chapter  47
Local delivery of low molecular weight heparins R Stefan Kiesz, M Marius Rozek and Jack L Martin
Pages 6

Restenosis following coronary stent implantation remains an important and costly therapeutic problem. Since intimal smooth muscle cell (SMC) proliferation is largely the culprit,1-4

various attempts to inhibit this process have been studied.5-10 Modulation of the stimuli for neointimal hyperplasia by appropriate pharmacologic agents would, in theory, permit vessel wall healing after coronary stent implantation without an exaggerated, obstructive proliferative response. Until recently, local drug delivery, using various agents and different methods of administration, has failed to affect restenosis rate after stenting (see further the discussion in Chapter 29).11,12 This may be related to the agent studied, and the design of the delivery device, as well as the timing of drug delivery with respect to stenting. Arterial injury triggers thrombus formation with release of growth factors known to stimulate neointimal proliferation: platelet-derived growth factor (PDGF), transforming growth factor (TGF)-, fibroblast growth factor (FGF) and others.13-15

STUDIES

Enoxaparin has been shown to inhibit smooth muscle cell proliferation at high tissue concentrations.16-18 However, it has not reduced the incidence of angiographic restenosis or clinical events after successful coronary angioplasty when administered systemically.19 In a baboon angioplasty model low molecular weight heparin (LMWH) blocked serum-induced but not PDGF-induced SMC proliferation and migration, suggesting heparin sensitive and insensitive pathways. If the assumption that human SMC are less sensitive to growth inhibition by heparin is true, one may consider the possibility that in-stent restenosis may be reduced by local prevention of early prothrombotic events. Enoxaparin is a potent inhibitor of factor Xa and thrombin.20,21 The strategy of local delivery of enoxaparin during predilation was specifically designed to modulate the magnitude of thrombin-mediated and thrombusmediated stimuli for neointimal proliferation. The purpose of enoxaparin delivery during predilation is to have an antithrombotic agent in place at the time of the initial balloon

deflation, when the injured vessel wall was first exposed to circulating prothrombotic elements. This hypothesis was tested in an atherosclerotic rabbit model where 10 mg of enoxaparin delivered during iliac angioplasty reduced neointimal proliferation as evidenced by reduced BRDU uptake compared with conventional angioplasty.18