Oxidative stress appears to be of fundamental relevance to diseases as diverse 
as atherosclerosis, cancer, and Alzheimer's disease. Observational data in 
humans have suggested that antioxidant vitamin intake is associated with reduced 
cardiovascular disease. Animal studies are largely consistent with the concept 
that dietary supplementation with antioxidant vitamins reduces the progression 
of atherosclerosis. However, recent prospective, controlled clinical trials of 
vitamin E, including the Cardiovascular Disease, Hypertension and 
Hyperlipidemia, Adult-Onset Diabetes, Obesity, and Stroke (CHAOS) study, the 
Heart Outcomes Prevention Evaluation (HOPE) trial, Gruppo Italiano per lo Studio 
della Sopravvivvenza nell'Infarto Miocardico (GISSI)-Prevenzione trial, the 
Secondary Prevention with Antioxidants of Cardiovascular Disease in End Stage 
Renal Disease (SPACE) trial, and the Heart Protection Study (HPS) present a 
confused picture. The various possibilities that have been advanced to explain 
this discrepancy are discussed in this review. A striking feature of these and 
other trials of antioxidants is the absence of a biochemical basis for patient 
inclusion or, indeed, dose selection. Patients with high levels of oxidant 
stress or depletion of natural antioxidant defense systems may be the most 
likely to benefit from antioxidant therapy. If this is the case, then reliable, 
quantitative indices of in vivo oxidant stress such as urinary isoprostane 
levels should be considered as an inclusion criterion for patient selection. 
Future trials of antioxidant therapy in cardiovascular disease should then be 
targeted toward such patients with high levels of oxidant stress or patients 
with depletion of natural antioxidant defense systems. Furthermore, the dose of 
antioxidant should be chosen based on a surrogate readout that is a reliable, 
reproducible, and easily obtainable in vivo measure of oxidant stress. In the 
interim, although the safety of vitamin E up to doses of 800 IU/day has been 
determined, the conflicting nature of the results published to date encourages 
us to avoid making premature recommendations with respect to vitamin E 
supplementation in the prevention and treatment of cardiovascular disease.