Daprodustat for the Treatment of Anemia in Patients Not Undergoing Dialysis

Ajay K Singh; Kevin Carroll; John J V McMurray; Scott Solomon; Vivekanand Jha; Kirsten L Johansen; Renato D Lopes; Iain C Macdougall; Gregorio T Obrador; Sushrut S Waikar; Christoph Wanner; David C Wheeler; Andrzej Więcek; Allison Blackorby; Borut Cizman; Alexander R Cobitz; Rich Davies; Tara L DiMino; Lata Kler; Amy M Meadowcroft; Lin Taft; Vlado Perkovic; ASCEND-ND Study Group

doi:10.1056/NEJMoa2113380

Daprodustat for the Treatment of Anemia in Patients Not Undergoing Dialysis

Ajay K Singh
, Kevin Carroll
, John J V McMurray
, Scott Solomon
, Vivekanand Jha
, Kirsten L Johansen
, Renato D Lopes
, Iain C Macdougall
, Gregorio T Obrador
, Sushrut S Waikar
, Christoph Wanner
, David C Wheeler
, Andrzej Więcek
, Allison Blackorby
, Borut Cizman
, Alexander R Cobitz
, Rich Davies
, Tara L DiMino
, Lata Kler
, Amy M Meadowcroft

Lin Taft, Vlado Perkovic, ASCEND-ND Study Group

Bristol Medical School (THS)

Research output: Contribution to journal › Article (Academic Journal) › peer-review

201 Citations (Scopus)

Abstract

BACKGROUND
Daprodustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor. In patients with chronic kidney disease (CKD) who are not undergoing dialysis, the efficacy and safety of daprodustat, as compared with the conventional erythropoiesis-stimulating agent darbepoetin alfa, are unknown.

METHODS
In this randomized, open-label, phase 3 trial with blinded adjudication of cardiovascular outcomes, we compared daprodustat with darbepoetin alfa for the treatment of anemia in patients with CKD who were not undergoing dialysis. The primary outcomes were the mean change in the hemoglobin level from baseline to weeks 28 through 52 and the first occurrence of a major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke).

RESULTS
Overall, 3872 patients were randomly assigned to receive daprodustat or darbepoetin alfa. The mean (±SD) baseline hemoglobin levels were similar in the two groups. The mean (±SE) change in the hemoglobin level from baseline to weeks 28 through 52 was 0.74±0.02 g per deciliter in the daprodustat group and 0.66±0.02 g per deciliter in the darbepoetin alfa group (difference, 0.08 g per deciliter; 95% confidence interval [CI], 0.03 to 0.13), which met the prespecified noninferiority margin of −0.75 g per deciliter. During a median follow-up of 1.9 years, a first MACE occurred in 378 of 1937 patients (19.5%) in the daprodustat group and in 371 of 1935 patients (19.2%) in the darbepoetin alfa group (hazard ratio, 1.03; 95% CI, 0.89 to 1.19), which met the prespecified noninferiority margin of 1.25. The percentages of patients with adverse events were similar in the two groups.

CONCLUSIONS
Among patients with CKD and anemia who were not undergoing dialysis, daprodustat was noninferior to darbepoetin alfa with respect to the change in the hemoglobin level from baseline and with respect to cardiovascular outcomes. (Funded by GlaxoSmithKline; ASCEND-ND ClinicalTrials.gov number, NCT02876835.)

Original language	English
Pages (from-to)	2313-2324
Number of pages	12
Journal	New England Journal of Medicine
Volume	385
Issue number	25
Early online date	5 Nov 2021
DOIs	https://doi.org/10.1056/NEJMoa2113380
Publication status	Published - 16 Dec 2021

Bibliographical note

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Aged
Anemia/drug therapy
Barbiturates/adverse effects
Cardiovascular Diseases/epidemiology
Darbepoetin alfa/adverse effects
Female
Glycine/adverse effects
Hematinics/adverse effects
Hemoglobins/analysis
Humans
Hypoxia-Inducible Factor-Proline Dioxygenases/antagonists & inhibitors
Intention to Treat Analysis
Male
Middle Aged
Myocardial Infarction/epidemiology
Renal Insufficiency, Chronic/blood
Stroke/epidemiology

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Singh, A. K., Carroll, K., McMurray, J. J. V., Solomon, S., Jha, V., Johansen, K. L., Lopes, R. D., Macdougall, I. C., Obrador, G. T., Waikar, S. S., Wanner, C., Wheeler, D. C., Więcek, A., Blackorby, A., Cizman, B., Cobitz, A. R., Davies, R., DiMino, T. L., Kler, L., ... ASCEND-ND Study Group (2021). Daprodustat for the Treatment of Anemia in Patients Not Undergoing Dialysis. New England Journal of Medicine, 385(25), 2313-2324. https://doi.org/10.1056/NEJMoa2113380

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title = "Daprodustat for the Treatment of Anemia in Patients Not Undergoing Dialysis",

abstract = "BACKGROUND Daprodustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor. In patients with chronic kidney disease (CKD) who are not undergoing dialysis, the efficacy and safety of daprodustat, as compared with the conventional erythropoiesis-stimulating agent darbepoetin alfa, are unknown. METHODS In this randomized, open-label, phase 3 trial with blinded adjudication of cardiovascular outcomes, we compared daprodustat with darbepoetin alfa for the treatment of anemia in patients with CKD who were not undergoing dialysis. The primary outcomes were the mean change in the hemoglobin level from baseline to weeks 28 through 52 and the first occurrence of a major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke). RESULTS Overall, 3872 patients were randomly assigned to receive daprodustat or darbepoetin alfa. The mean (±SD) baseline hemoglobin levels were similar in the two groups. The mean (±SE) change in the hemoglobin level from baseline to weeks 28 through 52 was 0.74±0.02 g per deciliter in the daprodustat group and 0.66±0.02 g per deciliter in the darbepoetin alfa group (difference, 0.08 g per deciliter; 95\% confidence interval [CI], 0.03 to 0.13), which met the prespecified noninferiority margin of −0.75 g per deciliter. During a median follow-up of 1.9 years, a first MACE occurred in 378 of 1937 patients (19.5\%) in the daprodustat group and in 371 of 1935 patients (19.2\%) in the darbepoetin alfa group (hazard ratio, 1.03; 95\% CI, 0.89 to 1.19), which met the prespecified noninferiority margin of 1.25. The percentages of patients with adverse events were similar in the two groups. CONCLUSIONS Among patients with CKD and anemia who were not undergoing dialysis, daprodustat was noninferior to darbepoetin alfa with respect to the change in the hemoglobin level from baseline and with respect to cardiovascular outcomes. (Funded by GlaxoSmithKline; ASCEND-ND ClinicalTrials.gov number, NCT02876835.)",

keywords = "Aged, Anemia/drug therapy, Barbiturates/adverse effects, Cardiovascular Diseases/epidemiology, Darbepoetin alfa/adverse effects, Female, Glycine/adverse effects, Hematinics/adverse effects, Hemoglobins/analysis, Humans, Hypoxia-Inducible Factor-Proline Dioxygenases/antagonists \& inhibitors, Intention to Treat Analysis, Male, Middle Aged, Myocardial Infarction/epidemiology, Renal Insufficiency, Chronic/blood, Stroke/epidemiology",

author = "Singh, \{Ajay K\} and Kevin Carroll and McMurray, \{John J V\} and Scott Solomon and Vivekanand Jha and Johansen, \{Kirsten L\} and Lopes, \{Renato D\} and Macdougall, \{Iain C\} and Obrador, \{Gregorio T\} and Waikar, \{Sushrut S\} and Christoph Wanner and Wheeler, \{David C\} and Andrzej Wi{\c e}cek and Allison Blackorby and Borut Cizman and Cobitz, \{Alexander R\} and Rich Davies and DiMino, \{Tara L\} and Lata Kler and Meadowcroft, \{Amy M\} and Lin Taft and Vlado Perkovic and \{ASCEND-ND Study Group\} and Albert Power",

note = "Copyright {\textcopyright} 2021 Massachusetts Medical Society.",

year = "2021",

month = dec,

day = "16",

doi = "10.1056/NEJMoa2113380",

language = "English",

volume = "385",

pages = "2313--2324",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachussetts Medical Society",

number = "25",

}

Singh, AK, Carroll, K, McMurray, JJV, Solomon, S, Jha, V, Johansen, KL, Lopes, RD, Macdougall, IC, Obrador, GT, Waikar, SS, Wanner, C, Wheeler, DC, Więcek, A, Blackorby, A, Cizman, B, Cobitz, AR, Davies, R, DiMino, TL, Kler, L, Meadowcroft, AM, Taft, L, Perkovic, V & ASCEND-ND Study Group 2021, 'Daprodustat for the Treatment of Anemia in Patients Not Undergoing Dialysis', New England Journal of Medicine, vol. 385, no. 25, pp. 2313-2324. https://doi.org/10.1056/NEJMoa2113380

TY - JOUR

T1 - Daprodustat for the Treatment of Anemia in Patients Not Undergoing Dialysis

AU - Singh, Ajay K

AU - Carroll, Kevin

AU - McMurray, John J V

AU - Solomon, Scott

AU - Jha, Vivekanand

AU - Johansen, Kirsten L

AU - Lopes, Renato D

AU - Macdougall, Iain C

AU - Obrador, Gregorio T

AU - Waikar, Sushrut S

AU - Wanner, Christoph

AU - Wheeler, David C

AU - Więcek, Andrzej

AU - Blackorby, Allison

AU - Cizman, Borut

AU - Cobitz, Alexander R

AU - Davies, Rich

AU - DiMino, Tara L

AU - Kler, Lata

AU - Meadowcroft, Amy M

AU - Taft, Lin

AU - Perkovic, Vlado

AU - ASCEND-ND Study Group

AU - Power, Albert

PY - 2021/12/16

Y1 - 2021/12/16

N2 - BACKGROUND Daprodustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor. In patients with chronic kidney disease (CKD) who are not undergoing dialysis, the efficacy and safety of daprodustat, as compared with the conventional erythropoiesis-stimulating agent darbepoetin alfa, are unknown. METHODS In this randomized, open-label, phase 3 trial with blinded adjudication of cardiovascular outcomes, we compared daprodustat with darbepoetin alfa for the treatment of anemia in patients with CKD who were not undergoing dialysis. The primary outcomes were the mean change in the hemoglobin level from baseline to weeks 28 through 52 and the first occurrence of a major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke). RESULTS Overall, 3872 patients were randomly assigned to receive daprodustat or darbepoetin alfa. The mean (±SD) baseline hemoglobin levels were similar in the two groups. The mean (±SE) change in the hemoglobin level from baseline to weeks 28 through 52 was 0.74±0.02 g per deciliter in the daprodustat group and 0.66±0.02 g per deciliter in the darbepoetin alfa group (difference, 0.08 g per deciliter; 95% confidence interval [CI], 0.03 to 0.13), which met the prespecified noninferiority margin of −0.75 g per deciliter. During a median follow-up of 1.9 years, a first MACE occurred in 378 of 1937 patients (19.5%) in the daprodustat group and in 371 of 1935 patients (19.2%) in the darbepoetin alfa group (hazard ratio, 1.03; 95% CI, 0.89 to 1.19), which met the prespecified noninferiority margin of 1.25. The percentages of patients with adverse events were similar in the two groups. CONCLUSIONS Among patients with CKD and anemia who were not undergoing dialysis, daprodustat was noninferior to darbepoetin alfa with respect to the change in the hemoglobin level from baseline and with respect to cardiovascular outcomes. (Funded by GlaxoSmithKline; ASCEND-ND ClinicalTrials.gov number, NCT02876835.)

AB - BACKGROUND Daprodustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor. In patients with chronic kidney disease (CKD) who are not undergoing dialysis, the efficacy and safety of daprodustat, as compared with the conventional erythropoiesis-stimulating agent darbepoetin alfa, are unknown. METHODS In this randomized, open-label, phase 3 trial with blinded adjudication of cardiovascular outcomes, we compared daprodustat with darbepoetin alfa for the treatment of anemia in patients with CKD who were not undergoing dialysis. The primary outcomes were the mean change in the hemoglobin level from baseline to weeks 28 through 52 and the first occurrence of a major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke). RESULTS Overall, 3872 patients were randomly assigned to receive daprodustat or darbepoetin alfa. The mean (±SD) baseline hemoglobin levels were similar in the two groups. The mean (±SE) change in the hemoglobin level from baseline to weeks 28 through 52 was 0.74±0.02 g per deciliter in the daprodustat group and 0.66±0.02 g per deciliter in the darbepoetin alfa group (difference, 0.08 g per deciliter; 95% confidence interval [CI], 0.03 to 0.13), which met the prespecified noninferiority margin of −0.75 g per deciliter. During a median follow-up of 1.9 years, a first MACE occurred in 378 of 1937 patients (19.5%) in the daprodustat group and in 371 of 1935 patients (19.2%) in the darbepoetin alfa group (hazard ratio, 1.03; 95% CI, 0.89 to 1.19), which met the prespecified noninferiority margin of 1.25. The percentages of patients with adverse events were similar in the two groups. CONCLUSIONS Among patients with CKD and anemia who were not undergoing dialysis, daprodustat was noninferior to darbepoetin alfa with respect to the change in the hemoglobin level from baseline and with respect to cardiovascular outcomes. (Funded by GlaxoSmithKline; ASCEND-ND ClinicalTrials.gov number, NCT02876835.)

KW - Aged

KW - Anemia/drug therapy

KW - Barbiturates/adverse effects

KW - Cardiovascular Diseases/epidemiology

KW - Darbepoetin alfa/adverse effects

KW - Female

KW - Glycine/adverse effects

KW - Hematinics/adverse effects

KW - Hemoglobins/analysis

KW - Humans

KW - Hypoxia-Inducible Factor-Proline Dioxygenases/antagonists & inhibitors

KW - Intention to Treat Analysis

KW - Male

KW - Middle Aged

KW - Myocardial Infarction/epidemiology

KW - Renal Insufficiency, Chronic/blood

KW - Stroke/epidemiology

U2 - 10.1056/NEJMoa2113380

DO - 10.1056/NEJMoa2113380

M3 - Article (Academic Journal)

C2 - 34739196

SN - 0028-4793

VL - 385

SP - 2313

EP - 2324

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 25

ER -

Daprodustat for the Treatment of Anemia in Patients Not Undergoing Dialysis

Abstract

Bibliographical note

UN SDGs

Keywords

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