darbepoetin alfa
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2021 ◽  
Vol 16 ◽  
Author(s):  
Nahla E. El-Ashmawy ◽  
Eman G. Khedr ◽  
Nahla S. Kotb ◽  
Fathi Salem ◽  
Amera O. Ibrahim

Background: Anemia is one of the most common complications of Chronic Kidney Disease (CKD). The vast majority of Egyptian CKD patients are interchangeably treated with Darbepoetin Alfa (DPA) and Epoetin Alfa (EPA) to achieve and maintain target hemoglobin levels. Our study aimed to compare the efficacy and safety of DPA versus EPA for managing anemia amongst Egyptian patients with CKD undergoing dialysis. Methods: A multicenter, open label, randomized, prospective, parallel study was conducted. Patients with CKD undergoing dialysis with Hb level <10 g/dl were enrolled. The primary efficacy endpoint was the change in hemoglobin concentration at the evaluation period (weeks 20-24). Pre-specified adverse events of interest following administration, including blood transfusions requirement, blood pressure and hemoglobin excursions, the relationship between C - Reactive Protein (CRP) and hemoglobin, were assessed. Findings:: Only 98 of 104 enrolled patients completed the study, fifty patients received EPA, and 48 patients received DPA. Our results showed that a significantly higher percentage of patients who achieved target Hb level ≥ 11 g/dL in DPA treated group vs. EPA as well as the meantime to achieve Hb level ≥ 10 g/dL was shorter in DPA treated group. Safety profiles of both treatments were similar. A negative correlation was observed between serum CRP and hemoglobin level in hemodialysis patients. Conclusion: Our study showed that DPA was more effective and well tolerated in achieving and maintaining Hb levels with lower dosing frequency compared to EPA. Furthermore, CRP is recommended to be routinely measured where patients with higher CRP require high ESA doses.


2021 ◽  
Author(s):  
Yasuyoshi Morita ◽  
Yasuhito Nannya ◽  
Motoshi Ichikawa ◽  
Hitoshi Hanamoto ◽  
Hirohiko Shibayama ◽  
...  

Abstract Darbepoetin alfa (DA) is often used in treating anemia of lower-risk (IPSS low or int-1) myelodysplastic syndromes (MDS). However, whether mutations can predict effectiveness of DA has not been examined. The present study aimed to determine gene mutations for predicting therapeutic effect of DA. Primary endpoint was correlation between the presence of highly frequent (≥10%) mutations and hematological improvement erythroid according to IWG criteria 2006 by DA (240 μg/week) until week 16. Included were 79 patients (age 29-90, median 77.0 years; 52 [65.8%] male). Frequently (≥10%) mutated genes were SF3B1 (24 cases, 30.4%), TET2 (20, 25.3%), SRSF2 (10, 12.7%), ASXL1 (9, 11.4%), and DNMT3A (8, 10.1%). Overall response rate to DA was 70.9%. Multivariable analysis including baseline erythropoietin levels and red blood cell transfusion volumes as variables revealed that erythropoietin levels and mutations of ASXL1 gene were significantly associated with worse response (odds ratio 0.146, 95% confidence interval 0.042-0.503; p=0.0023, odds ratio 0.175, 95% confidence interval 0.033-0.928; p=0.0406, respectively). This study indicated that anemic patients who show higher erythropoietin levels and harbor ASXL1 gene mutations may have poor response to DA. The alternative strategies are needed for the treatment of anemia in this population. Trial registration number and date of registration: UMIN000022185 & 09/05/2016.


2021 ◽  
Vol 9 (5) ◽  
pp. 387-399
Author(s):  
I. S. Krysanov ◽  
E. Yu. Ermakova ◽  
L. B. Vaskova ◽  
M. V. Tiapkina

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.


Author(s):  
Thor Ueland ◽  
Lars Gullestad ◽  
Lei Kou ◽  
James B. Young ◽  
Marc A. Pfeffer ◽  
...  

Abstract Aims We aimed to assess the value of GDF-15, a stress-responsive cytokine, in predicting clinical outcomes in patients with heart failure (HF) with reduced ejection fraction (HFrEF) and anemia Methods and results Serum GDF-15 was assessed in 1582 HFrEF and mild-to-moderate anemia patients who where followed for 28 months in the Reduction of Events by Darbepoetin alfa in Heart Failure (RED-HF) trial, an overall neutral RCT evaluating the effect darbepoetin alfa on clinical outcomes in patients with systolic heart failure and mild-to-moderate anemia. Association between baseline and change in GDF-15 during 6 months follow-up and the primary composite outcome of all-cause death or HF hospitalization were evaluated in multivariable Cox-models adjusted for conventional clinical and biochemical risk factors. The adjusted risk for the primary outcome increased with (i) successive tertiles of baseline GDF-15 (tertile 3 HR 1.56 [1.23–1.98] p < 0.001) as well as with (ii) a 15% increase in GDF-15 levels over 6 months of follow-up (HR 1.68 [1.38–2.06] p < 0.001). Addition of change in GDF-15 to the fully adjusted model improved the C-statistics (p < 0.001). No interaction between treatment and baseline or change in GDF-15 on outcome was observed. GDF-15 was inversely associated with several indices of anemia and correlated positively with ferritin. Conclusions In patients with HF and anemia, both higher baseline serum GDF-15 levels and an increase in GDF-15 during follow-up, were associated with worse clinical outcomes. GDF-15 did not identify subgroups of patients who might benefit from correction of anemia but was associated with several indices of anemia and iron status in the HF patients. Graphic abstract


PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0252439
Author(s):  
Chie Ogawa ◽  
Ken Tsuchiya ◽  
Naohisa Tomosugi ◽  
Kunimi Maeda

Background Hypoxia-inducible factor (HIF) prolyl hydroxylase domain inhibitors, which have recently become clinically available for treating renal anemia, are attracting attention for their novel mechanisms of action. Methods Relationships of reticulocyte hemoglobin content (CHr), which reflects recent Hb synthesis, with serum ferritin (s-ft) and transferrin saturation (TSAT) were examined in 30 patients on hemodialysis after switching from darbepoetin alfa (DA) to roxadustat (Rox). Iron deficiency was defined as CHr < 32.0 pg. Cutoff values of s-ft and TSAT were determined using receiver operating characteristic curves for the endpoint CHr ≥ 32.0 pg. Logistic analysis was performed with the reference group having s-ft or TSAT below the corresponding cutoff value (low vs high). Results With the endpoint CHr ≥ 32.0 pg on Day 0, cutoff values for s-ft and TSAT were respectively 49.7 ng/mL and 21.6% on Day 0 and 35.5 ng/mL and 16.2% on Day 28. With the endpoint CHr ≥ 32.0 pg on Day 28, cutoff values for s-ft and TSAT on Day 0 were 81.6 ng/mL and 23.9%, respectively. According to multivariable logistic analysis, the odds ratios of CHr ≥ 32.0 pg on Day 0 were significantly higher for high TSAT on Day 0 [34.7 (95% CI 2.42–131.0), p<0.003] and Day 28 [24.8 (95% CI 2.75–224.0), p = 0.004]. There were no significant differences by s-ft. Odd ratios of CHr ≥ 32.0 pg on Day 28 were also significantly higher for high s-ft on Day 0 [16.0 (95% CI 1.57–163.0), p = 0.019] and high TSAT on Day 0 [13.5 (95% CI 1.24–147.0), p<0.033]. Conclusions Our results suggest Hb synthesis was maintained with lower TSAT and s-ft during Rox therapy compared with DA therapy. To avoid iron deficiency during the 4 weeks after switching DA to Rox, ideal s-ft and TSAT levels before the switch are 81.6 ng/mL and 23.9%, respectively.


2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Vlado Perkovic ◽  
Allison Blackorby ◽  
Borut Cizman ◽  
Kevin Carroll ◽  
Alexander Cobitz ◽  
...  

Abstract Background and Aims The Anemia Study in Chronic kidney disease (CKD): Erythropoiesis via a Novel prolyl hydroxylase inhibitor (PHI) Daprodustat-Non-Dialysis (ASCEND-ND; NCT02876835) trial is evaluating the efficacy and safety of daprodustat when compared with darbepoetin alfa in CKD patients with anaemia not requiring dialysis. We report the trial design as well as key baseline characteristics of participants. Method Eligible patients from 39 countries were adults with CKD stages 3–5 who were able to provide informed consent and demonstrated adherence to daprodustat placebo tablets and study procedures during the run-in period. Patients were eligible if (1) they were not using erythropoiesis stimulating agents (ESAs) and had a screening haemoglobin (Hb) 8 to 10 g/dL or if (2) they were receiving ESAs with screening Hb of 8 to 12 g/dL. Patients were required to be iron replete [transferrin saturation (TSAT) &gt;20% and serum ferritin &gt;100 ng/mL] at screening. Participants were randomised to daprodustat or darbepoetin alfa (1:1) in an open-label (sponsor-blind) trial design with blinded endpoint assessment. An IDMC conducts regular reviews of unblinded safety and efficacy data and makes recommendations for additions or adjustments. An external, independent and blinded Clinical Events Classification (CEC) group, led by the Duke Clinical Research Institute, in collaboration with George Clinical, adjudicate predefined events. During the study, both groups had randomised treatment adjusted using a protocol-defined algorithm targeting a Hb range of 10 to 11 g/dL. Participants also followed protocol-defined iron management criteria to ensure they remained iron replete. Additionally, an anaemia rescue algorithm was in place to minimise the risk of extended periods of inadequate Hb response and to ensure consistent application of rescue therapy across the study. The co-primary endpoints are mean change in Hb between baseline and Evaluation Period (EP; Weeks 28 to 52, inclusive) and time to first adjudicated major adverse cardiovascular event (MACE; composite of all-cause mortality, non-fatal myocardial infarction, and non-fatal stroke). The study has more than 99% power for the Hb non-inferiority (NI) test with an NI margin of -0.75 g/dL for the treatment difference of mean change in Hb between baseline and EP, and approximately 90% power to exclude the NI margin of 1.25 for time to first adjudicated MACE, for daprodustat compared with darbepoetin alfa. Conditional on both co-primary endpoints achieving NI at the one-sided 2.5% level, statistical testing will progress to evaluate MACE and the principal secondary endpoint of CKD progression for superiority. These tests will be multiplicity adjusted. Results A total of 3872 patients were randomised (median age 67 years, 56% female; 55% white, 28% Asian, and 10% black). The median baseline Hb was 9.8 g/dL, serum ferritin was 274 ng/mL, TSAT 30%, and eGFR 18 mL/min/1.73 m2. Among randomised patients, 54% were ESA non-users, 57% reported a history of diabetes mellitus and 36% a history of cardiovascular disease. Median blood pressure was 135/74 mmHg. Sixty percent of participants were taking angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, while 57% were taking lipid modifying agents at baseline. The trial is expected to complete during 2021. Conclusion ASCEND-ND will define the efficacy and safety of daprodustat compared with darbepoetin alfa in the treatment of patients with anaemia associated with CKD not requiring dialysis.


2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Wolfgang Winkelmayer ◽  
James A Tumlin ◽  
Steven Fishbane ◽  
Youssef Farag ◽  
Dennis Vargo ◽  
...  

Abstract Background and Aims Vadadustat is a small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase being developed for treatment of anemia associated with chronic kidney disease (CKD). The vadadustat phase 3 program includes four efficacy and cardiovascular safety outcome trials of vadadustat versus the erythropoiesis-stimulating agent (ESA) darbepoetin alfa. Here we describe detailed results on hematologic efficacy in two of the four phase 3, randomized, open-label, sponsor-blind trials (the INNO2VATE trials) in adult patients with dialysis-dependent (DD) CKD and anemia, where vadadustat met prespecified noninferiority criteria compared with darbepoetin alfa with respect to cardiovascular safety and correction/maintenance of hemoglobin (Hb) target concentrations. Method The mean screening Hb range for the incident DD-CKD trial (NCT02865850) was 8.0-11.0 g/dL; for the prevalent DD-CKD trial (NCT02892149), it was 8.0-11.0 g/dL in the United States (US) and 9.0-12.0 g/dL for non-US. Patients in the incident and prevalent DD-CKD trials had initiated dialysis within &lt;16 weeks with limited or no prior ESA exposure and &gt;12 weeks with established ESA treatment prior to screening, respectively. Vadadustat starting dose was 300 mg/day for all patients, whereas initial darbepoetin alfa dose depended on each patient’s prior dose or product label. Both vadadustat and darbepoetin alfa doses were titrated according to prespecified dosing algorithms to achieve target Hb concentrations (US: 10-11 g/dL; non-US: 10-12 g/dL) during the primary evaluation period (PEP; weeks 24-36) and the secondary evaluation period (SEP; weeks 40-52). Herein, we present topline results from PEP and SEP endpoints, as well as other, more detailed hematologic erythrocyte parameters. Results A total of 3923 patients (369 with incident DD-CKD and 3554 with prevalent DD-CKD) were randomized 1:1 to vadadustat or darbepoetin alfa. Vadadustat was noninferior to darbepoetin alfa in achieving target-range Hb concentrations (primary efficacy endpoint) among patients who were new to, or established on, dialysis. The respective proportions of patients (vadadustat vs. darbepoetin alfa) with an average Hb value within the geography-specific target range in the PEP and SEP were 43.6% versus 56.9% and 39.8% versus 41.0% in the incident trial and 49.2% versus 53.2% and 44.3% versus 50.9% in the prevalent dialysis trial. The proportion of patients who achieved an Hb increase &gt;1.0 g/dL from baseline to week 52 was assessed only for the incident trial and was 84.0% (95% CI: 77.8%, 89.0%) for vadadustat versus 89.9% (95% CI: 84.7%, 93.8%) for darbepoetin alfa. Hematologic erythrocyte parameters at time points within the PEP and SEP are presented in Table 1. In the incident trial, reticulocyte count was slightly increased from baseline at 28 and 52 weeks for vadadustat, whereas for darbepoetin alfa, reticulocyte count was slightly decreased or unchanged in both trials. Erythrocyte mean corpuscular volume and erythrocyte mean corpuscular Hb showed increases by week 52 for both groups. Conclusion Vadadustat demonstrated similar profiles across erythrocyte parameters compared with darbepoetin alfa in the treatment of anemia associated with CKD in adults in both incident dialysis and prevalent dialysis settings.


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