Objectives

The objectives of the Coronary Drug Project were to 1) test efficacy and safety of several drugs in the long-term therapy of coronary heart disease in men with previous myocardial infarction; 2) obtain information on the natural history and clinical course of coronary heart disease; and 3) develop more advanced methodology for the design and conduct of long-term, large, collaborative clinical trials.

Background

The correlation of high levels of serum cholesterol with an increased incidence and prevalence of coronary heart disease (CHD) has been demonstrated repeatedly in prospective and cross-sectional epidemiological surveys. At the time of this study, it was not yet clear whether hyperlipidemia also influences risk of recurrent nonfatal and fatal CHD events in survivors of a first attack.

Many pharmaceutical agents lower serum lipid levels, and several had been extensively investigated by the start of this study. However, definitive knowledge was not yet available concerning long-term safety and efficacy of any preparation. Therefore, the Coronary Drug Project was initiated to investigate the long-term effects of several lipid lowering medications.

Participants

Eligible participants were men aged 30 to 64 who had a previous myocardial infarction (MI) categorized as New York Heart Association (NYHA) class I or II at least 3 months prior to enrollment. Exclusion criteria included previous surgery for coronary artery disease, major diseases or conditions that could affect long-term follow-up, and contraindication for use of the study drugs. At time of entry, participants could not be on lipid influencing medications or insulin.

8341 men were randomly assigned to treatment groups. 1101 men were randomly assigned to the low dose estrogen group, 1119 to the high dose estrogen group, 1103 to the clofibrate group, 1110 to the DT4-dextrothyroxine group, 1119 to the niacin group, and 2789 to the placebo group.

Design

The Coronary Drug Project was a randomized, double blind study conducted in 53 centers. There were separate randomization schedules for each clinic and for each of the two risk groups within each clinic. Low risk was defined as having only one previous MI with no complications and high risk was defined as having more than one previous MI or one MI with complications.

Participants were randomized following a two-month period on placebo medication. The treatment groups included: low-dose estrogen (2.5 mg/day), high-dose estrogen (5.0 mg/day), clofibrate (1.8 g/day), DT4-dextrothyroxine (6.0 mg/day), niacin (3.0 g/day), and placebo (3.8 mg lactose/day). All medications were dispensed in identical gelatin capsules. Each patient was started on one capsule three times a day, increased to two capsules three times a day after one month, and increased finally to three capsules three times a day after two months.

Follow-up visits occurred every four months for at least 5 years. A complete physical exam, including ECG, was performed annually.

The primary outcome was five-year all-cause mortality. Secondary outcomes included cause-specific mortality and nonfatal cardiovascular events.

Conclusions

Analysis indicated nonfatal adverse effects were occurring more often in the high-dose estrogen group than in the placebo group and treatment was discontinued in 1970. The DT4-dextrothyroxine group was discontinued late in 1971 because of an excess number of deaths compared with the placebo group. Based on no evidence of a positive therapeutic effect in terms of the project's primary endpoint, all-cause mortality, the low-dose estrogen group was discontinued in 1973.

The Coronary Drug Project: Initial Findings Leading to Modifications of Its Research Protocol. JAMA. 1970;214(7):1303–1313. doi:10.1001/jama.1970.03180070069012

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