Greater Epoetin alfa (EPO) doses and short-term mortality risk among hemodialysis patients with hemoglobin levels less than 11 g/dL

Pharmacoepidemiol Drug Saf. 2009 Oct;18(10):932-40. doi: 10.1002/pds.1799.


Purpose: We examined the association between high doses of Epoetin alfa (EPO), which are used to raise and maintain hemoglobin (Hb) levels within target ranges for hemodialysis patients, and short-term mortality risk using multivariable regression and an instrumental variable (IV) analysis.

Methods: We identified 32 734 patients receiving hemodialysis in 786 facilities from a large US dialysis provider between July 2000 and March 2002 who received care for >4 consecutive months, and had an Hb < 11 g/dL in the third month. We assessed dose titrations following the Hb < 11 g/dL and characterized facilities based on the percentage of patients with dose titrations >25% (instrument). We assessed deaths during the subsequent 90 days and evaluated the EPO dose-mortality association using conventional linear and IV regression.

Results: The study population had a mean (SD) age of 60.4 (15.0) years; 48% were white, 42% were black and 51% were male. In unadjusted analyses, high EPO doses were associated with 90-day mortality risk (Risk Difference, RD = 3.0 per 100 persons, 95%CI:2.3-3.6); mortality risk was attenuated after adjustment for confounding (RD = 1.5 per 100 persons, 95%CI:0.8-2.2) and not associated with high EPO dose in the pooled IV analysis, though confidence intervals (CI) were wide (RD = -0.4 per 100 persons, 95%CI:-3.2-2.4).

Conclusions: The difference in risk estimates between the adjusted linear regression and the IV regression suggests that the short-term mortality related to EPO dosing may be largely attributable to confounding-by-indication for higher doses. The IV method, which was employed to address the possibility of residual confounding, yielded near null though imprecise effect estimates.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Anemia / blood
  • Anemia / drug therapy*
  • Anemia / etiology
  • Anemia / mortality*
  • Biomarkers / blood
  • Confounding Factors, Epidemiologic
  • Epoetin Alfa
  • Erythropoietin / administration & dosage
  • Erythropoietin / adverse effects*
  • Female
  • Hematinics / administration & dosage
  • Hematinics / adverse effects*
  • Hemoglobins / metabolism*
  • Humans
  • Least-Squares Analysis
  • Linear Models
  • Male
  • Middle Aged
  • Recombinant Proteins
  • Renal Dialysis / adverse effects
  • Renal Dialysis / mortality*
  • Risk Assessment
  • Risk Factors
  • Time Factors
  • Treatment Outcome
  • United States / epidemiology


  • Biomarkers
  • Hematinics
  • Hemoglobins
  • Recombinant Proteins
  • Erythropoietin
  • Epoetin Alfa