Iron Deficiency, Anemia, and Iron Supplementation in Patients With Heart Failure: A Population-Level Study.

BACKGROUND: Studies have shown an association between iron deficiency (ID) and clinical outcomes in patients with heart failure (HF), irrespective of the presence of ID anemia (IDA). The current study used population-level data from a large, single-payer health care system in Canada to investigate the epidemiology of ID and IDA in patients with acute HF and those with chronic HF, and the iron supplementation practices in these settings. METHODS: All adult patients with HF in Alberta between 2012 and 2019 were identified and categorized as acute or chronic HF. HF subtypes were determined through echocardiography data, and ID (serum ferritin concentration <100 µg/L, or ferritin concentration between 100 and 300 µg/L along with transferrin saturation <20%), and IDA through laboratory data. Broad eligibility for 3 clinical trials (AFFIRM-AHF [Study to Compare Ferric Carboxymaltose With Placebo in Patients With Acute HF and ID], IRONMAN [Intravenous Iron Treatment in Patients With Heart Failure and Iron Deficiency], and HEART-FID [Randomized Placebocontrolled Trial of Ferric Carboxymaltose as Treatment for HF With ID]) was determined. RESULTS: Among the 17 463 patients with acute HF, 38.5% had iron studies tested within 30 days post-index-HF episode (and 34.2% of the 11 320 patients with chronic HF). Among tested patients, 72.6% of the acute HF and 73.9% of the chronic HF were iron-deficient, and 51.4% and 49.0% had IDA, respectively. Iron therapy was provided to 41.8% and 40.5% of patients with IDA and acute or chronic HF, respectively. Of ID patients without anemia, 19.9% and 21.7% were prescribed iron therapy. The most common type of iron therapy was oral (28.1% of patients). Approximately half of the cohort was eligible for each of the AFFIRM-AHF, intravenous iron treatment in patients with HF and ID, and HEART-FID trials. CONCLUSIONS: Current practices for investigating and treating ID in patients with HF do not align with existing guideline recommendations. Considering the gap in care, innovative strategies to optimize iron therapy in patients with HF are required.

Hierarchical End Points in Prior Heart Failure Trials and the HEART-FID Trial.

BACKGROUND: Clinical trials in heart failure (HF) traditionally use time-to-event analyses focusing on death and hospitalization for HF. These time-to-first event analyses may have more limited abilities to assess the probability of benefiting from a therapy, especially if that benefit manifests as improved functional status rather than reduced risk of death or HF hospitalization. Hierarchical end points including clinical outcomes and patient status measures allow for ranked evaluation of outcomes in 1 metric assessing whether patients randomized to intervention or control are more likely to derive an overall benefit while also allowing more patients to contribute to the primary outcome. METHODS: We review the rationale for using hierarchical end points in HF trials, provide examples of HF trials that used this type of end point, and discuss its use in the HEART-FID trial (Randomized Placebo-Controlled Trial of Ferric Carboxymaltose as Treatment for Heart Failure With Iron Deficiency), the largest HF trial to date implementing a hierarchical end point analysis for the primary outcome. RESULTS: Using a hierarchical end point as the primary outcome allows for the inclusion of different types of outcomes in 1 ranked end point, making it possible to more holistically assess the potential utility of a new therapy on patient well-being and outcomes. CONCLUSIONS: Hierarchical end points assess the potential utility of a new therapy on patient well-being and outcome more holistically than time-to-first event analysis. Trials that would not have been feasible due to decreasing rates of death and hospitalization in the HF population can use hierarchical end points to successfully power studies to identify promising HF therapies. The HEART-FID trial used hierarchical end points to better determine the role of intravenous ferric carboxymaltose in patients with HF. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03037931.

Protocol and statistical analysis plan for a randomized controlled trial of the effect of intravenous iron on anemia in Malawian pregnant women in their third trimester (REVAMP - TT).

Background: Anemia affects 40% of pregnant women globally, leading to maternal mortality, premature birth, low birth weight, and poor baby development. Iron deficiency causes over 40% of anemia cases in Africa. Oral iron supplementation is insufficient for Low-and-Middle-Income-Countries (LMICs) to meet current WHO targets. We hypothesized that a single intravenous dose of Ferric Carboxymaltose (FCM) may be more effective than oral iron treatment for anemia recovery, particularly in these settings where women present late for antenatal care. Methods: This is a two-arm parallel open-label individual-randomized controlled trial in third trimester, in malaria Rapid Diagnostic Test-negative pregnant women with moderate or severe anemia - capillary hemoglobin <10 g/dL - who are randomized to receive either parenteral iron - with FCM - or standard-of-care oral iron for the remainder of pregnancy. This is the sister trial to the second-trimester REVAMP trial, funded by the Bill and Melinda Gates Foundation (trial registration ACTRN12618001268235, Gates Grant number INV-010612). In REVAMP-TT, recruitment and treatment are performed within primary health centers. The trial will recruit 590 women across Zomba district, Malawi. The primary outcome is the proportion of anemic women - venous hemoglobin <11 g/dL - at 36 weeks' gestation or delivery (whichever occurs first). Other pre-specified key secondary clinical and safety outcomes include maternal iron-status and hypophosphatemia, neonate birth weight, infant growth and infant iron and hematological parameters. Discussion: This study will determine whether FCM, delivered within primary health centers, is effective, safe and feasible for treating moderate to severe anemia in third-trimester pregnant Malawian women. This intervention could have long-term benefits for maternal and child health, resulting in improved survival and child development.

High-Dose Intravenous Iron with Either Ferric Carboxymaltose or Ferric Derisomaltose: A Benefit-Risk Assessment.

The intravenous iron formulations ferric carboxymaltose (FCM) and ferric derisomaltose (FDI) offer the possibility of administering a large amount of iron in one infusion. This results in faster correction of anemia and the formulations being better tolerated than oral iron formulations. This triad of logistic advantages, improved patient convenience, and fast correction of anemia explains the fact that intravenous iron formulations nowadays are frequently prescribed worldwide in the treatment of iron deficiency anemia. However, these formulations may result in hypophosphatemia by inducing a strong increase in active fibroblast growth factor-23 (FGF-23), a hormone that stimulates renal phosphate excretion. This effect is much more pronounced with FCM than with FDI, and therefore the risk of developing hypophosphatemia is remarkably higher with FCM than with FDI. Repeated use of FCM may result in severe osteomalacia, which is characterized by bone pain, Looser zones (pseudofractures), and low-trauma fractures. Intravenous iron preparations are also associated with other adverse effects, of which hypersensitivity reactions are the most important and are usually the result of a non-allergic complement activation on nanoparticles of free labile iron-Complement Activation-Related Pseudo-Allergy (CARPA). The risk on these hypersensitivity reactions can be reduced by choosing a slow infusion rate. Severe hypersensitivity reactions were reported in < 1% of prospective trials and the incidence seems comparable between the two formulations. A practical guideline has been developed based on baseline serum phosphate concentrations and predisposing risk factors, derived from published cases and risk factor analyses from trials, in order to establish the safe use of these formulations.

[A case of chronic enteropathy associated with SLCO2A1 gene diagnosed by capsule endoscopy and successfully treated by ferric carboxymaltose].

Chronic non-specific multiple ulcers of the small intestine is a disease condition postulated in Japan. It is an uncommon gastrointestinal disease that causes chronic anemia and hypoalbuminemia by causing numerous ulcers without any histopathologically identifiable features. In recent years, it has been revealed that the mutations of SLCO2A1, which codes the prostaglandin transporter protein, are the cause of this disease;it is called the new name "chronic enteropathy associated with SLCO2A1 gene." The ileum, except the terminal ileum, is the most common place making it difficult to identify major lesions. Other than conservative treatments, such as nutrition therapy and iron supplements, no effective treatment has been identified so far. We present a case of chronic non-specific multiple ulcers of the small intestine diagnosed by capsule endoscopy and effectively treated by ferric carboxymaltose. A 48-year-old female had chronic iron deficiency anemia since around the age of 15. Because of severe anemia, the patient had upper and lower endoscopy at the age of 47 to find the source of the bleeding, but it was not detected. Except for the terminal ileum, the capsule endoscopy revealed ring-like ulcers, tape-like ulcers, and oblique ulcer scars in the ileum. Genetic analysis showed a homozygous mutation in intron 7, c.940+1G>A, indicating a definitive diagnosis of non-specific multiple ulcers of the small intestine. Anemia and anemia-related symptoms such as general malaise persisted despite continuous oral administration of iron drugs. Three intravenous injections of ferric carboxymaltose increased hemoglobin and enhanced the symptoms.

Analysis of transition from intravenous iron sucrose to ferric carboxymaltose infusions in pediatric patients with intestinal failure.

BACKGROUND: Iron supplementation is required for pediatric patients with intestinal failure (IF). There is a paucity of literature on optimal iron formulation and outcomes in this patient population that requires ongoing supplementation. The aim of this study was to assess outcomes in pediatric patients with IF receiving iron sucrose (IS) vs ferric carboxymaltose (FCM) iron infusions. METHODS: This was a single-center observational cohort study of pediatric patients with IF requiring ongoing intravenous iron supplementation. Patients were transitioned from IS to FCM as iron therapy. Longitudinal linear mixed-effects models and generalized estimating equations were used to compare outcomes, including hematologic, iron, and growth parameters for 12-month treatment duration on each iron formulation. Adverse effects were descriptively summarized. RESULTS: Twenty-three patients were included. Sixteen received IS and later switched to FCM, five received IS only, and two received FCM only. Most patients' etiology of IF was short bowel syndrome (FCM: 81%, IS: 83%). No differences were seen over time for iron, hematologic, and growth metrics between IS and FCM. The median number of infusions over 12 months for those taking IS was 15 (interquartile range [IQR] = 13-26) and 2 for FCM (IQR = 1-2). Asymptomatic hypophosphatemia was noted in both groups. Similar central line-associated bloodstream infection rates were noted. CONCLUSION: IS and FCM infusions both maintained hematologic and iron parameters with no significant difference noted between the two types of iron, though the number of FCM infusions was significantly less. No significant adverse effects were noted.

Does Postoperative Intravenous Ferric Carboxymaltose Hasten the Recovery of Hemoglobin in Patients Post Total Knee Arthroplasty?

BACKGROUND: Timely and effective iron supplementation may help reduce the incidence of postoperative anemia and its associated problems. In this study, we aim to assess the efficacy of intravenous ferric carboxy maltose (FCM) on improving hemoglobin(Hb) level posttotal knee arthroplasty (TKA). METHODS: We retrospectively reviewed 263 patients who had undergone unilateral TKA with 157 patients in the study group (year 2019) and 106 in the control group (year 2016). Patients in the study group received FCM (500 mg IV) on postoperative day 1, whereas patients in the control group did not receive FCM or any other iron supplementation postoperatively. Hb levels were recorded preoperatively (Pr-Hb), postoperatively on day 3 (Day3-Hb) and postoperatively at 5(+1) weeks (Week5-Hb). Statistical analysis was performed using student's paired and unpaired t-tests. RESULTS: Pr-Hb and Day3-Hb levels were comparable in the control and study group, while Week5-Hb levels were significantly higher (P < .001) in the study group. The drop in Hb at Day3 from preoperative values was comparable between the two groups (P = 1.0). The rise in Hb from Day3 to 5 weeks was significantly higher in the study group as compared to the control group (P < .001). The difference between Pr-Hb and Week5-Hb was significantly lower (P < .001) in the study group compared to the control group. However, Week5-Hb in both groups remained lower than Pr-Hb (P < .001) in all patients. CONCLUSION: Intravenous FCM (500 mg) was found to be a safe method of iron supplementation to improve hemoglobin levels rapidly and consistently, post-TKA. We need to further study the additive effect of higher dose FCM (1000 mg) on hemoglobin recovery.

Clinical efficacy and safety of intravenous ferric carboxymaltose treatment of pediatric restless legs syndrome and periodic limb movement disorder.

BACKGROUND: Iron supplementation is the most commonly considered treatment option for children with restless legs syndrome (RLS) or periodic limb movement disorder (PLMD); however, there is a scarcity of evidence on the effectiveness of intravenous preparations. In this study, we evaluated the effectiveness and tolerability of intravenous ferric carboxymaltose (IV FCM) on clinical symptoms and iron indices in children with RLS or PLMD. METHODS: This was a single-center retrospective data analysis. Children with a diagnosis of RLS or PLMD, who underwent a single infusion of IV FCM, were included. Clinical Global Impression (CGI) Scale scores, serum ferritin, and serum iron profile at baseline and after eight weeks post infusion were obtained. Adverse effects were assessed. RESULTS: Thirty-nine children received IV FCM, 29 with RLS and 10 with PLMD. Pre-infusion CGI-Severity revealed moderate illness, with post-infusion CGI-Improvement between "very much improved" and "much improved". Ferritin increased from 14.6 µg/L±7.01 to 112.4 µg/L±65.86 (p < 0.00001), together with improvements in iron, total iron binding capacity, and transferrin levels from baseline to post-treatment. When compared to children with RLS, those with PLMD had a similar improvement in clinical symptoms and laboratory parameters. Seven subjects (14.3%) experienced one or two adverse events; all were mild. CONCLUSIONS: Children with RLS and PLMD responded to IV iron supplementation with improvement in both clinical severity and laboratory parameters. Treatment was well tolerated. Although larger, randomized-controlled trials are needed, IV FCM appears to be a promising alternative to oral iron supplementation for the treatment of pediatric RLS or PLMD.

Comparison of Iron Dosing Strategies in Patients Undergoing Long-Term Hemodialysis: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Whether iron supplementation in patients on hemodialysis could be delivered by less frequent but higher single doses compared with the currently more common higher-frequency schedules of lower single iron doses is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We carried out an open-label, randomized, controlled noninferiority trial over 40 weeks in patients on prevalent hemodialysis (n=142). We administered in total 2 g iron as 100 mg iron sucrose biweekly in a continuous (20 × 100 mg) fashion or 500 mg ferric carboxymaltose every 10 weeks in a periodic (4 × 500 mg) fashion. The primary end point was the change in hemoglobin at week 40 from baseline with a noninferiority margin of -0.8 g/dl. Secondary end points were changes in ferritin, transferrin, transferrin saturation, and erythropoiesis-stimulating agent use. RESULTS: In total, 108 patients completed the study. At 40 weeks, hemoglobin changed by -0.27 g/dl (95% confidence interval, -0.64 to 0.09) in the iron sucrose arm and by -0.74 g/dl (95% confidence interval, -1.1 to -0.39) in the ferric carboxymaltose arm compared with baseline. Noninferiority was not established in the per-protocol population as hemoglobin changes compared with baseline differed by -0.47 g/dl (95% confidence interval, -0.95 to 0.01) in the ferric carboxymaltose arm compared with the iron sucrose arm. Proportional changes from baseline to week 40 differed by -31% (98.3% confidence interval, -52 to -0.1) for ferritin, by 1% (98.3% confidence interval, -7 to 10) for transferrin, and by -27% (98.3% confidence interval, -39 to -13) for transferrin saturation in the ferric carboxymaltose arm compared with the iron sucrose arm. Erythropoiesis-stimulating agent dosing did not differ between groups. The overall number of adverse events was similar; however, more infections were observed in the iron sucrose arm. CONCLUSIONS: An equal cumulative dose of ferric carboxymaltose administered less frequently did not meet noninferiority for maintaining hemoglobin levels compared with iron sucrose administered more frequently. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Comparison Study of Two Iron Compounds for Treatment of Anemia in Hemodialysis Patients (COPEFER), NCT02198495.

Rational formulation engineering of fraxinellone utilizing 6-O-α-D-maltosyl-ß-cyclodextrin for enhanced oral bioavailability and hepatic fibrosis therapy.

Although Fraxinellone (Frax) isolated from Dictamnus albus L. possessed excellent anti-hepatic fibrosis activity, oral administration of Frax suffered from the inefficient therapeutic outcome in vivo due to negligible oral absorption. At present, the oral formulation of Frax is rarely exploited. For rational formulation design, we evaluated preabsorption risks of Frax and found that Frax was rather stable while poorly dissolved in the gastrointestinal tract (78.88 µg/mL), which predominantly limited its oral absorption. Further solubility test revealed the outstanding capacity of cyclodextrin derivatives (CDs) to solubilize Frax (6.8-12.8 mg/mL). This led us to study the inclusion complexes of Frax with a series of CDs and holistically explore their drug delivery performance. Characterization techniques involving 1H-NMR, FT-IR, DSC, PXRD, and molecular docking confirmed the most stable binding interactions when Frax complexed with 6-O-α-D-maltosyl-ß-cyclodextrin (G2-ß-CD-Frax). Notably, G2-ß-CD-Frax exhibited the highest solubilizing capacity, fast dissolution rate, and superior Caco-2 cell internalization with no obvious toxicity. Pharmacokinetic studies demonstrated markedly higher oral bioavailability of G2-ß-CD-Frax (5.8-fold that of free drug) than other Frax-CDs. Further, long-term administration of G2-ß-CD-Frax (5 mg/kg) efficiently inhibited CCl4-induced hepatic fibrosis in the mouse without inducing any toxicity. Our results will inspire the continued advancement of optimal oral Frax formulations for anti-fibrotic therapy.

Ferric carboxymaltose in patients with pulmonary arterial hypertension and iron deficiency: a long-term study.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive disease with limited survival. Iron deficiency (ID) correlates with disease severity and mortality. While oral iron supplementation was shown to be insufficient in such patients, the potential impact of parenteral iron on clinical measures warrants further investigation. METHODS: We retrospectively analysed the long-term effects of intravenous ferric carboxymaltose (FCM) on iron status and clinical measures in patients with PAH and ID [ferritin < 100 µg/L or ferritin 100-300 µg/L and transferrin saturation (TSAT) < 20%] who were on stable targeted PAH therapy, compared with matched controls without ID. Patients with ID received a single infusion of FCM (500 to 1000 mg). Clinical measures monitored included exercise capacity, World Health Organization (WHO) functional class, ESC/ERS risk status, and hospitalizations. The observation period was up to 18 months. RESULTS: One hundred and seventeen patients (mean age 60.9 ± 16.1 years; 64.1% females) with confirmed PAH and on stable targeted therapy for ≥3 months were included (58 with and 59 patients without ID who did not receive FCM). In patients with ID, iron supplementation with FCM resulted in an immediate and sustained improvement of iron status for up to 18 months (serum iron, ferritin, TSAT, all P < 0.01). Fourteen patients in the FCM group received a second FCM infusion after 9.6 ± 4.8 months due to recurrent ID. At 6 and 18 months after FCM infusion, 6 min walk distance improved from 377.5 ± 15.9 at baseline to 412.5 ± 15.1 and 400.8 ± 14.5 m, respectively (both P < 0.05). WHO functional class (P < 0.05) and ESC/ERS risk status also improved, and there was a reduction of hospitalizations for worsening PAH in the 12 months post vs. prior to iron repletion (P = 0.029). No significant changes were observed in the control group. FCM was well tolerated in all patients, with no severe adverse events. CONCLUSIONS: In addition to targeted therapy, correction of ID by parenteral iron supplementation with FCM appears feasible and safe, has sustained effects on iron status, and may improve the clinical status and hospitalization rates in patients with PAH. Larger controlled studies are required to confirm this finding.

Rationale and design of the IRON-AF study: a double-blind, randomised, placebo-controlled study to assess the effect of intravenous ferric carboxymaltose in patients with atrial fibrillation and iron deficiency.

INTRODUCTION: Atrial fibrillation (AF) is associated with significantly impaired quality-of-life. Iron deficiency (ID) is prevalent in patients with AF. Correction of ID in other patient populations with intravenous iron supplementation has been shown to be a safe, convenient and effective way of improving exercise tolerance, fatigue and quality-of-life. The IRON-AF (Effect of Iron Repletion in Atrial Fibrillation) study is designed to assess the effect of iron repletion with intravenous ferric carboxymaltose in patients with AF and ID. METHODS AND ANALYSIS: The IRON-AF study is a double-blind, randomised controlled trial that will recruit at least 84 patients with AF and ID. Patients will be randomised to receive infusions of either ferric carboxymaltose or placebo, given in repletion and then maintenance doses. The study will have follow-up visits at weeks 4, 8 and 12. The primary endpoint is change in peak oxygen uptake from baseline to week 12, as measured by cardiopulmonary exercise testing (CPET) on a cycle ergometer. Secondary endpoints include changes in quality-of-life and AF disease burden scores, blood parameters, other CPET parameters, transthoracic echocardiogram parameters, 6-minute walk test distance, 7-day Holter/Event monitor burden of AF, health resource utilisation and mortality. ETHICS AND DISSEMINATION: The study protocol has been approved by the Central Adelaide Local Health Network Human Research Ethics Committee, Australia. The results of this study will be disseminated through publications in peer-reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12620000285954).

Attitude changes in prescribing intravenous iron supplementation in different settings at a hospital consortium in Italy.

BACKGROUND: Iron deficiency anaemia is a public health problem. In case oral iron treatment is ineffective, poorly tolerated or contraindicated, the intravenous route becomes the first choice. The aim of the study was to evaluate the shift between ferrous gluconate (FG) and ferric carboxymaltose (FCM) usage at our hospitals over the years. We also performed a cost comparison between pre and post-FCM availability periods, taking into account the acquisition costs of both intravenous iron and red blood cell units (PRBC). STUDY DESIGN AND METHODS: The amount and costs of FG and FCM released by hospital Pharmacy Services from 2010 to 2019 were analysed, along with the number of transfused PRBC units in the same timeframe. RESULTS: Overall, the proportion of FCM usage rose from 8.6 % in 2014 to 71.9 % in 2019, as percentage of total intravenous iron released. After exclusion of haemodialysis, where FG is still widely used, the FCM use in the last four years raised from 12.9% to 92.5%. Despite the higher FCM cost, the mean yearly expenditure for intravenous iron plus PRBC units did not differ between pre- and post-FCM eras (2010-2013, € 2,396,876 € versus 2014-2019, € 2,307,875 - p = 0.234), as a result of a net decrease of PRBC usage, namely from 15,083 to 12,654 (-16.1 %), respectively. DISCUSSION: Intravenous iron has a major role in treating iron deficiency anaemia in several settings. Third generation compounds are paving the way to more updated and safer treatments.

Ferric carboxymaltose vs. ferrous sulfate for the treatment of anemia in advanced chronic kidney disease: an observational retrospective study and cost analysis.

In non-dialysis-dependent chronic kidney disease (NDD-CKD), erythropoiesis-stimulating agents (ESAs) and iron supplementation are essential for anemia management. Ferric carboxymaltose (FCM) is a relatively novel intravenous iron formulation used in different clinical settings, although scarce data exist in NDD-CKD patients. Primary objective of this study was to retrospectively evaluate the efficacy of FCM compared with oral ferrous sulfate for the treatment of iron-deficiency anemia in a cohort of NDD-CKD patients, considering also the treatment costs. This was a monocentric, retrospective observational study reviewing 349 NDD-CKD patients attending an outpatient clinic between June 2013 and December 2016. Patients were treated by either FCM intravenous infusion or oral ferrous sulfate. We collected serum values of hemoglobin, ferritin and transferrin saturation (TSAT) and ESAs doses at 12 and 18 months. The costs related to both treatments were also analysed. 239 patients were treated with FCM intravenous infusion and 110 patients with oral ferrous sulfate. The two groups were not statistically different for age, BMI and eGFR values. At 18 months, hemoglobin, serum ferritin and TSAT values increased significantly from baseline in the FCM group, compared with the ferrous sulfate group. ESAs dose and rate of infusion decreased only in the FCM group. At 18 months, the treatment costs, analysed per week, was higher in the ferrous sulfate group, compared with the FCM group, and this was mostly due to a reduction in ESAs prescription in the FCM group. Routine intravenous FCM treatment in an outpatient clinic of NDD-CKD patients results in better correction of iron-deficiency anemia when compared to ferrous sulfate. In addition to this, treating NDD-CKD patients with FCM leads to a significant reduction of the treatment costs by reducing ESAs use.

Indirect comparison between ferric carboxymaltose and oral iron replacement in heart failure with reduced ejection fraction: a network meta-analysis.

Treatment of iron deficiency (ID) in patients with heart failure (HF) has improved symptoms, quality of life, exercise capacity and has reduced hospitalizations in randomized controlled trials (RCTs) and meta-analyses. Intravenous ferric carboxymaltose (FCM) provided convincing results in this field, while oral iron supplementation failed. However, FCM and oral iron were compared to placebo, and a comparison between the two strategies is still lacking. We aimed to fill this gap of knowledge with an indirect comparison between them by means of a network meta-analysis of RCTs. Five studies measuring exercise capacity (i.e. 6-minute walking test) and quality of life (i.e. Kansas City Cardiomyopathy Questionnaire) were eligible to be included in our review. Given the limitations of a network meta-analysis, our findings support the better efficacy of FCM than oral iron as regards exercise capacity, with a trend towards an improvement in quality of life, suggesting that FCM seems to be strategy of choice to correct ID in HF patients.

Intravenous iron supplementation after liver surgery: Impact on anemia, iron, and hepcidin levels-a randomized controlled trial.

BACKGROUND: Anemia is a recognized risk factor for perioperative related morbidity and mortality and is frequently reported in liver surgeries with an estimated incidence of 32%. We aim to assess the impact of intravenous iron administration in the immediate postoperative period on anemia and iron status as well as to determine the kinetics of hepcidin after liver surgery. METHODS: The HepciFer trial, a randomized controlled trial, included 50 patients undergoing liver surgery. In accordance with the randomization process, patients received either ferric carboxymaltose (15 mg/kg, maximum 1 g) or placebo 4 hours after surgery. RESULTS: The mean hemoglobin level, 7 days after surgery, did not differ significantly between the intervention and control group (11.1 ± 1.8 g/dL and 10.4 ± 1.6 g/dL, respectively) with a mean difference of +0.7 g/dL ([95% confidence interval, -0.3 to +1.7], P = .173). Within patients receiving intravenous iron supplementation, none presented biological signs of functional iron deficiency. Hepcidin levels remained significantly higher during the observation period in the intervention group. Inflammatory biomarkers, red blood cells transfusion rate and hospital duration of stay were similar between groups. CONCLUSION: Intravenous ferric carboxymaltose administration did not result in a significant increase of hemoglobin levels 7 days after surgery. However, this study suggests that intravenous iron supplementation in the immediate postoperative settings prevents functional iron deficiency. Intravenous iron supplementation overcame the hepcidin-mediated blockade of iron absorption and should be considered as the preferred route of administration in the postoperative period.

Refractory hypophosphatemia following ferric carboxymaltose administration.

Hypophosphatemia is a rare side effect of intravenous iron replacement. Urinary phosphate wasting due to increased FGF23 is the most likely mechanism. Here, we present a case of intractable hypophosphatemia in a 32-year-old female patient with history of ulcerative colitis (UC), who was primarily hospitalized due to UC flare-up. Her urinary fractional excretion of phosphate was inappropriately elevated at 70%. A careful history revealed that she had been treated with ferric carboxymaltose 2 weeks prior to hospitalization, leading to a diagnosis of iron-induced hypophosphatemia. She was treated with 5 weeks of intravenous sodium phosphate since she did not tolerate oral supplementation. In conclusion, clinicians should be aware of iron-induced hypophosphatemia and be cautious when prescribing intravenous iron.

Oral Sucrosomial Iron Is as Effective as Intravenous Ferric Carboxy-Maltose in Treating Anemia in Patients with Ulcerative Colitis.

Anemia is a frequent complication of ulcerative colitis, and is frequently caused by iron deficiency. Oral iron supplementation displays high rates of gastrointestinal adverse effects. However, the formulation of sucrosomial iron (SI) has shown higher tolerability. We performed a prospective study to compare the effectiveness and tolerability of oral SI and intravenous ferric carboxy-maltose (FCM) in patients with ulcerative colitis in remission and mild-to-moderate anemia. Patients were randomized 1:1 to receive 60 mg/day for 8 weeks and then 30 mg/day for 4 weeks of oral SI or intravenous 1000 mg of FCM at baseline. Hemoglobin and serum levels of iron and ferritin were assessed after 4, 8, and 12 weeks from baseline. Hemoglobin and serum iron increased in both groups after 4 weeks of therapy, and remained stable during follow up, without significant treatment or treatment-by-time interactions (p = 0.25 and p = 0.46 for hemoglobin, respectively; p = 0.25 and p = 0.26 for iron, respectively). Serum ferritin did not increase over time during SI supplementation, while it increased in patients treated with FCM (treatment effect, p = 0.0004; treatment-by-time interaction effect, p = 0.0002). Overall, this study showed that SI and FCM displayed similar effectiveness and tolerability for treatment of mild-to-moderate anemia in patients with ulcerative colitis under remission.

Parenteral iron therapy and phosphorus homeostasis: A review.

Phosphorus has an essential role in cellular and extracellular metabolism; maintenance of normal phosphorus homeostasis is critical. Phosphorus homeostasis can be affected by diet and certain medications; some intravenous iron formulations can induce renal phosphate excretion and hypophosphatemia, likely through increasing serum concentrations of intact fibroblast growth factor 23. Case studies provide insights into two types of hypophosphatemia: acute symptomatic and chronic hypophosphatemia, while considering the role of pre-existing conditions and comorbidities, medications, and intravenous iron. This review examines phosphorus homeostasis and hypophosphatemia, with emphasis on effects of iron deficiency and iron replacement using intravenous iron formulations.