From the Cardiovascular Biology Research Laboratory (R.G., A.P., V.T.,
J.B., J.J.B.), the Cardiovascular Institute (J.T.F., J.H.C., V.F.), and the
Department of Pathology (J.T.F.), Mount Sinai School of Medicine, New York,
NY.
Correspondence to Dr Juan J. Badimon, Cardiovascular Biology Research Laboratories, Zena and Michael A. Wiener, Cardiovascular Institute, One Gustave L. Levy Place, Box 1030, New York, NY 10029-6574. E-mail jbadimo{at}smtplink.mssm.edu
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 (bolus+0.7 mg/kg per
day for 2 days), and long-term (bolus+0.7 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% (58±3% versus
35±3%; P<.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.
© 1998 American Heart Association, Inc.
Basic Science Reports
Prolonged Thrombin Inhibition Reduces Restenosis After Balloon Angioplasty in Porcine Coronary Arteries
Key Words: restenosis • thrombin inhibition • angioplasty
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