EFFECT OF LOCAL-DELIVERY OF HEPARIN AND METHOTREXATE ON NEOINTIMAL PROLIFERATION IN STENTED PORCINE CORONARY-ARTERIES

Background: Multiple systemic agents have not prevented restenosis after percutaneous transluminal coronary angioplasty. Attention has focused more recently on developing local drug delivery systems that achieve significant focal concentrations of agents potentially effective against restenosis. Recent advances in polymer design allow specific drugs to be eluted within a defined period after polymer binding onto intracoronary stents. Preliminary results suggested heparin and methotrexate may inhibit the neointimal smooth muscle cell proliferation involved in restenosis. We investigated whether a local drug delivery system involving polymer binding of methotrexate, heparin, or both agents onto an intracoronary stent would inhibit neointimal smooth muscle cell proliferation in a model involving oversized stenting of porcine coronary arteries. Methods: Forty animals were randomly divided into four treatment groups. Ten pigs each received a flexible, balloon-expandable tantalum stent coated with a cellulose ester polymer that bound methotrexate, heparin, or a combination of both drugs; 10 animals received an uncoated tantalum control stent. All animals were fed a nonatherogenic diet and were killed 28 days after stenting. Morphometric analysis of stented arteries was performed; mean neointimal area and percent lumen area stenosis were compared between treatment groups. Results: No statistically significant differences were found between treatment groups by 2 x 2 factorial analysis with respect to either mean neointimal area or percent lumen area stenosis. Conclusions: This preliminary attempt to inhibit neointimal smooth muscle cell proliferation after vascular injury by local delivery of methotrexate and heparin with polymer-coated intracoronary stents was unsuccessful. Further efforts to refine polymer-based local drug delivery systems may involve more effective antiproliferative agents and more extensive surface areas for drug delivery.