To determine by sequential coronary arteriography whether a lipid-lowering diet with and without lipid-lowering drugs could reverse coronary artery disease in normocholesterolemic patients. Also, to test whether fish oil supplements could improve human coronary atherosclerosis. Finally, to determine the effect of combination therapy with lipid-reducing drugs in patients with coronary heart disease and "normal" cholesterol levels. At least three clinical trials were conducted.

BACKGROUND:

The prognosis of patients with coronary heart disease is closely related to the degree of coronary luminal obstruction. In population studies, the incidence and severity of coronary atherosclerosis on angiography is correlated with diet and plasma lipoprotein cholesterol. Previous clinical trials had shown that treatments that lowered plasma concentrations of low density lipoprotein cholesterol benefited some hypercholesterolemic patients with coronary heart disease. No similar benefit had been demonstrated in normocholesterolemic patients who make up the majority of patients with coronary heart disease.

DESIGN NARRATIVE:

In the cholesterol-lowering agent trial, all patients received Step 1 dietary instruction before randomization and every three months thereafter. Randomization was stratified by medical or surgical treatment for coronary disease and the ratio of total to HDL cholesterol. A total of 39 patients were assigned to placebo and 40 to active treatment with pravastatin, nicotinic acid, cholestyramine, and gemfibrozil stepwise as needed to reach the specified goal (total cholesterol less than or equal to 4.1 mmol/L, ratio of LDL/HDL cholesterol less than or equal to 2.0). Lipid concentrations were measured every six weeks. Baseline angiograms were compared to angiograms taken at 30 months.

In the fish oil trial, 41 patients were randomized to fish oil capsules containing 6 grams of n-3 fatty acids daily and 39 patients were randomized to olive oil placebo capsules for an average duration of 28 months. Each fish oil capsule contained 500 mg of n-3 polyunsaturated fatty acids composed of 240 mg of eicosapentaenoic acid, 160 mg of docosahexaenoic acid, and 100 mg of mainly docosapentaenoic acid. Randomization was stratified by medical or surgical treatment for coronary disease and the ratio of total to HDL cholesterol. The primary outcome variable was change in minimal diameter of coronary artery lesions expressed as a continuous variable. During the initial hospital stay for catheterization, dietary instruction was provided to every patient according to the National Cholesterol Education Program (NCEP) Step 1 guidelines. A seven-day diet record was collected at the randomization visit and every three months during the trial. Every twelve weeks, a research nurse reviewed with the patients side effects, diet, and concomitant medications and performed a pill count. Every 24 weeks, the patients received an interval medical history and physical examination by a physician. A fasting blood sample was obtained for lipid analysis at the 12- and 24-week visits and every 24 weeks thereafter. If the total cholesterol level of any patient increased to 250 mg/dl (6.43 mmol/liter) or greater on two consecutive measurements, intensified dietary instruction was given, followed by drug therapy with cholestyramine or nicotinic acid or both as needed to lower total cholesterol to less than 250 mg/dl. Twenty-one patients did not complete the protocol due to death, refusal to undergo the second cardiac catheterization, development of medical conditions precluding participation, intolerance to the capsules, and a missing initial angiogram.

In the combination therapy trial, patients were randomized to usual care or to stepped-care drug therapy with lipid-lowering agents including pravastatin, nicotinic acid, cholestyramine, and gemfibrozil to decrease total cholesterol levels to less than 160 mg/dl and the ratio of low density lipoprotein cholesterol to high density lipoprotein cholesterol to less than 2.0. Measurements included fasting serum lipoprotein profile, fasting apolipoprotein levels, and frequency of adverse effects. Patients were assessed every six weeks during drug titration and every three months thereafter for two -and-a-half years.

The study completion date listed in this record was obtained from the "End Date" entered in the Protocol Registration and Results System (PRS) record.

Men and women, normocholesterolemic, with 30 percent or greater narrowing of a coronary artery lumen as revealed by angiography. (Cholesterol-Lowering Agent Trial).

Men and women with angiographically-documented coronary heart disease (Fish Oil Tr