EARLY PLUS DELAYED HIRUDIN REDUCES RESTENOSIS IN THE ATHEROSCLEROTIC RABBIT MORE THAN EARLY ADMINISTRATION ALONE - POTENTIAL IMPLICATIONS FOR DOSING OF ANTITHROMBIN AGENTS

Background-A 2-hour infusion of r-hirudin at the time of balloon angio plasty limits restenosis in atherosclerotic rabbits. Because thrombin activity in the vessel wall after angioplasty remains high for 48 to 7 2 hours, we hypothesized that a second infusion of hirudin at 24 hours would reduce restenosis more than early treatment alone. Methods and Results-Femoral atherosclerosis was induced in 35 rabbits by air desic cation injury and a high-cholesterol diet. At the time of angioplasty, rabbits were randomly assigned to 1 of 4 groups: controls: heparin bo lus, saline infusion at 24 hours; early hirudin: hirudin bolus+2 hours ' infusion, saline infusion at 24 hours; delayed hirudin: heparin bolu s, hirudin infusion+/-bolus at 24 hours; and early+delayed hirudin: hi rudin bolus+2 hours' infusion, hirudin infusion+/-bolus at 24 hours. R abbits were euthanized after 28 days. The early+delayed hirudin treatm ent group had less loss of minimal lumen diameter by angiography at 28 days. By histomorphometry, cross-sectional area narrowing by plaque w as least in the early+delayed treatment group compared with controls ( P=0.0001), early hirudin (P=0.01), or delayed hirudin (P=0.001). The e arly+delayed hirudin group also had a significant reduction in absolut e plaque area and an improvement in lumen area compared with the other groups. No differences were observed between treatment groups with re spect to the cross-sectional area encompassed by the internal or exter nal elastic laminae. Conclusions-Combined early+delayed administration of hirudin significantly reduces angiographic restenosis and cross-se ctional area narrowing by plaque compared with early or late treatment alone. These results suggest that restenosis after balloon angioplast y is markedly influenced by thrombin-mediated events not only occurrin g early but also extending beyond the first 24 hours in this model.