Pharmacological inhibition of coronary restenosis: systemic and local approaches.

INTRODUCTION: Percutaneous coronary intervention (PCI) with stent implantation has revolutionized the treatment of obstructive coronary artery disease. However, the main limitation of this therapy is stent failure, which is usually caused by in-stent restenosis. AREAS COVERED: The aim of this article is to critically review the literature on the prevention of in-stent restenosis focusing on drug compounds that have reached clinical testing. EXPERT OPINION: The pathophysiological response following PCI includes many possible targets for antirestenosis treatment. Most notable success is seen with sirolimus (and its analogs) and paclitaxel, both of which target vascular smooth muscular cell proliferation. In view of the systemic side effects of both drugs, the high efficacy of local drug delivery methods reduced enthusiasm for systemic therapy. Cilastazol has shown benefit in restenosis reduction particularly in patients at high risk for stent failure, though further study in broader populations is warranted. Probucol showed variable results, but local drug delivery in combination with sirolimus seems promising. A hypothesized independent antirestenotic effect of pioglitazone in patients with diabetes has not been clearly demonstrated. Initial encouraging results with tranilast have not been replicated in a recent large-scale randomized trial. Colchicine and prednisone have shown promising results but require further investigation in larger clinical trials.

Effect of oral sirolimus therapy on inflammatory biomarkers following coronary stenting

We studied the effect of oral sirolimus, administered to prevent and treat in-stent restenosis (ISR), on the variation of serum levels of inflammatory markers following coronary stenting with bare metal stents. The mean age of the patients was 56 ± 13 years, 65 percent were males and all had clinically manifested ischemia. Serum levels of high sensitivity C-reactive protein (hs-CRP) concentration were determined by chemiluminescence and serum levels of all other biomarkers by ELISA. One group of patients at high risk for ISR received a loading oral dose of 15 mg sirolimus and 5 mg daily thereafter for 28 days after stenting (SIR-G). A control group (CONT-G) was submitted to stenting without sirolimus therapy. The increase in hs-CRP concentration was highest at 24 h after stenting in both groups. A significant difference between SIR-G and CONT-G was observed at 4 weeks (-1.50 ± 5.0 vs -0.19 ± 0.4, P = 0.008) and lost significance 1 month after sirolimus discontinuation (-1.73 ± 4.3 vs -0.01 ± 0.7, P = 0.0975). A continuous fall in MMP-9 concentration was observed in SIR-G, with the greatest reduction at 4 weeks (-352.9 ± 455 vs +395.2 ± 377, P = 0.0004), while a positive variation was noted 4 weeks after sirolimus discontinuation (227 ± 708 vs 406.2 ± 472.1, P = 0.0958). SIR-G exhibited a higher increase in P-selectin after sirolimus discontinuation at week 8 (46.1 ± 67.9 vs 5.8 ± 23.7, P = 0.0025). These findings suggest that the anti-restenotic actions of systemic sirolimus include anti-proliferative effects and modulation of the inflammatory response with inhibition of adhesion molecule expression.