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

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 mg/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.