Systemic drug therapy for restenosis: "déjà vu all over again".

Abstract

The problem of restenosis, a major limitation of angioplasty since its introduction in 1978, may finally be under control. The rate of restenosis has fallen from 30% to 40% to 15% to 20% with the advent and widespread use of coronary stents. Now, with the introduction of intravascular radiation therapy, in-stent restenosis seems to be reduced by 50%, and with the almost unbelievable preliminary results of drug-eluting stents, the rate of restenosis may be reduced to less than 5% in de novo lesions. Although these outcomes are truly remarkable, both intravascular radiation therapy and drug-eluting stents have a number of significant limitations. See p 2379 Radiation has safety issues and is limited by geographical miss, edge restenosis, and late stent thrombosis. Drug-eluting stents are likely to be expensive and are unproven in unfavorable anatomy. Even in optimal patients, restenosis can still occur with both types of treatment. A continued search for a simpler and effective means of controlling this problem seems reasonable given these limitations. In this issue of Circulation , Farb et al1 present evidence that everolimus, an oral analog of rapamycin, can reduce neointimal thickness by more than 40% after stent placement in a rabbit model of restenosis. Rapamycin is a naturally occurring macrolide antibiotic produced by the actinomycete Streptomyces hygroscopicus found on Eastern Island. It has been shown to be a potent inhibitor of cytokine and growth factor-mediated cell-proliferation.2 It is known to bind to a cellular receptor FKBP-12 and to inhibit the target of rapamycin (TOR), an important signaling pathway for protein synthesis and cell cycle progression. As a result, rapamycin arrests the cell at the end of the G1 cell cycle. Animal studies have shown a significant reduction in intimal hyperplasia and smooth muscle cell proliferation. Clinical trials have been remarkably positive. The …