Elsevier

The Lancet

Volume 360, Issue 9326, 6 July 2002, Pages 23-33
The Lancet

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MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20 536 high-risk individuals: a randomised placebo-controlled trial

https://doi.org/10.1016/S0140-6736(02)09328-5Get rights and content

Summary

Background

It has been suggested that increased intake of various antioxidant vitamins reduces the incidence rates of vascular disease, cancer, and other adverse outcomes.

Methods

20 536 UK adults (aged 40–80) with coronary disease, other occlusive arterial disease, or diabetes were randomly allocated to receive antioxidant vitamin supplementation (600 mg vitamin E, 250 mg vitamin C, and 20 mg β-carotene daily) or matching placebo. Intention-to-treat comparisons of outcome were conducted between all vitamin-allocated and all placebo-allocated participants. An average of 83% of participants in each treatment group remained compliant during the scheduled 5-year treatment period. Allocation to this vitamin regimen approximately doubled the plasma concentration of α-tocopherol, increased that of vitamin C by one-third, and quadrupled that of β-carotene. Primary outcomes were major coronary events (for overall analyses) and fatal or non-fatal vascular events (for subcategory analyses), with subsidiary assessments of cancer and of other major morbidity.

Findings

There were no significant differences in all-cause mortality (1446 [14·1%] vitamin-allocated vs 1389 [13·5%] placebo-allocated), or in deaths due to vascular (878 [8·6%] vs 840 [8·2%]) or non-vascular (568 [5·5%] vs 549 [5·3%]) causes. Nor were there any significant differences in the numbers of participants having non-fatal myocardial infarction or coronary death (1063 [10·4%] vs 1047 [10·2%]), non-fatal or fatal stroke (511 [5·0%] vs 518 [5·0%]), or coronary or non-coronary revascularisation (1058 [10·3%] vs 1086 [10·6%]). For the first occurrence of any of these “major vascular events”, there were no material differences either overall (2306 [22·5%] vs 2312 [22·5%]; event rate ratio 1·00 [95% CI 0·94–1·06]) or in any of the various subcategories considered. There were no significant effects on cancer incidence or on hospitalisation for any other non-vascular cause.

Interpretation

Among the high-risk individuals that were studied, these antioxidant vitamins appeared to be safe. But, although this regimen increased blood vitamin concentrations substantially, it did not produce any significant reductions in the 5-year mortality from, or incidence of, any type of vascular disease, cancer, or other major outcome.

Introduction

LDL-cholesterol may be rendered more atherogenic by oxidative modification that allows it to accumulate in the artery walls, and antioxidants have been shown to slow the progression of atherosclerosis in animal studies.1, 2, 3, 4 Vitamin E is a major antioxidant in LDL particles, and supplementation with vitamin E substantially prolongs the in-vitro resistance of LDL particles to oxidative damage, and has other potentially protective effects.3, 4, 5, 6, 7, 8 β-carotene, which can also function as a fat-soluble antioxidant in certain physiological circumstances, is carried with vitamin E in the fatty core of LDL particles.3, 4 Vitamin C is a major water-soluble antioxidant in the plasma, and it can help to regenerate oxidised vitamin E.4, 9, 10, 11 In several non-randomised observational studies in different populations, dietary intake or plasma concentrations of these antioxidant vitamins were inversely associated with vascular disease incidence and mortality,12, 13, 14, 15, 16, 17 and blood concentrations of autoantibodies to oxidised LDL and the degree of LDL susceptibility to oxidative damage have been associated with atherosclerosis.18, 19 Dietary intake of antioxidant vitamins has also been reported in observational studies to be inversely associated with the incidence of various types of cancer.16, 17, 20, 21, 22, 23 But, without large-scale randomised evidence, the possibility that these associations merely reflect the effects of other aspects of the diet or lifestyle on disease rates cannot be ruled out.20, 24

Promising results on the progression of atherosclerosis25, 26 and on the incidence of vascular disease27, 28 have been reported from some small randomised trials of a few years of vitamin E in people with pre-existing vascular disease. But, the available results from much larger randomised trials of several years of vitamin E have been unpromising.29, 30, 31, 32, 33, 34 Similarly, the results thus far available from large long-term randomised trials of β-carotene and of vitamin C have not provided good evidence of benefit.29, 30, 34, 35, 36, 37 Indeed, the results of some trials have even suggested that these vitamins have adverse effects (in particular on the incidence of haemorrhagic stroke and particular cancers30, 35), although this observation has not been confirmed by other trials.

The Heart Protection Study provides further evidence about the effects of these three antioxidant vitamins on vascular and non-vascular mortality and major morbidity by assessing 5 years of their supplementation in a large number of high-risk individuals.

Section snippets

Patients and methods

Details of the study objectives, design, and methods are reported elsewhere38, 39 (including the protocol on the study website: http://www.hpsinfo.org) and are summarised below. As well as comparing antioxidant vitamins versus matching placebo in 20 536 randomised participants (which is the subject of the present report), a “2X2 factorial” design was used to allow the separate assessment of cholesterol-lowering therapy (see accompanying report39).

Statistical analysis

The data analysis plan was prespecified either in the original protocol38 or in amendments (see study website) made before any analyses of the effects of treatment on clinical outcomes were available to the Steering Committee. All comparisons involved logrank analyses of the first occurrence of particular events during the scheduled treatment period after randomisation among all those allocated the vitamins versus all those allocated matching placebo capsules (ie, they were “intention-to-treat”

Role of the funding source

The study was designed, conducted, analysed, and interpreted by the investigators entirely independently of all funding sources.

Patient enrolment

A total of 20 536 individuals (15 454 men and 5082 women) were randomised (figure 1), with 5806 aged at least 70 years at study entry.39 Previous myocardial infarction was reported by 8510 (41% of those randomised), some other history of coronary disease by 4876 (24%), and no history of coronary disease by 7150 (35%). Among the 7150 participants without diagnosed coronary disease, 1820 had cerebrovascular disease, 2701 had peripheral arterial disease, and 3982 had diabetes mellitus (with some

No clear evidence of benefit or harm

The results of the Heart Protection Study indicate that 5 years of daily supplementation with 600 mg vitamin E, 250 mg vitamin C, and 20 mg β-carotene is safe. But, although this regimen substantially increased the plasma concentrations of these vitamins, no significant benefits were observed among the high-risk individuals that were studied. These results effectively rule out any substantial reductions—or, indeed, increases—in heart attacks, strokes, cancers, or other major adverse events

Conclusions

Based on the presumption that the likelihood of benefit outweighs any low probability of harm, daily supplementation with a few hundred mg of vitamin E (and with other vitamins) has been recommended for middle-aged and older people.7, 56 But, despite assessing the combined effects of several years of substantial daily doses of different antioxidant vitamins (including 600 mg of vitamin E) in a large number of high-risk people, the Heart Protection Study has not been able to demonstrate any

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    Collaborators and participating hospitals are listed in Lancet 2002; 360: 7–22

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