Aims: In observational studies, prolonged lower blood total cholesterol levels - down at least to 3 mmol. l-1 - are associated with lower risks of coronary heart disease. Cholesterol-lowering therapy may, therefore, be worthwhile for individuals at high risk of coronary heart disease events irrespective of their presenting cholesterol levels. Observational studies also suggest that increased dietary intake of antioxidant vitamins may be associated with lower risks of coronary heart disease. The present randomized trial aims to assess reliably the effects on mortality and major morbidity of cholesterol-lowering therapy and of antioxidant vitamin supplementation in a wide range of different categories of high-risk patients.
Methods and results: Men and women aged 40 to 80 years were eligible provided they were considered to be at elevated risk of coronary heart disease death because of past history of myocardial infarction or other coronary heart disease, occlusive disease of non-coronary arteries, diabetes mellitus or treated hypertension; had baseline blood total cholesterol of 3.5 mmol. l-1 or greater; and no clear indications for, or contraindications to, either of the study treatments. Eligible patients who completed a pre-randomization run-in phase on active treatment were randomly allocated to receive simvastatin (40 mg daily) or matching placebo tablets and, in a '2x2 factorial' design, antioxidant vitamins (600 mg vitamin E, 250 mg vitamin C and 20 mg beta-carotene daily) or matching placebo capsules. Follow-up visits after randomization are scheduled at 4, 8 and 12 months, and then 6-monthly, for at least 5 years. Between July 1994 and May 1997, 15 454 men and 5082 women were randomized, with 9515 aged over 65 years at entry. Diagnostic criteria overlapped, with 8510 (41%) having had myocardial infarction (most of whom were either female, or elderly or with low blood cholesterol), 4869 (24%) some other history of coronary heart disease, 3288 (16%) cerebrovascular disease, 6748 (33%) peripheral vascular disease, 5963 (29%) diabetes mellitus (of whom 3985 had no history of coronary heart disease) and 8455 (41%) treated hypertension. Baseline non-fasting total cholesterol levels were less than 5.5 mmol. l-1 in 7882 (38%) participants, and LDL (low density lipoprotein) cholesterol less than 3.0 mmol. l-1 in 6888 (34%). During a mean follow-up of 25 months (range: 13 to 47 months), no significant differences had been observed between the treatment groups in the numbers of patients with muscle symptoms, other possible side-effects leading to termination of study treatment, or elevated liver and muscle enzymes. After 30 months of follow-up, 81% of randomized patients remained compliant with taking their study simvastatin or placebo tablets, and allocation to simvastatin produced average reductions in non-fasting blood total and LDL cholesterol of about 1.5-1.6 mmol. l-1 and 1.1-1.2 mmol. l-1 respectively. Eighty-seven per cent of patients remained compliant with taking their vitamin or placebo capsules, and allocation to the vitamin supplement produced an average increase in plasma vitamin E levels of about 24 micromol. l-1. Based on this initial follow-up period, the estimated annual rate of non-fatal myocardial infarction or fatal coronary heart disease is 2.4%, annual stroke rate is 1.3%, and annual all-cause mortality rate is 2. 2%.
Conclusion: The Heart Protection Study is large, it has included a wide range of patients at high risk of vascular events, and the treatment regimens being studied are well-tolerated and produce substantial effects on blood lipid and vitamin levels. The study should, therefore, provide reliable evidence about the effects of cholesterol-lowering therapy and of antioxidant vitamin supplements on all-cause or cause-specific mortality and major morbidity in a range of different categories of individuals for whom uncertainty remains about the balance of benefits and risks of these treatments. Copyrig