In a double-blind trial lasting five years, sacks et al administered either 40 mg of pravastatin per day or placebo to 4159 patients (3583 men, 576 women) with myocardial infarction who had plasma total cholesterol levels below 240 mg/dL (mean, 139). The primary end point was a fatal coronary event or a nonfatal myocardial infarction.
The frequency of the primary end point was 10.2% in the pravastatin group and 13.2% in the placebo group. A 24% reduction in risk (95% CI, 9-36%; P = 0.003). Coronary bypass surgery was needed in 7.5% of the patients in the pravastatin group and 10% of those in the placebo group, a 26% reduction (P = 0.005), and coronary angioplasty was needed in 8.3% of the pravastatin group and 10.5% of the placebo group, a 23% reduction (P = 0.03). Pravastatin lowered the rate of coronary events more among women than among men. The reduction in coronary events was also greater in patients with higher pretreatment levels of LDL cholesterol.
These results demonstrate that the benefit of cholesterol-lowering therapy extends to the majority of patients with coronary disease who have average cholesterol levels. (Sacks FM, et al. N Engl J Med 1996;335:1001-1009.)
COMMENT BY RALPH R. HALL, MD, FACP
The task for the future is to be able to individualize the therapy of our patients, many of whom have complications for which patients were excluded from this and other studies. The combination drug therapy with moderate-to-low doses of statins with fibrates and niacin will result in better compliance. Most of the benefits of the cholesterol-lowering agents are achieved by moderate doses (i.e., 40 mg of pravastatin, 1.0-1.5 g of niacin). The incidence of side effects with moderate doses of cholesterol-lowering drugs is far less than when maximum doses are used. A recent study indicates that moderate doses of resins as used in this study are not as effective as either the fibrates or niacin.1
The authors put the data in everyday perspective that both patients and physicians understand by pointing out that "from treating 1000 patients, 151 cardiovascular events could be prevented and 51 patients could be spared at least one such event. If the treatment was limited to women or those over 60 years of age, the absolute benefits would be even greater."
As the authors note, the reduction in the rate of coronary events was influenced by the pretreatment level of LDL cholesterol. "The patient with baseline levels above 150 mg/dL had a 35% reduction in coronary events, as compared with a 26% reduction in those with baseline levels of 125-150 mg/dL." There was no benefit in those patients with LDL levels less than 125 mg/dL. Those results demonstrate that for patients with coronary disease, the average cholesterol level is too high.
Two observations in the study are thought-provoking. All of the myositis occurred in the placebo group. The occurrence of myositis with the statins in combination with the fibrates does not seem to be frequent enough to be of concern. This is contrary to the initial concerns because of a preliminary study indicating an increased incidence of myositis when the statins were used with the fibrates.
There was an increase in the incidence of breast cancer in the small group of women who were treated. This will need further observation. It is of note that the placebo group had a higher rate of estrogen use than the treatment group (although the difference was not statistically significant). As the authors point out, the likelihood that the breast cancer findings were the result of statin therapy is unlikely. None of the previous studies with statin has shown any increase in the incidence of breast cancer.
Cholesterol lowering does reduce the use of the hospital and the emergency room. This offsets much of the cost of this treatment.2 Thus, as pointed out by Kreisberg (in an article that all primary care physicians should read),3 "Failure to treat hypercholesterolemia is not only a disservice to the patient but is [also] poor business."
The problem that remains, however, is significant. Despite treatment, 7.5% of the patients needed coronary artery bypass surgery and 8.3% needed angioplasty. A number of patients in the treatment groups died of myocardial infarction or stroke. We need to do a better job of primary prevention and to look for other factors in addition to lipid abnormalities that take such a toll in death and disability from coronary artery disease.
References
1. Pasternak RC. Ann Intern Med 1996;125:529-539.
2. Pedersen TR, et al. Circulation 1996;93:1796-1802.
3. Kreisberg RA. Am J Med 1996;101:455-457.
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