Inhibition of neointimal proliferation after coronary angioplasty by low-molecular-weight heparin (clivarine) and polyethyleneglycol-hirudin

Proliferation of medial smooth muscle cells (SMC) plays a major role in restenosis after coronary angioplasty and can be inhibited by heparin. Platelets stimulate SMC proliferation, and their aggregation after angioplasty can be reduced by the direct thrombin inhibitor hirudin. In a porcine coronary stent-angioplasty model (16 animals, 4 per group), we studied the effect of 3- and 14-day treatment with a novel long-lasting polyethyleneglycol-conjugated (PEG-hirudin, LU 57291), at a dose of 1 mg/kg intravenously (i.v.) and then subcutaneously once daily as compared with chronic low molecular-weight heparin (LMWH) clivarine at a dose of 150 IU/kg as an intravenous bolus, followed by 10 IU/kg/h i.v. for 24 h, followed by 75 IU/kg twice daily, as compared with acute unfractionated heparin (100 IU/kg) as a control. Sixteen animals were randomly assigned to the four treatment groups. Four weeks after angioplasty, hearts were perfusion-fixed and six slices per angioplasty segment were analyzed for neointimal thickness and neointimal area (% of total vessel cross-sectional area). Maximal neointimal thickness was 1.10 +/- 0.2 mm in the control group (mean I-SD, n = 9 arteries) and was significantly lower in both PEG-hirudin (0.62 +/- 0.22 and 0.86 +/- 0.18 mm, 11 and 10 arteries) and in clivarine-treated animals (0.75 +/- 0.33 mm, 11 arteries, p < 0.01). Similarly, neointimal area was smaller in PEG-hirudin groups (20 +/- 12 and 21 +/- 12%) and in the clivarine group (24.8 +/- 13.2%) as compared with the control group (41 +/- 17%, p < 0.02). We conclude that PEG-hirudin and clivarine reduce neointimal proliferation in a coronary stent-angioplasty model. Prolonged PEG-hirudin has no better effect than therapy limited to 3 days.