high cholesterol.

“These are findings that are really going to impact the practice of cardiology in the country,” said Dr. Elizabeth G. Nabel, director of the National Heart, Lung and Blood Institute, which was not involved in the research. “It’s at a minimum an extremely important study and has the potential to be a landmark study.”

The study is sparking debate over who should take a blood test to check CRP and under what circumstances someone with high CRP should be given a statin. Because heart disease is a complex illness affected by many risk factors — including smoking, hypertension, being overweight and having a family history of heart disease — most researchers said high CRP alone should not justify prescribing statins to people who have never had heart problems.

Some experts cautioned against testing people for CRP unless they had other indications of being at risk for heart disease, and they said more research was needed to pinpoint the patients for whom the benefit of statins outweighs the risks. Others recommended testing more frequently and using statins for people with low cholesterol if they have high CRP and some other risk factors.

The study, called Jupiter, is also fueling a debate among scientists about CRP’s importance and inflammation’s role in heart disease.

Dr. Nabel said national panels were likely to revise their official guidelines for doctors, which she described as “silent on CRP,” to recommend CRP testing and statin therapy for some people not previously considered candidates.

Current practice, she said, is to treat people with high cholesterol with statins, and to counsel people at low risk for heart disease about diet and exercise.

“What cardiologists have never known what to do about is the intermediate range” of patients, Dr. Nabel said, who may be overweight, smoke or have hypertension, but do not have the most serious red flags of high cholesterol or diabetes. “I think CRP will emerge as a new risk factor added to traditional risk factors.”

The leader of the Jupiter study, Dr. Paul M. Ridker, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital in Boston, said his team estimated that expanding statin use to the types of patients he studied could prevent about 250,000 heart attacks, strokes, vascular procedures or cardiac deaths over five years.

Some experts not involved in the Jupiter study said several million more Americans should probably be taking statins. About 16 million to 20 million Americans are estimated to be taking statins.

“The Jupiter trial very convincingly used CRP as a way to identify another group of high-risk individuals who wouldn’t otherwise have been treated, and supports the concept that those people should be treated with a statin,” said Dr. Daniel J. Rader, a heart researcher at the University of Pennsylvania School of Medicine who was not connected to the study.

Several experts said that although the research was significant and would affect clinical practice, the study as published in the journal did not give enough detailed information to indicate exactly which patients should now be tested for CRP or given statins.

In an accompanying editorial, Dr. Mark A. Hlatky, a professor of health research at Stanford University, said among other things that the study, which tested people with CRP levels over two milligrams, did not indicate whether that level or a higher CRP level should be the threshold for treatment. The study also did not answer some questions about risks of giving statins to relatively healthy people, he wrote.

Dr. Sidney Wolfe, director of the health research group for Public Citizen, a nonprofit consumer advocacy organization, said the Jupiter study also did not give enough detail about the effect of statins on participants who had only high CRP, compared with those who also smoked or had a condition called metabolic syndrome. Some experts questioned whether stopping the trial early had limited the possibility of some more meaningful data.

Dr. Ridker said the published study, as well as unpublished data, indicated that all the statin-takers experienced the same benefit, including those considered “very low risk” because they have no risk factors other than high CRP. “We have no evidence at all that stopping early adversely impacted on anything,” he said in an e-mail response, adding, “I think people may simply not have had the time to carefully read the paper yet, and the data so much challenge what they believe to be true that it will take some time to sink in.”

The trial was one of the few to test statins that included many women, Hispanics and blacks, groups that all showed similar benefit from statins.

Like many clinical trials, Jupiter was sponsored by a pharmaceutical company, in this case AstraZeneca. It makes the drug in the trial, rosuvastatin, which is sold as Crestor. The most potent statin on the market, Crestor has been criticized by consumer health advocates who say it is more likely to cause some rare side effects of statins — muscle deterioration and kidney problems.

In 2005, the Food and Drug Administration rejected a petition by Public Citizen to ban Crestor, saying its risks were not substantially different from similar drugs.

In the Jupiter study, in which people either got rosuvastatin or a placebo, there was no increase in muscle or kidney problems for those taking the statin. There was a small increase in diabetes.

Dr. Timothy J. Gardner, president of the American Heart Association, said some recent statin trials “have been either negative or in some ways concerning in terms of complications,” but, he added, “this one is pretty clearly a winner for statin therapy.”

Dr. Ridker, a co-inventor of a CRP test, said he first sought federal financing for the study and was turned down. He and the other scientists interviewed for this article, except for Dr. Nabel, Dr. Gardner and Dr. Wolfe, have consulted for or received research money from companies that make statins.

Although Crestor, which has 9 percent of the American cholesterol-lowering market and costs about $3 a day, was used in this study, several experts said it seemed likely that the effect would be the same for other statins in appropriate doses, including generics, which are much cheaper.

Lisa Nanfra, executive director of commercial operations for AstraZeneca, said the company believed there was a “unique profile of Crestor” and that the drug was “the most effective statin at lowering” bad cholesterol. The company plans to use results from the Jupiter study to seek F.D.A. approval to widens its claim about Crestor’s effectiveness.

The role of CRP and inflammation in heart disease is hotly debated. Dr. Ridker believes inflammation plays an important role, probably by causing plaque in the coronary arteries to rupture.

“Screening for cholesterol alone is like having two passengers in a car but only one air bag,” he said. “If we’re not screening for CRP, we don’t have the opportunity to save that person’s life.”

Others say cholesterol is much more important. Dr. Scott Grundy, a heart expert at the University of Texas Southwestern Medical Center, pointed out that in the Jupiter study, the statin not only lowered CRP but also significantly cut already low cholesterol levels, raising questions about whether the benefit actually came from giving patients superlow cholesterol. And because CRP can rise with short-term infections unrelated to chronic inflammation, some experts said results of a CRP test needed to be weighed against other aspects of the patient’s health.

“CRP is not a standard test that everyone should have,” Dr. Rader said. “It is an additional test that you should do if you’re on the fence.”

Dr. Andrew M. Tonkin, head of cardiovascular research at Monash University in Melbourne, Australia, said though the results for those who took the statin were “strikingly positive,” given that the people in the study were relatively healthy, there needed to be a cost-benefit analysis to decide: “Are there people in whom the potential gains, although significant, are not so great as to warrant taking statins?”