Combination Antioxidant Primary Prevention Trials

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Because observational studies of antioxidants found that individuals with a higher intake of vitamin E or beta-carotene also had a higher intake of other antioxidants and micronutrients,4,21,25,57,58 it is possible that a combination of antioxidants work together as cofactors to confer a beneficial effect. For example, vitamin E alone can be oxidized to a harmful radical, while vitamin C reduces the radical back to alpha-tocopherol. Vitamin E alone can have neutral, pro-, or antioxidant effects under various cellular conditions.59 As a result, trials of a single antioxidant supplement may lead to a null result, but an appropriate combination of antioxidants may provide a clinical benefit. Several trials have tested combinations of antioxidants, and the primary prevention trials are summarized in Table 3.6.

The Chinese Cancer Prevention Trial randomized 29,584 poorly nourished residents of Linxian, China to one of eight treatment arms testing various combinations of vitamins and minerals.60 For participants assigned to a combination of a low dose of vitamin E (30 mg daily), beta-carotene (15 mg daily), and selenium (50 |g daily), there was a reduction in total mortality (RR = 0.91; 95% CI, 0.84-0.99) after nearly 6 years of treatment; most of the mortality benefit was due to a reduction in stomach cancer deaths (RR = 0.79; 95% CI, 0.64-0.99). It is unclear which components of the combination treatment led to any benefit, and the findings may not be generalizable to a well-nourished population with different baseline health risks than this study group.

Table 3.6 Completed and ongoing randomized clinical trials of combinations of antioxidants in the primary prevention of cardiovascular disease (CVD)

Effect of combination



Population; Country


Duration (years)


RR (95% CI)

Chinese Cancer

29.584 men and women;

Cocktail of vitamin E



0.90 (0.76-1.07)

Prevention Trial


(30mg/d), beta-caro-tene (15mg/d), and selenium (50mg/d)


Beta-Carotene and

18.314 men and women

Beta-carotene (30mg/d)


CVD mortality

1.26 (0.99-1.61)

Retinol Efficacy

who were smokers

and retinol

Trial (CARET)

or had been exposed to asbestos; United States



13.017 men and women

Cocktail of vitamin E


Major fatal and nonfa

0.97 (0.77-1.20)

en Vitamines

aged 35-60 years;

(30mg/d), vitamin C

tal ischemic cardio

et Minéraux


(120mg/d), beta-

vascular events

AntioXydants Study

carotene (6mg/d),


selenium (100|ig/d). zinc (20mg/d)

Physicians' Health

15.000 male physicians

Vitamin E (400IU


CVD mortality + MI +


Study II (PHS II)

aged >55 years; United States

alternate days), beta-carotene (50 mg every other day), vitamin C (500mg/d), multivitamin (daily), or a combination (2x2x2x2 factorial design)


a All trials were placebo controlled.

a All trials were placebo controlled.

The Beta-Carotene and Retinol Efficacy Trial (CARET) evaluated a combined treatment of beta-carotene (30 mg daily) and retinol (25,000 IU daily) in 18,314 men and women at elevated risk of lung cancer due to cigarette smoking and/or occupational exposure to asbestos.61 The trial was stopped early due to lack of benefit and an increased incidence of lung cancer in the active treatment group (RR = 1.28; 95% CI, 1.04-1.57). After 4 years, the group assigned to the antioxidant combination had an increased risk of total mortality (RR = 1.17; 95% CI, 1.03-1.33) and a trend toward increased CVD mortality (RR = 1.26; 95% CI, 0.99-1.61).

The Supplementation en VItamines et Minéraux AntioXydants (SU.VI.MAX) Study evaluated the efficacy of a balanced combination of antioxidants and minerals in the primary prevention of cancer and CVD.62 By using a daily combination of vitamin C (120 mg), vitamin E (30 mg), beta-carotene (6 mg), selenium (100 |Ug), and zinc (20 mg), nutritional-level doses of supplements were tested in a representative sample of the French population. In this randomized trial, 13,017 participants (7,876 women aged 35-60 years and 5,141 men aged 45-60 years) were followed for a median of 7.5 years and antioxidant supplementation did not reduce ischemic CVD (RR = 0.97; 95% CI, 0.77-1.20).63

The ongoing Physicians' Health Study II (PHS II) randomized nearly 15,000 healthy U.S. male physicians aged > 55 years into a 2 x 2 x 2 x 2 factorial design to test beta-carotene (50 mg every other day), vitamin E (400 IU every other day), vitamin C (500mg daily), and a multivitamin daily.36 The vitamin C and multivitamin arms will provide the first randomized data on whether these agents can prevent CVD, cancer, or age-related eye disease. The beta-carotene arm was stopped, and the vitamin E, vitamin C, and multivitamin arms are continuing into 2007.

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