Use Of Erythropoiesis-stimulating Agents Research Articles

Nephrology referral slows the progression of chronic kidney disease, especially among patients with anaemia, diabetes mellitus, or hypoalbuminemia: A single-centre, retrospective cohort study.

The Kidney Disease Improving Global Outcomes guidelines recommend nephrology referral for patients with chronic kidney disease (CKD) stages 4 to 5, significant proteinuria and persistent microscopic haematuria. However, the recommendations are opinion-based and which patients with CKD benefit more from nephrology referral has not been elucidated. In this retrospective cohort study, patients referred to our nephrology outpatient clinic from April 2017 to March 2019 were included. We excluded patients considered to have an acute decline in kidney function (annual decline in estimated glomerular filtration rate [eGFR] >10 mL/min/1.73 m2). The slopes of eGFR before and after nephrology referral were estimated and compared by linear mixed effects models. Interaction between time and referral status (before or after referral) was assessed and effect modifications by the presence of diabetes, proteinuria (defined by urine dipstick protein 2+ or more), urine occult blood, hypoalbuminemia (defined by albumin levels less than 3.5 g/dL) and anaemia (defined by haemoglobin levels less than 11.0 g/dL) were evaluated. The eGFR slope significantly improved from -2.05 (-2.39 to -1.72) to -0.96 (-1.36 to -0.56) mL/min/1.73 m2/year after nephrology referral (p < .001). The improvement in eGFR slope was more prominent among those with diabetes mellitus, anaemia, and hypoalbuminemia (all p-values for three-way interaction <.001 after adjustment for covariates). Further adjustments for time-dependent haemoglobin levels, the use of erythropoiesis-stimulating agents, iron supplementation, anti-hypertensives and anti-diabetic medications did not change the significance of the interactions. Nephrology referral slows CKD progression, especially among those with hypoalbuminemia, diabetes or anaemia. Patients with hypoalbuminemia, diabetes or anaemia might benefit more from specialized care and lifestyle modifications by nephrologists. The inclusion of anaemia and hypoalbuminemia in nephrology referral criteria should be considered.

Prognostic impact of erythropoietin-stimulating agent use during front-line chemotherapy in patients with ovarian cancer: A Korean multicenter cohort study.

To evaluate whether treatment with erythropoiesis-stimulating agents (ESAs) for chemotherapy-induced anemia affects progression-free survival (PFS) in patients receiving front-line chemotherapy following surgery for ovarian cancer (OC). We retrospectively reviewed all consecutive patients who received front-line chemotherapy after surgery between 2013 and 2019 at six institutions. The patients were divided according to the use of ESAs during front-line chemotherapy. The primary endpoint was PFS. The secondary endpoint was the occurrence of thromboembolism. Propensity score matching (PSM) analysis was used to compare survival between matched cohorts. Overall, 2147 patients (433 receiving ESA and 1714 for no-ESA) were identified, with a median follow-up of 44.0 months. The ESA group showed a significantly higher proportion of stage III/IV disease (81.8% vs 61.1%; P < 0.001) and postoperative gross residual disease (32.3% vs 21.2%; P < 0.001) than the no-ESA group. In the multivariable Cox regression analysis, the use of ESAs did not affect PFS (adjusted hazard ratio, 1.03; 95% confidence interval [CI]: 0.89-1.20; P = 0.661). The incidence of thromboembolism was 10.2% in the ESA group and 4.6% in the no-ESA group (adjusted odds ratio, 6.58; 95% CI: 3.26-13.28; P < 0.001). When comparing the well-matched cohorts after PSM, PFS did not differ between the ESA (median PFS 23.5 months) and no-ESA groups (median PFS 22.2 months) (P = 0.540, log-rank test). The use of ESAs during front-line chemotherapy did not negatively affect PFS in patients with OC after surgery but increased the risk of thromboembolism.

Identification and management of preoperative anaemia in adults: A British Society for Haematology Guideline update.

This updated British Society for Haematology guideline provides an up-to-date literature review and recommendations regarding the identification and management of preoperative anaemia. This includes guidance on thresholds for the diagnosis of anaemia and the diagnosis and management of iron deficiency in the preoperative context. Guidance on the appropriate use of erythropoiesis-stimulating agents and preoperative transfusion is also provided.

A survey of iron supplementation, iron status surveillance, and erythropoiesis stimulating agent use in level III NICUs in the United States.

A survey of iron supplementation, iron status surveillance, and erythropoiesis stimulating agent use in level III NICUs in the United States.

Identifying individuals at risk of needing CKD associated medications in a European kidney disease cohort

BackgroundThe consequences of chronic kidney disease (CKD) can be addressed with a range of pharmacotherapies primarily prescribed by nephrologists. More accurate information regarding future CKD-related pharmacotherapy requirements could guide clinical decisions including follow-up frequency.MethodsFollowing assignment to derivation and validation groups (2,1), variables predicting individually future use of vitamin D receptor agonists (VDRA), phosphate binders, erythropoiesis stimulating agents (ESAs) and iron were identified using logistic regression in a prospective cohort study containing demography, comorbidity, hospitalization, laboratory, and mortality data in patients with CKD stage G4/G5 across six European countries. Discriminative ability was measured using C-statistics, and predicted probability of medication use used to inform follow-up frequency.ResultsA total of 2196 patients were included in the analysis. During a median follow-up of 735 days 648 initiated hemodialysis and 1548 did not. Combinations of age, diabetes status and iPTH, calcium, hemoglobin and serum albumin levels predicted the use of ESA, iron, phosphate binder or VDRA, with C-statistics of 0.70, 0.64, 0.73 and 0.63 in derivation cohorts respectively. Model performance in validation cohorts were similar. Sixteen percent of patients were predicted to have a likelihood of receiving any of these medications of less than 20%.ConclusionsIn a multi-country CKD cohort, prediction of ESA and phosphate binder use over a two-year period can be made based on patient characteristics with the potential to reduce frequency of follow-up in individuals with low risk for requiring these medications.

The Risk of Venous Thrombosis for Erythropoiesis Stimulating Agents and Blood Transfusions in Cancer Patients: A Nationwide Population-Based Study in Korea

Introduction: Several previous studies have indicated that both erythropoiesis-stimulating agents (ESAs) and blood transfusions elevate the risk of venous thrombosis in cancer patients. Nevertheless, there has been inconsistency in the evidence regarding whether ESAs or blood transfusions are more closely linked to thrombotic complications. To address this, nationwide population data was analyzed to explore the association between the use of ESAs, blood transfusions, and the risk of venous thrombosis in cancer patients. Methods: This study utilized a case-crossover design and analyzed the National Health Insurance Database of Korea. A total of 710,910 patients diagnosed cancer (ICD-10 code: C00.x-C26.x, C30.x-C34.x, C37.x-C41.x, C45.x-C58.x, C60.x-C76.x, C81.x-C85.x, C88.3, C88.7, C88.9, C90.0, C90.1, C91.x-C93.x, C94.0-C94.3, C94.5, C94.7, C95.x, C96.x) between January 1, 2011, and December 31, 2020 were included. Of these, 57,256 (8.03%) identified with venous thrombosis (ICD-10 code: I80.x). The hazard period, starting from the week of thrombosis and going back 12 weeks, was compared to an earlier 12-week control period separated by a 24-week gap. Secondary analyses were conducted with different durations for the hazard/control periods (8 and 4 weeks) to assess the robustness of the results. Patients served as their own controls, and time-dependent covariates such as granulocyte colony-stimulating factor and chemotherapy were evaluated for their association with thrombotic risk. Patients were categorized based on occurrences of inpatient hospitalization, red blood cell transfusion, platelet transfusion, central venous catheter placement, and major surgery during hazard and control periods, and these variables were compared using χ2 tests. Finally, conditional logistical regression was employed to compare the odds of exposure to ESAs, blood transfusions, and other thrombosis risk factors during the hazard period to the exposure odds during the control period. Results: There were similar rates of ESA use during the hazard period and the control period (0.88% vs. 0.28%; P = 0.477). However, red blood cell transfusions (6.85% vs. 1.79%; P &amp;lt;0.001), platelet transfusions (1.92% vs. 0.48%; P = 0.003), insertion of a central venous catheter (3.34% vs. 0.74%; P &amp;lt;0.001), hospitalizations (11.79% vs. 2.77%; P &amp;lt;0.001), and major surgery (5.70% vs. 2.00%; P &amp;lt;0.001) differed significantly between the two exposure periods. All of these factors were more frequent during the hazard period compared to the control period. In the crude conditional logistical regression model, the odds ratio (OR) for ESA use was significantly increased (OR = 3.14; 95% CI: 2.63, 7.75). However, after controlling for other covariates including red blood cell transfusions, platelet transfusions, central venous catheter insertion, hospitalization, and major surgery in an adjusted model, ESA use was found to be non-significant (OR = 1.12; 95% CI: 0.93, 1.36). In contrast to ESA use, red blood cell transfusion was associated with an increased risk of thrombosis in both the crude model (OR = 3.83; 95% CI: 3.58, 4.11) and the adjusted model (OR = 1.44; 95% CI: 1.32, 1.58). This study also investigated whether varying the lengths of the hazard and control periods (8 and 4 weeks) would affect the association between ESA use, red blood cell transfusions, and thrombotic events. The results showed that the association remained consistent regardless of the duration of the periods. Overall, these findings suggest that while there was an increased risk of thrombosis associated with red blood cell transfusions, the use of ESAs did not show a significant association with thrombotic events after adjusting for other relevant factors. Conclusions: This study revealed a stronger association between red blood cell transfusions and thrombotic complications in cancer patients. These findings suggest that red blood cell transfusions may have a higher thrombotic risk compared to ESAs in this particular patient population. Furthermore, the results indicate that the use of ESAs in cancer patients might not increase the risk of thrombotic complications depending on the exposure duration. Further studies are needed to assess the impact of ESAs and blood transfusions on thrombotic risk in different populations.

Addressing Chronic Anemia in Sickle Cell Disease: Characterizing Erythropoiesis-Stimulating Agent (ESA) Utilization and Practice Patterns Among Providers

Background: Chronic anemia exerts profound impacts on the morbidity, mortality, and quality of life in individuals with sickle cell disease (SCD), but therapeutic options are limited. Erythropoietin-stimulating agents (ESAs) are the standard of care for managing anemia in chronic kidney disease (CKD). However, their utilization in SCD remains ad hoc, with limited literature and no guidelines supporting the use of ESAs in SCD. To address this knowledge gap, we present preliminary findings from a survey designed to evaluate provider practices and identify factors influencing the use of ESAs in SCD. Methods: We conducted a cross-sectional web-based survey from March-July 2023 among providers taking care of patients with SCD in the United States (US) and internationally. Survey items were developed to assess provider demographic characteristics, practice environments, and provider practices around ESA use in SCD. The data was collected and managed using REDCap electronic data capture tools hosted at the University of Pittsburgh. Descriptive statistics were used to report the data. Results: The survey has been completed by 33 providers as of a cut date of July 23, 2023. Most providers were hematologists who practiced in an academic setting (23/33, 69.7%), with an equal gender distribution (Table 1). The number of patients with SCD seen annually varied, with 101-300 patients being the most common cohort size (13/33, 39.4%). In the 12 months prior to survey completion, 15/33 (45.5%) providers treated at least 1 patient with SCD with ESAs, usually outpatient (Table 2). Commonly reported barriers to outpatient ESA therapy included lack of insurance approval/coverage or cost concerns, lack of provider experience, and patient tolerability/adherence or inability to perform self-injections. Fewer respondents reported no barriers to prescribing ESAs in the outpatient setting, compared to in the acute/inpatient setting (18.2% vs. 48.5%). The most commonly reported indications for starting ESAs in the outpatient setting were chronic anemia from end-stage renal disease or CKD, reduction of blood transfusion requirement, and chronic anemia in patients refractory to approved therapies. Less commonly reported indications include severe or symptomatic anemia alone and chronic anemia in the setting of cardiopulmonary disease. Respondents reported several contraindications to starting ESAs, including a history of venous thromboembolism (VTE), malignancy, stroke, coronary artery disease, hypertension, and frequent vaso-occlusive crises. Respondents also expressed concerns about the cost/insurance coverage, efficacy, safety, patient burden, and appropriate dosing of ESAs in patients with SCD. Only 18/33 (54.5%) respondents reported ever treating outpatients with SCD with ESAs; nearly all of them used 1 st generation ESAs, and a majority used 2 nd generation ESAs. For 1 st generation ESAs, the most common starting dose was 3500-7000 units (U) (50-100 U/kg; 22.2%) or 7001-14000 U (101-200 U/kg; 22.2 %). Once weekly was the most common dosing interval (50%), followed by three times a week (TIW; 27.8%) and twice a week (16.7%). The maximum dose used was 56001-70000 U (801-1000 U/kg) TIW. For 2 nd generation ESAs, the most common starting dose was 141-210 mcg (2.1-3.0 mcg/kg) (22.2%), and administration often occurred once every 2 weeks (44.4%) or weekly (27.8%). The maximum dose used was 211-315 mcg (3.1-4.5 mcg/kg) weekly. Outpatient ESAs were most often initiated for hemoglobin (Hb) &amp;lt; 6 g/dL (8/18, 44.4%), and Hb &amp;gt; 9 g/dL was the most common treatment target (6/18, 33.3%). ESAs were often combined with hydroxyurea, voxelotor, and simple transfusions (Table 2). Conclusion: These preliminary survey results show considerable variability in how ESAs are currently being used in people with SCD. These variations in clinical practice highlight both significant ambiguity about what works in this setting and the need for further research into the optimal use of ESAs for the management of chronic anemia in SCD (ongoing clinical trial: ACHiEvE-SCD, NCT05451940). Future directions include evaluating differences in practice patterns among adult vs. pediatric and US-based vs. non-US-based providers.

Daprodustat, a Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitor, Improves Hematological Insufficiency without Progression of Myelodysplastic Syndrome with Chronic Kidney Disease

Introduction Hematological insufficiency is a critical issue in the treatment of myelodysplastic syndrome (MDS). The current standard treatment for cytopenia in MDS involves blood transfusion and the administration of erythropoiesis stimulating agents (ESAs). However, ESAs are only effective in certain patients with low erythropoietin levels; patients who are not suitable candidates for allogeneic hematopoietic stem cell transplantation (allo-HSCT) require lifelong blood transfusions. As a result, there is a growing demand for new treatments for cytopenia in MDS, and researchers have been exploring various molecular-targeted drugs in recent years. One promising option is the hypoxia-inducible factor -prolyl hydroxylase inhibitor (HIF-PHi). This inhibitor stabilizes HIF1α, which in turn normalizes endogenous erythropoietin production and iron metabolism, leading to improved renal anemia. It is believed that HIF-PHi could potentially enhance MDS-related anemia by increasing erythropoietin levels. However, despite some case reports, there have been no comprehensive clinical studies evaluating the effectiveness and safety of HIF-PH inhibitors for MDS. Moreover, it is essential to address concerns related to HIF1α overexpression, which has been associated with exacerbating various malignant tumors, including MDS. To assess the safety and effectiveness of HIF-PHi for MDS, we conducted a prospective clinical trial evaluating an oral HIF-PHi called daprodustat. Methods The study included MDS patients with chronic kidney disease (CKD) stage ≥ 3, considering daprodustat's approval in Japan, at Ebina General Hospital. Patients with MDS who were treated with deoxyribonucleic acid methylation inhibitors and/or who underwent allo-HSCT were excluded. Participants were administered daprodustat at the approved dose for renal anemia and underwent regular blood sampling and bone marrow examination. The primary and secondary endpoints were the leukemia rate within 1 year after HIF-PHi administration and hematological improvement (HI), respectively. The study was conducted in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki) and was approved by the Institutional Review Board of the Ebina General Hospital (approval number: JMA-388). Written informed consent was obtained from all participants. Results Seventeen patients with MDS, with a median age of 81years, were included in the analysis. Revised International Prognostic Scoring System scores (IPSS-R) were very low, low, intermediate, high, and very high in 1, 11, 3, 1, and 1 patients, respectively. Five cases were changed from ESA treatment. Within 1 year after HIF-PHi administration, no patients developed leukemia, and both peripheral blood Wilms tumor 1 protein concentrations and bone marrow myeloblast counts remained unchanged from pre-treatment levels. HI was observed in 8 patients within 6 months, and the median dose was 6 (range, 2-12) mg for HI achievement. On univariate analysis, pretreatment transferrin saturation (TSAT, P = 0.002, Figure 1) and ferritin concentration ( P = 0.016) were inversely associated with HI achievement. However, pretreatment hepcidin concentration, erythropoietin concentration, previous ESA use, and IPSS-R were not associated with HI achievement. Notably, when a TSAT cutoff of &amp;lt; 45% was used, achieving HI showed a sensitivity and specificity of 87.5% and 100.0%. Moreover, patients with TSAT &amp;lt; 45% showed significant improvement in anemia after 3 months and beyond (Figure 2). No significant differences were observed in neutrophil and platelet counts between the two groups. Throughout the study, eleven adverse events occurred, including 6 infections, and 1 case each of myocardial infarction, eosinophilia, erythema multiforme, organizing pneumonia, and spinal fracture. Conclusion HIF-PHi administration did not lead to MDS progression. Notably, in MDS patients with CKD, low TSAT was a predictor for achieving HI by HIF-PHi.

Safety and Preliminary Efficacy of DFV890 in Adult Patients with Myeloid Diseases: A Phase 1b Study

Background and Significance: Patients (pts) with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) have a high unmet medical need, with limited standard-of-care therapeutic approaches, particularly after failure of response to first-line agents, and with allogeneic hematopoietic transplant as the only potential curative option. Through the production of interleukin (IL)-1β and IL-18, the NLRP3 inflammasome has been implicated as a major driver of inflammation associated with acute and chronic inflammatory diseases. The NLRP3 pathway is activated in hematopoietic stem and progenitor cells and in the marrow microenvironment in myeloid neoplasms such as MDS and CMML contributing to ineffective hematopoiesis and clonal progression (Hamarsheh 2020; Basiorka 2016). DFV890, a small molecule NLRP3 inhibitor, blocks IL-1β and IL-18 secretion and pyroptotic cell death in response to a wide variety of NLRP3-dependent danger signals, both in vitro and in vivo. Therefore, DFV890 may disrupt the smoldering inflammation and provide disease-modifying benefits to pts by improving hematopoiesis. Study Design and Methods: This is an open-label, phase 1b, multicenter study with a randomized dose-optimization part and a dose-expansion part consisting of two groups evaluating DFV890 in pts with very low, low, or intermediate risk MDS (LR-MDS) per revised International Prognostic Scoring System (IPSS-R) criteria and low or intermediate-1 risk CMML (LR-CMML) per CMML-specific Prognostic Scoring System (CPSS) criteria (NCT05552469). Eligible pts must be 18 years of age, with an Eastern Cooperative Oncology Group performance status ≤2, candidates for serial bone marrow assessments who are willing to undergo a bone marrow aspirate/biopsy during the trial, and meet one of the following: (a) IPSS-R-defined LR-MDS who failed to respond to or did not tolerate erythropoiesis-stimulating agents (ESAs) or luspatercept or hypomethylating agents (HMAs) and pts with del 5q who failed to respond to or did not tolerate lenalidomide; (b) CPSS-defined LR-CMML who failed to respond to or did not tolerate hydroxyurea or HMAs. Key exclusion criteria include treatment with systemic antineoplastic or any experimental therapies within 28 days (or 5 half-lives, whichever longer); unresolved treatment-related toxicities prior to the first dose of study treatment; previous treatment with agents targeting the NLRP3 inflammasome and the IL-1 pathways; prior use (≤1 week or 5 half-lives, whichever is longer) of hematopoietic colony-stimulating growth factors, thrombopoietin mimetics or ESAs; and concomitant medications, known to modulate cytochrome P450 enzymes. DFV890 is administered orally twice daily (bid) for a minimum of 24 weeks (6 cycles of treatment [1 cycle=28 days]) until treatment discontinuation. In the dose-optimization part, pts are randomized to receive either low dose or high dose bid and stratified by indications. The recommended dose (RD) determined from this part is further explored in the dose-expansion part to confirm safety and tolerability of DFV890 and explore preliminary efficacy. The primary objective is to assess safety (incidence and severity of adverse events, and dose-limiting toxicities) and tolerability to then determine the optimal RD for DFV980. Secondary objectives include assessment of DFV890 pharmacokinetics, evaluation of the preliminary efficacy of DFV890 on transfusion burden, and hematologic improvement: time to onset of transfusion independence; duration of response, best overall response, overall response rate, progression-free survival, and time to progression; and reduction in spleen volume (for CMML). Key exploratory objectives include patient perceptions of tolerability as measured by patient-reported outcomes; and determination of genetic characteristics and potential predictive markers of efficacy and/or resistance. The study is currently enrolling in Singapore, Hong Kong, and the USA with plans to treat approximately 80 pts. The first patient first visit was achieved on May 8, 2023.

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.

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.

Association of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors with Cardiovascular Events and Death in Dialysis Patients: A Systematic Review and Meta-Analysis

Background: Anemia is a common finding among patients with advanced chronic kidney disease, especially those on dialysis. The recent introduction of hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) has raised some concerns about the cardiovascular and thrombotic complications of this class of drugs. Objectives: This meta-analysis aimed to assess the safety of HIF-PHIs in patients with end-stage kidney disease (ESKD) versus standard therapy with erythropoiesis-stimulating agents (ESAs). Methods: Databases were searched on April 2022. Studies that reported incidence of all-cause mortality; major cardiovascular adverse events (MACEs); myocardial infarction (MI); stroke and thrombotic events in the use of HIF-PHIs or ESA on ESKD patients in hemodialysis or peritoneal dialysis were evaluated. Data were extracted from published reports, and quality assessment was performed per Cochrane recommendations. Results: 12,821 patients from ten randomized controlled trials were included in this study. Most patients (83%) were on hemodialysis. 6,461 (50.3%) were using HIF-PHIs, and 6,360 (49.6%) were in the ESA group. The pooled estimated incidence of all-cause mortality was 769 in the HIF-PHIs group (relative-risk ratios (RR): 1.04; confidence interval (CI): 0.95–1.14; p = 0.52; I² = 0%). There was no difference in the groups regarding the outcomes of MACE in the analysis of the three studies that reported this outcome (RR: 0.95; CI: 0.87–1.04; p = 0.69; I² = 0%). In addition, there was no statistical difference among the outcomes of MI, stroke, or thrombotic events. Conclusions: Among patients with ESKD on dialysis, the use of HIF-PHIs was non-inferior regarding the safety outcomes when compared to standard of care therapy.

#5644 SELECTED CARDIOVASCULAR AND NON-CARDIOVASCULAR EVENTS IN INCIDENT AND PREVALENT DIALYSIS PATIENTS IN THE US MEDICARE POPULATION

Abstract Background and Aims The ASCEND-D/ID trial reported safety and efficacy of daprodustat in patients receiving dialysis [1,2]. Rates and types of clinical outcomes vary between incident and prevalent dialysis patients. This study assessed events, of which most were described as safety events in ASCEND-D/ID trial, among incident dialysis patients on erythropoiesis-stimulating agents (ESAs) and prevalent dialysis patients in the US Medicare population. Method This is a retrospective, observational cohort study using United States Renal Data System data. The study included incident dialysis-dependent (IDD) patients from 2017–2019 and, separately, prevalent dialysis-dependent (PDD) patients as of January 1, 2018. For IDD patients, the index date was the dialysis initiation date; for PDD patients, the index date was January 1, 2018. To establish the cohorts, we further required patients to have at least 6 continuous months of Medicare Parts A and B coverage prior to, and be aged ≥18 years on, the index date. For IDD patients, we also required ESA use on the index date to better support comparability to the PDD patients. Patients with a history of kidney transplant or who had cancer during the year prior to, or who had a hospitalization for heart failure (HF), myocardial infarction (MI), or a stroke in the 4 weeks before, the index date were excluded. Patients were followed from index date (for IDD patients, follow-up started from index date plus 60 days to ascertain dialysis modality stability) to the earliest date of death, loss of Medicare coverage, kidney transplantation, or December 31, 2019. Events assessed were cardiovascular (CV: all-cause death, HF, MI, stroke, thromboembolic events [TEE], major adverse CV events [MACE: composite of death, MI, stroke], and MACE+HF) and non-CV (cancer, gastric erosions, ocular events, seizures, serious infection) events, derived from medical claims in the follow-up period using ICD-10 diagnosis, Healthcare Common Procedure Coding System, and Current Procedural Terminology codes in the follow-up period. HF, MI, stroke, and serious infection events were defined as inpatient events. TEEs included vascular access thrombosis (VAT), deep venous thrombosis (DVT), and pulmonary embolism (PE). First event rates were calculated separately for IDD and PDD cohorts and expressed as number of events per 100 patient-years. Results The IDD cohort contained 23,909 patients; the PDD cohort, 230,055. Median follow-up time was 12.6 months for the IDD cohort and 24.0 months for PDD cohort. Mean ages of the IDD and PDD cohorts were 70.3 and 63.3 years, respectively. Compared with the PDD cohort, patients in the IDD cohort were more likely to be female (48.2% vs 43.7%), of non-Hispanic White race (61.6% vs 40.4%), less likely be of lower-income status (33.0% vs 47.4% for Medicare/Medicaid dual enrollment and 38.6% vs 57.0% for Part D low-income subsidy) and with higher proportion of comorbidities. First event rates are shown in the Table for the IDD and PDD cohorts. Compared with the PDD cohort, patients in the IDD cohort had higher rates of all-cause mortality (17.3 vs 16.8 per 100 patient-years), stroke (1.8 vs 1.4), VAT (109.4. vs 67.2, hemodialysis patients only), and MACE (20.9 vs 20.3); however, they had lower rates of MI (3.1 vs 3.5), HF (7.1 vs 8.9), DVT (3.2 vs 4.0), and MACE+HF (25.6 vs 26.9). For non-CV events, patients in the IDD cohort had lower event rates for nearly all events except malignancies. Conclusion ESA-treated IDD patients had higher event rates for some CV events but lower rates for most non-CV events compared with PDD patients. As expected, however, rates of VAT were higher in IDD patients than PDD patients. These background event rates in real-world populations with wide ESA use provide context when considering potential alternative treatments for anemia. Limitation of this descriptive study includes the reporting of crude (unadjusted) rates, and therefore should be interpreted with caution. Funding: GSK (study 217316).

#6131 ANEMIA IN PERITONEAL DIALYSIS

Abstract Background and Aims Anemia is one of the most frequent complications of chronic kidney disease (CKD), affects quality of life and increases morbidity and mortality. Prevalence of anemia in patients on peritoneal dialysis (PD) is 83% according to the RIKAS study. Diagnosis of anemia in CKD is set at a hemoglobin (Hb) below 13 g/dL in men and less than 12 g/dL in women. These values serve to define the diagnosis, but not to indicate treatment. Treatment is based on the use of erythropoiesis stimulating agents (ESA) and iron therapy. Absolute iron deficiency (ferritin less than 100 ng/ml and transferrin saturation index (TSAT) less than 20%) and functional iron deficiency (TSAT less than 20% with normal ferritin), require correction with oral or intravenous iron before the use of ESA. Treatment with ESA is indicated when Hb is below 10g/dL despite adequate iron stores. The goal is to achieve Hb values between 10-12g/dL. The aims are evaluating the situation of patients in our PD program with respect to anemia, its prevalence, treatment and its results. Method This is an observational, descriptive, cross-sectional and single-center study. Inclusion criteria were patients older than 18 years with at least 3 months of permanence in our PD program. We collected: age, sex, cause of CKD, type of PD, time on PD, origin (pre-dialysis, hemodialysis, kidney transplant), residual diuresis, diabetes mellitus (DM), high blood pressure (HBP), ischemic heart disease, bleeding, urea, creatinine, albumin, calcium, phosphorus, Hb, hematocrit, iron, ferritin, TSAT, C-reactive protein (CRP), transfusions and treatments (ESA and/or iron therapy). Descriptive statistical analysis (mean, standard deviations, maximums and minimums) and comparative analysis between variables was performed using Chi-square test and ANOVA for qualitative and quantitative variables, respectively. Results N = 58 patients, 64% men and 36% women. The mean age was 61.3+/- 15.54 years. 31% of patients were CKD secondary to glomerulonephritis (predominant etiology). 5% had no cardiovascular risk factors (CVRF), 48% between one and two and 47% more than three. 74% on continuous ambulatory peritoneal dialysis (CAPD). Mean time on dialysis 28.74 +/- 25.05 months. Mean residual diuresis in 24 hours 1199.22 +/- 703.14 cc. Prevalence of anemia 74%. Mean Hb of 10.97 +/-1.29 g/dL with 78% of patients with values between 10-12 g/dl. Mean ferritin of 356.79 +/-226.84 mg/dL with 79% of patients between 100-500 mg/dl. 83% received treatment with ESA, 33% with intravenous iron. No patient received oral iron. 4 patients needed of blood transfusion and 3 of them due to bleeding (2 gastrointestinal bleeding and 1 urinary bleeding). We observed a statistically significant association between higher residual diuresis volume and adequate anemia control (P = .042) and between lower creatinine values and target Hb values (P = .0005). No statistically significant association was observed between adequate anemia control and type of dialysis (p= 0.106), time on dialysis (P = .28), sex (P = .224) and DM (p= 0.139). Conclusion The high prevalence of anemia continues to be a major problem in PD in our program, but similar to other series. Under treatment (ESA and iron therapy) is achieved an adequate control in most patients, although in approximately 20% of patients do not reach the established target. Higher residual diuresis and lower creatinine values (probably due to increased residual renal function) are associated with better anemia control.

#5864 EFFECT OF IV FERRIC CARBOXYMALTOSE ON PHYSICAL PERFORMANCE AND QOL IN PATIENTS WITH CKD NOT ON DIALYSIS, MILD ANEMIA AND IRON DEFICIENCY

Abstract Background and Aims Iron deficiency (ID) in patients with chronic kidney disease (CKD) is highly prevalent and contributes to a poorer quality of life. According to current guidelines, treatment with intravenous (IV) iron is limited to CKD patients with ID and anemia to avoid/delay the use of erythropoiesis-stimulating agents (ESAs) or the reduce the doses of ESA in patients treated with these drugs. Considering the effects of the correction of ID in other settings, we hypothetized that treatment with IV iron in patients with ID and borderline anemia can improve physical performance and their quality of life, independent of the effects on hemoglobin. Method Prospective, unicentric, single-arm study in CKD patients with ID, mild anemia and with-out heart failure. The inclusion criteria were: age ≥ 18 years, CKD patients stages 3–5 not on dialysis, iron deficiency (ferritin &amp;lt;100 ng/ml or ferritin &amp;lt;200 ng/ml if TSAT &amp;lt;20%), mild anaemia (Hb 10.5-11.5 g/dL). At the baseline visit, after all the studies were performed, iv ferric carboxymaltose was administered in a single dose, according to the degree of ID calculated by the Ganzoni´s formula. The co-primary outcome was the change in physical performance, evaluated through the 6 minute-walk test (6MWT) at one week and at four weeks. Secondary end-points: Patient's global assessment (PGA) and quality of life (EQ-5D), Piper's fatigue test, serum phosphorous at four week. Laboratory data, PGA, EQ-5D and Piper test questionnaires were evaluated at baseline, and at weeks 1 and 4 after receiving IV ferric carboximaltose. Results 41 patients completed the study. Primary end-point: the 6MWT increased significantly from 296 ± 101 m to 314 ± 106 m at week 1 (p&amp;lt;0.01), and to 325 ±111 meters at week 4 (p&amp;lt;0.01). at week 4 (p = 0.083). A significant improvement in the PGA test values was detected when compared baseline vs 4 weeks (adjusted p value = 0.031). No significant differences were found between the baseline and week 1 (adjusted p value = 0.083), and week 1 and week 4 visits (adjusted p value = 0.086). No significant differences were found between the initial, 1-week, and 4-week visits in the EQ-5D quality of life questionnaire nor Piper's fatigue test. Phosphorus levels decreased significantly at week 1 from baseline (3.16 ± 0.7 vs 3.72 ± 0.6) (adjusted p&amp;lt;0.001), with a partial recovery of serum levels in week 4 (3.57 ± 0.7 mg/dL). There were no significant increases in hemoglobin concentration between the different time periods. Conclusion IV ferric carboximaltose administration significantly improved the functional capacity of CKD patients with ID in short term. PGA also improved slightly but significantly. Effects that were independent of hemoglobin changes, suggesting a role of ID for a lower physical performance in CKD patients without heart failure, independent of the presence of anemia.

A retrospective database analysis of erythropoiesis-stimulating agent treatment patterns and associated healthcare resource use in patients with non-dialysis-dependent chronic kidney disease-related anaemia in Japan.

This study was conducted to evaluate clinical characteristics, treatment patterns, and healthcare resource use (HCRU) for patients in Japan with non-dialysis-dependent chronic kidney disease (CKD) and anaemia. This retrospective, longitudinal, epidemiological database extraction study used the JMDC Claims Database, comprising ~9.4 million unique beneficiaries. The observation period for anaemia and erythropoiesis-stimulating agent (ESA)/iron treatment was 1 January 2015 to 31 December 2018, and for HCRU and costs was 1 April 2016 to 31 March 2018. The non-dialysis-dependent CKD anaemia population, and the ESA treatment, iron treatment, and no-treatment cohorts were evaluated. Patient characteristics, treatment patterns, and outcomes were summarised descriptively. The non-dialysis-dependent CKD anaemia population included 5908 patients (7.9%), with 464 patients in the ESA treatment cohort, 809 patients (13.7%) in the iron treatment cohort (13.7%), and 4405 (74.6%) patients in the no-treatment cohort. The prevalence of patients prescribed an antihypertensive, antidiabetic, and/or antihyperlipidaemic medication generally increased with increasing baseline CKD stage. Proportions of no treatment for anaemia decreased while ESA treatment increased with increasing CKD stage; ESA treatment increased with decreasing baseline haemoglobin levels. Patients in the ESA treatment cohort generally had more frequent events associated with HCRU and higher costs from HCRU-associated activities (e.g., inpatient and outpatient care, pharmacy). As CKD severity increased, anaemia management changed from iron use or no treatment to ESA use; however, anaemia may be undertreated across all CKD stages. ESA-treated patients incurred greater HCRU-associated costs relative to other patients with non-dialysis-dependent CKD anaemia in Japan.

Efficacy and Safety of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Therapy for Anemia in Renal Transplantation Patients by Prior Erythropoiesis Stimulating Agent Use

BackgroundThe present study aimed to clarify the efficacy and safety of hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) therapy for anemia in renal transplant (RTx) patients. MethodsAfter successful RTx, 26 patients requiring treatment for anemia were divided into 2 groups (erythropoiesis-stimulating agent [ESA] group and non-ESA group) based on whether an ESA was used before starting HIF-PHI therapy. The chronological changes in hemoglobin (Hb) values during the 6 months after the start of HIF-PHI therapy were investigated in each group, and the incidence of adverse events was compared. ResultsThere were 18 patients in the ESA group and 8 patients in the non-ESA group. The median (IQR) Hb values in the 2 groups were 11.35 (10.4–12.3) and 10.15 (8.9–10.4) g/dL, respectively. The chronological changes in the median (IQR) Hb values pre-HIF-PHI and 1, 3, and 6 months after starting HIF-PHI were 11.4 (10.4–12.4), 12.0 (10.7–12.4), 11.9 (10.9–13.4), and 11.5 (10.6–12.7) g/dL, respectively, in the ESA group, and 10.2 (8.7–10.4), 11.0 (10.4–11.7), 12.2 (11.6–13.2), and 12.5 (11.3–12.7) g/dL, respectively, in the non-ESA group. In the ESA group, Hb values were not significantly decreased after HIF-PHI administration (P = .14); in the non-ESA group, Hb values improved significantly (P = .002). Two patients developed diarrhea in the ESA group, and one patient developed appetite loss in the non-ESA group. ConclusionsHypoxia-inducible factor prolyl hydroxylase inhibitor was effective and safe for RTx patients regardless of prior ESA use.

Effect of roxadustat on red blood cell lifespan in patients with long-term haemodialysis: a single-centre, prospective, single-arm study.

Reduced survival of red blood cells (RBCs) in patients with chronic kidney disease (CKD) is thought to contribute to renal anaemia. Although renal anaemia improved greatly because of the wide use of erythropoiesis-stimulating agents (ESAs) and the advancement of dialysis techniques, RBC longevity seems not to be obviously ameliorated. In this single-centre, single-arm trial, patients who had been undergoing haemodialysis and ESA therapy with epoetin alfa for at least 12weeks changed their anti-anaemia drugs from epoetin alfa to oral roxadustat three times per week for 24weeks. The primary endpoint was the change in RBC lifespan from baseline at week 24. The change in the circulating percentage of eryptotic RBCs, RBC deformability and RBC oxygen transport ability were also assessed. A total of 27 patients were enrolled, with 26 completing the full course of intervention. At baseline, the average RBC lifespan was 60.1days [standard deviation (SD) 14.4; n=27]. At the end of the study period, 26 patients had an RBC lifespan measurement (83.9days on average; SD 21.9). The RBC lifespan increased by 22.8days on average [95% confidence interval (CI) 15.5-30.0, P<.001]. This equated to an average RBC lifespan increase of 39.2% (95% CI 27.8-50.6). The percentage of circulating eryptotic RBCs, erythrocyte filtration index and the pressure at which haemoglobin is 50% saturated decreased significantly from baseline to week 24 (1.39±0.44% versus 0.89±0.25%, P<.0001; 0.29±0.12 versus 0.16±0.08, P<.0001 and 32.54±4.83 versus 28.40±2.29, P<.001, respectively). Roxadustat prolonged RBC lifespan in patients with long-term haemodialysis.

The ASCEND-NHQ randomized trial found positive effects of daprodustat on hemoglobin and quality of life in patients with non-dialysis chronic kidney disease

The ASCEND-NHQ trial evaluated the effects of daprodustat on hemoglobin and the Medical Outcomes Study 36-item Short Form Survey (SF-36) Vitality score (fatigue) in a multicenter, randomized, double-blind, placebo-controlled trial. Adults with chronic kidney disease (CKD) stages 3-5, hemoglobin 8.5-10.0 g/dl, transferrin saturation 15% or more, and ferritin 50 ng/ml or more without recent erythropoiesis-stimulating agent use were randomized (1:1) to oral daprodustat or placebo to achieve and maintain target hemoglobin of 11-12 g/dl over 28 weeks. The primary endpoint was the mean change in hemoglobin between baseline and the evaluation period (Weeks 24-28). Principal secondary endpoints were proportion of participants with a 1 g/dl or more increase in hemoglobin and mean change in the Vitality score between baseline and Week 28. Outcome superiority was tested (1-sided alpha level of 0.025). Overall, 614 participants with non-dialysis-dependent CKD were randomized. The adjusted mean change in hemoglobin from baseline to the evaluation period was greater with daprodustat (1.58 vs 0.19 g/dl). The adjusted mean treatment difference (AMD) was significant at 1.40 g/dl (95% confidence interval 1.23, 1.56). A significantly greater proportion of participants receiving daprodustat showed a 1 g/dl or greater increase in hemoglobin from baseline (77% vs 18%). The mean SF-36 Vitality score increased by 7.3 and 1.9 points with daprodustat and placebo, respectively; a clinically and statistically significant 5.4 point Week 28 AMD increase. Adverse event rates were similar (69% vs 71%); relative risk 0.98, (95% confidence interval 0.88, 1.09). Thus, in participants with CKD stages 3-5, daprodustat resulted in a significant increase in hemoglobin and improvement in fatigue without an increase in the overall frequency of adverse events.

Prevalence of anemia and its predictors among patients with chronic kidney disease admitted to a teaching hospital in Ethiopia: A hospital-based cross-sectional study.

Anemia is a common complication of chronic kidney disease (CKD) and is associated with adverse patient outcomes. However, data on the prevalence of anemia in CKD patients is sparse, particularly in resource-limited settings. Therefore, this study aimed to assess the prevalence of anemia and its predictors among patients with CKD admitted to the Jimma medical center, southwest Ethiopia. A hospital-based prospective cross-sectional study was conducted from September 1 to November 30, 2020. All adult patients with CKD aged ≥18 years who fulfilled the inclusion criteria were consecutively recruited into the study. Data were entered into the Epi data manager version 4.4.1 and then exported to SPSS version 22 (IBM Corp., Armonk, NY) for analysis. The predictors of anemia were determined using multivariable logistic regression analysis. Statistical significance was set at P < .05. A total of 150 patients were included in this study. Of these, 64.67% were male, 56.67% had stage 5 CKD, 78% had a CKD duration of less than 1 year, and 74% had proteinuria. Hypertension (40.7%) and diabetes (14.7%) were the common causes of CKD. The prevalence of anemia was 85.33%. Of the patients, 28.67%, 40.67%, and 16% had mild, moderate, and severe anemia, respectively. On multivariate logistic regression, stage 4 CKD (adjusted odds ratio [AOR] 3.2, confidence interval [CI]: 1.78-12.91, P = .025), stage 5 CKD (AOR 4.03, CI: 1.17-13.73, P = .016), and CKD duration of less than 1 year (AOR 3, CI: 1.19-9.11, P = .007) were significantly associated with anemia. The prevalence of anemia among stage 3 to 5 CKD patients was very high. Anemia was significantly associated with the severity and duration of CKD. Therefore, serial follow-up of patients with a long duration and advanced stages of CKD may help prevent anemia and its adverse consequences.