title: Erythropoiesis-stimulating agents for anaemia in adults with chronic kidney disease: a network meta-analysis.
abstract: BACKGROUND
  Several erythropoiesis-stimulating agents (ESAs) are available for treating anaemia in people with chronic kidney disease (CKD). Their relative efficacy (preventing blood transfusions and reducing fatigue and breathlessness) and safety (mortality and cardiovascular events) are unclear due to the limited power of head-to-head studies.
  
  
  OBJECTIVE
  To compare the efficacy and safety of ESAs (epoetin alfa, epoetin beta, darbepoetin alfa, or methoxy polyethylene glycol-epoetin beta, and biosimilar ESAs, against each other, placebo, or no treatment) to treat anaemia in adults with CKD.
  
  
  METHODS
  We searched the Cochrane Renal Group's Specialised Register to 11 February 2014 through contact with the Trials' Search Co-ordinator using search terms relevant to this review.
  
  
  METHODS
  Randomised controlled trials (RCTs) that included a comparison of an ESA (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta, or biosimilar ESA) with another ESA, placebo or no treatment in adults with CKD and that reported prespecified patient-relevant outcomes were considered for inclusion.
  
  
  METHODS
  Two independent authors screened the search results and extracted data. Data synthesis was performed by random-effects pairwise meta-analysis and network meta-analysis. We assessed for heterogeneity and inconsistency within meta-analyses using standard techniques and planned subgroup and meta-regression to explore for sources of heterogeneity or inconsistency. We assessed our confidence in treatment estimates for the primary outcomes within network meta-analysis (preventing blood transfusions and all-cause mortality) according to adapted GRADE methodology as very low, low, moderate, or high.
  
  
  RESULTS
  We identified 56 eligible studies involving 15,596 adults with CKD. Risks of bias in the included studies was generally high or unclear for more than half of studies in all of the risk of bias domains we assessed; no study was low risk for allocation concealment, blinding of outcome assessment and attrition from follow-up. In network analyses, there was moderate to low confidence that epoetin alfa (OR 0.18, 95% CI 0.05 to 0.59), epoetin beta (OR 0.09, 95% CI 0.02 to 0.38), darbepoetin alfa (OR 0.17, 95% CI 0.05 to 0.57), and methoxy polyethylene glycol-epoetin beta (OR 0.15, 95% CI 0.03 to 0.70) prevented blood transfusions compared to placebo. In very low quality evidence, biosimilar ESA therapy was possibly no better than placebo for preventing blood transfusions (OR 0.27, 95% CI 0.05 to 1.47) with considerable imprecision in estimated effects. We could not discern whether all ESAs were similar or different in their effects on preventing blood transfusions and our confidence in the comparative effectiveness of different ESAs was generally very low. Similarly, the comparative effects of ESAs compared with another ESA, placebo or no treatment on all-cause mortality were imprecise.All proprietary ESAs increased the odds of hypertension compared to placebo (epoetin alfa OR 2.31, 95% CI 1.27 to 4.23; epoetin beta OR 2.57, 95% CI 1.23 to 5.39; darbepoetin alfa OR 1.83, 95% CI 1.05 to 3.21; methoxy polyethylene glycol-epoetin beta OR 1.96, 95% CI 0.98 to 3.92), while the effect of biosimilar ESAs on developing hypertension was less certain (OR 1.18, 95% CI 0.47 to 2.99). Our confidence in the comparative effects of ESAs on hypertension was low due to considerable imprecision in treatment estimates. The comparative effects of all ESAs on cardiovascular mortality, myocardial infarction (MI), stroke, and vascular access thrombosis were uncertain and network analyses for major cardiovascular events, end-stage kidney disease (ESKD), fatigue and breathlessness were not possible. Effects of ESAs on fatigue were described heterogeneously in the available studies in ways that were not useable for analyses.
  
  
  CONCLUSIONS
  In the CKD setting, there is currently insufficient evidence to suggest the superiority of any ESA formulation based on available safety and efficacy data. Directly comparative data for the effectiveness of different ESA formulations based on patient-centred outcomes (such as quality of life, fatigue, and functional status) are sparse and poorly reported and current research studies are unable to inform care. All proprietary ESAs (epoetin alfa, epoetin beta, darbepoetin alfa, and methoxy polyethylene glycol-epoetin beta) prevent blood transfusions but information for biosimilar ESAs is less conclusive. Comparative treatment effects of different ESA formulations on other patient-important outcomes such as survival, MI, stroke, breathlessness and fatigue are very uncertain.For consumers, clinicians and funders, considerations such as drug cost and availability and preferences for dosing frequency might be considered as the basis for individualising anaemia care due to lack of data for comparative differences in clinical benefits and harms.
authors.affiliation: Department of Medicine, University of Otago Christchurch, 2 Riccarton Ave, PO Box 4345, Christchurch, 8140, New Zealand. suetonia.palmer@otago.ac.nz.
authors.forename: Suetonia C
authors.initials: SC
authors.lastname: Palmer
authors.forename: Valeria
authors.initials: V
authors.lastname: Saglimbene
authors.forename: Dimitris
authors.initials: D
authors.lastname: Mavridis
authors.forename: Georgia
authors.initials: G
authors.lastname: Salanti
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Craig
authors.forename: Marcello
authors.initials: M
authors.lastname: Tonelli
authors.forename: Natasha
authors.initials: N
authors.lastname: Wiebe
authors.forename: Giovanni F M
authors.initials: GF
authors.lastname: Strippoli
mesh_terms: D000328:Adult; D000740:Anemia / Q000188:drug therapy*; D059451:Biosimilar Pharmaceuticals / Q000009:adverse effects; D000068256:Darbepoetin alfa; D000068817:Epoetin Alfa; D004921:Erythropoietin / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D006397:Hematinics / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D051436:Renal Insufficiency, Chronic / Q000150:complications*
chemical_list: D059451:Biosimilar Pharmaceuticals; D006397:Hematinics; D011994:Recombinant Proteins; C508420:continuous erythropoietin receptor activator; C103998:epoetin beta; D004921:Erythropoietin; D000068256:Darbepoetin alfa; D011092:Polyethylene Glycols; D000068817:Epoetin Alfa