Greater epoetin alfa responsiveness is associated with improved survival in hemodialysis patients

Abstract

Background and objectives: Among hemodialysis patients, achieved hemoglobin is associated with Epoetin alfa dose and erythropoietin responsiveness. A prospective erythropoietin responsiveness measure was developed and its association with mortality evaluated.

Design, setting, participants, & measurements: Data from 321 participants were used and randomized to the hematocrit normalization arm of the Normal Hematocrit Cardiac Trial. Subjects were to receive a 50% Epoetin alfa dose increase at randomization. The prospective erythropoietin responsiveness measure was defined as the ratio of weekly hematocrit change (over the 3 wk after randomization) per Epoetin alfa dose increase (1000 IU/wk) corresponding to the mandated 50% dose increase at randomization. The distribution of responsiveness was divided into quartiles. Over a 1-yr follow-up, Cox proportional hazard modeling evaluated associations between this responsiveness measure and mortality.

Results: Erythropoietin responsiveness values ranged from -2.1% to 2.4% per week per 1000 IU. Although subjects were similar across response quartiles, mortality ranged between 14% and 34% among subjects in the highest and lowest response quartiles (P = 0.0004), respectively. After adjusting for baseline prognostic indicators, highest versus lowest responsiveness was associated with a hazard ratio of 0.41 (95% confidence interval, 0.20 to 0.87).

Conclusion: Lower erythropoietin responsiveness is a strong, independent predictor of mortality risk and should be considered when evaluating associations between clinical outcomes and potential prognostic indicators, such as Epoetin alfa dose and achieved hemoglobin values.

Figure 1.

Representative example illustrating the calculation of the erythropoietin response measure. Total weekly Epoetin alfa dose in units (Υ) and weekly hematocrit values (•) are shown. The hematocrit slope is calculated as the simple linear regression of hematocrit on study week during weeks 1 through 3. Epoetin alfa increase is the change in dose from the first prestudy week (week −1) to the first on-study week (week 1). In this example, erythropoietin response = hematocrit slope (1.35% per week) per Epoetin alfa increase (13,500 − 9000 IU = 4500 IU) = (0.0003% per week) per IU. Hematocrit values were calculated by multiplying hemoglobin concentrations (g/dl) by 3.

Figure 2.

(A) Erythropoietin response for all subjects, plotted by numerator and denominator of the measure. Subjects were characterized by value of the erythropoietin response measure, which was categorized into quartiles (1st (○) 2nd (▪) 3rd (▴) and 4th (♦)). For each subject, the quartile of erythropoietin response was plotted by the increase in Epoetin alfa dose at randomization (denominator of the response measure) on the horizontal axis, and hematocrit response (numerator of the response measure, which was the hematocrit slope derived from a simple linear regression of study week on hematocrit) on the vertical axis. (B) Erythropoietin response as a function of prestudy (baseline) Epoetin alfa dose. Erythropoietin response values (•) on the vertical axis are shown plotted against baseline Epoetin alfa dose (×1000 U/wk) on the horizontal axis. A histogram showing the number of subjects at each level of baseline dose is shown in the background.

Figure 3.

Association between erythropoietin response quartile, and all-cause 1-yr mortality assessed using a Cox proportional hazard model. (A) Results from models at three levels of adjustment are plotted: unadjusted (•), case-mix (▪), and full (Δ). (B) Results are presented in a tabular format. CI, confidence interval

Figure 4.

Lack of association between baseline Epoetin alfa dose and all-cause 1-yr mortality within each erythropoietin response quartile. A Cox proportional hazard model was used to evaluate the association between baseline Epoetin alfa dose (U) and mortality within quartiles of erythropoietin response. The hazard ratio is the relative hazard per 1000 IU baseline Epoetin alfa dose. (A) Results from models at three levels of adjustment are plotted: unadjusted (•), case-mix (▪), and full (Δ). (B) Results are presented in a tabular format. CI, confidence interval