A double-blind, multicenter, placebo-controlled, dose comparison study of orally administered defibrotide: preliminary results in patients with peripheral arterial disease

Abstract

Defibrotide is a polydeoxyribonucleotide drug known to modulate the endothelial cell release of t-PA, PAI, and PGI-2 and to improve blood flow and perfusion. A double-blind, multicenter, placebo-controlled, dose comparison study was carried out to test the long-term efficacy and safety of defibrotide in patients with PAD (Leriche stage 2). Informed patients suffering from PAD were enrolled, and after a 15-day washout period were randomly allocated in a double-blind fashion to one of the three following treatments: defibrotide 400 mg (1 cps) b.i.d. for 6 months, defibrotide 400 mg o.d., or placebo. Absolute walking distance (AWD, treadmill) and ankle-arm pressure ratio (Winsor Index, WI) were evaluated at the beginning and after 30, 90, and 180 days after therapy. Two hundred twenty seven patients were recruited and 193 patients were included in the final analysis (800 mg: 67; 400 mg: 60; placebo: 66). All treatments brought about an increase in AWD placebo = +17%; 400 mg = +47%, 800 mg = +52%); however, patients treated with defibrotide exhibited a significantly better AWD at the end of treatment in comparison with placebo (p less than 0.01). AWD was not significantly different in the 400-mg and 800-mg groups. There was a trend indicating a possible improvement of WI after defibrotide, with higher WI in 800-mg patients in comparison with placebo (p less than 0.05). However, this difference was partly due to a decrease in arterial blood pressure elicited by the drug. The tolerability in all groups was optimal. These results indicate that orally administered defibrotide exerts symtomatic benefit in PAD patients and daily doses of 400 or 800 mg seem to be equivalent.