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American Journal of Kidney Diseases

Epoetin requirements predict mortality in hemodialysis patients

      Background: Anemia is a frequent complication of end-stage renal disease. Poor responsiveness to epoetin therapy hampers the management of anemia. Escalating epoetin doses often are used to overcome epoetin resistance. The objective of this study is to examine the relationship between epoetin dose requirements and mortality. Methods: Using United States Renal Data System administrative claims data, we conducted a retrospective cohort study of 94,569 prevalent hemodialysis patients in 2000 and 2001. A Cox proportional hazard regression analysis, adjusted for baseline variables, and a 5-knot cubic regression spline were used to model the dose-response relationship between epoetin and all-cause mortality. Results: Significant interpatient variation exists in epoetin dose requirements to attain defined hematocrit levels. For every hematocrit cohort studied, patients administered higher doses of epoetin had significantly lower hematocrit values and greater mortality rates. Using the cubic spline function, a significant nonlinear relationship between increased epoetin dose and mortality was found regardless of hematocrit (P < 0.0001), with the steepest increase in relative risk for death found after the 72.5th dose percentile. Conclusion: Epoetin dose requirement is an independent predictor of total mortality in hemodialysis patients after adjustment for hematocrit. Poor responders who continue to have low hematocrit values despite the administration of high epoetin doses may not necessarily benefit from more epoetin, but perhaps should be considered for other adjunctive therapies. In contrast to conventional wisdom, this study suggests that epoetin dosing requirements could provide important prognostic information beyond that predicted by hematocrit alone.

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      Linked Article

      • In Reply
        American Journal of Kidney DiseasesVol. 51Issue 5
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          In our analysis,1 we sought to evaluate the sensitivity of previously reported epoetin alfa (EPO) dose-mortality associations2,3 to: (1) more comprehensive adjustment for confounding, and (2) use of time-dependent exposure and covariate measures. In these previous analyses,2,3 data on important confounding variables (eg, albumin) were unavailable, and cross-sectional exposure measures were evaluated, ignoring EPO dose changes over time.
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      • Relative Mortality and Epoetin Alfa Dose in Hemodialysis Patients
        American Journal of Kidney DiseasesVol. 51Issue 5
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          The paper by Bradbury et al1 confirms our previous findings indicating that time-dependent confounding between epoetin dose, achieved hematocrit, and level of sickness for individual patients exists and is complex. Similar to hematocrit, epoetin dose requirement has an important role and must be considered in models that predict patient mortality, as clearly shown in our analyses published in the Journal of Clinical Epidemiology2 and the American Journal of Kidney Diseases.3 We applaud the authors for considering exposure as a possible explanatory factor.
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      • Relative Mortality and Epoetin Alfa Dose Among Hemodialysis Patients
        American Journal of Kidney DiseasesVol. 51Issue 5
        • Preview
          Bradbury et al1 found higher epoetin doses were associated with improved survival or a neutral effect using lagged time-dependent analyses, contrary to previous association studies2 and randomized trials.3,4 They report administered epoetin dose declines from approximately 21,000 units per week 8 weeks before death to approximately 8,000 units per week 3 weeks before death and attribute this to missed doses from hospitalization as they collected only in-center data. However, the increasing rate of missed doses cannot account for the dramatic decline.
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      • In Reply
        American Journal of Kidney DiseasesVol. 51Issue 5
        • Preview
          The purpose of our analysis1was to evaluate the sensitivity of previously reported epoetin alfa (EPO) dose-mortality associations2,3 from observational studies to comprehensive adjustment for confounding and time-varying assessments of EPO dose and hemoglobin levels. We observed marked changes in hazard ratio estimates versus previous analyses, suggesting that previous analyses2,3 were biased away from the null. We did not state that our results were definitive. Rather, we suggested that confounding needs to be better addressed in future observational studies of EPO dose and mortality.
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