A randomized, placebo-controlled trial of pentoxifylline on erythropoiesis-stimulating agent hyporesponsiveness in anemic patients with CKD: The handling erythropoietin resistance with oxpentifylline (HERO) trial

David W. Johnson, Elaine M Pascoe, Sunil V Badve, Kim Dalziel, Alan Cass, Philip Clarke, Paolo Ferrari, Stephen P. McDonald, Alicia T. Morrish, Eugenie Pedagogos, Vlado Perkovic, Donna Reidlinger, Anish Scaria, Rowan Walker, Liza A Vergara, Carmel M. Hawley, on behalf of the HERO Study Collaborative Group

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Background: Erythropoiesis-stimulating agent (ESA)-hyporesponsive anemia is common in chronic kidney disease (CKD). Pentoxifylline shows promise as a treatment for ESA-hyporesponsive anemia, but has not been rigorously evaluated. 

Study Design: Multicenter, double-blind, randomized, controlled trial. 

Setting & Participants: 53 adult patients with CKD stage 4 or 5 (including dialysis) and ESA-hyporesponsive anemia (hemoglobin ≤ 120 g/L and ESA resistance index [calculated as weight-adjusted weekly ESA dose in IU/kg/wk divided by hemoglobin concentration in g/L] ≥ 1.0 IU/kg/wk/g/L for erythropoietin-treated patients and ≥0.005 μg/kg/wk/g/L for darbepoetin-treated patients). 

Interventions: Pentoxifylline (400 mg/d; n 5 26) or matching placebo (control; n 5 27) for 4 months. 

Outcomes: Primary outcome: ESA resistance index at 4 months; secondary outcomes: hemoglobin concentration, ESA dose, blood transfusion requirement, serum ferritin level and transferrin saturation, C-reactive protein level, adverse events, quality of life, and health economics. 

Results: There was no statistically significant difference in ESA resistance index between the pentoxifylline and control groups (adjusted mean difference, 20.39 [95% CI, 20.89 to 0.10] IU/kg/wk/g/L; P 5 0.1). Pentoxifylline significantly increased hemoglobin concentration relative to the control group (adjusted mean difference, 7.6 [95%CI, 1.7-13.5] g/L; P 5 0.01). There was no difference in ESA dose between groups (220.8 [95% CI, 267.2 to 25.7] IU/kg/wk; P 5 0.4). No differences in blood transfusion requirements, adverse events, or quality of life were observed between groups. Pentoxifylline cost A$88.05 (US $82.94) per person over the trial and produced mean savings in ESA cost of A$1,332 (US $1,255). The overall economic impact over the trial period was a saving of A$1,244 (US $1,172) per person for the pentoxifylline group compared with controls. 

Limitations: Sample size smaller than planned due to slow recruitment. 

Conclusions: Pentoxifylline did not significantly modify ESA hyporesponsiveness, but increased hemoglobin concentration. Further studies are warranted to determine whether pentoxifylline therapy represents a safe strategy for increasing hemoglobin levels in patients with CKD with ESA-hyporesponsive anemia.

Original languageEnglish
Pages (from-to)49-57
Number of pages9
JournalAmerican Journal of Kidney Diseases
Issue number1
Publication statusPublished - 2015
Externally publishedYes


  • Anemia
  • chronic kidney disease (CKD)
  • darbepoetin
  • drug sensitivity
  • epoetin
  • erythropoiesis- stimulating agent (ESA)
  • ESA hyporesponsiveness
  • ESA resistance index (ERI)
  • erythropoietin
  • pentoxifylline
  • hemoglobin
  • dialysis
  • randomized controlled trial

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