Antioxidants and atherosclerosis: emerging drug therapies.

Inflammation has a fundamental role in mediating all stages of atherosclerotic disease. The key role of oxidation in linking lipids and inflammation to atherosclerosis is compelling and supported by experimental evidence. However, the relevance of the antioxidant hypothesis for the treatment of patients with atherosclerosis has not been definitively proven. Probucol has reduced post-percutaneous coronary intervention (PCI) restenosis and progression of carotid atherosclerosis in clinical trials. The antioxidant/vascular protectant AGI-1067 has also been effective at preventing atherosclerosis in all tested animal models. The nonintervened reference coronary segments of the PCI vessel demonstrated improvements with AGI-1067 in the Canadian Antioxidant Restenosis Trial-1 (CART-1), evidence supportive of a clinical effect on slowing atherosclerosis progression. Results of randomized trials with the "antioxidant" vitamins have been disappointing, but there are potentially important problems associated with their use, including their potential pro-oxidant effects. Two important trials that test the antioxidant/anti-inflammatory hypothesis are ongoing with AGI-1067: CART-2, which assesses its value for the reduction of both atherosclerosis progression in non-PCI vessels and post-PCI restenosis; and Aggressive Reduction of Inflammation Stops Events (ARISE), which is evaluating the effects of AGI-1067 on hard cardiovascular outcomes.