The aim of this review is to give an overview of the field of restenosis prevention with
antioxidants, put in the perspective of their potential use for the prevention of
atherosclerosis progression. Compelling evidence points to oxidative stress as an important trigger in the complex chain of events leading to
atherosclerosis. There is also evidence that oxidative stress occurs early after angioplasty.
Reactive oxygen species (ROS) can induce endothelial dysfunction and macrophage activation, resulting in the release of
cytokines and
growth factors that stimulate matrix remodeling and smooth muscle cell proliferation. The accumulation of new extracellular matrix and smooth muscle cells will result in the neointimal formation responsible for lumen narrowing after
stent deployment and which contributes to that after balloon angioplasty. In addition, oxidation processes are involved in the cross-linking of
collagen fibers, and this coupled with smooth muscle cell contraction and endothelial dysfunction may result in long-term vascular constriction or lack of adaptive
vascular remodeling after balloon angioplasty. The powerful
antioxidant probucol has been shown to prevent
coronary restenosis after balloon angioplasty in the Multivitamins and
Probucol (MVP) trial and other clinical studies. However, prolongation of the QT interval with
probucol remains a long-term safety concern.
AGI-1067, a metabolically stable analog of
probucol, is a vascular protectant with strong
antioxidant properties as potent to those of
probucol. There has been no evidence of prolongation of the QT interval with
AGI-1067 in initial clinical studies. The anti-restenosis properties of
AGI-1067 are being assessed in the Canadian
Antioxidant Restenosis Trial (CART)-1. Considering that oxidative stress and
inflammation may persist for a prolonged period after
stent placement, treatment with
AGI-1067 for the entire period of risk after
percutaneous coronary intervention (PCI) [instead of only 4 weeks in CART-1] may result in enhanced protection against
luminal renarrowing. This hypothesis will be tested in the randomized, multicenter CART-2 trial.
AGI-1067 has been effective at preventing
atherosclerosis in all tested animal models, including the
low density lipoprotein receptor-deficient and apo-E knockout mice. This has potentially important implications, as PCI and local approaches to prevent restenosis such as coated
stents are not expected to prevent
atherosclerosis progression,
myocardial infarction and cardiovascular death. As the ultimate goal of
therapy for patients with
coronary artery disease must remain prevention of
disease progression and
atherosclerosis-related events, CART-2 will test the value of
AGI-1067 for the reduction of both post-PCI restenosis and
atherosclerosis progression.