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Kidney Week

Abstract: TH-PO231

Erythropoietin Stimulating Agents (ESA) Hyporesponsiveness and Outcomes: Patient Characteristics and Major Adverse Cardiovascular Events (MACE)

Session Information

Category: Anemia and Iron Metabolism

  • 201 Anemia and Iron Metabolism: Basic


  • Smith, Helen T., GSK, London, United Kingdom
  • Cizman, Borut, GSK, London, United Kingdom
  • Lisle, Rebecca M., GSK, London, United Kingdom
  • Chen, Yong, GSK, London, United Kingdom
  • Zhou, Zhou, Analysis Group, Boston, Massachusetts, United States
  • Meiselbach, Mark, Analysis Group, Boston, Massachusetts, United States
  • Reiff, Julie, Analysis Group, Boston, Massachusetts, United States
  • Xie, Jipan, Analysis Group, Boston, Massachusetts, United States
  • Wu, Eric, Analysis Group, Boston, Massachusetts, United States
  • Coyne, Daniel W., Washington University School of Medicine, St. Louis, Missouri, United States

Studies of ESA hyporesponsivness prior to 2011 showed increased morbidity and mortality potentially associated with high doses of ESA. US ESRD payment change (bundling), introduced in 2011, contributed to lower ESA use and lower targeted hemoglobin and may have altered the relationship of ESA hyporesponse to clinical outcomes.


Using the CROWNWEB clinical database from 2012-14, we characterised ESA hyporesponder patients (HR) on dialysis and, using inpatient diagnosis codes, evaluated rates of MACE in this population compared to ESA normoresponders (NR). MACE outcomes were modelled using negative binomial regressions. HR were identified using ESA resistance index (ERI) or dose; for epoetin alfa an ERI of ≥2.0 U/kg/wk/g/L or dose of ≥450 U/kg/wk was used.


119,742 patients met inclusion criteria; 43% (51,544) were classified as HR. At baseline, most were on hemodialysis (HD) (95.7% HR and 97.0% NR) and receiving epoetin alfa (97.0% HR and 95.6% NR); the mean dose (U/kg/wk) in the 2 months prior to index date was 336.0 in HR and 69.5 in NR. HR had a longer dialysis duration (5.7 vs. 4.9 years) and more comorbidities, with a Charlson Comorbidity Index of 3.8 vs. 3.2. Heart failure and coronary artery disease were more common in HR vs. NR, 47.8% vs. 36.3% and 41.1% vs. 35.0%, respectively. However, rates of T2DM were similar (51.5% in HR vs. 53.9% in NR).
Over one year of follow up, 23% of patients died (24.1% HR vs. 22.6% NR). MACE and thromboembolic event-related hospitalizations were significantly higher for HR vs. NR (0.14 vs. 0.09 hospitalizations per patient-month). Non-adjusted and adjusted models for MACE incidence rate ratio comparing HR vs. NR are presented in the table below.


Our analysis showed ESA HR and NR have similar one year mortality rates despite epoetin alfa doses 4.8 times higher in HR. However, ESA hyporesponsivness was associated with increased risk of MACE and thromboembolic event related hospitalizations.

MACE event model results
 Unadjusted model HR vs. NRAdjusted model HR vs. NR
Hospitalizations related to:Incidence rate ratio(95% CI) p-valueIncidence rate ratio(95% CI) p-value
Heart-failure1.58(1.55; 1.62) < 0.0011.38(1.36; 1.41) < 0.001
Myocardial infarction1.27(1.22; 1.33) < 0.0011.16(1.11; 1.22) < 0.001
Stroke1.29(1.24; 1.35) < 0.0011.21(1.16; 1.26) < 0.001
Thromboembolic event1.63(1.56; 1.70) < 0.0011.37(1.31; 1.43) < 0.001


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