Evidence from both basic research and epidemiology indicates that enhanced lipid peroxidation is associated with accelerated atherogenesis [1–6], whereas that from randomized clinical trials is very limited and controversial [5–7]. Whilst epidemiological studies suggest that lipid peroxidation might be most relevant in early phases of atherosclerotic lesion development [1, 2, 4, 5] and that vitamin E may have a protective effect, if any, in clinically healthy persons [8, 9], there are no previous randomized trials testing the hypothetical preventive effect of either vitamin E or C on atherosclerotic progression in clinically healthy subjects.
Vitamin E and vitamin C are considered two of the most important dietary antioxidants [4, 5, 9, 10]. Vitamin E may also have other anti-atherogenic properties [11–15]. When vitamin E works as an antioxidant it is oxidized to harmful α-tocopheroxyl radicals, which need to be reduced back to α-tocopherol. Vitamin C can regenerate α-tocopheroxyl radical to α-tocopherol . Theoretically, supplementing high-risk individuals with high doses of vitamin E alone could even promote rather than reduce lipid peroxidation . Also, in our prospective population study, vitamin C deficiency was associated with increased risk of coronary events . For these reasons we designed a randomized clinical trial in which not only vitamin E but also vitamin C was supplemented.
The ASAP study was designed to test the main study hypothesis that the supplementation of 45–69 year-old smoking and nonsmoking men and postmenopausal women twice daily with a formulation containing either 91 mg of d-α-tocopherol or 250 mg of vitamin C or both vitamins to retard the progression of common carotid atherosclerosis. As men and cigarette smokers have enhanced oxidative stress and lipid peroxidation [1, 5], a greater effect was hypothesized a priori in men and in smokers than in women and in nonsmokers. Because of the synergism between vitamins E and C in the human body, the greatest protective effect was hypothesized by the combined supplementation.