The epidemiologic relationship between serum cholesterol levels and the risk of coronary heart disease (CHD) is well documented. Treatments designed to lower serum cholesterol levels in patients with moderately high cholesterol have had limited effect. Patients receiving cholesterol-lowering therapy experience fewer coronary events, but overall coronary mortality is reduced by only about 10 percent. Because of the slight increase in deaths from noncoronary causes, the effects of cholesterol-lowering therapy on overall mortality in patients with high cholesterol levels, and the risk of coronary events in patients with lower cholesterol levels remain uncertain. The Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) study group conducted a double-blind, randomized trial to study the effects of lowering cholesterol levels with the HMG-CoA reductase inhibitor pravastatin in patients with a history of myocardial infarction or unstable angina.
The LIPID group recruited patients aged 31 to 75 years from 87 sites in Australia and New Zealand. Patients were eligible for the study if they had a hospital discharge diagnosis of myocardial infarction or unstable angina in the previous three to 36 months. Plasma cholesterol levels had to be from 155 to 271 mg per dL (4.0 to 7.0 mmol per L). Fasting triglyceride levels had to be less than 445 mg per dL (5.0 mmol per L).
During an initial eight-week placebo period, patients received dietary instruction aimed at reducing fat intake to less than 30 percent of the daily caloric intake. Patients were then given either 40 mg of pravastatin or placebo daily, along with continued dietary advice. Cholesterol levels were obtained at randomization, after six months and then annually until the end of the six-year study period. High-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglyceride levels were also obtained, but at slightly different intervals.
The primary outcome of the study was death from CHD. Secondary outcomes included death from any cause, stroke, need for heart surgery, number of days in the hospital and reduction in serum lipid levels.
Between 1990 and 1992, a total of 9,014 patients were randomly assigned to receive either 40 mg of pravastatin or placebo daily. Baseline characteristics were similar between the groups. Patients were predominantly male and had a median age of 62 years. The median cholesterol level in both groups was 218 mg per dL (5.6 mmol per L). Reductions in total and LDL cholesterol in the group receiving pravastatin were 18 and 25 percent greater than in the placebo group. By the end of the study, 19 percent of the patients in the treatment group had stopped taking pravastatin, and 24 percent of patients in the placebo group had crossed over to therapy with a cholesterol-lowering drug.
The effect of treatment with pravastatin was encouraging. The incidence of death from CHD was 6.4 percent in patients receiving pravastatin, compared with 8.3 percent in patients receiving placebo, for a relative risk reduction of 24 percent. Overall mortality decreased by 22 percent in the pravastatin group, and mortality from cardiovascular causes decreased by 25 percent. In addition, the incidence of myocardial infarction and stroke, the rate of bypass surgery and angioplasty, and the rate of hospitalization and number of hospitalized days were also lower for patients in the treatment group.
The authors conclude that in patients with CHD, using pravastatin to lower cholesterol levels reduces mortality rates from cardiovascular disease and all causes combined. The risk of myocardial infarction and stroke is also reduced. Pravastatin appears to be safe and well tolerated, as the authors found no significant increases in adverse events associated with taking the medication. At present, approximately 30 percent of patients are given lipid-lowering drugs following acute myocardial infarction. Given these results, the authors recommend that treatment with lipid-lowering drugs be considered in all patients with CHD.