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

Forni V, Bianchi G, Ogna A, Salvadé I, Vuistiner P, Burnier M, Gabutti L - BMC Nephrol (2013)

Bottom Line: The benefit of reducing the administration interval was however lessened by the variability induced by more frequent dosage adjustments.No difference was found in the mean values of biological parameters (hemoglobin, reticulocytes, and ferritin) between the 4 strategies.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.

View Article: PubMed Central - HTML - PubMed

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.

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Related in: MedlinePlus

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.
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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.

Mentions: Concerning ESAs, when analyzing the start and final dose utilized in both study phases, we observed that: Darbepoetin alfa monthly dose significantly increased from mean (sd) 180 (145) to 266 (172) μg over P1-2 (p = 0.002), without significant change over P3-4, from mean (sd) 202 (185) to 170 (168) μg (p = 0.3) (Figure 4); C.E.R.A monthly dose was unchanged over P1-2, from mean (sd) 161 (106) to 202 (167) μg (p = 0.3) , but significantly decreased over period P3-4, from 244 (222) to 151 (154) μg (p = 0.01) (Figure 5) (secondary outcome). After adjustment for confounding factors (ESAs administration interval, cumulated ESAs dose prior to the event, cumulated iron dose), the risk of Hb overshooting (defined as Hb > 12.0 g/dl) was found to be predicted from ESA type, with a higher risk for C.E.R.A. (OR 2.7, p = 0.01) (secondary outcome). ESAs type and administration interval were not found to predict Hb values < 10 g/dl, which were correlated with cumulated ESA dose (p = 0.02).


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

Forni V, Bianchi G, Ogna A, Salvadé I, Vuistiner P, Burnier M, Gabutti L - BMC Nephrol (2013)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3733800&req=5

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.
Mentions: Concerning ESAs, when analyzing the start and final dose utilized in both study phases, we observed that: Darbepoetin alfa monthly dose significantly increased from mean (sd) 180 (145) to 266 (172) μg over P1-2 (p = 0.002), without significant change over P3-4, from mean (sd) 202 (185) to 170 (168) μg (p = 0.3) (Figure 4); C.E.R.A monthly dose was unchanged over P1-2, from mean (sd) 161 (106) to 202 (167) μg (p = 0.3) , but significantly decreased over period P3-4, from 244 (222) to 151 (154) μg (p = 0.01) (Figure 5) (secondary outcome). After adjustment for confounding factors (ESAs administration interval, cumulated ESAs dose prior to the event, cumulated iron dose), the risk of Hb overshooting (defined as Hb > 12.0 g/dl) was found to be predicted from ESA type, with a higher risk for C.E.R.A. (OR 2.7, p = 0.01) (secondary outcome). ESAs type and administration interval were not found to predict Hb values < 10 g/dl, which were correlated with cumulated ESA dose (p = 0.02).

Bottom Line: The benefit of reducing the administration interval was however lessened by the variability induced by more frequent dosage adjustments.No difference was found in the mean values of biological parameters (hemoglobin, reticulocytes, and ferritin) between the 4 strategies.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.

View Article: PubMed Central - HTML - PubMed

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.

Show MeSH
Related in: MedlinePlus