Reticulocyte dynamic and hemoglobin variability in hemodialysis patients treated with Darbepoetin alfa and C.E.R.A.: a randomized controlled trial

Abstract

Background: In a simulation based on a pharmacokinetic model we demonstrated that increasing the erythropoiesis stimulating agents (ESAs) half-life or shortening their administration interval decreases hemoglobin variability. The benefit of reducing the administration interval was however lessened by the variability induced by more frequent dosage adjustments. The purpose of this study was to analyze the reticulocyte and hemoglobin kinetics and variability under different ESAs and administration intervals in a collective of chronic hemodialysis patients.

Methods: The study was designed as an open-label, randomized, four-period cross-over investigation, including 30 patients under chronic hemodialysis at the regional hospital of Locarno (Switzerland) in February 2010 and lasting 2 years. Four subcutaneous treatment strategies (C.E.R.A. every 4 weeks Q4W and every 2 weeks Q2W, Darbepoetin alfa Q4W and Q2W) were compared with each other. The mean square successive difference of hemoglobin, reticulocyte count and ESAs dose was used to quantify variability. We distinguished a short- and a long-term variability based respectively on the weekly and monthly successive difference.

Results: No difference was found in the mean values of biological parameters (hemoglobin, reticulocytes, and ferritin) between the 4 strategies. ESAs type did not affect hemoglobin and reticulocyte variability, but C.E.R.A induced a more sustained reticulocytes response over time and increased the risk of hemoglobin overshooting (OR 2.7, p = 0.01). Shortening the administration interval lessened the amplitude of reticulocyte count fluctuations but resulted in more frequent ESAs dose adjustments and in amplified reticulocyte and hemoglobin variability. Q2W administration interval was however more favorable in terms of ESAs dose, allowing a 38% C.E.R.A. dose reduction, and no increase of Darbepoetin alfa.

Conclusions: The reticulocyte dynamic was a more sensitive marker of time instability of the hemoglobin response under ESAs therapy. The ESAs administration interval had a greater impact on hemoglobin variability than the ESAs type. The more protracted reticulocyte response induced by C.E.R.A. could explain both, the observed higher risk of overshoot and the significant increase in efficacy when shortening its administration interval.

Trial registration: ClinicalTrials.gov: NCT01666301.

Figure 1

Study design. Schema representing the four-period cross-over investigation, composed of 2 periods with ESAs administration scheduled at 4 weeks intervals (Q4W) and 2 periods with ESAs administration scheduled at 2 weeks intervals (Q2W).

Figure 2

Hemoglobin and reticulocyte time course, Q4W administration interval. Hb, ret and ESA dose as a function of time at 4 weeks ESAs-administration interval; C.E.R.A. black dash line, Darbepoietin alfa black solid line. Vertical lines correspond to ESA administration.

Figure 3

Hemoglobin and reticulocyte time course, Q2W administration interval. Hb, ret and ESA dose as a function of time at 4 weeks ESAs-administration interval; C.E.R.A. black dash line, Darbepoietin alfa black solid line. Vertical lines correspond to ESA administration.

Figure 4

Start- and end- monthly ESA dose, Darbepoetin alfa. Starting and end-monthly dose of Darbepoietin alfa at 4 weeks (Q4W) and 2 weeks (Q2W ) administration intervals. Boxes represent 25th and 75th percentiles, whiskers 5th and 95th percentiles. N = 19.

Figure 5

Start- and end- monthly ESA dose, C.E.R.A. Starting and end-monthly dose of C.E.R.A at 4 weeks (Q4W) and 2 weeks (Q2W) administration intervals. Boxes represent 25th and 75th percentiles, whiskers 5th and 95th percentiles. N = 19.