Oral Heparin Prevents Neointimal Hyperplasia After Arterial Injury

Abstract

Background — In animal models, heparin delivered as a continuous intravenous infusion or via frequent (BID) subcutaneous dosing inhibits neointimal hyperplasia after balloon injury or stent implantation. However, human trials of subcutaneous heparin after percutaneous intervention have proven ineffective against restenosis. It may be that these failures are due to unfavorable heparin pharmacokinetics. Recently, the drug delivery agent sodium N -[8-(2-hydroxybenzoyl)amino] caprylate (SNAC) has been found to facilitate the gastric absorption of heparin. Methods and Results — To investigate the effects of orally delivered heparin on neointimal hyperplasia after varying forms of arterial injury, 57 New Zealand White rabbits underwent iliac artery balloon dilatation. In half of the rabbits, endovascular stents were implanted and heparin was delivered through a variety of methods. Arteries were harvested at 14 days. Neointimal area was assessed with computer-aided morphometry. After balloon injury, both intravenous (0.3 mg/kg per hour) and oral heparin (90 mg/kg BID) effectively inhibited neointimal hyperplasia (0.11±0.02 and 0.09±0.07 mm 2 , respectively, versus 0.16±0.06 mm 2 in control; P <0.05). After stent implantation, intravenous administration of heparin (0.3 mg/kg per hour) effectively inhibited neointimal growth (0.35±0.05 mm 2 versus 0.51±0.09 mm 2 in control; P <0.05), but oral heparin at 90 mg/kg BID and 180 mg/kg BID (0.48±0.04 and 0.49±0.08 mm 2 , respectively; P =NS versus control) did not. A dose of 120 mg/kg TID, however, was effective (0.40±0.10 mm 2 ; P <0.05 versus control). Conclusions — These data suggest that oral heparin may be an effective therapy against restenosis after percutaneous intervention. Stented arteries required higher and more frequent dosing for efficacy. These data suggest that differences in the type of vascular injury must be considered in the design of drug delivery.