title: Reduced responsiveness to epoetin at re-exposure after prolonged epoetin-free period in anemic hemodialysis patients with end-stage renal disease.
abstract: OBJECTIVE
  To determine if temporary discontinuation of epoetin therapy in anemic patients with end stage renal disease (ESRD) influences their responsiveness to epoetin.
  
  
  METHODS
  We performed a post hoc analysis of the data from two consecutive single-center randomized trials (T1 and T2) comparing the efficacy of two epoetin products (E1 and E2) in anemic patients with ESRD. The analysis included a subset of 44 patients who participated in both trials and were not receiving epoetin in the period (median, 12 months; range 5-15) between the trials due to epoetin shortage. Two co-primary outcomes were average weekly hemoglobin difference from the baseline and average weekly epoetin dose.
  
  
  RESULTS
  With adjustment for potential differences between E1 and E2, average weekly hemoglobin difference of 1.21 g/dL from the baseline was lower in T2 than that of 1.71 g/dL in T1: difference -0.49 (95% confidence interval [CI], -0.68 to -0.29; P<0.001). Average weekly epoetin dose of 107 IU/kg in T2 was higher than 96 IU/kg in T1 (ratio, 1.13; 95% CI, 1.04-1.24; P=0.009). With additional adjustment for within-subject changes in baseline covariates from T1 to T2 (baseline hemoglobin, body mass index, serum albumin, ferritin and transferrin saturation, intact parathormone, C-reactive protein, dialysis dose, and use of angiotensin converting enzyme inhibitors), hemoglobin response remained lower (adjusted difference, -0.44 g/dL; 95% CI, -0.73 to -0.16; P=0.004) and weekly epoetin dose remained higher in T2 than inT1 (adjusted ratio, 1.17; 95% CI, 1.03-1.34; P=0.016).
  
  
  CONCLUSIONS
  In patients with ESRD, responsiveness to epoetin was lower in T2 after a period of epoetin therapy discontinuation than in T1 epoetin trial. Since this could not be explained by within-subject changes in factors known to affect response to epoetin, a prolonged withdrawal of epoetin in patients with ESRD might independently contribute to a reduced responsiveness to epoetin at a later re-exposure.
  
  
  BACKGROUND
  ClinicalTrials.gov Identifier for T1 trial: NCT00322413.
authors.affiliation: Department of Nephrology and Dialysis and Clinical Pharmacology Unit, Holy Ghost General Hospital, Zagreb, Croatia.
authors.forename: Slobodan
authors.initials: S
authors.lastname: Milutinović
authors.forename: Vladimir
authors.initials: V
authors.lastname: Trkulja
mesh_terms: D000740:Anemia / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D000068817:Epoetin Alfa; D004921:Erythropoietin / Q000627:therapeutic use*; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D007676:Kidney Failure, Chronic / Q000150:complications*; D008875:Middle Aged; D016032:Randomized Controlled Trials as Topic; D011994:Recombinant Proteins; D006435:Renal Dialysis; D016896:Treatment Outcome
chemical_list: D006454:Hemoglobins; D011994:Recombinant Proteins; D004921:Erythropoietin; D000068817:Epoetin Alfa