Intravenous iloprost treatment of Raynaud's phenomenon and ischemic ulcers secondary to systemic sclerosis. Infusion of iloprost, a prostacyclin analogue, for treatment of Raynaud's phenomenon in systemic sclerosis. Intravenous iloprost infusion in patients with Raynaud phenomenon secondary to systemic sclerosis. A multicenter, placebo-controlled, double-blind study. Successful treatment of Raynaud's syndrome with Iloprost, a chemically stable prostacyclin analogue. Oral iloprost as a treatment for Raynaud's syndrome: a double blind multicentre placebo controlled study. Placebo controlled study showing therapeutic benefit of iloprost in the treatment of Raynaud's phenomenon. [Treatment of systemic scleroderma with ketanserin. Randomized, double-blind 6-months study of 27 cases]. Treatment of limb threatening ischaemia with intravenous iloprost: a randomised double-blind placebo controlled study. U.K. Severe Limb Ischaemia Study Group. Low-dose iloprost infusions compared to the standard dose in patients with peripheral arterial occlusive disease Fontaine stage IV. DAWID Study Group.
We conducted this study to assess the clinical usefulness and physiologic effects of intravenous iloprost in patients with Raynaud's phenomenon secondary to systemic sclerosis.
                Thirty-five patients with Raynaud's phenomenon secondary to systemic sclerosis, including 11 with digital ischemic ulcerations, were enrolled in a double blind placebo controlled parallel study in 2 centers. Following a 2 week washout, subjects received intravenous iloprost (0.5-2.0 ng/kg/min) or saline by continuous infusion for 6 h on 5 consecutive days. Clinical assessments, status of digital ulcers, measures of in vivo platelet activation and detailed studies of peripheral vascular response to cold challenge, were performed at entry, at 5 days of therapy and at biweekly intervals for 10 weeks.
                Complete healing of all cutaneous lesions (ulcers, fissures, and paronychia) was observed 10 weeks after treatment in 6 of 7 patients receiving iloprost versus none of 4 receiving placebo (p = 0.015). Ischemic digital tip ulcers completely healed in all 4 patients with ulcers in the iloprost group, but none in the placebo group (p = 0.029). Patient diaries of frequency, duration and symptoms of Raynaud's phenomenon showed improvement in both groups. Critical ischemic temperature (finger temperature during controlled cold challenge at which Raynaud's or loss of detectable digital blood flow occurred) progressively decreased in the iloprost group from 21.3 +/- 7.3 degrees C at baseline to a minimum of 16.1 +/- 3.2 degrees C at 8 weeks after treatment (p = 0.076), whereas no consistent changes were observed in the placebo group. Treatment was associated with improvement in the rate of skin temperature recovery following cold challenge. No changes were noted in ambient digital skin temperature, total digital blood flow, finger systolic pressure or in measures of in vivo platelet activation. One subject dropped out with chest pain, but adverse effects of nausea, vomiting, headache and jaw pain were otherwise limited to the 5 days of drug infusion.
                Iloprost appears useful for the treatment of digital ulcers in systemic sclerosis and is associated with evidence of prolonged physiologic improvement although the mechanism of this effect remains unclear. Iloprost, a stable prostacyclin analogue, was given by intravenous infusion to 29 patients with severe Raynaud's phenomenon, 26 of whom had systemic sclerosis (SS), and compared with placebo infusion in a double blind crossover trial. Iloprost significantly lessened the number and the severity of attacks compared with placebo. Nine patients expressed a preference for effectiveness of treatment, eight of these in favour of Iloprost. Thermography failed to show any long term effect of Iloprost. Side effects of headache, flushing, nausea, and vomiting were common, and the inconvenience of intravenous administration may limit its routine use. To evaluate the efficacy and safety of iloprost, a prostacyclin analog, administered intravenously in patients with Raynaud phenomenon secondary to systemic sclerosis.
                Multicenter, randomized, parallel placebo-controlled, double-blind study.
                University medical centers.
                131 patients with systemic sclerosis (101 women, 30 men) ages 20 to 79 years.
                Patients were randomly assigned to receive one of two parallel treatments of five daily sequential, 6-hour intravenous infusions of iloprost (0.5 to 2.0 ng/kg per min) or to receive a similar volume of placebo.
                Frequency of Raynaud attacks, Raynaud severity score, physician's overall rating of treatment effect, and digital cutaneous lesion healing.
                Of the 131 patients enrolled, 126 completed the 5-day infusion and 114 (87%) completed at least 6 weeks of follow-up. Sixty-four patients were randomly assigned to receive iloprost and 67 patients, to receive placebo. The mean weekly number of Raynaud attacks decreased 39.1% with iloprost and 22.2% with placebo (P = 0.005). In addition, the mean percentage of improvement in a global Raynaud severity score during the entire 9-week follow-up was greater in patients given iloprost (34.8%) than in those receiving placebo (19.7%) (P = 0.011). The physician's overall rating of treatment effect showed greater improvement with iloprost than with placebo at week 6 (52.4% compared with 27.4%; P = 0.008) and week 9 (60.9% compared with 26.9%; P < 0.001). At week 3, 14.6% more patients receiving iloprost had 50% or more lesions heal compared with those given placebo (95% CI, 0.9% to 30%). During the infusion, 59 (92%) of the patients receiving iloprost had one or more side effects compared with 38 (57%) of the patients receiving placebo.
                Iloprost is effective for the short-term palliation of severe Raynaud phenomenon in patients with systemic sclerosis. Twelve female patients with severe secondary Raynaud's phenomenon were treated in a randomized order with both placebo and Iloprost infusions. Infusions were for 5 hours on 3 consecutive days and Iloprost was administered at variable dosage from 1.0 to 3.0 ng/kg/min. A 6-week follow-up period was used between the two sets of infusions. A significant number of patients reported Iloprost had improved Raynaud's symptomatology compared with placebo and this effect lasted for up to 6 weeks. The number of attacks of Raynaud's as recorded by patients in diary books was similarly reduced after Iloprost. Digital and nail-bed blood flows measured by laser-Doppler methods were increased for up to 6 weeks after Iloprost, but not after placebo infusions. Iloprost may be a useful therapeutic agent in the treatment of severe secondary Raynaud's syndrome. To compare the efficacy, tolerance and safety of 50-150 micrograms orally administered iloprost given twice a day versus placebo in patients with Raynaud's syndrome.
                The study was multicentre (n = 3), double blind and placebo controlled. Sixty three patients who had eight or more vasospastic attacks per week were enrolled. After a one week run-in period, all patients received either iloprost or placebo treatment to a maximum tolerated dose of 150 micrograms twice a day for 10 days. Diary cards assessed the duration and severity of the vasospastic attacks. Side effects were monitored by direct questioning. A global assessment of treatment efficacy was made by the patient at the end of treatment and two weeks later.
                Patient opinion tended to favour iloprost at the end of the 10 day treatment phase (p = 0.09) and this was significant at day 24 (the follow up visit) (p = 0.011). Although the duration and severity of attacks tended to decrease in the iloprost treated group, these results tended not to reach statistical significance (for severity p = 0.06 at end of treatment, p = 0.09 on day 24).
                Iloprost administered intravenously has been shown to be of benefit in the treatment of the Raynaud's syndrome associated with systemic sclerosis, but this route of administration is inconvenient. This study evaluated the use of iloprost administered orally to patients with Raynaud's syndrome. Patient documented improvement was significantly improved by iloprost. Diary card analysis showed a trend in favour of iloprost, but these results did not reach statistical significance. Iloprost is a chemically stable analog of prostaglandin I2 showing the same properties as the naturally occurring substance, but with advantages of ease of handling and administration to patients. A double blind within patient comparison of intravenous iloprost and placebo was undertaken in 13 patients with Raynaud's phenomenon severe enough to warrant short term hospitalization for intravenous dilator therapy; thermography was used as one form of assessment. Our results, while showing improvements in frequency of Raynaud's attacks after iloprost compared with placebo, show no significant effects on other variables. Twenty-seven patients with systemic scleroderma and Raynaud's phenomenon underwent a randomised double blind therapeutic trial: monotherapy with Ketanserine (80 mg/day for 6 months) against Placebo. The secondary effects were comparable in both groups as were the withdrawals from the trial for aggravation of Raynaud's phenomenon (one in each group). No significant difference was observed between the two groups as regards the evolution of the Raynaud's phenomenon or skin changes. Dysphagia was improved in the Ketanserine group (p less than 0.05) but not in the Placebo group. Some patients in the Ketanserine group experienced an improvement in the Raynaud's phenomenon at the end of the trial period; there were no improvements in the Placebo group. Three haemorrheological parameters (total blood viscosity, plasma viscosity and thixotropism) were abnormal at the beginning of the trial and did not improve by the end in the Ketanserine group. The K infinity coefficient of Quemada's law was normal at the start of the trial and increased after treatment (p less than 0.05). 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. 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.
Intravenous Iloprost is effective in the treatment of Raynaud's phenomenon secondary to scleroderma at decreasing the frequency and severity of attacks and preventing or healing digital ulcers. The effect seems to be prolonged after the intravenous infusion is given. Oral Iloprost may have less efficacy than intravenous Iloprost. However, Cisaprost has minimal or no efficacy when given orally for the treatment of Raynaud's phenomenon secondary to scleroderma.