Intravenous Iron Compounds Research Articles

The differential effect of modern intravenous iron on fibroblast growth factor 23 and phosphate in non-dialysis dependent CKD – the exploratory randomized controlled double-blind ExplorIRON-CKD study

BackgroundIntravenous iron is commonly used in patients with non-dialysis-dependent chronic kidney disease (CKD). Modern intravenous iron compounds (e.g. ferric derisomaltose (FDI), ferric carboxymaltose (FCM)) are increasingly utilized with similar efficacy. A differential effect in terms of hypophosphatemia has been noted following administration of FCM, which may be related to fibroblast growth factor 23 (FGF23). This study was designed to examine the comparative effects of FDI and FCM on FGF23, phosphate and other markers of bone turnover.MethodsThe single-center double-blind randomized controlled trial “Iron and Phosphaturia – ExplorIRON-CKD” primarily assessed the effects of FCM and FDI on intact FGF23 and phosphate, whilst also studying the impact on vitamin D, parathyroid hormone and phosphaturia. Bone markers including alkaline phosphatase, bone-specific alkaline phosphatase, procollagen type 1 N-terminal propeptide and carboxy-terminal collagen cross-linked telopeptide were monitored. Non-dialysis-dependent CKD patients (stage 3a-5) with iron deficiency with/without anemia (serum ferritin < 200 µg/L or transferrin saturation = 20% and serum ferritin 200-299 µg/L) were randomized to receive FDI or FCM in a 1:1 ratio. At baseline 1000 mg of intravenous iron was administered followed by 500-1000 mg at 1 month to achieve replenishment. Measurements were performed at baseline, 1–2 days following iron administration, 2 weeks, 1 month (second iron administration), 1–2 days following second administration, 2 months and 3 months following initial infusion.ResultsTwenty-six patients participated in the trial; 14 randomized to FDI and 12 to FCM. Intact FGF23 increased following administration of iron, and the increase was significantly higher with FCM compared to FDI (Baseline to 1–2 days following 1st administration: FDI: 3.0 (IQR: - 15.1 - 13.8) % vs. FCM: 146.1 (IQR: 108.1–203.1) %; p < 0.001 and Baseline to 1–2 days following 2nd administration: FDI: 3.2 (IQR: - 3.5 – 25.4) % vs. FCM: 235.1 (138.5–434.6) %; p = 0.001). Phosphate levels decreased in the FCM group, causing a significant difference versus FDI 2 weeks following administration of the first dose. A significantly greater decrease in 1,25 (OH)2 Vitamin D was noted with FCM. Several markers of bone turnover significantly changed following administration of FCM but not FDI.ConclusionsThe study suggests a differential effect on FGF23 following administration of FCM compared to FDI in non-dialysis-dependent CKD patients, similar to other patient groups. This may lead to changes consistent with hypovitaminosis D and alterations in bone turnover with potential clinical consequences. Further definitive studies are required to understand these differences of intravenous iron compounds.Trial registrationEuropean Union Drug Regulating Authorities Clinical Trials Database (EudraCT) number: 2019–004370-26 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004370-26/GB) (First date of trial registration: 03/12/2019).

Perioperative Tracking of Intravenous Iron in Patients Undergoing On-Pump Cardiac Surgery: A Prospective, Single-Center Pilot Trial.

Preoperative intravenous iron administration is a frequently used patient blood management procedure. If the timeframe of intravenous iron administration before surgery is short, (1) the concentration of the intravenous iron compound might still be high in patients' plasma when undergoing surgery and (2) this iron in patients' plasma is at risk to be lost due to blood loss. The aim of the current study was, therefore, to track the iron compound ferric carboxymaltose (FCM) before, during, and after cardiac surgery requiring cardiopulmonary bypass, with an emphasis on intraoperative iron losses in shed blood and potential recovery through autologous cell salvage. Concentrations of FCM were analyzed in patients' blood using a hyphenation of liquid chromatography and inductively coupled plasma-mass spectrometry to distinguish between pharmaceutical compound FCM and serum iron. In this prospective, single-center pilot trial, 13 anemic and 10 control patients were included. Anemic patients with hemoglobin levels ≤12/13 g/dL in women and men were treated with 500 milligrams (mg) intravenous FCM 12 to 96 hours before elective on-pump cardiac surgery. Patients' blood samples were collected before surgery and at days 0, 1, 3, and 7 after surgery. One sample each was taken of the cardiopulmonary bypass, the autologous red blood cell concentrate generated by cell salvage, and the cell salvage disposal bag. Patients who had received FCM <48 hours before surgery had higher FCM serum levels (median [Q1-Q3], 52.9 [13.0-91.6]) compared to ≥48 hours (2.1 [0.7-5.1] µg/mL, P = .008). Of 500-mg FCM administered <48 hours, 327.37 (257.96-402.48) mg were incorporated compared to administration ≥48 hours with 493.60 (487.78-496.70) mg. After surgery, patients' plasma FCM concentration in the FCM <48 hours group was decreased (-27.1 [-30 to -5.9] µg/mL). Little FCM was found in the cell salvage disposal bag (<48 hours, 4.2 [3.0-25.8] µg/mL, equivalent to 29.0 [19.0-40.7] mg total; equivalent to 5.8% or 1/17th of the 500 mg FCM initially administered), almost none in the autologous red blood cell concentrate (<48 hours, 0.1 [0.0-0.43] µg/mL). The data generate the hypotheses that nearly all FCM is incorporated into iron stores with administration ≥48 hours before surgery. When FCM is given <48 hours of surgery, the majority is incorporated into iron stores by the time of surgery, although a small amount may be lost during surgical bleeding with limited recovery by cell salvage.

POS-252 THE DIFFERENTIAL IMPACT OF TWO NOVEL INTRAVENOUS IRON AGENTS ON FIBROBLAST GROWTH FACTOR 23, PHOSPHATE AND OTHER CLINICAL AND FUNCTIONAL MARKERS: METHODOLOGY AND BASELINE DATA

Third generation intravenous (IV) iron preparations are increasingly used in the treatment of non-dialysis dependent chronic kidney disease (CKD) associated iron deficiency. Such compounds allow rapid delivery of large concentrations of iron safely at a single sitting. Evidence suggests that their use may lead to improved cardiovascular outcomes. Nonetheless, concerns exist regarding the potential induction of hypophosphatemia via fibroblast-growth-factor 23 (FGF-23) following the use of certain compounds. Raised FGF-23 has been associated with mineral bone and cardiac disorders, alongside prognostic implications. No prior study has provided a head-to-head comparison between iron preparations in CKD. This pilot study is designed to primarily investigate the differential impact of two different IV iron compounds on FGF-23 and phosphate in patients with CKD; secondarily we examine the impact of these compounds on bone markers and functional status, quality of life and cardiovascular function. This is a randomized controlled double-blinded pilot study recruiting patients with CKD stage 3a – 5 (non-dialysis) and iron deficiency +/- anemia. Patients are randomized to receive either ferric carboxymaltose or ferric derisomaltose over two infusions (one-month apart) to achieve full repletion. The initial dose administered is 1000 mg for both medications, with 500 mg or 1000 mg reserved for the second dose depending on weight and hematinics. Follow up is over a period of three months following the first infusion with measurements of intact FGF-23, phosphate, phosphaturia, vitamin D, parathyroid hormone, bone metabolism markers, functional status and quality of life and cardiac markers (figure 1). 168 patients were referred to the specialist renal anemia services for pre-screening. Ninety-nine were contacted for interest to participate, with 64 individuals declining to join. The commonest reason for not participating, was the COVID-19 pandemic (43.3%) with patients not keen to travel. Thirty-five patients were screened, and 27 patients enrolled in the study, of which 26 were randomized to receive iron (figure 2). One patient withdrew from the study, as they were unable to attend appointments following successful screening. In our baseline cohort the median age was 67.9 (12.4) and 17 participants were male. Mean hemoglobin was 100.3 (13.5) and hematinic markers consistent were consistent with iron deficiency. Median eGFR was 18.0 (11.3) ml/min/1.73 m2; the population as expected had a raised intact FGF-23 (212.1 (116.4) pg/ml). Serum calcium and phosphate were within normal parameters, while parathyroid hormone and 1,25 (OH)2 Vitamin D were deranged (Table 1). ExplorIRON-CKD, like a number of trials, experienced significant disruption in recruitment due to COVID-19. This study will provide further insight to the potential induction of FGF-23 following administration of specific intravenous iron compounds, and identify whether such a differential effect exists in patients with CKD. The effect of such induction in terms of phosphate and other markers of bone metabolism, functional status and cardiac functioning will be observed. The results will aid in hypothesis generation for further studies to identify the potential long-term impact of iatrogenic FGF-23 increase in patients with CKD.

Hypophosphataemia, fibroblast growth factor 23 and third-generation intravenous iron compounds: a narrative review.

Third-generation intravenous (i.v.) iron preparations are safe and efficacious and are increasingly used in the treatment of iron-deficiency anaemia. Hypophosphataemia is emerging as an established side-effect following the administration of certain compounds. Symptoms of hypophosphataemia can be masked by their similarity to those of iron-deficiency anaemia and both acute and chronic hypophosphataemia can be detrimental. Hypophosphataemia appears to be linked to imbalances in the metabolism of the phosphatonin fibroblast growth factor 23. In this narrative review, we discuss the possible pathophysiology behind this phenomenon, the studies comparing third-generation i.v. iron compounds, and the potential implications of the changes in fibroblast growth factor 23 and hypophosphataemia. We also present an algorithm of how to approach such patients requiring i.v. iron in anticipation of hypophosphataemia and how the impact related to it can be minimized.

An evaluation of ferric derisomaltose as a treatment for anemia

ABSTRACT Introduction: Originally approved in Europe in 2009, ferric derisomaltose is the most recently authorized intravenous iron compound in the United States of America (2020). Ferric derisomaltose given as a rapid high-dose infusion can allow complete iron repletion in a single dose and it is now widely used in the treatment of iron deficiency. Areas covered: The chemistry, pharmacodynamics and pharmacokinetics of ferric derisomaltose are reviewed. Results from phase II, III and IV trials regarding efficacy and safety are presented. Mechanisms behind minor infusion reactions, hypersensitivity and hypophosphatemia are discussed. The economic impact of ferric derisomaltose use is presented. Data pertaining to the use of ferric derisomaltose in iron deficiency anemia, chronic kidney disease, inflammatory bowel disease, chronic heart failure, perioperative care and other patient groups are comprehensively covered. Expert opinion: Ferric derisomaltose is an effective intravenous iron formulation with a good safety profile, providing rapid, cost-effective iron repletion. Ferric derisomaltose releases low quantities of labile iron relative to older compounds. Anaphylaxis is extremely rare, and ‘Fishbane’ reactions are uncommon. Hypophosphatemia following ferric derisomaltose administration is infrequent in comparison to other intravenous irons such as ferric carboxymaltose. The scope of ferric derisomaltose use is growing with increasing research in these areas.

P044 The comparative safety of different intravenous iron preparations in inflammatory bowel disease: A systematic review and network meta-analysis

BACKGROUND: Anemia is the most frequent systemic complication of IBD, with a prevalence of up to 74%. Oral iron compounds are of limited efficacy in IBD, due to gastrointestinal side effects and poor compliance. Modern intravenous (IV) iron compounds have been demonstrated to be safe and effective in IBD patients and are recommended by international guidelines. However, some safety concerns remain. Compounds currently approved for iron deficiency anemia (IDA) in IBD are ferric carboxymaltose (FCM), ferumoxytol (FOX), iron sucrose/saccharate (IS), iron isomaltoside (ISM) and iron dextran (IDX). We compared the tolerability of different IV iron compounds used to treat IDA in IBD patients in a systematic review and network metaanalysis (NMA). METHODS: A literature search was performed in PUBMED, SCOPUS, Web of Science and the Cochrane Library to identify studies. No date restrictions were imposed, the last search was completed August 2018. Primary outcome measure was the pooled total of drug-related adverse events (AEs) and serious adverse events (SAEs) in proportion to the safety population. Secondary outcome measure was identification of the commonest adverse events. Bayesian NMA was performed using Markov Chain Monte Carlo Methods to calculate the tolerability of each iron therapy relative to all comparators. Heterogeneity was tested with I2, using the Higgins and Thompson method to indicate the percentage of variance attributable to study heterogeneity, and a random effect model (ROM) was used for analysis. Results were presented as Odds Ratios (OR) in relation to response rate to iron treatment. Bias risk of eligible studies was assessed using the Cochrane Collaboration’s Risk of Bias tool in Review Manager (RevMan 5). RESULTS: 2,730 papers were found. After duplication removal and detailed review, 25 eligible studies were included: 4 RCTs (NMA) and 21 others (systematic review only). No eligible studies for FOX and no RCTs for IDX were found. Bayesian NMA was performed on 4 eligible RCTs (n = 1,052). ROM showed no evidence of inconsistency between direct and indirect evidence in all networks; all p-values were statistically insignificant at 5%. The ROM fit the data adequately with no evidence of inconsistency (DIC = 15.7). No statistically significant difference was found between different IV iron products or oral iron (vs oral iron: OR = 0.87, 95% CrI [0.43;1.7] for FCM, OR = 0.80, 95% CrI [0.36;1.8] for IS, OR = 1.5, 95% CrI [0.64;3.7] for ISM). The systematic review (n = 2,619) showed overall AE rates of 83/1,028 (8.1%) for FCM, 78/481 (16.2%) for IS, 89/475 (18.7%) for ISM and 10/83 (12%) for IDX. Drug-related SAEs occurred at pooled rates of 0.1%, 2.2%, 0.0%, 1.1%, for FCM, IS, IDX and ISM, respectively. For oral iron, AE/SAE rates were 22.6%, 1.4%. CONCLUSION(S): While the systematic review indicates FCM to be associated with fewer adverse events, its statistical significance remains unproven due to the lack of data from randomised controlled trials. Although hypophosphatemia has been reported to be associated with IV iron administration, especially FCM, it was temporary and asymptomatic, if reported at all. There were no reports of hypophosphatemia-related bone manifestations. Further comprehensive trials are needed to draw conclusions concerning the comparative safety of different IV iron substances.

P043 Update of a network meta-analysis of efficacy and safety of different intravenous iron compounds in patients with IBD and anemia

BACKGROUND: Iron deficiency anemia (IDA) is a frequent complication of inflammatory bowel disease (IBD) associated with reduced quality of life and increased hospitalization rates. Modern intravenous iron compounds have been demonstrated to be safe and effective in IBD patients, facilitating rapid correction of hemoglobin levels and repletion of body iron stores. International guidelines recommend intravenous (IV) administration of iron in IBD patients with IDA. Compounds currently approved for IDA in IBD are ferric carboxymaltose (FCM), ferumoxytol (FOX), iron sucrose/saccharate (IS), iron isomaltoside (ISM) and iron dextran (IDX). Slight variances in the core size and the composition and density of the surrounding carbohydrate cause variations in the efficacy and tolerability of IV iron formulations. Here, we searched for new data to augment a first network metaanalysis (NMA) and systematic review of IV iron preparations in IBD carried out in 2016 (PROSPERO registration number: 42016046565). METHODS: Using the same search methodology, we performed a new search using the PubMed, Scopus, Web of Science and Cochrane databases to identify articles published since the original systematic review and NMA, i.e., between July 2016 and August 2018. Primary outcome measure was hematopoietic response (% of patients), defined as hemoglobin (Hb) normalization or Hb increase of ≥2 g/dL. Secondary outcomes included number of adverse events (AEs) as percentage of safety population. RESULTS: Our search criteria produced 151 studies. We identified 4 prospective observational studies (2 FCM and 2 ISM) not included in the original systematic review and NMA, making 18 studies in total. Eligible studies evaluating FOX were not found. Since no additional RCTs eligible for the NMA were identified, the NMA of 4 studies could not be augmented. In total, the updated systematic review included 7 studies with 798 patients for FCM, 2 studies with 78 patients for IDX, 8 studies with 508 patients for IS, and 3 studies with 423 patients for ISM as infusion or bolus injection. Overall response rates were FCM; 599/798 (78%), IDX; 33/78 (42%), IS; 344/508 (68%), ISM; 265/423 (63%). In general, all IV iron products were reported to be well tolerated with some risks of AEs. Overall rates of AEs and serious AEs were 66/836 (7.9%) and 1/836 (0.1%) for FCM; 10/83 (12%) and 0/83 for IDX; 72/471 (15.3%) and 1/471 (0.2%) for IS; 54/454 (12.7%) and 5/424 (1.2%) for ISM, respectively. Only FCM was significantly more effective than oral iron (Odds Ratio = 1.9, 95% CrI [1.1;3.2]). IS and ISM also had better response rates than oral iron but without statistical significance. p-values of &lt;0.05 for the node-splitting analysis of the Bayesian analyses indicated insignificant inconsistency. CONCLUSION(S): Our findings indicate that FCM remains the most effective IV iron formulation as monotherapy, followed by iron sucrose. In addition, FCM tended to have a better safety profile, with fewer AEs. The totality of evidence showed that further studies are unlikely to overturn this result. Nevertheless, further studies are needed to improve the level of evidence available to establish the comparative efficacy of different IV iron compounds in IBD patients with IDA.

P719 Update of a network meta-analysis of efficacy and safety of different intravenous iron compounds in patients with IBD and anaemia

P719 Update of a network meta-analysis of efficacy and safety of different intravenous iron compounds in patients with IBD and anaemia

Safety and efficacy of parenteral iron in children with inflammatory bowel disease.

Iron deficiency anaemia frequently complicates inflammatory bowel disease (IBD) in children and adults. Oral iron may exacerbate gastrointestinal symptoms and absorption may be insufficient in intestinal inflammation. Even where oral iron is successful, repletion of iron stores can be unacceptably slow. Intravenous iron compounds were in the past associated with serious adverse reactions and historically were considered a last resort in children. New generation preparations have a safer profile in adults, although reluctance to use them in children may persist, where safety data are lacking. We investigate the safety and efficacy of ferric carboxymaltose and iron sucrose in children. We retrospectively identified all children with IBD who received parenteral iron over a 38-month period in a single regional referral centre. Safety, tolerability and adverse events were established by case note review. Efficacy was assessed by change in haematinic indices pre- and post-treatment. Forty-one children (18 male; median age 14years, range 3-17) received a total of 104 iron infusions. Of these, 44% (18) had Crohn's disease; 56% (23) ulcerative colitis. Thirty-five received ferric carboxymaltose, seven iron sucrose and one both. Three children developed mild rash post infusion which resolved quickly with chlorphenamine. Mean increase in haemoglobin was 2.5gdl-1 (0.3-5.8). Iron levels increased by a mean of 8.4gdl-1 (1-25), transferrin saturation by 16.2% (2-47). Transferrin decreased by 0.84gdl-1 (0.3-3.4). New generation parenteral iron preparations are safe, well tolerated and efficacious in children with iron deficiency anaemia and IBD.

Markers of oxidative/nitrosative stress and inflammation in lung tissue of rats exposed to different intravenous iron compounds.

Iron deficiency anemia is a frequent complication in clinical conditions such as chronic kidney disease, chronic heart failure, inflammatory bowel disease, cancer, and excessive blood loss. Given the ability of iron to catalyze redox reactions, iron therapy can be associated with oxidative stress. The lung is uniquely susceptible to oxidative stress, and little is known about the effects of intravenous iron treatment in this organ. This study characterized changes in markers of oxidative/nitrosative stress and inflammation in the lung of non-iron deficient, non-anemic rats treated with five weekly doses (40 mg iron per kg body weight) of low molecular weight iron dextran (LMWID), iron sucrose (IS), ferric carboxymaltose (FCM), ferumoxytol (FMX), iron isomaltoside 1000 (IIM), or saline (control). Rats treated with LMWID, FMX, or IIM showed significant changes in most measures of oxidative/nitrosative stress, inflammation, and iron deposition compared to the saline-treated controls, with greatest changes in the LMWID treatment group. Increases in products of lipid peroxidation (thiobarbituric acid reactive substances) and protein nitrosation (nitrotyrosine) were consistent with increases in the activity of antioxidant enzymes (catalase, Cu,Zn-SOD, GPx), decreases in antioxidative capacity (reduced:oxidized GSH ratio), increased levels of transcription factors involved in the inflammatory pathway (NF-κB, HIF-1α), inflammatory cytokines (TNF-α, IL-6), adhesion molecules (VCAM-1), markers of macrophage infiltration (ED-1), and iron deposition (Prussian blue, ferritin). Since changes in measured parameters in FCM- or IS-treated rats were generally modest, the results suggest that FCM and IS have a low propensity to induce lung inflammation. The relevance of these findings to clinical safety profiles of the tested intravenous iron products requires further investigation.

P620 Network meta-analysis of efficacy and safety of different intravenous iron compounds for the treatment of iron deficiency anaemia in patients with inflammatory bowel disease

P620 Network meta-analysis of efficacy and safety of different intravenous iron compounds for the treatment of iron deficiency anaemia in patients with inflammatory bowel disease

VP151 Endovenous Iron Deficiency Anemia Treatment In Inflammatory Bowel Disease: Hospital-based Health Technology Assessment

INTRODUCTION:Iron Deficiency Anemia (IDA), a common cause of anemia in the world, is a frequently neglected disease that represents the main extraintestinal manifestation affecting patients with inflammatory bowel disease (IBD) (1). The release of new intravenous (IV) iron compounds represents a great opportunity for both physicians and patients, but the higher costs might hold back their optimal diffusion. A Health Technology Assessment (HTA) approach was used to provide insights on the sustainability of the IV iron formulations in a hospital setting, with a special focus on ferric carboxymaltose.METHODS:Epidemiology of IBD, as well as IDA associated with these conditions, was assessed with a systematic appraisal of the published literature. Data on efficacy and safety of IV iron formulations currently used in Italy were retrieved from the available medical electronic databases. A hospital based cost-analysis of the outpatient delivery of IV iron treatments was performed. Organizational and ethical implications were discussed.RESULTS:The reported prevalence of anemia in patients with IBD varies markedly from 10 to 73 percent for Crohn's Disease and from 9 to 67 percent for Ulcerative Colitis. Although there are no studies on direct comparison of different IV iron preparations, the literature indicates good efficacy and safety profiles of these formulations. However, ferric carboxymaltose seemed to provide a better and faster correction of hemoglobin and serum ferritin levels in iron-deficient patients (2,3). Our analyses indicated that ferric carboxymaltose, in spite of a greater price, would have positive benefits for the hospital, in terms of reduced costs related to individual patient management, and for the patients themselves, by reducing the number of infusions and accesses to health facilities.CONCLUSIONS:This hospital-based HTA reports an overall positive organizational, economic and ethical evaluation for the sustainable introduction of ferric carboxymaltose in the Italian outpatient setting.

Intravenous ferric carboxymaltose for the treatment of iron deficiency anemia.

Nutritional iron deficiency anemia is the most common deficiency disorder, affecting more than two billion people worldwide. Oral iron supplementation is usually the first choice for the treatment of iron deficiency anemia, but in many conditions, oral iron is less than ideal mainly because of gastrointestinal adverse events and the long course needed to treat the disease and replenish body iron stores. Intravenous iron compounds consist of an iron oxyhydroxide core, which is surrounded by a carbohydrate shell made of polymers such as dextran, sucrose or gluconate. The first iron product for intravenous use was the high molecular weight iron dextran. However, dextran-containing intravenous iron preparations are associated with an elevated risk of anaphylactic reactions, which made physicians reluctant to use intravenous iron for the treatment of iron deficiency anemia over many years. Intravenous ferric carboxymaltose is a stable complex with the advantage of being non-dextran-containing and a very low immunogenic potential and therefore not predisposed to anaphylactic reactions. Its properties permit the administration of large doses (15 mg/kg; maximum of 1000 mg/infusion) in a single and rapid session (15-minute infusion) without the requirement of a test dose. The purpose of this review is to discuss some pertinent issues in relation to the history, pharmacology, administration, efficacy, and safety profile of ferric carboxymaltose in the treatment of patients with iron deficiency anemia.

Iron deficiency: the hidden miscreant in inflammatory bowel disease.

Iron deficiency (ID) and anemia of chronic diseases (ACD) are the most common causes of anemia in inflammatory bowel disease (IBD), and frequently coexist. In these circumstances, detection of ID may be difficult as inflammation influences the parameters of iron metabolism. The prevalence of iron deficiency anemia (IDA) ranges between 36% and 76% in this population of patients. Anemia may impair physical condition, quality of life (QOL), and cognitive function, negatively affecting almost every aspect of daily life. Furthermore, it may be one of the causes of death in IBD. Consequently, iron replacement therapy should be initiated as soon as ID or IDA is detected, together with the treatment of underlying inflammation. Oral iron therapy is a simple and cheap treatment, but often is poorly tolerated and may worsen the intestinal damage. Moreover, in inflammatory states, duodenal iron absorption is blocked by a cytokine-mediated mechanism. Consequently, intravenous iron therapy is preferred in the presence of severe anemia, intolerance or lack of response to oral iron, and moderately to severely active disease. Recently, new intravenous iron compounds (iron carboxymaltose, iron isomaltoside 1000, ferumoxytol) have become available. Iron carboxymaltose has been shown to be safe and effective in IBD patients with IDA. Furthermore, it allows for rapid administration of high single doses, saving time and costs. If proven to be efficacious and well tolerated, it may become the standard therapy in the near future.

Intravenous iron therapy in non-dialysis CKD patients

Iron deficiency anaemia in non-dialysis-dependent chronic kidney disease patients is common, with a study (admittedly from more than 10 years ago) suggesting that >800 000 such patients in the USA are affected [1]. This may significantly impact on quality of life and exercise capacity, and it is also associated with significant morbidity and mortality. Correction of the anaemia will require iron replacement therapy, with or without erythropoiesis-stimulating agents (ESAs). The optimum route of administration of iron is controversial, with a wide variability in clinical practice among different countries, different renal units and indeed among different nephrologists within the same unit. The use of oral versus intravenous iron as the first-line management of this condition varies, partly because of the individual nephrologist’s beliefs and also partly due to a paucity of scientific evidence in this clinical setting, but is also influenced by the accessibility to a service that is readily able to provide intravenous iron supplementation. Thus, in primary care, general practitioners are likely to start with oral iron, whereas renal units that support an intravenous iron clinic (usually nurse-led) are more likely to start with intravenous iron. Reimbursement policies for intravenous iron in the non-dialysis CKD setting are also variable throughout the world, and this too may impact on the relative use of IV versus oral iron. Until recently, with the exception of iron dextran-containing preparations (which themselves have generated concerns about anaphylactic or hypersensitivity reactions), the available intravenous iron compounds were unable to provide high doses of iron as a single administration. Thus, for iron gluconate (used in the USA, Italy and Germany), doses of 62.5–125 mg of iron were the maximum recommended at a single sitting [2], whereas for iron sucrose (IS) - used widely in the USA, Europe, and Australia, bolus doses of up to only 200 mg were recommended [3]. Thus, many patients were required to attend for repeated boluses of IV iron, e.g. three or more injections of IS, 200 mg at a time, to replenish their iron deficits. Within the last few years, three new intravenous iron preparations have been licensed [4]. These include ferumoxytol (Feraheme® in the USA; Rienso® in Europe), ferric carboxymaltose (FCM, Ferinject® in Europe; Injectafer® in the USA) and iron isomaltoside-1000 (Monofer® in Europe). Data comparing these new preparations to the more traditional IV iron compounds are sparse, with small numbers of patients included in the clinical trials, most of which were not randomized, and with short follow-up. Qunibi et al .[ 5] performed a randomized controlled trial comparing intravenous FCM with oral iron for the treatment of iron deficiency anaemia in nondialysis-dependent chronic kidney disease patients, and showed that the response to intravenous iron was slightly greater with intravenous iron compared with oral iron, with an acceptable safety profile. However, the total number of patients exposed to intravenous FCM was 152 and the period of follow-up was only 8 weeks. In another recent randomized controlled trial, Charytan et al .[ 6] administered 15 mg/kg of FCM intravenously up to a maximum of 1000 mg in 204 nondialysis CKD patients and compared the haemoglobin responses with a group of patients treated with standard medical care (IV, oral or no iron, as determined by the investigator). Otherwise, head-to-head comparisons of IV iron preparations in the non-dialysis CKD population have been lacking. Onken et al. [7], in this issue of Nephrology Dialysis Transplantation, however, have gone some way to correcting this deficit in the evidence base, by reporting the results of the REPAIR-IDA trial. This was a large randomized controlled

A Randomized, Open-Label, Non-Inferiority Study of Intravenous Iron Isomaltoside 1,000 (Monofer) Compared With Oral Iron for Treatment of Anemia in IBD (PROCEED)

OBJECTIVES:In the largest head-to-head comparison between an oral and an intravenous (IV) iron compound in patients with inflammatory bowel disease (IBD) so far, we strived to determine whether IV iron isomaltoside 1,000 is non-inferior to oral iron sulfate in the treatment of iron deficiency anemia (IDA).METHODS:This prospective, randomized, comparative, open-label, non-inferiority study was conducted at 36 sites in Europe and India. Patients with known intolerance to oral iron were excluded. A total of 338 IBD patients in clinical remission or with mild disease, a hemoglobin (Hb) <12 g/dl, and a transferrin saturation (TSAT) <20% were randomized 2:1 to receive either IV iron isomaltoside 1,000 according to the Ganzoni formula (225 patients) or oral iron sulfate 200 mg daily (equivalent to 200 mg elemental iron; 113 patients). An interactive web response system method was used to randomize the eligible patient to the treatment groups. The primary end point was change in Hb from baseline to week 8. Iron isomaltoside 1,000 and iron sulfate was compared by a non-inferiority assessment with a margin of −0.5 g/dl. The secondary end points, which tested for superiority, included change in Hb from baseline to weeks 2 and 4, change in s-ferritin, and TSAT to week 8, number of patients who discontinued study because of lack of response or intolerance of investigational drugs, change in total quality of life (QoL) score to weeks 4 and 8, and safety. Exploratory analyses included a responder analysis (proportion of patients with an increase in Hb ≥2 g/dl after 8 weeks), the effect of regional differences and total iron dose level, and other potential predictors of the treatment response.RESULTS:Non-inferiority in change of Hb to week 8 could not be demonstrated. There was a trend for oral iron sulfate being more effective in increasing Hb than iron isomaltoside 1,000. The estimated treatment effect was −0.37 (95% confidence interval (CI): −0.80, 0.06) with P=0.09 in the full analysis set (N=327) and −0.45 (95% CI: −0.88, −0.03) with P=0.04 in the per protocol analysis set (N=299). In patients treated with IV iron isomaltoside 1,000, the mean change in s-ferritin concentration was higher with an estimated treatment effect of 48.7 (95% CI: 18.6, 78.8) with P=0.002, whereas the mean change in TSAT was lower with an estimated treatment effect of −4.4 (95% CI: −7.4, −1.4) with P=0.005, compared with patients treated with oral iron. No differences in changes of QoL were observed. The safety profile was similar between the groups. The proportion of responders with Hb ≥2 g/dl (IV group: 67% oral group: 61%) were comparable between the groups (P=0.32). Iron isomaltoside 1,000 was more efficacious with higher cumulative doses of >1,000 mg IV. Significant predictors of Hb response to IV iron treatment were baseline Hb and C-reactive protein (CRP).CONCLUSIONS:We could not demonstrate non-inferiority of IV iron isomaltoside 1,000 compared with oral iron in this study. Based on the dose–response relationship observed with the IV iron compound, we suggest that the true iron demand of IV iron was underestimated by the Ganzoni formula in our study. Alternative calculations including Hb and CRP should be explored to gauge iron stores in patients with IBD.

314 Evaluation of Oxidative Stress and Nitrositive Stress in Lung of Rats Treated with Different Intravenous Iron Compounds

314 Evaluation of Oxidative Stress and Nitrositive Stress in Lung of Rats Treated with Different Intravenous Iron Compounds

Effects of administration of iron isomaltoside 1000 in patients with chronic heart failure. A pilot study

SUMMARYIntravenous iron preparations have shown benefit in patients with chronic heart failure (CHF) and iron deficiency. Iron isomaltoside 1000 (Monofer) is a novel intravenous iron compound with low immunological activity of the isomaltoside and low free‐iron‐related toxicity. The primary objective of this open‐label, non‐comparative, multicenter pilot study was to test the safety of iron isomaltoside 1000 in patients with CHF and anemia. In addition, its effect on markers of iron deficiency, anemia and on quality of life was assessed. Twenty patients with CHF and iron deficiency anemia attended six visits during the 8‐week study period. Iron isomaltoside 1000 was infused at baseline (mean dose 868 mg, range 650–1000 mg). No treatment‐related adverse reactions, no acute anaphylactic or delayed allergic reactions and no clinically significant changes in routine clinical laboratory safety tests or vital signs were observed. Markers of iron deficiency, anemia and quality of life improved from baseline with increase in mean value of 49% at 4 weeks in overall quality of life. Iron isomaltoside 1000 administered as a fast single infusion without a test dose to patients with CHF improved quality‐of‐life assessments and was well tolerated in this pilot safety study.

Comparison of the renal, cardiovascular and hepatic toxicity data of original intravenous iron compounds

Intravenous (i.v.) iron is essential for managing haemoglobin levels in haemodialysis patients. However, i.v. iron may cause variable degrees of toxicity. This is mainly related to the pharmacological characteristics of any given i.v. iron compound. This blinded study examines the effects of five i.v. iron preparations on haemodynamic and functional parameters. Sixty Sprague-Dawley rats (n = 10/group) received high or low molecular weight (HMW/LMW) iron dextran, ferric gluconate (FG), ferric carboxymaltose (FCM), iron sucrose (ISC) or isotonic saline solution (control). Five i.v. doses of iron (40 mg iron/kg) or saline were administered over 4 weeks. Systolic blood pressure was significantly reduced in the LMW dextran group, whereas serum iron and percentage transferrin saturation were significantly elevated in all treatment groups. Creatinine clearance was reduced and urinary protein excretion increased in the FG group only (P < 0.01). Liver enzyme levels in the blood were increased (P < 0.01) in the FG and two dextran groups compared with the FCM and ISC groups. Analysis of liver, heart and kidney homogenates showed a significant increase in catalase and malondialdehyde levels in the FG group, and an increase in CuZn-superoxide dismutase and glutathione (GSH) peroxidase activity accompanied with a decrease in the reduced-to-oxidized GSH ratio in the FG and two dextran groups (P < 0.01). Tumour necrosis factor alpha and interleukin-6 levels were significantly elevated in liver, heart and kidney samples from the FG and two dextran groups but not the FCM, ISC or control groups. These findings indicate that FG and HMW/LMW iron dextran have less favourable safety profiles than FCM and ISC in normal rats.

Is There a Difference in the Preclinical Safety Parameters of Different Intravenous Iron Compounds?.

Abstract 5097 BackgroundIntravenous (i.v.) iron has been effectively used to manage anemia in hemodialysis, chemotherapy-induced anemia and cardiac failure patients. However, i.v. iron preparations may cause different degree of oxidative stress and tissue inflammation. In the current study the effects of five i.v. iron preparations on haemodynamic, oxidative stress and inflammatory response were examined. MethodsSixty rats (n=10/group) received high molecular weight (HMW) iron dextran (Dexferrum®, American Regent, Inc., USA), low molecular weight (LMW) iron dextran (INFeD®, Watson Pharmaceuticals, USA/CosmoFer®, Vitaline Pharma, UK), ferric gluconate (Ferrlecit®, Watson Pharmaceuticals, USA), ferric carboxymaltose (Ferinject®, Vifor Pharma, Switzerland), iron sucrose (Venofer®, Vifor Pharma, Switzerland) or isotonic saline solution (control) in a blinded controlled study. Five i.v. doses of iron (40 mg iron/kg) or saline were administered over 4 weeks. ResultsSystolic blood pressure was significantly reduced in the LMW dextran group, whereas serum iron and percentage transferrin saturation were significantly elevated in all treatment groups. Creatinine clearance was reduced and proteinuria increased in the ferric gluconate group only (p<0.01) (day 1 to 29). Liver enzyme levels in the blood were significantly increased in the ferric gluconate and two dextran groups on days 1, 8 and 29 compared with the ferric carboxymaltose and iron sucrose groups. Analysis of liver, heart and kidney homogenates on day 29 showed a significant increase in catalase and malondialdehyde levels in the ferric gluconate group, and an increase in CuZn-superoxide dismutase and glutathione peroxidase activity accompanied with a decrease in the reduced-to-oxidized glutathione ratio in the ferric gluconate and two dextran groups (p<0.01). TNF-α and IL6 levels were significantly elevated in liver, heart and kidney samples from the ferric gluconate and two dextran groups but not the ferric carboxymaltose, iron sucrose or control groups on day 29. DiscussionIn this study, there was a difference in the hemodynamic and functional response to the different i.v. iron preparations. These findings indicate that HMW/LMW iron dextran and ferric gluconate have less favourable safety profiles in rats than ferric carboxymaltose and iron sucrose. DisclosuresToblli:Vifor Pharma: Research Funding.