Chertow GM, Pergola PE, Farag YMK, et al. - Researchers performed comparisons of vadadustat (an oral hypoxia-inducible factor prolyl hydroxylase inhibitor) vs darbepoetin alfa [erythropoiesis-stimulating agent (ESA)] among patients with non–dialysis-dependent chronic kidney disease (NDD-CKD) not previously managed with an ESA who exhibited a hemoglobin level of less than 10 g per deciliter as well as in those with ESA-treated NDD-CKD and a hemoglobin level of 8 to 11 g per deciliter (in the United States) or 9 to 12 g per deciliter (in other countries), in two phase 3, randomized, open-label, active-controlled, noninferiority trials. The primary safety endpoint, evaluated in a time-to-event analysis, was the first major adverse cardiovascular event (MACE), pooled across the two trials. Expanded MACE, defined as MACE plus hospitalization for either heart failure or a thromboembolic event, were the secondary safety endpoints. In each trial, primary and key secondary efficacy endpoints included the mean alteration in hemoglobin level from baseline during two assessment periods: weeks 24 through 36 and weeks 40 through 52. Findings demonstrated that the prespecified noninferiority criterion for hematologic efficacy was met by vadadustat in patients with NDD-CKD, relative to darbepoetin alfa. However, vadadustat vs darbepoetin alfa failed to meet the prespecified noninferiority criterion for cardiovascular safety in NDD-CKD population.