Association of Different Definitions of Erythropoiesis-Stimulating Agent Hyporesponsiveness with Major Adverse Cardiovascular Events: Insights From ASCEND-D.

Background: Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) is a common clinical problem and is associated with major adverse cardiovascular events (MACE). Although several definitions have been proposed, data examining associations with MACE in clinical trials are limited.

Methods: ASCEND-D (NCT02879305), a large event-driven cardiovascular outcomes trial, randomized 2,964 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) HypoR1: an erythropoietin resistance index (ERI) ≥2U/kg/wk/g/L or prior ESA dose/estimated dry weight ≥450 U/kg/wk; 2) HypoR2: ERI ≥1.5U/kg/wk/g/L; 3) HypoR3: baseline ESA dose (U/week) in top 20th percentile. Adjusted Cox regression models were fit to examine the association of each definition with the adjudicated MACE composite (death, non-fatal myocardial infarction, non-fatal stroke).

Results: Baseline ESA hyporesponsiveness was present in 12%, 20%, and 20% of patients according to definitions HypoR1, HypoR2, and HypoR3, respectively. Compared to those without hyporesponsiveness, all definitions were associated with a higher risk of the composite MACE outcome: adjusted hazard ratio [HR] 1.32 (95%CI 1.04, 1.68) for HypoR1; HR 1.33; 95%CI 1.08, 1.63) for HypoR2; HR 1.36 (95%CI 1.12, 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 pre-specified definitions were similarly associated with a higher risk of MACE.