By Howell Sasser, PhD
Understanding of the role of oxidative stress in human health has grown considerably in recent years. With it has grown interest in the potential benefit of antioxidants for disease prevention. As the leading cause of death in the United States, heart disease—and its inflammatory component—have received special attention in this respect. A number of agents, including vitamins C and E, beta-carotene, and selenium, have shown promise in observational studies. As well-controlled clinical trials begin to report results, the likely value of various agents is being re-evaluated. This review summarizes the literature to date on one of the better-studied compounds, vitamin E.
Mechanism of Action
The mechanism of action of vitamin E in processes associated with heart disease is the subject of continuing debate. The most commonly offered explanation focuses on inhibition of low-density lipoprotein (LDL) cholesterol peroxidation.1 Changes in LDL have been shown to be important both in new atherogenesis and in destabilization of existing plaques. As lipophilic molecules, the various isomers of vitamin E incorporate readily into unsaturated fats, effectively pre-empting the action of free-radical oxidants. However, this property also can have negative consequences. In the right circumstances, vitamin E can also act as a pro-oxidant, prompting the observation that vitamins E and C are more effective together, with vitamin C acting as a restorative agent to return vitamin E to its stable form.2
Other potential mechanisms have been suggested, and some have been tested in vitro or in experimental studies in humans. These include a role for vitamin E in suppressing the expression of adhesion molecules that have a role in atherogenesis, and inhibition of endothelial cell proliferation.3,4 Neither of these possibilities is as well characterized as the oxidative stress hypothesis, which has been the underlying rationale in most of the trials conducted so far.
There is a bewildering variety of commercial preparations of vitamin E available, each with evidence that it is absorbed and mobilized by the body better than the others. The two classes most widely available commercially are the tocopherols and the tocotrienols. Each has eight isomers, of which only four are maintained in human tissue.5 Both natural and synthetic forms are produced, and esterified forms (a-tocopherol acetate or a-tocopherol succinate) usually are used to improve shelf-life. Animal studies and a few human studies have found that natural forms are more bioavailable than synthetic forms, in a ratio of about 1:1.36.6 However, it also has been shown that this difference in biological activity does not translate into meaningful differences in antioxidant activity.7
The d-a-tocopherol species is the most widely studied and is believed to be the most biologically important.8 The various forms are not interconvertible in humans and do not have the same metabolic action. Commercial vitamin E supplements commonly advertise that they contain all the natural varieties, but given that only four of eight are maintained in human tissue, presumably about half of what they contain is of little or no value.
On the basis of promising observational data, several large prospective, controlled trials were started in the mid-1990s. The gathering evidence is increasingly negative, but the variety of doses and endpoints used means that the findings published to date still are somewhat confusing and not easily summarized.
The CHAOS trial enrolled 2,002 patients with proven cardiac disease and randomized half to either 400 or 800 IU/d (268 and 536 mg, respectively) of vitamin E.9 After a median follow-up of 510 days, those taking vitamin E had a significantly lower rate of non-fatal myocardial infarction (MI) (Relative Risk [RR] = 0.53), but not death, as compared to those taking placebo.
The SPACE trial enrolled 196 patients with end-stage renal disease, with random assignment to an 800 IU/d (536 mg) or placebo.10 Those taking vitamin E had a significantly reduced rate of a composite cardiovascular endpoint (including sudden death) (RR = 0.54) and a reduced rate of MI (RR = 0.45), as compared to the placebo group. It is worth noting that the study population in this case was distinct enough medically to make these results, more than any of the others, of questionable generalizability.
An Australian study of young Type 1 diabetics (n = 41) showed significantly improved flow-mediated vasodilation (FMD)—a measure of vascular endothelial function correlated with cardiac events—after a three-month course of 1,000 IU/d of vitamin E (670 mg).11 Brachial FMD rose from 2.6 ± 0.6% at baseline to 7.0 ± 0.7% (P < 0.005) at study completion. However, there was no significant change in systemic arterial compliance, a generalized measure of arterial stiffness and vascular resistance.
A small number of studies have found benefit specifically with the tocotrienol isomers. A Pakistani study of 90 healthy volunteers found that daily supplementation with tocotrienol in varying doses produced significant reductions in total cholesterol, LDL cholesterol, and apolipoprotein-B.12 In vitro studies from Asia also have produced evidence that tocotrienol may inhibit endothelial proliferation in the vascular wall, and that it may reduce expression of adhesion molecules (e.g., VCAM-1, E-Selectin) that play a role in atherogenesis.3,4
At least as many studies have reported only mild or no apparent benefit, and some suggest the possibility of harm. The GISSI-Prevenzione trial enrolled more than 11,000 Italian patients within three months of an MI.13 Randomization was factorial, with assignment to vitamin E (300 mg/448 IU daily) or placebo, and to n-3 polyunsaturated fatty acids (PUFA) or not. Neither the vitamin E + PUFA group, nor the vitamin E alone group showed significant improvement in a combined cardiovascular endpoint after an average of 3.5 years. However, there was some indication of potential benefit in the vitamin E alone group with specific cardiac endpoints. Reductions of 20-35% in various categories of cardiovascular death were reported.
The HOPE study randomized 3,654 diabetics, also in a factorial design, to vitamin E (400 IU/268 mg daily) or placebo, and ramipril or placebo.14 After an average of 4.5 years, there was no significant difference in a composite outcome of MI, stroke, and cardiovascular death, in any of the individual components, or in any secondary outcome by vitamin E status. The results did not change appreciably when those taking ramipril were excluded.
The Primary Prevention Project (PPP) was primarily a low-dose aspirin study that also included vitamin E (300 mg/448 IU daily) with the goal of preventing first cardiac events in those with major risk factors.15 Both study agents were given on an open-label basis. When the trial was stopped (in response to strong evidence from other trials for the efficacy of aspirin), there were 4,495 patients enrolled with an average of 3.6 years of follow-up. No significant protective effect was noted for vitamin E in the pre-specified cardiac endpoints or death. However, there was a significantly lower incidence of peripheral vascular disease (PVD) (RR = 0.54) in the vitamin E group, as compared to placebo.
The Heart Protection Study (HPS) enrolled 20,536 patients with coronary or vascular disease, or diabetes, and randomized them by a factorial design to simva-statin or placebo, and a cocktail of antioxidants including vitamin E (600 mg/896 IU/d) or placebo.16 After five years of follow-up, there was no significant reduction in all-cause mortality, deaths due to vascular causes, non-fatal MI, fatal or non-fatal stroke, or need for a revascularization procedure in the vitamin supplement group. There were small and statistically non-significant increases in total mortality and LDL cholesterol. The latter finding is especially important given the concomitant use of a statin in the trial.
The ATBC study randomized 1,862 men to vitamin E (50 mg/75 IU daily), beta-carotene, both, or placebo.17 All participants were smokers between 50 and 69 years of age. After an average of 5.3 years of follow-up, there were no significant differences in major coronary events (non-fatal MI and fatal coronary heart disease) in any of the supplement groups. There was a non-significant elevation in the risk of death in the vitamin E group (RR = 1.33, P = 0.2).
The ASAP study enrolled 520 patients and assigned them in a factorial design to a relatively low dose of vitamin E (136 IU/91 mg daily) or placebo, and vitamin C or placebo.18 The main outcome parameter was change in intima-media thickness (IMT) of the common carotid artery, a well-studied marker for atherosclerotic progression. After three years, there was no significant benefit with either supplement alone, although there was with the combination. Change in carotid IMT was significantly less in the combined therapy group, a finding that the authors inferred would translate into reduced clinical events, although these were not counted in this study.
An intriguing mechanistic hypothesis also has been put forward to explain the apparent lack of cardioprotection with vitamin E that has been observed in many trials. This involves a series of small, transient ischemic events in the heart, a phenomenon called preconditioning.19 It is theorized that the heart’s response to these events enables it to better withstand a subsequent major event, such as an MI. There is evidence that antioxidants can interfere with this process.20 If vitamin E supplementation prevents preconditioning, it would be expected that those taking vitamin E would experience proportionally more fatal cardiac events. As yet, there is little clinical evidence to support or refute this idea.
Strengths and Limitations of the Evidence
Although there appears to be a consensus developing in the trial literature, it still amounts to similar words being sung to different tunes. Several issues should color how the evidence is weighed.
A basic issue is the size of the studies reported to date. The outcome events are very rare, even in very large studies. It is impractical to conduct studies large enough to use a single class of event (i.e., death or MI) as the outcome, so composite endpoints are used. Disparities in the etiology and severity of the component events may mask genuine effects of the intervention. However, it should also be noted that consistency of the results across most endpoints bolsters confidence in the results for any one endpoint.
With the exception of the Primary Prevention Project, all of the major studies have enrolled patients with confirmed coronary disease or another major health problem. This would be expected to maximize the number of outcome events, but it begins the intervention late in the disease process. Studies of younger and healthier people would have to be larger and last longer (and thus be much more expensive), but would round out the picture with evidence from the pre-acute period.
There also is little similarity across studies in vitamin E dosage or concomitant medication. This observation cuts both ways. On the one hand, it can be difficult to tease out the effect of vitamin E from the noise of other agents. Studies with factorial designs often are not powered to permit analyses of the vitamin E-only arm, and two-way analyses that simply ignore the other active agent seem likely to produce results on which the heterogeneity in both groups has some (unquantifiable) influence. Conversely, the consistency of findings across different dosages and combinations of other medications suggests that the findings of any single study are unlikely to result from conditions unique to it.
Although a few trials have shown clinical benefit from vitamin E supplementation for preventing cardiovascular events, much of the evidence is against it (see Table). Numerous trials, in disparate populations, with varying outcomes and large sample sizes, have produced similar findings: Vitamin E, even in large doses, produces results that are similar to, or not statistically better than, placebo. The preponderance of evidence for the lack of benefit from vitamin E supplementation in those with established cardiovascular disease should motivate clinical researchers to move on to other compounds.
There appears to be little cardioprotective benefit of vitamin E in common supplemental doses once cardiovascular disease is established. However, this should not call into question the value of proper intake of vitamins and minerals as part of a well-balanced diet, or through use of a multivitamin supplement, if necessary. The benefit of a variety of agents in recommended daily amounts—especially from whole-food sources—is well established and should be reinforced.
Dr. Sasser is Director, Research Epidemiology, R. Stuart Dickson Institute for Health Studies, Carolinas HealthCare System, Charlotte, NC.
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