A new study provides the first evidence that people with average cholesterol levels can substantially reduce their risk of heart attack by taking a drug that drives their cholesterol levels even lower.
The study, financed by Merck & Company, involved 6,605 middle-aged-to-elderly men and women, half of whom took Merck's powerful and expensive cholesterol-lowering drug, lovastatin; the rest took a dummy pill. After five years, those who had taken lovastatin had had 37 percent fewer heart attacks and other serious signs of heart disease than those who had taken the placebo.
Medical experts said that the study had been well conducted and that its results were solid. Dr. Claude Lenfant, director of the National Heart, Lung and Blood Institute, described it as "a great study."
But already the results are opening a debate among medical experts: How hard should people try to reduce their cholesterol levels below what is now considered acceptable? And how much should the nation pay to save a few more people from heart disease?
In their paper, being published today in The Journal of the American Medical Association, the authors said that if the study's findings were put into practice, the population eligible for cholesterol-lowering drugs would triple, to six million adult Americans from the two million who qualify for drug treatment today.
An editorial accompanying the paper said the annual cost of the drug for just 1,000 patients would be $1,420,500 -- an average of more than $1,400 -- not including the costs of doctor visits and laboratory tests.
Many doctors themselves, who heard the study results when they were reported at a meeting of the American Heart Association in November, have already begun taking lovastatin or another of the newest group of cholesterol-lowering drugs, called statins. One who is not on statins said he used to ask his doctor friends if they were taking one.
Now, he said, the more usual question is, Which statin are you taking?
Medical experts said that doctors' prescribing patterns were hard to know but that at least some doctors appeared to be prescribing statins for people with average cholesterol levels. Dr. Jeffrey Isner, chief of vascular medicine and cardiovascular research at St. Elizabeth's Hospital in Boston, a referral specialist who speaks to cardiolgists daily, said that "some doctors are being very aggressive" about prescribing the drugs and have told him so.
A lead author of the paper, Dr. Antonio M. Gotto Jr., dean of the Weill Medical College of Cornell University, said he hoped that the study would "redefine what we consider normal" in cholesterol levels.
Until now, Dr. Gotto said, no one gave statins to patients like those in the study because medical experts "thought it probably wouldn't do any good." The study, he said, shows that this perception is not correct.
Dr. Gotto added that Merck's patent on lovastatin, the first of the statins to be approved for marketing, was due to expire in 2001, which should lower its cost.
But some, like Dr. Alan Garber, director of the Center for Primary Care and Outcomes Research at Stanford University, are uneasy with prescribing statins for so many people at relatively low risk of heart disease.
Yes, Dr. Garber said, the drugs seem safe in short-term studies. And yes, some studies with groups at very high risk of heart disease have found that statins can prevent death. But, he said, there is no information on whether there are long-term side effects. For people with high cholesterol levels, the drugs' benefits outweigh uncertainty about complications that may occur many years later, he said. But, he said, that may not be true for people with average cholesterol levels.
Current guidelines for cholesterol lowering, determined by the National Heart, Lung and Blood Institute, use cholesterol levels, age, sex and the presence or absence of other factors like high blood pressure and cigarette smoking to determine who should take a cholesterol-lowering drug. Although most of the participants in this study had one or more risk factors for heart disease other than cholesterol levels, most did not have cholesterol levels high enough to warrant medical treatment under those guidelines.
The participants were 5,608 men from 45 to 73 years old, and 997 women from 55 to 78, who had no signs or history of heart disease. Their average cholesterol level was 221 milligrams per deciliter of blood, which put them smack in the middle of the American cholesterol range, in the 51st percentile, the researchers reported.
But their levels of high density lipoproteins, or H.D.L.'s, the cholesterol carriers that protect against heart disease, were low. The men's average H.D.L. levels were 36 milligrams per deciliter of blood, placing them in the 25th percentile of all American men. The average H.D.L. level for the women was 40, placing them in the 16th percentile of American women.
In addition to taking lovastatin or a dummy pill, the participants were asked to eat a low-fat diet.
After five years, 183 people taking the dummy pill had had a heart attack or other serious symptom of heart disease. But just 116 of those taking lovastatin, or 37 percent fewer, had had such a symptom.
The lovastatin effect began appearing in the first year of the study, Dr. Gotto said, and held up.
Dr. Gotto added that the drug was so effective that it essentially wiped out the adverse effect of a risk factor for heart disease. For example, if people in the study smoked cigarettes and took lovastatin, their risk became that of someone with the same cholesterol level who did not take the drug and did not smoke.
The study was not designed to look for differences in mortality rates, and so it remains possible that even if statins reduce heart attacks in people with average cholesterol levels, they may not save lives.
Dr. Lenfant, director of the National Heart, Lung and Blood Institute, praised the research and said that if he had a cholesterol level in the range of those of the people in the study and had even one other factor that increased his chances of developing heart disease -- like cigarette smoking, high blood pressure, diabetes or a family history of heart disease -- he would take a statin.
But in an editorial accompanying the paper, Dr. Thomas A. Pearson, chairman of the department of community medicine at the University of Rochester School of Medicine, asked a thorny question: How much is this benefit worth?
Dr. Pearson said in an interview that since there seemed to be so many who could potentially benefit from statins, "some of my more exuberant colleagues are talking of putting this in the water supply." Facetiousness aside, he added, the drugs cost a great deal -- $900 to $1,800 a year for each patient, depending on the dose -- and many must take them in order for a few to realize the actual benefit.
Dr. Pearson noted that if 1,000 people like those in the study took lovastatin for five years, 12 heart attacks would be prevented, as would 7 cases of unstable angina, a type of chest pain that indicates severe heart disease. In addition, 17 medical procedures to open blocked blood vessels would be avoided.
Dr. Scott Grundy, director of the Center for Human Nutrition at the University of Texas Southwestern Medical School in Dallas, who is a spokesman for the American Heart Association, asked who should pay for the drugs, especially since many people with an average cholesterol level can lower it by eating a low-fat diet, exercising and losing weight.
"If you're going to increase my health insurance because my next-door neighbor has borderline high cholesterol," Dr. Grundy said, "and if he's sitting around and watching TV and eating and getting fat, do you want me to pay for that?"
Many insurers would pay for statins if doctors prescribed them for patients with average cholesterol levels, several experts said. The reason, explained Dr. Brian Strom, chairman of the department of epidemiology and biostatistics at the University of Pennsylvania, is that insurers rarely know the laboratory results that correspond to drug prescriptions. They will know that a blood test has been ordered and that a cholesterol drug has been prescribed, "but they don't know the actual results" of the test, Dr. Strom said.
On the other hand, he added, insurers "may change the rules in response to this."
Already Dr. Garber of Stanford is seeing the momentum for statins build.
"I was at a meeting of cardiologists and venture capitalists," he said. "One asked, 'How many are taking statins?' About half raised their hands. A good fraction of them had normal cholesterol levels but decided this was a good thing to do."
And so, Dr. Garber said, "the pressure is definitely on to use these things." As a result, he said, "the public will be clamoring for them too."
But, he said, "men and women should ask, Is this the best possible way for me to prevent heart disease?" For example, he said, taking an aspirin every other day also substantially reduces the risk of heart attack -- although it does not reduce cholesterol levels -- and at a cost of pennies a day.
"One thing is certain" about statins, Dr. Garber said.
"This is a very expensive way to prevent heart disease."