A Randomized Trial Of Strategies Using Darbepoetin Alfa To Avoid Transfusions In Ckd

Significance Statement Erythropoietin-stimulating agents (ESAs) have historically been titrated to achieve a predefined hemoglobin concentration when treating patients with CKD and anemia. It is unknown whether an alternative dosing strategy might reduce the need for red blood cell transfusions, mitigate potential factors contributing to increased cardiovascular risk associated with use of high ESA doses, and decrease cumulative dose exposure. This randomized trial was designed to describe the benefits and potential risks of a new treatment strategy, using a low fixed dose of darbepoetin alfa compared with a hemoglobin-based, titration-dose algorithm. The authors show that use of a low fixed dose of darbepoetin may be an alternative to a dose-titration approach to minimize red blood cell transfusions in patients with CKD and anemia, and may result in a smaller cumulative dose.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 mu g/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 mu g) compared with the titration-dose group (53.6 mu g 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) mu g and 53.6 (31.1, 89.9) mu g, respectively; the median of the difference between treatment groups was -22.1 (95% CI, -26.1 to -18.1) mu g. 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.