A study conducted in 19 countries, the Heart Outcomes Prevention Evaluation (HOPE) Study, evaluated more than 9,000 patients older than 55 years of age with a history of previous ischemic heart disease, stroke, or peripheral artery disease (HOPE Study Investigators, 2000). Similar to the GISSI-Prevenzione Trial, after 4.5 years of supplementation with either 400 IU (268 mg)/day of RRR-α-tocopherol or a placebo, vitamin E had a neutral effect on total mortality, cardiovascular death, myocardial infarction, or stroke. This study is continuing to determine whether any benefit of vitamin E in preventing cardiovascular disease outcomes or cancer will emerge after a longer duration of follow-up.

The discordant results of these four trials may be related to the different doses of vitamin E that were used, as it has been demonstrated that the effectiveness of vitamin E in protecting circulating LDL against ex vivo oxidation depends on both dose and experimental design. Some protection has been observed at doses as low as 25 IU/day (Princen et al., 1995), but a maximum degree of protection requires dosages greater than 200 IU/day (Jialal et al., 1995). At the ATBC Study dose of 50 mg/day, there is some protection, but it is minimal. However, at the GISSI Prevenzione trial dose of 300 mg/day and the HOPE Study dose of 400 IU (268 mg)/day, protection was neutral. Another possible difference between the four trials is that the coronary artery lesions in the Finnish smokers, Italians, and HOPE participants may have been much further advanced than those in the British population studied.

A smaller trial examined the effects of all rac-α-tocopherol supplementation (1,200 IU/day) for 4 months on re-stenosis after angioplasty (DeMaio et al., 1992) and found a small nonstatistically significant reduction in the treated group.

Summary. The hypothesis that reactive oxygen species (ROS) and reactive nitrogen species (RNS) play a role in atherosclerosis rests on a solid basic science foundation and is strongly supported by studies in animal models. At the clinical level, a variety of correlational studies and studies of biochemical markers are consistent with the hypothesis. However, only four published, large-scale, randomized, double-blind clinical intervention studies have tested the ability of vitamin E to prevent myocardial infarction. One of these, a secondary prevention trial supplementing with 400 or 800 IU (268 or 567 mg)/day of RRR-α-tocopherol, was strongly positive (Stephens et al., 1996). The other three, one carried out in a group of high-risk cigarette smokers using 50 mg/day of all rac-α-tocopherol (ATBC Cancer Prevention Study Group, 1994) and two carried out

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