Beischer W, Dembski J C, Gruss J D, Hofgärtner F, Horsch A, Horsch S, Kuhlmann H W, Loose D A, Mietaschk A, Schwilden E D, Spengel F, Spitzer W, Staben P, Stallkamp B, Stürzebecher C S, Tokhi M, von Bilderling P
Klinische Entwicklung Herz-Kreislauf und Zentrales Nervensystem, Schering AG, Berlin.
Vasa. 1998 Feb;27(1):15-9.
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.
在患有Ⅲ/Ⅳ期外周动脉闭塞性疾病（PAOD）的患者中，已表明从0.5 ng/kg/min滴定至2.0 ng/kg/min的静脉注射伊洛前列素与安慰剂相比，在6个月时可显著改善营养性病变的愈合、缓解静息痛，并降低大截肢或死亡的发生率。该作用被认为与微循环的改善有关。本试验的目的是通过研究每日4种剂量（25、50、75和100微克）的伊洛前列素，确定关于治疗反应和耐受性的最佳剂量。
302例Ⅳ期PAOD患者通过双盲方式随机分配至4种剂量组之一。主要终点是治疗结束时的反应率。反应者定义为根据病变愈合和疼痛缓解判断具有非常好或良好总体疗效的患者。记录副作用并计算预先定义的获益/风险指数。
未观察到伊洛前列素在主要或次要终点方面的剂量依赖性。反应率在48.7% - 53.5%之间。主要与血管扩张相关的副作用呈剂量依赖性增加（p < 0.001，卡方检验），获益/风险指数从2.19 ± 1.19显著降至1.64 ± 0.97（p = 0.012，方差分析）。反应者在6个月时的结局比无反应者更好（大截肢或死亡发生率高2.6倍；生命表分析）。
得出的结论是，伊洛前列素应滴定至最佳而非最大耐受剂量，因为在较高剂量下观察到与治疗反应增加无关的副作用发生率更高。
