#2063 Safety and efficacy of vadadustat vs darbepoetin alfa in patients on maintenance dialysis by prespecified subgroups of baseline ESA dose

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Abstract Background and Aims Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved in Europe, Australia, Japan for the treatment of anemia in patients with dialysis-dependent (DD)-CKD. In the INNO2VATE global phase 3 trials in patients with DD-CKD, including 2 separate trials in patients new to dialysis [NCT02865850] and on maintenance dialysis [NCT02892149], vadadustat was noninferior to the erythropoiesis -stimulating agent (ESA) darbepoetin alfa for cardiovascular safety and hemoglobin efficacy. Among patients with DD-CKD, high ESA dose requirements have been associated with an increased risk of cardiovascular complications. In this secondary analysis, we compared cardiovascular safety and hematological efficacy of vadadustat and darbepoetin alfa across baseline ESA dose categories. Method In the INNO2VATE trials, 3554 patients on maintenance dialysis were randomized 1:1 to vadadustat or darbepoetin alfa, stratified according to geographic region, New York Heart Association heart failure classification, and hemoglobin concentration at trial entry. Data were analyzed for prespecified subgroups of patients categorized by their baseline ESA (epoetin alfa/equivalents) dose: low (<90 U/kg/week), intermediate (90-299 U/kg/week), or high (≥300 U/kg/week). Within these dose subgroups, the key safety endpoint was the first occurrence of an adjudicated major adverse cardiovascular event (MACE: first occurrence of all-cause mortality, nonfatal myocardial infarction [MI], or nonfatal stroke) using a time-to-event analysis. Primary and secondary efficacy endpoints were mean change in hemoglobin concentration from baseline during the primary (weeks 24-36) and secondary (weeks 40-52) evaluation periods, respectively. Results More participants were in the low (vadadustat: n = 916 [53%], darbepoetin alfa: n = 968 [55%]) and intermediate (vadadustat: n = 724 [42%], darbepoetin alfa: n = 693 [39%]) than in the high (vadadustat: n = 102 [6%], darbepoetin alfa: n = 98 [6%]) baseline ESA dose subgroups. Hazard ratios for the occurrence of first MACE between vadadustat and darbepoetin alfa in the 3 baseline ESA dose subgroups were as follows: low dose, 0.99 (95% CI, 0.81 to 1.23); intermediate dose, 0.93 (95% CI, 0.74 to 1.18); and high dose, 0.62 (95% CI, 0.34 to 1.14) (Fig.). Similar results were observed for other key MACE-related endpoints, including all-cause mortality, MACE plus hospitalizations for heart failure or thromboembolic events, cardiovascular MACE (first occurrence of cardiovascular mortality, nonfatal MI, or nonfatal stroke), and cardiovascular death. Mean hemoglobin concentrations increased in both treatment groups throughout the trial period. The least squares mean treatment difference (vadadustat compared to darbepoetin alfa) for change in hemoglobin concentration from baseline to the primary efficacy period was –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 the low, intermediate, and high baseline ESA dose subgroups, respectively. Similar results were observed for the secondary efficacy period. Across baseline ESA dose subgroups, the proportion of patients whose average hemoglobin concentration was within target range was similar between the vadadustat and darbepoetin alfa arms during the primary efficacy period (low: odds ratio [OR], 0.89; 95% CI, 0.74, 1.08; intermediate: OR, 0.87; 95% CI, 0.70, 1.09; high: OR, 0.90; 95% CI 0.49, 1.64). Similar results were observed during the secondary efficacy period. Conclusion The cardiovascular safety and efficacy of vadadustat was similar to darbepoetin alfa in patients with DD-CKD irrespective of baseline ESA dose. In patients requiring higher ESA doses at baseline, the risk of MACE was numerically (but not significantly) lower in vadadustat-treated patients. Further investigation is required to confirm or refute this trend.