The ILAILL Study: Iloprost as Adjuvant to Surgery for Acute Ischemia of Lower Limbs

Acute limb ischemia (ALI) is a serious medical emergency leading to high rate of complications, being not only limb- but even life-threatening, often despite early successful revascularization.1 Improvements in surgical techniques and perioperative patient care may have reduced the incidence of major complications in ALI patients over the years, but the results of trials published recently seem to document a persistent high risk, with reported 30-day amputation rate of 5% to 12%, mortality risk at 10% to 38%, combined incidence of amputation and death of 25% to 37.5%, at 1- to 6-month follow-up.2–7 Concomitant underlying diseases, the metabolic derangement that seems as a result of the acute insult, and a possible reperfusion injury following revascularization may account for this severe prognosis.8 Only anticoagulation, fasciotomy (when indicated), and perioperative supportive treatment are established strategies in ALI patients.1,8,9 Possible benefit from cardiovascular active therapies has recently been suggested in patients undergoing peripheral revascularization or noncardiac major surgical intervention.10,11 Moreover, several categories of compounds, potentially acting on pathobiological mechanisms of ischemia-reperfusion syndrome, have been tested in experimental models, but none of them has as yet been proven effective in clinical studies in patients with ALI.12–18 Because of their pharmacologic profile, prostanoids represent a potentially interesting category as adjuvant treatment of ALI patients.19 Several ischemia-reperfusion studies described the use of prostaglandins for reduction of postischemic tissue injuries, and even recently both PGE1 and PGI2 appeared as potent inhibitors of reflow-paradox in a preclinical model of reperfusion injury.20 Iloprost is a widely studied synthetic analogue of prostacyclin, with a 10-fold higher half-life than the native compound, and indicated in the treatment of severe chronic limb ischemia.1,21–23 Results from pilot studies and case reports also described the positive effects of iloprost in the management of acute ischemia secondary to various causes, particularly after accidental intra-arterial administration of drugs or toxic agents.24–26 Several preclinical studies have assessed the effects of iloprost in experimental ischemia-reperfusion injury and documented the actions of the compound on different pathophysiologic mechanisms potentially relevant for damage following ALI.27–32 A diagram indicating where iloprost can interfere in the mechanisms, leading from ischemia and reperfusion, to the development of no-reflow and reflow-paradox, is reported in Figure 1. 33 FIGURE 1. Pathobiological mechanisms leading from ischemia-reperfusion, to “no-reflow”/“reflow-paradox.” Points where iloprost can act are indicated (from de Donato et al33). Some years ago, we performed a placebo-controlled, double-blind pilot study in 30 patients with ALI undergoing Fogarty's thromboembolectomy. Encouraging results were obtained with the use of intraoperative and postoperative iloprost (lower incidence of major clinical events, more evident metabolic improvement by means of transcutaneous tensiometry).34 In this paper, we report the results of ILoprost in Acute Ischemia of Lower Limbs (ILAILL) study, a larger, multicenter trial including patients undergoing all types of surgical revascularization, who received iloprost or placebo administration during intervention and therefore for 4 to 7 days, and were observed for a 3-month postoperative period.