CONTRASTING EFFECTS OF THE INTERMITTENT AND CONTINUOUS ADMINISTRATION OF HEPARIN IN EXPERIMENTAL RESTENOSIS

Background Heparin inhibits proliferation of smooth muscle cells in culture and intimal hyperplasia in experimental animals but paradoxically exacerbates vascular injury in clinical trials. To determine whether the difference in the means by which heparin was administered explained the benefit in animals and aggravation in humans, we examined the vascular effects of a range of heparin treatments. Methods and Results When laboratory rats were injected subcutaneously with heparin (55.5 IU, approximate to 1.0 mg/kg) per clinical trial protocols, intimal hyperplasia after arterial injury was exacerbated rather than alleviated. The intima to media area ratio was increased 22.5% with every-other-day injections and was increased 16.8% with daily injections. When the daily dose of heparin was increased to 7.2 mg/kg or when injections were initiated a week before injury, intimal hyperplasia was made even worse (52.2% and 59.9% above control). Twice-daily heparin, 7 and 17 hours apart, had no demonstrable effect one way or the other, and it was not until the heparin was administered at 12-hour intervals that intimal hyperplasia and cell proliferation were lessened (44.6% decrease). The greatest reduction in intimal hyperplasia was obtained when the heparin was administered continuously. The continuous osmotic pump intravenous infusion of heparin inhibited 62.5% of the expected proliferation, and perivascular polymeric device release of heparin blocked the response by 74.2%. While subcutaneous injections transiently increased activated partial thromboplastin time, neither mode of continuous delivery altered coagulation. Conclusions We might reconsider the use of heparin in vascular diseases and not neglect this promising compound because of inappropriate extrapolation from the laboratory to clinical use.