Effects of the dose of erythropoiesis stimulating agents on cardiovascular events, quality of life, and health-related costs in hemodialysis patients: the clinical evaluation of the dose of erythropoietins (C.E. DOSE) trial protocol

Giovanni F M Strippoli, Clinical Evaluation of the DOse of Erythropoietins Study Group (C.E. DOSE), Valeria Saglimbene, Ausilia Maione, Mariacristina Vecchio, Antonio Nicolucci, Fabio Pellegrini, Sankar D Navaneethan, Suetonia Palmer, Jonathan C Craig, Giorgio Triolo, Deni A Procaccini, Antonio Santoro, Salvatore Di Giulio, Carmen Bonifati, Lucia Di Micco, Sandra La Rosa, Angelo Murgo, Rinaldo Di Toro Mammarella, Marialucia Sambati, Nicola D'Ambrosio, Virginia Greco, Filippo Dagostino, Giuliano Giannoccaro, Alessandro Flammini, Michela Tedesco, Eligio Boccia, Damiano Di Franco, Moreno Malaguti, Mariano Falco, Giuseppina Montalto, Salvatore Amarù, Michele Fici, Luigi Amoroso, Daniela D'Alonzo, Miriam Valentini, Roberto Palumbo, Gisella Vischini, Elena Gori, Luigi Vernaglione, Domenica Casu, Marcora Mandreoli, Marialuisa Querques, Jorgen Hegbrant, David W Johnson, Gianni Tognoni, Giovanni F M Strippoli, Giovanni F M Strippoli, Clinical Evaluation of the DOse of Erythropoietins Study Group (C.E. DOSE), Valeria Saglimbene, Ausilia Maione, Mariacristina Vecchio, Antonio Nicolucci, Fabio Pellegrini, Sankar D Navaneethan, Suetonia Palmer, Jonathan C Craig, Giorgio Triolo, Deni A Procaccini, Antonio Santoro, Salvatore Di Giulio, Carmen Bonifati, Lucia Di Micco, Sandra La Rosa, Angelo Murgo, Rinaldo Di Toro Mammarella, Marialucia Sambati, Nicola D'Ambrosio, Virginia Greco, Filippo Dagostino, Giuliano Giannoccaro, Alessandro Flammini, Michela Tedesco, Eligio Boccia, Damiano Di Franco, Moreno Malaguti, Mariano Falco, Giuseppina Montalto, Salvatore Amarù, Michele Fici, Luigi Amoroso, Daniela D'Alonzo, Miriam Valentini, Roberto Palumbo, Gisella Vischini, Elena Gori, Luigi Vernaglione, Domenica Casu, Marcora Mandreoli, Marialuisa Querques, Jorgen Hegbrant, David W Johnson, Gianni Tognoni, Giovanni F M Strippoli

Abstract

Background: Anemia is a risk factor for death, adverse cardiovascular outcomes and poor quality of life in patients with chronic kidney disease (CKD). Erythropoietin Stimulating Agents (ESA) are commonly used to increase hemoglobin levels in this population. In observational studies, higher hemoglobin levels (around 11-13 g/dL) are associated with improved survival and quality of life compared to hemoglobin levels around 9-10 g/dL. A systematic review of randomized trials found that targeting higher hemoglobin levels with ESA causes an increased risk of adverse vascular outcomes. It is possible, but has never been formally tested in a randomized trial, that ESA dose rather than targeted hemoglobin concentration itself mediates the increased risk of adverse vascular outcomes. The Clinical Evaluation of the DOSe of Erythropoietins (C.E. DOSE) trial will assess the benefits and harms of a high versus a low fixed ESA dose for the management of anemia in patients with end stage kidney disease.

Methods/design: This is a randomized, prospective open label blinded end-point (PROBE) trial due to enrol 2204 hemodialysis patients in Italy. Patients will be randomized 1:1 to 4000 IU/week versus 18000 IU/week of intravenous epoietin alfa or beta, or any other ESA in equivalent doses. The dose will be adjusted only if hemoglobin levels fall outside the 9.5-12.5 g/dL range. The primary outcome will be a composite of all-cause mortality, non fatal stroke, non fatal myocardial infarction and hospitalization for cardiovascular causes. Quality of life and costs will also be assessed.

Discussion: The C.E.DOSE study will help inform the optimal therapeutic strategy for the management of anemia of hemodialysis patients, improving clinical outcomes, quality of life and costs, by ascertaining the potential benefits and harms of different fixed ESA doses.

Trial registration: Clinicaltrials.gov NCT00827021.

Figures

Figure 1
Figure 1
Flow chart describing the selection, randomization and follow-up process of the Clinical Evaluation of the Dose of Erythropoietins (C.E. DOSE) trial.
Figure 2
Figure 2
Summary of key practical aspects of the Clinical Evaluation of the DOSe of Erythropoietin (C.E.DOSE) trial.

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Source: PubMed

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