PARENTERAL TREATMENT WITH DEFIBROTIDE FOR PATIENTS WITH CHRONIC PERIPHERAL OCCLUSIVE ARTERIOPATHY

The duration of the therapeutic effects of defibrotide after discontinuation of therapy was explored in a random, double-blind study versus placebo. After completing a 14-day washout period, 40 ambulatory patients with intermittent claudication (Leriche's stage 2) were randomly assigned to one of two treatment groups. Group A (n = 20) received defibrotide 200 mg (one ampule) BID intramuscularly for 14 consecutive days. Treatment was then discontinued to day 28, when it was replaced by defibrotide 200 mg IM every other day in open fashion for a further 32 days. Group B (n = 20) received an indistinguishable placebo for the first 14 days, followed by discontinuation to day 28 and then defibrotide 200 mg IM on alternate days for 32 days. At enrollment (day - 14), at baseline, and on days 14, 21, 28, and 60 of the trial, each patient underwent a standard treadmill exercise test with measurements of relative walking distance (RWD) and absolute walking distance (AWD). At day 14, only patients in group A showed a significant increase in RWD (+20%, P < 0.01) and AWD (+19%, P < 0.02), but the differences between treatments were not statistically significant. After discontinuation, the increase in RWD and AWD seen in the patients in group A persisted to day 28. In the next period, when defibrotide dosing was resumed at a lower level, there were no striking changes in test parameters; however, the difference for AWD between days 0 and 60 was significantly greater in group A than in group B (P < 0.05), while a similar, but nonsignificant trend was seen for RWD. These data indicate that the therapeutic effect of defibrotide in patients with intermittent claudication continues for at least 14 days after withdrawal of an intramuscular treatment consistently of 400 mg daily. The lower dosage schedule used in this study, namely, 200 mg IM on alternate days, may be considered of value only as maintenance therapy.