title: 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.
abstract: 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.
  
  
  METHODS
  Multicenter, double-blind, randomized, controlled trial.
  
  
  METHODS
  53 adult patients with CKD stage 4 or 5 (including dialysis) and ESA-hyporesponsive anemia (hemoglobin≤120g/L and ESA resistance index [calculated as weight-adjusted weekly ESA dose in IU/kg/wk divided by hemoglobin concentration in g/L]≥1.0IU/kg/wk/g/L for erythropoietin-treated patients and ≥0.005μg/kg/wk/g/L for darbepoetin-treated patients).
  
  
  METHODS
  Pentoxifylline (400mg/d; n=26) or matching placebo (control; n=27) for 4 months.
  
  
  RESULTS
  
  
  
  METHODS
  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, -0.39 [95%CI, -0.89 to 0.10] IU/kg/wk/g/L; P=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=0.01). There was no difference in ESA dose between groups (-20.8 [95%CI, -67.2 to 25.7] IU/kg/wk; P=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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia; Department of Nephrology, Princess Alexandra Hospital, Brisbane, Australia; Translational Research Institute, Brisbane, Australia. Electronic address: david.johnson2@health.qld.gov.au.
authors.forename: David W
authors.initials: DW
authors.lastname: Johnson
authors.affiliation: Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia.
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Pascoe
authors.affiliation: Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia; Department of Nephrology, Princess Alexandra Hospital, Brisbane, Australia.
authors.forename: Sunil V
authors.initials: SV
authors.lastname: Badve
authors.affiliation: Center for Health Policy, Programs & Economics, University of Melbourne, Melbourne, Australia.
authors.forename: Kim
authors.initials: K
authors.lastname: Dalziel
authors.affiliation: Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia; Menzies School of Health Research, Darwin, Australia.
authors.forename: Alan
authors.initials: A
authors.lastname: Cass
authors.affiliation: Center for Health Policy, Programs & Economics, University of Melbourne, Melbourne, Australia.
authors.forename: Philip
authors.initials: P
authors.lastname: Clarke
authors.affiliation: Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia; Department of Renal Medicine, Fremantle Hospital, Fremantle, Australia.
authors.forename: Paolo
authors.initials: P
authors.lastname: Ferrari
authors.affiliation: Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia; Department of Nephrology and Transplantation Services, University of Adelaide at Central Northern Adelaide Renal and Transplantation Services, Adelaide, Australia.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: McDonald
authors.affiliation: Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia.
authors.forename: Alicia T
authors.initials: AT
authors.lastname: Morrish
authors.affiliation: Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia; Department of Nephrology, Royal Melbourne Hospital, Melbourne, Australia.
authors.forename: Eugenie
authors.initials: E
authors.lastname: Pedagogos
authors.affiliation: Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia; George Institute, Sydney, Australia.
authors.forename: Vlado
authors.initials: V
authors.lastname: Perkovic
authors.affiliation: Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia.
authors.forename: Donna
authors.initials: D
authors.lastname: Reidlinger
authors.affiliation: Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia.
authors.forename: Anish
authors.initials: A
authors.lastname: Scaria
authors.affiliation: Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia; Department of Renal Medicine, The Alfred Hospital, Melbourne, Australia.
authors.forename: Rowan
authors.initials: R
authors.lastname: Walker
authors.affiliation: Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia.
authors.forename: Liza A
authors.initials: LA
authors.lastname: Vergara
authors.affiliation: Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia; Department of Nephrology, Princess Alexandra Hospital, Brisbane, Australia.
authors.forename: Carmel M
authors.initials: CM
authors.lastname: Hawley
mesh_terms: D000328:Adult; D000368:Aged; D000740:Anemia / Q000097:blood / Q000188:drug therapy / Q000209:etiology; D017046:Cost Savings; D004311:Double-Blind Method; D016903:Drug Monitoring / Q000379:methods; D004351:Drug Resistance / Q000187:drug effects; D004357:Drug Synergism; D004920:Erythropoiesis / Q000187:drug effects*; D004921:Erythropoietin / Q000008:administration & dosage / Q000009:adverse effects; D006401:Hematologic Agents / Q000008:administration & dosage / Q000009:adverse effects; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D008875:Middle Aged; D010431:Pentoxifylline / Q000008:administration & dosage / Q000009:adverse effects; D011788:Quality of Life; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000191:economics / Q000523:psychology; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D006401:Hematologic Agents; D006454:Hemoglobins; D014665:Vasodilator Agents; D004921:Erythropoietin; D010431:Pentoxifylline
keywords: Anemia; ESA hyporesponsiveness; ESA resistance index (ERI); chronic kidney disease (CKD); darbepoetin; dialysis; drug sensitivity; epoetin; erythropoiesis-stimulating agent (ESA); erythropoietin; hemoglobin; pentoxifylline; randomized controlled trial