Safety and Efficacy of Vadadustat Versus Darbepoetin Alfa for Chronic Kidney Disease–Related Anemia in Patients Receiving Dialysis by Baseline Erythropoiesis‐Stimulating Agent Dose

Introduction Erythropoiesis‐stimulating agents (ESAs) and iron supplementation are standard treatments for chronic kidney disease (CKD)–related anemia. Targeting higher hemoglobin values in CKD increases cardiovascular risk. Whether the increased risk is from higher ESA doses or higher hemoglobin levels is uncertain, but alternative therapies are sought for patients requiring high ESA doses. Phase 3 INNO 2 VATE trials in patients with dialysis‐dependent CKD (DD‐CKD) demonstrated vadadustat's noninferiority compared with darbepoetin alfa. To determine vadadustat's potential to treat anemia, including in patients requiring high ESA doses, its safety and efficacy were compared with those of darbepoetin alfa across prespecified baseline ESA dose subgroups in the prevalent DD‐CKD INNO 2 VATE trial. Methods We compared the safety and efficacy of vadadustat versus darbepoetin alfa across prespecified baseline ESA dose subgroups (low [≤ 90 U/kg/week], intermediate [> 90 and < 300 U/kg/week], or high [≥ 300 U/kg/week]) in the INNO 2 VATE prevalent trial. The primary safety endpoint was time to first adjudicated major adverse cardiovascular event (MACE). Primary and secondary efficacy endpoints were mean hemoglobin level change from baseline at weeks 24–36 and weeks 40–52, respectively. Findings Compared with darbepoetin alfa, first MACE hazard ratios for vadadustat were 0.99 (95% CI, 0.81–1.23), 0.93 (95% CI, 0.74–1.18), and 0.62 (95% CI, 0.34–1.14) for low, intermediate, and high baseline ESA dose subgroups, respectively (interaction p = 0.92). Vadadustat was noninferior to darbepoetin alfa in hemoglobin change from baseline to primary evaluation period, with mean differences (vadadustat–darbepoetin alfa) of −0.10 g/dL (95% CI, −0.19 to −0.02), −0.20 g/dL (95% CI, −0.30 to −0.09), and −0.39 g/dL (95% CI, −0.67 to −0.11) for low, intermediate, and high ESA dose subgroups, respectively. Discussion Comparing safety and efficacy by baseline ESA dose among patients with CKD on maintenance dialysis, vadadustat was noninferior to darbepoetin alfa for all ESA dose subgroups, including patients with high baseline ESA requirements.