LOCAL-DELIVERY OF R-HIRUDIN BY A DOUBLE-BALLOON PERFUSION CATHETER PREVENTS MURAL THROMBOSIS AND MINIMIZES PLATELET DEPOSITION AFTER ANGIOPLASTY

Background The major morbidity of percutaneous transluminal coronary a ngioplasty is acute thrombosis and restenosis of the dilated lesion. P latelet-thrombus deposition occurs within minutes after injury, is pri marily mediated by thrombin, causes acute occlusion, and contributes t o late restenosis. Experimentally, specific thrombin inhibitors have p revented mural thrombosis. However, local therapy may be more effectiv e than systemic treatment. We tested the hypothesis that high local co ncentrations of an antithrombin drug at the site of arterial injury fo llowing balloon angioplasty inhibit platelet thrombus formation equall y or better than conventional systemic treatment and at lower systemic anticoagulant levels. Methods and Results Balloon angioplasty of the carotid arteries of 29 pigs was performed using systemic intravenous t reatment with heparin (100 U/kg, groups I and II), suboptimal r-hirudi n (0.3 mg/kg, group III), and higher-dose r-hirudin (0.7 mg/kg, group TV), which is the lowest dose that completely inhibited arterial throm bosis in the pig. Immediately after balloon angioplasty of the first c arotid, additional local therapy with placebo (group I) or r-hirudin ( groups II, III, and IV; 0.3 mg/kg in 1 mt) was administered with dista l perfusion through a new percutaneous double-balloon catheter. After 1 hour of local drug delivery, angioplasty of the contralateral caroti d was performed. Reflow for 1 hour was permitted to both carotids to c ompare the short-term effect of local plus systemic treatment with sys temic treatment on quantitative In-111-labeled platelet deposition and macroscopic mural thrombus formation on deeply injured carotid segmen ts. Local drug delivery of placebo compared with systemic heparin trea tment resulted in no change of platelet deposition (x10(6)/cm(2), mean +/-SEM) in controls (group I, 91.0+/-23.5 versus 80.8+/-19.4), but loc al delivery of r-hirudin resulted in a significant reduction in group II (15+/-2.5 versus 71.3+/-14.5; P<.02) and group III (11.4+/-2.5 vers us 80.5+/-11.4; P<.01) and was borderline in group IV (7.4-+/-1.8 vers us 14.1+/-7.4; P=.05), respectively. The incidence of macroscopic mura l thrombus formation with local and systemic treatment was 86% and 75% in group I, 16% and 70% in group II, 14% and 71% in group III, and 0% and 16% in group IV, respectively. Conclusions Local therapy with the specific thrombin inhibitor r-hirudin significantly reduces short-ter m quantitative platelet deposition and macroscopic mural thrombus form ation following balloon angioplasty compared with systemic treatment o f conventional doses of heparin and hirudin and requires a significant ly smaller amount of the recombinant drug.