Coronary Disease

POSITIVE REDUCTION: Frank M. Sacks (left) of Brigham and Women's Hospital and Harvard University led a study that demonstrated that lowering cholesterol in patients from average to low levels significantly reduced the number of recurrent coronary events. The research team also included Lemuel A. Moye (right) of the University of Texas School of Public Health in Houston. F.M. Sacks, M.A. Pfeffer, L.A. Moye, J.L. Rouleau, J.D. Rutherford, T.G. Cole, L. Brown, J.W. Warnica, J.M.O. Arnold, C.C. Wun, B.R. Davis, E. Braunwald, "The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels," The New England Journal of Medicine, 335(14):1001-9, 1996. (Cited more than 290 times to date) Comments by Frank M. Sacks, associate professor of medicine and nutrition, Brigham and Women's Hospital and Harvard University. Since the mid-1980s, physicians have known some of the health benefits from lowering cholesterol in patients with coronary disease. For example, one study of more than 360,000 men showed that half of all deaths from heart disease were associated with high levels of cholesterol and recommended intensive treatment for those patients (M.J. Martin et al., Lancet, 2:933-6, 1986). What wasn't so clear is if the effort to reduce cholesterol in patients with average-to-low levels is worthwhile. Frank M. Sacks, an associate professor of medicine and nutrition at Brigham and Women's Hospital and Harvard University, gave physicians an answer with the Cholesterol and Recurrent Events (CARE) trial. He led a team of researchers that demonstrated that lowering cholesterol in patients from average (139 mg per deciliter) to low levels (97 mg per deciliter) significantly reduced the number of recurrent coronary events. Between 1989 and 1991, the research team at 80 centers in Canada and the United States recruited 4,159 patients with myocardial infarction and cholesterol below levels considered to be high (240 mg per deciliter total cholesterol, 175 mg per deciliter low-density lipoprotein [LDL] cholesterol). The research team included Eugene Braunwald and Marc A. Pfeffer at Brigham & Women's Hospital, Jean L. Rouleau of the Montreal Heart Institute, and Lemuel A. Moye at the University of Texas School of Public Health in Houston. In a double-blind trial lasting five years, patients were given a placebo or 40 mg pravastatin, made by Bristol-Myers Squibb Co. in New York. The compound inhibits HMG-CoA reductase, an enzyme that blocks cholesterol biosynthesis. The most significant finding of the CARE trial was that pravastatin effectively lowered cholesterol and reduced both fatal and nonfatal heart attacks by 24 percent in patients. Reduction in risk for patients at higher levels of LDL cholesterol (above 150 mg per deciliter) was 35 percent. In comparison, patients at lower levels (125-150 mg) saw risk fall by 26 percent. Bypass surgery was needed in 7.5 percent of all patients taking pravastatin compared to 10 percent in the placebo group. The need for angioplasty fell to 8.3 percent in the drug group compared to 10.5 percent in the placebo group. Prior to the study, the exact relation between risk of heart attack and cholesterol was controversial. While the benefit of reducing high cholesterol was established, many researchers were divided over whether reducing average-to-low levels of cholesterol produced any health benefit. "Our investigation really showed for the first time that even an average cholesterol level in patients with coronary disease is too high and contributed to them getting additional heart attacks and other coronary problems," Sacks explains. "We also found the incremental benefit decreased as LDL cholesterol fell to lower levels in patients; i.e. within the low range, 70-125 mg per deciliter, reduction of coronary events was similar. Prior to the trial, this also was a major point of contention because of the widely accepted point of view that any level of cholesterol is harmful." The CARE study also weighed in on another controversy regarding cholesterol and risk of heart attack. In prior studies, researchers had not established whether cholesterol levels in women and older patients were associated with increased risk of heart attack. In fact, some epidemiology studies suggested that cholesterol was not a risk factor for any of these groups. However, the CARE trial research team found that pravastatin reduced risk of recurrent coronary incidents in women by almost 50 percent. The effect of the drug on recurrent coronary events also did not diminish in patients as old as 75 years. Why has the study been so widely cited? According to Sacks: "The trial [indicated] that nearly all patients with coronary disease should seek treatment of cholesterol. This was by no means a foregone conclusion. We were able to provide answers in several areas of controversy. In effect, the study has helped to extend cholesterol treatment in patients with heart disease from a small to a large proportion of the population." The research team also found that pravastatin reduces a patient's risk of stroke. Sacks notes this finding was surprising: "In the general population, cholesterol typically was not thought of as a strong or well-established risk factor for stroke. The CARE trial was the first to give us evidence for the efficacy of lowering cholesterol to prevent stroke in a population with average cholesterol levels." In March, the U.S. Food and Drug Administration approved the drug for use in the treatment of stroke. An earlier study by a University of Glasgow research team that showed that pravastatin prevents heart disease in men with high cholesterol (J. Shepherd et al., New England Journal of Medicine, 333:1301-7, 1995) has been cited more than 600 times to date.

Coronary Disease

The Scientist Staff

Interested in reading more?

Become a Member of


POSITIVE REDUCTION: Frank M. Sacks (left) of Brigham and Women's Hospital and Harvard University led a study that demonstrated that lowering cholesterol in patients from average to low levels significantly reduced the number of recurrent coronary events. The research team also included Lemuel A. Moye (right) of the University of Texas School of Public Health in Houston.