Vitamin E Primary Prevention Trials

Clinical trials of vitamin E have focused on alpha-tocopherol, the major component of vitamin E and the predominant antioxidant in circulating lipoproteins.28 Large randomized trials that examined vitamin E alone in the primary prevention of CVD are summarized in Table 3.2.

Table 3.2 Completed and ongoing randomized clinical trials of vitamin E supplementation in the primary prevention of cardiovascular disease (CVD)

Effect of

vitamin E









RR (95% CI)


29,133 male



CVD mortality

0.98 (0.89-1.08)


smokers aged


Fatal ischemic heart disease

0.95 (0.85-1.05)

Cancer Prevention

50-69 years;

vitamin E

Fatal ischemic stroke

0.84 (0.59-1.19)

Trial (ATBC)


(50mg/d), or both

Fatal hemorrhagic stroke

1.50 (1.03-2.20)

Primary Prevention

4,495 men and women

Vitamin E (300mg/d);


CVD mortality + MI + stroke

1.07 (0.74-1.56)

Project (PPP)

aged >50 years, with

aspirin (lOOmg/d);

CVD mortality

0.86 (0.49-1.52)

>1 CVD risk

open-label design

Nonfatal MI

1.01 (0.56-2.03)


Nonfatal stroke

1.56 (0.77-3.13)

Women's Health

39,876 female

Beta-carotene (50 mg


CVD mortality + MI + stroke

0.93 (0.82-1.05)

Study (WHS)

health professionals

every other day).

CVD mortality

0.76 (0.59-0.98)

aged >45 years;

vitamin E (600IU every


1.01 (0.82-1.23)

United States

other day), aspirin (lOOmg every other day), or a combination (2x2x2 factorial design)


0.98 (0.82-1.17)

Physicians' Health

15,000 male

Vitamin E (400 IU every


CVD mortality + MI + stroke


Study II (PHS II)

physicians aged >55 years; United States

other day), beta-carotene (50mg every other day), vitamin C (500mg/d), multivitamin (daily), or a combination (2x2 x 2 x 2 factorial design)

aAll trials were placebo controlled, except for the Primary Prevention Project (PPP), which used an open-label design.

aAll trials were placebo controlled, except for the Primary Prevention Project (PPP), which used an open-label design.

The Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study was the first large-scale randomized trial of antioxidant vitamins in a well-nourished population. This 2 x 2 factorial trial tested the effect of synthetic vitamin E (50 mg/d) and beta-carotene (20 mg/d) in the prevention of lung cancer among 29,133 Finnish male smokers aged 50-69 years.29 After a median of 6.1 years, vitamin E supplementation did not reduce the risk of lung cancer (the primary endpoint). There was also no clear reduction in risk of death due to ischemic heart disease (RR = 0.95; 95% CI, 0.85-1.05) or ischemic stroke (RR = 0.84; 95% CI, 0.59-1.19) although the risk of developing angina was lower among those assigned to vitamin E (RR = 0.91; 95% CI, 0.83-0.99).30 It was initially thought that the lack of convincing beneficial effect may have been due to inadequate dosing of vitamin E or a short follow-up time, but post-trial results with 8 more years of follow-up found no effect of alpha-tocopherol on total mortality (RR = 1.01; 95% CI, 0.96-1.05).31

The Primary Prevention Project (PPP) was an open-label 2 x 2 factorial trial of vitamin E (300 mg/d) and low-dose aspirin in 4,495 Italian men and women with one or more of the following CVD risk factors: hypertension, hypercholesterolemia, diabetes, obesity, family history of premature MI, or age >65 years.32 Since there was convincing evidence that aspirin was beneficial, the trial was stopped early after a mean follow-up of 3.6 years. At that time, vitamin E had no effect on any prespecified endpoint including the main combined endpoint of CVD death, nonfatal MI, and nonfatal stroke (RR = 1.07; 95% CI, 0.74-1.56). The negative result may have been due to insufficient statistical power or inadequate dosing of vitamin E.

In the Vitamin E Atherosclerosis Prevention Study (VEAPS), 353 men and women aged >40 years with an LDL >130 mg/dL and no evidence of CVD were randomized to vitamin E (400 IU) or placebo, and followed every 3 months for an average of 3 years.33 Vitamin E supplementation increased plasma vitamin E levels, decreased circulating oxidized LDL and decreased LDL oxidative susceptibility, but there was no difference in the primary endpoint of progression of common carotid artery intima-media thickness. In this group of low-risk participants, vitamin E did not reduce the progression of subclinical atherosclerosis.

The Women's Health Study (WHS) was designed to test whether vitamin E supplementation decreases the risk of CVD and cancer among a cohort of initially healthy women.34 Beginning in 1992, this clinical trial enrolled 39,876 U.S. female health professionals and evaluated the effect of vitamin E (600 IU every other day) on CVD events with a mean follow-up of 10.1 years.35 For the primary combined CVD outcome (nonfatal MI, nonfatal stroke, or CVD death), vitamin E supplementation did not have a significant effect (RR = 0.93; 95% CI, 0.82-1.05). For individual endpoints, vitamin E did not have an effect on MI (RR = 1.01; 95% CI, 0.82-1.23), stroke (RR = 0.98; 95% CI, 0.82-1.17), or total mortality (RR = 1.04; 95% CI, 0.93-1.16); however, there was a reduction in CVD death (RR = 0.76; 95% CI, 0.59-0.98). The WHS was the largest trial to date to evaluate clinical outcomes over an extended time period, and the results of this important study did not support the use of vitamin E supplementation for the prevention of CVD among healthy women.

In summary, trials of vitamin E supplementation have provided inconsistent results in the primary prevention of CVD, with a recent large study (WHS) that failed to show convincing CVD benefit for long-term use of vitamin E. One ongoing clinical trial, the Physicians' Health Study II (PHS II), is a large study assessing several antioxidants, including vitamin E (400 IU every other day) and results are expected in 2007.36 The PHS II will provide additional data to help identify the potential benefits and possible risks of vitamin E supplementation in the primary prevention of CVD.

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