Low versus high dose erythropoiesis-stimulating agents in hemodialysis patients with anemia: A randomized clinical trial

PLoS One. 2017 Mar 1;12(3):e0172735. doi: 10.1371/journal.pone.0172735. eCollection 2017.

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.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Anemia* / blood
  • Anemia* / drug therapy
  • Anemia* / etiology
  • Anemia* / mortality
  • Cardiovascular Diseases / blood
  • Cardiovascular Diseases / chemically induced
  • Cardiovascular Diseases / mortality
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Follow-Up Studies
  • Hematinics / administration & dosage*
  • Hematinics / adverse effects
  • Hemoglobins / metabolism
  • Humans
  • Male
  • Middle Aged
  • Quality of Life*
  • Renal Dialysis / adverse effects*

Substances

  • Hematinics
  • Hemoglobins

Grants and funding

The study received funding from the Italian Medicines Agency (Agenzia Italiana del Farmaco [AIFA]: grant number FARM6X822T). This trial was funded by the Italian Medicines Agency (Agenzia Italiana del Farmaco [AIFA]). The funder required the inclusion of specified outcomes during trial conduct, but played no role in finalizing the study design, data analysis, data interpretation, or report writing. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. One or more of the authors are employed by a commercial company (Diaverum Renal Services Group: VS, MR, JH, GFMS, Quintiles srl: MV, Global Medical Biogen Idec: FP). These funding organizations did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors' salaries. The funders provided support in the form of salaries for authors VS, MR, JH, GS, MV, FP but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.