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. 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. Lay SummaryMany people with chronic kidney disease (CKD) suffer from anemia. Anemia occurs when there are not enough hemoglobin-containing red blood cells to carry oxygen to the body's organs. This can cause symptoms of fatigue in patients, potentially leading to a poorer quality of life. The usual treatment for anemia requires injections of man-made versions of the hormone erythropoietin, which controls red blood cell production. Daprodustat is a new oral tablet for anemia treatment that can also increase the production of red blood cells. In the ASCEND-NHQ clinical trial, 614 patients with CKD and anemia had an equal likelihood of receiving daily daprodustat or an identical placebo pill for 28 weeks. By the end of the study, people treated with daprodustat had a larger increase in hemoglobin and improvements in fatigue compared with those who received placebo and compared with their starting hemoglobin and fatigue levels. Many people with chronic kidney disease (CKD) suffer from anemia. Anemia occurs when there are not enough hemoglobin-containing red blood cells to carry oxygen to the body's organs. This can cause symptoms of fatigue in patients, potentially leading to a poorer quality of life. The usual treatment for anemia requires injections of man-made versions of the hormone erythropoietin, which controls red blood cell production. Daprodustat is a new oral tablet for anemia treatment that can also increase the production of red blood cells. In the ASCEND-NHQ clinical trial, 614 patients with CKD and anemia had an equal likelihood of receiving daily daprodustat or an identical placebo pill for 28 weeks. By the end of the study, people treated with daprodustat had a larger increase in hemoglobin and improvements in fatigue compared with those who received placebo and compared with their starting hemoglobin and fatigue levels. Anemia frequently develops among patients with chronic kidney disease (CKD), and its severity increases as kidney function declines. Mild anemia contributes to the symptom burden of patients with advanced CKD, particularly causing or exacerbating fatigue and dyspnea.1Gregg L.P. Jain N. Carmody T. et al.Fatigue in nondialysis chronic kidney disease: correlates and association with kidney outcomes.Am J Nephrol. 2019; 50: 37-47Crossref PubMed Scopus (23) Google Scholar,2Mathias S.D. Blum S.I. Sikirica V. et al.Symptoms and impacts in anemia of chronic kidney disease.J Patient Rep Outcomes. 2020; 4: 64Crossref PubMed Scopus (8) Google Scholar Early placebo-controlled trials of recombinant human erythropoietin (rhEPO) showed substantial anemia improvement and reductions in rates of red blood cell transfusion among transfusion-dependent patients with advanced CKD or kidney failure. Increases in hemoglobin (Hb) with rhEPO were accompanied by amelioration of fatigue, physical symptoms, and physical function, compared with placebo or the untreated comparator group in these small, randomized studies.3Canadian Erythropoietin Study GroupAssociation between recombinant human erythropoietin and quality of life and exercise capacity of patients receiving haemodialysis.BMJ. 1990; 300: 573-578Crossref PubMed Google Scholar, 4US Recombinant Human Erythropoietin Predialysis Study GroupDouble-blind, placebo-controlled study of the therapeutic use of recombinant human erythropoietin for anemia associated with chronic renal failure in predialysis patients.Am J Kidney Dis. 1991; 18: 50-59Abstract Full Text PDF PubMed Scopus (139) Google Scholar, 5Revicki D.A. Brown R.E. Feeny D.H. et al.Health-related quality of life associated with recombinant human erythropoietin therapy for predialysis chronic renal disease patients.Am J Kidney Dis. 1995; 25: 548-554Abstract Full Text PDF PubMed Scopus (265) Google Scholar However, in the few sizeable, blinded studies that systematically evaluated the effects of treating anemia related to CKD with erythropoiesis-stimulating agents (ESAs) in patients with non-dialysis-dependent CKD, the benefits to health-related quality of life (HRQoL), including those relating to fatigue and physical functioning, were smaller and inconsistent.6Drüeke T.B. Locatelli F. Clyne N. et al.Normalization of hemoglobin level in patients with chronic kidney disease and anemia.N Engl J Med. 2006; 355: 2071-2084Crossref PubMed Scopus (1822) Google Scholar, 7Lewis E.F. Pfeffer M.A. Feng A. et al.Darbepoetin alfa impact on health status in diabetes patients with kidney disease: a randomized trial.Clin J Am Soc Nephrol. 2011; 6: 845-855Crossref PubMed Scopus (53) Google Scholar, 8Singh A.K. Szczech L. Tang K.L. et al.Correction of anemia with epoetin alfa in chronic kidney disease.N Engl J Med. 2006; 355: 2085-2098Crossref PubMed Scopus (2338) Google Scholar Thus, significant uncertainty remains about HRQoL benefits of ESA treatment in non-dialysis patients with CKD with mild anemia. Recently, a novel class of medications, known as hypoxia inducible factor (HIF) stabilizers or prolyl hydroxylase inhibitors, has been developed and tested in large clinical trials of participants with anemia related to CKD. These agents inhibit the degradation of HIF, activating various genes, including the erythropoietin gene that stimulates endogenous erythropoietin production. HIF–prolyl hydroxylase inhibitors have several potential advantages over traditional ESAs in that they are administered orally and may lead to a stable increase in plasma erythropoietin concentration.9Meadowcroft A.M. Cizman B. Holdstock L. et al.Daprodustat for anemia: a 24-week, open-label, randomized controlled trial in participants on hemodialysis.Clin Kidney J. 2019; 12: 139-148Crossref PubMed Scopus (80) Google Scholar Oral anemia treatment is particularly convenient for non-dialysis-dependent patients and those on home dialysis, but it requires adherence to taking oral medication, which has been shown to be suboptimal in patients with CKD.10Mechta Nielsen T. Frøjk Juhl M. Feldt-Rasmussen B. et al.Adherence to medication in patients with chronic kidney disease: a systematic review of qualitative research.Clin Kidney J. 2018; 11: 513-527Crossref PubMed Scopus (46) Google Scholar The choice of injectable versus oral therapy should thus be part of shared decision-making of patients and their physicians. Multi

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