title: Frequency of administration of erythropoiesis-stimulating agents for the anaemia of end-stage kidney disease in dialysis patients.
abstract: BACKGROUND
  The benefits of erythropoiesis-stimulating agents (ESA) for dialysis patients have been demonstrated. However, it remains unclear whether the efficacy and safety of new, longer-acting ESA given less frequently is equivalent to recombinant human erythropoietin (rHuEPO) preparations. This is an update of a review first published in 2002 and last updated in 2005.
  
  
  OBJECTIVE
  This review aimed to establish the optimal frequency of ESA administration in terms of effectiveness (correction of anaemia, and freedom from adverse events) and efficiency (optimal resource use) of different ESA dose regimens.
  
  
  METHODS
  We searched the Cochrane Renal Group's Specialised Register to 21 March 2013 through contact with the Trials' Search Co-ordinator using search terms relevant to this review.
  
  
  METHODS
  We included randomised control trials (RCTs) comparing different frequencies of ESA administration in dialysis patients.
  
  
  METHODS
  Two authors independently assessed study eligibility, risk of bias and extracted data. Results were expressed as risk ratio (RR) or risk differences (RD) with 95% confidence intervals (CI) for dichotomous outcomes. For continuous outcomes the mean difference (MD) or standardised mean difference (SMD) with 95% confidence intervals (CI) was used. Statistical analyses were performed using the random-effects model.
  
  
  RESULTS
  This review included 33 studies (5526 participants), 22 of which were added for this update. Risk of bias was generally high; only nine studies were assessed at low risk of bias for sequence generation and 14 studies for allocation concealment. Although only four studies were placebo-controlled, all were considered to be at low risk of performance or detection bias because the primary outcome of haemoglobin level was a laboratory-derived assessment and unlikely to be influenced by lack of blinding. We found that 16 studies were at low risk of attrition bias and five were at low risk of selection bias; only one study reporting sources of support was not funded by a pharmaceutical company.We compared four different interventions: Continuous erythropoietin receptor agonists (CERA) versus other ESA (darbepoetin or rHuEPO); different frequencies of darbepoetin administration; darbepoetin versus rHuEPO; and different frequencies of rHuEPO administration.There were no significant differences in maintaining final haemoglobin between CERA administered at two weekly intervals (4 studies, 1762 participants: MD 0.08 g/dL, 95% CI -0.04 to 0.21) or four weekly intervals (two studies, 1245 participants: MD -0.03 g/dL, 95% CI -0.17 to 0.12) compared with rHuEPO administered at two to three weekly intervals. In one study comparing CERA administered every two weeks with darbepoetin administered once/week, there was no significant difference in final haemoglobin (313 participants: MD 0.30 g/dL, 95% CI 0.05 to 0.55). In comparisons of once/week with once every two weeks darbepoetin (two studies, 356 participants: MD 0.04 g/dL, 95% CI -0.45 to 0.52) and once every two weeks with monthly darbepoetin (one study, 64 participants: MD 0.40 g/dL, 95% CI -0.37 to 1.17) there were no significant differences in final haemoglobin levels. There was marked heterogeneity among studies comparing weekly darbepoetin with once every two weeks and was possibly related to different administration protocols. Eight studies compared weekly darbepoetin with rHuEPO given two to three times/week; no statistical difference in final haemoglobin was demonstrated (6 studies, 1638 participants: MD 0.02 g/dL, 95% CI -0.09 to 0.12). Fourteen studies compared different frequencies of rHuEPO. No statistical difference was demonstrated in final haemoglobin (7 studies, 393 participants: SMD -0.17 g/dL, 95% CI -0.39 to 0.05). Adverse events did not differ significantly within comparisons; however, mortality and quality of life were poorly reported, particularly in earlier publications.
  
  
  CONCLUSIONS
  Longer-acting ESA (darbepoetin and CERA) administered at one to four week intervals are non-inferior to rHuEPO given one to three times/week in terms of achieving haemoglobin targets without any significant differences in adverse events in haemodialysis patients. Additional RCTs are required to evaluate different frequencies of ESA in peritoneal and paediatric dialysis patients and to compare different longer-acting ESA (such as darbepoetin compared with CERA).
authors.affiliation: Department of Nephrology, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW, Australia, 2145.
authors.forename: Deirdre
authors.initials: D
authors.lastname: Hahn
authors.forename: June D
authors.initials: JD
authors.lastname: Cody
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Hodson
mesh_terms: D000740:Anemia / Q000188:drug therapy* / Q000209:etiology; D004334:Drug Administration Schedule; D004921:Erythropoietin / Q000008:administration & dosage*; D006397:Hematinics / Q000008:administration & dosage*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000628:therapy*; D016032:Randomized Controlled Trials as Topic; D011994:Recombinant Proteins / Q000008:administration & dosage; D006435:Renal Dialysis / Q000009:adverse effects*
chemical_list: D006397:Hematinics; D011994:Recombinant Proteins; D004921:Erythropoietin