Association of Different Definitions of Erythropoiesis-Stimulating Agent Hyporesponsiveness with Major Adverse Cardiovascular Events

Key Points Among patients receiving maintenance dialysis, an inadequate hemoglobin response to erythropoiesis-stimulating agents (ESAs) is associated with a higher risk of adverse outcomes. Among patients in ASCEND-D, all three different prespecified definitions of ESA hyporesponsiveness were similarly associated with major adverse cardiovascular event outcomes. ESA hyporesponsiveness should be considered an important clinical parameter for risk-stratifying patients with kidney failure requiring dialysis. Background Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) is a common clinical problem and is associated with major adverse cardiovascular events (MACEs). Although several definitions have been proposed, data examining associations with MACE in clinical trials are limited. Methods Anemia Studies in Chronic Kidney Disease: Erythropoiesis via a Novel Prolyl Hydroxylase Inhibitor Daprodustat-Dialysis (ASCEND-D, NCT02879305), a large event-driven cardiovascular outcomes trial, randomized 2964 patients receiving maintenance dialysis to either daprodustat or conventional ESAs. All patients received an ESA for at least 6 weeks before randomization and were managed with dosing algorithms for iron and randomized treatment. Three definitions of ESA hyporesponsiveness were prespecified: ( 1 ) ESA hyporesponsiveness definition 1 (HypoR1): an erythropoietin resistance index ≥2 U/kg per week per gram per liter or prior ESA dose/estimated dry weight ≥450 U/kg per week, ( 2 ) ESA hyporesponsiveness definition 2 (HypoR2): erythropoietin resistance index ≥1.5 U/kg per week per gram per liter, and ( 3 ) ESA hyporesponsiveness definition 3 (HypoR3): baseline ESA dose (U/wk) in top 20th percentile. Adjusted Cox regression models were fit to examine the association of each definition with the adjudicated MACE composite (death, nonfatal myocardial infarction, and nonfatal stroke). Results Baseline ESA hyporesponsiveness was present in 12%, 20%, and 20% of patients according to definitions HypoR1, HypoR2, and HypoR3, respectively. Compared with those without hyporesponsiveness, all definitions were associated with a higher risk of the composite MACE outcome: adjusted hazard ratio (HR) 1.32 (95% confidence interval [CI], 1.04 to 1.68) for HypoR1, HR 1.33 (95% CI, 1.08 to 1.63) for HypoR2, and HR 1.36 (95% CI, 1.12 to 1.66) for HypoR3. There was no evidence for effect modification by randomized treatment ( P interaction > 0.40 for all). Conclusions Baseline ESA hyporesponsiveness is a potent predictor of MACE among patients receiving maintenance dialysis in ASCEND-D. All prespecified definitions were similarly associated with a higher risk of MACE. Clinical Trial registry name and registration number: NCT02879305.