Administration Of Erythropoiesis-stimulating Agents Research Articles

The impact of erythropoiesis-stimulating agents administration concomitantly with adjuvant anti-HER2 treatments on the outcomes of patients with early breast cancer: a sub-analysis of the ALTTO study.

To assess whether erythropoiesis-stimulating agents (ESA) administration impacts the outcomes of patients with HER2-positive early breast cancer (EBC). ALTTO (NCT00490139) patients were categorized by ESA use during adjuvant anti-HER2 treatment. Disease-free-survival (DFS), overall survival (OS), and time-to-distant recurrence (TTDR) were analyzed by ESA administration, with subgroup analyses according to prognostic factors. Log-rank tests and Cox modeling were performed. Adverse events (AEs) of ESA-interest were compared. Among 8381 patients recruited in ALTTO, 123 (1.5%) received ESA concomitantly with study treatment. The median age of patients receiving ESA was 54years, 39.0% premenopausal, most had tumor size > 2cm (56.9%), node-positive (58.5%), and positive estrogen receptor expression (61.8%). Median follow-up was shorter in the ESA group [6.1years (IQR 5.3-7.0) vs. 6.9years (6.0-7.1); p < 0.001]. There was no DFS difference by ESA administration (log-rank p = 0.70), with 3- and 7-year DFS of 89.2% (95% CI 81.8-93.8%) and 81.6% (71.4-88.5%) in ESA group vs. 88.3% (87.6-89.0%) and 80.0% (79.1-80.9%) in No-ESA group. In subgroup analyses, the interaction of ESA administration with menopausal status was statistically significant (unadjusted p = 0.024; stratified p = 0.033), favoring premenopausal women receiving ESA. We observed no significant association of ESA administration with OS (log-rank p = 0.57; 7-year OS in ESA 88.6% vs. 90.0% in non-ESA) or TTDR. ESA-interest AEs were experienced by eight (6.5%) patients receiving ESA and 417 (5.1%) in the No-ESA group (p = 0.41). ESA administration to patients receiving adjuvant anti-HER2 treatment for HER2-positive EBC was safe and not associated with a negative impact on survival outcomes.

The Setting of Administration of Erythropoiesis-Stimulating Agents Among Home Dialysis Patients in a Mid-Sized Dialysis Provider

The Setting of Administration of Erythropoiesis-Stimulating Agents Among Home Dialysis Patients in a Mid-Sized Dialysis Provider

Symptom burden, fatigue, sleep quality and perceived social support in hemodialysis patients with musculoskeletal discomfort: a single center experience from Egypt

Background and aimsMusculoskeletal disorders (MSDs) are commonly encountered in hemodialysis (HD) patients. However, the causes linked to these disorders are still partially defined. The aim of this study was to determine the frequency of MSDs and their relationship to a variety of clinico-social characteristics such as sleep quality, mood disorders, fatigue, and social support, in addition to the patients’ clinical and therapeutic profile.MethodThe study included 94 patients on maintenance HD. Clinical and Sociodemographic data was gathered. To investigate the prevalence and trends of MSDs, the Nordic Musculoskeletal Questionnaire (NMQ-E) was employed. Patients completed the modified Edmonton Symptom Assessment System, Pittsburgh Sleep Quality Index (PSQI), multidimensional Fatigue Inventory (MFI-20), and Perceived Social Support from Family Scales. Univariate and multivariate regression analysis were used to assess the determinants of MSDs.ResultsThe patients' mean age was 49.73 and 59.6% were males. Seventy-two percent of patients were afflicted by MSDs. Knee pain (48.9%), low back pain (43.6%), shoulder pain (41.6%), hip/thigh pain (35.1%), and neck pains (35.1%) were the most reported MSD domains. Pain (p = 0.001), fatigue (p = 0.01), depression (p = 0.015), and anxiety (p = 0.003) scores were substantially higher in patients with MSDs. Furthermore, patients with MSDs engaged in less physical activity (p = 0.02) and perceived less social support (p = 0.029). Patients with MSDs had lower subjective sleep quality, daytime dysfunction domains, and global PSQI scores (p = 0.02, 0.031, 0.036, respectively). Female gender (p = 0.013), fatigue (p = 0.012), depression (p = 0.014), anxiety (p = 0.004), lower activity (p = 0.029), and PSQI score (0.027), use of erythropoiesis-stimulating agents (ESAs), antihypertensive drugs, calcium and Iron supplementation were all significantly associated with MSDs. At the multivariable regression model, administration of ESAs (p = 0.017) and pain score (p = 0.040) were the only independent variables associated with the outcome.ConclusionMSDs are quite common among HD patients. Female gender, pain, fatigue, depression, anxiety, reduced activity, poor sleep quality, and use of ESAs are all significantly associated with MSDs in HD patients. Patients with MSD perceived less social support compared to the other group. Patients treated with antihypertensive drugs, calcium and iron supplements were more likely to suffer MSDs.

Predictors of Hyporesponsiveness to Erythropoiesis-Stimulating Agents in Patients with Non-Dialysis-Dependent Chronic Kidney Disease (RADIANCE-CKD Study)

Introduction: Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) has been associated with increased mortality and cardiovascular events in patients with chronic kidney disease. We hypothesized that the prediction of ESA resistance during ESA administration would be very useful in deciding on a treatment plan. Methods: Patients enrolled in a randomized controlled trial to evaluate renal prognosis in anemic patients with non-dialysis-dependent chronic kidney disease with hyporesponsiveness to ESA were included; the patients had different target hemoglobin levels. A landmark analysis was performed at 3 months into the study. To construct a predictive model for the severe ESA hypo-responder group, in which there was no increase in hemoglobin even with active treatment, background factors and serum test items that affect anemia at study entry were included in a logistic regression model, the area under the curve (AUC) and 95% confidence intervals (CI) were estimated, and sensitivity and specificity were calculated. This study was a post hoc sub-analysis of a randomized controlled trial. Results: The AUC for the 19 existing risk factors as predictors was 0.783 (95% CI: 0.711–0.855). Among the 19 risk factors, the combination of six factors (hemoglobin level, systolic blood pressure, weight, gender, smoking status, and hypertensive retinopathy) with the largest χ² statistics were selected by multiple logistics regression. The AUC for these 6 predictors was 0.716 (95% CI: 0.634–0.799). To the six existing risk factors, five serum test items that affect anemia (vitamin B12, vitamin B6, folic acid, parathyroid hormone, and 25-hydroxyvitamin D) were added, for a total of 11 risk factors, with a similar AUC of 0.736 (95% CI: 0.655–0.817), sufficient to predict ESA resistance. Conclusions: Our results suggest that existing risk factors and serum test items can be used to predict ESA resistance in patients with non-dialysis-dependent chronic kidney disease on ESA.

#3258 MECHANISMS OF HEMOGLOBIN CYCLING IN ANEMIC END-STAGE RENAL DISEASE PATIENTS TREATED WITH ERYTHROPOIESIS-STIMULATING AGENTS

Abstract Background and Aims A considerable fraction of renal anemia patients treated with erythropoiesis-stimulating agents (ESAs) experience hemoglobin ‘cycling’ periods during which hemoglobin levels periodically over- and undershoot a specified target range [1]. This is an undesired condition, which also necessitates frequent adjustment of the drug dose. The causes of hemoglobin cycling are not understood on a fundamental level. Through a combination of biomedical simulations and quantitative data analysis, we aimed at identifying mechanisms of hemoglobin cycling and the physiological and treatment-related factors contributing to cycling. Method We developed a biomedical modeling and simulation scheme that captures the essential features of ESA therapy involving a minimal feedback model for the delayed hemoglobin response after ESA administration and a stereotypic ESA dosing algorithm [2]. In this model, hemoglobin cycling emerged as a consequence of the delayed feedback between a patient's physiological response to ESA administrations and the resulting dose adjustments, which mutually maintain themselves in a causal loop. Guided by this model, we developed a set of statistical indicators that can detect this type of self-sustained hemoglobin cycling in clinical time series, including the Pearson cross correlation between hemoglobin levels and given ESA doses and hemoglobin standard deviation. Results A model analysis showed that physiological and treatment-related delays in hemoglobin response and ESA dose adjustment and administration were a major driver of hemoglobin cycling. Such delays are caused, e.g., by the cell cycle and maturation times of erythroid progenitors in response to ESA administration on one hand and restrictions in ESA dose changes and typical administration intervals on the other hand. In clinical time series, this was reflected by a systematic delay between bursts of ESA administrations and hemoglobin cycles. We quantified 1134 such datasets from hemodialysis patients and found that more persistent cycling was associated with negative correlation coefficients between hemoglobin levels and ESA doses. Using model simulations with similar behavior, we found that many patient- and therapy-related factors affect the hemoglobin dynamics in several (sometimes competing) ways, obfuscating their overall effect. For example, a larger RBC lifespan generally both entails higher hemoglobin levels but also prolongs the effect of ESA misdosings. However, model simulations suggested that longer RBC lifespans generally have a favorable effect in requiring less ESA on average and preventing hemoglobin cycling. Moreover, the model showed that for a given patient, ESA-specific properties such as its half-life may have a ‘sweet spot’ range of values within which hemoglobin cycling was suppressed while still showing a desired effect on the hemoglobin dynamics. Furthermore, the choice of the hemoglobin target window had an impact on hemoglobin stability. If the window was chosen too small, more frequent dose adjustments could initiate and maintain a cycling behavior. Conclusion Hemoglobin cycling in renal anemia patients often emerges from a complex interplay of multiple physiological and ESA treatment-related factors, with delays between ESA administration, hemoglobin response and subsequent ESA dose adjustment being a key driver of cycling. Biomedical modeling and simulation can aid in systematically exploring these interplays and find improved dosing strategies.

#3648 INDIVIDUALIZED ANEMIA THERAPY IMPROVES HEMOGLOBIN OUTCOMES AND DECREASES EPOETIN BETA DRUG EXPOSURE IN HEMODIALYSIS PATIENTS

Abstract Background and Aims Anemia is a common complication in hemodialysis (HD) patients. Its treatment with erythropoiesis-stimulating agents (ESAs) is challenging due to a nonlinear dose-response relationship and time delays between ESA administration and hemoglobin (Hgb) response. Anemia treatment protocols are frequently used in clinical settings. However, high variability of patient-specific disease characteristics complicate attainment and maintenance of desired Hgb levels. We developed a novel fully personalized ESA dose recommendation tool and present clinical results of a multi-center, randomized controlled trial (RCT) using this software. Method We conducted an RCT in adult HD patients in six dialysis facilities in the US. Patients were randomized 1:1 and treated with our personalized ESA dose recommendation tool for twenty-six weeks (intervention group) or continued to be treated using an anemia protocol that was used as part of standard of care in those clinics (control group). The recommendation tool utilized a physiology-based model of anemia to estimate patient-specific physiological key characteristics, such as red blood cell lifespan, to create a patient-individual model from recent routine clinical data (gender, height, weight, Hgb measurements, and ESA treatment). These key characteristics and model-based outcome predictions were used to generate patient-specific ESA dose recommendations to stabilize Hgb levels in a target window of 10–11 g/dL. Dose recommendations were disseminated to the anemia managers of patients enrolled in the study for evaluation and further decision-making (Figure 1). This procedure was repeated biweekly with updated clinical data. Results Ninety-six patients were enrolled in the RCT. Patients were included in the statistical analysis when they remained in the clinical study for at least 30 days (n = 45 control group, n = 46 intervention group). We evaluated outcome measures showing efficacy and efficiency of the treatment in achieving target Hgb levels. Hgb-related outcomes were significantly different between the two study groups, with an improved Hgb control in the intervention arm, manifesting in a reduction of the Hgb distance to target by more than 30%. Epoetin-beta utilization in the intervention group was decreased by over 20%, while iron-related parameters showed no difference between the two arms (Table 1). Acceptance rate of dose recommendations was high; roughly 95% of the recommendations were accepted and implemented by the clinical staff. Conclusion A therapy software for personalized anemia management was developed for use with epoetin beta. The model-based ESA dose recommendation tool was evaluated in a clinical RCT in HD patients. Hgb control improved significantly in the group using the novel software tool, while ESA usage decreased, thus providing more efficient anemia management for the individual patient while reducing epoetin-beta drug exposure.

Altitude Pre-Acclimatization with an Erythropoiesis-Stimulating Agent.

High altitude illness is a complication of rapid ascent above 2,500 m elevation. Ventilatory, circulatory and haematological adjustments, known as acclimatization, occur to maintain adequate delivery of oxygen. Although (non-)pharmaceutical strategies that modulate ventilation and circulation have long been accepted, the haematological approach has not. This report describes the application of a comprehensive strategy, including prior pre-acclimatization using an erythropoiesis-stimulating agent (ESA), in two healthy subjects ascending from sea level to 6,268 m. Following ESA administration 30 days prior to ascent, the subjects had a cumulative haemoglobin rise of 7.1% and 11.9%, respectively. Both subjects experienced minimal symptoms during four incremental ascents to the final altitude and no adverse events occurred. This report has limited external validity, lacking both a sample size and controls, but can serve as practical exploration of the concept. Administration of an ESA may be a safe and useful pre-acclimatization strategy but cannot be recommended based on current evidence. More comprehensive research is needed. High altitude illness (HAI) is a debilitating syndrome with potentially lethal consequences caused by ascent to a hypobaric atmosphere without acclimatization.Pharmacological strategies aimed at increasing oxygen delivery may be used to prevent and treat HAI.Administration of an erythropoiesis-stimulating agent may be a safe and useful pre-acclimatization strategy but cannot be recommended based on current evidence alone.

Unmet needs about iron deficiency in peritoneal dialysis: a Delphi consensus panel

BackgroundAnaemia and iron deficiency (ID) are common in chronic kidney disease (CKD) patients and related to outcomes. There is growing interest about the role of iron supplementation in CKD, particularly ferric carboxymaltose (FCM), also in relation to the use of erythropoiesis stimulating agents (ESAs). Despite a greater knowledge on ID management in patients receiving haemodialysis, a paucity of data exists about peritoneal dialysis (PD). Furthermore, the aim of this paper is to provide the results of a nationwide Italian survey about ID in PD using the Delphi method.MethodsA list of 16 statements (48 items) was developed about four main topics: (1) approach to iron therapy in PD; (2) management experience about iron therapy in PD; (3) ESA and iron in PD; (4) pharmacoeconomic impact. Using the Delphi methodology, the survey was distributed online to 36 Italian nephrologists with expertise in PD, who rated their level of agreement with each item on a 5-point Likert scale. Consensus was predefined as more than 66% of the panel agreeing/disagreeing with any given statement.ResultsTwenty-five experts (70%) answered the survey. 35 items (73%) achieved a consensus (8 negative and 27 positive). In particular, the diagnosis of ID is widely known, but some doubts exist about how frequently test it. The use of I.V. iron seems to be routinary and can save money reducing the administration of ESAs. However, internal protocols are welcome.ConclusionsExpert PD nephrologists know well the problem of ID and feel the necessity of shared protocols to optimize the iron therapy and consequently the use of ESAs.

Adverse events of iron and/or erythropoiesis-stimulating agent therapy in preoperatively anemic elective surgery patients: a systematic review

BackgroundIron supplementation and erythropoiesis-stimulating agent (ESA) administration represent the hallmark therapies in preoperative anemia treatment, as reflected in a set of evidence-based treatment recommendations made during the 2018 International Consensus Conference on Patient Blood Management. However, little is known about the safety of these therapies. This systematic review investigated the occurrence of adverse events (AEs) during or after treatment with iron and/or ESAs.MethodsFive databases (The Cochrane Library, MEDLINE, Embase, Transfusion Evidence Library, Web of Science) and two trial registries (ClinicalTrials.gov, WHO ICTRP) were searched until 23 May 2022. Randomized controlled trials (RCTs), cohort, and case-control studies investigating any AE during or after iron and/or ESA administration in adult elective surgery patients with preoperative anemia were eligible for inclusion and judged using the Cochrane Risk of Bias tools. The GRADE approach was used to assess the overall certainty of evidence.ResultsData from 26 RCTs and 16 cohort studies involving a total of 6062 patients were extracted, on 6 treatment comparisons: (1) intravenous (IV) versus oral iron, (2) IV iron versus usual care/no iron, (3) IV ferric carboxymaltose versus IV iron sucrose, (4) ESA+iron versus control (placebo and/or iron, no treatment), (5) ESA+IV iron versus ESA+oral iron, and (6) ESA+IV iron versus ESA+IV iron (different ESA dosing regimens). Most AE data concerned mortality/survival (n=24 studies), thromboembolic (n=22), infectious (n=20), cardiovascular (n=19) and gastrointestinal (n=14) AEs. Very low certainty evidence was assigned to all but one outcome category. This uncertainty results from both the low quantity and quality of AE data due to the high risk of bias caused by limitations in the study design, data collection, and reporting.ConclusionsIt remains unclear if ESA and/or iron therapy is associated with AEs in preoperatively anemic elective surgery patients. Future trial investigators should pay more attention to the systematic collection, measurement, documentation, and reporting of AE data.

The role of anemia on admission in acute coronary syndrome - An umbrella review of systematic reviews and meta-analyses

IntroductionThe role of erythrocytes in the acute coronary syndrome (ACS) is complex. The aim of this review in terms of PICO (P: patients; I: intervention; C: comparison; O: outcome) was to summarize systematic reviews in patients (P) with acute coronary syndrome, evaluating the effects of (I) 1) iron deficiency, 2) administration of an erythropoiesis-stimulating agent (ESA), 3) anemia on admission, 4) red blood cell transfusion, 5) a restrictive transfusion strategy in comparison (C) to 1) no iron deficiency, 2) no ESA 3) no anemia on admission, 4) no red blood cell transfusion, 5) a liberal transfusion strategy on mortality (O). MethodsWe used AMSTAR2 to assess the methodological quality of systematic reviews and grade the available research. The primary endpoint was all-cause mortality. ResultsUsing the data from 2,787,005 patients, the following conditions were associated with worse outcome in patients with ACS: anemia on admission (RR 2.08 95%CI 1.70–2.55) and transfusion (1.93 95%CI 1.12–3.34) of red blood cells. A liberal transfusion (RR 0.86 95%CI 0.70–1-05), administration of ESA (RR 0.55 95%CI 0.22–1.33) and iron deficiency (OR 1.24 95%CI 0.12–13.13) were not associated with altered all-cause mortality. ConclusionPatients suffering from ACS and anemia on admission are at particular risk for adverse outcome. There is evidence of associations between adverse outcomes and receiving red blood cell transfusions.

High-dose intravenous iron supplementation after preoperative autologous blood donation is useful to prevent post-donation/preoperative anemia

To estimate the effectiveness of high-dose intravenous (IV) iron supplementation for iron deficiency anemia after preoperative autologous blood donation (PAD), 155 donors who visited the donation office of the University of Tokyo Hospital from December 2020 to June 2021 and showed suspected post-donation anemia were analyzed. The participants were treated with high-dose intravenous (IV) iron supplementation (high-dose group, n = 30) or a combination of low-dose IV iron and oral iron supplementation (low-dose group, n = 125). The preoperative hemoglobin (Hb) and Hb decreasing ratios during PAD (ΔHb) were compared between the two groups. Multivariate linear regression analyses were also performed to identify the confounding factors associated with preoperative Hb and ΔHb as well as high-dose IV iron supplementation. Preoperative Hb level was slightly higher in the high-dose group than in the low-dose group (12.1 ± 1.1 vs. 11.9 ± 1.1 g/dL, p = 0.27). ΔHb was significantly higher in the high-dose group than in the low-dose group (3.7 % ± 8.8 % vs. 7.7 % ± 6.5 %, p = 0.011). On the multivariate linear regression analyses, high-dose IV iron supplementation was significantly associated with higher preoperative Hb and lower ΔHb levels (p = 0.021 and 0.017, respectively) as well as the donation available period (period from the first visit to the donation office to the operation) and administration of erythropoiesis-stimulating agents. High-dose IV iron supplementation after PAD will be useful in the treatment of post-donation anemia.

Clinical significance of a novel reticulocyte-based erythropoietin resistance index in HD patients: A retrospective study.

The erythropoietin resistance index (ERI) is an indicator of erythropoiesis-stimulating agent (ESA) responsiveness and is typically calculated using Hb. However, Hb does not directly reflect ESA-induced erythropoiesis because of its long-term nature. We thus designed a novel ERI calculated with reticulocyte Hb (RetHb), a real-time index, and investigated its association with mortality in HD patients. We calculated the ERI using the change in RetHb before and after ESA administration (ERIΔRetHb ) and retrospectively analyzed its association with 3-year all-cause mortality using Kaplan-Meier survival curves and Cox regression analyses. A total of 102 patients were included. Patients with the highest ERIΔRetHb had the worst prognosis according to the Kaplan-Meier survival curves (Log-rank p=0.02). Multivariate Cox regression analysis showed that the ERIΔRetHb was significantly and independently associated with all-cause mortality (hazard ratio: 9.82, 95% CI [1.50, 64.41], p=0.02). The ERIΔRetHb was significantly and independently associated with all-cause mortality in HD patients.

Costs associated with the administration of erythropoiesis-stimulating agents for the treatment of anemia in patients with non-dialysis-dependent chronic kidney disease: a US societal perspective.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) are commonly used to treat anemia due to chronic kidney disease (CKD). In addition to drug acquisition costs, the administration of ESAs can include direct and indirect costs due to the needle-based route of administration (eg, time spent by health care staff administering therapy, and patients' and caregivers' time spent receiving or assisting with therapy). However, a comprehensive assessment of the costs associated with the administration of ESAs is lacking. OBJECTIVE: To estimate the excess costs associated with the needle-based administration of ESAs for the treatment of anemia due to non-dialysis-dependent (NDD) CKD in the United States in 2019 from a societal perspective. METHODS: Excess costs associated with ESA administration were estimated as the sum of annual costs that could be avoided with the introduction of an oral treatment with comparable safety and efficacy to ESAs. Cost components included direct health care costs, transportation costs, and work productivity loss costs from the perspective of both patients and caregivers (as applicable). Costs were estimated based on scientific publications, governmental agencies, and the results of a recent survey of US patients and caregivers of patients with anemia and CKD. The setting of the administration (ie, at home vs in clinic), frequency of administration, and insurance type were considered. RESULTS: At the societal level, annual excess costs associated with ESA administration were estimated at $2.5 billion in the United States in 2019, based on an estimated 462,005 patients with anemia and NDD-CKD treated with ESAs. Overall, 94.4% ($2.4 billion) of these costs were incurred from in-clinic ESA administration. When stratifying costs by insurance type, Medicare-insured patients accounted for 79.4% ($2.0 billion) of total annual excess costs. The largest contributor to total annual excess costs was direct health care costs ($1.4 billion, 54.9%), followed by patient work productivity loss costs ($846 million, 33.9%), caregiver work productivity loss costs ($197 million, 7.9%), and transportation costs ($81 million, 3.3%). Total annual excess costs of in-clinic administration ranged from $2,572 per patient receiving monthly administration to $20,948 per patient receiving thrice-weekly administration, while the total annual excess costs of at-home administration ranged from $1,123 per patient receiving monthly administration to $2,109 per patient receiving thrice-weekly administration. At the ESA administration level (ie, for each ESA administration), total excess costs were estimated at $128 per in-clinic ESA administration and $7 per at-home ESA administration, excluding monitoring costs. CONCLUSIONS: The needle-based administration of ESAs in patients with NDD-CKD is associated with a substantial economic burden. The introduction of an oral treatment has the potential to result in important cost savings from a societal perspective. DISCLOSURES: This study was funded by Otsuka Pharmaceutical Development & Commercialization, Inc., and Akebia Therapeutics, Inc. The study sponsors participated in the study design, data collection, analysis, interpretation of the data, writing of the report, and in the decision to submit the manuscript for publication. Gauthier-Loiselle, Cloutier, Serra, Bungay, and Guérin are employees of Analysis Group, Inc., a consulting firm that received funding from Otsuka Pharmaceutical Development & Commercialization, Inc., for the conduct of this study. Michalopoulos was an employee of Otsuka Pharmaceutical Development & Commercialization, Inc., at the time the study was conducted. Szabo is an employee of Akebia Therapeutics, Inc.

Erythropoietin therapy improves endothelial function in patients with non-dialysis chronic kidney disease and anemia (EARNEST-CKD): A clinical study.

Background:This study investigated whether administering erythropoiesis-stimulating agents (ESAs) improves endothelial function in patients with non-dialysis chronic kidney disease (CKD) and anemia.Methods:This single-center, prospective, single-arm comparison study enrolled patients with non-dialysis CKD (stages 4-5) and hemoglobin levels <10 g/dL. ESA administration followed the Kidney Disease: Improving Global Outcomes guideline. The primary endpoint was the change in flow-mediated dilatation after ESA administration in individual patients. The secondary endpoints were changes in 6-minute walk test results, blood pressure, New York Heart Association class, and echocardiographic parameters. The echocardiographic parameters examined included chamber quantification, Doppler parameters, and systolic and diastolic function parameters.Results:Initially, 13 patients were screened, but 2 discontinued due to either heart failure or voluntary withdrawal. The mean flow-mediated dilatation values significantly increased by 10.59% (from 1.36% ± 1.91% to 11.95% ± 8.11%, P = .001). Echocardiographic findings showed that the left ventricular mass index decreased by 11.9 g/m2 (from 105.8 ± 16.3 to 93.9 ± 19.5 g/m2, P = .006), and the left atrial volume index decreased by 10.8 mL/m2 (from 50.1 ± 11.3 to 39.3 ± 11.3 mL/m2, P = .004) after 12 weeks of ESA administration. There were no significant differences between pre- and post-ESA treatment 6-minute walk test results. No significant side effects were observed during the study period.Conclusions:This is the first clinical study to demonstrate that an ESA improves endothelial dysfunction, left ventricular hypertrophy, and left atrial volume in patients with non-dialysis CKD. Thus, ESAs may be considered as adjunctive therapy for reducing cardiovascular risk in these patients.

Efficacy and Cardiovascular Adverse Effects of Erythropoiesis Stimulating Agents in the Treatment of Cancer-Related Anemia: A Systematic Review of Randomized Controlled Trials.

Anemia is a common complication of cancer. Treatment of anemia in cancer is crucial as anemia adversely affects the quality of life, therapeutic outcomes, and overall survival. Erythropoiesis stimulating agents (ESAs) are valuable drugs for treating cancer-related anemia. Cardiovascular adverse effects are a significant concern with ESA therapy, and there is wide variability in therapeutic goals and characteristics of patients who undergo treatment with ESAs. As a result, a careful analysis of the currently available data on the efficacy and safety of these drugs is necessary. This data analysis will aid in the rational use of ESAs for the treatment of anemia in cancer. The objective of this systematic review is to elucidate the pathogenesis of anemia in cancer, assess the effectiveness of ESAs in treating anemia in cancer, and the overall risk of cardiovascular adverse effects associated with the use of ESAs and their impact on prognosis.We searched literature from online databases - PubMed, PubMed Central, MEDLINE, Cochrane Library, and clinical trials register (clinicaltrials.gov) to identify prospective phase II and phase III randomized controlled trials (RCTs). We chose RCTs that directly compared patients with cancer who were treated with ESAs to those who were not treated with ESAs. January 2008 was taken as the lower date limit and May 2021 as the upper date limit. Only English language literature and human studies were included. The quality appraisal was completed using the Cochrane risk bias assessment tool, and data from a total of 10,738 patients with cancer in 17 RCTs were identified and included for systematic review.Our review concludes that ESAs effectively reduce the necessity for blood transfusions and increase mean hemoglobin levels in anemic cancer patients. ESA therapy is associated with cardiovascular adverse effects, including venous thromboembolism, thrombophlebitis, hypertension, ischemic heart disease, cardiac failure, arrhythmia, arterial thromboembolism, and cardiac arrest. Aggressive ESA dosing to achieve higher hemoglobin levels and preexisting uncontrolled hypertension increases these cardiovascular side effects. Venous thromboembolism is the most significant adverse effect attributed to ESA therapy. However, there is no major change in overall survival with ESA therapy, and administration of ESAs can be carried out in anemic cancer patients with careful assessment of thromboembolism risk factors, risk-benefit ratio, and monitoring of hemoglobin levels.

Holding Iron Measurement to a Gold Standard: Comparing Reticulocyte Hemoglobin Content to Traditional Biomarkers in Predicting Response to Intravenous Iron Supplementation in Hemodialysis Patients

Background: Patients suffering from end stage renal disease (ESRD) commonly develop functional and absolute iron deficiency due to various etiologies, requiring regular intravenous iron supplementation. Current methods of quantifying iron stores, such as serum iron and transferrin saturation (TSAT), may be inaccurate measures for detecting functional iron deficiency. This increases the likelihood of incomplete correction of iron deficiency or the risk of developing iron overload, both resulting in higher healthcare and administrative costs. Recent studies focusing on reticulocyte hemoglobin content (CHr) have shown it to be a specific and sensitive indicator of absolute and functional iron deficiency.Aims: To determine whether CHr is a more sensitive and accurate surrogate measure of response to iron infusion than traditional measurements such as serum iron and TSAT.Methods: We performed a retrospective chart review of patients aged ≥18 years with ESRD receiving dialysis and regular intravenous iron infusions at University of Iowa Hospitals and Clinics between October 2016 and March 2017 who also had applicable serial laboratory monitoring. Parameters analyzed included hemoglobin, hematocrit, CHr, serum iron, TSAT, total iron binding capacity, and ferritin. 3 months later, along with the total dose of iron infused over that specific timeframe, we obtained subsequent sets of these values.Results: Fifty-three eligible patients were identified, of which 63% were male and 37% female with a median age of 59 years. The median time interval between initial and subsequent laboratory testing was 91 days; the median cumulative iron infusion was 300 mg with doses ranging from 0 to 2100 mg. Correlation between variables of interest and iron dosing were calculated for serum iron (p = 0.49), TSAT (p = 0.16), and CHr (p = 0.99). With removal of subjects who had received the median 300 mg dose, correlation coefficients were recalculated for serum iron (p = 0.49), TSAT (p = 0.21), and CHr (p = 0.93).Conclusions: Contrary to published data, our study did not show any statistically significant support for CHr as a superior predictor of response to iron infusion when compared to traditional biomarkers. Our negative finding could be tempered by small sample size; this data was also not adjusted for other factors including hemoglobin level or erythropoiesis-stimulating agent administration. Given their reported resilience in response to acute fluctuations in patient inflammatory states and potentially decreased cost of testing versus the traditional iron panel, interest in reticulocyte parameters remains high. We plan to control for or identify any confounding factors by performing a prospective cohort study on a larger population to further elucidate the validity of this finding. DisclosuresNo relevant conflicts of interest to declare.

Trends in Erythropoiesis-stimulating agent use and blood transfusions for chemotherapy-induced anemia throughout FDA's risk evaluation and mitigation strategy lifecycle.

Erythropoiesis-stimulating agents (ESAs), indicated for treating some patients with chemotherapy-induced anemia (CIA), may increase the risk of tumor progression and mortality. FDA required a Risk Evaluation and Mitigation Strategy (REMS) to mitigate these risks. We assessed REMS impact on ESA administration and red blood cell (RBC) transfusion as surrogate metrics for REMS effectiveness. Retrospective cohort study including data from January 1, 2006 to December 31, 2018 for beneficiaries ≥65 years enrolled in Centers for Medicare & Medicaid Services (CMS) Medicare Parts A/B with a cancer diagnosis; patients with other indications for ESA use were excluded. Study time was divided into five periods demarcated by issuance of CMS National Coverage Determination (NCD) (Pre-NCD, Pre-REMS) and REMS milestones (Grace Period, REMS, post-REMS). Study outcomes were monthly proportion of chemotherapy episodes (CTEs) with concomitant ESA administration, with post-CTE ESA administration, and with RBC transfusions. Of 1 778 855 beneficiaries treated with CT, 308742 received concomitant ESA for CIA. The proportion of CTEs with concomitant and post-CTE ESA administration decreased Pre-REMS (9.0 percentage points [pp] and 3.5 pp, respectively). There were no significant post-REMS changes in the proportion of CTEs with concomitant (0.0 pp) and post-CTE ESA administration (0.1 pp). Fluctuation in RBC transfusions was <4 pp throughout the study period. Medicare beneficiaries showed a substantive decrease in ESA administration after NCD, with minimal impact by the REMS and its removal. Small changes in RBC transfusion over the study period were likely due to a national secular trend.

Factors associated with hepcidin-25 levels in maintenance hemodialysis patients.

This study aimed to investigate the factors that are independently associated with hepcidin-25 and its relationship with doses of erythropoiesis-stimulating agents (ESAs) and intravenous iron in stable maintenance hemodialysis patients (smHD) stratified by ESAs administration. In 103 adult smHD (ESAs therapy (N=64) and ESAs-free (N=39)), median values of biologically active hepcidin-25 (chemiluminescent direct ELISA assay) and ferritin levels were significantly higher whereas red blood cell count, hemoglobin, and hematocrit values were lower in ESAs therapy compared to ESAs-free group (P < .001, for all). Our results suggest that ESAs-independent smHD exhibit supposedly normal hepcidin-25 levels and preserved iron homeostasis, with a lower degree of anemia. The results of our multivariable model indicate that hepcidin-25 levels are independently and positively associated with iron stores and inflammation, and inversely with active erythropoiesis, regardless of ESAs administration. Maintenance ESAs and the intravenous iron dose were not related to hepcidin-25 levels.

Renal prognoses by different target hemoglobin levels achieved by epoetin beta pegol dosing to chronic kidney disease patients with hyporesponsive anemia to erythropoiesis-stimulating agent: a multicenter open-label randomized controlled study.

There is no evidence regarding appropriate target hemoglobin levels in chronic kidney disease (CKD) patients with an erythropoiesis-stimulating agent (ESA)-hyporesponsiveness. Therefore, we conducted a randomized controlled study in non-dialysis dependent CKD (NDD-CKD) patients with ESA-hyporesponsiveness, comparing results of intensive versus conservative treatment to maintain hemoglobin levels. This was a multicenter, open-label, randomized, parallel-group study conducted at 89 institutions. Among NDD-CKD patients, those with ESA-hyporesponsive renal anemia were randomly assigned to an intensive treatment group, to which epoetin beta pegol was administered with target hemoglobin level of 11g/dL or higher, or conservative treatment group, in which the hemoglobin levels at enrollment (within ± 1g/dL) were maintained. The primary endpoint was the time to the first kidney composite event defined as (1) transition to renal replacement therapy (dialysis or renal transplantation); (2) reduction of estimated glomerular filtration rate (eGFR) to less than 6.0mL/min/1.73m2; or (3) reduction of eGFR by 30% or more. Secondary endpoints were kidney function (change rate in eGFR), cardiovascular (CV) events, and safety. Between August 2012 and December 2015, 385 patients were registered, and 362 patients who met the eligibility criteria were enrolled. There was no significant difference in kidney survival or in CV events between the two groups. However, the incidences of the 3 types of kidney composite events tended to differ. In NDD-CKD patients with ESA-hyporesponsive renal anemia, the aggressive administration of ESA did not clearly extend kidney survival or result in a significant difference in the incidence of CV events.

The Role of Eryptosis in the Pathogenesis of Renal Anemia: Insights From Basic Research and Mathematical Modeling.

Red blood cells (RBC) are the most abundant cells in the blood. Despite powerful defense systems against chemical and mechanical stressors, their life span is limited to about 120 days in healthy humans and further shortened in patients with kidney failure. Changes in the cell membrane potential and cation permeability trigger a cascade of events that lead to exposure of phosphatidylserine on the outer leaflet of the RBC membrane. The translocation of phosphatidylserine is an important step in a process that eventually results in eryptosis, the programmed death of an RBC. The regulation of eryptosis is complex and involves several cellular pathways, such as the regulation of non-selective cation channels. Increased cytosolic calcium concentration results in scramblase and floppase activation, exposing phosphatidylserine on the cell surface, leading to early clearance of RBCs from the circulation by phagocytic cells. While eryptosis is physiologically meaningful to recycle iron and other RBC constituents in healthy subjects, it is augmented under pathological conditions, such as kidney failure. In chronic kidney disease (CKD) patients, the number of eryptotic RBC is significantly increased, resulting in a shortened RBC life span that further compounds renal anemia. In CKD patients, uremic toxins, oxidative stress, hypoxemia, and inflammation contribute to the increased eryptosis rate. Eryptosis may have an impact on renal anemia, and depending on the degree of shortened RBC life span, the administration of erythropoiesis-stimulating agents is often insufficient to attain desired hemoglobin target levels. The goal of this review is to indicate the importance of eryptosis as a process closely related to life span reduction, aggravating renal anemia.