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      A meta-analysis of the relative doses of erythropoiesis-stimulating agents in patients undergoing dialysis

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          Abstract

          Background. Erythropoiesis-stimulating agents (ESAs) such as epoetin alfa and beta, and darbepoetin alfa have improved the management of anaemia secondary to chronic kidney disease. Numerous studies have reported a dose reduction when patients receiving dialysis were converted from epoetin to darbepoetin alfa using the starting dose conversion of 200:1 as indicated on the prescribing label by the European Medicines Agency. The objective of this meta-analysis was to summarize the existing body of scientific evidence to evaluate the potential dose savings when comparing epoetin alfa or beta to darbepoetin alfa.

          Method. Medline and EmBase were searched to identify all published trials investigating ESA treatment in anaemic patients receiving dialysis and converted from epoetins to darbepoetin alfa. We selected prospective randomized controlled, non-randomized and observational studies involving patients on dialysis that compared epoetin and darbepoetin alfa dosing.

          Results. Of 573 articles identified, 9 studies met the eligibility criteria and were included in our analysis. The overall percentage dose savings attained when dialysis patients were converted from epoetin to darbepoetin alfa was 30% (range: 4%–44%). Greater dose savings were noted with intravenous administration (33%) compared with subcutaneous (27%) and between switch-over studies (31%) and RCTs (27%). In all studies, target haemoglobin levels were maintained before and after conversion.

          Conclusion. This meta-analysis demonstrates that when using an initial 200:1 conversion ratio, as indicated on the European label, from epoetin to darbepoetin, a subsequent reduction in dose was observed and an average 30% dose savings could be achieved.

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          Most cited references33

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          Treatment of the anemia of progressive renal failure with recombinant human erythropoietin.

          To examine the effects of erythropoietin on the anemia of chronic renal disease and on the rate of renal deterioration, we administered recombinant human erythropoietin to 17 patients with anemia and progressive renal failure who did not yet require dialysis (serum creatinine level, 353 to 972 mumol per liter [4.0 to 11.0 mg per deciliter]). The dose of erythropoietin (50 to 150 units per kilogram of body weight) was adjusted according to the hematocrit response. In all 17 patients the anemia responded to erythropoietin. The median hematocrit increased from 0.27 to 0.37. The rate of the response depended on the initial erythropoietin dose and was similar to that observed in patients who were on dialysis. Hypertension was present in 14 patients before therapy, developed during therapy in 2 of the normotensive patients, and worsened in 9 patients, who required additional antihypertensive medications. The rate of the decline in renal function, as measured by serial determination of the reciprocal of the serum creatinine level, did not change significantly as the hematocrit rose (P = 0.78 by the paired t-test) during erythropoietin therapy. All the patients reported improvements in appetite, activity level, and sense of well-being. We conclude that erythropoietin therapy is effective in correcting the anemia of patients with progressive renal failure without affecting renal function, although it may be associated with an increase in blood pressure.
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            Pharmacokinetics of novel erythropoiesis stimulating protein compared with epoetin alfa in dialysis patients.

            Novel erythropoiesis stimulating protein (NESP) is a hyperglycosylated analogue of recombinant human erythropoietin (Epoetin) which has an increased terminal half-life in animal models. The aim of this study was to extend these observations to humans. Using a double-blind, randomized, cross-over design, the single-dose pharmacokinetics of Epoetin alfa (100 U/kg) and an equivalent peptide mass of NESP were compared following intravenous bolus in 11 stable peritoneal dialysis patients. This was followed by an open-label study to determine the single-dose pharmacokinetics of an equivalent peptide mass of NESP by subcutaneous injection in six of these patients. The mean terminal half-life for intravenous NESP was threefold longer than for intravenous Epoetin (25.3 versus 8.5 h), a difference of 16.8 h (95% confidence interval, 9.4 to 24.2 h, P = 0.0008). The area under the serum concentration-time curve was significantly greater for NESP (291.0 +/- 7.6 ng x h per ml versus 131.9 +/- 8.3 ng x h per ml; mean +/- SEM; P < 0.0005), and clearance was significantly lower (1.6 +/- 0.3 ml/h per kg versus 4.0 +/- 0.3 ml/h per kg; mean +/- SEM; P < 0.0005). The volume of distribution was similar for NESP and Epoetin (52.4 +/- 2.0 ml/kg versus 48.7 +/-2.1 ml/kg; mean +/-SEM). The mean terminal half-life for subcutaneous NESP was 48.8 h. The peak concentration of subcutaneous NESP was approximately 10% of that following intravenous administration, and bioavailability was approximately 37% by the subcutaneous route. The longer half-life of NESP is likely to confer a clinical advantage over Epoetin by allowing less frequent dosing in patients treated for anemia.
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              Anemia: an early complication of chronic renal insufficiency.

              The strong association between anemia and cardiovascular complications among patients with end-stage renal disease suggests that anemia during chronic renal insufficiency (CRI) may also have important consequences. We performed a retrospective cohort study to identify factors associated with severe anemia (hematocrit [Hct] < 30%) and examine anemia management practices in CRI. The CRI cohort was composed of 604 adult patients with elevated serum creatinine levels. There was a direct correlation between predicted glomerular filtration rate and Hct (r = 0.49) and an inverse correlation between serum creatinine level and Hct (r = -0.37). Anemia was noted early in CRI; 45% of patients with serum creatinine levels of 2 mg/dL or less had an Hct less than 36%, and 8% had an Hct less than 30%. During the course of the study, mean Hct decreased from 35.1% +/- 5.6% to 31.8% +/- 5.6%. Iron studies were obtained in only 19% of patients, and among these, the prevalence of iron deficiency (transferrin saturation < 20%) was 54%. Only 30% and 26% of patients were administered recombinant human erythropoietin (rHuEPO) and iron, respectively. Multivariate analyses showed that diabetes as the cause of renal disease, greater serum creatinine level, and having a single nephrology visit were associated with greater odds for the presence of anemia. A lower Hct and having a single nephrology visit were associated with greater odds for rHuEPO use. These results show that anemia begins early in the course of CRI, and management of anemia is suboptimal, even among patients under the care of nephrologists. Educational programs to optimize anemia management among patients with CRI are needed.
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                Author and article information

                Journal
                NDT Plus
                NDT Plus
                ckj
                ndtplus
                NDT Plus
                Oxford University Press
                1753-0784
                1753-0792
                October 2009
                4 August 2009
                4 August 2009
                : 2
                : 5
                : 347-353
                Affiliations
                [1 ]Department of Pharmacy, University Hospital Germans Trias i Pujol , Badalona, Spain
                [2 ]Kantonsspital Aarau, Aarau, Switzerland
                [3 ]Amgen Ltd, Uxbridge, UK
                [4 ]Klinikum Hannover-Oststadt, Hannover, Germany
                [5 ]Eurodial, Dialysis Unit, Leiria, Portugal
                [6 ]Pharm Ideas, , Research & Consulting Inc, Oakville, Ontario, Canada
                [7 ]Amgen Europe GmbH, Zug, Switzerland
                Author notes
                Correspondence and offprint requests to: Xavier Bonafont; E-mail: xbonafont.germanstrias@ 123456gencat.cat
                Article
                sfp097
                10.1093/ndtplus/sfp097
                4421401
                85d8e65f-b77b-4faf-8c5f-b7a885581451
                © The Author [2009]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 11 December 2008
                : 6 July 2009
                Categories
                In-Depth Clinical Review

                Nephrology
                darbepoetin alfa,dialysis,dose savings,epoetin,meta-analysis
                Nephrology
                darbepoetin alfa, dialysis, dose savings, epoetin, meta-analysis

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