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American Journal of Health-system... Oct 2023Post-transplantation anemia (PTA) is common in kidney transplant recipients, with patients frequently treated with erythropoietin-stimulating agents such as darbepoetin...
PURPOSE
Post-transplantation anemia (PTA) is common in kidney transplant recipients, with patients frequently treated with erythropoietin-stimulating agents such as darbepoetin alfa. The optimal dosing for darbepoetin alfa remains controversial.
METHODS
This retrospective cohort study involved kidney transplant recipients who received darbepoetin alfa at 2 clinics. Patients were stratified into 2 groups: those who received a fixed dose of 200 μg and those who received a weight-based dose of 0.45 μg/kg. The dosing interval varied depending on clinical response, clinic visit timing, and frequency allowed by insurance. The primary outcome was achieving a hemoglobin concentration of at least 10 g/dL without blood transfusion by 12 weeks after darbepoetin alfa initiation.
RESULTS
Of the 110 patients in the study, 45% received weight-based dosing and 55% received fixed dosing. Darbepoetin alfa was initiated significantly earlier after transplantation in the fixed-dose group (median of 14 vs 20 days; P = 0.003). The weight-based group received more doses of darbepoetin alfa (median of 4 vs 2 doses; P = 0.002) and had a significantly lower cumulative exposure to darbepoetin alfa (125 vs 590 μg; P < 0.001). The median time between doses was 9 days (interquartile range, 7-14 days) in the weight-based group and 12 days (7-32 days) in the fixed-dose group (P = 0.04). Patients in the weight-based group more frequently achieved the primary outcome (67.3% vs 47.5%; P = 0.059). There was no significant difference in secondary or safety outcomes between the groups.
CONCLUSION
Weight-based and fixed dosing approaches for darbepoetin alfa were not different in the achievement of a hemoglobin concentration of at least 10 g/dL without blood transfusion at 12 weeks after darbepoetin alfa initiation, with significantly lower cumulative darbepoetin alfa utilization in the weight-based group. Weight-based dosing of darbepoetin alfa in PTA appears to be safe and effective, with the potential for significant patient and health-system cost savings.
Topics: Humans; Darbepoetin alfa; Kidney Transplantation; Retrospective Studies; Anemia; Hemoglobins; Hematinics; Treatment Outcome
PubMed: 37471466
DOI: 10.1093/ajhp/zxad163 -
Indian Journal of Pediatrics Feb 2023Neonates with Rhesus hemolytic disease can present with anemia beyond 1 wk of age due to bone marrow suppression and low erythropoietin secretion. Erythropoietin...
Neonates with Rhesus hemolytic disease can present with anemia beyond 1 wk of age due to bone marrow suppression and low erythropoietin secretion. Erythropoietin stimulating agents (ESA) were tried to manage anemia in these neonates. Darbepoetin alfa (DA) is a long-acting ESA used to treat anemia in premature neonates and in children with chronic kidney disease or on cancer chemotherapy. The authors present their experience of using DA to treat late-onset hyporegenerative anemia in 3 neonates with Rhesus isoimmunization. Darbepoetin alfa 4 mcg/kg was given subcutaneously at a 1-2-wk interval to target hemoglobin of 10-12 g/dL. No adverse effects were observed, and the treated infants had a reduced need for the packed red blood cell transfusions.
Topics: Humans; Female; Darbepoetin alfa; Hematinics; Anemia; Erythropoietin; Epoetin Alfa; Hemoglobins; Erythroblastosis, Fetal
PubMed: 36460815
DOI: 10.1007/s12098-022-04411-w -
American Journal of Kidney Diseases :... Jun 2023The optimum starting dose of intravenous continuous erythropoietin receptor activator (C.E.R.A.) has been previously determined; this study ascertains the optimum...
RATIONALE & OBJECTIVE
The optimum starting dose of intravenous continuous erythropoietin receptor activator (C.E.R.A.) has been previously determined; this study ascertains the optimum starting dose of subcutaneous C.E.R.A. administration in pediatric patients.
STUDY DESIGN
Phase 2, open-label, single-arm, multicenter study.
SETTING & PARTICIPANTS
Patients aged 3 months to 17 years with renal anemia and chronic kidney disease (CKD; including those treated with maintenance dialysis and those not treated with dialysis) who were receiving maintenance treatment with erythropoiesis-stimulating agents (ESAs).
INTERVENTION
Subcutaneous C.E.R.A. administration every 4 weeks (starting dose was based on defined conversion factors).
OUTCOME
The primary outcome was the change in hemoglobin concentration between the baseline and evaluation period for each patient. Secondary efficacy measures and safety were also evaluated.
RESULTS
Forty patients aged 0.4-17.7 years were enrolled. The study achieved its primary outcome: the mean change in hemoglobin concentration was an increase of 0.48g/dL; the 95% confidence interval (0.15-0.82) and standard deviation (±1.03) were within the prespecified boundaries (-1 to 1g/dL and<1.5g/dL, respectively). Mean hemoglobin concentrations were maintained within the target 10-12g/dL range in 24 of 38 patients and within±1g/dL of the baseline in 19 of 38 patients, and the median C.E.R.A. subcutaneous dose decreased over time. Efficacy in key subgroups (age group, dialysis type, prior ESA treatment) was consistent with the primary outcome. Thirty-eight patients completed the core period; 25 chose to enter the safety extension period. Safety was consistent with prior studies, with no new signals.
LIMITATIONS
Single-arm and open-label study; small sample size.
CONCLUSIONS
Pediatric patients with anemia secondary to CKD who were on, or not on, dialysis could be safely and effectively switched from maintenance ESAs to subcutaneous C.E.R.A. administered every 4 weeks, using defined dose-conversion factors to determine the optimum starting dose.
FUNDING
F. Hoffmann-La Roche Ltd.
TRIAL REGISTRATION
The SKIPPER trial registered at ClinicalTrials.gov with study number NCT03552393.
PLAIN-LANGUAGE SUMMARY
Anemia, a complication of chronic kidney disease, is associated with poor quality of life and an increased risk of hospitalization and mortality. The current treatments for anemia include iron therapy and erythropoiesis-stimulating agents (ESAs); however, the relatively short half-lives of the ESAs epoetin alfa/beta or darbepoetin alfa may require more frequent dosing and hospital visits compared with the ESA known as continuous erythropoietin receptor activator (C.E.R.A.). A previous study demonstrated that children aged 5 years or more with anemia associated with chronic kidney disease who were on hemodialysis could be switched to intravenous C.E.R.A. from their existing epoetin alfa/beta or darbepoetin alfa treatment. This study provides evidence that subcutaneous C.E.R.A. can safely and effectively treat anemia in children, including those aged<5 years and regardless of whether they were on dialysis or the type of dialysis they received (peritoneal dialysis or hemodialysis).
Topics: Humans; Child; Darbepoetin alfa; Epoetin Alfa; Quality of Life; Erythropoietin; Anemia; Hematinics; Renal Insufficiency, Chronic; Renal Dialysis; Hemoglobins
PubMed: 36587890
DOI: 10.1053/j.ajkd.2022.11.006 -
American Journal of Nephrology 2022Anemia frequently occurs in chronic kidney disease (CKD), is associated with poor quality of life and cardiovascular outcomes, and its treatment represents a... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Anemia frequently occurs in chronic kidney disease (CKD), is associated with poor quality of life and cardiovascular outcomes, and its treatment represents a considerable economic burden to the healthcare system. Although effective, the current standard of care for the treatment of anemia in chronic kidney disease patients with erythropoiesis-stimulating agents requires chronic/ongoing injections, making the treatment less accessible or desirable to patients not treated by in-center maintenance hemodialysis. Furthermore, safety concerns, including an increased risk of cardiovascular events and mortality, have emerged from their use in studies targeting hemoglobin concentrations in the normal or near-normal range. The orally active hypoxia-inducible factor prolyl hydroxylase inhibitor vadadustat may offer advantages over erythropoiesis-stimulating agents by correcting anemia via pathways activating endogenous erythropoietin production.
METHODS
To comprehensively analyze the safety profile of vadadustat in patients with dialysis-dependent and non-dialysis-dependent CKD-related anemia, we pooled the safety populations from each of the four trials in the phase 3 clinical program (n = 7,373) and compared the risk of treatment-emergent adverse events (TEAEs) for each treatment arm.
RESULTS
In patients randomized to vadadustat versus darbepoetin alfa, rates of TEAEs (88.9% vs. 89.3%), treatment-emergent serious adverse events (58.0% vs. 59.3%), and TEAEs leading to death (16.1% vs. 16.2%) were similar, as were rates of adverse events of special interest, including cardiovascular-, hepatic-, and neoplasm-related adverse events.
DISCUSSION/CONCLUSION
Among patients with CKD-related anemia treated with vadadustat, we observed similar rates of adverse events relative to those treated with darbepoetin alfa.
Topics: Humans; Darbepoetin alfa; Quality of Life; Anemia; Erythropoietin; Renal Insufficiency, Chronic; Hematinics; Renal Dialysis; Hemoglobins
PubMed: 36450264
DOI: 10.1159/000528443 -
Clinical and Experimental Nephrology Feb 2021Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) is associated with cardiovascular events and poor renal outcome in patients with chronic kidney disease...
BACKGROUND
Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) is associated with cardiovascular events and poor renal outcome in patients with chronic kidney disease (CKD). This study aimed to investigate the initial responsiveness to darbepoetin alfa (DA) and its contributing factors using the data from the BRIGHTEN.
METHODS
Of 1980 patients enrolled at 168 facilities, 1695 were included in this analysis [285 patients were excluded mainly due to lack of hemoglobin (Hb) values]. The initial ESA response index (iEResI) was defined as a ratio of Hb changes over 12 weeks after DA administration per weight-adjusted total DA dose and contributing factors to iEResI were analyzed.
RESULTS
The mean age was 70 ± 12 years (male 58.8%; diabetic nephropathy 27.6%). The median creatinine and mean Hb levels at DA initiation were 2.62 mg/dL and 9.8 g/dL, respectively. The most frequent number of DA administration during 12 weeks was 3 times (41.1%), followed by 4 (15.6%) times with a wide distribution of the total DA dose (15-900 μg). Remarkably, 225 patients (13.3%) did not respond to DA. Multivariate analysis showed that male gender, hypoglycemic agent use, iron supplementation, high eGFR, low Hb, low CRP, low NT-proBNP, and low urinary protein-creatinine ratio were independently associated with better initial response to DA (P = < 0.0001, 0.0108, < 0.0001, 0.0476, < 0.0001, 0.0004, 0.0435, and 0.0009, respectively).
CONCLUSIONS
Non-responder to DA accounted for 13.3% of patients with non-dialysis CKD. Iron supplementation, low CRP, low NT-proBNP, and less proteinuria were predictive and modifiable factors associated with better initial response to DA.
Topics: Aged; Aged, 80 and over; Anemia; Cardiovascular Diseases; Darbepoetin alfa; Female; Humans; Male; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic
PubMed: 32949295
DOI: 10.1007/s10157-020-01969-7 -
Frontiers in Pharmacology 2021Vadadustat is a novel drug for treating anemia patients with chronic kidney disease (CKD), but its effect and safety remain uncertain. This study aimed to summarize the... (Review)
Review
Vadadustat is a novel drug for treating anemia patients with chronic kidney disease (CKD), but its effect and safety remain uncertain. This study aimed to summarize the evidence for vadadustat in the treatment of CKD patients with anemia. PubMed, Ovid Medline, Embase, Cochrane CENTRAL, Wanfang Data, China National Knowledge Infrastructure and an international trial register were searched from their inception to June 2021 for randomized controlled trials (RCTs) comparing the efficacy and safety of vadadustat to those of placebo or erythropoiesis-stimulating agents (ESAs) in treating anemia in CKD patients. Data were pooled in a meta-analysis, with results expressed as the mean difference for continuous outcomes and relative risk for categorical outcomes with 95% confidence intervals (95% CIs). The certainty of evidence was rated according to Cochrane methods and the GRADE approach. Ten RCTs comparing vadadustat with placebo (4 RCTs) or darbepoetin alfa (6 RCTs) were included ( = 8,438 participants). Compared with placebo, vadadustat increased the hemoglobin (Hb) response rate (risk ratio 5.27; 95% CI: 2.69 to 10.31; < 0.001; high certainty of evidence) and Hb level from baseline (∆Hb) (mean difference (MD) 1.28; 95% CI: 0.83 to 1.73; < 0.001; low certainty of evidence). Compared with placebo or darbepoetin alfa, vadadustat decreased hepcidin (MD -36.62; 95% CI: -54.95 to -18.30; < 0.001) and ferritin (MD -56.24; 95% CI: -77.37 to -35.11; < 0.001) levels and increased iron-binding capacity (MD 24.38; 95% CI: 13.69 to 35.07; < 0.001), with a low to moderate certainty of evidence. Moderate to high certainty evidence suggested that compared with placebo or darbepoetin alfa, vadadustat significantly increased the risk of nausea and diarrhea but did not significantly increase the risk of serious adverse events, especially all-cause mortality, cardiac events and nonfatal stroke. Vadadustat may safely improve Hb levels and promote iron utilization in CKD patients with anemia without increasing the incidence of serious adverse events.
PubMed: 35115942
DOI: 10.3389/fphar.2021.795214 -
Therapeutic Apheresis and Dialysis :... Aug 2022Enarodustat, a newly developed hypoxia-inducible factor prolyl hydroxylase inhibitor, is used in clinical practice in Japan. Several clinical studies showed that... (Review)
Review
Enarodustat, a newly developed hypoxia-inducible factor prolyl hydroxylase inhibitor, is used in clinical practice in Japan. Several clinical studies showed that enarodustat corrected and maintained hemoglobin (Hb) levels by stimulating endogenous erythropoietin production and improving iron utilization in anemic patients with chronic kidney disease, regardless of whether they were on dialysis. In addition, Phase III comparative studies demonstrated that enarodustat was noninferior to darbepoetin alfa in controlling Hb levels. Furthermore, enarodustat was well tolerated during the treatment. Enarodustat is currently being developed in the Republic of Korea and China and is expected to be developed worldwide. This article reviews the data on enarodustat, including the findings from preclinical studies, pharmacokinetics/pharmacodynamics, and efficacy and safety results of clinical studies.
Topics: Anemia; Erythropoietin; Hematinics; Humans; N-substituted Glycines; Prolyl-Hydroxylase Inhibitors; Pyridines; Renal Insufficiency, Chronic; Triazoles
PubMed: 35218616
DOI: 10.1111/1744-9987.13820 -
PloS One 2020Renal anemia is predominantly caused by a relative deficiency in erythropoietin (EPO). Conventional treatment for renal anemia includes the use of recombinant human EPO...
Renal anemia is predominantly caused by a relative deficiency in erythropoietin (EPO). Conventional treatment for renal anemia includes the use of recombinant human EPO (rhEPO) or a long-acting erythropoiesis-activating agent named darbepoetin alfa, which is a modified rhEPO with a carbohydrate chain structure that differs from native hEPO. We have developed a biosimilar to darbepoetin alfa designated JR-131. Here, we comprehensively compare the physicochemical and biological characteristics of JR-131 to darbepoetin alfa. JR-131 demonstrated similar protein structure to the originator, darbepoetin alfa, by peptide mapping and circular dichroism spectroscopy. Additionally, mass spectroscopic analyses and capillary zone electrophoresis revealed similar glycosylation patterns between the two products. Human bone marrow-derived erythroblasts differentiated and proliferated to form colonies with JR-131 to a similar degree as darbepoetin alfa. Finally, JR-131 stimulated erythropoiesis and improved anemia in rats similarly to darbepoetin alfa. Our data show the similarity in physicochemical and biological properties of JR-131 to those of darbepoetin alfa, and JR-131 therefore represents a biosimilar for use in the treatment of renal anemia.
Topics: Anemia; Animals; Biosimilar Pharmaceuticals; CHO Cells; Cricetinae; Cricetulus; Darbepoetin alfa; Disease Models, Animal; Electrophoresis, Capillary; Erythropoiesis; Glycosylation; Kidney; Male; Molecular Weight; Nephrectomy; Peptide Mapping; Protein Structure, Secondary; Rats, Sprague-Dawley; Sugars; Treatment Outcome
PubMed: 32302352
DOI: 10.1371/journal.pone.0231830 -
Clinical and Experimental Nephrology Aug 2023Erythropoiesis-stimulating agents (ESAs) are the standard treatment for patients with renal anemia to increase hemoglobin (Hb) levels and reduce the need for blood... (Clinical Trial)
Clinical Trial
BACKGROUND
Erythropoiesis-stimulating agents (ESAs) are the standard treatment for patients with renal anemia to increase hemoglobin (Hb) levels and reduce the need for blood transfusions. However, treatments targeting high Hb levels require high doses of ESAs administered intravenously, which is associated with an elevated risk of adverse cardiovascular events. Furthermore, there have been some problems such as hemoglobin variability and low achievement of target hemoglobin due to the shorter half-lives of ESAs. Consequently, erythropoietin-promoting medications, such as hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors, have been developed. This study aimed to evaluate changes in the Treatment Satisfaction Questionnaire for Medicine version II (TSQM-II) domain scores relative to baseline in each trial, to assess patient satisfaction with molidustat versus darbepoetin alfa.
METHODS
This post-hoc analysis of two clinical trials compared treatment satisfaction with an HIF-PH inhibitor, molidustat, versus a standard ESA, darbepoetin alfa, as part of therapy in patients with non-dialysis chronic kidney disease (CKD) and renal anemia.
RESULTS
Exploratory outcome data using the TSQM-II showed that both arms in both trials had enhanced treatment satisfaction over the course of the study period, as well as improvements in most TSQM-II domains at week 24 of treatment. Molidustat was associated with convenience domain scores at multiple time points depending on the trial. More patients were highly satisfied with the convenience of molidustat than that of darbepoetin alfa. Patients treated with molidustat had increased global satisfaction domain scores compared with those treated with darbepoetin alfa; however, the differences in global satisfaction domain scores were not significant.
CONCLUSION
These patient-reported satisfaction outcomes support the use of molidustat as a patient-centered treatment option for CKD-related anemia.
REGISTRATION OF CLINICAL TRIALS
ClinicalTrials.gov Identifier: NCT03350321 (November 22, 2017).
CLINICALTRIALS
gov Identifier: NCT03350347 (November 22, 2017).
Topics: Humans; Anemia; Chronic Disease; Darbepoetin alfa; Erythropoietin; Hematinics; Hemoglobins; Patient Satisfaction; Renal Insufficiency, Chronic
PubMed: 37095342
DOI: 10.1007/s10157-023-02353-x -
[Rinsho Ketsueki] the Japanese Journal... 2020Myelodysplastic syndromes (MDS) are neoplastic diseases of the hematopoietic stem cells, caused by genetic mutations. The clinical courses of MDS are highly variable...
Myelodysplastic syndromes (MDS) are neoplastic diseases of the hematopoietic stem cells, caused by genetic mutations. The clinical courses of MDS are highly variable based on the underlying genetic aberrations, ranging from slowly progressing cytopenia to rapidly-manifesting fatal diseases, including the development of acute myelogenous leukemia. The management of lower-risk MDS, which is risk-stratified based on the revised International Prognostic Scoring System (IPSS-R), mainly consists of a supportive therapy, including blood transfusion to treat anemia and thrombocytopenia. Recently, three novel drugs were approved, which became available in Japan. These include darbepoetin alfa, an erythropoiesis-stimulating agent; lenalidomide, which is specifically active for anemia of 5q- syndrome; and deferasirox, an oral iron-chelating agent. Decision analyses also provide evidence in determining the optimal timing for the potentially curative allogeneic hematopoietic stem cell transplantation for lower-risk MDS. Thus, the management of lower-risk MDS should be optimized using these novel agents and newly available evidence.
Topics: Anemia, Macrocytic; Darbepoetin alfa; Humans; Japan; Lenalidomide; Myelodysplastic Syndromes; Risk Assessment
PubMed: 33162518
DOI: 10.11406/rinketsu.61.1212