A Randomized Trial of Strategies Using Darbepoetin Alfa To Avoid Transfusions in CKD

Abstract

Background: Exposure to high doses or a high cumulative dose of erythropoiesis-stimulating agents (ESAs) may contribute to cardiovascular events in patients with CKD and anemia. Whether using a low fixed ESA dose versus dosing based on a hemoglobin-based, titration-dose algorithm in such patients might reduce risks associated with high ESA doses and decrease the cumulative exposure-while reducing the need for red blood cell transfusions-is unknown.

Methods: In this phase-3, randomized trial involving 756 adults with stage-3 to -5 CKD and anemia, we evaluated incidence of red blood cell transfusions for participants randomized to receive darbepoetin given as a fixed dose (0.45 µg/kg every 4 weeks) versus administered according to a hemoglobin-based, titration-dose algorithm, for up to 2 years. Participants received transfusions as deemed necessary by the treating physician.

Results: There were 379 patients randomized to the fixed-dose group, and 377 to the titration-dose group. The percentage of participants transfused did not differ (24.1% and 24.4% for the fixed-dose and titration-dose group, respectively), with similar time to first transfusion. The titration-dose group achieved significantly higher median hemoglobin (9.9 g/dl) compared with the fixed-dose group (9.4 g/dl). The fixed-dose group had a significantly lower median cumulative dose of darbepoetin (median monthly dose of 30.9 µg) compared with the titration-dose group (53.6 µg median monthly dose). The FD and TD group received a median (Q1, Q3) cumulative dose per 4 weeks of darbepoetin of 30.9 (21.8, 40.0) µg and 53.6 (31.1, 89.9) µg, respectively; the median of the difference between treatment groups was -22.1 (95% CI, -26.1 to -18.1) µg.

Conclusions: These findings indicate no evidence of difference in incidence of red blood cell transfusion for a titration-dose strategy versus a fixed-dose strategy for darbepoetin. This suggests that a low fixed dose of darbepoetin may be used as an alternative to a dose-titration approach to minimize transfusions, with less cumulative dosing.

Keywords: blood transfusion; chronic kidney disease; darbepoetin; dosing strategy.

Copyright © 2021 by the American Society of Nephrology.

Figures

Figure 1.

Kaplan–Meier plot of time to first RBC transfusion shows similarity between FD and TD group. The hazard ratio and 95% CI estimates are obtained from the Cox proportional hazards model. Stratification factors are RBC transfusion received within 12 months before randomization, yes versus no; and site practice setting, nephrology versus non-nephrology.

Figure 2.

Histogram of cumulative dose of darbepoetin during the study shows the titration-dose (TD) group receiving higher cumulative dose than the maximum seen in fixed-dose (FD) group. The cumulative dose is the sum of all darbepoetin doses received from all study visits. The median cumulative doses in the TD arm and FD arm are 740.0 and 480.0 μg, respectively. Hb, hemoglobin.

Figure 3.

Hemoglobin concentration at each study visit (median and interquartile range) while receiving investigational product is numerically higher in TD group compared to FD group.