European Review for Medical and Pharmacological Sciences 2016; 20: 3720-3726 Efficacy, safety and feasibility of intravenous in the domiciliary treatment of patients with ischemic disease of the lower limbs

R. POLIGNANO1, C. BAGGIORE1, F. FALCIANI2, U. RESTELLI3, N. TROISI4, S. MICHELAGNOLI4, G. PANIGADA5, S. TATINI1, A. FARINA6, G. LANDINI1

1Medical Department, USL Centro Toscana, Florence, Italy 2Skin Lesions Observatory, USL Centro Toscana, Florence, Italy 3School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; Centre for Research on Health Economics, Social and Health Care Management, Carlo Cattaneo University – LIUC, Castellanza (Varese), Italy 4Department of Surgery, Vascular and Endovascular Surgery Unit, San Giovanni di Dio Hospital, Florence, Italy 5Internal Medicine Unit, Santi Cosma e Damiano Hospital, Pescia, Italy 6Medical Affairs Department, Italfarmaco S.p.A., Cinisello Balsamo, Milan, Italy

Abstract. – OBJECTIVE: Intravenous iloprost Introduction is an important option in the treatment of isch- emic disease of the lower limbs; however, the administration of therapy is frequently compro- The term ischemic disease of the lower limbs mised because of the need for long cycles of in- defines a wide number of pathological conditions fusion in a hospital setting. The aim of the study of both large and small peripheral arteries and is to evaluate the efficacy, safety, feasibility, and veins, including peripheral artery disease (PAD), the economic impact of infusion therapy in the diabetic microangiopathy, thromboangiitis oblite- outpatient setting. PATIENTS AND METHODS: rans or Buerger’s disease, and other inflammatory Twenty-four con- 1 secutive patients were treated with iloprost at vasculitis . Although these conditions are cha- their homes where they were administered a slow racterized by different pathogenetic mechanisms, rate of infusion for 24 hours a day, during 9.9 ± 2.3 similar clinical manifestations may occur due to days, with a portable syringe pump (Infonde®). the common mismatch between the supply of RESULTS: The clinical condition of patients oxygen and nutrients and the metabolic demand evaluated with the modified SVS/ISCVS scale sig- nificantly improved after treatment (+1.29 ± 1.04 of tissues, with microcirculatory defects including points vs. baseline, p<0.001). The drug was well endothelial dysfunction, altered hemorheology, tolerated; neither significant adverse events as- white cell activation and inflammation, and sociated with nor problems related maldistribution of the cutaneous microcirculation1. to venous access were recorded at home. Nine- Symptoms may be more or less severe, depending ty-six percent of patients successfully complet- on the seriousness and location of the disease, and ed the entire treatment cycle, and the evaluation questionnaire showed a high acceptance of the may range from intermittent claudication during therapy. From the perspective of the hospital au- exercise to the most serious manifestation of cri- thority, lower direct medical costs were estimat- tical limb ischemia (CLI). CLI represents a major ed for the domiciliary infusion process compared healthcare issue, since it is characterized by a poor with the inpatient infusion setting. long-term prognosis, a high occurrence of major CONCLUSIONS: Treatment with iloprost in the outpatient setting is effective, safe, feasible, cardiovascular events and a high degree of disabi- and more acceptable to patients than infusion at lity because of frequent and severe rest pain, ulcers the hospital. In addition, it has a favorable eco- and amputations of the lower limbs1,2. nomic and organizational impact on the medi- The primary goals of the treatment are to im- cal ward. prove patient function and quality of life, relieve Key Words: ischemic pain, heal ischemic ulcers, prevent limb Critical limb ischemia, Iloprost, Home treatment, loss, and, possibly, prolong survival2. Revascu- Quality of life. larization could optimally achieve some of these

3720 Corresponding Author: Alberto Farina, Pharm.D; e-mail: [email protected] Domiciliary treatment with intravenous iloprost goals, but the severity of comorbidities, along wi- other vasculitis) for which the treatment with intra- th the durability of the reconstruction in patients venous iloprost was deemed clinically appropriate, with CLI, demands a risk-benefit analysis to de- at the Hospital of Florence, Italy. The study was termine the optimal therapy. Some patients who conducted in accordance with current ethical stan- turn to vascular surgeons for surgical or endova- dards and with the Declaration of Helsinki. Inclu- scular procedures are poor candidates for such sion criteria involved ability (though reduced) to interventions because of medical comorbidities, walk, adequate ability to understand instructions, non-ambulatory status, or poor outflow vessels in cooperative family, adequate tolerability to the the limb3. Thus, medical treatment, including ag- first infusion of iloprost received in a hospital gressive modification of cardiovascular risk fac- setting, normal standard blood tests and ECG, tors, control of pain and infection in the ischemic informed consent. Patients with severe medical leg, prevention of progression of systemic athero- conditions requiring hospitalization were excluded sclerosis, and restoration of microcirculation, is a from the study. Patients that matched the inclusion crucial option in the management of CLI4-6. and exclusion criteria were offered the opportunity To date, the only pharmacotherapy for CLI to continue the treatment at home. Figure 1 descri- recommended by current guidelines in patients bes the complete operative procedure. unsuitable for revascularization is represented by Iloprost was administered with a low infusion , particularly intravenous iloprost1,5,6. rate, equal to 0.5 ng/kg/min for 6 hours in a ho- Several randomized studies have shown that ilo- spital setting on the first day of treatment and at prost administration has a favorable impact on the fixed rate of 2 μg/hour for 24 hours/day the patient function, pain, ulcer healing, amputation following days, at the patient’s home. A low rate rates, and mortality7-9. Moreover, a pharmacologi- of infusion was used to promote the tolerability of cal approach to improve the microcirculation may the treatment and to administer the whole conten- enhance the results of revascularization1,10. ts of a vial of medication avoiding any waste of an One of the main issues related to iloprost treat- active ingredient. The length of treatment ranged ment is the need for prolonged cycles of admini- from 6 to 16 days depending on the clinical con- stration, consisting of many hours per day up to 4 ditions of the patients. consecutive weeks, in a hospital setting, as indica- Clinical evaluations included the clinical con- ted by the manufacturer recommendations. This dition of the patient measured by the modified approach is no longer consistent with the current SVS/ISCVS (Society for Vascular Surgery/In- needs of the National Health System (NHS), which ternational Society for Cardiovascular Surgery) increasingly requires the optimization of resources scale11, the occurrence of adverse events, the by reducing the number of hospitalizations, health percentage of completion of treatment, and the care staff, and budgets. Moreover, many patients satisfaction of patients at the end of the treatment show a poor compliance to such treatments, be- period, which lasted 9.9 ± 2.3 days. Patient sa- cause of the need to stay in the hospital for a long tisfaction was evaluated by a questionnaire that period. Altogether, these factors may limit the ac- included three statements to which patients were cess to important treatments for a large number of asked to assign a score ranging from 1 (comple- patients, and, when administered, such treatments tely disagree) to 10 (completely agree), and one are often inadequate from the economic and orga- question. The statements were: “I am in favor of nizational point of view. home therapy”; “I consider home therapy safe”; In this paper, we report the clinical and eco- “I can perform my daily tasks easily”; and the nomic results obtained with the home admini- question was “If I could choose between treat- stration of intravenous iloprost in a group of ment at home or in the hospital, which one would outpatients with peripheral vascular diseases of I choose?”. In case of loss to follow-up (1 patient), the lower limbs at the Hospital of Florence, Italy. the scores were considered as “totally disagree” and “not willing to repeat the treatment at home”.

Patients and Methods Statistical Analysis Data were expressed as means ± standard de- This was a prospective observational study that viations (SD). The SVS/ISCVS score at follow-up included 24 consecutive patients with periphe- was compared with baseline using a paired sam- ral vascular diseases (peripheral arterial disease, ples t-test. Statistical significance was considered diabetic microangiopathy, Buerger’s disease, and at p-values <0.05.

3721 R. Polignano, C. Baggiore, F. Falciani, U. Restelli, N. Troisi, S. Michelagnoli et al.

Figure 1. Operative procedure for the domiciliary treatment with intravenous iloprost.

Economic Analysis Among the devices on the market, Infonde® is To evaluate the economic impact of the ma- the one that best fits the home administration of nagement of domiciliary iloprost from the point iloprost thanks to its small size, ease of use and of view of the hospital authority and the Italian the option for patients to stop infusions in the NHS, we investigated the process of infusion in case of side effects. both an outpatient and a domiciliary setting. The process analyses were performed through inter- views with 8 key opinion leaders (with a medical Results background), to assess the phases of the proces- ses and the related consumption of resources of a The study included 24 patients with ischemic standard patient without complications. diseases of the lower limbs who had indications for the treatment with intravenous iloprost. The Portable Syringe Pump Infonde® overall characteristics of the population are de- Infonde® (Italfarmaco S.p.A., Milan, Italy) is a scribed in Table I. portable syringe pump with reduced dimensions As expected, treatment with iloprost was ef- (84.9 x 49.3 x 32.1 mm) and a weight of 118 g. It fective in improving the clinical condition of is specifically designed for the controlled admi- patients: the SVS/ISCVS score at the end of the nistration of intravenous iloprost, and uses de- treatment was significantly improved compared dicated syringes 25.5 ml. The pump administers to baseline (+1.29 ± 1.04, p<0.001). doses of 7.44 μl at intervals that depend on the The treatment was generally well tolerated by flow set. The programming software is specifical- patients, with a low occurrence of side effects both ly designed for the administration of iloprost and, at the beginning of treatment in the hospital setting for the set up of the infusion, only patient weight and during its continuation at the patient’s home and flow velocity need to be entered. The infusion (Figure 2). During the home stay, no significant duration may vary from 1 to 24 hours. problems related to venous access were registered.

3722 Domiciliary treatment with intravenous iloprost

The home therapy proved feasible because 96% Table I. Characteristics of the study population. of patients (23 of 24) completed the entire treatment Number of patients 24 cycle which lasted an average of 9.9 ± 2.3 days. Age (mean ± SD) 62 ± 14 The analysis of the evaluation questionnaire re- Sex 100% M vealed a high acceptance of the therapy (Figure 3). Number of infusions at home 237 Number of infusions per patient ± SD 9.9 ± 2.3 Economic Analysis Diagnosis The economic analysis, in terms of direct me- – PAD 58.3% dical costs, showed that the two processes (inpa- – Buerger’s disease/vasculitis 33.3% – Microangiopathy 8.3% tient and outpatient) do not differ in terms of drug Cardiovascular comorbidity costs and usage of disposables. A lower use of – None 29.2% human resources was observed in the outpatient – Diabetes mellitus 45.8% setting, due to lower nursing time dedicated to – Hypercholesterolemia 20.8% patients (estimated by key opinion leaders to be – Arterial hypertension 12.5% on average 180 minutes per patient, considering – Ischemic heart disease 4.2% a total of 10 infusions). The lower direct medi- – Chronic kidney disease 4.2% Concomitant cal costs for the hospital authority related to the – Antiplatelet 91.7% domiciliary treatment of patients are estimated – 4.2% to account for € 86 per patient’s infusion cycle. – Statin 25.0% Therefore, we saved a total of approximately € – Antihypertensive 12.5% 2,064 for the 24 patients included in the study. From the point of view of the Italian NHS, there are no differences between the two different Discussion settings in terms of reimbursement of the health service delivered and the impact of the domici- Our results confirm the efficacy and tolera- liary treatment is therefore considered nil. bility of slow prolonged infusions and indicate

Figure 2. Overall adverse events recorded in the cohort of patients (n=24).

3723 R. Polignano, C. Baggiore, F. Falciani, U. Restelli, N. Troisi, S. Michelagnoli et al.

Figure 3. Results of the evaluation questionnaires administered to patients (n=24).

the feasibility of treatment with iloprost at the during the stay at home and come back regularly patient’s home. As expected, the home therapy to the hospital to start the new infusions or to was appreciated by the patients, and it is estima- return the device at the end of therapy. Moreover, ted to be a cost-saving strategy for the hospital patients should be accompanied by caregivers, authority. usually members of the family or friends. The decision to treat patients with peripheral Our results are consistent with those from pre- vascular disease with iloprost at home came from vious clinical trials in which patients were succes- the need to optimize the resources of our depart- sfully treated with iloprost at home12-16. However, ment and from the availability of a new portable in the present study, a specific portable syringe syringe pump specifically designed for the admi- pump for iloprost infusion was used for the first nistration of iloprost, a device which has replaced time, unlike previous studies in which elastome- the old bulky syringe pumps that significantly ric pumps, not designed for the administration of restricted the mobility of patients. Our results iloprost, were used. The use of Infonde® provides confirm that home therapy is a safe, effective greater reliability in the controlled administration and convenient option, provided that some pre- of iloprost, and users can stop the infusion in case cautions related to the clinical conditions and the of need. To date, this is the only portable device behavior of the patient are followed. In particular, for iloprost infusion. Previous studies suggest we would like to emphasize that it is important that Infonde® is an appropriate device for iloprost that patients undergo an accurate clinical eva- administration in a hospital setting, with remar- luation in order to rule out serious heart compli- kable satisfaction both from patients and health cations and to evaluate the thrombotic/bleeding care personnel17,18 and a favorable economic and risk. In fact, patients with peripheral vascular organizational impact19. In particular, a recent disease are often treated with dual antiplatelet or Health Technology Assessment showed that the oral anticoagulant therapy, so physicians should use of Infonde® allowed nurses to save up to consider the possible withdrawal of at least one 66% of the time spent monitoring patients when of the oral agents during the administration of compared with other devices, thus potentially re- iloprost, due to a possible enhancement of the quiring a lower number of nurses (e.g. 1 instead effect. This assessment must be of 3) to perform this activity19. Our study suggests carefully made by physicians, on the basis of the that Infonde® is also suitable for infusion outside clinical profile of each patient. Another important hospitals. aspect is the willingness of the patient to follow Our economic analysis considered direct me- the instructions provided by healthcare profes- dical costs, however, indirect costs are likely to sionals, e.g. not perform strenuous movements be reduced by the use of domiciliary infusions as

3724 Domiciliary treatment with intravenous iloprost well. Patients and caregivers would need to go to Working Group. Inter-society consensus for the the hospital only once a day to have their pumps management of peripheral arterial disease (Tasc set by the nursing and medical staff, with a poten- II). Eur J Vasc Endovasc Surg 2007; 33: S1-75. tial reduction of absences from work and with the 3) Varu VN, Hogg ME, Kibbe MR. Critical limb ische- opportunity for patients to continue the infusion mia. J Vasc Surg 2010; 51: 230-241. Hernando FJS, Conejero AM. at their workplace. Moreover, from an organiza- 4) Peripheral artery di- sease: pathophysiology, diagnosis and treatment. tional point of view, the home setting for infusion Rev Esp Cardiol 2007; 60: 969-982. may lead to an increased number of patients tre- 5) Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Crea- ated within each healthcare center, thanks to the ger MA, Halperin JL, Hiratzka LF, Murphy WR, Olin avoided need to use armchairs and beds inside the JW, Puschett JB, Rosenfield KA, Sacks D, Stanley JC, medical ward and to the fewer activities required Taylor LM Jr, White CJ, White J, White RA, Antman EM, Smith SC Jr, Adams CD, Anderson JL, Faxon DP, by the nursing staff which attend patients recei- Fuster V, Gibbons RJ, Hunt SA, Jacobs AK, Nishimura ving iloprost. This might have further positive R, Ornato JP, Page RL, Riegel B; American Asso- effects on shortening waiting lists. ciation for Vascular Surgery; Society for Vascular This study has some limitations mainly due to Surgery; Society for Cardiovascular Angiography the observational and single-center design that and Interventions; Society for Vascular Medicine and Biology; Society of Interventional Radiology; may reduce the generalizability of results. The ACC/AHA Task Force on Practice Guidelines questionnaire – although similar to those admi- Writing Committee to Develop Guidelines for the nistered in previous studies17,18 – were not vali- Management of Patients With Peripheral Arterial dated for the assessment of patient satisfaction Disease; American Association of Cardiovascular or quality of life. Even if the number of patients and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular included was relatively low, unequivocal results Nursing; TransAtlantic Inter-Society Consensus; were obtained. Vascular Disease Foundation. ACC/AHA 2005 practice guidelines for the management of pa- tients with peripheral arterial disease (lower ex- Conclusions tremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Asso- ciation for Vascular Surgery/Society for Vascular Our results demonstrate the efficacy, safety Surgery, Society for Cardiovascular Angiography and feasibility of home iloprost infusion with the and Interventions, Society for Vascular Medicine portable syringe pump Infonde®. The outpatient and Biology, Society of Interventional Radiolo- gy, and the ACC/AHA Task Force on Practice setting seems to be an appropriate and convenient Guidelines (Writing Committee to Develop Gui- therapeutic strategy also from the point of view delines for the Management of Patients With Pe- of health economics and organization. Due to ripheral Arterial Disease). Circulation 2006; 113: the relatively small number of patients enrolled e463-e654. and single-center design, the results need to be 6) Alonso-Coello P, Bellmunt S, McGorrian C, Anand confirmed in larger populations. SS, Guzman R, Criqui MH, Akl EA, Olav Vandvik P, Lansberg MG, Guyatt GH, Spencer FA; Ameri- can College of Chest Physicians. Antithrombotic Therapy and Prevention of Thrombosis 9th ed: Conflicts of interest American College of Chest Physicians. Evidence Alberto Farina is an employee of Italfarmaco S.p.A., based clinical practice guidelines. Antithrombotic Cinisello Balsamo, Milan, Italy. 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