Vadadustat is noninferior to darbepoetin alfa in hematologic efficacy but not in cardiovascular (CV) safety in patients with nondialysis-dependent chronic kidney disease (NDD-CKD).

An oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), vadadustat was investigated for the treatment of anemia in adults not on dialysis (PRO2TECT) and on dialysis (INNO2VATE) in 4 trials. The primary safety endpoint was the first major adverse CV event (MACE), a composite of death from any cause, nonfatal myocardial infarction, and nonfatal stroke. The primary efficacy outcome was the mean change in hemoglobin (Hb).

In the NDD-CKD trials, a first MACE occurred in 382 of 1739 patients (22.0%) in the vadadustat group and in 344 of 1732 patients (19.9%) in the darbepoetin alfa group. Vadadustat had a 1.17 hazard ratio for MACE, which did not meet the prespecified noninferiority criteria of 1.25, Glenn Chertow, MD, MPH, of Stanford University School of Medicine in Palo Alto, California, and colleagues reported in the New England Journal of Medicine. A key secondary endpoint, expanded MACE including hospitalization for heart failure or a thromboembolic event, occurred in 451 patients (25.9%) in the vadadustat group and in 424 (24.5%) in the darbepoetin alfa group. Vadadustat had a 1.11 hazard ratio for expanded MACE compared with darbepoetin alfa.

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In the dialysis trials, a first MACE occurred in 355 of 1958 patients (18.2%) in the vadadustat group and in 377 of 1965 patients (19.3%) in the darbepoetin alfa group, a nonsignificant difference between the groups. The hazard ratios for MACE and expanded MACE among vadadustat-treated patients were 0.96 and 0.96, respectively, Kai-Uwe Eckardt, MD, of the Charité in Berlin, Germany, and collaborators reported. Lower risks were observed for all components of MACE and cardiovascular death.

In terms of hematologic efficacy, vadadustat was noninferior to darbepoetin alfa in both the NDD-CKD and dialysis trials. The mean difference between the vadadustat and darbepoetin alfa groups in the change in Hb levels was 0.05 g/dL at weeks 24 through 36 in the NDD-CKD trial of patients not previously treated with an erythropoiesis-stimulating agent (ESA) and −0.01 g/dL in the NDD-CKD trial of ESA-treated patients, which met the prespecified noninferiority margin of −0.75 g/dL. In the dialysis trials, the difference in mean Hb was -0.31 g/dL at weeks 24 to 36 and -0.07 g/dL at weeks 40 to 52 in incident dialysis patients and -0.17 g/dL and -0.18 g/dL, respectively, in prevalent dialysis patients.

In the NDD-CKD trials, serious adverse events (SAEs) in the vadadustat groups occurred in 65.3% and 58.5% of patient in the trial of previously ESA-untreated and ESA-treated patients, respectively. In the darbepoetin groups, 64.5% and 56.6%, respectively, experienced SAEs.

In the dialysis trials, SAEs in the vadadustat groups occurred in 49.7% of those in the incident dialysis trial and 55.0% of those in the prevalent dialysis trial, compared with 56.5% and 58.3%, respectively, in the darbepoetin alfa groups.

“The kidney community has been eagerly awaiting peer-reviewed publication of comprehensive and straight-forward analyses of cardiovascular safety and hematological efficacy results of a Phase 3 program evaluating the treatment of anemia associated with CKD with a novel HIF-PHI,” Dr Chertow stated in a press release from Akebia Therapeutics, which along with Otsuka Pharmaceutical sponsored the trials. “We are honored to have vadadustat’s global Phase 3 clinical program published in the New England Journal of Medicine. These publications reflect the clinical relevance, scientific rigor and transparency of the vadadustat development program.”

In an accompanying editorial, Adeera Levin, MD, of the University of British Columbia in Vancouver, Canada, said more research is needed:

“The data are convincing that vadadustat is effective in increasing hemoglobin concentrations in both dialysis-dependent and non-dialysis-dependent populations but are less convincing with respect to safety. The issues raised in these trials should motivate us to answer critical questions regarding goals of therapy, risks, and benefits, with trials specifically designed to do so. To enable us to have informed discussions with our patients, many more questions need to be asked and answered.”

Disclosure: The clinical trials were supported by Akebia and Otsuka Pharmaceutical. Please see the original references for a full list of authors’ disclosures.


Chertow GM, Pergola PE, Farag YMK, et al. Vadadustat in patients with anemia and non–dialysis-dependent CKD.N Engl J Med. 384:1589-1600. doi:10.1056/NEJMoa2035938

Eckardt K-U, Agarwal R, Aswad A, et al. Safety and efficacy of vadadustat for anemia in patients undergoing dialysis. N Engl J Med. 384:1601-1612. doi:10.1056/NEJMoa2025956

Levin A. Therapy for anemia in chronic kidney disease — New interventions and new questions. N Engl J Med. 384:1657-1658. doi:10.1056/NEJMe2103937

New England Journal of Medicine publishes results of global phase 3 clinical program of vadadustat for the treatment of anemia due to chronic kidney disease [press release]. Akebia Therapeutics; April 28, 2021.