Table 2. (continued)
Physician Health Study I
Study population aged 40-84 years
18,314 men and women at high risk of lung cancer
Study design and follow-up placebo-controlled, 12-year follow-up
Randomized, double-blind, placebo-controlled trial
Stephens et al. a CHAOS
ATBC trial 
2002 patients with angiographically proven coronary atherosclerosis.
29,133 male smokers aged 50-69 years
Randomized, double-blind, placebo-controlled with a 1.4-year follow-up
Randomized, double-blind, placebo-controlled with 5-8 years follow-up
Blot et al.  Nutrition intervention trials in Linxian, China
29,584 Chinese participants aged 40-69 years
Double-blind, randomized, placebo-controlled, 5.4-year follow-up
Antioxidants assessed Results of study
Patients either received 30 mg of (3-carotene and 25,000 IU retinal palmitate taken daily or placebo
Patients either received 400 or 800 IU of vitamin E or placebo
There was no cardioprotective effect of combination of P-carotene and vitamin A. Increased incidence of lung cancer was observed in patients on supplementation Participants receiving 400 IU but not 800 IU vitamin E had a reduced rate of non-fatal MI
a-tocopherol 50mg/day and P-carotene 20 mg/day, given alone or in combination
Daily supplementation with one of the following: (a) Retinol 5,000 IU + zinc 22.5mg
There was an increased incidence of lung cancer and cardiovascular events observed in patients taking carotene. There was slightly more incidence of hemorrhagic strokes in patients on vitamin E Reduction in total mortality, in cancer death and incidence especially for stomach cancer was seen in patients on the
Lee et al.  Women's Health Study
39,876 healthy women aged 45 years or older
Randomized, double blind, placebo-controlled, 2 X 2 factorial design, followed up for an average of 10.1 years
(b) Riboflavin 3.2mg + niacin 40 mg
(c) Ascorbic acid 120 mg + molybdenum 30 ^g
(d) ß-carotene 15 mg + selenium 50 ^g + a-tocopherol 30 mg
Vitamin E 600IU and aspirin 100 mg given on alternate days combination regimen of ß-carotene, selenium and a-tocopherol
Vitamin E did not decrease risk of CHD
Reproduced with some modifications from Hasanain and Mooradian .
ATBC = Alpha-Tocopherol Beta Carotene; ASAP = Antioxidant Supplementation in Atherosclerosis Prevention; CARET = Beta Carotene and Retinol Efficacy Trial; CVD = cardiovascular disease; GISSI-P = Gruppo Italiano per lo Studio della Sopravivenza nell'Infarto miocardico-Prevenzione; MI = myocardial infarction.
50 ^g + a-tocopherol 30 mg. Supplementation with p-carotene, vitamin E, and selenium was associated with a significant reduction in mortality, mostly secondary to the reduced rate of gastric cancers . However, the subjects in this study may have had some nutritional deficiencies at baseline. Another limitation of the study is that the precise component of the antioxidant supplement that was responsible for the beneficial outcome could not be ascertained. It is possible that the combination of the three antioxidants synergized the antioxidant properties of each other.
Several other large randomized trials, such as the Heart Outcomes Prevention Evaluation (HOPE) study , the GISSI-P (Gruppo Italiano per lo Studio della Sopravivenza nell'Infarto miocardico-Prevenzione) trial  and the Alpha-Tocopherol, Beta Carotene Cancer Prevention (ATBC) study  and the Heart Protection trial (HPS)  failed to demonstrate any significant cardioprotective effect of vitamin E either alone or in combination with vitamin C and p-carotene. Of concern is that in the ATBC trial , there was a greater incidence of lung cancer observed in a subset of men who were smokers and who were taking vitamin A supplements. Similar observations were made in the p-Carotene and Retinol Efficacy Trial (CARET)  where the incidence of lung cancer was increased in patients who were smokers or who had a history of asbestos exposure and were on vitamin A supplementation. These observations underscore the potential hazards of consuming large amounts of antioxidants. It is also disconcerting that antioxidants such as vitamin C, vitamin E, p-carotene and selenium may hamper the beneficial effects of simvastatin and niacin on lipid profile .
Additional interventional trials [43-46] are listed in table 2. The most recently published study is that of Women's Health Study . In this study vitamin E supplements (600 mg every other day) did not protect healthy women against heart attacks, stroke or cancer.
The preponderance of evidence in these interventional trials, unlike that of the observational trials, suggests that supplementation with conventional antioxidants, notably vitamin E, does not reduce the risk of CVD. However, the outcome of interventional studies may vary depending on the baseline nutritional status of the study population. Furthermore increased consumption of vitamins does not always translate into effective absorption and availability at critical cellular targets.
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