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      Once-Monthly Continuous Erythropoietin Receptor Activator (C.E.R.A.) in Patients with Hemodialysis-Dependent Chronic Kidney Disease: Pooled Data from Phase III Trials

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          Abstract

          Introduction

          Erythropoiesis-stimulating agents and iron are commonly used in patients with chronic kidney disease with the aim of correcting anemia and maintaining stable hemoglobin levels. We analyzed pooled data from 13 studies with similar designs included in the Umbrella Continuous Erythropoietin Receptor Activator (C.E.R.A.) program to investigate the effects of continuous erythropoiesis receptor activator in clinically relevant subgroups of patients with chronic kidney disease and to determine whether the efficacy and safety outcomes demonstrated in the overall chronic kidney disease population are maintained in specific subgroups.

          Methods

          Data from 13 Phase III trials set up with similar design were retrospectively pooled for this analysis. Patients with chronic kidney disease who had previously been receiving epoetin or darbepoetin were switched to continuous erythropoiesis receptor activator once-monthly after a 4- to 8-week screening period. Patients entered a 16-week continuous erythropoiesis receptor activator dose-titration period followed by an 8-week evaluation period. In total, 2060 patients were included in the analysis. Subgroups were defined based on: hemoglobin target range [lower (10.0–12.0 g/dL)/upper (10.5–13.0 g/dL)], gender (female/male), age (<65/≥65), baseline N-terminal pro-B-type natriuretic peptide levels (<5000/≥5000), cardiovascular risk factors (diabetes/cardiac/vascular/none).

          Results

          Across all subgroups analyzed, switching from shorter-acting erythropoiesis-stimulating agents to continuous erythropoiesis receptor activator once-monthly maintained stable hemoglobin concentrations in a high proportion of patients (78%), with only moderate hemoglobin fluctuations and a low number of dose changes. The safety profile across subgroups was as expected based on pre-existing risk factors; observed increases in adverse events were attributable to underlying risk factors rather than study drug.

          Conclusions

          This retrospective analysis of 13 trials showed that continuous erythropoiesis receptor activator once-monthly maintained stable hemoglobin levels across a number of clinically relevant patient subgroups, including those with higher inherent cardiovascular risk. The safety profile was consistent with that previously established in the chronic kidney disease population.

          ClinicalTrials.gov identifiers

          NCT00413894/NCT00545571/NCT00517413/NCT00560404/NCT00882713/NCT00550680/NCT00576303/NCT00660023/NCT00717821/NCT00642850/NCT00605293/NCT00661505/NCT00699348.

          Funding

          F. Hoffmann-La Roche Ltd, Basel, Switzerland.

          Electronic supplementary material

          The online version of this article (doi:10.1007/s12325-016-0309-6) contains supplementary material, which is available to authorized users.

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          Most cited references20

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          Kidney Disease: Improving Global Outcomes guidelines on anaemia management in chronic kidney disease: a European Renal Best Practice position statement.

          Recently, the Kidney Disease: Improving Global Outcomes (KDIGO) group has produced comprehensive clinical practice guidelines for the management of anaemia in CKD patients. These guidelines addressed all of the important points related to anaemia management in CKD patients, including therapy with erythropoieis stimulating agents (ESA), iron therapy, ESA resistance and blood transfusion use. Because most guidelines were 'soft' rather than 'strong', and because global guidelines need to be adapted and implemented into the regional context where they are used, on behalf of the European Renal Best Practice Advisory Board some of its members, and other external experts in this field, who were not participants in the KDIGO guidelines group, were invited to participate in this anaemia working group to examine and comment on the KDIGO documents in this position paper. In this article, the group concentrated only on those guidelines which we considered worth amending or adapting. All guidelines not specifically mentioned are fully endorsed.
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            Anaemia management in patients with chronic kidney disease: a position statement by the Anaemia Working Group of European Renal Best Practice (ERBP).

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              Association of anemia with outcomes in men with moderate and severe chronic kidney disease.

              Anemia is a common complication of chronic kidney disease (CKD), but the outcomes associated with lower hemoglobin (Hgb) levels in patients with CKD not yet on dialysis are not well characterized. Analyses exploring outcomes associated with a single baseline Hgb value also do not account for the longitudinal variation of this measure. After collecting all Hgb measurements (N=17 194, median (range): 12 (1-168)) over a median follow-up period of 2.1 years in a historical prospective cohort of 853 male US veterans with CKD Stages 3-5 not yet on dialysis, we examined the association of time-averaged Hgb levels with predialysis all-cause mortality, end-stage renal disease (ESRD), and a composite end point of both. Kaplan-Meier survival analysis and Cox models adjusted for age, race, body mass index, smoking status, blood pressure, diabetes mellitus, cardiovascular disease, categories of estimated glomerular filtration rate, serum concentrations of albumin and cholesterol, and proteinuria were examined. Lower time-averaged Hgb was associated with significantly higher hazard of the composite end point (hazard ratio (95% confidence interval) in the adjusted model for time-averaged Hgb of 130 g/l: 2.57 (1.85-3.58), 1.97 (1.45-2.66), 1.19 (0.86-1.63), P(trend)<0.001). Lower time-averaged Hgb was associated with both significantly higher pre-dialysis mortality and higher risk of ESRD, when analyzed separately. Anemia (especially time-averaged Hgb <120 g/l) is associated with both higher mortality and increased risk of ESRD in male patients with CKD not yet on dialysis.
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                Author and article information

                Contributors
                f.locatelli@ospedale.lecco.it
                Journal
                Adv Ther
                Adv Ther
                Advances in Therapy
                Springer Healthcare (Cheshire )
                0741-238X
                1865-8652
                10 March 2016
                10 March 2016
                2016
                : 33
                : 610-625
                Affiliations
                [ ]Nephrology, Dialysis and Transplantation Department, Alessandro Manzoni Hospital, Lecco, Italy
                [ ]Nephrology, Dialysis and Transplantation Department, CHU Amiens and University of Picardie Jules Verne, Amiens, France
                [ ]Roche Australia, Dee Why, Australia
                [ ]Roche Pharma AG, Medical Affairs, Grenzach-Wyhlen, Germany
                [ ]Department of Internal Medicine IV, Saarland University Medical Centre, Homburg/Saar, Germany
                Article
                309
                10.1007/s12325-016-0309-6
                4846713
                26965694
                6fc5646a-e493-48ad-aa13-e461551fde7f
                © The Author(s) 2016
                History
                : 8 January 2016
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100007013, F. Hoffman-La Roche;
                Categories
                Original Research
                Custom metadata
                © Springer Healthcare 2016

                anemia, chronic kidney disease,continuous erythropoiesis,hemodialysis,receptor activator,efficacy,patient subgroups,pooled analysis

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