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

Abstract

Key Points:

1. Among patients receiving maintenance dialysis, an inadequate hemoglobin response to erythropoiesis-stimulating agents (ESAs) is associated with a higher risk of adverse outcomes.

2. Among patients in ASCEND-D, all three different prespecified definitions of ESA hyporesponsiveness were similarly associated with major adverse cardiovascular event outcomes.

3. 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.

Keywords: anemia; cardiovascular events; chronic dialysis; chronic hemodialysis; clinical trial; erythropoietin; hypoxia.