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Vadadustat for treatment of anemia in patients with dialysis-dependent chronic kidney disease receiving peritoneal dialysis
Sarnak MJ, Agarwal R, Boudville N, Chowdhury PCP, Eckardt KU, Gonzalez CR, Kooienga LA, Koury MJ, Ntoso KA, Luo W, et al
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2023
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Abstract
BACKGROUND Hypoxia-inducible factor prolyl hydroxylase inhibitors such as vadadustat may provide an oral alternative to injectable erythropoiesis-stimulating agents for treating anemia in patients receiving peritoneal dialysis. In two randomized (1:1), global, phase 3, open-label, sponsor-blind, parallel-group, active-controlled noninferiority trials in patients with dialysis-dependent chronic kidney disease (INNO2VATE), vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and hematological efficacy. Vadadustat's effects in patients receiving only peritoneal dialysis is unclear. METHODS We conducted a post hoc analysis of patients in the INNO2VATE trials receiving peritoneal dialysis at baseline. The prespecified primary safety endpoint was time to first major cardiovascular event (MACE; defined as all-cause mortality or nonfatal myocardial infarction or stroke). The primary efficacy endpoint was mean change in hemoglobin from baseline to the primary efficacy period (weeks 24-36). RESULTS Of the 3923 patients randomized in the two INNO2VATE trials, 309 were receiving peritoneal dialysis (vadadustat, n = 152; darbepoetin alfa, n = 157) at baseline. Time to first MACE was similar in the vadadustat and darbepoetin alfa groups (hazard ratio 1.10; 95% CI 0.62, 1.93). In patients receiving peritoneal dialysis, the difference in mean change in hemoglobin concentrations was -0.10 g/dL (95% CI -0.33, 0.12) in the primary efficacy period. The incidence of treatment-emergent adverse events (TEAEs) was 88.2% versus 95.5%, and serious TEAEs was 52.6% versus 73.2% in the vadadustat and darbepoetin alfa groups, respectively. CONCLUSIONS In the subgroup of patients receiving peritoneal dialysis in the phase 3 INNO2VATE trials, safety and efficacy of vadadustat were similar to darbepoetin alfa.
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Erythropoietic effects of vadadustat in patients with anemia associated with chronic kidney disease
Koury MJ, Agarwal R, Chertow GM, Eckardt KU, Fishbane S, Ganz T, Haase VH, Hanudel MR, Parfrey PS, Pergola PE, et al
American journal of hematology. 2022
Abstract
Patients with chronic kidney disease develop anemia largely because of inappropriately low erythropoietin production and insufficient iron available to erythroid precursors. In four phase 3, randomized, open-label, clinical trials in dialysis-dependent and non-dialysis-dependent patients with chronic kidney disease and anemia, the hypoxia-inducible factor prolyl hydroxylase inhibitor, vadadustat, was non-inferior to the erythropoiesis-stimulating agent, darbepoetin alfa, in increasing and maintaining target hemoglobin concentrations. In these trials, vadadustat increased the concentrations of serum erythropoietin, the numbers of circulating erythrocytes, and the numbers of circulating reticulocytes. Achieved hemoglobin concentrations were similar in patients treated with either vadadustat or darbepoetin alfa, but compared with patients receiving darbepoetin alfa, those receiving vadadustat had erythrocytes with increased mean corpuscular volume and mean corpuscular hemoglobin, while the red cell distribution width was decreased. Increased serum transferrin concentrations, as measured by total iron-binding capacity, combined with stable serum iron concentrations, resulted in decreased transferrin saturation in patients randomized to vadadustat compared with patients randomized to darbepoetin alfa. The decreases in transferrin saturation were associated with relatively greater declines in serum hepcidin and ferritin in patients receiving vadadustat compared with those receiving darbepoetin alfa. These results for serum transferrin saturation, hepcidin, ferritin, and erythrocyte indices were consistent with improved iron availability in the patients receiving vadadustat. Thus, overall, vadadustat had beneficial effects on three aspects of erythropoiesis in patients with anemia associated with chronic kidney disease: increased endogenous erythropoietin production, improved iron availability to erythroid cells, and increased reticulocytes in the circulation. This article is protected by copyright. All rights reserved.
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Economic Burden and Health-Related Quality of Life Associated with Current Treatments for Anaemia in Patients with CKD not on Dialysis: A Systematic Review
Pergola PE, Pecoits-Filho R, Winkelmayer WC, Spinowitz B, Rochette S, Thompson-Leduc P, Lefebvre P, Shafai G, Bozas A, Sanon M, et al
PharmacoEconomics - open. 2019
Abstract
BACKGROUND The cost and health-related quality of life (HRQoL) burden associated with treatments for anaemia of chronic kidney disease (CKD) is not well characterized among non-dialysis-dependent (NDD) patients. OBJECTIVE Our objective was to review the literature on costs and HRQoL associated with current treatments for anaemia of CKD among NDD patients. METHODS The Cochrane Library, MEDLINE, Embase, NHS EED, and NHS HTA databases were searched for original studies published in English between 1 January 2000 and 17 March 2017. The following inclusion criteria were applied: adult population; primary focus was anaemia of CKD; patients received iron supplementation, red blood cell transfusion, or erythropoiesis-stimulating agents (ESAs); and reported results on HRQoL and/or costs. Studies that included NDD patients, did not compare different treatments, and had relevant designs were retained. HRQoL and cost outcomes were summarized in a narrative synthesis. RESULTS In total, 16 studies met the inclusion criteria: six randomized controlled trials, four prospective single-arm trials, three retrospective studies, one prospective observational study, one simulation study, and one cross-sectional survey. All included ESAs. Treatment of anaemia (compared with no treatment) was associated with HRQoL improvements in five of six studies and lower costs in four of four studies. Treatment aiming for higher haemoglobin targets (compared with lower targets) resulted in modest HRQoL improvements, higher healthcare resource utilization (HRU), and higher costs. CONCLUSIONS In NDD patients, untreated anaemia of CKD leads to higher costs, higher HRU, and lower HRQoL compared with initiating anaemia treatment. Relative to aiming for lower haemoglobin targets with ESAs, higher targets conferred modest HRQoL improvements and were associated with higher HRU.
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Mortality risk of darbepoetin alfa versus epoetin alfa in patients with CKD: systematic review and meta-analysis
Wilhelm-Leen ER, Winkelmayer WC
American Journal of Kidney Diseases. 2015;66((1)):69-74.
Abstract
BACKGROUND Epoetin alfa (EPO) and darbepoetin alfa (DPO) are erythropoiesis-stimulating agents that are widely and interchangeably used for the treatment of anemia in patients with advanced chronic kidney disease and end-stage renal disease. No study has specifically compared the risks of hard study outcomes between EPO and DPO, including mortality. STUDY DESIGN Systematic review of the literature and meta-analysis. SETTING & POPULATION Patients enrolled in randomized trials comparing EPO versus DPO for the treatment of anemia in adults with chronic kidney disease, including those requiring dialysis. SELECTION CRITERIA FOR STUDIES We conducted a systematic search of the literature (PubMed, CENTRAL, SCOPUS, and EMBASE, all years) and industry resources, using predefined search terms and data abstraction tools. We then summarized key characteristics and findings of these trials and performed a random-effects meta-analysis of trials with at least 3 months' duration to identify the summary OR of mortality between patients randomly assigned to DPO versus EPO. INTERVENTION DPO versus EPO. OUTCOME All-cause mortality. RESULTS We identified 9 trials that met the stated inclusion criteria. Overall, 2,024 patients were included in the meta-analysis, of whom 126 died during follow-up, which ranged from 20 to 52 weeks. We found no significant difference in mortality between patients randomly assigned to DPO versus EPO (OR, 1.33; 95% CI, 0.88-2.01). No treatment heterogeneity across studies was detected (Q statistic=4.60; P=0.8). LIMITATIONS Generalizability to nontrial populations is uncertain. CONCLUSIONS Few trials directly comparing DPO and EPO have been conducted and follow-up was limited. In aggregate, no effect of specific erythropoiesis-stimulating agent on mortality was identified, but the confidence limits were wide and remained compatible with considerable harm from DPO. Absent adequately powered randomized trials, observational postmarketing comparative effectiveness studies comparing these erythropoiesis-stimulating agents are required to better characterize the long-term safety profiles of these agents.Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.