Mortality and cardiovascular morbidity associated with haemoglobin levels: a pooled analysis of randomised controlled trials

Nephron Clin Pract. 2014;128(3-4):323-32. doi: 10.1159/000366478. Epub 2014 Dec 5.


Background/aims: 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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cardiovascular Diseases / blood
  • Cardiovascular Diseases / etiology*
  • Cause of Death
  • Female
  • Hematinics / adverse effects
  • Hematinics / therapeutic use*
  • Hemoglobins / drug effects*
  • Humans
  • Kaplan-Meier Estimate
  • Kidney Failure, Chronic / blood
  • Kidney Failure, Chronic / complications*
  • Kidney Failure, Chronic / drug therapy*
  • Kidney Failure, Chronic / mortality*
  • Male
  • Middle Aged
  • Randomized Controlled Trials as Topic
  • Renal Dialysis
  • Risk Factors


  • Hematinics
  • Hemoglobins