Antioxidants and prevention of restenosis after directional coronary atherectomy.

Directional Coronary Atherectomy To the Editor: The negative results obtained with carvedilol in the European Carvedilol Atherectomy Restenosis (EUROCARE) trial led Serruys et al1 to question the value of antioxidants for the prevention of restenosis after coronary angioplasty. An important flaw in study design, however, invalidates the conclusions reached by the authors. The antioxidant probucol has been shown to prevent restenosis in several clinical studies, including the MultiVitamins and Probucol (MVP) trial2 and the Probucol Angioplasty Restenosis Trial (PART). Indeed, the only study in which probucol did not prevent restenosis after coronary balloon angioplasty allowed for only 24 hours of pretreatment. There is a massive release of reactive oxygen species very early after balloon injury,3 and adequate accumulation of a powerful antioxidant needs to have occurred at the time of angioplasty to control this oxidative stress. This was the basis for the pretreatment phase with probucol and for the bolus before angioplasty in MVP. In contrast, the duration of pretreatment in EUROCARE was not tailored to the pharmacokinetic profile of carvedilol. Angioplasty was performed 2 hours after the third dose of carvedilol in EUROCARE and no bolus was administered. Plasma levels of carvedilol were not at steadystate at the time of angioplasty, a critical factor that is not contested by the authors. It follows that the antioxidant protection afforded by carvedilol at tissue level was suboptimal after such a short duration of pretreatment. Animal studies have shown that carvedilol prevents neointimal formation following vascular injury after 72 hours of pretreatment. In contrast to the authors contention, however, carvedilol did not inhibit neointima formation at the site of restenosis (crosssection 1 in each animal) when given only 2 hours before angioplasty.4 When LDLs are incubated with macrophages to assess the oxidation induced by biologically derived reactive oxygen species, the inhibitory concentrations of probucol and carvedilol are 0.8 and 3.8 mmol/L, respectively.5 Interestingly, the inhibitory concentration is reduced to 1.8 mmol/L when carvedilol is added to the cell culture medium for 72 hours before the addition of LDL, which again denotes the importance of long-term exposure of cells to carvedilol. EUROCARE confirmed that the duration of pretreatment needs to be tailored to the pathophysiology and to the pharmacokinetic profile of the antioxidant agent.