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Daprodustat for the treatment of anaemia in patients not undergoing dialysis

What was known?

Anaemia is a common complication of chronic kidney disease (CKD), and is associated with poor clinical outcomes. Erythropoiesis-stimulating agents (ESAs), are commonly used in the treatment of anaemia but have been associated with increased risks of cardiovascular events, venous thromboembolism and death. Daprodustat, an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, offers an alternative treatment approach but its efficacy and safety compared with the conventional ESA darbepoetin alfa, in patients with CKD who were not undergoing dialysis, are unknown.

Objective(s):

The aim of this study was to compare the efficacy and safety of daprodustat with that of darbepoetin alfa in patients with CKD who were not undergoing dialysis.

What this study adds:

This is the first study to demonstrate that daprodustat is noninferior to darbepoetin alfa in terms of increasing haemoglobin (Hb) levels and in cardiovascular outcomes.

Clinical implications:

Daprodustat provides a convenient, oral treatment option with superior cardiovascular outcomes compared to current standard of care for patients who are suffering from anaemia due to CKD.

Study design:

The ASCEND-ND study (NCT02876835) was a randomised, open-label, Phase III trial with blinded adjudication of cardiovascular outcomes. The trial comprised screening, placebo run-in, treatment, and follow-up periods. Patients were evaluated at least every 4 weeks during the first year of the trial and at least every 12 weeks afterwards. Participants (n=3872) were randomly assigned 1:1 to receive either oral daprodustat or subcutaneous darbepoetin alfa. A trial-specific algorithm was used in both treatment groups to achieve and maintain the Hb level in the target range of 10.0 to 11.0 g/dL. The trial was originally designed to enrol approximately 4500 patients, with follow-up until 945 adjudicated first major adverse cardiovascular event (MACE) had occurred in order to exclude a noninferiority margin of 1.20. This was adjusted to 1.25 during the COVID-19 pandemic.

Primary endpoints:

  • Mean change in the Hb level from baseline to the primary evaluation period (weeks 28 to 52)
  • First occurrence of an adjudicated MACE (a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke)

Secondary endpoints:

  • First occurrence of a MACE (as above but tested for superiority rather than noninferiority)
  • First occurrence of a MACE or a thromboembolic event
  • First occurrence of a MACE or hospitalisation for heart failure
  • First occurrence of CKD progression

Inclusion criteria:

  • Age: 18 to 99 years
  • CKD stage: Kidney Disease Outcomes Quality Initiative CKD stages 3, 4, or 5 defined by estimated glomerular filtration rate using the CKD Epidemiology Collaboration formula
  • ESAs: Group 1 (not using ESAs): No ESA use within the 6 weeks prior to screening and no ESA use between screening and randomisation (Day 1). Group 2 (ESA users): Use of any approved ESA for the 6 weeks prior to screening and continuing between screening and randomisation
  • Hb level: For Group 1 (not using ESAs), Hgb concentration at Week -8 and Week 1 should be 8 to 10 g/dL. For Group 2 (ESA users), Hgb concentration at Week -8 should be 8 to 12 g/dL and at Week 1 should be 8 to 11 g/dL

Notable exclusion criteria:

  • On dialysis or clinical evidence of impending need to initiate dialysis within 90 days of study start
  • Planned living-related or living-unrelated kidney transplant within 52 weeks of study start
  • Ferritin: ≤100 ng/ mL at screening

Findings:

  • A total of 3872 patients were randomly assigned to receive daprodustat or darbepoetin alfa
  • Daprodustat was discontinued prematurely for reasons other than death in 29.5% of patients, and darbepoetin alfa in 28.9%
  • The mean (±SE) change in the Hb level from baseline to weeks 28 through 52 was 0.74±0.02 g/dL in the daprodustat group and 0.66±0.02 g/dL in the darbepoetin alfa group (difference, 0.08 g/dL; 95% confidence interval [CI], 0.03 to 0.13)
  • A first MACE occurred in 19.5% of the daprodustat group and in 19.2% of the darbepoetin alfa group (hazard ratio, 1.03; 95% CI, 0.89–1.19); meeting the prespecified noninferiority margin
  • The results were generally consistent across prespecified subgroups
  • Superiority testing showed no significant differences between the groups for the for the four key secondary outcomes
  • Serious adverse events that started or worsened after the initiation of trial treatment occurred in 43.9% of the daprodustat group and 36.4% of the darbepoetin alfa group. Cancer-related death and tumour progression and recurrence, as well as oesophageal and gastric erosions, occurred significantly more commonly in the daprodustat group

Interpretation:

Daprodustat was noninferior to darbepoetin alfa in increasing and maintaining Hb levels in patients with CKD and anaemia who were not receiving dialysis, and was equivalent to darbepoetin alfa in terms of cardiovascular safety. Although the safety profile of the two drugs were similar, cancer-related death and tumour progression and recurrence, as well as oesophageal and gastric erosions, were more common among patients who received daprodustat, and these warrant further investigation.

Limitations:

  • The open-label design and patient awareness of treatment assignment may have biased reporting of adverse events
  • Since HIF activates cytokine transcription, there is the potential for long term adverse events and a longer follow-up period is needed to fully assess the risks
  • Darbepoetin was used as the ESA comparator but inferiority to other ESAs is not known
  • The prespecified definitions for MACE during the treatment period did not account for the different dosing frequencies

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