Prolonged Thrombin Inhibition Reduces Restenosis After Balloon Angioplasty in Porcine Coronary Arteries

Abstract

Background-Arterial injury after percutaneous transluminal coronary angioplasty (PTCA) triggers acute thrombus formation and thrombin generation. Hirudin, a potent and direct thrombin inhibitor, prevents thrombus formation after arterial injury. Two large clinical trials showed marked reduction in acute clinical events but no long-term benefits in reducing restenosis during short-term administration of thrombin inhibitors. Our hypothesis is that adequate, maintained thrombin inhibition, by inhibiting all the thrombin-dependent mechanisms, will reduce neointima formation after PTCA. Methods and Results-Thirty-six pigs received three different regimens of hirudin: bolus (1 mg/kg), short-term (bolusϩ0.7 mg/kg per day for 2 days), and long-term (bolusϩ0.7 mg/kg per day for 14 days). The results on neointima formation at 4 weeks after coronary angioplasty were compared with the control group (100 IU heparin/kg bolus). Hirudin was continuously administered for 2 weeks through an infusion pump. In vivo thrombin generation was persistently increased up to 2 weeks after angioplasty. Inhibition of thrombin activity for 14 days reduced luminal narrowing by 40% (58Ϯ3% versus 35Ϯ3%; PϽ.001). No differences were observed among the bolus and short-term hirudin groups and the control group. Conclusions-Our results indicate that there is a continued, marked thrombin generation that lasts for at least 2 weeks after PTCA. Administration of r-hirudin for 2 weeks significantly reduces neointima formation after PTCA. This observation, 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 thrombin inhibitors is needed to "passivate" the thrombogenic substrate (disrupted arterial wall) and achieve full benefit of this therapeutic approach. (Circulation. 1998;97:581-588.)

Hirulog-1 Reduces Expression of Platelet-Derived Growth Factor in Neointima of Rat Carotid ArteryInduced by Balloon Catheter Injury

“…No description on the start time of hirudin treatment related to angioplasty. Results from more recent studies in atherosclerotic rabbits or pigs indicated prolonged infusion of hirudin for 2 weeks or early start plus delayed infusion of hirudin (second infusion at 24 h after angioplasty) significantly reduced angioplasty-induced restenosis [7, 8]. Those findings suggest that hirudin infusion potentially reduces angioplasty-induced restenosis through the modification of regimens.…”

“…Hirudin treatment reduced early cardiac events but did not bring long-term benefit to post-angioplasty patients [6]. Recent studies indicated that prolonged or early started infusion of hirudin may considerably reduce restenosis in experimental animal vascular injury models [7, 8]. Results from large-scale clinical trials indicated that hirudin treatment causes significantly higher incidence of intracranial or other major bleeding complications compared to conventional heparin treatment [9, 10, 11].…”

Hirulog-Like Peptide Reduces Balloon Catheter Injury Induced Neointima Formation in Rat Carotid Artery without Increase in Bleeding Tendency

“…A long-term beneficial effect of thrombin inhibitors on restenosis has not been shown in humans [5, 6]. Recent studies demonstrated that the modification of the administration of hirudin through early and/or prolonged infusions substantially improved its preventive effects on the development of restenosis in experimental animal models [7, 8]. Results of phase III clinical trials indicated that hirudin significantly increased the frequency of intracerebral or major hemorrhage [9]which limits its clinical application.…”

Lipid Oxidation Enhances the Function of Activated Protein C

“…First, the mechanism by which new thrombi or newly injured vessels which are very thrombogenic become less so with time, a process known as "passivation" (50,51). The ability of phospholipid oxidation, a time-dependent process, to enhance APC anticoagulant function would be expected to contribute to this process.…”