COMPARISON OF THE EFFECTS OF THE THROMBIN INHIBITOR R-HIRUDIN IN 4 ANIMAL-MODELS OF NEOINTIMA FORMATION AFTER ARTERIAL INJURY

Thrombin has been implicated as a contributing factor to restenosis af ter vessel reopening procedures. We compared the ability of the direct thrombin inhibitor recombinant (r-) hirudin to reduce neointimal grow th in different animal models of arterial injury. Carotid arteries of rats, rabbits, and hypercholesterolemic minipigs were injured by withd rawal of an inflated balloon catheter. In addition, we used a double-l esion model in rabbits, which involved balloon angioplasty of a preexi sting lesion induced by carotid denudation 4 weeks earlier. r-Hirudin was given in all four animal models as a short-term application (bolus of 1 mg/kg IV immediately before injury, followed by infusion of 1 mg . kg(-1) . h(-1) for 2 hours, and an injection of 6 mg/kg SC). Additi onally, we investigated the effects of prolonged treatment (intravenou s infusion for 3 and 14 days) in rats. Inhibition of thrombin was moni tored by determination of activated partial thromboplastin time, and h istomorphometric analysis of the arteries was performed after 2 (rats) or 4 (rabbits and minipigs) weeks. In rabbits, short-term r-hirudin t reatment reduced neointimal area by 59% (single-injury model, P=.05) a nd 44% (double-injury model, P=.02). In rats and minipigs no inhibitio n of neointimal growth was observed after short-term r-hirudin applica tion. A 3- or 14-day infusion of r-hirudin in rats, however, resulted in 25% (P=.007) and 27% (P=.003) reductions in neointimal area, respec tively. In conclusion, there is considerable interspecies variation in the time frame of susceptibility for reduction of neointimal growth b y inhibition of thrombin after arterial injury. These results demonstr ate the importance of testing potential antirestenotic treatments in a n array of different animal models.