A stable prostacyclin analogue (iloprost) in the treatment of ischaemic ulcers of the lower limb. A Scandinavian-Polish placebo controlled, randomised multicenter study. Reduction of ischaemic rest pain in advanced peripheral arterial occlusive disease. A double blind placebo controlled trial with iloprost. [Prostaglandin E1 in stage III and IV arterial occlusive diseases. results of a multicenter study]. The effect of ciprostene in patients with peripheral vascular disease (PVD) characterized by ischemic ulcers. The Ciprostene Study Group. Low-dose iloprost infusions compared to the standard dose in patients with peripheral arterial occlusive disease Fontaine stage IV. DAWID Study Group. Two randomised and placebo-controlled studies of an oral prostacyclin analogue (Iloprost) in severe leg ischaemia. The Oral Iloprost in severe Leg Ischaemia Study Group. Microcirculation and tolerability following i.v. infusion of PGE1 and iloprost: a randomized cross-over study in patients with critical limb ischemia. Intra-arterial prostacyclin compared to Praxilene in the management of severe lower limb ischaemia: a double blind trial. Prostaglandin E1 in severe lower limb ischaemia: a double-blind controlled trial. Treatment of limb threatening ischaemia with intravenous iloprost: a randomised double-blind placebo controlled study. U.K. Severe Limb Ischaemia Study Group. [Iloprost in the treatment of ischemic tissue lesions in diabetics. Results of a placebo-controlled multicenter study with a stable prostacyclin derivative]. [Placebo controlled, double-blind study of the effectiveness of i.v. prostaglandin E1 in diabetic patients with stage IV arterial occlusive disease]. Epoprostenol (prostacyclin) and severe arterial disease. A double-blind trial. Clinical effects of intravenously administered prostaglandin E1 in patients with rest pain due to peripheral obliterative arterial disease (POAD)--a preliminary report on a placebo-controlled double-blind study.
The clinical efficacy of the prostacyclin analogue iloprost was studied during a 2 week treatment and 6 month follow-up period in 103 patients with ischaemic ulcers who were randomised to receive active treatment or placebo. Responders were defined as those patients who achieved healing of at least one third of the ulcer area during the study period. The overall responder rate was 41.3%, compared with 25% for the control group (P = 0.086). Side effects including flushing and headache, were common. The study population had a mortality of 23% during the 6 month period, the amputation rate was 43.5% for iloprost and 50% for placebo treated patients. In this severely diseased population of patients a treatment period limited to 2 weeks did not sufficiently improve ulcer healing. Severe pain at rest is a major symptom of advanced peripheral arterial occlusive disease (PAOD). Preliminary studies of treatment with iloprost, a prostacyclin analogue, showed encouraging results in patients with ischaemic rest pain. Therefore a randomized, placebo-controlled multicentre study was undertaken in 113 patients admitted to hospital with rest pain of at least 2 weeks duration caused by severe PAOD. The patients were randomly assigned to receive 2-week placebo or iloprost infusions for 6 hours per day at a dose of 0.5-0.2 ng/kg/min in addition to conventional care. Demographic data and arteriographic findings were similar in the two groups. Eleven patients withdrew from the study before completion and 102 patients could be included in the final analysis. Significantly more patients in the iloprost group (62.5% of 48) than in the placebo group (42.6% of 54) had complete relief of pain without analgesic therapy during at least five consecutive days at the end of the treatment period (p less than 0.05, chi 2-test). Facial flush, headache and nausea were the most common side effects during iloprost infusion. Serious adverse reactions did not occur. Thus, a 2-week iloprost infusion was shown to be safe and effective as a treatment for ischaemic rest pain caused by PAOD. In a controlled randomized trial at four centers, using a common protocol, 57 patients with advanced chronic arterial occlusive disease (21 in stage III, 36 in stage IV) were treated with prostaglandin E1 (PGE1) or adenosine triphosphate (ATP) for three weeks. Both substances were administered intraarterially over 60 min. Daily dose of PGE1 was 20 micrograms, of ATP 30 mg. Both produced a significant reduction in resting pain at the end of the treatment phase, in stage III significantly better with PGE1. There was also a clear reduction in the use of analgesics, significantly more so with PGE1. Healing or improvement of ulcers was significantly better with PGE1, while there was no significant differences between the two drugs as regards stage improvement. Three amputations had to be performed in the PGE1 group, nine in the ATP group, a significant difference. Side effects in the form of reddening, pain and swellings occurred in 15 patients of the PGE1 group and six of the ATP group. Final verdict by the treating doctor about the success of treatment was significantly more favorable for PGE1. This randomized, double-blind study investigated the effect of ciprostene, a stable epoprostenol (prostacyclin) analog in patients with peripheral vascular disease (PVD) characterized by ischemic ulcers. A total of 211 patients (106 ciprostene, 105 placebo) received IV infusions of ciprostene (120 ng/kg/min in 8-hour daily infusions for 7 days) or placebo. The two groups were comparable with regard to demographic data. Only 45% of the patients receiving ciprostene and 55% of the placebo patients completed the trial. The groups were similar in frequency of amputations, vascular surgery, and development of new ulcers. Among those who completed the trials an insignificantly higher percentage of patients receiving ciprostene had all ulcers heal completely. The reduction of ulcer size by at least 50% was higher in the ciprostene-treated group at month 4 (P = .005). Both ciprostene and placebo reduced the severity of a patient's rest pain. There was no difference in the ankle brachial index between the groups. Ciprostene induced a higher incidence of headache, nausea, and flushing during infusion when compared with the placebo group. The results confirmed inherent problems with studies in PVD, namely, scarcity of patients with ischemic ulcers, inclusion of severely ill patients leading to a high dropout rate, and a high placebo effect. Good tolerance and safety of ciprostene was documented in this patient population, and the therapeutic benefit was limited to partial reduction of ulcer size. Selection of patients with less advanced disease and a longer infusion of ciprostene may improve the clinical benefit of this agent. Intravenous iloprost, titrated from 0.5 up to 2.0 ng/kg/min has been shown in patients with PAOD III/IV to significantly improve healing of trophic lesions, relief of rest pain, and reduce the rate of major amputation or death at 6 months as compared to placebo. The effect is considered related to improvement of the microcirculation. The aim of the present trial was to identify an optimum dose regarding treatment response and tolerability, by studying 4 doses of 25, 50, 75 and 100 micrograms iloprost daily.
                302 patients with PAOD IV were randomised via a double-blind fashion to one of the 4 doses. The primary endpoint was the responder rate at end of treatment. Responders were defined as patients with very good or good global efficacy, as judged by lesion healing and pain relief. Side effects were documented and a pre-defined benefit/risk index was calculated.
                No dose-dependency of iloprost regarding primary or secondary endpoints was observed. The rate of responders ranged between 48.7-53.5%. Side effects, mainly related to vasodilation, increased dose-dependently (p < 0.001, chi 2-test), with a significant decrease of the benefit/risk index from 2.19 +/- 1.19 to 1.64 +/- 0.97 (p = 0.012, ANOVA). Responders had a better outcome at 6 months than non-responders (2.6 fold higher rate of major amputation or death; life table analysis).
                It is concluded that iloprost should be titrated to the optimum rather than maximum tolerated dose, since a higher incidence of side effects not associated with an increased treatment response was observed at higher doses. Two separate studies are described using the same prostacyclin analogue in a similar group of patients.
                to assess the tolerability and efficacy of two dose regimens of oral Iloprost compared with placebo in the treatment of patients with ischaemic ulcers, gangrene or rest pain due to severe arterial disease over a period of 4 weeks (Study A) and one year (Study B).
                multicentre, placebo controlled, double-blind, randomized prospective studies.
                178 (study A) and 624 (study B) patients with trophic skin lesions (ulcers or gangrene) or ischaemic rest pain due to severe arterial disease. To confirm severe arterial disease patients were required to have a systolic ankle Doppler pressure of 70 mmHg or less or a toe systolic Doppler pressure of 50 mmHg or less in one leg. In both studies patients were randomly allocated to three treatment groups: placebo, low dose Iloprost (50-100 microgram twice a day) or high dose (150-200 microgram twice a day) In Study A the main outcome measures were tolerability of different doses of Iloprost and death, major amputation, healing of trophic lesions and relief of rest pain at the end of the follow up, which was 5 months after the end of the treatment. In Study B the primary end point was time to major amputation and stroke or death up to 12 months. Secondary pre-defined end points included the combined end point of patients alive without amputation, no trophic skin changes, no rest pain and not on regular analgesics.
                the proportion of patients who completed the 4-week treatment period in Study A at the intended dose was 58%, 43%, 45% respectively in the placebo, low dose and high dose Iloprost groups. In an intention to treat analysis the proportion of patients who survived without major amputation, ulcers or gangrene and had no rest pain was 11% in the placebo group, 19% in the low dose iloprost group and 28% in the high dose Iloprost group. The pooled Iloprost groups showed a statistically significantly better result than the placebo group (p=0.04), as did the high dose Iloprost group compared to the placebo (p=0.014). In Study B there was no treatment benefit in terms of a primary end point of amputation and death. However the secondary combined end point of patients who survived without a major amputation, ulcers or gangrene and had no rest pain, nor a need for regular analgesia was favourable for Iloprost, with 18% of patients in the placebo group reaching this optimal secondary end point, compared to 23% in the low dose Iloprost group and 26% in the higher dose Iloprost group (p<0.05).
                oral Iloprost administered for a year showed no clear benefit in patients with advanced severe leg ischaemia (PAOD III and IV). The results obtained with 4 weeks' treatment in Study A and in previous trials of intravenous Iloprost could not be reproduced
                Copyright 2000 Harcourt Publishers Ltd. In a randomized cross-over study, the effect of PGE(1) and iloprost on microcirculation as well as the tolerability was investigated in 36 patients with peripheral arterial occlusive disease stage III and IV according to Fontaine. Patients received PGE(1) and iloprost by single 3-h i.v. infusions on two different days at doses recommended by the manufacturers or in previous studies (PGE(1): first hour 20 microg, next 2h 30 microg each. Iloprost: first hour 0.5 ng/kg/min, next 2h 1.0 ng/kg/min). Transcutaneous oxygen pressure (tcPO(2)) values increased much more with PGE(1). Median tcPO(2) increase over baseline 30 min after the end of infusion was 9 and 2 mmHg for PGE(1) and iloprost, respectively, corresponding to median AUC differences from baseline of 1050 and 210 min mmHg. Because of its exploratory character, the study was not powered to test for significance. Adverse effects occurred in 19.4% (PGE(1)) and 30.6% (iloprost) of patients. Dose reduction was required in 3 patients receiving iloprost (hypotension, nausea, irritation of the infused vein), and in none receiving PGE(1). The effectiveness of a 72 h. intra-arterial prostacyclin infusion has been compared to that of naftidrofuryl oxalate (Praxilene) in a double blind study of 29 patients with ischaemic rest pain in 30 legs. Long-term relief of symptoms was achieved in 14 legs (47%) and major limb amputation avoided in 18 (60%). No significant difference was demonstrated between the results of prostacyclin infusion and those of Praxilene. Thirty patients with ischaemic ulceration or rest pain due to lower limb atherosclerosis were treated with intravenous prostaglandin E1 (PGE1) or placebo in a prospective double-blind controlled trial. There was no significant improvement of rest pain, nor was PGE1 effective in promoting ulcer healing. This study provides no support for the use of intravenous PGE1 in the treatment of end-stage lower limb atherosclerotic disease. A number of patients (151) with ischaemia of the lower limb presenting as ulcers or gangrene and/or rest pain were entered into a multicentre randomised double-blind controlled study of intravenous iloprost or placebo given for 14-28 days. Patients were assessed for evidence of ulcer healing as judged by reduction in size with granulation at the base and relief of rest pain sufficient for discharge from hospital. Based on these criteria, 45% in the iloprost and 29% in the placebo group showed evidence of improvement of clinical status at the end of treatment (p less than 0.05). At 6 months follow-up improvement was maintained in 42% of iloprost patients and 26% of placebo patients (p less than 0.01). At this follow up 64% of the iloprost patients and 42% of the placebo patients were alive with a viable limb. Thirty-one per cent of the iloprost patients and 47% of the placebo patients underwent major amputation (p less than 0.05). It has been shown that iloprost significantly improves patients with ischaemic ulcers or gangrene compared with placebo. This improvement is maintained for up to 6 months after treatment resulting in a reduced major amputation rate. The efficacy of iloprost, a stable prostacyclin analog, was investigated in a placebo-controlled trial in 109 diabetics with ischemic lesions. 56 patients were randomly allocated to iloprost and 53 patients to placebo. Iloprost was intravenously applied for 6 hours daily on 28 consecutive days at an individually tolerated dose up to 2 ng/kg/min. The control group received identical solvent volumes. In addition all patients had an intensive basic, mainly local, therapy. At the end of the treatment in the iloprost group 31 of 50 patients (62%) showed partial (greater than 30%) or total healing of the lesion(s). In the placebo group this was the case in 12 of 51 patients (22.5%). The difference of 38.5% was statistically significant (p less than 0.05, chi 2-test, alpha = 0.05, beta = 0.1). The percentage of patients who were free of pain increased from 23% to 42% (+19%) in the iloprost group and from 38% to 48% (+10%) in the placebo group. After dose-titration iloprost was well tolerated. Flush, headache and abdominal complaints were the most frequent side effects. Heart rate and blood pressure were not influenced and the control of diabetes was not altered. nan A 96 h infusion of epoprostenol (prostacyclin) or placebo was given as a treatment for rest pain to 28 patients with severe peripheral arterial disease. 24 h after the end of the infusion patients given epoprostenol had significantly less pain and took fewer analgesics tablets than did the controls. In some patients the epoprostenol effect lasted for over 1 month. nan
Despite some positive results regarding rest-pain relief, ulcer healing and amputations, there is no conclusive evidence based on this meta-analysis of the long-term effectiveness and safety of different prostanoids in patients with CLI. Further well-conducted, high quality randomised double-blinded trials should be performed.