iloprost and Leg-Ulcer

Peripheral arterial occlusive disease (PAOD) is a common cause of morbidity and mortality due to cardiovascular disease in the general population. Although numerous treatments have been adopted for patients at different disease stages, no option other than amputation is available for patients presenting with critical limb ischaemia (CLI) unsuitable for rescue or reconstructive intervention. In this regard, prostanoids have been proposed as a therapeutic alternative, with the aim of increasing blood supply to the limb with occluded arteries through their vasodilatory, antithrombotic, and anti-inflammatory effects. This is an update of a review first published in 2010.. To determine the effectiveness and safety of prostanoids in patients with CLI unsuitable for rescue or reconstructive intervention.. For this update, the Cochrane Vascular Information Specialist searched the Specialised Register (January 2017) and the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 1). In addition, we searched trials registries (January 2017) and contacted pharmaceutical manufacturers, in our efforts to identify unpublished data and ongoing trials.. Randomised controlled trials describing the efficacy and safety of prostanoids compared with placebo or other pharmacological control treatments for patients presenting with CLI without chance of rescue or reconstructive intervention.. Two review authors independently selected trials, assessed trials for eligibility and methodological quality, and extracted data. We resolved disagreements by consensus or by consultation with a third review author.. For this update, 15 additional studies fulfilled selection criteria. We included in this review 33 randomised controlled trials with 4477 participants; 21 compared different prostanoids versus placebo, seven compared prostanoids versus other agents, and five conducted head-to-head comparisons using two different prostanoids.We found low-quality evidence that suggests no clear difference in the incidence of cardiovascular mortality between patients receiving prostanoids and those given placebo (risk ratio (RR) 0.81, 95% confidence interval (CI) 0.41 to 1.58). We found high-quality evidence showing that prostanoids have no effect on the incidence of total amputations when compared with placebo (RR 0.97, 95% CI 0.86 to 1.09). Adverse events were more frequent with prostanoids than with placebo (RR 2.11, 95% CI 1.79 to 2.50; moderate-quality evidence). The most commonly reported adverse events were headache, nausea, vomiting, diarrhoea, flushing, and hypotension. We found moderate-quality evidence showing that prostanoids reduced rest-pain (RR 1.30, 95% CI 1.06 to 1.59) and promoted ulcer healing (RR 1.24, 95% CI 1.04 to 1.48) when compared with placebo, although these small beneficial effects were diluted when we performed a sensitivity analysis that excluded studies at high risk of bias. Additionally, we found evidence of low to very low quality suggesting the effects of prostanoids versus other active agents or versus other prostanoids because studies conducting these comparisons were few and we judged them to be at high risk of bias. None of the included studies assessed quality of life.. We found high-quality evidence showing that prostanoids have no effect on the incidence of total amputations when compared against placebo. Moderate-quality evidence showed small beneficial effects of prostanoids for rest-pain relief and ulcer healing when compared with placebo. Additionally, moderate-quality evidence showed a greater incidence of adverse effects with the use of prostanoids, and low-quality evidence suggests that prostanoids have no effect on cardiovascular mortality when compared with placebo. None of the included studies reported quality of life measurements. The balance between benefits and harms associated with use of prostanoids in patients with critical limb ischaemia with no chance of reconstructive intervention is uncertain; therefore careful assessment of therapeutic alternatives should be considered. Main reasons for downgrading the quality of evidence were high risk of attrition bias and imprecision of effect estimates.

Topics: Alprostadil; Amputation, Surgical; Epoprostenol; Humans; Iloprost; Ischemia; Leg; Leg Ulcer; Nafronyl; Nicotinic Acids; Pentoxifylline; Peripheral Vascular Diseases; Prostaglandins; Randomized Controlled Trials as Topic; Vasodilator Agents

Peripheral arterial disease (PAD) is a common circulatory problem that can lead to reduced blood flow to the limbs, which may result in critical limb ischaemia (CLI), a painful manifestation that occurs when a person is at rest. The mainstay of treatment for CLI is surgical or endovascular repair. However, when these means of treatment are not suitable, due to anatomical reasons or comorbidities, treatment for pain is limited. Lumbar sympathectomy and prostanoids have both been shown to reduce pain from CLI in people who suffer from non-reconstructable PAD, but there is currently insufficient evidence to determine if one treatment is superior. Due to the severity of the rest pain caused by CLI, and its impact on quality of life, it is important that people are receiving the best pain relief treatment available, therefore interest in this area of research is high.. To compare the efficacy of lumbar sympathectomy with prostanoid infusion in improving symptoms and function and avoiding amputation in people with critical limb ischaemia (CLI) due to non-reconstructable peripheral arterial disease (PAD).. The Cochrane Vascular Information Specialist (CIS) searched the Specialised Register (last searched 29 March 2017) and CENTRAL (2017, Issue 2). The CIS also searched clinical trials databases for ongoing or unpublished studies.. Randomised controlled trials (RCTs), with parallel treatment groups, that compared lumbar sympathectomy (surgical or chemical) with prostanoids (any type and dosage) in people with CLI due to non-reconstructable PAD.. Three review authors independently selected trials, extracted data and assessed risk of bias. Any disagreements were resolved by discussion. We performed fixed-effect model meta-analyses, when there was no overt sign of heterogeneity, with risk ratios (RRs) and 95% confidence intervals (CIs). We graded the quality of evidence according to GRADE.. We included a single study in this review comparing lumbar sympathectomy with prostanoids for the treatment of CLI in people with non-reconstructable PAD. The single study included 200 participants with Buerger's disease, a form of PAD, 100 in each treatment group, but only 162 were actually included in the analyses. The study compared an open surgical technique for lumbar sympathectomy with the prostanoid, iloprost, and followed participants for 24 weeks.Risk of bias was low for most evaluated domains. Due to the nature of the treatment, blinding of the participants and those providing the treatment would be impossible as a surgical procedure was compared with intravenous injections. It was not mentioned if blinded assessors evaluated the study outcomes, therefore, we judged subjective outcomes (i.e. pain reduction) to be at unclear risk of detection bias and objective outcomes (i.e. ulcer healing, amputation and mortality) at low risk of detection bias. We also rated the risk of attrition bias as unclear; 38 out of 200 (19%) participants were not included in the analysis without clear explanation (16 of 100 in the iloprost arm and 22 of 100 in the sympathectomy arm). The quality of evidence was low due to serious imprecision because the study numbers were low and there was only one study included.The single included study reported on the outcome of complete healing without pain or major amputation, which fell under three separate outcomes for our review: relief of rest pain, complete ulcer healing and avoidance of major amputation. We chose to keep the outcome as a singularly reported outcome in order to not introduce bias into the outcomes, which may have been the case if reported separately. The limited evidence suggests participants who received prostaglandins had improved complete ulcer healing without rest pain or major amputation when compared with those who received lumbar sympathectomy (RR 1.63, 95% CI 1.30 to 2.05), but as it was the only included study, we rated the data as low-quality and could not draw any overall conclusions. The study authors stated that more participants who received prostaglandins reported adverse effects, such as headache, flushing, nausea and abdominal discomfort, but only one participant experienced severe enough adverse effects to drop out. Five participants who underwent lumbar sympathectomy reported minor wound infection (low-quality evidence). There was no reported mortality in either of the treatment groups (low-. Low-quality evidence from a single study in a select group of participants (people with Buerger's disease) suggests that prostaglandins are superior to open surgical lumbar sympathectomy for complete ulcer healing without rest pain or major amputation, but possibly incur more adverse effects. Further studies are needed to better understand if prostaglandins truly are more efficacious than open surgical lumbar sympathectomy and if there are any concerns with adverse effects. It would be of great importance for future studies to include other forms of PAD (as Buerger's disease is a select type of PAD), other methods of sympathectomy as well as data on quality of life, complications and cost-effectiveness.

Topics: Humans; Iloprost; Ischemia; Leg Ulcer; Pain Management; Peripheral Arterial Disease; Prostaglandins; Sympathectomy; Thromboangiitis Obliterans; Vasodilator Agents

Peripheral arterial occlusive disease (PAOD) is a common cause of morbidity and mortality due to cardiovascular diseases in the general population. While numerous treatments have been adopted for different disease stages, there is no option other than amputation for patients presenting with critical limb ischaemia (CLI), unsuitable for rescue or reconstructive intervention.. To determine the effectiveness and safety of prostanoids in patients presenting with CLI.. The Cochrane Peripheral Vascular Diseases Group searched their trials register (last searched October 2009) and the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (last searched 2009, Issue 4) for publications describing randomised controlled trials (RCTs) of prostanoids for CLI. We ran additional searches in MEDLINE, EMBASE, LILACS, and SciSearch, and we also contacted pharmaceutical companies and experts, in order to identify unpublished data and trials still underway.. Randomised controlled trials describing efficacy and safety of prostanoids compared with placebo or other pharmacological control treatments, in patients presenting with CLI, without chance of rescue or reconstructive intervention.. Two authors independently selected trials, assessed trials for eligibility and methodological quality, and extracted data. Disagreements were resolved by consensus or by the third author.. We retrieved 532 citations which after the first screening resulted in 111 potential studies. Finally, after exclusion of studies of poor quality and a lack of sufficient information, 20 trials were included in the review.Prostanoids seem to have efficacy regarding rest-pain relief (risk ratio (RR) 1.32, 95% confidence interval (CI) 1.10 to 1.57; P = 0.003), and ulcer healing (RR 1.54, 95% CI 1.22 to 1.96). Iloprost also shows favourable results regarding major amputations (RR 0.69, 95% CI 0.52 to 0.93). The more frequently reported adverse events when using prostanoids were headache, facial flushing, nausea, vomiting and diarrhoea.. Despite some positive results regarding rest-pain relief, ulcer healing and amputations, there is no conclusive evidence based on this meta-analysis of the long-term effectiveness and safety of different prostanoids in patients with CLI. Further well-conducted, high quality randomised double-blinded trials should be performed.

Topics: Alprostadil; Amputation, Surgical; Epoprostenol; Humans; Iloprost; Ischemia; Leg; Leg Ulcer; Peripheral Vascular Diseases; Prostaglandins; Randomized Controlled Trials as Topic; Vasodilator Agents

Venous ulceration remains a common problem and a significant challenge to the physicians treating it. Many theories have been advanced in the past to explain its causes but there is little evidence to support tissue hypoxia as the main factor, as was once thought. In recent years attention has focussed on the inflammatory events which attend venous disease and the development of venous ulceration. It has been proposed that these form a major contribution to the development of venous leg ulcers. In the arterial system an analogous series of events appears to cause damage following severe ischemia. Massive neutrophil activation in the microcirculation following reperfusion of a tissue results in severe, ischemic damage to that tissue. A similar series of events is proposed to explain venous disease. During venous hypertension leukocytes are sequestrated in the microcirculation of the lower limb. It has been shown that these undergo activation whilst they are in the leg. The exact location of leukocyte sequestration is unclear but it is suggested that this may occur in the skin. The damage caused to the lower limb skin components can be identified by measuring plasma levels of endothelial adhesion molecules, which are shed into the circulation following a period of venous hypertension. In the long term this leads to a chronic inflammatory state in the skin in some patients where venous hypertension is sustained or there is susceptibility to venous hypertension. The resulting inflammatory process is referred to as "lipodermatosclerosis" and has a number of well known clinical features. There is proliferation of the dermal capillaries eventually leading to a "glomerulus" like appearance. In the skin and subcutaneous tissues there is fibrosis. The microcirculation in the papillary dermis is surrounded by an inflammatory cellular infiltrate. The importance of understanding the mechanisms of the development of venous ulceration is in creating new treatments for this problem. Compression treatment has been effective in healing leg ulcers for thousands of years. Surgical treatment offers a possible cure in patients where superficial venous reflux is the main problem. Deep vein reconstruction is only suitable for a few patients. Many venous ulcers can be healed by compression, only to recur within a few months. Pharmacological treatments may offer the possibility of more rapid ulcer healing and the maintenance of an ulcer-free state if the correct pathophysiological

Topics: Alprostadil; Cell Adhesion Molecules; Chronic Disease; Humans; Iloprost; Leg Ulcer; Leukocytes; Neutrophils; Pentoxifylline; Vasodilator Agents; Venous Insufficiency

Topics: Alprostadil; Arterial Occlusive Diseases; Aspirin; Bandages; Electric Stimulation Therapy; Exercise Therapy; Humans; Iloprost; Infections; Leg Ulcer; Pain Management; Risk Factors; Spinal Cord; Vascular Surgical Procedures; Venous Insufficiency; Walking

Topics: Anti-Infective Agents, Local; Epoprostenol; Humans; Iloprost; Ischemia; Leg; Leg Ulcer; Platelet Aggregation Inhibitors; Tibial Arteries; Vasodilator Agents

We conducted a study using an intravenous (i.v.) infusion of iloprost in the treatment of venous ulcers to verify whether the association of i.v. iloprost + local therapy + elastic compression has a favorable effect when compared with traditional treatment with local therapy and elastic compression.. We evaluated the effects of iloprost in 98 consecutive patients with noncomplicated venous ulcers of lower limbs subdivided into 2 groups: the first group (48 patients) received iloprost in saline solution for 3 weeks and the second group (50 patients) received a venous infusion of a saline solution. The patients were examined at baseline time 0 (first visit) and then after 15, 30, 45, 60, 75, 90, 105, 120, 135, and 150 days.. In the first group, after 90 days, all the ulcers had healed, whereas in the second group only 50% of ulcers had healed after 105 days. At the end of the study, in the second group only 84.09% of ulcers had healed. The statistical analysis showed a significant difference between the first (iloprost group) and the second group (placebo group). Besides, in the first group the cicatrization of the ulcer happened in a shorter period (27.90% after 60 days; 41.86% after 75 days; and 100% after 100 days) whereas in the second group, at the end of the study, in 15.91% of patients the ulcers had not recovered.. Iloprost can significantly reduce healing time for venous leg ulcers through several actions.

Topics: Anti-Infective Agents, Local; Combined Modality Therapy; Debridement; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Iloprost; Infusions, Intravenous; Leg Ulcer; Male; Middle Aged; Platelet Aggregation Inhibitors; Single-Blind Method; Stockings, Compression; Treatment Outcome

To evaluate the long term efficacy of treatment with intravenous iloprost for severe Raynaud's phenomenon (RP) and ischemic leg ulcers in patients with autoimmune systemic diseases.. Prospective observational study over 2 years with iloprost (intravenous infusions, 0.5 to 2 ng/kg/min, initial cycle of 5 consecutive days and maintenance infusions during 24 h monthly, lengthened when it was needed) in patients with severe RP and ischemic leg ulcers whithout response to conventional therapy. Treatment was halted in patients with a good response after one year of treatment, with regular clinical controls.. We treated 23 patients. Iloprost reduced significantly the mean number (SD) of monthly episodes of RP (150.38 [102.04] initially and 40.05 [78.06] at the end; p < 0.0005), the mean highest duration of episodes of RP (21.86 [26.96] min initially and 7.14 [9.87] min at the end; p = 0.013), the associated pain (p = 0.005), and the mean number of ischemic digital (4.25 [2.86] initially and 0.63 [2.25] at the end; p = 0.003) and leg ulcers (1.67 [0.52] initially and 0.33 [0.52] at the end; p = 0.01). Articular symptoms and inflammatory markers did not improve. Treatment was stopped in 8 patients (in 5 for a very good evolution and in 3 for other causes), and only 1 of them needed to be treated again. Side effects were seen in all cases but always disappeared after slowing infusion.. Iloprost was effective in the long term treatment of severe RP and ischemic leg ulcers in patients with autoimmune systemic diseases.

Topics: Adult; Autoimmune Diseases; Female; Humans; Iloprost; Ischemia; Leg; Leg Ulcer; Male; Prospective Studies; Raynaud Disease; Severity of Illness Index; Time Factors; Vasodilator Agents

The flux distribution within ischemic ulcers and adjacent skin and its change by prostanoids was investigated using laser Doppler flux scanning. A prostanoid-induced increase in ulcer flux could be a rationale for the improved wound healing. In a single-blind prospective study 18 patients received prostaglandin E1 (PGE1) (333.3 ng/min.), iloprost (41.7 ng/min final dose), and 0.9% saline in a randomized order. The average laser Doppler flux within the ulcer (LFU, x +/- SEM, arbitrary units) or in the adjacent skin (LFS) was evaluated before and 30, 60, 90, and 120 min after prostanoid/saline infusion. LFU increased with PGE1 from 2.30 +/- 0.27 to 3.08 +/- 0.31 (+33.9%; P < 0.001) and with iloprost from 2.37 +/- 0.26 to 3.03 +/- 0.27 (+27.8%; P < 0.001) after 120 min, respectively. Saline did not change LFU significantly: 2.19 +/- 0.18 vs 2.55 +/- 0.26 (+16.4%; P > 0.05). Simultaneously, LFS was not significantly changed when pretreatment values were compared with mean flux at 120 min: PGE1 2.13 +/- 0.27 vs 2.54 +/- 0.34, iloprost 2.03 +/- 0.26 vs 1.94 +/- 0.21, and saline 1.74 +/- 0.27 vs 1.92 +/- 0.30 (P > 0.05, each), respectively. The laser Doppler flux scanning technique might be a tool to study the distribution of laser Doppler flux within ischemic ulcers. This might be useful to study the physiological or pathophysiological control of flux within ischemic ulcers as well as possible therapeutic approaches.

Topics: Adult; Aged; Alprostadil; Arterial Occlusive Diseases; Cross-Over Studies; Female; Foot Ulcer; Humans; Iloprost; Ischemia; Laser-Doppler Flowmetry; Leg; Leg Ulcer; Male; Middle Aged; Ultrasonography; Vasodilator Agents

Leg ulcers are a recognised manifestation of cutaneous vasculitis in connective tissue diseases (CTDs) including rheumatoid arthritis (RA). Iloprost a stable prostacyclin analogue has been successfully used to treat Raynaud's phenomenon and digital ulcers associated with CTD's. Our aim was to assess iloprost in the treatment of vasculitic leg ulcers in CTD. In this paper we describe eight cases of vasculitic leg ulceration in association with RA and CTD, treated with intravenous iloprost. The iloprost was administered for 6-8 hours daily and continued for 21-28 days. Immunosuppressive therapy was required in three patients with severe necrotising vasculitis (RAnv). Complete ulcer healing was achieved in four patients within 6 weeks of commencing therapy while rapid improvement occurred in the other four patients. This suggests that iloprost may be useful as an adjunct to therapy for vasculitic leg ulcers. A double-blind placebo controlled study of iloprost therapy for RA leg ulcers is under way.

Topics: Aged; Aged, 80 and over; Arthritis, Rheumatoid; Connective Tissue Diseases; Drug Administration Schedule; Female; Humans; Iloprost; Immunosuppressive Agents; Infusions, Intravenous; Leg Ulcer; Male; Middle Aged; Treatment Outcome; Vasculitis

In a randomized, double-blind, placebo controlled study in patients with venous leg ulcers, the efficacy and tolerability of topical applications of a prostacylin hydrogel (iloprost) was investigated. 34 patients were allocated to the placebo treatment and 65 patients were allocated to the iloprost treatment. The iloprost treatment commenced with 10 micrograms/ml for the first 3 days and was increased to 40 micrograms/ml for the remaining treatment period if well tolerated. Maximally 3 ml of the hydrogel were applied daily on the ulcer base for a period of 8 weeks. The total area of the ulcers at the last individual assessment was chosen as the main criterion for evaluation of efficacy. Both concentrations of iloprost were well tolerated with almost the entire trial population on iloprost being treated with the 40 micrograms/ml iloprost hydrogel. With regards to efficacy, no significant difference was found in favour of the iloprost treatment.

Topics: Administration, Cutaneous; Aged; Double-Blind Method; Female; Gels; Humans; Iloprost; Leg Ulcer; Male; Middle Aged; Prospective Studies; Treatment Failure

The clinical efficacy of the prostacyclin analogue iloprost was studied during a 2 week treatment and 6 month follow-up period in 103 patients with ischaemic ulcers who were randomised to receive active treatment or placebo. Responders were defined as those patients who achieved healing of at least one third of the ulcer area during the study period. The overall responder rate was 41.3%, compared with 25% for the control group (P = 0.086). Side effects including flushing and headache, were common. The study population had a mortality of 23% during the 6 month period, the amputation rate was 43.5% for iloprost and 50% for placebo treated patients. In this severely diseased population of patients a treatment period limited to 2 weeks did not sufficiently improve ulcer healing.

Topics: Adult; Aged; Aged, 80 and over; Amputation, Surgical; Female; Humans; Iloprost; Ischemia; Leg; Leg Ulcer; Male; Middle Aged

Topics: Alprostadil; Amputation, Surgical; Cardiovascular Agents; Clinical Trials as Topic; Epoprostenol; Humans; Iloprost; Infusions, Intravenous; Leg Ulcer; Vascular Diseases

Topics: Humans; Iloprost; Ischemia; Leg; Leg Ulcer; Skin; Ulcer

The authors present the results of preoperative and postoperative prostacyclin analog treatment with skin grafting in a large ulceration of a chronic critical ischemic leg in a man who had lost his contralateral extremity 5 years ago. Healing was uneventful at the 6-month follow-up.

Topics: Humans; Iloprost; Ischemia; Leg; Leg Ulcer; Male; Middle Aged; Skin Transplantation; Vasodilator Agents; Wound Healing

The authors report the case of a patient with a large leg ulcer secondary to polyarteritis nodosa unresponsive to corticosteroid, cytotoxic, and anticoagulant therapy who was successfully treated with iloprost.

Topics: Adult; Humans; Iloprost; Leg Ulcer; Male; Platelet Aggregation Inhibitors; Polyarteritis Nodosa; Vasodilator Agents

Iloprost, a prostaglandin I2, is chemically stable and it has been successfully used by intravenous infusion in severe limb ischemia. Usually Iloprost is diluted in 0.9% sodium chloride solution and infused intravenously for six hours each day for 28 days in hospital.. In the present study after the first three days of infusion with a traditional pump in hospital, a home pump has been utilised for the infusion of Iloprost at home. This device allows the continue infusion of Iloprost at a flow rate of 2 ml/h for six days, then the pump is filled with a new solution. The home pump consists of a protective shell in polycarbonate (10 x 12 cm), 270 ml of volume, inside there is a balloon reservoir (3 membranes) which is filled with Iloprost. The structure of Iloprost does not change into the home pump as evidenced by HPLC studies and its continue infusion allows plasmatic high levels of its active isomers during the 28 days of therapy. In 30 patients, 25 men and 5 women (mean age 61 years) with Fontaine stage IIB (6), III (5) and IV (19) POAD Iloprost has been infused with the home pump. The follow-up period was 1 to 16 months.. The results have shown 4 major amputations and 1 death, in 9 patients complete pain relief and ulcer healing, and in 6 patients only improvement in relief of rest pain and ulcers.. All the patients appreciated this system of infusion because they had a normal life; in addition it is less expensive because the patients stay in hospital only 3 days.

Topics: Female; Humans; Iloprost; Infusions, Intravenous; Ischemia; Leg; Leg Ulcer; Male; Middle Aged; Vasodilator Agents

Iloprost, a stable prostacyclin analogue, is known to have beneficial effects on the disturbed microcirculation. To develop a topical application for venous leg ulcers it is necessary to know the extent to which iloprost might be absorbed through the ulcer base. The aim of this study was to measure the absorption kinetics of iloprost solutions in increasing concentrations and doses (0.004% [15 micrograms]-0.006% [30 micrograms]) in 23 patients. There was considerable variation amongst the patients in the amount of iloprost absorbed. In 40% of patients no iloprost could be detected in the plasma, whereas in others up to 82% of the iloprost applied was absorbed through the ulcer base. High iloprost plasma levels provoked flushing in two patients. The highest plasma levels were always reached during the first hour after application. There was no direct relation between the ulcer size and the amount of iloprost absorbed. Iloprost concentrations up to the highest concentration applied (0.006%) were well tolerated locally.

Topics: Administration, Cutaneous; Adult; Aged; Aged, 80 and over; Female; Humans; Iloprost; Leg Ulcer; Male; Middle Aged; Skin; Skin Absorption; Skin Ulcer