Why have antioxidants failed in clinical trials?

Antioxidant therapies have been evaluated in placebo-controlled trials involving tens of thousands of patients. Despite pathophysiologic, epidemiologic, and mechanistic data suggesting otherwise, these clinical trial results have been, to date, mostly negative in the setting of chronic preventative therapy. On the other hand, a much smaller number of trials involving handfuls of patients have been much more encouraging in terms of the acute benefit of antioxidants reflected by the data on N-acetylcysteine. However, the seemingly overwhelmingly data not supporting a role for antioxidants in the chronic suppression of atherosclerosis must be kept in perspective. Most antioxidant therapies that have been tested were not chosen because they were proved to be the best antioxidants, but rather because of their easy availability. An excellent example is vitamin E. Although easily available, it has many limitations as an antioxidant. In fact, in some studies, vitamin E has been shown to have some prooxidant effects. Another possible explanation for the lack of benefit in clinical trials is that the trials have not lasted long enough. It may be impossible to show the benefits of antioxidant therapy over several years if the therapy is trying to reverse the results of several decades of oxidative stress. It is critical to remember that the lack of benefits seen in clinical trials to date does not disprove the central role of oxidative stress in atherosclerosis. Rather, these results challenge us to evaluate optimal antioxidant therapies, the ideal study patients to study, and the appropriate trial duration.