Intravenous Iron Dose Research Articles

#2742 Artificial intelligence accurately approximates MGPE dose response relationship in a North American Dialysis Population

Abstract Background and Aims The Anemia Control Model (ACM) is a certified medical device aimed at optimizing the management of CKD-related anemia among patients on dialysis. ACM is based on an artificial neural network (ANN) trained on over 900’000 patients treated in the European Nephrocare Network. Over the years, ACM has offered physicians hundreds of thousands of erythropoietin stimulating agent (ESA) and intravenous iron dosing suggestions and ensured high hemoglobin target achievement rate while minimizing drug use. However, evidence concerning its validity in non-European samples is still limited. Apollo Dial DB is the largest, fully anonymized, collaborative, international database of dialysis patients. The database includes detailed clinical information of more than 500,000 patients over millions of patient-months of observation with an extensive representation over geographies as well as ethnic groups. Given its detailed medical information and size, the database may offer unprecedented opportunities to develop and test equitable and fair decision support systems based on artificial intelligence. In this study we sought to re-train and validate and assess the accuracy of the ACM in an ethnically diverse sample of North American dialysis patients in Apollo Dial DB. Method We constructed the cohort for training and validation of this new ACM version by including a random sample of patients treated in the North American Fresenius Medical Care Dialysis Network. The sample accounted for 20% of the entire North American Section of the Apollo Dial DB dataset. Each patient history has been segmented in a collection of patient-months, which was the unit of analysis. The initial cohort was split in 3 datasets for training (70%), validation (20%) and test (10%). The input variables included laboratory test results, body weight, treatment data, age, sex, and previous ESA and iron prescription. The outcome of interest was the variation in serum hemoglobin concentration over 1 month of follow up. We compared the accuracy of the original ACM based on ANN (baseline model) with a newly trained algorithm based on high-performance light GBM. Results We included 44,220 patients followed by 2,277,276 patient-months overall. The mean age=60.9 ± 13.4, 59.2% were male, 56.4% were Caucasians, 32.2% African American, 3.2% Asians and 8.2% were others. At baseline, mean Hb= 10.9 ± 1.2. The original EMEA version of the Anemia Control Model (ACM) was still accurate in North American patients (mean absolute error, MAE = 0.65 g/dL). The fine-tuned light GBM model achieved a 16% reduction in error rate (MAE = 0.55 g/dL; Fig. 1). No difference in MAE was observed across sex and ethnic groups. Conclusion This study demonstrates the excellent predictive performance of the original ANN-based ACM in the North American dialysis population. Fine tuning by re-training ACM on the dataset further improved the accuracy of the model with substantial equivalence in performance across different demographics, thus ensuring algorithmic fairness. ACM is a promising tool for anemia management in ethnically diverse dialysis population and different healthcare settings.

RAPIDIRON Trial follow-up study — the RAPIDIRON-KIDS Study: protocol of a prospective observational follow-up study

BackgroundAnemia is a worldwide problem with iron deficiency being the most common cause. When anemia occurs in pregnancy, it increases the risk of adverse maternal, fetal, and postnatal outcomes. It induces preterm births and low birth weight (LBW) deliveries, long-term neurodevelopmental sequelae, and an increased risk of earlier onset of postnatal iron deficiency. Anemia rates are among the highest in South Asia, and India’s National Family Health Survey (NFHS-5) for 2019–2021 indicated that over half of pregnant women, and more than 65% of children, in the country are classified as anemic (Sciences IIfP, National Family Health Survey-5, 2019–21, India Fact Sheet). In 2021, the parent RAPIDIRON Trial (Derman et al., Trials 22:649, 2021) was initiated in two states in India, with the goal of assessing whether a dose of intravenous (IV) iron given to anemic women during early pregnancy results in a greater proportion of participants with normal hemoglobin concentrations in the third trimester and a lower proportion of participants with LBW deliveries compared to oral iron. As a follow-up to the RAPIDIRON Trial, the RAPIDIRON-KIDS Study will follow the offspring of previously randomized mothers to assess, neurobehavioral, hematological, and health outcomes.MethodsThis prospective observational cohort study will follow a subset of participants previously randomized as part of the RAPIDIRON Trial and their newborns. Study visits occur at birth, 6 weeks, 4 months, 12 months, 24 months, and 36 months and include blood sample collection with both maternal and infant participants and specific neurobehavioral assessments conducted with the infants (depending on the study visit). The primary outcomes of interest are (1) infant iron status as indicated by both hemoglobin and ferritin (a) at birth and (b) at 4 months of age and (2) the developmental quotient (DQ) for the cognitive domain of the Bayley Scales of Infant Development Version IV (BSID-IV) at 24 months of age.DiscussionThis RAPIDIRON-KIDS Study builds upon its parent RAPIDIRON Trial by following a subset of the previously randomized participants and their offspring through the first 3 years of life to assess neurodevelopmental and neurobehavioral (infants, children), hematological, and health outcomes.Trial registrationClinicalTrials.gov NCT05504863, Registered on 17 August 2022. Clinical Trials Registry – India CTRI/2022/05/042933. Registered on 31 May 2022.

Testing Equivalence of Two Doses of Intravenous Iron to Treat Iron Deficiency in Pregnancy: A Randomized Controlled Trial

(BJOG. 2023;130:15–23) The most common nutritional disorder worldwide is iron deficiency (ID). Iron is vital for many bodily functions, so when women who are pregnant suffer from ID they are more likely to experience complications during pregnancy as well as deliver babies at risk for neonatal complications. It is estimated that about 47% of women suffer from ID during pregnancy even though it is a treatable disorder. Intravenous iron (IVI) has been proven to help pregnant women who are nonresponsive to oral iron intake. This study compared the effects of 2 different doses of IVI in pregnant women.

82 Management of Very Severe Iron Deficiency Anemia: Is Transfusion Always Necessary?

Abstract Background Paediatric iron deficiency anemia (IDA) is a common condition in Canadian children; however, little is known about the natural history of extreme cases. This deficit makes it challenging to determine how to approach management when these patients present acutely to the emergency department (ED). Objectives To describe the clinical features and management of children presenting to the ED with very severe IDA with hemoglobin < 40 g/L. Design/Methods Retrospective chart reviews were performed for paediatric patients with IDA and hemoglobin < 40 g/L over a 5-year period (June 2017 – June 2022) at a Canadian tertiary care children’s hospital. Results Chart reviews were completed for 19 patients. The mean case rate was 3.1 patients annually (SD 2.14) with 11(58%) presenting in 2021–2022. Patients were young (median age 24 months; IQR 18–32) and predominantly female (79%). Nutritional deficiencies were the most common etiology (n=16, 84%). Median presenting hemoglobin was 25 g/L (IQR 22–36 g/L). The most common clinical features documented at presentation were pallor (n=19, 100%), tachycardia (n=17, 89%), and systolic ejection murmur (n=14, 74%). Thirteen (68%) patients had a ferritin measured in ED, 11(58%) had a chest x-ray, four (21%) had a lactate measured. One (5%) patient had an echocardiogram, and four (21%) had bedside cardiac ultrasounds documented. Eight (42%) patients with median hemoglobin 35 g/L (IQR 25–36 g/L) were managed without blood transfusion (PO iron only: n=3, 16%; IV iron only: n=5, 26%). Of the 11 (63%) patients who received blood, 2 (18%) had transfusion-related adverse events, with one patient undergoing intubation for transfusion-associated circulatory overload while admitted. All patients (100%) were initiated on oral iron supplementation. Ten patients (53%) received intravenous (IV) iron (dose 5–7 mg/kg) with one experiencing a mild reaction. Fifteen patients (79%) were hospitalized, with two (10%) admitted directly to the Paediatric Intensive Care Unit. Median duration of hospitalization was 5 days (IQR 2–9 days). Patients followed after transfusion-free management (n=5) demonstrated median hemoglobin increase of 21 g/L (IQR 20–32 g/L) within 12 days. No patient returned to the ED for anemia within 30 days. Conclusion Paediatric patients with very severe IDA do not always require transfusion. Some patients were effectively managed with IV iron alone. Investigation and management of these patients appears heterogenous. Given the risks of blood transfusion and the increased availability of IV iron, guidelines outlining evidence-based management of severe IDA are needed. These guidelines should promote optimization of iron therapy and guide judicious administration of blood transfusion.

Market Competition and Anemia Management in the United States Following Dialysis Payment Reform.

Whether market competition influences health care provider responses to national reimbursement reforms is unknown. We examined whether changes in anemia management after the expansion of Medicare's dialysis payment bundle varied with market competition. With data from the US dialysis registry, we used a difference-in-differences (DID) design to estimate the independent associations of market competition with changes in anemia management after dialysis reimbursement reform. A total of 326,150 patients underwent in-center hemodialysis in 2009 and 2012, representing periods before and after reimbursement reform. Outcomes were erythropoiesis-stimulating agent (ESA) and intravenous iron dosage, the probability of hemoglobin <9g/dL, hospitalizations, and mortality. We also examined serum ferritin concentration, an indicator of body iron stores. We used a dichotomous market competition index, with less competitive areas defined as effectively having <2 competing dialysis providers. Compared with areas with more competition, patients in less competitive areas had slightly more pronounced declines in ESA dose (60% vs. 57%) following reimbursement reform (DID estimate: -3%; 95% CI, -5% to -1%) and less pronounced declines in intravenous iron dose (-14% vs. -19%; DID estimate: 5%; 95% CI, 1%-9%). The likelihoods of hemoglobin <9g/dL, hospitalization, and mortality did not vary with market competition. Serum ferritin concentrations in 2012 were 4% (95% CI, 3%-6%) higher in less competitive areas. After the expansion of Medicare's dialysis payment bundle, ESA use declined by more, and intravenous iron use declined by less in concentrated markets. More aggressive cost-reduction strategies may be implemented in less competitive markets.

Intravenous iron: an update.

Iron deficiency is the most common nutritional deficiency worldwide, with significant adverse health consequences in the presence or absence of anaemia. Total dose intravenous iron replacement is recommended for replacement of iron in patients with severe iron deficiency, especially in the presence of anaemia, intolerance or inefficacy following oral iron, or states of inflammation where upregulation of hepcidin may impair gastrointestinal absorption of iron. Currently, available intravenous iron formulations have been demonstrated to have an excellent overall safety profile, but potential adverse effects, including skin staining, infusion-related reactions and hypophosphataemia, have been described. Knowledge of differences in administration and safety profiles of currently available iron formulations will allow appropriate prescription, counselling, as well as recognition and management of adverse events in patients requiring intravenous iron.

Efficacy and safety of hypoxia-inducible factor prolyl hydroxylase inhibitors in patients with chronic kidney disease: meta-analysis of phase 3 randomized controlled trials.

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are new therapeutic agents for anaemia in chronic kidney disease (CKD). We evaluated by meta-analysis and meta-regression the efficacy and safety of HIF-PHIs in patients with CKD-related anaemia. We selected phase 3 randomized clinical trials (RCTs) comparing HIF-PHIs and erythropoiesis-stimulating agents (ESAs) in dialysis and non-dialysis patients. Efficacy outcomes were the changes from baseline of haemoglobin, iron parameters (hepcidin, serum iron, TIBC, TSAT, ferritin) and intravenous iron dose; as safety outcomes we considered cancer, adjudicated major adverse cardiovascular events (MACE), MACE+ (MACE plus hospitalization for hearth failure or unstable angina or thromboembolic event), thrombotic events (deep vein thrombosis, pulmonary embolism), arterovenous fistula (AVF) thrombosis and death. We included 26 RCTs with 24387 patients. Random effect meta-analysis of the unstandardized mean difference between HIF-PHIs and ESAs showed a significant change in haemoglobin levels from baseline of 0.10g/dL (95% CI 0.02 to 0.17). Meta-regression analysis showed a significantly higher haemoglobin change for HIF-PHIs in younger patients and versus short-acting ESA (0.21g/dL, 95% CI 0.12 to 0.29 versus -0.01, 95% CI -0.09 to 0.07 in studies using long-acting ESA, P<.001). No significant effect on heterogeneity was found for type of HIF-PHIs. In comparison with ESAs, HIF-PHIs induced a significant decline in hepcidin and ferritin and a significant increase in serum iron and TIBC, while TSAT did not change; intravenous iron dose was lower with HIF-PHI (-3.1mg/week, 95% CI -5.6 to -0.6, P=.020). Rate ratio of cancer (0.93, 95% CI 0.76 to 1.13), MACE (1.00, 95% CI 0.94 to 1.07), MACE+ (1.01, 95% CI 0.95 to 1.06), thrombotic events (1.08, 95% CI 0.84 to 1.38), AVF thrombosis (1.02, 95% CI 0.93 to 1.13) and death (1.02, 95% CI 0.95 to 1.13) did not differ between HIF-PHIs and ESAs. HIF-PHIs at the doses selected for the comparisons are effective in correcting anaemia in comparison with ESA therapy with a significant impact on iron metabolism without notable difference among various agents. No safety signals emerge with use of HIF-PHIs.

#4424 FREQUENCY OF RED BLOOD CELL TRANSFUSION USE IN PATIENTS WITH ANEMIA OF CHRONIC KIDNEY DISEASE (CKD) IN EUROPE: A SYSTEMATIC LITERATURE REVIEW

Abstract Background and Aims Anemia of CKD is common and managed with oral or intravenous iron, erythropoiesis-stimulating agents (ESAs) and, when necessary, red blood cell transfusions (RBCT). Reducing RBCT use is a goal in the management of anemia of CKD due to known short term (e.g., hyperkalaemia, heart failure) and longer term risks (e.g., allosensitization), but there is limited collated data on their use in Europe. A systematic literature review was conducted to evaluate the frequency of RBCT use among dialysis dependent (DD) and non-dialysis (ND) patients, and associated data reported for predictors of RBCT receipt, complications, healthcare resource use (HCRU), and costs. Method A comprehensive search strategy was used to retrieve real-world (RW) studies and randomized controlled trials (RCTs) conducted in DD and ND CKD patients with anemia using Embase and Medline (1980 to June 2022). Searches of conference abstracts, bibliographies and grey literature were also conducted. Studies which included European patients’ data are described here. Results Of the 3495 citations retrieved, 182 relevant studies were identified including 54 studies with European patients. Thirteen were RW studies including 12 quantifying the frequency of RBCT use (Table). In RW studies, the overall frequency of RBCT use ranged from 4.3–35.0% across studies and for key subgroups (n=10 studies: DD only studies, 8.4–33.9%; ND only studies, 4.3–35.0%). The number of RBCT units per patient-year (PY) ranged from 1.4–2.7 among DD patients (n=2 studies; no ND studies found). RBCT use appeared to vary by patient factors (iron/ESA use, CKD stage), by study design (e.g., length of follow-up) and across countries (but with no clear patterns in geographic variation). For the 41 RCTs including European patients (single country, n=3 studies, multi-country, n=38 studies), the overall frequency of RBCT use ranged from 0–21.6% (DD only studies, 0.4–21.6%; ND only studies, 0–14.8%), which was lower than those recorded in the RW studies. The rate of RBCT use in trials ranged from 3.5–66.0 events per 100 PY overall (DD only studies, 3.5–66.0; ND only study, 8.0); the number of RBCT units per PY ranged from 0.20–1.65 among DD patients (n=2 studies; no ND studies found). No studies used statistical modelling to quantify predictors of RBCT use while adjusting for potential differences between groups. One RW study from 1986 reported detection of human T-lymphotropic virus type III (HTLV-III; subsequently known as HIV) antibodies in 4 patients who had received RBCT (in a sample of 276 screened chronic HD patients). Of three RW studies reporting data on costs, two were &amp;gt;30 years old and one provided costs relating to receipt of inpatient RBCT in ND patients stratified by oral iron, low dose, or high dose intravenous iron use from 2013–2015 (n=111). Conclusion RBCT use forms part of the management of anemia of CKD in Europe and its use is variable but not infrequent. RBCT risk in RW studies appeared elevated compared to RCTs. There were no consistent patterns in geographic variation, but risk varied by patient factors and study design. There is currently limited European data reporting on frequency of associated complications, predictors of RBCT use, associated HCRU and costs. Funding: GSK (Study 218929).

Erythropoietin resistance-secondary to watermelon stomach: a forgotten story in chronic kidney disease patients.

Watermelon stomach, also known as gastric antral vascular ectasia (GAVE), is a rarely seen cause of acute upper gastrointestinal bleeding or chronic iron deficient anemia, revealed when gastroscopy is performed. GAVE affects predominantly women of advanced aged and is usually associated with certain underlying co-morbidities including liver cirrhosis, autoimmune diseases and chronic kidney disease. Based on the above, we report the case of a 75-year old woman under hemodialysis for six consecutive years due to end-stage renal disease attributable to hypertensive nephrosclerosis. The patient also suffered from chronic ischemic heart disease, severe peripheral artery disease and an unidentified connective tissue-disease characterized by high levels of anti-nuclear antibodies and clinical symptoms restrained in flares of non-erosive polyarthritis. Six months prior, she developed hyporesponsiveness to recombinant human erythropoietin (rEPO) due to iron deficiency despite the administration of the appropriate dose of intravenous iron as well as the exclusion of other co-existing causes of resistance, namely inadequate hemodialysis, inflammation, malnutrition, severe hyperparathyroidism and underlying hematologic disorders. Surprisingly, the patient experienced a sudden episode of severe upper gastrointestinal bleeding characterized by hemodynamic instability, hemoglobin fall and melena that required blood transfusions. Once hemodynamic stabilization was achieved, an upper endoscopic exam was performed showing the pathognomonic extensive vascular ectasias and patchy erythematosus lesions at the distal antrum. Thus, GAVE should be considered in the differential diagnosis of chronic kidney disease patients who present not only with acute blood loss but also with resistance to rEPO due to inadequate iron stores.

Anemia and Iron Deficiency in Outpatients with Inflammatory Bowel Disease: Ubiquitous Yet Suboptimally Managed.

Iron deficiency (ID) and anemia in patients with Inflammatory Bowel Disease (IBD) are associated with a reduced quality of life. We assessed the prevalence of ID and anemia in Dutch outpatients with IBD and compared routine ID(A) management among medical professionals to the European Crohn's and Colitis Organisation (ECCO) treatment guidelines. Between January and November 2021, consecutive adult outpatients with IBD were included in this study across 16 Dutch hospitals. Clinical and biochemical data were extracted from medical records. Additionally, medical professionals filled out questionnaires regarding routine ID(A) management. In total, 2197 patients (1271 Crohn's Disease, 849 Ulcerative Colitis, and 77 IBD-unclassified) were included. Iron parameters were available in 59.3% of cases. The overall prevalence of anemia, ID, and IDA was: 18.0%, 43.4%, and 12.2%, respectively. The prevalence of all three conditions did not differ between IBD subtypes. ID(A) was observed more frequently in patients with biochemically active IBD than in quiescent IBD (ID: 70.8% versus 23.9%; p &lt; 0.001). Contrary to the guidelines, most respondents prescribed standard doses of intravenous or oral iron regardless of biochemical parameters or inflammation. Lastly, 25% of respondents reported not treating non-anemic ID. One in five patients with IBD suffers from anemia that-despite inconsistently measured iron parameters-is primarily caused by ID. Most medical professionals treat IDA with oral iron or standard doses of intravenous iron regardless of biochemical inflammation; however, non-anemic ID is often overlooked. Raising awareness about the management of ID(A) is needed to optimize and personalize routine care.

Iron Infusions, Their Reactions and Efficacy Related to Dosing - a Single Center Retrospective Study

Background: Intravenous (IV) iron infusions are associated with a variety of adverse drug reactions (ADRs) including anaphylactic reactions. The Commonly used IV iron formulations are Iron sucrose (Venofer), Ferric carboxymaltose (Injectafer), Sodium ferric gluconate complex (Ferrlecit), and others. Iron sucrose has been approved by the FDA (Food and Drug Administration) for patients with iron deficiency who also have kidney disease. It is also often used off-label for iron deficiency anemia on its own. In our facility, multiple ADRs were noted with Venofer compared to other formulations. Hence, we aimed to study: 1. If altering the dose of Venofer will result in a lesser incidence of allergic reactions. 2. To determine if one preparation of IV iron has a higher incidence of adverse events than another. 3. To evaluate the efficacy after 6 to 8 weeks of completion of iron infusions, by comparing the response to various dosages and formulations. Methods: This is a retrospective chart review of 274 patients ages 18-92 who received at least one dose of Intravenous Iron at Einstein Medical Center Montgomery Outpatient Infusion Center from 01/01/21 to 10/31/21. Patients were divided into two groups based on the Venofer dosing schedule. Group D1 included patients that received any IV iron formulation from January to May 2021. In this group, Venofer dosing was 400mg x 1 followed by 300mg x2. Multiple ADRs were noticed in group D1 hence Group D2 was created. This group included patients that received any IV iron formulation from June to October 2021, where Venofer dosing was changed to 300mg x 3 doses or 300mg x 2 followed by 400mg. We collected data on age, gender, race, preparation, strength, pregnancy status, prior history of allergies and transfusion reactions, adverse drug reactions, the timing of reaction, total doses received, pre/post-medications provided to prevent or treat a reaction, outcomes of reaction, hemoglobin, iron studies before and after the infusions. Patient characteristics in both D1 and D2 groups were well balanced. Data were analyzed and summarized in descriptive measures. Efficacy of intravenous iron treatment was measured as a rise in Hemoglobin by 2gm/dl. Results: Out of 120 patients in group D1, 71 patients (59.2%) received Injectafer, out of these, 12 patients (16.9%) had ADRs, the most common reaction was hypotension, and 1 patient had an anaphylactic reaction requiring Emergency Room (ER) visit. Responders in this group were 28/71(39.4%). 10/71 (14.1%) were lost to follow-up. 48 patients (40%) received Venofer, out of which 11 patients (22.9%) had ADRs, the most common being pain in the back, and 2 patients required ER visits. Responders to the infusion in this group were 11/48 (22.9%) with 10/48 (20%) lost to follow-up. 1 patient (0.8%) received ferumoxytol, with no ADRs to report. In the D2 group, which involved a total of 154 patients, 76 patients (49.3%) received Injectafer, out of which 14 patients (18.4%) had ADRs, again the most common being hypotension, and 2 patients required an ER visit. Responders in this group were 29/76 (38.1%) and 10/76 (13.2%) were lost to follow-up. 77 patients (50%) received Venofer, out of which 9 patients (11.7%) had ADRs, the most common being hypotension and this group has not had any ER visits. Responders to the infusion in this group were 36/77(46.8%) and 9/77 (11.7%) were lost to follow-up. 1 patient (0.6%) received Ferumoxytol with no ADRs. [See Table 1]. Conclusions: Injectafer was overall the most used iron formulation in our institution. It was associated with more ADRs when compared to Venofer, including anaphylactic reactions. The most common ADR was hypotension with Injectafer, and back pain with Venofer. We found that Venofer dosing with 400mg x 1 followed by 300mg x2 was associated with the highest incidence of ADRs. Both strategies of Venofer dose modification with 300mg x 3 and schedule modification, 300x 2 followed by 400mg had greater efficacy and lesser frequency of ADRs as compared to Venofer 400mg followed by 300mg x2. Other studies have shown the benefit of Venofer in non-renal disease patients with iron deficiency. Although our study was not planned to demonstrate this outcome, our data may suggest that Venofer is beneficial for this group of patients. This should be looked into with further studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Relation of Liver Siderosis to Liver Fibrosis in Hemodialysis Patients With Severe Hyperferritinemia Secondary to High Doses of Intravenous Iron Supplementation

ObjectiveAggressive iron substitution in hemodialysis (HD) patients leads to iron overload. The association between liver siderosis and fibrosis is still debatable. We studied the association of liver siderosis with liver fibrosis in HD patients. Furthermore, we studied the performance of liver stiffness measurements (LSMs) in identifying advanced liver fibrosis. We investigated the performance of biochemical indicators of iron status in identifying advanced liver fibrosis. MethodsFifty-five HD patients (average HD duration 6 ± 2 years) with hyperferritinemia secondary to intravenous iron supplementation (weakly iron dose 252.7 ± 63 mg; median blood transfusions 3 [2-5]) were recruited. The liver fibrosis grade was determined with Fibroscan, aminotransferase-to-platelet ratio index (APRI), and Fib-4 index. Liver iron concentration (LIC) was estimated with magnetic resonance imaging (MRI). Iron parameters and liver function biochemical indicators were also assessed. ResultsThe median serum ferritin and transferrin saturation (TSAT) were 3531 μg/L and 77%, respectively. 34.5%, 20%, and 45.5% of the patients showed mild, moderate, or severe liver siderosis, respectively. All patients with severe liver siderosis showed advanced liver fibrosis. Patients with severe liver siderosis and advanced liver stiffness showed higher serum iron, TSAT, aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum bilirubin, APRI, and Fib-4 index scores than those with mild liver siderosis. Serum iron and TSAT showed good utility in identifying advanced liver fibrosis determined with Fibroscan, APRI, and Fib-4 index. Liver stiffness exhibited good utility in identifying advanced liver fibrosis diagnosed with APRI and Fib-4 index. ConclusionsHigh weekly intravenous iron dose associated with severe hyperferritinemia, high serum iron, and TSAT might lead to severe liver siderosis and concomitant liver fibrosis in HD patients. Serum iron, TSAT, Fibroscan, Fib-4, and APRI scores might offer noninvasive tools for identifying advanced liver fibrosis in those patients.

Intravenous versus oral iron for iron deficiency anaemia in pregnant Nigerian women (IVON): study protocol for a randomised hybrid effectiveness-implementation trial

BackgroundAnaemia in pregnancy is highly prevalent in African countries. High-dose oral iron is the current recommended treatment for pregnancy-related iron deficiency anaemia (IDA) in Nigeria and other African countries. This oral regimen is often poorly tolerated and has several side effects. Parenteral iron preparations are now available for the treatment of IDA in pregnancy but not widely used in Africa.The IVON trial is investigating the comparative effectiveness and safety of intravenous ferric carboxymaltose versus oral ferrous sulphate standard-of-care for pregnancy-related IDA in Nigeria. We will also measure the implementation outcomes of acceptability, feasibility, fidelity, and cost-effectiveness for intravenous ferric carboxymaltose.MethodsThis is an open-label randomised controlled trial with a hybrid type 1 effectiveness-implementation design, conducted at 10 health facilities in Kano (Northern) and Lagos (Southern) states in Nigeria. A total of 1056 pregnant women at 20–32 weeks’ gestational age with moderate or severe anaemia (Hb < 10g/dl) will be randomised 1:1 into two groups. The interventional treatment is one 1000-mg dose of intravenous ferric carboxymaltose at enrolment; the control treatment is thrice daily oral ferrous sulphate (195 mg elemental iron daily), from enrolment till 6 weeks postpartum.Primary outcome measures are (1) the prevalence of maternal anaemia at 36 weeks and (2) infant preterm birth (<37 weeks’ gestation) and will be analysed by intention-to-treat. Maternal full blood count and iron panel will be assayed at 4 weeks post-enrolment, 36 weeks’ gestation, delivery, and 6 weeks postpartum. Implementation outcomes of acceptability, feasibility, fidelity, and cost will be assessed with structured questionnaires, key informant interviews, and focus group discussions.DiscussionThe IVON trial could provide both effectiveness and implementation evidence to guide policy for integration and uptake of intravenous iron for treating anaemia in pregnancy in Nigeria and similar resource-limited, high-burden settings. If found effective, further studies exploring different intravenous iron doses are planned.Trial registration ISRCTN registry ISRCTN63484804. Registered on 10 December 2020Clinicaltrials.govNCT04976179. Registered on 26 July 2021The current protocol version is version 2.1 (080/080/2021).

Single-dose intravenous ferric carboxymaltose infusion versus multiple fractionated doses of intravenous iron sucrose in the treatment of post-operative anaemia in colorectal cancer patients: a randomised controlled trial.

Recent clinical guidelines suggest that treatment of postoperative anaemia in colorectal cancer surgery with intravenous iron reduces transfusion requirements and improves outcomes. The study aimed at comparing two intravenous iron regimens in anaemic patients after colorectal cancer surgery. This was a single-centre, open-label, randomised, controlled trial in patients undergoing elective colorectal cancer surgery. Patients with moderate to severe anaemia (haemoglobin [Hb] <11 g/dL) after surgery were randomly assigned 1:1 to receive ferric carboxymaltose (FC; 1,000 mg, single dose) or iron sucrose (IS; 200 mg every 48 hours until covering the total iron deficit or discharge). Randomisation was stratified by Hb level: <10 g/dL (Group A) or ≥10-10.9 (Group B). The primary endpoint was the change in Hb concentration at postoperative day 30. Secondary endpoints included iron status parameters, transfusion requirements, complications, and length of hospital stay. From September 2015 to May 2018, 104 patients were randomised (FC 50, IS 54). The median intravenous iron dose was 1,000 mg and 600 mg in the FC and IS groups, respectively. There were no between-group differences in mean change in Hb from postoperative day 1 to postoperative day 30 (FC: 2.5 g/dL, 95% CI: 2.1-2.9; IS: 2.4 g/dL, 95% CI: 2.0-2.8; p=0.52), in transfusion requirements or length of stay. The infection rate was lower in the FC group compared with the IS group (9.8% vs 37.2%, respectively). The administration of approximately 500 mg of IS resulted in an increase in Hb at postoperative day 30 similar to that of 1,000 mg of FC, but it was associated with a higher infection rate. Future research will be needed to confirm the results, and to choose the best regime in terms of effectiveness and side effects to treat postoperative anaemia in colorectal cancer patients.

Comparative evaluation of iron status by reticulocyte haemoglobin content (CHr) in chronic kidney disease patients on haemodialysis and erythropoietin

Due to the inflammatory state associated with uraemia, diagnosing iron deficiency using currently available assays is difficult in individuals with chronic kidney disease (CKD). The goal of this study was to see how useful reticulocyte haemoglobin (CHr) is as a diagnostic tool for iron deficiency and a predictor of intravenous iron therapy in a group of CKD patients in Sri Lanka who were on haemodialysis. A hundred (100) individuals with CKD on regular haemodialysis and erythropoietin participated in this descriptive cross-sectional study. Serum ferritin, transferrin saturation, and reticulocyte haemoglobin were used to divide patients into groups (CHr). A single dose of intravenous (IV) iron 500 mg was given to all individuals with CHr&lt;29 pg.To examine the response, the CHr was measured 72 hours after the IV iron treatment. Mean haemoglobin was 9.27 g/dL, mean serum ferritin was 243.5 ng/mL, mean transferrin saturation was 18.6%, and mean CHr was 29.2 pg in the population. Thirty-three of the 100 patients (33%) received IV iron therapy, which resulted in a significant increase in CHr 72 hours following treatment (p&lt;0.001).

Analysis of oxidative stress, inflammation and endothelial function following intravenous iron in chronic kidney disease in the Iron and Heart Trial

Iron deficiency commonly affects patients with chronic kidney disease and has an important burden in disease trajectory and quality of life; nonetheless current guidelines do not advocate treatment of iron-deficiency without anemia in this patient group. Concerns exist regarding the potential effects of intravenous iron on oxidative stress, inflammation, and endothelial function. As part of a multicenter double-blinded randomized controlled clinical trial, we examined the effects of a single dose of intravenous iron vs. placebo on biomarkers of oxidative stress, inflammation and endothelial function in non-anemic iron deficient patients (serum ferritin < 100 μg/L and/or transferrin saturation < 20%) with chronic kidney disease (stage 3b-5). Fifty-four individuals were randomized to receive ferric derisomaltose (n = 26) or placebo (n = 28). Ferric derisomaltose was associated with a non-significant decrease in mean F2-isoprostane and no effect on thiobarbituric acid reactive substances when compared to placebo throughout follow up. No effect on inflammatory markers was observed. A modest but statistically significant rise in E-selectin was noted in the intravenous iron group at 1 month and 3 month follow-up (p = 0.030 and p = 0.002 respectively). These results suggest ferric derisomaltose administration in non-dialysis dependent chronic kidney disease patients who are iron deficient does not induce prolonged oxidative stress or inflammation. Larger trials are required to quantify the benefit of intravenous iron administration in this patient group.

Efficacy and Safety of Daprodustat for Treatment of Anemia of Chronic Kidney Disease in Incident Dialysis Patients

Daprodustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, is being evaluated as an oral alternative to conventional erythropoiesis-stimulating agent (ESA) therapy. Few studies of anemia treatment in an incident dialysis (ID) population have been reported. To evaluate the efficacy and safety of daprodustat vs darbepoetin alfa in treating anemia of chronic kidney disease in ID patients. This prospective, randomized, open-label clinical trial was conducted from May 11, 2017, through September 24, 2020, in 90 centers across 14 countries. Patients with advanced CKD were eligible if they planned to start dialysis within 6 weeks from screening or had started and received hemodialysis (HD) or peritoneal dialysis (PD) within 90 days before randomization, had a screening hemoglobin (Hb) concentration of 8.0 to 10.5 g/dL (to convert to grams per liter, multiply by 10) and a randomization Hb of 8.0 to 11.0 g/dL, were ESA-naive or had received limited ESA treatment, and were iron-replete. Randomized 1:1 to daprodustat or darbepoetin alfa. The primary analysis in the intent-to-treat population evaluated the mean change in Hb concentration from baseline to evaluation period (weeks 28-52) to assess noninferiority of daprodustat vs darbepoetin alfa (noninferiority margin, -0.75 g/dL). The mean monthly intravenous (IV) iron dose from baseline to week 52 was the principal secondary end point. Rates of treatment-emergent and serious adverse events (AEs) were also compared between treatment groups to assess safety and tolerability. A total of 312 patients (median [IQR] age, 55 [45-65] years; 194 [62%] male) were randomized to either daprodustat (157 patients; median [IQR] age, 52.0 [45-63] years; 96 [61%] male) or darbepoetin alfa (155 patients; median [IQR] age, 56.0 [45-67] years; 98 [63%] male); 306 patients (98%) completed the trial. The mean (SD) Hb concentration during the evaluation period was 10.5 (1.0) g/dL for the daprodustat and 10.6 (0.9) g/dL for the darbepoetin alfa group, with an adjusted mean treatment difference of -0.10 g/dL (95% CI, -0.34 to 0.14 g/dL), indicating noninferiority. There was a reduction in mean monthly IV iron use from baseline to week 52 in both treatment groups; however, daprodustat was not superior compared with darbepoetin alfa in reducing monthly IV iron use (adjusted mean treatment difference, 19.4 mg [95% CI, -11.0 to 49.9 mg]). Adverse event rates were 76% for daprodustat vs 72% for darbepoetin alfa. This randomized clinical trial found that daprodustat was noninferior to darbepoetin alfa in treating anemia of CKD and may represent a potential oral alternative to a conventional ESA in the ID population. ClinicalTrials.gov Identifier: NCT03029208.

Efficacy and safety of intravenous iron with different frequencies for renal anaemia: A systematic review and meta-analysis.

To evaluate the efficacy and safety of intravenous iron supplementation in patients with renal anaemia. We searched the PubMed, Embase, Cochrane Library, and Web of Science from their inception until 17 September 2021, for randomized controlled trials (RCTs) to evaluate the efficacy and safety of intravenous iron at different frequencies. The observed efficacy indicators included transfer saturation (TSAT), serum ferritin (SF) and haemoglobin (HGB). Outcomes of interest included allergies, infections, all-cause mortality and cardiovascular events. Of the 751 eligible studies, 7 RCTs met the inclusion criteria. The RCTs showed that there were no significant differences between the low-frequency high-dose group (1-2 doses, >200mg/dose) and the high-frequency low-dose group (4-5 doses, ≤200mg/dose) in the increase in TSAT (WMD=1.90; 95% CI=-2.04 to 5.84; I2 =0%), SF (WMD=15.70; 95% CI=-32.20 to 70.61; I2 =0%) and HGB (WMD=-0.00; 95% CI=-0.43 to 0.42; I2 =0%). There was also no significant difference in the occurrence of outcome events, including allergies (RR=1.84; 95% CI=0.95 to 3.57; I2 =45%), infections (RR=0.61; 95% CI=0.20-1.86; I2 =0%), cardiovascular events (RR=0.88; 95% CI=0.67-1.15; I2 =48%) and all-cause mortality (RR=0.74; 95% CI=0.40-1.35; I2 =0%). Frequencies of intravenous iron supplementation with similar doses share similar safety and efficacy in patients with renal anaemia. However, a single dose or two doses of intravenous iron are more cost-effective and patient friendly. These findings may provide evidence for the clinical application of intravenous iron supplementation for patients with renal anaemia.

Ferric citrate hydrate is associated with a reduced cost of drugs and a smaller change in red blood cell distribution width

The ASTRIO study was a randomised, multicentre, 24-week study that compared the effects of ferric citrate hydrate (FC) and non-iron-based phosphate binders (control) on anaemia management in haemodialysis (HD) patients receiving erythropoiesis-stimulating agents (ESAs). In that study, FC reduced the doses of ESAs and intravenous iron without affecting haemoglobin (Hb); however, the cost-effectiveness of FC was unclear. We retrospectively implemented a cost-effectiveness analysis comparing the incremental cost-effectiveness ratios (ICERs) in FC (n = 42) and control (n = 40) groups in patients with serum phosphate and Hb controlled within the ranges of 3.5–6.0 mg/dL and 10–12 g/dL, respectively. Costs included drug costs of phosphate binders, ESAs, and intravenous iron. Elevated red cell distribution width (RDW) has been reported to be associated with mortality in HD patients and was therefore used as an effectiveness index. The mean (95% confidence interval) differences in drug costs and RDW between the FC and control groups were US$ − 421.36 (− 778.94 to − 63.78, p = 0.02) and − 0.83% (− 1.61 to – 0.05, p = 0.04), respectively. ICER indicated a decrease of US$ 507.66 per 1% decrease in RDW. FC was more cost-effective than non-iron-based phosphate binders. Iron absorbed via FC could promote erythropoiesis and contribute to renal anaemia treatment.

The Effects of Intravenous Iron Infusion on Preoperative Hemoglobin Concentration in Iron Deficiency Anemia: Retrospective Observational Study.

BackgroundAn iron infusion pathway using Ferrinject (ferric carboxymaltose) was implemented at Southend University Hospital for preoperative surgical patients with iron deficiency anemia undergoing major surgery. This was based on a treatment algorithm proposed by Munting and colleagues according to the international consensus statement on perioperative management of anemia and the UK National Institute for Health and Care Excellence (NICE) guidelines. These guidelines state that intravenous iron is indicated when oral iron is poorly tolerated or ineffective, there is insufficient time to surgery, or due to a functional iron deficiency.ObjectiveThe objective of this study was to evaluate the change in adult hemoglobin (Hb) concentration (g/L) after Ferrinject infusion at the time of surgery.MethodsData were retrospectively collected on all surgical patients that received an iron infusion preoperatively for iron deficiency anemia from July 2019 to April 2020. Nonsurgical, obstetric, and pediatric patients, and those without a postinfusion Hb level measurement were excluded. Data collected included the Hb, ferritin, and transferrin levels pre and postinfusion; correct dose of intravenous iron received; and any adverse reactions noted.ResultsThirty-two surgical patients with iron deficiency anemia received intravenous iron between July 2019 and April 2020 prior to surgery. The average pre and post iron infusion Hb concentration across the cohort was 97 g/L and 114 g/L, respectively (18% increase; P=.001). Two (6%) patients had a posttransfusion Hb level ≥130 g/L prior to surgery after infusion. Nine patients had both a pre and postinfusion ferritin level recorded, which showed an increase from 12 ng/mL preinfusion to 94 ng/mL postinfusion (P=.02). Twenty-three (72%) patients did not receive the full dose of intravenous iron based on their Hb level and weight. Twenty-four (75%) patients received an iron infusion >2 weeks prior to surgery and the other 8 (25%) patients received the infusion <2 weeks before their surgery. There was an average increase in Hb of 22% (21 g/L, 95% CI 13-28) and 5% (5 g/L, 95% CI 1-10), respectively, across the two groups (P=.03). There were no documented adverse reactions to intravenous iron.ConclusionsIntravenous iron is an effective intervention to improve the Hb concentration in patients with iron deficiency anemia despite the majority of patients not receiving the full dose based on their baseline Hb level and weight. Increasing the interval time between infusion and surgery was associated with a greater increase in Hb, with only a minimal increase observed if given less than 2 weeks prior to surgery.