The available scientific studies offer little evidence that supplementation with vitamin E has any benefit on cardiovascular disease prevention or treatment. Indeed, supplementation with vitamin E at the doses tested appears to provide no benefit: large placebo-controlled, randomized trials have reported no benefit in terms of all-cause mortality, cardiovascular mortality, myocardial infarction, or blood lipids (e.g., the MRC/BHF trial, GISSI, HOPE, PPP, ATBC). Isolated examples of possible benefits for vitamin E supplementation reported for specific outcomes in particular trials failed to be confirmed by other outcomes in the same trials or in other trials. Either these disparate results within and across trials are due to chance, or the mechanism of action of vitamin E with respect to MI is very complicated. This lack of consistency in the evidence casts doubt on any of the reported associations having a cause-and-effect relationship. There is good evidence that vitamin E supplementation has no clinically important effect on lipid levels.
After finishing our report, 2 new reviews have been published assessing the effect of vitamin E on cardiovascular disease. The first was a meta-analysis of vitamin E and beta-carotene.48
This meta-analysis restricted its selection criteria to only very large studies, and therefore included fewer studies than ours and used somewhat different methods for assessing outcomes. However, despite these differences, this meta-analysis also concluded that vitamin E supplementation has no appreciable effect on mortality or cardiovascular outcomes. The second review was performed for the U.S. Prevention Services Task Force.49
This review searched fewer databases, included cohort studies, and synthesized their evidence qualitatively rather than quantitatively. They included fewer RCTs assessing mortality and myocardial infarction outcomes than our review, but included studies assessing angina outcomes that we did not assess. This review concluded that the randomized trial evidence showed “no effect” on cardiovascular events or cardiovascular or all-cause mortality. Taken together, these 3 reviews, conducted independently, using somewhat different inclusion criteria and methods for synthesis, provide strong convergent validity that supplementary use of vitamin E has no effect on cardiovascular outcomes.
An explanation that has been proposed for the lack of effect reported in many of the reviewed trials is that the vitamin E was not administered in a sufficient dose or combined with other agents essential for its success, or given for a long enough period of time, or given to a population sufficiently likely to benefit. Both the GISSI study and the HOPE study were prematurely terminated due to evidence of benefits from other intervention arms. It has been suggested that if these studies had been allowed to continue for longer, a benefit of antioxidants would have become more apparent. Some experts have called for new ways to identify populations most likely to benefit, such as selecting participants based on some measure of oxidative stress or low levels of antioxidants. Whether higher doses or different formulations or longer treatment durations will prove more effective is unknown. The findings we report here make it less likely, in our view, that a particular antioxidant intervention will be found that proves to be markedly beneficial.
Our review and meta-analysis have several limitations. The first, common to many systematic reviews, is the quality of the original studies. Only a third of our trials achieved a Jadad score of 3 or more. Other elements of the design and execution of the studies may also be important. For example, the Linxian trial was not designed to assess cardiovascular disease outcomes as its primary purpose, hence the baseline data on cardiovascular disease were not as complete as those from some of the other studies. However, recent attempts to define elements of study design and execution that are related to bias have shown that in many cases, proposed criteria and scales are not reproducible and do not distinguish studies based on their results.50,51
Heterogeneity existed in the trial design, populations, size, interventions, and outcomes and affected our ability to pool studies. We describe explicitly the clinical judgments we made about pooling studies. We tested other combinations of studies in sensitivity analyses; no differences in results were seen. Furthermore, almost without exception, individual studies also failed to demonstrate a benefit of antioxidant supplementation. Therefore, while there was heterogeneity among studies, we do not think our choices for pooling studies introduced significant bias in either direction.
In summary, there is good evidence that supplements of the antioxidant vitamin E do not substantially affect cardiovascular disease either positively or adversely.