Comparison of Iron Dosing Strategies in Patients Undergoing Long-Term Hemodialysis: A Randomized Controlled Trial

Abstract

Background and objectives: Whether iron supplementation in patients on hemodialysis could be delivered by less frequent but higher single doses compared with the currently more common higher-frequency schedules of lower single iron doses is unknown.

Design, setting, participants, & measurements: We carried out an open-label, randomized, controlled noninferiority trial over 40 weeks in patients on prevalent hemodialysis (n=142). We administered in total 2 g iron as 100 mg iron sucrose biweekly in a continuous (20 × 100 mg) fashion or 500 mg ferric carboxymaltose every 10 weeks in a periodic (4 × 500 mg) fashion. The primary end point was the change in hemoglobin at week 40 from baseline with a noninferiority margin of -0.8 g/dl. Secondary end points were changes in ferritin, transferrin, transferrin saturation, and erythropoiesis-stimulating agent use.

Results: In total, 108 patients completed the study. At 40 weeks, hemoglobin changed by -0.27 g/dl (95% confidence interval, -0.64 to 0.09) in the iron sucrose arm and by -0.74 g/dl (95% confidence interval, -1.1 to -0.39) in the ferric carboxymaltose arm compared with baseline. Noninferiority was not established in the per-protocol population as hemoglobin changes compared with baseline differed by -0.47 g/dl (95% confidence interval, -0.95 to 0.01) in the ferric carboxymaltose arm compared with the iron sucrose arm. Proportional changes from baseline to week 40 differed by -31% (98.3% confidence interval, -52 to -0.1) for ferritin, by 1% (98.3% confidence interval, -7 to 10) for transferrin, and by -27% (98.3% confidence interval, -39 to -13) for transferrin saturation in the ferric carboxymaltose arm compared with the iron sucrose arm. Erythropoiesis-stimulating agent dosing did not differ between groups. The overall number of adverse events was similar; however, more infections were observed in the iron sucrose arm.

Conclusions: An equal cumulative dose of ferric carboxymaltose administered less frequently did not meet noninferiority for maintaining hemoglobin levels compared with iron sucrose administered more frequently.

Clinical trial registry name and registration number: Comparison Study of Two Iron Compounds for Treatment of Anemia in Hemodialysis Patients (COPEFER), NCT02198495.

Keywords: anemia; clinical trial; dialysis; end stage kidney disease; ferritins; hemodialysis; iron.

Copyright © 2021 by the American Society of Nephrology.

Figures

Graphical abstract

Figure 1.

Patient flow. *One patient who did not consent was accidentally randomized due to a confusion of names.

Figure 2.

Timeline of iron administrations according to the study arm. Bars indicate iron administrations at the respective points in time (light gray bars: 100 mg iron sucrose; dark gray bars: 500 mg ferric carboxymaltose). Large arrows indicate study appointments with assessment of hemoglobin, ferritin, transferrin, transferrin saturation, and safety parameters (platelets, leukocytes, C-reactive protein, aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transpeptidase, and inorganic phosphate). Small arrows indicate intermittent hemoglobin measurements.

Figure 3.

Hemoglobin and serum markers of iron status at study appointments according to study arm. (A) Hemoglobin concentration during the 40 weeks of periodic ferric carboxymaltose or continuous iron sucrose therapy. (B) Ferritin serum concentration during the 40 weeks of periodic ferric carboxymaltose or continuous iron sucrose therapy. (C) Serum transferrin during the 40 weeks of periodic ferric carboxymaltose or continuous iron sucrose therapy. (D) Serum transferrin saturation during the 40 weeks of periodic ferric carboxymaltose or continuous iron sucrose therapy. Boxes extend from the first quartile to the third quartile. The lower (upper) whisker extends to the minimum (maximum) within 1.5 interquartile ranges below the first (above the third) quartile. Observations exceeding 1.5 interquartile ranges from the box are indicated by single-plot symbols. TSAT, transferrin saturation.