title: Mortality and cardiovascular morbidity associated with haemoglobin levels: a pooled analysis of randomised controlled trials.
abstract: OBJECTIVE
  Several randomised controlled trials (RCTs) have raised concerns about potential harm associated with erythropoiesis-stimulating agents (ESAs) in chronic kidney disease patients, especially when haemoglobin (Hb) levels above 13 g/dl were targeted. We report the relationship between Hb levels and outcomes in the methoxy polyethylene glycol-epoetin beta RCT programme.
  
  
  METHODS
  We assessed the association between Hb and a composite end point, as well as its components [all-cause mortality, myocardial infarction (MI) or cerebrovascular events (CVE)], in multiple post hoc analyses of 9 prospective RCTs (3,405 chronic kidney disease patients). Mean Hb levels over time and deviation from target were analysed using a Cox regression model. Time-adjusted average Hb, deviation from target, the last Hb, Hb slope and within-patient Hb variability preceding an event were analysed using a time-dependent Cox model. Hazard ratios and 95% confidence intervals were calculated.
  
  
  RESULTS
  Average Hb <10 g/dl, decrease from stable baseline Hb >1 g/dl, last Hb <10 g/dl, Hb decline >1.5 g/dl/4 weeks and increased Hb variability were associated with a higher risk of the composite end point and all-cause mortality. An increased risk for CVE and MI was found with a last Hb <10 g/dl and with a decrease from baseline >1 g/dl in the preceding month.
  
  
  CONCLUSIONS
  In multiple analyses from a large programme of prospective clinical trials of ESA treatment, risk of all-cause mortality and cardiovascular morbidity risk was consistently higher at Hb <10 g/dl and in patients whose Hb fell below target.
authors.affiliation: Ospedale Alessandro Manzoni, Lecco, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Locatelli
authors.forename: Angel
authors.initials: A
authors.lastname: de Francisco
authors.forename: Gilbert
authors.initials: G
authors.lastname: Deray
authors.forename: Danilo
authors.initials: D
authors.lastname: Fliser
authors.forename: Gillian
authors.initials: G
authors.lastname: Armstrong
authors.forename: Frank C
authors.initials: FC
authors.lastname: Dougherty
authors.forename: Patricia
authors.initials: P
authors.lastname: Ehrhard
mesh_terms: D002318:Cardiovascular Diseases / Q000097:blood / Q000209:etiology*; D002423:Cause of Death; D005260:Female; D006397:Hematinics / Q000009:adverse effects / Q000627:therapeutic use*; D006454:Hemoglobins / Q000187:drug effects*; D006801:Humans; D053208:Kaplan-Meier Estimate; D007676:Kidney Failure, Chronic / Q000097:blood / Q000150:complications* / Q000188:drug therapy* / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D016032:Randomized Controlled Trials as Topic; D006435:Renal Dialysis; D012307:Risk Factors
chemical_list: D006397:Hematinics; D006454:Hemoglobins