SUSTAINED-RELEASE LOCAL HIRULOG THERAPY DECREASES EARLY THROMBOSIS BUT NOT NEOINTIMAL THICKENING AFTER ARTERIAL STENTING

Adventitial heparin delivery has been shown to inhibit thrombosis and neointimal thickening in a rat carotid injury model. To determine whet her sustained, local delivery of hirulog, a potent antithrombin agent, inhibits thrombus formation and neointimal thickening after arterial stenting, silicone polymers containing hirulog were formulated at a co ncentration of 5.8% by weight and were tested in vitro to determine th e rate of drug release. An oversized metallic stent was implanted in t he carotid artery of 18 juvenile farm pigs. Hirulog-impregnated silico ne polymers were placed around the adventitial surface of one stented segment of each animal and a control polymer was placed contralaterall y. Intravenous hirulog (4 mg/kg/hr) was infused for the duration of th e procedure to maintain the activated clotting time of >300 sec. Ex vi vo testing estimated the release of hirulog to be 1.54 mu g/mg matrix/ day with no loss of anticoagulant activity of the released peptide. In four pigs killed on days 3 through 5, macroscopic thrombus was very f aintly visible on the stent struts of one arterial segment treated wit h sustained-release hirulog but was readily evident in all control art eries. However, electron microscopy showed platelet adhesion and micro scopic thrombus formation on each stent of both treated and untreated sides. Fourteen pigs were killed 32 +/- 4 days after stenting. Histolo gic analysis showed no difference between hirulog-treated and control sides in the volume of neointima (540 +/- 129 units vs 357 +/- 95 unit s, p = 0.27) or in the average intima to media ratio (0.44 +/- 0.12 vs 0.34 +/- 0.24, p = 0.47) over the length of the stented segment. Late thrombotic occlusion occurred in two hirulog-treated and two control arteries. In this model, local adventitial hirulog delivery at the dos e and delivery rate used may reduce, but does not prevent, thrombus fo rmation and does not reduce the severity of neointimal thickening afte r carotid stent implantation.