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Corresponding author. G. de Donato, MD, Department of Surgery, Unit of Vascular and Endovascular Surgery, University of Siena, Policlinico Le Scotte, Viale Bracci, 53100 Siena, Italy.
To evaluate the effects of iloprost, in addition to surgery, on the outcome of acute lower limb ischemia (ALLI).
Design
Post-hoc analysis of a randomized, double-blind, placebo-controlled study.
Methods
In the context of the ILAILL (ILoprost in Acute Ischemia of Lower Limbs) study, 192 elderly patients (>70 years old) undergoing surgery for ALLI 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 (iloprost: n=100; placebo: n=92). Patients were followed-up for three-months following surgical revascularization.
Results
The combined incidence of death and amputation (primary study end-point) was significantly reduced in patients treated with iloprost (16.0% vs 27.2% in the placebo group; hazard ratio 1.99, 95% confidence interval 1.05–3.75, p=0.03). A statistically significant lower mortality (6.0%) was reported in patients receiving iloprost, compared to controls (15.2%) (hazard ratio 2.93, 1.11–7.71, p=0.03). The overall incidence of death and major cardiovascular events was lower in patients receiving iloprost compared to those assigned placebo (24.0% and 35.9%, respectively), at the limits of statistical significance (relative risk 1.64, 0.97–2.79, p=0.06).
Conclusions
These results confirm the poor outcome in elderly patients with ALLI. Based on a subgroup analysis iloprost, as an adjuvant to surgery, appears to reduce the combined end-point of death and amputation.
Under the endorsement of Italian Society for Vascular and Endovascular Surgery (S.I.C.V.E.), we performed a randomized, placebo-controlled, phase III study (ILAILL), to assess the effects of perioperative treatment with iloprost in 300 patients with ALLI undergoing surgical revascularization (thromboembolectomy or by-pass, in native vessel or graft). In this study a significant reduction of mortality and incidence of total major cardiovascular events was shown in patients treated with iloprost.
The ILAILL study: iloprost as adjuvant to surgery for acute ischemia of lower limbs. A randomized, placebo-controlled, double-blind study by the Italian Society for Vascular and Endovascular Surgery.
The incidence of combined death and amputation in the ILAILL study was significantly related to age (21.3% in patients > 70 years, vs 9.3% in patients less than 70 years, p<0.01). As a post-hoc analysis we therefore focused our attention on the effects of iloprost as adjuvant to surgery in this group of elderly patients with a high rate of complications.
Materials and Methods
One-hundred and ninety-two patients (92 in the placebo and 100 in the iloprost group) over 70 years old were enrolled in ILAILL. Patients were considered for inclusion if they presented with acute onset (less than 14 days) of symptoms suggestive of ischemia of lower limbs (native vessels and/or graft occlusions) and were to be treated with surgical revascularization. Patients with lower limb ischemia due to trauma were excluded. Other exclusion criteria included: acute myocardial infarction or stroke within the last 6 months prior to enrolment; cardiac failure (NYHA Class > I); unstable angina; angina pectoris (Canadian classification > II); hyperkinetic ventricular arrhythmias; severe hypertension (sitting systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥110 mmHg) or hypotension (systolic blood pressure <90 mmHg); haemorrhagic diathesis; concomitant clinical conditions in which iloprost might increase the risk of bleeding (i.e. active peptic ulcer, trauma, cerebral haemorrhage); thrombocytopenia (<80.000/mm3) or thrombocytosis (>500.000/mm3); severe hepatic failure (cirrhosis); renal failure requiring dialysis treatment.
Iloprost (Endoprost®, Italfarmaco S.p.A., Milan, Italy, under licence of Schering AG, Berlin, Germany) or placebo were administered as an intra-arterial bolus of 3000 ng over 1–3 minutes immediately after revascularization and in the same affected artery. Starting from the first day after surgery, a daily 6-hour intravenous infusion of iloprost (or placebo) at doses of 0.5–2.0 ng/kg/min was performed for 4–7 days (7 days recommended), depending on the length of hospital stay. Patients were followed-up for 90±5 days after surgery, for occurrence of major clinical events. The primary efficacy end-point of ILAILL was the combined incidence of death and amputation during a three-month follow-up period. Secondary efficacy end-points were the incidence of each single major clinical event (acute myocardial infarction, stroke, peripheral embolism, pulmonary embolism, other major cardiovascular events, amputation and death) during the study, and the total event rate (death plus major cardiovascular events).
Baseline continuous variables were compared between the two treatment groups by unpaired t-test, categorical variables were compared by Chi-square test or Fisher exact test, as appropriate. Multivariable analyses, adjusting for potential confounders, were performed using the Cox proportional hazard regression model, to compare the outcomes (combined death+amputation, death, total event rate) in the two treatment groups. Apart from experimental treatment (placebo vs iloprost), the following variables were selected for the multivariable analyses, on the basis of their clinical importance: duration of ischemia (>24 hours vs ≤ 24 hours); class of ischemia according to SVS–ISCVS–TASC criteria
(IIb-III vs IIa-I); previous cardiovascular event(s) (acute myocardial ischemia, stroke, peripheral revascularization, yes vs no); type of surgery (thromboembolectomy vs other modalities). Proportional hazard assumption were tested for all the covariates included and no relevant violations were found. All statistical tests were two-sided and p-values below 0.05 were considered as significant. Statistical analyses were performed by using SAS software (version 8.2, SAS Institute, Cary, NC, USA), on the basis of the intention-to-treat.
The study was conducted according to the ethical principles stated in the Declaration of Helsinki and local regulations. The protocol was approved by the Ethics Committee of each participating center, and written informed consent was obtained by all patients before randomization.
Further details on study design, and overall results of the trial, have been described elsewhere.
The ILAILL study: iloprost as adjuvant to surgery for acute ischemia of lower limbs. A randomized, placebo-controlled, double-blind study by the Italian Society for Vascular and Endovascular Surgery.
Baseline characteristics of the two groups of patients were similar (Table 1). The duration of treatment did not differ between the experimental and control group (Table 2). Concomitant therapies during follow-up were very similar for the two groups (heparin 83.7% and 85.0%, oral anticoagulants 27.2% and 29.0%, antiplatelet therapies 27.2% and 24.0%, anti-hypertensive 52.2% and 56.0% in placebo and iloprost groups, respectively). Withdrawal from study without completion of follow-up and without occurrence of major clinical events requiring study discontinuation occurred in 13.0% and 12.0% of patients in the placebo and iloprost group, respectively, due to Investigator's judgement of lack of effect (6.5% for placebo and 3.0% for iloprost), non-compliance or patient lost to follow-up.
Table 1Baseline characteristics of patients. All comparison between study groups were statistically non-significant*. PAD=peripheral arterial disease
Characteristic
Placebo (N=92)
Iloprost (N=100)
Age – yr
81.0±6.5
80.3±6.1
Sex – M/F
47/45
50/50
Medical history/Concomitant conditions (%)
Ischemic cardiopathy
22.8
24.0
Cerebrovascular disease
27.2
23.0
Atrial fibrillation/arrhythmias
59.8
57.0
Chronic PAD
12.0
18.0
Prev. revascularization lower limb(s)
22.8
28.0
Hypertension
69.6
64.0
Diabetes
17.4
15.0
Tumor
16.3
22.0
Duration of symptoms (%)
0–6 hrs
15.3
19.2
6–24 hrs
37.4
38.4
>24 hrs
47.3
42.4
Clinical category of acute ischemia (%)
Class I–IIa
33.7
36.5
Class IIb–III
66.3
63.5
Type of intervention (%)
Thromboembolectomy
78.3
77.8
By-pass
15.2
16.2
Combined
6.5
6.0
*comparison between treatment groups, t-test or Chi square test, as appropriate.
The incidences of outcomes and the relevant results of the multivariable analyses (Cox regression model) are reported in Fig. 1. The combined incidence of death and amputation (primary study end-point) was significantly reduced in patients treated with iloprost (16.0% vs 27.2% in the placebo group; hazard ratio 1.99, 95% confidence interval 1.05–3.75, p=0.03). A statistically significant lower mortality (6.0%) was reported in patients receiving iloprost, compared to controls (15.2%) (hazard ratio 2.93, 1.11–7.71, p=0.03). The Kaplan-Meier curve for survival is shown in Fig. 2. The overall incidence of fatal plus major cardiovascular events was lower in iloprost patients vs placebo group (24.0% and 35.9%, respectively), at the limits of statistical significance (relative risk 1.64, 0.97–2.79, p=0.06). In Table 3 more specific information on the major complications are shown.
Fig. 1Incidence (%) and Hazard Ratios (HR) of major events in the two treatment groups.
On multivariable analysis, occurrence of death or amputation appeared significantly related to class of ischemia (≥IIb), and less frequent for patients undergoing thromboembolectomy (vs other surgical procedures) (Table 4). No serious adverse reactions occurred after iloprost administration, nor significant differences in the incidence of bleeding (2.2% placebo vs 3.0% iloprost) or hypotension (8.7% placebo vs 9.0% iloprost) between treatment groups.
Table 4Cox regression model analysis for the primary study end-point (combined death and amputation). HR=Hazard Ratio; CV=cardiovascular; TE=thromboembolectomy
The results of ILAILL study confirm the poor clinical outcome in elderly patients with ALLI. The combined incidence of death and amputation in patients older than 70 years was 27.2% in the control group. Iloprost, as an adjuvant to surgery, significantly reduced the combined incidence of death and amputation (primary study end-point) and mortality in this group of high risk patients. The beneficial effect of iloprost on the systemic component of the reperfusion syndrome is supported by a high relative risk reduction in mortality (65.9%) in treated patients. Iloprost is known to interfere with many of the mechanisms involved in the inflammatory response and systemic damage following ischemia and reperfusion (i.e. through its effects on platelet activation and blood clotting, the reduction of free radicals and cytokines production, and lower expression of intercellular adhesion molecules
Iloprost. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in peripheral vascular disease, myocardial ischaemia and extracorporeal circulation procedures.
). An early modulation of inflammatory self-perpetuating response following ischemia and reperfusion by perioperative iloprost may therefore produce prompt and later benefit in patients' outcome, as assessed by the 3-month follow-up of ILAILL study. Amputation incidence and the occurrence of overall major local complications (amputation+additional revascularization+recurrent acute limb ischemia) were quite similar in the two treatment groups (amputation 11.9% vs 10.0%, overall complications 18.4% vs 15.0% for control and treatment, respectively). These findings are surprising given the hypothesis that iloprost would reduce peripheral complications by improving microcirculation. However, the timing of amputations, quite early after revascularization (median, 8 and 13 days after placebo and iloprost respectively) seems to suggest a critical role for surgery in determining patient outcome. Moreover, the high rate of patients presenting in grade IIb-III acute limb ischemia (around two thirds in the two treatment groups), has probably reduced the potential to detect an effect of the drug. Iloprost was well tolerated in this elderly sick population. This appears to us of relevance, since in our study iloprost was used in emergency conditions, and not in patients with chronic diseases, or as adjuvant to elective surgery, as previously reported.
Major complications in this study were related to the severity of limb ischemia but not influenced by duration of ALLI. Our study was not powered to address these issues therefore these results have to be considered with caution. However, the absence of a clear relationship between duration of ischemia and major events, together with the evidence of a high amputation-free survival in patients with ischemia classified as “irreversible” (60.5%) seems to support a more aggressive treatment strategy in patients with late presentation and severe peripheral ischaemia, particularly if referred to specialized care units (the setting of centres participating in the ILAILL study). A minor occurrence of complications in patients experiencing previous cardiovascular events seems to support the hypothesis of a less intense inflammatory response to ischemia in atherosclerotic “stabilized” patients,
and a possible influence of a more frequent use of concomitant therapies active at cardiovascular and metabolic levels. Furthermore, a role for the protective effects of ischemic preconditioning in humans was recently claimed in the setting of cerebrovascular disease.
In conclusion, our results confirm the poor clinical outcome of ALLI, particularly in elderly patients. In this high-risk group, iloprost as an adjuvant to surgery significantly reduced the combined incidence of death and amputation. Further data and efforts are needed to support this finding.
Acknowledgments
We are indebted to the Italian Society for Vascular and Endovascular Surgery (S.I.C.V.E.) for the endorsement to ILAILL; to Carlo Bianchini for his scientific advice; to Patrizia Ronchetti and Luisa Siori for secretarial assistance; to Evelina Curatolo, Laura Filiberti, Agostino Lazzaro, Milena Meo, Marzia Martusciello, Matteo Mondellini, Laura Omoboni, Giuseppe Portera, Rossella Rivolta, Elisa Robberto, Antonella Stroppolo, actually or formerly at MDS Pharma Services, Milan, Italy, for monitoring of the study and data management; to Georg Groetzbach (Schering AG, Berlin, Germany) and Laura Ottolenghi (Schering Italy, Milan) for kindly providing study drug; to the Physicians and Nurses of Centres of Vascular Surgery (see list below) participating to the ILAILL study; and to the patients, for whom this study has been planned, for their trust and support.
Sources of financial and material support: The ILAILL project was supported by a grant from Italfarmaco S.p.A., Milan Italy. Experimental treatments were kindly provided by Schering AG, Berlin, Germany.
Possible conflicts of interest: G. Gussoni was formerly an employee of Italfarmaco S.p.A., Milan.
Appendix.
Contributors
The Members of the ILAILL Study Group were as follows:
Steering Committee: G. de Donato (Chairman), G . Paroni, C. Setacci, P. Settembrini; Safety Committee: E. Bonizzoni, A. Mazzone, A. Odero; Data Analysis: F. Veglia; Endorsement: Italian Society for Vascular and Endovascular Surgery (S.I.C.V.E.); Clinical Centers (and Principal Investigators): Department of Vascular Surgery, Hospital “San Giovanni Bosco”, Naples: G. de Donato, R. de Laurentiis, G. Bianco; Unit and Chair of Vascular Surgery, Policlinico “Le Scotte”, University of Siena: C. Setacci, G. de Donato, I. Baldi; Unit and Chair of Vascular Surgery, Hospital “Careggi”, University of Florence: C. Pratesi, R. Pulli, E. Romano; Unit of Vascular Surgery, Hospital “Civico”, Palermo: A. Martino, G. La Marca; Vascular Surgery, Hospital “San Maurizio”, Bolzano: H. Ebner, P. Sbraga, F. Zaraca; Department of Vascular Surgery, University of Messina: F. Spinelli, T. Mandolfino, F. Benedetto, D. Baccellieri; Vascular Surgery Unit, Hospital “Cisanello”, Pisa: M. Ferrari, D. Adami, A. Del Corso; Department of Vascular Surgery, Hospital “Casa Sollievo della Sofferenza”, S. Giovanni Rotondo: G. Paroni, M. Ruggieri; Department of Vascular Surgery, Hospital “S. Croce e Carle”, Cuneo: C. Novali, B. Mangiacotti; Unit of Vascular Surgery 1, Hospital “San Giovanni Battista”, Turin: F. Ponzio, G. Capaldi; Department of Vascular Surgery, University of Perugia: P. Cao, B. Parente, G. Parlani; Chair of Vascular Surgery, University of Milan, Hospital “S. Carlo”: P. Settembrini, P. Maltempi; Department of Vascular Surgery, Hospital “S. Martino”, Genoa: S. Ferrero, P. Colotto, L. Nardella, S. Pastorino, G. Rauti; Chair of Vascular Surgery, “Vita-Salute” University, Scientific Institute H. San Raffaele, Milan: R. Chiesa, E.M. Marone, F. Setacci; Deparment of Surgery, Unit of Vascular Surgery, ASL 1, Imperia: C. Bertoglio, A.M. Cristiani, T. Carissimi; Chair of Vascular Surgery, University of Padua: G. Deriu, M. Antonello; Department of Vascular Surgery, Hospital “Mauriziano”, Turin: D. Palombo, F. Nessi, P. Cumbo, E. Ferrero; Department of Vascular Surgery, Hospital “G.Salvini”, Garbagnate Milanese: R. Mattassi, E. Callini; Chair of Vascular Surgery, University Tor Vergata, Rome: A. Ippoliti, A. Ascoli Marchetti, L. Di Giulio; Department of Vascular Surgery, University of l'Aquila: C. Spartera, C. Petrassi, G. Saracino; Chair of Vascular Surgery, University of Milan, Hospital “Bassini”, Cinisello Balsamo: G. Biasi, P. Mingazzini, Y. Thsomba; Division of Vascular and Endovascular Surgery, University Hospital Policlinico, Bari: G. Regina, G. Impedovo, A. Lillo, D. Angiletta, V. Marotta.
The ILAILL study: iloprost as adjuvant to surgery for acute ischemia of lower limbs. A randomized, placebo-controlled, double-blind study by the Italian Society for Vascular and Endovascular Surgery.
Iloprost. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in peripheral vascular disease, myocardial ischaemia and extracorporeal circulation procedures.
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