PROLONGED THROMBIN INHIBITION REDUCES RESTENOSIS AFTER BALLOON ANGIOPLASTY IN PORCINE CORONARY-ARTERIES

Background-Arterial injury after percutaneous transluminal coronary an gioplasty (PTCA) triggers acute thrombus formation and thrombin genera tion. Hirudin, a potent and direct thrombin inhibitor, prevents thromb us formation after arterial injury, Two large clinical trials showed m arked reduction in acute clinical events but no long-term benefits in reducing restenosis during short-term administration of thrombin inhib itors. Our hypothesis is that adequate, maintained thrombin inhibition , by inhibiting all the thrombin-dependent mechanisms, will reduce neo intima formation after PTCA. Methods ann Results-Thirty-six pigs recei ved three different regimens of hirudin, bolus (1 mg/kg), short-term ( bolus+O.7 mg/kg per day for 2 days), and long-term (bolus+0.7 mg/kg pe r day for 14 days). The results on neointima formation at 4 weeks afte r coronary angioplasty were compared with the control group (100 IU he parin/kg bolus). Hirudin was continuously administered for 2 weeks thr ough an infusion pump. In vivo thrombin generation was persistently in creased up to 2 weeks after angioplasty. Inhibition of thrombin activi ty for 14 days reduced luminal narrowing by il 40% (58 +/- 3% versus 3 5 +/- 3%; P<.001). No differences were observed among the bolus and sh ort-term hirudin groups and the control group, Conclusions-Our results indicate that there is a continued, marked thrombin generation that l asts for at least 2 weeks after PTCA. Administration of r-hirudin for 2 weeks significantly reduces neointima formation after PTCA. This obs ervation, if extrapolated to humans, could explain the lack of effect on restenosis observed in the clinical trials with antithrombin agents despite the clear benefits on reducing acute thrombotic complications after PTCA, Therefore an adequate and prolonged administration of thr ombin inhibitors is needed to ''passivate'' the thrombogenic substrate (disrupted arterial wall) and achieve full benefit of this therapeuti c approach.