The Potential Role of Iloprost as Adjuvant to Surgery for Acute Limb Ischemia: Findings from the ILAILL Study

Abstract

Background. Acute limb ischemia (ALI) is a clinical emergency with a high rate of morbidity and mortality, despite the technical success of surgical revascularization. Elderly patients are at a particularly high risk of severe local and systemic complications. Due to its pharmacological profile, iloprost seems to be a suitable candidate as an adjuvant to surgery in patients with ALI. To assess this hypothesis, we performed a randomized, placebo-controlled, phase III study (ILAILL). Methods. Three-hundred patients undergoing surgery for ALI were assigned to receive perioperative iloprost (intra-arterial, intra-operative bolus of 3000 ng, plus intravenous infusion of 0.5–2.0 ng/kg/min for six hours/day for 4–7 days following surgery) or placebo. The primary efficacy outcome was the combined incidence of death and amputation at 3-month follow up. Secondary endpoints were the incidence of each single major complication, total event rate, and tolerability. Results. The combined incidence of death and amputation was 19.9% in the placebo and 14.1% in the iloprost group in the overall study population (relative risk [RR]: 1.56, p = 0.12), and 27.2 vs 16.0% (RR: 1.99, p = 0.03) in the subgroup of patients > 70 years. A statistically significant lower mortality was reported in patients receiving iloprost, both in the overall study population and elderly patients (4.7 vs 10.6%, RR: 2.61, p = 0.03; and 6.0 vs 15.2%, RR: 2.93, p = 0.03, respectively). No serious adverse reactions occurred after iloprost administration or differences in the incidence of bleeding or hypotension between treatment groups. Conclusions. Waiting for further data to support these findings, our opinion is that iloprost is worth considering as an adjuvant treatment to surgery in ALI patients.

Introduction

A severe prognosis has been reported in patients with acute limb ischemia (ALI), which represents both a limb- and life-threatening clinical emergency, despite improvements in surgical-endovascular techniques and perioperative patient care over the years. The results of available trials document a persistently high medical need, with a reported 30-day amputation rate of 5–12%, mortality risk at 10–38%, combined incidence of amputation, and death of 25–37.5% at 1- to 6-month follow up.^1–6 Elderly patients were reported at a particularly high risk for severe local and systemic complications.⁴ Recent data indicate improved rate of amputation-free survival by combining intra-arterial thrombolysis with catheter-based clot removal,⁷ but based on the results of randomized trials, there is no clear superiority for thrombolysis versus surgery on limb salvage or mortality.^8,9 In the presence of a very high rate of early success for surgical revascularization, concomitant underlying diseases, the metabolic derangement related to the acute insult, and a possible reperfusion injury following revascularization have been claimed as possible explanations for this severe prognosis.¹⁰ According to TASC II guidelines, only anticoagulation, fasciotomy (in the case of compartment syndrome), and perioperative supportive treatment are established strategies in ALI patients undergoing surgical revascularization.⁹

Due to its pharmacological profile iloprost, a synthetic prostacyclin analogue seems a like suitable candidate as treatment adjuvant to surgery in patients with ALI.¹¹ Iloprost is a widely studied molecule with a ten-fold higher half-life than the native compound, and is indicated in the treatment of severe chronic limb ischemia (CLI).¹² Results from pilot studies and case reports described the positive effects of iloprost in the management of acute limb ischemia secondary to the administration of drugs or toxic agents.^13–14 Pharmacodynamic properties of iloprost, most of them potentially relevant for damage following ALI, have been documented in pre-clinical and clinical studies,^12,15–19 such as:

- potent inhibition of platelet activation and aggregation;

- reduced activation of coagulation cascade;

- increase in microcirculatory blood flow;

- reduction/inhibition of the expression of intercellular adhesion molecules;

- reduced release of oxygen free radicals;

- tissue cytoprotection at organ level in the context of ischemia-reperfusion.

 In 1994 we performed a double-blind, placebo-controlled pilot trial to evaluate the effects of intra- and postoperative iloprost in a group of 30 patients with ALI who underwent Fogarty-catheter thromboembolectomy.²⁰ In the iloprost-treated group, we observed a trend towards a reduction in amputation and mortality incidences (3 cases versus 5), and more evident improvements at metabolic levels, as documented by transcutaneous tensiometry. Following these encouraging preliminary results, under the endorsement of the Italian Society for Vascular and Endovascular Surgery (SICVE), we performed a larger phase III multicenter trial (ILoprost in Acute Ischemia of Lower Limbs [ILAILL]), including patients with acute limb ischemia undergoing all types of surgical revascularization, who received iloprost or placebo administration during intervention, and therefore, for 4–7 days and were observed for a 3-month postoperative period.

Patients and Methods

The ILAILL study was a multicenter, randomized, placebo-controlled, double-blind study performed in 22 Italian departments of vascular surgery, aiming to evaluate the effects on clinical outcome of intra- and postoperative treatment with iloprost in patients with acute ischemia of lower limbs undergoing surgical revascularization. Patients who presented with acute rising ( I), unstable angina; angina pectoris (Canadian classification > II), hyperkinetic ventricular arrhythmias, severe hypertension (sitting systolic blood pressure ≥ 180 mmHg or sitting diastolic blood pressure ≥ 110 mmHg) or hypotension (systolic blood pressure 500.000/mm3); severe hepatic failure (cirrhosis); and renal failure requiring dialysis treatment. Iloprost (Endoprost®, Italfarmaco S.p.A., Milan, Italy, under licence of Schering AG, Berlin, Germany) or a placebo (in a ratio 1:1) was administered as an intra-arterial bolus of 3000 ng over 1–3 minutes after revascularization and in the affected artery, according to previous clinical experiences.^21,22 Starting from the first day after surgery, a daily 6-hour intravenous infusion of iloprost (or placebo) at doses recommended for chronic CLI was performed for 4–7 days (7 days recommended), depending on the length of hospital stay. The initial intravenous infusion rate corresponded to 0.5 ng/kg/min for 30 minutes. At 30-minute intervals, it was possible to increase the infusion rate (by 0.5 ng/kg/min) to the maximum tolerated dose, up to 2.0 ng/kg/min. This phase of dose adjustment occurred during the first 3 days after surgery.

Subsequently, the individual dose was maintained throughout the remaining treatment period. During infusion of the experimental drug, strict monitoring of the blood pressure and heart rate was requested. The concomitant use of drugs potentially affecting blood coagulation and pressure was allowed with caution. In the case of bleeding or hypotension, discontinuation or dose reduction of the study drug was required. Patients were followed for 90 ± 5 days after surgery. The primary efficacy outcome of ILAILL was defined by the combined incidence of death and amputation in the two treatment groups during a 3-month follow-up period. Secondary efficacy endpoints were the incidence of each major clinical event during the study (acute myocardial infarction, stroke, peripheral embolism, pulmonary embolism, other major cardiovascular events, amputation, and death) and the total event rate (fatal plus major cardiovascular events). Safety assessments consisted of recording all the adverse events observed as well as those spontaneously reported by patients during the trial, consisting of the results of routine laboratory, blood pressure, and heart rate tests throughout drug infusion and immediately after its interruption. An independent safety committee reviewed all serious adverse events registered during the study at three steps (after 50%, 75% of patients completed, and at the end of the trial).

According to the available data concerning the incidence of death and amputation in the above-mentioned pilot study²⁰ and the clinical experience of the study’s steering committee, it was calculated that the sample size required to demonstrate a reduction in composite endpoint from 35 to 20% by means of a 2-sided test with an alpha error of 0.05 and a beta error of 0.2 was 150 patients per group. The protocol was approved by the ethics committee of each participating center, and written informed consent was obtained from all patients before randomization. Further details on study design and statistical methods have been described in two papers, one concerning the overall study population,23 and the other, a post-hoc analysis focusing on the subgroup of elderly (> 70 years) patients.²⁴

Results

A total of 300 patients (151 in the placebo and 149 in the iloprost group) were evaluable for the efficacy and safety analyses. Baseline characteristics were similar between the two groups of patients, including prevalence of concomitant diseases.²³ To note, patients > 70 years old were 92 (60.9%) and 100 (67.1%) in placebo and iloprost group, a high proportion of patients had symptoms lasting for more than 24 hours (53.0% and 45.2% in the placebo and iloprost group, respectively), and many cases (62.5% and 63.5% of placebo and iloprost patients, respectively) were classified as IIb or III category (“immediately threatened” or “irreversible”), according to SVS/ISCVS – TASC criteria.^9,25 Moreover, no differences were noted for either concomitant anticoagulation or other therapies during the study period, and experimental treatments were administered for similar duration in the two groups. The incidence of major events in the two study groups is reported, both for total study population and in patients > 70 years old. This subgroup of patients has been recognized as at higher risk of complications (the incidence of combined death and amputation was 21.3% in patients > 70 years, versus 9.3 in patients 70 years old. The Kaplan-Meier curve for survival in the overall patient population is reported, showing that the reduction of mortality in the iloprost group becomes evident 3–4 weeks after revascularization. No relevant difference between the iloprost and placebo group occurred in the incidence of amputation, while a trend in favor of iloprost was documented as for the occurrence of overall major peripheral complications (amputation + additional revascularization + recurrent acute limb ischemia), particularly in high-risk elderly patients (15.0 vs 18.4% in controls). Multivariable analyses, by means of the Cox proportional hazard regression model, were performed for composite incidence of death + amputation, death alone, and combined event rate (fatal plus major cardiovascular events) to evaluate the possible relationship between study results and potential clinical predictors, such as experimental treatment, age, type of surgery, class of ischemia, and patient’s history. In the case of death, and considering the overall ILAILL population, age > 70 years was significantly related with a higher risk. A trend towards increased mortality was documented for the class of ischemia ≥ IIb, while a lower incidence of fatal outcome occurred in patients undergoing thromboembolectomy (versus other surgical procedures) and for those experiencing a previous cardiovascular event. Headache and flushing were reported in more patients treated with iloprost than in controls (p 70 years old, if compared to the total study population.

Discussion

One of the unsolved issues in vascular surgery is the severe prognosis of patients with ALI undergoing revascularization, even with the high risk in the elderly population. Since immediate success of surgical or endovascular procedures is presently very high, it is reasonable that possible further advances in these techniques could marginally reduce the incidence of major complications in this setting, and the potential role of adjuvant pharmacological agents is therefore of interest. Our hypothesis was that iloprost, a synthetic prostacyclin analogue, could be helpful to improve the patient’s outcome after surgical revascularization, and we tested this strategy in a randomized, placebo-controlled phase III study. As first evidence in ILAILL, overall amputation-free survival was higher than expected on the basis of available data at the time of study planning. Possible explanations for this fact are the development of recent improvements in surgical techniques and patient care, and the setting of centers participating in this study, including a restricted number of highly specialized vascular surgery units. This fact may have affected the statistical power of the study to detect a significant difference between experimental treatments. As a consequence, in the overall study population, iloprost reduced the combined incidence of death and amputation (primary study endpoint), but the difference compared to the placebo was not statistically significant. The reduction of death and amputation incidence in patients treated with iloprost was, however, statistically significant in higher risk, elderly patients. In this subgroup, the incidence of complications was more similar to what was estimated on the basis of the study hypothesis, and the relative risk reduction with iloprost was even higher than expected. Only slight reduction in the incidence of peripheral complications occurred in patients receiving iloprost. This result may be surprising, if related to the hypothesis that iloprost could reduce peripheral major complications by improving microcirculation. However, the timing of the amputations we observed that were performed early after revascularization (median, 8 and 13 days after placebo and iloprost, respectively) seems to suggest a critical role for surgery in determining the patient’s outcome. Moreover, the high rate of patients presenting with a grade IIb-III acute limb ischemia (around two thirds in the two treatment groups), has probably reduced the potential to detect the effect of the drug and claims for an even more aggressive therapy for limb salvage in these patients.

Conversely, and in our opinion, a major finding of the study, iloprost significantly reduced mortality, both in the overall study population and in the high-risk subgroup of patients > 70 years old. One possible explanation for this result might be the potential effect of iloprost on the mechanisms of damage by ischemia-reperfusion. There are two components to the reperfusion syndrome, a local one that can result in increasing the regional damage from ischemia, and a systemic component potentially leading to secondary failure of organs remote from ischemic tissues. In the ILAILL study, the causes of death were related largely to failure of organs (heart, kidney, lung) known as the typical targets of reperfusion syndrome. Iloprost is able to modulate different mechanisms following ischemia and reperfusion (i.e., oxygen free radicals production, hypercoagulability, release of cytokines, activation of neutrophils, endothelial cells dysfunction)11,26,27 that contribute to the development of an inflammatory response, and set up a vicious cycle that may remain primarily local or be active both at the regional and systemic level.¹⁰ Early modulation of this inflammatory self-perpetuating response by iloprost may attenuate systemic consequences of reperfusion syndrome, and at the same time, with the known long-lasting effects of the drug,^28,29 may constitute a possible explanation for the finding of a delayed effect on mortality. In the ILAILL study, the use of iloprost was associated with good tolerability. This was relevant in our study since iloprost was used in emergency conditions, and not in patients with chronic diseases, or as adjuvant to elective surgery, as previously reported.²² Moreover, good tolerability of the drug was confirmed in the subgroup of elderly, vulnerable patients.

Bleeding episodes were mild in the iloprost group and with similar incidence, if compared to controls. This was also significant in our study because iloprost was administered in combination with anticoagulant treatments in a large proportion of our patients. Some ancillary findings provide further indications for discussion in the context of management of patients with ALI. First, no significant relationship was shown between the duration of ischemia and the patients’ outcome. To assess this variable, we tested a cut-off of 24 hours and 6 hours and obtained the same qualitative result. The duration of ischemia has been reported as a predictor of the occurrence of major complications in patients with ALI, and data from our study, since it was not powered to address this point, cannot conflict with this indication. However, this finding, together with the evidence that in our study amputation-free survival of patients classified as class III (“irreversible”) was 70.3% (and 59.6% of class III patients were free of serious events during the observation period), suggests the opportunity of considering a more aggressive treatment strategy, even in patients with severe conditions or late presentation, particularly if they are admitted to specialized care units. Further, a minor occurrence of complications was observed in patients experiencing previous cardiovascular events. This finding seems to support the hypothesis of a less intense inflammatory response to ischemia in atherosclerotic “stabilized” patients,³⁰ and a possible influence of a more frequent use of concomitant therapies active at the cardiovascular and metabolic level. Furthermore, a role for protective effects of ischemic preconditioning in humans was recently claimed in the setting of cerebrovascular disease.31 In conclusion, though at lower levels than previously reported, results of the ILAILL study confirm the severity of ALI, with a high rate of complications in patients receiving technically successful surgery.

At present, no pharmacological treatment other than anticoagulation is recommended in these patients. In this randomized, placebo-controlled trial, iloprost as an adjuvant to revascularization significantly reduced all-cause mortality and overall major event rate and improved amputation-free survival. These results were even more evident in the subgroup of high-risk elderly patients. Waiting for further data to support these findings, our opinion is that iloprost could be worth considering as an adjuvant treatment to surgery in ALI patients.

Acknowledgments

We are indebted to the Centers of Vascular Surgery (see Appendix) participating to the ILAILL Study, and to the patients included in this study, for their trust and support. We would like to thank Italfarmaco S.p.A., Milan, Italy for grant support and Schering AG (Berlin, Germany) for kindly providing the study drug.

Appendix

Clinical Centers and Principal Investigators (at the time of ILAILL study) – Department of Vascular Surgery, Hospital “San Giovanni Bosco”, Naples: G. de Donato; Unit and Chair of Vascular Surgery, Policlinico “Le Scotte”, University of Siena: C. Setacci; Unit and Chair of Vascular Surgery, Hospital “Careggi”, University of Florence: C. Pratesi; Unit of Vascular Surgery, Hospital “Civico”, Palermo: A. Martino; Vascular Surgery, Hospital “San Maurizio”, Bolzano: H. Ebner; Department of Vascular Surgery, University of Messina: F. Spinelli; Vascular Surgery Unit, Hospital “Cisanello”, Pisa: M. Ferrari; Department of Vascular Surgery, Hospital “Casa Sollievo della Sofferenza”, S. Giovanni Rotondo: G. Paroni; Department of Vascular Surgery, Hospital “S. Croce e Carle”, Cuneo: C. Novali; Unit of Vascular Surgery 1, Hospital “San Giovanni Battista”, Turin: F. Ponzio; Department of Vascular Surgery, University of Perugia: P. Cao; Chair of Vascular Surgery, University of Milan, Hospital “S. Carlo”: P. Settembrini; Chair of Vascular Surgery, Hospital “S. Martino”, Genoa: S. Ferrero, P. Colotto; Chair of Vascular Surgery, “Vita-Salute” University, Scientific Institute H. San Raffaele, Milan: R. Chiesa; Deparment of Surgery, Unit of Vascular Surgery, ASL 1, Imperia: C. Bertoglio; Chair of Vascular Surgery, University of Padua: G. Deriu; Department of Vascular Surgery, Hospital “Mauriziano”, Turin: D. Palombo, F. Nessi; Department of Vascular Surgery, Hospital “G.Salvini”, Garbagnate Milanese: R. Mattassi; Chair of Vascular Surgery, University Tor Vergata, Rome: A. Ippoliti; Department of Vascular Surgery, University of L’Aquila: C. Spartera; Chair of Vascular Surgery, University of Milan, Hospital “Bassini”, Cinisello Balsamo: G. Biasi; Division of Vascular and Endovascular Surgery, University Hospital Policlinico, Bari: G. Regina.

Author Affiliations: From the ¹Department of Surgery, Vascular and Endovascular Surgery Unit, University of Siena; ²FADOI Study Center, Roma; ³Department of Surgery, Vascular Surgery Unit, San Giovanni Bosco Hospital, II University of Naples, Italy. @The ILAILL Study Group participants are listed in the Appendix.

Correspondence: Dr. Gianmarco de Donato, Department of Surgery, Vascular and Endovascular Surgery Unit, University of Siena, Italy. E-mail: dedonato@unisi.it.

Manuscript submitted September 19, 2008, provisional acceptance given October 9, 2008, accepted October 17, 2008.

This study was supported by a grant from Italfarmaco S.p.A., Milan, Italy. The study drug was provided by Schering AG (Berlin, Germany). The authors report no financial relationship or conflicts of interest regarding the content herein.