MRC BHFHeart Protection Study of cholesterol-lowering therapy and of antioxidant vitamin supplementation in a wide range of patients at increased risk of coronary heart disease death: early safety and efficacy experience

Aims In observational studies, prolonged lower blood total cholesterol leve ls - down at least to 3 mmol . l(-1) - are associated with lower risks of c oronary heart disease. Cholesterol-lowering therapy may, therefore, be wort hwhile for individuals at high risk of coronary heart disease events irresp ective of their presenting cholesterol levels. Observational studies also s uggest that increased dietary intake of antioxidant vitamins may be associa ted with lower risks of coronary heart disease. The present randomized tria l aims to assess reliably the effects on mortality and major morbidity of c holesterol-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 provide d they were considered to be at elevated risk of coronary heart disease dea th 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 nmol . l( -1) or greater and no clear indications for, or contraindications to, eithe r of the study treatments. Eligible patients who completed a pre-randomizat ion run-in phase on active treatment were randomly allocated to receive sim vastatin (40 mg daily) or matching placebo tablets and, in a '2 x 2 factori al' design: antioxidant vitamins (600 mg vitamin E, 250 mg vitamin C and 20 mg beta-carotene daily) or matching placebo capsules. Follow-up visits aft er randomization are scheduled at 4, 8 and 12 months, and then 6-monthly, f or 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 fema le, or elderly or with low blood cholesterol), 4869 (24%) some other histor y of coronary heart disease, 3288 (16%) cerebrovascular disease, 6748 (33%) peripheral vascular disease? 5963 (29%) diabetes mellitus (of whom 3985 ha d 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) choleste rol less than 3.0 mmol . l(-1) in 6888 (34%). During a mean follow-up of 25 months (range: 13 to 47 months), no significa nt differences had been observed between the treatment groups in the number s 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 simva statin produced average reductions in non-fasting blood total and LDL chole sterol 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 vit amin or placebo capsules, and allocation to the vitamin supplement produced an average increase in plasma vitamin E levels of about 24 mu mol . l(-1). Based on this initial follow-up period, the estimated annual rate of non-f atal 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 rang e of patients at high risk of vascular events, and the treatment regimens b eing studied are well-tolerated and produce substantial effects on blood li pid and vitamin levels. The study should, therefore, provide reliable evide nce about the effects of cholesterol-lowering therapy and of antioxidant vi tamin supplements on all-cause or cause-specific mortality and major morbid ity in a range of different categories of individuals for whom uncertainty remains about the balance of benefits and risks of these treatments.