Epoetin Dose Research Articles

#1533 The relationship between the severity of anemia, the level of inflammation markers and the dose of epoetin in patients in pre-dialysis stages of CKD

Abstract Background and Aims Inflammation is known to be an important factor associated with hemoglobin variability in patients with anemia of chronic disease. However, the question remains whether high levels of C-reactive protein, a widely used marker of inflammatory activity, and other inflammatory markers predict less stable anemia control in patients with CKD. The purpose of this study was to establish the relationship between the severity of anemia with the levels of inflammatory markers (C-reactive protein, IL-6) and the dose of epoetin in patients with pre-dialysis stages of CKD. The purpose of our study was to study the age-related characteristics of the nutritional status in patients with CKD of the dialysis stages who are on parenteral nutrition. Method 180 patients (96 men and 84 women) with CKD as a result of nephropathies of diabetic and non-diabetic etiology were examined. Chronic pyelonephritis was diagnosed in 96 patients, chronic glomerulonephritis - in 73, polycystic kidney disease - in 11 patients. Glomerular filtration rate was calculated based on serum creatinine concentration using the CKD-EPI formula (2011). The patients were divided into 2 groups, depending on the achievement of the target hemoglobin value. Thus, group 1 included patients with CKD C3, C4, whose hemoglobin concentration was above 110 g/l (n = 101). Group 2 included patients whose hemoglobin concentration was less than 110 g/l in at least one analysis (n = 79). Results In the examined patients, a significant correlation was found between the range of hemoglobin concentration and the range of CRP concentration (p < 0.05), as well as between the range of hemoglobin concentration and the variation in the percentage of hypochromic erythrocytes (p < 0.05), between the range of hemoglobin concentration and the variation of ferritin ( p < 0.05). The change in the percentage of hypochromic erythrocytes also correlated with the change in IL-6 (p < 0.05) and the change in CRP ( p < 0.05). We found an association between the average weekly dose of epoetin and the levels of CRP, IL-6 and TNF-α. Patients with TNF-α levels ≥2 ng/mL and IL-6 ≥40 ng/mL required a significantly higher dose of epoetin than patients with lower levels of these markers (128 U/kg per week versus 57 U/kg at week). Conclusion The establishment of a relationship between inflammatory markers and hemogram and iron parameters suggests that inflammation had an indirect effect on the increase in hemoglobin through its effect on iron metabolism. The results of the study indicate the presence of diabetic and non-diabetic etiology of systemic inflammation in CKD, more so in the group of patients with type 2 diabetes mellitus.

Opportunities to improve the management of anemia in peritoneal dialysis patients: lessons from a national study in routine clinical practice.

Current guidelines establish the same hemoglobin (Hb) and iron biomarkers targets for hemodialysis (HD) and peritoneal dialysis (PD) in patients receiving erythropoiesis-stimulating agents (ESAs) even though patients having PD are usually younger, more active and less comorbid. Unfortunately, specific renal anemia [anemia in chronic kidney disease (aCKD)] trials or observational studies on PD are scanty. The aims of this study were to describe current aCKD management, goals and adherence to clinical guidelines, identifying opportunities for healthcare improvement in PD patients. This was a retrospective, nationwide, multicentre study including patients from 19 PD units. The nephrologists collected baseline data, demographics, comorbidities and data related to anemia management (laboratory values, previously prescribed treatments and subsequent adjustments) from electronic medical records. The European adaptation of KDIGO guidelines was the reference for definitions, drug prescriptions and targets. A total of 343 patients (mean age 62.9years, 61.2% male) were included; 72.9% were receiving ESAs and 33.2% iron therapy [20.7% intravenously (IV)]. Eighty-two patients were receiving ESA without iron therapy, despite 53 of them having an indication according to the European Renal Best Practice guidelines. After laboratory results, iron therapy was only started in 15% of patients. Among ESA-treated patients, 51.9% had an optimal control [hemoglobin (Hb) 10-12g/dL] and 28.3% between 12-12.9g/dL. Seventeen patients achieved Hb >13g/dL, and 12 of them remained on ESA after overshooting. Only three patients had Hb <10g/dL without ESAs. Seven patients (2%) met criteria for ESA resistance (epoetin dose >300IU/kg/week). The highest tertile of erythropoietin resistance index (>6.3 UI/kg/week/g/dL) was associated with iron deficiency and low albumin corrected by renal replacement therapy vintage and hospital admissions in the previous 3months. Iron therapy continues to be underused (especially IV). Low albumin, iron deficiency and prior events explain most of the ESA hyporesponsiveness. Hb targets are titrated to/above the upper limits. Thus, several missed opportunities for adequate prescriptions and adherence to guidelines were identified.

#4237 EFFICACY AND TOLERABILITY OF DIRECT-ACTING ANTIVIRALS IN HEMODIALYSIS PATIENTS WITH CHRONIC HEPATITIS C

Abstract Background and Aims Hepatitis C virus (HCV) infection is common in hemodialysis (HD) patients and is associated with increased morbidity and mortality. In recent years major progress in the treatment of HCV infection has been made with the entry into use of direct-acting antivirals (DAA), which target viral proteins, leading to increases in sustained virological response (SVR) and a marked decrease in side effects. The aim of the study was to evaluate the efficacy and frequency of side-effects of DAA therapy in HD patients with HCV infection. Method The multicentric prospective cohort study included 42 HD patients with HCV infection over the last two years. DAAs therapy was administered according to HCV genotype and drug interactions considering guidelines for a period of 12 weeks (for HCV genotype 1: Elbasvir/Grazoprevir or Ombitasvir/Paritaprevir/Ritonavir/Dasabuvir, and for HCV genotype 4: Elbasvir/Grazoprevir or Ombitasvir/Paritaprevir/Ritonavir). The following clinical parameters at weeks 0, 4, 8, 12, and 24 (12 weeks after the completion of treatment with DAA) were analyzed: presence of side effects, PCR HCV titer (ref. range: &amp;lt;12 IU/ml negative), hemoglobin (Hgb-g/L), epoetin dose (IU/kg/week), alanine aminotransferase level (ALT-U/L), and gamma-glutamyl transferase level (GGT-U/L). Before treatment with DAA liver fibrosis score (F0-F4) was defined by Fibroscan and the patients with liver stiffness over 12,5 kPa (Fibrosis score F4) were considered cirrhotic, but only patients with compensated cirrhosis (Child-Pugh score class A) were treated. For statistical analysis chi-square test and combined analysis of variance for repeated measures were performed by IBM SPSS softver. PCR HCV titer was analyzed with logarithmic transformation of data. Results Over the observed period 42 HD patients with HCV infection (25M and 17F) with the average age 56,78±11,6 years and average HD vintage 159±75 months were included in the study. Twenty-six patients (61,9%) were with HCV genotype 1 and 16 patients (38,1%) with HCV genotype 4. Ten patients (23,8%) were with compensated cirrhosis (F4 fibrosis score by Fibroscan). Three patients (7,1%) had mild gastrointestinal side effects and only one patient (2,4%) discontinuated the therapy during the first week due to intolerancy to DAA. All 41 patients (100%) who completed 12 weeks DAA therapy were PCR HCV negative at 4 weeks of treatment and achieved rapid virological response (RVR) and 12 weeks after the completion of treatment and achieved sustained virological response (SVR12) that was statistically significant (p&amp;lt;0.001). In regard to PCR HCV titer before DAA therapy there was no statistically significant difference among HD patients according to cirrhotic status and HCV genotype. There was no statistically significant change of hemoglobin level and epoetin dose in HD patients during the DAA therapy. The ALT and GGT levels statistically significantly decreased at weeks 12 and 24 compared to week 0 in all treated patients with DAA (ALTweek0 = 35,2±21,7; ALTweek12 = 21,8±16,2; ALTweek24 = 23,5±13,1; p&amp;lt;0.001 and GGTweek0 = 53,3±67; GGTweek12 = 18,6±6,8; GGTweek24 = 19,4±11,5; p = 0.042 respectively). The therapy with DAA was equally effective in patients with compensated cirrhosis and in patients without cirrhosis and there was statistically significant decrease of ALT and GGT levels in both groups of patients (p = 0.002 and p&amp;lt;0.05 respectively). In regard to HCV genotype DAA were equally effective in patients with HCV genotype 1 and in patients with HCV genotype 4 and ALT and GGT levels significantly decreased in both groups of patients (p&amp;lt;0.001 and p&amp;lt;0.05 respectively). Conclusion The therapy with DAA in HD patients with HCV infection was extremely effective and SVR12 was achieved in 100% of treated patients. The administered DAA were equally effective in patients with compensated cirrhosis and in patients without cirrhosis, and in patients with HCV genotype 1 and HCV genotype 4. The therapy with DAA was well tolerated, 7,1% of patients had mild side effects and 2,4% of patients discontinuated the therapy due to intolerance.

#4445 ANAEMIA MANAGEMENT IN PERITONEAL DIALYSIS: FROM GUIDELINES TO ROUTINE CLINICAL PRACTICE

Abstract Background and Aims The evidence on the management of renal anemia in peritoneal dialysis (PD) is much weaker than in hemodialysis (HD). Current guidelines establish the same haemoglobin (Hb) target for patients under eritropoietin stimulating agents (ESAs) in both dialysis techniques (PD, HD), although patients in PD are usually younger, more active and lesss comorbid. Unfortunately, there is not randomized controlled trials evaluating the efficacy and safety the effect of different Hb target on clinical outcomes. The aim is to describe the current situation of anaemia prevalence, treatments, and achievement of clinical guidelines recommendations in this population. Method Retrospective nationwide multicenter study including patients from 19 PD units. All prevalent PD patients that were active in the technique in November 2019 for at least 3 months was included (to avoid COVID pandemic interferences). Exclusion criteria were a previous kidney transplant failure and being on PD due to a cardiorenal syndrome with a residual renal function over 20 ml/min/1.73 m2. The nephrologists collected baseline data, demographics, comorbidities, and data related to anemia management (ie, laboratory values, previously prescribed treatments, and subsequent adjustments) from electronic medical records. The European adaptation of KDIGO guidelines was the reference for iron and Hb limits, prescriptions and targets. Results A total of 343 patients (mean age 62.9 years, 61.2% male) were included. Regarding anaemia-treatment prescription, 72.9% were receiving ESAs and 33.2% iron therapy (20.7% intravenously-IV and 12.5% orally). Eighty-two (32.8%) patients were receiving ESA without iron therapy, despite to have an indication to do it according ERBP guidelines in 53 out of them. After knowing lab results, iron therapy was only started in 8 (15%) patients. Among ESA-treated patients, 58.8% had an optimal control (Hb 10–12 g/dl). Seventeen patients had haemoglobin over 13 g/dl, and 12 of them continued receiving ESA after knowing lab results. Only three patients had persistent haemoglobin &amp;lt;10 g/dl. Seven patients (2%) met criteria for ESA resistance (epoetin dose &amp;gt;300 IU/kg/week). Patients in the highest tertile of erythropoietin resistance index (ERI) (&amp;gt;6.3 UI/kg/week/g/dl) were more inflamed, had lower albumin levels and lower residual renal function. Conclusion Anaemia prevalence is high in this population and its management in PD Units could be improved according to the ERBP guidelines. The lack of iron therapy in patients who should have received it and the excessive tolerance to high Hb levels are the most relevant opportunities to improve compliance with clinical guidelines.

Resistance to Erythropoiesis-Stimulating Agents among Patients on Hemodialysis Is Typically Transient

Introduction: This study examines factors associated with erythropoiesis-stimulating agent (ESA) hyporesponsiveness, the duration of ESA hyporesponsiveness, the frequency of new episodes, and variation across countries. Methods: We used international Dialysis Outcomes and Practice Patterns Study data from 2015 to 2018 (N = 26,656) to investigate changes in ESA Resistance Index (ERI), calculated as epoetin dose divided by [hemoglobin × body weight] in patients on hemodialysis. We illustrated the proportion of patients who moved to other ERI quintiles over 12 months, and we studied the incidence and duration of ESA resistance. We examined case-mix factors associated with quintiles of ERI. Results: Most patients migrated out of their original ERI quintile within 4 months. Only 22% of patients in the top quintile of ERI at baseline (4.4% of all patients) remained in the top quintile during all 12 months of follow-up. A total of 42% of patients manifested an upper-quintile ERI during at least 1 month. Median duration of a new episode of ESA resistance was 2 months. Catheter hemoaccess, elevated C-reactive protein, lower transferrin saturation, lower serum albumin concentration, and recent hospitalization occurred more frequently among patients in the highest ERI quintile at baseline. ERI values were highest in the USA, Italy, and Mideastern nations and lowest in Russia and Japan. Discussion/Conclusion: It is a misconception to envision a sizable, fixed segment of the population with permanent resistance to ESA – resistance fluctuates frequently. The implications of these findings for prescription of ESAs and of hypoxia-inducible factor-prolyl hydroxylase inhibitors are discussed.

COST-MINIMIZATION ANALYSIS OF USING SHORT AND LONG-ACTING ERYTHROPOESIS-STIMULATING AGENTS FOR CORRECTION OF NEPHROGENIC ANEMIA AGAINST THE BACKGROUND OF SUBSTITUTION THERAPY

Clinical trials conducted in various countries indicate that the use of epoetin alfa in patients with nephrogenic anemia in chronic kidney disease can increase the effectiveness of treatment, reduce the incidence of cardiovascular and infectious complications, and reduce mortality in patients with chronic kidney disease.The aim of the article was to conduct a comparative clinical and economic assessment of the treatment costs of nephrogenic anemia in adult dialysis patients with recombinant human erythropoietins: epoetin alfa, darbepoetin and long-acting methoxy polyethylene glycol – epoetin beta.Materials and methods. The study took into account direct medical costs of nephrogenic anemia pharmacotherapy on the basis of 1 year maintenance therapy according to the following scheme: epoetin alfa – 3 times per week, darbepoetin alfa – once per week, methoxy polyethylene glycol – epoetin beta – once per 2 or 4 weeks. A “costs minimization” analysis was performed for equivalent maintenance epoetins doses for intravenous and subcutaneous administrations. Epoetin alpha equivalents were calculated for an average patient weighing 75 kg by converting a weekly dose of short-acting epoetin (7500 IU) into equivalent doses using dose conversion factors.Results. In the hypothetical cohort of patients under study, epoetin alfa, darbepoetin alfa, and methoxy polyethylene glycol – epoetin beta not differ in effectiveness in achieving target Hb values and in safety. With the equal effectiveness of the investigated drugs, in the studied patients, intravenous epoetin alfa can be less expensive drug therapy relative to the equivalent doses obtained by the calculation: darbepoetin by 14–24% and methoxy polyethylene glycol – epoetin beta by 4–30%. The change-over of patients to the subcutaneous administration makes it possible to decline a weekly dose of epoetin alfa by 20–30% by reducing the frequency of taking the drug to twice a week, and to reduce the cost of drug therapy by a third.Conclusion. Intravenous and subcutaneous administrations of epoetin alfa 2500 IU may be a more economical drug therapy in comparison with the equivalent doses of darbepoetin and methoxy polyethylene glycol – epoetin beta.

Role of Hepcidin as a biomarker for iron status in patients on regular hemodialysis after treatment of hepatitis C virus

Abstract Background Hepcidin, an acute phase reactant protein produced in the liver, is a key regulator of iron homeostasis. Because of its renal elimination and regulation by inflammation, it is possible that progressive renal insufficiency leads to altered hepcidin metabolism. Aim of the work to assess effect of HCV treatment on hepcidin levels in regular heamodialysis patients and its relation to iron status. Patients and Methods This cross sectional study was conducted on 45 ESRD patients on regular hemodialysis. All candidates included in this study subjected to careful history taking, full clinical examination and investigations (including complete blood count, HCVAb, HBVsAg and HIVAb). All patients had positive antibodies for hepatitis C; however, all of them had negative PCR and negative HIV, HBV antibodies. Results In our study, dry weight ranged from 46 to 117 kg with mean 77.36. Weight gain ranged from 2 to 5 kg with mean 3.09.About 87% of patients had LTAVF access. About 12 patients (27%) received blood transfusion once. Timing of transfusion ranged from 4 to 60 month with median of 24 months. Regarding frequency of epoetin dose, 11 patients (24.4%) did not receive epoetin, 16 patients (35.6%) received it twice/week. Only 3 patients (6.7%) received iron therapy for time ranging from 3 to 5 months with mean of 4 months. Mean Hb concentration in our study population was 10.11 ±1.64 gm/dl. The mean of iron was 64.22 ±19.52, TIBC was 409.96 ± 67.85, ferritin was 394.56 ± 239.22 and TSAT% was 22.6 ±7.36. The mean serum hepcidin was 218.51 ±127. Our study demonstrated that increase in serum hepcidin is associated with lower serum Hb and iron levels. On the other hand, there is statistically significant positive correlation between serum hepcidin and both serum ferritin and transferrin saturation. Conclusion Median hepcidin value is elevated in dialysis ESRD patients due to increased inflammation and decreased clearance of hepcidin. Also serum hepcidin levels were lowered in HCV patients. Therefore ESRD patients on maintenance HD after treatment of HCV infection showed elevated levels of serum hepcidin.

Study design and baseline characteristics of patients on dialysis in the ASCEND-D trial.

BackgroundThe Anemia Studies in chronic kidney disease (CKD): Erythropoiesis via a Novel prolyl hydroxylase inhibitor Daprodustat-Dialysis (ASCEND-D) trial will test the hypothesis that daprodustat is noninferior to comparator epoetin alfa or darbepoetin alfa for two co-primary endpoints: hemoglobin (Hb) efficacy and cardiovascular (CV) safety.MethodsWe report the trial design, key demographic, clinical and laboratory findings, and baseline therapies of 2964 patients randomized in the open-label (sponsor-blinded) active-controlled, parallel-group, randomized ASCEND-D clinical trial. We also compare baseline characteristics of ASCEND-D patients with patients who are on dialysis (CKD G5D) enrolled in other large CV outcome trials (CVOTs) and in the most relevant registries.ResultsThe median age of patients was 58 years, 43% were female; 67% were White and 16% were Black. The median Hb at baseline was 10.4 g/dL. Among randomized patients, 89% were receiving hemodialysis and 11% peritoneal dialysis. Among key comorbidities, 42% reported a history of diabetes mellitus and 45% a history of CV disease. Median blood pressure was 134/74 mmHg. The median weekly dose of epoetin was 5751 units. Intravenous and oral iron uses were noted in 64 and 11% of patients, respectively. Baseline demographics were similar to patients with CKD G5D enrolled in other CVOTs and renal patient registries.ConclusionsASCEND-D will evaluate the efficacy and safety of daprodustat compared with epoetin alfa or darbepoetin alfa in the treatment of patients with anemia with CKD G5D.This trial is registered with ClinicalTrials.gov: NCT02879305. EudraCT Number: 2016-000541-31; Sponsor Protocol Number: 200807.

P1373ERYTHROPOETIN RESISTANCE IN PRE-DIALYSIS PERIOD AND ITS RELATION TO PROGNOSIS IN JAPANESE INCIDENT DIALYSIS PATIENTS

Abstract Background and Aims Erythropoiesis stimulating agents (ESA) are essential for better quality of life and longer life expectancy in end-stage kidney disease patients (ESKD). Resistance to ESA leads to worse prognosis in hemodialysis and peritoneal dialysis patients. Resistance to ESA exists in pre-dialysis period. We studied the clinical significance of pre-dialysis resistance to ESA by investigating the erythropoietin resistance index (ERI) in patients with ESKD prior to dialysis induction and its association with mortality and cause of death in three-year follow-up after dialysis initiation. Method Subjects included 1,420 patients in 17 centers participating in Aichi Cohort Study of Prognosis in Patients Newly Initiated into Dialysis (AICOPP) from Oct. 2011 to Sep. 2013. ESA responsiveness was estimated by using erythropoietin resistance index (ERI) (U/kg/week/g/dL), which was calculated as weekly weight-adjusted epoetin dose divided by the hemoglobin (Hb) concentration before starting dialysis. We excluded 302 patients because ERI was not available. Thus, 1,118 subjects were enrolled. Subjects were divided into four categories of ERI; ERI &amp;lt; 5, 5≤ ERI &amp;lt;10, 10≤ ERI &amp;lt;15 and 15≤ ERI. Cumulative survival rates from all-cause, cardiovascular disease (CVD), infection and malignancy were compared by Kaplan-Meier method according to ERI categories. Three-year mortality was analyzed by logistic regression analysis adjusted by age, gender, Charlson comorbidity index (CCI), and ERI categories. Results During three-year follow-up period, 191 (17.1%) patients died. Age and female gender share were higher in proportion to ERI. Diabetes, coronary artery disease (CAD), and values of albumin (Alb) and brain natriuretic peptide (BNP) were not correlated with ERI (Table 1). Kaplan-Meier survival curve showed that patients with the highest ERI (15≤ ERI) had a higher all-cause mortality (Log rank test p=0.002, Figure 1). Concerning the cause of death, mortality from infection (p=0.023, Figure 2) and malignancy (p=0.031) were high in the highest ERI category, however there was no significant difference in each ERI category regarding CVD mortality (p=0.33). According to multivariate analysis analyses by logistic regression model, all-cause (odd ratio [OD]: 1.65, 95% confidence interval [CI]: 1.14-2.38, p=0.008) and infection-related mortality (OR: 2.13, 95% CI: 1.08-4.11, p=0.029) were significantly correlated with the highest ERI category, but unexpectedly CVD mortality was not (OR: 1.04, 95% CI: 0.59-1.75, p=0.90). Mortality from malignancy did not reach the significant level (OR: 1.92, 95% CI: 0.96-3.73, p=0.063) and may require longer observation period for analysis. Conclusion Pre-dialysis ERI is a prognostic marker in Japanese dialysis patients and predicts the susceptibility to infection.

End of an era for erythropoiesis-stimulating agents in oncology.

Erythropoiesis-stimulating agents (ESAs) are available to treat chemotherapy-induced anemia (CIA). In 2007-2008, regulatory notifications advised of venous thromboembolism and mortality risks while the Center for Medicare and Medicaid Services' restricted ESA initiation to patients with hemoglobin <10 g/dl. In 2010, a Risk Evaluation and Mitigation Strategies required consent prior to administration. We evaluated ESA utilization from 2003 to 2012 and obtained private health insurer claims data for persons with lung, colorectal, or breast cancer from 2001 to 2012. ESA use for CIA was determined by an ESA claim after chemotherapy, up to 6 months after treatment. We identified 839,948 commercially insured patients, including 24,785 patients with ESA-treated CIA (3.2%). Darbepoetin use increased 3.9-fold from 2003 to 2007 (12.3% to 48.7%) and then decreased 95% to 2.6% by 2012. Epoetin use decreased 90% from 2003 to 2012 (30.3% to 3.1%). Between 2003 and 2012, mean epoetin dosing decreased 0.8-fold (244,979 in 2003 vs. 196,216 units in 2012), but increased 1.8-fold for darbepoetin-treated CIA (262 in 2003 to 467 μg in 2012). Among CIA patients, transfusions were low (4.5%) in 2002-2007, then increased 2.2-fold between 2008 and 2012. Safety initiatives between 2007 and 2010 facilitated reductions in ESA use combined with changes in coverage. These data show the efficacy of regulatory efforts, publication of adverse events and changes in reimbursement in reducing use of ESAs. Future studies are warranted to optimize deimplementation strategies to improve patient safety.

Surgical prescription of epoetin alfa in contemporary total hip arthroplasty: a prospective comparative study

PurposePre-operative anaemia treatment has been associated with reduced morbidity in joint arthroplasty. This study examined the impact of a surgical prescription of epoetin (EPO) in contemporary total hip arthroplasty (THA).MethodsWe conducted a comparative study in a series of 1402 primary THAs performed in patients all having a pre-operative haemoglobin (Hb) level documented four to eight weeks before THA surgery. In group A (647 hips), one subcutaneous injection of 40,000 IU EPO once a week for four weeks was prescribed at the discretion of anaesthetist during the pre-operative visit in patients with pre-operative Hb between 10 and 13 g/dl. In group S comprising the remaining 755 hips, an amended EPO therapy including two injections of 20,000 to 40,000 IU was prescribed by the surgeon in patients with Hb less than 12 g/dl deemed at high risks to be transfused following THA. Primary study endpoint was the bleeding index (BI).ResultsEPO therapy was delivered in 43 patients (6.7%) in group A and in 26 patients (3.4%) in group S (p = 0.006). The mean total dose of EPO administrated was 115,349 IU in group A versus 75,200 IU in group S (p < 0.001). The mean BI were 2.7 ± 1.0 in group A and 2.8 ± 1.0 g/dl in group S (p = 0.375). No patient was blood-transfused up to post-operative day seven in group S versus five patients in group A (p = 0.021).ConclusionsThe amended protocol does not lead to increased peri-operative bleeding. Advances in intra-operative methods to reduce the bleeding allow changing indications of EPO in patients undergoing THA with a low level of Hb.

Randomized Controlled Trial of Subcutaneous Epoetin Alfa-epbx Versus Epoetin Alfa in End-Stage Kidney Disease

IntroductionThis double-blind, randomized controlled trial compared the safety and efficacy of subcutaneous epoetin alfa-epbx, an epoetin alfa biosimilar, with the reference product, epoetin alfa, in hemodialysis patients with end-stage kidney disease (ESKD) and anemia who were receiving epoetin alfa maintenance treatment.MethodsEligible patients (n = 320) were randomized (1:1) to subcutaneous epoetin alfa-epbx or epoetin alfa in a titration phase; patients who demonstrated stable subcutaneous dosing (n = 246) were re-randomized to receive subcutaneous epoetin alfa-epbx or epoetin alfa 1 to 3 times per week in a 16-week maintenance phase. Co-primary endpoints were least-squares mean difference between treatments in mean weekly hemoglobin concentration and mean weekly epoetin dose per kilogram body weight (BW) during the last 4 weeks of treatment in the maintenance phase.ResultsThe least-squares mean difference (95% confidence interval [CI]) between treatments in weekly hemoglobin was 0.04 g/dl (−0.17 to 0.24 g/dl) and weekly epoetin dose/kg BW was −2.34 U/kg per week (−14.51 to 9.82 U/kg per week). The 95% CIs were contained within the prespecified equivalence margins of ±0.5 g/dl (weekly hemoglobin) and ±45 U/kg per week (weekly epoetin dose/kg BW). In the epoetin alfa-epbx and epoetin alfa groups, respectively, 4.0% and 4.1% of patients required blood transfusions, 69.7% and 70.5% reported adverse events, 18.9% and 27.0% reported serious adverse events, and 3 and 2 deaths were reported. Five patients were confirmed positive for anti-recombinant human erythropoietin antibody, 2 of whom tested positive at baseline. All patients tested negative for neutralizing antibodies.ConclusionsThis comparative clinical trial demonstrated equivalence in efficacy and similar safety of subcutaneously administered epoetin alfa-epbx to epoetin alfa.

Comparing Therapeutic Efficacy and Safety of Epoetin Beta and Epoetin Alfa in the Treatment of Anemia in End-Stage Renal Disease Hemodialysis Patients

Background: Anemia is one of the most prevalent complications in patients with chronic kidney disease, which is believed to be caused by the insufficient synthesis of erythropoietin by the kidney. This phase III study aimed to compare the efficacy and safety of CinnaPoietin® (epoetin beta, CinnaGen) with Eprex® (epoetin alfa, Janssen Cilag) in the treatment of anemia in ESRD hemodialysis patients. Methods: In this randomized, active-controlled, double-blind, parallel, and non-inferiority trial, patients were randomized to receive either CinnaPoietin® or Eprex® for a 26-week period. The primary endpoints of this study were to assess the mean hemoglobin (Hb) change during the last 4 weeks of treatment from baseline along with the evaluation of the mean weekly epoetin dosage per kilogram of body weight that was necessary to maintain the Hb level within 10–12 g/dL during the last 4 weeks of treatment. As the secondary objective, safety was assessed along with other efficacy endpoints. Results: A total of 156 patients were included in this clinical trial. There was no statistically significant difference between treatment groups regarding the mean Hb change (p = 0.21). In addition, the mean weekly epoetin dosage per kg of body weight for maintaining the Hb level within 10–12 g/dL showed no statistically significant difference between treatment arms (p = 0.63). Moreover, both products had comparable safety profiles. However, the incidence of Hb levels above 13 g/dL was significantly lower in the CinnaPoietin® group. Conclusion: CinnaPoietin® was proved to be non-inferior to Eprex® in the treatment of anemia in ESRD hemodialysis patients. The trial was registered in Clinicaltrials.gov (NCT03408639).

Effect of long-acting erythropoiesis-stimulating agents on hemoglobin levels at the initiation of dialysis

The goal of the present study was to explore the differences in effects between erythropoiesis-stimulating agent (ESA) types on hemoglobin (Hb) level at the initiation of maintenance dialysis. This was a cross-sectional study. From January 2006 to October 2012, 2920 patients with end-stage kidney disease commenced hemodialysis (HD) at nine participating hospitals. The criteria for exclusion from the database were (1) presence of cancer or gastrointestinal bleeding and (2) serum C-reactive protein ≥0.3 mg/dL. A total of 1263 patients were entered into the final database. We explored the association of yearly trend of Hb level just before the first HD session with the different types of ESA in the predialysis period. During the 7-year study period, patients’ Hb levels at the initiation of dialysis dramatically increased from 8.6 to 9.1 g/dL. Parallel to this increase, the use of long-acting ESA also increased from 0 to 80 %. A higher level of Hb was confirmed in the long-acting ESA group compared with the short-acting group (9.5 vs. 8.7 g/dL, P < 0.01). Multivariate regression analysis showed a strong association of Hb level with the use of long-acting ESA (r = 0.155, P = 0.003), even after adjusting for confounding variables and estimated dose of epoetin. The change in the type of ESA used from short-acting to long-acting played a role in the increase of patients’ Hb levels at the initiation of dialysis. A long-acting ESA has the potential effect of maintaining an optimal Hb level even in the advanced stages of CKD.

Ergocalciferol Supplementation in Hemodialysis Patients With Vitamin D Deficiency: A Randomized Clinical Trial.

Locally produced 1,25-dihydroxyvitamin D3 may have pleiotropic effects outside of bone. Experimental and observational studies suggest that nutritional vitamin D may enhance erythropoiesis in settings of 25-hydroxy vitamin D (25(OH)D) deficiency. We conducted a double-blind, placebo-controlled, randomized clinical trial to assess the effects of supplementation with ergocalciferol on epoetin utilization and other secondary outcomes in patients on hemodialysis with serum 25(OH)D <30 ng/ml. In all, 276 patients were randomized to 6 months of ergocalciferol or placebo. Mean±SD serum 25(OH)D increased from 16.0±5.9 ng/ml at baseline to 39.2±14.9 ng/ml in the ergocalciferol arm and did not change (16.9±6.4 ng/ml and 17.5±7.4 ng/ml, respectively) in the placebo arm. There was no significant change in epoetin dose over 6 months in the ergocalciferol or placebo arms (geometric mean rate 0.98 [95% confidence interval (95% CI), 0.94 to 1.02] versus 0.99 [95% CI, 0.95 to 1.03], respectively) and no difference across arms (P=0.78). No change occurred in serum calcium, phosphorus, intact parathyroid hormone, or C-reactive protein levels, cinacalcet use, or phosphate binder or calcitriol dose in either study arm. Rates of all-cause, cardiovascular, and infection-related hospitalizations did not differ by study arm, although statistical power was limited for these outcomes. In conclusion, 6 months of supplementation with ergocalciferol increased serum 25(OH)D levels in patients on hemodialysis with vitamin D insufficiency or deficiency, but had no effect on epoetin utilization or secondary biochemical and clinical outcomes.

Peginesatide to Manage Anemia in Chronic Kidney Disease Patients on Peritoneal Dialysis

♦ Peginesatide is a novel, synthetic, peptide-based pegylated erythropoiesis-stimulating agent that is designed specifically to stimulate the erythropoietin receptor. The purpose of the present study was to assess, for the first time, the efficacy and safety of peginesatide in chronic kidney disease (CKD) patients receiving peritoneal dialysis (PD) and previously on epoetin treatment. ♦ In this open-label multicenter study, 59 PD patients with CKD were converted from epoetin (alfa or beta) to once-monthly peginesatide. Doses were titrated to maintain hemoglobin levels between 10 g/dL and 12 g/dL during the 25 weeks of the study. The primary endpoint was change from baseline in mean hemoglobin values during the evaluation period (weeks 20 - 25). ♦ The mean hemoglobin value during the evaluation period was 11.3 ± 1.07 g/dL, and the mean change from baseline was 0.10 ± 1.15 g/dL (95% confidence limits: -0.24, 0.44 g/dL). During the evaluation period, most patients maintained hemoglobin levels between 10 g/dL and 12 g/dL (63.0%) and within ±1.0 g/dL of baseline (60.9%). The median weekly epoetin dose at baseline was 96.0 U/kg, and the median starting peginesatide dose was 0.047 mg/kg. Forty-three patients (72.9%) completed the study. Six patients (10.2%) received red blood cell transfusions. The observed adverse event profile was consistent with underlying conditions in the PD patient population. The most common adverse event was peritonitis (20.3%), a complication commonly associated with PD. Four deaths occurred during the study (2 related to septic shock, and 1 each to myocardial ischemia and myasthenia gravis). ♦ In this study, once-monthly peginesatide maintained hemoglobin levels in PD patients after conversion from epoetin.

Major Declines in Epoetin Dosing after Prospective Payment System Based on Dialysis Facility Organizational Status

Background: Epoetin therapy used to treat anemia among ESRD patients has cost Medicare ∼$40 billion. Since January 2011, epoetin has been reimbursed via a new bundled prospective payment system (PPS). Our aim was to determine changes in epoetin dosing and hematocrit levels in response to PPS by different types of dialysis providers. Methods: Data from the USRDS were used to identify 187,591 and 206,163 Medicare-eligible ESRD patients receiving hemodialysis during January 2010 (pre-PPS) and December 2011 (post-PPS). Standardized weekly mean epoetin dose administered pre- and post-PPS and adjustment in dose (titration) based on previous hematocrit level in each facility was disaggregated by profit status, chain membership and size. Results: Major declines in epoetin use, dosing and achieved hematocrit levels were observed after PPS. Among the three largest dialysis chains, the decline in standardized epoetin dose was 29% at Fresenius, 47% at DaVita, and 52% at DCI. The standardized weekly epoetin dose among profit and nonprofit facilities declined by 38 and 42%, respectively. Changes in titration patterns suggest that a new hematocrit target of 30-33% was in place after PPS, replacing the erstwhile 33-36% hematocrit target used before PPS. Conclusion: Historically, important differences in anemia management were evident by dialysis organizational status. However, the confluence of financial incentives bundling epoetin payments and mounting scientific evidence linking higher hematocrit targets and higher epoetin doses to adverse outcomes have culminated in lower access to epoetin and lower doses across all dialysis providers in the first year after PPS.

Erythropoiesis-stimulating agent hyporesponsiveness in end-stage renal disease patients.

Approximately 5-10% of patients with end-stage renal disease (ESRD) exhibit hyporesponsiveness to erythropoiesis-stimulating agents (ESAs), defined as a continued need for higher than 300 IU/kg/week doses of epoetin or a 1.5 mg/kg/week dose of darbepoetin. ESA hyporesponsiveness contributes to the morbidity, mortality and health-care economic burden of ESRD patients. The most common causes of ESA resistance are absolute or functional iron deficiency and inflammation. Maintaining adequate iron stores is clearly accepted as the most important strategy for reducing the ESA requirement and for enhancing ESA efficacy. Recent clinical studies have shown that iron administration to ESRD patients is associated with an increased risk of infection and atherosclerosis. ESA hyporesponsiveness due to chronic inflammation in ESRD patients has been reported to be improved by a number of interventions, including the use of biocompatible hemodialysis membranes, ultrapure dialysate, ascorbic acid therapy, vitamin E supplementation, and statin therapy. Other causes of ESA hyporesponsiveness include inadequate dialysis, hyperparathyroidism, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, primary bone marrow disorders, myelosuppressive agents, hemoglobinopathies, hemolysis, and hypersplenism. This article summarizes the common causes of ESA hyporesponsiveness and the proposed therapeutic interventions.

Evaluating epoetin dosing strategies using observational longitudinal data

Epoetin is commonly used to treat anemia in chronic kidney disease and End Stage Renal Disease subjects undergoing dialysis, however, there is considerable uncertainty about what level of hemoglobin or hematocrit should be targeted in these subjects. In order to address this question, we treat epoetin dosing guidelines as a type of dynamic treatment regimen. Specifically, we present a methodology for comparing the effects of alternative treatment regimens on survival using observational data. In randomized trials patients can be assigned to follow a specific management guideline, but in observational studies subjects can have treatment paths that appear to be adherent to multiple regimens at the same time. We present a cloning strategy in which each subject contributes follow-up data to each treatment regimen to which they are continuously adherent and artificially censored at first nonadherence. We detail an inverse probability weighted log-rank test with a valid asymptotic variance estimate that can be used to test survival distributions under two regimens. To compare multiple regimens, we propose several marginal structural Cox proportional hazards models with robust variance estimation to account for the creation of clones. The methods are illustrated through simulations and applied to an analysis comparing epoetin dosing regimens in a cohort of 33,873 adult hemodialysis patients from the United States Renal Data System.

Effect of occasional epoetin use in combination with a stable darbepoetin dosage on anemia management in hemodialysis patients.

AimTaking advantage of the characteristics of both darbepoetin (DA) and epoetin (EPO) might be a reasonable option for stabilizing hemoglobin (Hb) control in hemodialysis (HD) patients. The effect of DA assisted by EPO (DA/EPO) on Hb control was evaluated retrospectively in comparison with that of EPO monotherapy.MethodsTwenty-six HD patients whose annual mean Hb values were available for both an EPO monotherapy period and a DA/EPO period were selected for analysis. During the DA/EPO period, DA was given on the second HD day of a week, and EPO was given if needed on the first and third HD days. Under stable DA dosage, when Hb rose >12 g/dL, EPO was eliminated. When Hb decreased <10 g/dL, EPO was added again. The variability of annual mean Hb values from the 26 HD patients during the DA/EPO period was compared with that during the EPO period. Additionally, the distance in Hb (d-Hb; absolute value of difference) between the annual mean Hb values and the target Hb (11 g/dL) during the DA/EPO period was compared with that during the EPO period.ResultsThe variability of annual mean Hb values during the DA/EPO period was significantly smaller than that during the EPO period (11.2±0.25 g/dL versus [vs] 11.0±0.50 g/dL; the F-test for equality of variance, P<0.001). Additionally, the d-Hb during the DA/EPO period was significantly smaller than that during the EPO period (0.22±0.21 g/dL vs 0.38±0.31 g/dL, P<0.03). The total doses (as EPO equivalents) of DA with EPO were reduced to 82.2% of the baseline EPO dose during the EPO monotherapy period. The expenditure for the DA/EPO period was significantly reduced to 80.9% of that for the EPO monotherapy. Also, the annual total amount of intravenous iron supplementation during the DA/EPO period was significantly reduced compared with that during the EPO period (546±304 mg/year vs 684±314 mg/year, P<0.05).ConclusionThe occasional use of EPO in combination with a stable DA dosage may be useful for Hb control within a narrow range of the target level.