There is general agreement that elevated blood cholesterol levels are an important cause of coronary heart disease (CHD), and so various cholesterol-lowering treatments have been devised and tested over the past few decades. Previous randomised trials of these older drugs or diets did, in combination, demonstrate that within just a few years of lowering cholesterol there are reductions both in non-fatal myocardial infarction (MI) and in fatal CHD. Some of those older trials were large, but the cholesterol reductions produced by the treatments studied in them were too small (only about 10%) and the numbers of CHD deaths were too few (since many of those randomised were at low risk of death from CHD) to provide reliable direct evidence about the effects on total mortality. Moreover, overall, non-CHD deaths in those trials were (perhaps by chance) slightly more common in the treatment groups than in the control groups. So, although the demonstrated reduction in fatal CHD provides some indirect evidence that total mortality is reduced within just a few years of initiating therapy, there is still substantial uncertainty both in the medical profession and in the general population about the overall survival benefits of such treatments.
Now, however, a new class of drugs (the HMG CoA reductase inhibitors: simvastatin, lovastatin, pravastatin and fluvastatin) is available that can produce much larger sustained reductions (20-25%) in blood cholesterol. These drugs are well tolerated and appear to have few short-term side-effects. Consequently, they provide an opportunity to address directly the questions: "Does cholesterol lowering with these drugs in people at high risk of CHD produce a definite reduction in total mortality and, if so, which particular types of high-risk patient can expect worthwhile benefit?". But, even a systematic overview (or "meta-analysis") of the current trials of reductase inhibitors may well not be large enough to answer these questions reliably, especially if there are some serious long-term side-effects. Hence, the MRC/BHF Heart Protection Study (HPS) aims to randomise at least 20,000 patients considered on the basis of their age and past medical history to be at high risk of CHD (3 main risk groups: those with coronary artery disease; with occlusive disease of non-coronary arteries; or with diabetes) to compare at least 5 years of simvastatin treatment versus placebo. As well as providing unequivocal evidence about the net effects of several years of such treatment on total mortality among high-risk patients, the study will provide uniquely reliable assessments of the separate effects on CHD mortality and on specific non-cardiac causes of death. It will also assess its effects on total CHD, on other vascular diseases (e.g. stroke), on the need for vascular surgery, on cancer and on any non-vascular diseases that are sufficiently severe to involve hospital treatment. Such evidence will be particularly important because of concerns that have been expressed about possible hazards of various cholesterol-lowering treatments.
Prospective epidemiological studies indicate that a prolonged difference of one mmol/l in blood cholesterol in middle age is associated with about a halving in the risk of CHD throughout the usual UK cholesterol range of 5-7 mmol/l, and down at least to 3-4 mmol/l. Cholesterol- lowering drug therapy may, therefore, be worthwhile not only for patients with above-average cholesterol levels but also for those who are at high risk (e.g. because they have a history of vascular disease or diabetes) despite having cholesterol levels that are below the UK average. Hence, patients with below-average cholesterol levels are eligible for this study provided that they are considered on the basis of other factors to be at substantial 5-year risk of CHD. The study will provide reliable evidence about the effects on fatal CHD in each of the three main risk groups studied, and will also be sufficiently powerful to assess the effects on CHD incidence within several smaller subgroups where there is still substantial uncertainty about the benefits of such cholesterol-lowering treatments e.g. women, the elderly (65-75 years), those with below-average cholesterol (3.5 to 6 mmol/l), hypertensives, etc.
The MRC/BHF Heart Protection Study will also address the question of whether dietary supplementation with antioxidant vitamins has any effect on CHD. Low-density lipoprotein (LDL) cholesterol in the blood may be importantly atherogenic only after oxidative modification, so antioxidants that can protect LDL from such modification may help avoid CHD. Vitamin E is the major antioxidant in LDL particles, beta-carotene (which can also function as a fat-soluble antioxidant) is also carried in these particles, and vitamin C is the major water-soluble antioxidant in the plasma. Dietary supplementation with a combination of these vitamins can substantially prolong the resistance of LDL to oxidative damage, and has been shown in animal studies to reduce atherosclerotic lesions. Observational studies indicate that increased dietary intake and plasma levels of antioxidant vitamins are associated with lower levels of CHD. Hence, as well as being randomised to compare simvastatin versus placebo, all 20,000 high-risk patients in the MRC/BHF Heart Protection Study will also be randomised to compare antioxidant vitamin supplementation (with vitamins E and C and beta-carotene) versus placebo in a "2 x 2 factorial" design. Such a design allows all patients to contribute fully to assessment of the separate effects of the cholesterol-lowering drug and of the antioxidant vitamin supplement (without any material effect on study cost or sample size requirements), whilst also providing information about their combined effects.
To randomise at least 20,000 patients, the MRC/BHF Heart Protection Study is "streamlined": data collection and other extra work for collaborating hospitals have both been kept to an absolute minimum, with support provided to cover this minimised workload. If, as a result of this, the study can be really large and include a wide range of high-risk patients then it is likely to be of much wider relevance than a smaller or more homogeneous study would be.
August 1994HPS * Front Cover * Contents * Section 1 * Section 2 * Section 3 * Appendix * References * Back Cover