Short-term effect of low-dose roxadustat combined with erythropoiesis-stimulating agent treatment for erythropoietin-resistant anemia in patients undergoing maintenance hemodialysis.

Background: Erythropoietin resistance is present in some patients with chronic kidney disease, especially in those undergoing hemodialysis, and is often treated using roxadustat rather than iron supplements and erythropoiesis-stimulating agents (ESAs). However, some patients cannot afford full doses of roxadustat. This retrospective study investigated the efficacy of low-dose roxadustat combined with recombinant human erythropoietin (rhuEPO) therapy in 39 patients with erythropoietin-resistant renal anemia undergoing maintenance hemodialysis (3-4 sessions/week). Methods: The ability of the combination of low-dose roxadustat and rhuEPO to increase the hemoglobin concentration over 12 weeks was assessed. Markers of iron metabolism were evaluated. Eligible adults received 50-60% of the recommended dose of roxadustat and higher doses of rhuEPO. Results: The mean hemoglobin level increased from 77.67 ± 11.18 g/dL to 92.0 ± 8.35 g/dL after treatment, and the hemoglobin response rate increased to 72%. The mean hematocrit level significantly increased from 24.26 ± 3.99% to 30.04 ± 3.69%. The soluble transferrin receptor level increased (27.29 ± 13.60 mg/L to 38.09 ± 12.78 mg/L), while the total iron binding capacity (49.22 ± 11.29 mg/L to 43.91 ± 12.88 mg/L) and ferritin level (171.05 ± 54.75 ng/mL to 140.83 ± 42.03 ng/mL) decreased. Conclusion: Therefore, in patients with ESA-resistant anemia who are undergoing hemodialysis, the combination of low-dose roxadustat and rhuEPO effectively improves renal anemia and iron metabolism.

Efficacy of ferric carboxymaltose on haemoglobin response among older patients with gastrointestinal bleeding: a randomised clinical trial.

BACKGROUND: Acute gastrointestinal bleeding (AGIB) is common in older patients but the use of iron in this context remains understudied. AIMS: This study aimed to evaluate prospectively the efficacy of ferric carboxymaltose to treat anaemia in older patients after AGIB. METHODS: This randomised double-blinded placebo-controlled clinical trial was conducted in 10 French centres. Eligible patients were 65 years or more, had controlled upper or lower gastrointestinal bleeding and a haemoglobin level of 9-11 g/dl. Patients were randomly assigned, in a 1:1 ratio, to receive either one intravenous iron injection of ferric carboxymaltose or one injection of saline solution. The primary endpoint was the difference in haemoglobin level between day 0 and day 42. Secondary endpoints were treatment-emergent adverse events, serious adverse events, rehospitalisation and improvement of quality of life (QOL) at day 180. RESULTS: From January 2013 to January 2017, 59 patients were included. The median age of patients was 81.9 [75.8, 87.3] years. At day 42, a significant difference in haemoglobin level increase was observed (2.49 g/dl in the ferric carboxymaltose group vs. 1.56 g/dl in the placebo group, P = 0.02). At day 180, QOL, measured on European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, improved by 10.5 points in the ferric carboxymaltose group and by 8.2 points in the placebo group (P = 0.56). Rates of adverse events and rehospitalisation were similar in the two groups. CONCLUSIONS: Intravenous iron seems safe and effective to treat anaemia in older patients after AGIB and should be considered as a standard-of-care treatment. ClinicalTrials.gov (NCT01690585).

Household Water Lead and Hematologic Toxic Effects in Chronic Kidney Disease.

Importance: The consequences of low levels of environmental lead exposure, as found commonly in US household water, have not been established. Objective: To examine whether commonly encountered levels of lead in household water are associated with hematologic toxicity among individuals with advanced kidney disease, a group known to have disproportionate susceptibility to environmental toxicants. Design, Setting, and Participants: Cross-sectional analysis of household water lead concentrations and hematologic outcomes was performed among patients beginning dialysis at a Fresenius Medical Care outpatient facility between January 1, 2017, and December 20, 2021. Data analysis was performed from April 1 to August 15, 2023. Exposure: Concentrations of lead in household water were examined in categorical proportions of the Environmental Protection Agency's allowable threshold (15 µg/L) and continuously. Main Outcomes and Measures: Hematologic toxic effects were defined by monthly erythropoiesis-stimulating agent (ESA) dosing during the first 90 days of incident kidney failure care and examined as 3 primary outcomes: a proportion receiving maximum or higher dosing, continuously, and by a resistance index that normalized to body weight and hemoglobin concentrations. Secondarily, hemoglobin concentrations for patients with data prior to kidney failure onset were examined, overall and among those with concurrent iron deficiency, thought to increase gastrointestinal absorption of ingested lead. Results: Among 6404 patients with incident kidney failure (male, 4182 [65%]; mean [SD] age, 57 [14] years) followed up for the first 90 days of dialysis therapy, 12% (n = 742) had measurable lead in household drinking water. A higher category of household lead contamination was associated with 15% (odds ratio [OR], 1.15 [95% CI, 1.04-1.27]) higher risk of maximum monthly ESA dosing, 4.5 (95% CI, 0.8-8.2) µg higher monthly ESA dose, and a 0.48% (95% CI, 0.002%-0.96%) higher monthly resistance index. Among patients with pre-kidney failure hemoglobin measures (n = 2648), a higher household lead categorization was associated with a 0.12 (95% CI, -0.23 to -0.002) g/dL lower hemoglobin concentration, particularly among those with concurrent iron deficiency (multiplicative interaction, P = .07), among whom hemoglobin concentrations were 0.25 (95% CI, -0.47 to -0.04) g/dL lower. Conclusion: The findings of this study suggest that levels of lead found commonly in US drinking water may be associated with lead poisoning among susceptible individuals.

Early erythroferrone levels can predict the long-term haemoglobin responses to erythropoiesis-stimulating agents.

BACKGROUND AND PURPOSE: Our previous study reported that erythroferrone (ERFE), a newly identified hormone produced by erythroblasts, responded to recombinant human erythropoietin (rHuEPO) sensitively but its dynamics was complicated by double peaks and circadian rhythm. This study intends to elucidate the underlying mechanisms for the double peaks of ERFE dynamics and further determine whether early ERFE measurements can predict haemoglobin responses to rHuEPO. EXPERIMENTAL APPROACH: By using the purified recombinant rat ERFE protein and investigating its deposition in rats, the production of ERFE was deconvoluted. To explore the role of iron in ERFE production, we monitored short-term changes of iron status after injection of rHuEPO or deferiprone. Pharmacokinetic/pharmacodynamic (PK/PD) modelling was used to confirm the mechanisms and examine the predictive ability of ERFE for long-term haemoglobin responses. KEY RESULTS: The rRatERFE protein was successfully purified. The production of ERFE was deconvoluted and showed two independent peaks (2 and 8 h). Transient iron decrease was observed at 4 h after rHuEPO injection and deferiprone induced significant increases of ERFE. Based on this mechanism, the PK/PD model could characterize the complex dynamics of ERFE. In addition, the model predictions further revealed a stronger correlation between ERFE and haemoglobin peak values than that for observed values. CONCLUSIONS AND IMPLICATIONS: The complex dynamics of ERFE should be composited by an immediate release and transient iron deficiency-mediated secondary production of ERFE. The early peak values of ERFE, which occur within a few hours, can predict haemoglobin responses several weeks after ESA treatment.

Comparative Safety of Long-Acting vs. Short-Acting Erythropoiesis-Stimulating Agents Among Patients Undergoing Hemodialysis.

Both short-acting (epoetin alfa or beta) and long-acting (darbepoetin alfa or PEG-epoetin) erythropoiesis-stimulating agents (ESAs) are commonly prescribed for patients with kidney failure undergoing maintenance hemodialysis. We compared the risks of major adverse cardiovascular events (MACE) and of all-cause mortality associated with receipt of short- vs. long-acting ESAs. This retrospective cohort analysis included Medicare hemodialysis beneficiaries aged ≥ 18 years in the United States Renal Data System from January 2015 to December 2017. We included adults who survived > 90 days after initiating hemodialysis and received either short- or long-acting ESAs. Outcomes were MACE (first occurrence of stroke, acute myocardial infarction, or cardiovascular-related mortality) and all-cause mortality. After stabilized inverse probability of treatment weighting, Cox proportional hazards regression models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for each outcome. Of 68,607 patients (mean age: 65 years, 45% females), 33,658 (49%) received long-acting ESAs and 34,949 (51%) received short-acting ESAs. There was no difference in the risk of MACE associated with receipt of short- vs. long-acting ESAs (HR: 1.02 (95% CI: 0.98-1.08)). However, long-acting (vs. short-acting) ESA receipt was associated with a lower risk of all-cause mortality (HR: 0.91 (95% CI: 0.87-0.96)). Compared with short-acting ESAs, long-acting ESAs were associated with a lower risk of all-cause mortality, with no difference in the risk of MACE. Future studies with a longer follow-up are needed to confirm these findings.

Theranova versus FX80: The impact on anemia management in hemodialysis.

BACKGROUND: Middle uremic toxins (MUTs) can cause anemia and erythropoietin hyporesponsiveness. Theranova dialyzers may improve anemia management by removing MUTs. Hence, the impact of Theranova dialyzers on erythropoietin responsiveness was studied. METHODS: This exploratory single-center prospective observational study, encompassing 50 patients undergoing dialysis with either the Theranova-400 or FX80 membrane for 6 months, involved monthly tracking of hemoglobin levels, weight-adjusted erythropoiesis-stimulating agent (w-ESA) dosing, and erythropoietin resistance index (ERI), with ESA treatment decisions guided by a proprietary algorithm. RESULTS: The groups were similar in terms of demographics and baseline laboratory test results. The median hemoglobin levels, w-ESA and ERI, were found to be similar between FX80 and Theranova-400 groups at both baseline (11.06 vs 10.57, p = 0.808; 92.3 vs 105.2, p = 0.838; 8.1 vs 10.48, p = 0.876) and the end of the study (11.43 vs 11.03, p = 0.076; 48.7 vs 71.5; 4.48 vs 6.41, p = 0.310), respectively. There was a trend toward lower w-ESA and ERI at the end of the study compared to baseline in both groups, but the difference was non-significant. CONCLUSIONS: Based on this study of 50 patients undergoing high-flux dialysis with near-target hemoglobin levels, switching to Theranova 400 dialyzers compared to FX80 dialyzers did not show statistically significant differences in maintaining hemoglobin levels, reducing ESA dose, or lowering ERI. The non-randomized design and small sample size limit the study's power to detect true differences. Larger, randomized trials are needed to confirm findings and definitively assess Theranova 400's benefits.

The Association between High-Dose Allopurinol and Erythropoietin Hyporesponsiveness in Advanced Chronic Kidney Disease: JOINT-KD Study.

INTRODUCTION: The aim of the study was to explore the association between urate-lowering agents and reduced response to erythropoietin-stimulating agents in patients suffering from chronic kidney disease G5. METHODS: We conducted a cross-sectional, multicenter study in Japan between April and June 2013, enrolling patients aged 20 years or older with an estimated glomerular filtration rate of ≤15 mL/min/1.73 m2. Exclusion criteria encompassed patients with a history of hemodialysis, peritoneal dialysis, or organ transplantation. The patients were categorized into four groups based on the use of urate-lowering drugs: high-dose allopurinol (>50 mg/day), low-dose allopurinol (≤50 mg/day), febuxostat, and no-treatment groups. We used a multivariable logistic regression model, adjusted for covariates, to determine the odds ratio (OR) for erythropoietin hyporesponsiveness, defined by an erythropoietin resistance index (ERI) of ≥10, associated with urate-lowering drugs. RESULTS: A total of 542 patients were included in the analysis, with 105, 36, 165, and 236 patients in the high-dose allopurinol, low-dose allopurinol, febuxostat, and no-treatment groups, respectively. The median and quartiles of ERIs were 6.3 (0, 12.2), 3.8 (0, 11.2), 3.4 (0, 9.8), and 4.8 (0, 11.2) in the high-dose allopurinol, low-dose allopurinol, febuxostat, and no-treatment groups, respectively. The multivariate regression model showed a statistically significant association between the high-dose allopurinol group and erythropoietin hyporesponsiveness, compared to the no-treatment group (OR = 1.98, 95% confidence interval: 1.10-3.57). CONCLUSIONS: Our study suggests that the use of high-dose allopurinol exceeding the optimal dose may lead to hyporesponsiveness to erythropoiesis-stimulating agents.

Individualization of the Dosage Regimen of Erythropoietin is Crucial in End-stage Renal Disease Patients.

The objective of this study was to understand the utilization pattern of erythropoietin in end-stage renal disease patients, along with the effect of body weight and sex on the patients' responses. In this retrospective single-center study, 120 patients were included who were on a once weekly (n = 79), twice weekly (n = 37), or thrice weekly (n = 4) regimen. The doses of erythropoiesis-stimulating agents (ESA) were collected, and the erythropoietin resistance index (ERI) was determined. The Kruskal-Wallis test was used to evaluate the dose schedules, and the once-weekly regimen produced a greater response (P = 0.001). The asymptotic significance of Pearson's Chi-square-test equating the mean ERI and body mass index (BMI) was 0.034. No statistically significant correlation was estimated between sex and mean ERI (P = 0.201). Our study demonstrated that the once-weekly regimen dominated over the others in terms of efficacy, and individuals with a higher BMI were found to respond better to the ESA therapy.

Acute Dyspnea and Hemoptysis in an 84-Year-Old Man With Multiple Comorbidities.

CASE PRESENTATION: An 84-year-old man with an active smoking habit presented to the ED with dyspnea, hemoptysis, and thick phlegm that was difficult to clear. He reported no weight loss, no fever, and no chest pain or dysphonia. He denied both international travel and previous contact with confirmed cases of TB or SARS-CoV-2. He had no known occupational exposures. The patient's personal history included a resolved complete atrioventricular block that required a permanent pacemaker, moderate-to-severe COPD, rheumatoid arthritis (treated with oral prednisone, 2.5 mg/d) and B-chronic lymphocytic leukemia (treated with methotrexate and prophylactic oral supplements of ferrous sulfate). Moreover, he was in medical follow up because of a peptic ulcer, atrophic gastritis, and colonic diverticulosis. The patient also had a history of thoracic surgery after an episode of acute mediastinitis from an odontogenic infection, which required ICU management and temporal tracheostomy.

IV Sodium Ferric Gluconate Complex in Patients Hospitalized Due to Acute Decompensated Heart Failure and Iron Deficiency.

Background: Patients suffering from heart failure (HF) and iron deficiency (ID) have worse outcomes. Treatment with intra-venous (IV) ferric carboxymaltose has been shown to reduce HF rehospitalizations and to improve functional capacity and symptoms in patients with HF and reduced ejection fraction (HFrEF). However, IV ferric carboxymaltose is significantly more expensive than IV sodium ferric gluconate complex (SFGC) limiting its availability to most HF patients around the globe. Methods: A retrospective analysis comparing patients admitted to internal medicine or cardiology departments between January 2013 to December 2018 due to acute decompensated HF (ADHF) and treated with or without IV SFGC on top of standard medical therapy. Results: During the study period, a total of 1863 patients were hospitalized due to ADHF with either HFrEF or HF with preserved ejection fraction (HFpEF). Among them, 840 patients had laboratory evidence of iron deficiency (absolute or functional) and met the inclusion criteria. One hundred twenty-two of them (14.5%) were treated with IV SFGC during the index hospitalization. Patients treated with IV iron were more likely to have history of ischemic heart disease, atrial fibrillation, and chronic kidney disease. The rate of readmissions due to ADHF was similar between the groups at 30 days, 3 months, and 1 year. Conclusion: High risk patient hospitalized to ADHF and treated with IV SFGC showed comparable ADHF readmission rates, compared to those who did not receive iron supplementation.

Intravenous iron to treat anaemia following critical care: a multicentre feasibility randomised trial.

BACKGROUND: Anaemia is common and associated with poor outcomes in survivors of critical illness. However, the optimal treatment strategy is unclear. METHODS: We conducted a multicentre, feasibility RCT to compare either a single dose of ferric carboxymaltose 1000 mg i.v. or usual care in patients being discharged from the ICU with moderate or severe anaemia (haemoglobin ≤100 g L-1). We collected data on feasibility (recruitment, randomisation, follow-up), biological efficacy, and clinical outcomes. RESULTS: Ninety-eight participants were randomly allocated (49 in each arm). The overall recruitment rate was 34% with 6.5 participants recruited on average per month. Forty-seven of 49 (96%) participants received the intervention. Patient-reported outcome measures were available for 79/93 (85%) survivors at 90 days. Intravenous iron resulted in a higher mean (standard deviation [sd]) haemoglobin at 28 days (119.8 [13.3] vs 106.7 [14.9] g L-1) and 90 days (130.5 [15.1] vs 122.7 [17.3] g L-1), adjusted mean difference (10.98 g L-1; 95% confidence interval [CI], 4.96-17.01; P<0.001) over 90 days after randomisation. Infection rates were similar in both groups. Hospital readmissions at 90 days post-ICU discharge were lower in the i.v. iron group (7/40 vs 15/39; risk ratio=0.46; 95% CI, 0.21-0.99; P=0.037). The median (inter-quartile range) post-ICU hospital stay was shorter in the i.v. iron group but did not reach statistical significance (5.0 [3.0-13.0] vs 9.0 [5.0-16.0] days, P=0.15). CONCLUSION: A large, multicentre RCT of i.v. iron to treat anaemia in survivors of critical illness appears feasible and is necessary to determine the effects on patient-centred outcomes. CLINICAL TRIAL REGISTRATION: ISRCTN13721808 (www.isrctn.com).

Oral Iron Absorption Test: A Simple Test with Relevance in the Clinical Setting.

BACKGROUND: Iron deficiency anemia is a widespread problem. Although oral and intravenous therapy are available, iron malabsorption is a distinct possibility. OBJECTIVES: To evaluate the applicability of the oral iron absorption test (OIAT) as a simple and effective means of determining the degree of oral iron absorption. METHODS: The study comprised 81 patients diagnosed with iron deficiency anemia who were referred to a hematology outpatient clinic. Participants were given two ferrous sulphate tablets. Iron levels in the blood were evaluated at intervals from 30 to 180 minutes after iron administration. RESULTS: We divided patients into three distinct groups. The first group consisted of patients with little iron absorption with a maximum iron increment (Cmax) in the blood of 0-49 ug/dl. The second group had a moderate maximum absorption of 50-100 ug/dl, while a third group had considerable absorption of with maximum iron increase of over 100 ug/dl. CONCLUSIONS: The oral iron absorption test, although not clearly standardized, is easy to conduct in any outpatient clinic. This test can readily and clearly determine absorption or nonabsorption of iron. This test can have major implications on the need of oral or intravenous iron therapy and can also determine the need for further gastrointestinal evaluation of the small intestine, where iron absorption takes place and the success of therapy on subsequent iron absorption.

High-dose versus low-dose iron sucrose in individuals undergoing maintenance haemodialysis: a retrospective study.

BACKGROUND: Intravenous iron sucrose is becoming a prevailing treatment for individuals undergoing maintenance haemodialysis, but comparisons of dosing regimens are lacking. The aim of this retrospective review was to evaluate the safety and efficacy of proactively administered high-dose iron sucrose versus reactively administered low-dose iron sucrose in patients undergoing maintenance haemodialysis. METHODS: We analysed the data of 1500 individuals with maintenance haemodialysis who were treated with either high-dose iron sucrose that was proactively administered (Group HD) or low-dose iron sucrose that was reactively administered (Group LD) at the First Affiliated Hospital of Chongqing Medical University from Jan 1, 2008, to Dec 31, 2020. The primary endpoints were the cumulative doses of iron and erythropoiesis-stimulating agent; the secondary endpoints were the events of nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, infection rate, and death from any cause. RESULTS: Of the 2124 individuals, 624 individuals were excluded because they met one or more of the exclusion criteria, thus resulting in 1500 individuals who were eligible for inclusion in the study (Group HD, n = 760 and Group LD, n = 740). The median follow-up for the two cohorts was 32 months (range: 25-36). A significant median difference was detected in the monthly iron dose between the groups (1121 mg [range: 800-1274] in the HD group vs. 366 mg [range: 310-690] in the LD group; p < 0.05). The median dose of an erythropoiesis-stimulating agent was 26,323 IU/month (range: 17,596-44,712) in the HD group and 37,934 IU/month (range: 22,402-59,380) in the LD group (median difference: - 7901 IU/month; 95% CI: - 9632--5013; p = 0.000). A significant difference was detected in the secondary endpoints (266 events in 320 cases in the HD group vs. 344 events in 385 cases in the LD group) (HR: 0.62; 95% CI: 0.51-0.79; p < 0.001). A significant difference was not observed in death from any cause (HR: 0.57; 95% CI: 0.48-1.00; p = 0.361). CONCLUSIONS: For individuals undergoing maintenance haemodialysis, high-dose iron sucrose that was proactively administered may be superior to low-dose iron sucrose that was reactively administered with low doses of erythropoiesis-stimulating agent.

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.

Variation in health plan coverage of ESAs for anemia due to chronic kidney disease.

BACKGROUND: Because health plans each issue their own policies, drug coverage can vary. This variation can result in patients having unequal access to treatment. In this study, we evaluate commercial health plans' coverage policies for erythropoiesis-stimulating agents (ESAs) for patients with anemia resulting from chronic kidney disease (CKD). OBJECTIVES: To assess how a set of US commercial health plans cover ESAs for patients with anemia due to CKD. Our second objective was to examine the evidence that the plans reviewed when formulating their coverage policies. METHODS: We used the Tufts Medical Center Specialty Drug and Evidence and Coverage Database to identify coverage policies issued by 17 of the largest US commercial health plans for ESAs. The following drugs were indicated for anemia due to CKD: darbepoetin alfa, methoxy polyethylene glycol-epoetin beta, epoetin alfa (available as two brands), and epoetin alfa-epbx. Coverage policies were current as of May 2019. We determined whether the health plans applied any restrictions, such as step therapy protocols or patient subgroup restrictions, in their coverage policies. We categorized the evidence that plans cited to support their policies into seven categories: randomized controlled trials (RCTs), real-world evidence (RWE) studies (studies based on data collected in a real-world setting), other clinical studies (eg, single arm trials), systematic reviews and/or meta-analyses, clinical or treatment guidelines, health technology assessments, and economic evaluations. RESULTS: We categorized 72.5% of coverage policies (58/80 policies) as equivalent to the FDA label and 27.5% (22/80 policies) as more restrictive. In restricted policies, plans most often applied step therapy protocols (18/22 policies), followed by prescriber requirements (4/22 policies), and patient subgroup restrictions (3/22 policies). Five health plans applied restrictions in at least half of their coverage policies; seven plans did not apply restrictions in any policy. Plans that cited evidence reviewed an average of 10 citations across their ESA coverage policies, ranging from one to 29 studies. Plans varied with respect to the types of cited studies: at least 50% of evidence cited by five health plans was RCTs, while half or more of the evidence cited by four health plans was clinical or treatment guidelines. CONCLUSIONS: Health plans varied in how they covered ESAs for patients with anemia due to CKD and in the evidence cited in their coverage policies. Inconsistencies in plans' coverage policies may have implications for patients' access to ESAs. DISCLOSURES: This study was funded by Otsuka Pharmaceutical Development and Commercialization. Sanon, Redmond, and Mogahadam are employed by Otsuka Pharmaceutical. Michalopoulos was employed by Otsuka Pharmaceutical at the time of this study. Margaretos, Panzer, and Chambers are employed by Tufts Medical Center, Institute for Clinical Research and Health Policy Studies, Center for the Evaluation of Value and Risk in Health. Lai was with Tufts Medical Center, Institute for Clinical Research and Health Policy Studies, Center for the Evaluation of Value and Risk in Health at the time of this study.

Addition of oral iron bisglycinate to intravenous iron sucrose for the treatment of postpartum anemia-randomized controlled trial.

BACKGROUND: Studies that have compared the effectiveness of oral with intravenous iron supplements to treat postpartum anemia have shown mixed results. The superiority of one mode of treatment vs the other has yet to be demonstrated. Therefore, despite guidelines and standards of care, treatment approaches vary across practices. A single 500 mg dose of iron sucrose, which is higher than what is usually administered, has not been evaluated to treat postpartum moderate to severe anemia. OBJECTIVE: This study aimed to compare the efficacy of intravenous iron sucrose alone with intravenous iron sucrose in combination with oral iron bisglycinate supplementation in treating moderate to severe postpartum anemia. STUDY DESIGN: A randomized controlled trial was conducted between February 2015 and June 2020. Women with postpartum hemoglobin level of ≤9.5 g/dL were treated with 500 mg intravenous iron sucrose after an anemia workup, which ruled out other causes for anemia. In addition to receiving intravenous iron, women were randomly allocated to receive either 60 mg of oral iron bisglycinate for 45 days or no further iron supplementation. The primary outcome was hemoglobin level at 6 weeks after delivery. Secondary outcomes were iron storage parameters and quality of life. RESULTS: Of 158 patients who participated, 63 women receiving intravenous and oral iron, and 44 women receiving intravenous iron-only, completed the study and were included in the analysis. Baseline and obstetrical characteristics were similar between the study cohorts. Although statistically significant, postpartum hemoglobin levels were only 0.4 g/dL higher in the intravenous and oral iron than intravenous iron-only cohort (12.4 g/dL vs 12.0 g/dL, respectively; P=.03), with a respective increase from baseline of 4.2 g/dL vs 3.7 g/dL (P=.03). There was no difference in the rate of women with hemoglobin level of <12.0 or 11.0 g/dL. Iron storage and health quality were not different between the cohorts. Oral iron treatment was associated with 29% rate of adverse effects. Compliance and satisfaction from treatment protocol were high in both cohorts. CONCLUSION: Intravenous 500 mg iron sucrose treatment alone is sufficient to treat postpartum anemia without the necessity of adding oral iron treatment.

Effects of altitude and recombinant human erythropoietin on iron metabolism: a randomized controlled trial.

Current markers of iron deficiency (ID), such as ferritin and hemoglobin, have shortcomings, and hepcidin and erythroferrone (ERFE) could be of clinical relevance in relation to early assessment of ID. Here, we evaluate whether exposure to altitude-induced hypoxia (2,320 m) alone, or in combination with recombinant human erythropoietin (rHuEPO) treatment, affects hepcidin and ERFE levels before alterations in routine ID biomarkers and stress erythropoiesis manifest. Two interventions were completed, each comprising a 4-wk baseline, a 4-wk intervention at either sea level or altitude, and a 4-wk follow-up. Participants (n = 39) were randomly assigned to 20 IU·kg body wt-1 rHuEPO or placebo injections every second day for 3 wk during the two intervention periods. Venous blood was collected weekly. Altitude increased ERFE (P ≤ 0.001) with no changes in hepcidin or routine iron biomarkers, making ERFE of clinical relevance as an early marker of moderate hypoxia. rHuEPO treatment at sea level induced a similar pattern of changes in ERFE (P < 0.05) and hepcidin levels (P < 0.05), demonstrating the impact of accelerated erythropoiesis and not of other hypoxia-induced mechanisms. Compared with altitude alone, concurrent rHuEPO treatment and altitude exposure induced additive changes in hepcidin (P < 0.05) and ERFE (P ≤ 0.001) parallel with increases in hematocrit (P < 0.001), demonstrating a relevant range of both hepcidin and ERFE. A poor but significant correlation between hepcidin and ERFE was found (R2 = 0.13, P < 0.001). The findings demonstrate that hepcidin and ERFE are more rapid biomarkers of changes in iron demands than routine iron markers. Finally, ERFE and hepcidin may be sensitive markers in an antidoping context.

Comparative efficacy and safety of intravenous ferric carboxymaltose and iron sucrose for iron deficiency anemia in obstetric and gynecologic patients: A systematic review and meta-analysis.

INTRODUCTION: Iron deficiency anemia (IDA) is common among obstetric and gynecologic patients. This systematic review aimed to assess the comparative efficacy and safety of commonly used intravenous (IV) iron formulations, ferric carboxymaltose (FCM), and iron sucrose (IS) in the treatment of IDA in obstetric and gynecologic patients. METHODS: We systematically searched PubMed, EMBASE, Cochrane CENTRAL, and Google Scholar for eligible randomized controlled trials (RCTs) comparing IV iron replacement using FCM and IS up to October 2019. The primary outcome was to compare the efficacy of FCM and IS, assessed by measuring serum hemoglobin (Hb) and ferritin levels before and after iron replacement. The secondary outcome was to compare the safety of FCM and IS, assessed by the incidence of adverse events during iron replacement. The meta-analysis was performed using RevMan 5.3. RESULTS: We identified 9 RCTs with 910 patients (FCM group, n = 456; IS group, n = 454). Before iron replacement, FCM and IS group patients had similar baseline Hb (mean difference [MD], 0.04 g/dL; 95% confidence interval [CI], -0.07 to 015; I2 = 0%; P = 0.48) and ferritin levels (MD, -0.42 ng/mL; 95% CI, -1.61 to 0.78; I2 = 45%; P = 0.49). Following iron replacement, patients who received FCM had higher Hb (MD, 0.67; 95% CI, 0.25-1.08; I2 = 92%; P = 0.002) and ferritin levels (MD, 24.41; 95% CI, 12.06-36.76; I2 = 75%; P = 0.0001) than patients who received IS. FCM group showed a lower incidence of adverse events following iron replacement than IS group (risk ratio, 0.53; 95% CI, 0.35-0.80; I2 = 0%; P = 0.003). Serious adverse events were not reported in any group. CONCLUSION: FCM group showed better efficacy in increasing Hb and ferritin levels and a favorable safety profile with fewer adverse events compared with IS group for IDA treatment among obstetric and gynecologic patients. However, this meta-analysis was limited by the small number of RCTs and high heterogeneity. TRIAL REGISTRATION: The review was prospectively registered with the International Prospective Registry of Systematic Reviews (https://www.crd.york.ac.uk/prospero/, registration number CRD42019148905).

Drug safety in thalassemia: lessons from the present and directions for the future.

Introduction: Beta-thalassemia is an autosomal recessive hereditary anemia characterized by reduced or absent ß-globin chain synthesis, affecting about 60,000 people peryear. Management for ß-thalassemia major includes regular blood transfusions followed by iron chelating therapy and drug targeting ineffective erythropoiesis.Areas covered: The safety of licensed drugs for the management of ß-thalassemia is reviewed, using evidence from clinical trials and observational research. Such drugs include the iron chelators and the erythrocyte maturation agent luspatercept. The safety of emerging treatment, such as hydroxyurea and thalidomide is also reviewed.Expert opinion: Beta-thalassemia is arare disease, and is not surprising that there are limited studies investigating the safety of drugs used in this disease. Indeed, although observational studies are the main source of drug safety information in areal-world setting, only eleven studies were identified for iron-chelators and none of these estimated the risk of agiven safety outcome. Future work should aim to better leverage existing sources of real-world datato investigate drug safety in thalassemia.