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Trial of iloprost versus aspirin treatment for critical limb ischaemia of thromboangiitis obliterans. The TAO Study. Fiessinger J N,Schäfer M Lancet (London, England) 152 patients with thromboangiitis obliterans (Buerger's disease) and pain from critical leg ischaemia were randomly allocated to receive iloprost, a chemically stable prostacyclin analogue, or low-dose aspirin, for 28 days in a double-blind trial. On review, 19 patients did not fulfil the stringent entry criteria. Of the other 133 patients, 98 also had leg ulcers. After 21-28 days, 58 (85%) of 68 iloprost-treated patients showed ulcer healing or relief of ischaemic pain, compared with 11 (17%) of 65 in the aspirin-treated group. 43 (63%) on iloprost treatment had complete relief of pain, compared with 18 (28%) on aspirin. Ulcers healed completely in 18 of 52 (35%) who received iloprost compared with 6 of 46 (13%) who received aspirin. 6 months after the start of treatment, the response rate was 45 of 51 (88%) patients treated with iloprost compared with 12 of 44 (21%) patients treated with aspirin. 10.1016/0140-6736(90)90346-7
Use of the prostacyclin analogue iloprost in the treatment of patients with critical limb ischaemia. Dormandy J Therapie Five large, placebo-controlled, randomised prospective multicentre trials have been completed in several European countries, including a total of 728 patients with critical limb ischaemia (CLI). 593 had ulceration or gangrene and it is these which will be analysed in detail. Only patients with CLI who were unsuitable for further reopening procedures were entered and approximately a third of the patients had already had attempts at surgical revascularisation or interventional radiology. The maximum tolerated dose up to 2 ng/kg/min was determined during the first three days and then continued as a six-hourly intravenous infusion every day for two to four weeks, depending on the study. Pooled results showed a significant overall 21% increase in ulcer healing rate due to iloprost (p less than 0.001) compared with placebo. The improvement was greater in the three studies when treatment was continued for four weeks. The very hard end point of a major amputation or death during a 3 to 6 month follow up was available in three of the studies. Analysis of these together demonstrated a significantly lower incidence of major amputations after iloprost treatment (p less than 0.05). Thus the existing weight of evidence from a large number of patients suggests that a course of intravenous iloprost is useful in the management of patients with CLI and trophic skin changes, who are unsuitable for reconstructive surgery or catheter procedures.
Treprostinil sodium (Remodulin), a prostacyclin analog, in the treatment of critical limb ischemia: open-label study. Berman Scott,Quick Rhonda,Yoder Pam,Voigt Sonia,Strootman Deborah,Wade Michael Vascular The purpose of this study was to assess the safety of continuous subcutaneous therapy with treprostinil sodium (Remodulin), a prostacyclin analog, and its effect on ischemic rest pain and ischemic wound healing in subjects with critical limb ischemia (CLI) and no planned revascularization procedure. This was a 12-week, open-label, single-center pilot study enrolling 10 subjects (mean age 82.4 years) with Fontaine stage III to IV (Rutherford class 4-6) peripheral arterial disease and ankle brachial indices less than 0.55. The primary end point was safety, and the secondary end points were the effects of treatment on ischemic rest pain, limb salvage, and wound healing. There was a 62% reduction in mean worst rest pain and a 57% reduction in mean average rest pain at week 12, with most subjects using less pain medication. Three subjects experienced complete healing of their wounds. No subject developed a new wound during the trial. Treprostinil was generally well tolerated. Subcutaneous infusion-site pain was the most frequently reported side effect, with one subject withdrawing from the study as a result. Jaw pain was reported by two subjects. One subject experienced two serious adverse events considered unrelated to treprostinil (cholecystitis and congestive heart failure). This study demonstrates that chronic, continuous subcutaneous treprostinil is safe and can be useful in the treatment of ischemic pain and wounds in subjects with CLI. Future controlled studies are needed to evaluate these effects and determine appropriate patient selection. 10.2310/6670.2006.00028
Acute and long-term effects of prostaglandin E1 assessed by clinical and microcirculatory parameters in critical limb ischemia: a pilot study. Stricker H,Kaiser U,Frei J,Mahler F International journal of microcirculation, clinical and experimental We treated 14 patients suffering from critical limb ischemia (CLI) as defined by the Consensus Document, and in whom possibilities of surgical or percutaneous arterial reconstruction were excluded, by PGE1 60 micrograms i.v. daily during 3 weeks. Effects were evaluated by clinical, macrocirculatory and microcirculatory parameters during a follow-up of 1 year. After treatment with PGE1, we noted a significant reduction in analgesic use and in pain score. The average tcpO2 values on the forefoot in the supine and sitting positions, with or without inhalation of O2 through a face mask, showed a significant improvement after 3 weeks, as well as capillary stage. Laser Doppler flux did not change, but was significantly higher in diabetic patients than in nondiabetics with CLI. In 4 patients (28%) no improvement could be found after 3 weeks' treatment. Although in 6 patients the improvement lasted for up to 4 months, the legs eventually deteriorated. In 4 patients (28%) the legs were preserved after 1 year without further active therapy. No patient with initial tcpO2 values above 40 mm Hg in the supine and 100 mm Hg in the sitting positions during O2 inhalation lost a leg. Although other effects like local care could have influenced the outcome favorably, we noticed a beneficial albeit transient effect of PGE1 for the majority of our patients with CLI. TcpO2 measurements with O2 inhalation might be a valuable predictor of a positive long-term result. 10.1159/000179151
A stable prostacyclin analogue (iloprost) in the treatment of ischaemic ulcers of the lower limb. A Scandinavian-Polish placebo controlled, randomised multicenter study. Norgren L,Alwmark A,Angqvist K A,Hedberg B,Bergqvist D,Takolander R,Claes G,Lundell A,Holm J,Jivegård L European journal of vascular surgery 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. 10.1016/s0950-821x(05)80784-4
The effect of ciprostene in patients with peripheral vascular disease (PVD) characterized by ischemic ulcers. The Ciprostene Study Group. Journal of clinical pharmacology 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.
Treatment of ischaemic digital ulcers and prevention of gangrene with intravenous iloprost in systemic sclerosis. Zachariae H,Halkier-Sørensen L,Bjerring P,Heickendorff L Acta dermato-venereologica Twelve patients with systemic sclerosis were treated with intravenous infusions of the prostacyclin-stable analogue iloprost 0.5-2.0 ng/kg/min for 6 h from 8 to 13 days. Imminent gangrene was stopped in 2 patients and followed by healing. In 4 of 6 patients iloprost led to complete healing of ischaemic ulcers and in the remaining 2 patients to partial healing. One patient with severe Raynaud's phenomenon discontinued the study after 3 days due to severe headache. The 2 remaining patients with Raynaud's phenomenon as an indication improved, while no improvement was recorded in a patient with vasculitis of the lower leg. Side-effects such as headache, nausea and flushing were the reason that only 5 patients reached the maximum infusion rate. No statistical differences were recorded in digital bloodflow before and after the study or in plasma endothelin in the 9 patients investigated. Three of the 6 patients with healing ulcers, however, showed a pronounced decrease in plasma endothelin. Iloprost appears useful as a treatment of imminent gangrene and ischaemic ulcers in systemic sclerosis. This reparatory capacity could also be of a more general importance in therapy of this disease. 10.2340/0001555576236238
[Iloprost for severe Raynaud's phenomenon and ischaemic ulcers related with systemic diseases]. García Hernández Francisco José,Ocaña Medina Celia,Mateos Romero Luis,Molinillo López Juan,Arias Zambrano Andrés,González León Rocío,Sánchez Román Julio Medicina clinica BACKGROUND AND OBJECTIVE:To evaluate the long term efficacy of treatment with intravenous iloprost for severe Raynaud's phenomenon (RP) and ischemic leg ulcers in patients with autoimmune systemic diseases. PATIENTS AND METHOD:Prospective observational study over 2 years with iloprost (intravenous infusions, 0.5 to 2 ng/kg/min, initial cycle of 5 consecutive days and maintenance infusions during 24 h monthly, lengthened when it was needed) in patients with severe RP and ischemic leg ulcers whithout response to conventional therapy. Treatment was halted in patients with a good response after one year of treatment, with regular clinical controls. RESULTS:We treated 23 patients. Iloprost reduced significantly the mean number (SD) of monthly episodes of RP (150.38 [102.04] initially and 40.05 [78.06] at the end; p < 0.0005), the mean highest duration of episodes of RP (21.86 [26.96] min initially and 7.14 [9.87] min at the end; p = 0.013), the associated pain (p = 0.005), and the mean number of ischemic digital (4.25 [2.86] initially and 0.63 [2.25] at the end; p = 0.003) and leg ulcers (1.67 [0.52] initially and 0.33 [0.52] at the end; p = 0.01). Articular symptoms and inflammatory markers did not improve. Treatment was stopped in 8 patients (in 5 for a very good evolution and in 3 for other causes), and only 1 of them needed to be treated again. Side effects were seen in all cases but always disappeared after slowing infusion. CONCLUSIONS:Iloprost was effective in the long term treatment of severe RP and ischemic leg ulcers in patients with autoimmune systemic diseases.
Prostanoids for chronic critical leg ischemia. A randomized, controlled, open-label trial with prostaglandin E1. The ICAI Study Group. Ischemia Cronica degli Arti Inferiori. Annals of internal medicine BACKGROUND:No effective pharmacologic intervention is available for critical leg ischemia, a severe clinical condition associated with high morbidity and mortality. OBJECTIVE:To assess the safety and efficacy of prostaglandin E1 in improving the prognosis and quality of life in patients with critical leg ischemia. DESIGN:Multicenter, centrally randomized, controlled, open-label trial. SETTING:56 vascular surgery and angiology departments of the Italian National Health Service. PATIENTS:1560 patients with chronic critical leg ischemia. INTERVENTIONS:In addition to routine treatments practiced in each center, patients were randomly assigned to receive either a daily intravenous infusion of 60 microg of prostaglandin E1 in the form of alprostadil-alpha-cyclodextrine (n = 771) or no prostaglandin E1 (n = 789) during their hospital stay. The treatment period lasted for up to 28 days. MEASUREMENTS:A combined end point consisting of death and peripheral and cardiocerebrovascular illness (major amputation or persistence of critical leg ischemia, acute myocardial infarction, or stroke) evaluated at hospital discharge and during 6 months of follow-up. RESULTS:The incidence of the combined outcome measure was lower in the alprostadil group than in controls at hospital discharge (493 [63.9%] patients compared with 581 [73.6%] patients; relative risk, 0.87 [95% CI, 0.81 to 0.93]; P < 0.001) but differed only modestly at 6 months (348 of 661 [52.6%] patients compared with 387 of 673 [57.5%] patients; relative risk, 0.92 [CI, 0.83 to 1.01]; P = 0.074). Most of the observed benefit was due to recovery from critical leg ischemia. CONCLUSIONS:Short-term treatment with alprostadil-alpha-cyclodextrine provides patients with critical leg ischemia clinical benefit that is apparent in the short term but decreases over time.