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
T. Meade et al., 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, EUR HEART J, 20(10), 1999, pp. 725-741
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.