US Pharm. 2006;10:37-42.

A recent survey estimated that 40% of the U.S. population uses vitamins and mineral supplements weekly.1 Vitamin E is the single-source vitamin most often taken for a cardiovascular purpose. 2,3 According to findings from the National Health and Nutrition Examination Survey, 37% of adult respondents used vitamin E supplements. Of these individuals, 11.3% had a daily vitamin E intake of 400 IU or higher. Furthermore, participants who had a history of coronary heart disease, angina pectoris, stroke, or diabetes were more likely to use high doses of vitamin E than were participants without these conditions.4

Alpha-tocopherol, the most active form of vitamin E in humans, has traditionally been viewed as a preventive treatment for cardiovascular disease due to its antioxidant properties. Animal studies have demonstrated that vitamin E reduces atherosclerotic lesions, smooth muscle cell proliferation, platelet adherence and aggregation, and protein kinase C activation. In addition, human studies have shown improvement in endothelial function following vitamin E therapy.5

In recent clinical trials and meta-analyses, however, the benefit of vitamin E has come into question.5-11 Although using supplements such as vitamin E can make patients feel more in control of their health, problems can occur if the patient–health care provider relationship is weak or if patients overmedicate, thinking that "more is better."2,12 Several studies suggest that certain dosages of vitamin E can have a harmful effect.

Most data supporting the use of vitamin E have originated from epidemiological and observational studies.13-15 However, in recent years, findings from these types of studies, which demonstrate benefits of various medications, have not been substantiated when tested in prospective, randomized clinical trials.5-8 In addition, significant risks associated with the use of some medications have been discovered, as was the case with hormone replacement therapy.16,17 During the past 10 years, numerous prospective, randomized, double-blind, placebo-controlled trials have been conducted in an attempt to more clearly define the role of vitamin E supplementation in cardiovascular disease. 5-11 The outcomes of these studies have forced clinicians to reevaluate the clinical benefit of vitamin E use. This article provides pharmacists with an update on current clinical literature evaluating the safety and efficacy of vitamin E for the prevention of cardiovascular disease.

Methods
A PubMed/Medline search of articles published from 1980 to 2006 was conducted by combining the terms alpha-tocopherol, vitamin E, dietary supplements, antioxidants, and multivitamins with the terms cardiovascular health, heart disease, prevention of cardiovascular disease, coronary artery disease, myocardial infarction, and heart failure. Only English-language articles were extracted from the literature search and used in this review.

Discussion
Original Observational Studies: Two large observational studies, the Nurses' Health Study and the Health Professionals Follow-Up Study, showed a reduction in the risk of heart disease following preventive treatment with vitamin E. The Nurses' Health Study demonstrated that female nurses ages 34 to 59 who took 100 IU/day or more of vitamin E for at least two years had a 41% reduction in the risk of heart disease and a 21% reduction in the risk of ischemic stroke, compared with women who did not take vitamin E supplements.13 Similarly, in the Health Professionals Follow-Up Study, men ages 40 to 75 who took 100 to 350 IU/day of vitamin E showed a 37% reduction in risk of heart disease compared with non–supplement users.14 Both studies were non–randomized controlled trials and evaluated only patients with a low risk for cardiovascular disease. Nonetheless, health care practitioners have based their current support for the use of vitamin E on these, and several other, observational trials, without putting vitamin E through the rigorous clinical trials process required of new medications.13-15

Primary Prevention Trials: In the recent Women's Health Study, a total of 39,876 healthy women 45 and older received either vitamin E (600 IU every other day for approximately 10 years) or placebo.6 Preventive treatment with vitamin E did not affect the incidence of myocardial infarction or stroke. The investigators concluded that the results of the Women's Health Study do not support the use of vitamin E supplementation for cardiovascular disease prevention. Their findings are consistent with current guidelines, which state that the use of antioxidant vitamins is not justified for cardiovascular disease risk reduction.6

Despite these findings, there was a significant 24% reduction in the secondary end point of cardiovascular deaths. In a small subgroup analysis, women 65 and older who took vitamin E had a 49% reduction in the risk of cardiovascular death, a 34% reduction in the risk of myocardial infarction, and 26% reduction in the risk of major cardiovascular events. The investigators noted that the results of this subgroup analysis differ from findings of other studies and suggested that this subset of women be studied further.

Another study, the Physicians' Health Study II, is expected to be reported in 2008 and will provide more conclusive data on the safety and effectiveness of vitamin E for the prevention of cardiovascular disease in healthy patients.18

Secondary Prevention Trials and Meta-Analyses: In the Primary Prevention Project Trial, investigators found a substantial lack of effect of antioxidant vitamin supplementation in preventing major cardiovascular events in at-risk patients.7 In this study, a group of 509 patients with diabetes received 300 mg (447 IU) per day of vitamin E for a median follow-up period of 3.7 years.7 

In another study, the Heart Protection Study, a total of 20,536 patients with cardiovascular disease were given antioxidant vitamin supplementation (600 mg [1,333 IU] vitamin E, 250 mg of vitamin C, and 20 mg of beta-carotene) or placebo.8 Patients were monitored for major coronary events, as well as fatal or nonfatal vascular events, for a period of five years. Among the high-risk individuals who were studied, these antioxidant vitamins appeared to be safe, but they did not reduce five-year mortality rates or incidence of any type of vascular disease.8

The Health Outcomes Prevention Evaluation--The Ongoing Outcomes (HOPE-TOO) trial, an extension of the original HOPE trial, evaluated the safety and efficacy of vitamin E (400 IU/day) versus placebo in 7,030 patients with diabetes or cardiovascular disease.5,19 After a median follow-up period of seven years, investigators found results, consistent with most recent clinical trials, showing that long-term vitamin E supplementation (longer than five years) had no significant effect on myocardial infarction, stroke, cardiovascular death, unstable angina, revascularization, or total mortality.5

The Cambridge Heart Antioxidant Study tested the effects of vitamin E (400 or 800 IU/day) versus placebo on the risk of cardiovascular death and nonfatal myocardial infarction in 2,002 patients with overt clinical and angiographic coronary atherosclerosis. Researchers found that treatment with vitamin E significantly reduced the rates of major cardiovascular events and nonfatal myocardial infarction but had no positive effect on cardiovascular death.20 In addition, total mortality was slightly, but not significantly, greater in the alpha-tocopherol group than in those who took placebo. The researchers suggested that the effect of alpha-tocopherol treatment on cardiovascular deaths requires further study. 20

In addition, several meta-analyses of randomized controlled trials have been reported in the past three years, showing strong support for a lack of effect of vitamin E on cardiovascular disease outcomes. 9-11

Safety of Vitamin E: While the Heart Protection Study, the Primary Prevention Project trial, and the Women's Health Study all found vitamin E to be safe and well tolerated compared with placebo, the HOPE-TOO trial did not. The final analysis of the HOPE-TOO trial demonstrated an increased risk of heart failure among patients taking vitamin E compared with those taking placebo.5 The risk of heart failure increased by 13%, with a relative risk of 1.19. In patients with the longest duration of vitamin E treatment and observation, the risk of heart failure increased by 19% and the risk of heart failure–related hospitalizations increased by 40%.5 In an echocardiographic substudy, which evaluated the effects of ramipril and vitamin E on left ventricular mass, volumes, and function in 506 patients, baseline left ventricular ejection fractions were similar among placebo and vitamin E users. However, at the conclusion of the substudy, there was a mean (SD) decrease in left ventricular ejection fraction of 1.86% in the vitamin E group and 0.58% in the placebo group.5 In another recent trial, the Gissi-Prevenzione trial, researchers found that among patients who had had a heart attack within the past three months and an ejection fraction of less than 50%, those who were given 300 mg/day of vitamin E had a statistically significant 50% increase in the risk of heart failure compared with those who received n-3 polyunsaturated fatty acids, both vitamin E and n-3 polyunsaturated fatty acids, or neither. 21

In a recent meta-analysis of 19 trials by Miller et al., a dose-dependent relationship between vitamin E supplementation and all-cause mortality was observed.9 Specifically, all-cause mortality progressively increased when doses of 150 IU/day or greater of vitamin E were used. Patients taking 400 IU/day of vitamin E had a 10% higher risk of dying than those not taking vitamin E.9 The HOPE-TOO researchers, as well as Miller et al., noted that their findings were based on patients with preexisting cardiovascular disease and that the generalization of this data to healthy adult populations could not be made.

The mechanism for this observed increased risk of heart failure and possible increased risk of mortality is not completely understood. Proposed mechanisms include the potential for vitamin E to become a pro-oxidant when given in increased doses.5,22 It is also thought that vitamin E may displace other fat-soluble antioxidants, disrupting the natural balance of antioxidant systems and increasing the vulnerability to oxidative damage. Vitamin E may also in­ hibit human cytosolic glutathione S-transferases, which help detoxify drugs and endogenous toxins.9,23,24 These studies therefore suggest that the increased risk must be taken into account when considering vitamin E supplementation in patients with cardiovascular disease.

Several important drug interactions with vitamin E have also been reported in the clinical literature. A dose-dependent interaction with antiplatelet and anticoagulant medications has been observed. These effects appear to be clinically relevant at doses greater than 800 IU/day.25-27 Also, in the Alpha-Tocopherol, Beta Carotene Cancer Prevention Study (ATBC), researchers found that a dose of 50 mg (74 IU) per day of vitamin E led to an increased risk in hemorrhagic stroke, compared with beta-carotene or placebo.28 Vitamin E and other antioxidant vitamins reportedly blunt statin- and niacin-induced increases in HDL cholesterol level.29 The importance of these drug interactions in the cardiovascular patient population cannot be overlooked, and patients should be monitored closely if these medications are being taken concomitantly.

Conclusion
Why do findings from randomized controlled trials differ significantly from those of original epidemiological and observational studies? In an editorial that appeared in JAMA, Rita Redberg, MD, MSc, attempted to explain the benefits observed in early observational studies of vitamin E by suggesting the idea of the "healthy user." She hypothesized that the healthy lifestyle behaviors of individuals who take various supplements are actually responsible for better health, not the supplements themselves. The "healthy user" bias is minimized with a rigorous trial design, such as that seen in the Women's Health Study. 30

This literature review points out that routine vitamin E supplementation for primary or secondary prevention of cardiovascular disease has not shown any significant benefit and could possibly have adverse effects. Further studies are needed to examine the potential for increased risk of heart failure and all-cause mortality in healthy individuals who take vitamin E for primary prevention of cardiovascular disease.

Through the Internet and other media, consumers have access to the most up-to-date and relevant medical information; however, they also have access to misleading information. Pharmacists should have current, accurate medical information to properly educate the public about the best health care decisions. For many years, vitamin E has been a frequently used OTC product for the prevention of cardiovascular disease; the time has come for pharmacists to reconsider that recommendation.

Even though there is little support for the use of vitamin E as an agent to help prevent or treat cardiovascular disease, pharmacists still have many treatment options to recommend to their patients. Pharmacists should encourage a healthy lifestyle that focuses on proper diet and exercise, smoking cessation, and the management of hypertension, diabetes, and hypercholesterolemia. All of these lifestyle adjustments have been shown to decrease the risk of cardiovascular disease and its complications.

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