Daprodustat for the Treatment of Anemia in Patients Not Undergoing Dialysis

N Engl J Med. 2021 Dec 16;385(25):2313-2324. doi: 10.1056/NEJMoa2113380. Epub 2021 Nov 5.

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.).

Publication types

  • Clinical Trial, Phase III
  • Comparative Study
  • Equivalence Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Barbiturates
  • GSK1278863
  • Hematinics
  • Hemoglobins
  • Darbepoetin alfa
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • Glycine

Associated data

  • ClinicalTrials.gov/NCT02876835

Grant support