How low can you go? How low should you go? Suddenly heart research has become a limbo contest, and the question is how low people with heart risk should push the level of LDL, the blood lipid commonly known as "bad" cholesterol. Two powerful studies presented last week at the annual science meeting of the American College of Cardiology shredded the prevailing wisdom, that for people with heart disease it's enough to push their LDL blood level below 100 milligrams per deciliter. The impact in doctors' offices everywhere will be stunning.

People with heart disease or at high risk for it, diabetics, and the obese are among those taking cholesterol-lowering statin drugs who can expect their doctors to bump up their dose or move them to a more muscular statin. Some physicians already have made the move. "I think there will be substantial changes in just a few months," says Lee Green, a family practitioner in Ann Arbor, Mich., whose high-risk patients have found their Lipitor dose suddenly doubled. But no one yet can answer the question: Is there a threshold that might be risky to cross?

The two headline-grabbing studies, tagged PROVE-IT and ALLIANCE, squared off Lipitor, a potent statin and also the world's bestselling prescription drug, against Pravachol--a weaker statin but a long-established standard choice for safely reducing LDL, or low-density lipoprotein-- or the physician's choice of statin. The PROVE-IT study--principally funded by Bristol-Myers Squibb, which markets Pravachol--looked at more than 4,000 patients hospitalized because of heart attack or the severe and uncontrolled chest pain called unstable angina. Upon discharge, half were treated aggressively with 80 milligrams a day of Lipitor, while the other half got 40 milligrams of the weaker Pravachol.

The PROVE-IT acronym was deliberate. It was what researchers call a "noninferiority trial." In essence, that means Bristol-Myers hoped and expected the trial would demonstrate that Lipitor, although it is more potent and was being used at the highest dose, would not beat out Pravachol in effectiveness over a two-year period. Given Lipitor's potency and the high dose, that may seem unlikely. Not so, says cardiologist Christopher Cannon of Brigham and Women's Hospital in Boston, PROVE-IT's lead researcher: "It's actually very hard to be better than a standard effective therapy." But some cardiology researchers felt the study was stacked by limiting the follow-up to two years, because it usually takes at least that long for patients on different drugs to start showing meaningful differences.

Short but sweet. To the surprise of many, including scientists at Bristol-Myers Squibb, PROVE-IT proved that sometimes two years is long enough. The risk of a second heart attack or comparable event in the Lipitor group was 16 percent lower than in the Pravachol group, and differences between the two groups began to appear as early as 30 days. The study, which will be published in an upcoming issue of the New England Journal of Medicine, was released early for the heart meeting.

The results meshed nicely with the results of a trial called REVERSAL. Using ultrasound, Steven Nissen of the Cleveland Clinic showed that the fatty plaque that builds up inside the walls of the coronary arteries of people at risk for heart disease stopped accumulating in patients given Lipitor. In many of them, the fatty deposits actually shrank. In the patients who got Pravachol, the rate of accumulation slowed, but the effects of Lipitor were clearly superior. In short, all the evidence seemed to be pointing toward an aggressive statin attack. What this means for the average person with elevated cholesterol is less clear (On Health, Page 54).

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