Low versus high dose erythropoiesisstimulating agents in hemodialysis patients with anemia: A randomized clinical trial

Valeria Saglimbene, Suetonia Palmer, Jonathan Craig, Marinella Ruospo, Antonio Nicolucci, Marcello Tonelli, David Johnson, Giuseppe Lucisano, Gabrielle Williams, Miriam Valentini, Daniela D'Alonzo, Fabio Pellegrini, Paolo Strippoli, Mario Salomone, Antonio Santoro, Stefano Maffei, Jorgen Hegbrant, Gianni Tognoni, Giovanni Strippoli

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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.

Original languageEnglish
Article numberE0172735
Number of pages18
JournalPLoS One
Volume12
Issue number3
DOIs
Publication statusPublished - 2017

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    Saglimbene, V., Palmer, S., Craig, J., Ruospo, M., Nicolucci, A., Tonelli, M., Johnson, D., Lucisano, G., Williams, G., Valentini, M., D'Alonzo, D., Pellegrini, F., Strippoli, P., Salomone, M., Santoro, A., Maffei, S., Hegbrant, J., Tognoni, G., & Strippoli, G. (2017). Low versus high dose erythropoiesisstimulating agents in hemodialysis patients with anemia: A randomized clinical trial. PLoS One, 12(3), [E0172735]. https://doi.org/10.1371/journal.pone.0172735