title: Low versus high dose erythropoiesis-stimulating agents in hemodialysis patients with anemia: A randomized clinical trial.
abstract: The increased risks of death and adverse events with erythropoiesis-stimulating agent (ESA) therapy targeting a higher hemoglobin level are established. It is uncertain whether the adverse effects of ESA therapy are related to dose and are mitigated when a fixed low ESA dose is used. We conducted a multicenter, prospective randomized open-label, blinded-endpoint (PROBE) trial to evaluate fixed low versus high dose ESA therapy on patient outcomes. We intended to recruit 2104 hemodialysis patients >18 years with anemia or receiving ESA treated at dialysis clinics in Italy. The intervention was fixed low (4000 IU epoetin alfa equivalent weekly) or high (18,000 IU epoetin alfa equivalent weekly) dose ESA for 12 months. Primary outcomes were serum transferrin, ferritin, albumin, C-reactive protein and ESA dose. Secondary outcomes were the composite of death or cardiovascular event, all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, cardiovascular hospitalization, and quality of life. Study recruitment was terminated after inclusion of 656 participants with convergence of ESA dose between groups during follow up. Fixed low dose ESA had uncertain effects on serum ferritin (delta of delta (DD) 3.9 ng/ml, 95% CI -85.0 to 92.8), transferrin (9.2 mg/dl, -6.3 to 24.8), transferrin saturation (3.7%, -5.0 to 12.3), serum albumin (-0.03 g/dl, -0.2 to 0.1), or C-reactive protein (-0.6 mg/l, -3.3 to 2.1). In addition, fixed dose therapy had inconclusive effects on the composite endpoint of mortality and cardiovascular events (hazard ratio [HR] 0.95, 95% CI 0.66 to 1.37), death (0.98, 0.64 to 1.52), nonfatal myocardial infarction (0.52, 0.18 to 1.52), nonfatal stroke (no events), hospital admission for cardiovascular causes (0.93, 0.50 to 1.72) or health-related quality of life. A fixed low ESA dose in hemodialysis patients has uncertain effects on serum parameters, mortality, cardiovascular events, and quality of life. Hemoglobin targets may be so entrenched in nephrology practice that a trial of ESA dose is no longer possible.
authors.affiliation: Sydney School of Public Health, Edward Ford Building, The University of Sydney, New South Wales, Australia.|Diaverum Renal Services Group, Lund, Sweden.
authors.forename: Valeria
authors.initials: V
authors.lastname: Saglimbene
authors.affiliation: Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand.
authors.forename: Suetonia C
authors.identifier: http://orcid.org/0000-0001-7765-5871
authors.initials: SC
authors.lastname: Palmer
authors.affiliation: Sydney School of Public Health, Edward Ford Building, The University of Sydney, New South Wales, Australia.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Craig
authors.affiliation: Diaverum Renal Services Group, Lund, Sweden.|Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
authors.forename: Marinella
authors.initials: M
authors.lastname: Ruospo
authors.affiliation: Center for Outcomes Research and clinical Epidemiology (CORESEARCH), Pescara, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Nicolucci
authors.affiliation: Cumming School of Medicine, Health Sciences Centre, University of Calgary, Foothills Campus, Calgary, Alberta, Canada.
authors.forename: Marcello
authors.initials: M
authors.lastname: Tonelli
authors.affiliation: Department of Renal Medicine, Division of Medicine, University of Queensland at the Princess Alexandra Hospital, Woolloongabba, Queensland, Australia.|Translational Research Institute, University of Queensland, Woolloongabba, Queensland, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Johnson
authors.affiliation: Center for Outcomes Research and clinical Epidemiology (CORESEARCH), Pescara, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lucisano
authors.affiliation: Sydney School of Public Health, Edward Ford Building, The University of Sydney, New South Wales, Australia.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Williams
authors.affiliation: Quintiles srl, Milan, Italy.
authors.forename: Miriam
authors.initials: M
authors.lastname: Valentini
authors.affiliation: ASL, Lanciano Vasto, Chieti, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: D'Alonzo
authors.affiliation: Global Medical Biogen Idec, Cambridge, Massachusetts, United States of America.
authors.forename: Fabio
authors.initials: F
authors.lastname: Pellegrini
authors.affiliation: Department of Nephrology and Dialysis, Ospedale " A. Perrino", Brindisi, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Strippoli
authors.affiliation: Department of Nephrology and Dialysis, Ospedale Maggiore di Chieri, Chieri, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Salomone
authors.affiliation: Department of Nephrology and Dialysis, Policlinico S. Orsola-Malpighi, Bologna, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Santoro
authors.affiliation: Department of Nephrology and Dialysis, Ospedale Maggiore di Chieri, Chieri, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Maffei
authors.affiliation: Diaverum Renal Services Group, Lund, Sweden.
authors.forename: Jörgen
authors.initials: J
authors.lastname: Hegbrant
authors.affiliation: Mario Negri Institute for Pharmacological Research, Milano, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Tognoni
authors.affiliation: Sydney School of Public Health, Edward Ford Building, The University of Sydney, New South Wales, Australia.|Diaverum Renal Services Group, Lund, Sweden.|Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
authors.forename: Giovanni F M
authors.identifier: http://orcid.org/0000-0002-6936-0616
authors.initials: GF
authors.lastname: Strippoli
mesh_terms: D000368:Aged; D000740:Anemia / Q000097:blood / Q000188:drug therapy / Q000209:etiology / Q000401:mortality; D002318:Cardiovascular Diseases / Q000097:blood / Q000139:chemically induced / Q000401:mortality; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006397:Hematinics / Q000008:administration & dosage* / Q000009:adverse effects; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D011788:Quality of Life; D006435:Renal Dialysis / Q000009:adverse effects*
chemical_list: D006397:Hematinics; D006454:Hemoglobins