Combination Antioxidant Secondary Prevention Trials

Trials testing combinations of antioxidants in secondary prevention are summarized in Table 3.7. The HDL-Atherosclerosis Treatment Study (HATS) was a trial of 160 patients with CHD, normal LDL cholesterol, and low HDL cholesterol who were randomized to a relatively high-dose combination of four antioxidants (800IU of vitamin E, 1,000mg of vitamin C, 25 mg of beta-carotene, and 100 |g of selenium) and/or lipid-modifying therapy (simvastatin to lower LDL and niacin to raise HDL) vs. placebo.64 After 3 years, simvastatin/niacin therapy decreased both coronary stenosis (P = 0.004 vs. placebo) and the event rate for a combined endpoint of death from coronary causes, MI, stroke, or revascularization (3% vs. 24% for placebo, P = 0.03). The antioxidant-only group did not show a reduction in coronary stenosis (P = 0.16 vs. placebo) or CVD events. While supplemental antioxidants attenuated the angiographic benefits of lipid-modifying therapy (P for interaction = 0.02) and diminished the clinical benefits as well (P for interaction = 0.13), the confidence intervals were wide and some of the interactions may have been due to chance. This small study raised the possibility that adding antioxidants to an effective lipid-modifying regimen may be harmful, but bigger and longer studies were needed.

Table 3.7 Completed and ongoing randomized clinical trials of combinations of antioxidants in the secondary prevention of cardiovascular disease (CVD)

Effect of combination supplementation (RR, 95% CI)


Population; Country Agent(s)a

Duration (years) Endpoint

HDL-Atherosclerosis Treatment Study (HATS)

Heart Protection Study (HPS)

Women's Angiographic Vitamin and Estrogen (WAVE) Women's Antioxidant Cardiovascular Study (WACS)

142 men and 18

women with CHD, low HDL, and normal LDL levels, mean age = 53 years; United States

20,536 men and women aged 40-80 years, with CHD, diabetes or treated hypertension; United Kingdom 423 postmenopausal women with coronary artery disease 8,171 female health professionals aged >45 years, with CVD or >3 coronary risk factors; United States

Simvastatin and niacinb; combination of vitamin E (800IU/d), vitamin C (l,000mg/d), beta-carotene (25mg/d), selenium (100 Hg/d); or both

Simvastatin (40mg/d); cocktail of vitamin E (600mg/d), beta-carotene (20mg/d), and vitamin C (250mg/d); or both Vitamin E (400IU twice daily) + vitamin C (500 mg twice daily) Beta-carotene (50 mg every other day), other antioxidant11, or a combination (2x2x2x2 factorial design)

MI + stroke + revascularization + death

Nonfatal MI + CHD mortality

Nonfatal MI + CHD mortality + stroke + revascularization

Nonfatal MI + stroke + death

CVD mortality + MI + stroke + revascularization

Simvastatin/niacin alone: 3%" Antioxidants alone: 21%

Simvastatin/niacin + Antioxidant: 14% Placebo: 24% 1.02 (0.94-1.11)

  1. 00 (0.94-1.06)
  2. 5 (0.80-2.9)

Completed in 2006; final results for combinations not yet available

All trials were placebo controlled.

Initial simvastatin dose was 10 mg if baseline LDL < llOmg/dL, and 20 mg if LDL > llOmg/dL, with subsequent dose adjustment dependent on LDL level. Initial niacin dose was 250mg twice per day, increasing to l.OOOmg twice per day over a 4-week period.

" The comparison between simvastatin/niacin alone with placebo was statistically significant {p < 0.05); other comparisons were not.

dBeta-carotene (50mg every other day); vitamin C (500mg daily); or combination of folic acid (2.5mg daily), vitamin B6 (50mg daily), and vitamin B12 (1 mg daily).

In the much larger Heart Protection Study (HPS), 20,536 participants with CHD, diabetes, or treated hypertension were randomized in a 2 x 2 factorial trial to either a daily antioxidant combination (600mg of vitamin E, 250 mg of vitamin C, and 20 mg of beta-carotene), simvastatin 40 mg daily, both, or neither. After 5 years, simvastatin proved effective in reducing major vascular events (CVD death, MI, stroke, or revascularization)65 while the antioxidant combination did not (RR = 1.00; 95% CI, 0.94-1.06).66 There was no increased harm observed in the antioxidant group, and in contrast to the HATS study, there were no adverse interactions between the study groups. This large study demonstrated neither harm nor benefit to taking large daily doses of antioxidants over a substantial amount of time.

In the Women's Angiographic Vitamin and Estrogen (WAVE) trial, 423 post-menopausal women with coronary artery disease were randomized to a combination of vitamin E (400 IU twice daily) and vitamin C (500 mg twice daily) or placebo.67 After a mean follow-up of 2.8 years, those assigned to the high-dose antioxidant combination had the suggestion of an increased risk of death, stroke, or nonfatal MI (RR = 1.5; 95% CI, 0.80-2.9), but the confidence intervals were wide. This study suggested that there may be an increased risk associated with antioxi-dant combination supplements.

In the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) trial, 520 Finnish men and postmenopausal women with hypercholesterolemia were assigned to one of four treatment arms: vitamin E (136 IU twice daily), slow-release vitamin C (250 mg twice daily), placebo, or both. After 3 years of follow-up, men assigned to both antioxidants had a slowing of the progression of carotid atherosclerosis that was not seen in participants assigned to placebo or a single antioxidant.68 Three more years of an open-label follow-up comparing the combination therapy and placebo confirmed the initial findings that moderate doses of vitamin E and vitamin C safely slowed atherosclerotic disease, particularly in men.69

Because transplant patients are under increased oxidative stress and often have accelerated atherosclerosis, antioxidant supplements may be particularly beneficial in this group. In a small study of 40 patients who had received a heart transplant within the last 2 years, a combination of vitamin E (400IU twice daily) and vitamin C (500 mg twice daily) was compared to placebo. After 1 year, the progression of transplant-associated coronary atherosclerosis was significantly slowed in the group assigned to the antioxidant combination.70

The WACS was a secondary prevention trial that utilized a 2 x 2 x 2 factorial design to evaluate vitamin C (500 mg daily), vitamin E (600 IU every other day), and beta-carotene (50 mg every other day). In this trial, 8,171 U.S. female health professionals at high risk of CVD either because of preexisting CVD or the presence of three or more CVD risk factors were randomized in a study design that allowed for analyses of multiple interactions between antioxidants.56 In this study of high-risk individuals, supplementation with vitamin E, beta-carotene, or vitamin C did not have a beneficial effect on CVD outcomes, and there were no significant interactions between the antioxidants.48

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