Vadadustat Matches Darbepoetin Across ESA Doses in DD-CKD, finds research

Anemia is a frequent complication of chronic kidney disease and is generally treated with erythropoiesis-stimulating agents (ESAs) and iron therapy. High hemoglobin concentrations have been linked to an increased risk of cardiovascular events, and it is unclear whether this is due to the high ESA doses, the high hemoglobin concentrations, or both. Vadadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, was compared to darbepoetin alfa in prespecified baseline ESA dose subgroups in the INNO2VATE prevalent study.

Patients with CKD-related anemia often require increasing doses of ESAs to reach target hemoglobin concentrations. Observational and randomized clinical trials have suggested that higher hemoglobin targets in CKD are associated with increased cardiovascular risk, including major adverse cardiovascular events (MACE). Whether such risk is due to the attainment of supraphysiological hemoglobin concentrations, high exposure to ESAs, or underlying comorbidities is unclear.

Vadadustat activates endogenous erythropoietin production by stabilizing hypoxia-inducible factor pathways, which may provide a novel mechanistic approach to anemia management, distinct from the traditional ESA, darbepoetin alfa. The phase 3 INNO2VATE trials have already established the noninferiority of vadadustat compared with darbepoetin alfa in patients with DD-CKD. The present subgroup analysis sought to explore whether safety and efficacy outcomes were consistent across different strata of baseline ESA dose requirements.

Key findings

Participants were categorized into three prespecified baseline ESA dose subgroups:

• Low dose: ≤ 90 U/kg/week

• Intermediate dose: > 90 and < 300 U/kg/week

• High dose: ≥ 300 U/kg/week

The hazard ratios (HRs) for first MACE with vadadustat versus darbepoetin alfa were:

• Low ESA dose subgroup: HR 0.99 (95% CI, 0.81–1.23)

• Intermediate ESA dose subgroup: HR 0.93 (95% CI, 0.74–1.18)

• High ESA dose subgroup: HR 0.62 (95% CI, 0.34–1.14)

The mean differences in hemoglobin (vadadustat minus darbepoetin alfa) were:

• Low ESA dose subgroup: −0.10 g/dL (95% CI, −0.19 to −0.02)

• Intermediate ESA dose subgroup: −0.20 g/dL (95% CI, −0.30 to −0.09)

• High ESA dose subgroup: −0.39 g/dL (95% CI, −0.67 to −0.11)

In patients with dialysis-dependent chronic kidney disease on maintenance dialysis, vadadustat was noninferior to darbepoetin alfa for cardiovascular safety and hemoglobin efficacy in low, intermediate, and high baseline ESA dose groups. These results suggest that vadadustat is equally safe and effective in patients with high baseline ESA doses and could serve as an alternative treatment for anemia in this high-risk population.

Reference:

Jardine, A., Burke, S. K., Luo, W., Minga, T., Sarnak, M. J., Winkelmayer, W. C., Agarwal, R., Chertow, G. M., Eckardt, K.-U., & Koury, M. J. (2026). Safety and efficacy of vadadustat versus darbepoetin Alfa for chronic kidney disease-related anemia in patients receiving dialysis by baseline erythropoiesis-stimulating agent dose. Hemodialysis International. International Symposium on Home Hemodialysis, 30(1), 80–100. https://doi.org/10.1111/hdi.70034