A randomized, masked, placebo-controlled study of darbepoetin alfa in preterm infants

Abstract

Background: A novel erythropoiesis stimulating agent (ESA), darbepoetin alfa (Darbe), increases hematocrit in anemic adults when administered every 1 to 3 weeks. Weekly Darbe dosing has not been evaluated in preterm infants. We hypothesized that infants would respond to Darbe by decreasing transfusion needs compared with placebo, with less-frequent dosing than erythropoietin (Epo).

Methods: Preterm infants 500 to 1250 g birth weight and ≤48 hours of age were randomized to Darbe (10 μg/kg, 1 time per week subcutaneously), Epo (400 U/kg, 3 times per week subcutaneously) or placebo (sham dosing) through 35 weeks' gestation. All received supplemental iron, folate, and vitamin E, and were transfused according to protocol. Transfusions (primary outcome), complete blood counts, absolute reticulocyte counts (ARCs), phlebotomy losses, and adverse events were recorded.

Results: A total of 102 infants (946 ± 196 g, 27.7 ± 1.8 weeks' gestation, 51 ± 25 hours of age at first dose) were enrolled. Infants in the Darbe and Epo groups received significantly fewer transfusions (P = .015) and were exposed to fewer donors (P = .044) than the placebo group (Darbe: 1.2 ± 2.4 transfusions and 0.7 ± 1.2 donors per infant; Epo: 1.2 ± 1.6 transfusions and 0.8 ± 1.0 donors per infant; placebo: 2.4 ± 2.9 transfusions and 1.2 ± 1.3 donors per infant). Hematocrit and ARC were higher in the Darbe and Epo groups compared with placebo (P = .001, Darbe and Epo versus placebo for both hematocrit and ARCs). Morbidities were similar among groups, including the incidence of retinopathy of prematurity.

Conclusions: Infants receiving Darbe or Epo received fewer transfusions and fewer donor exposures, and fewer injections were given to Darbe recipients. Darbepoetin and Epo successfully serve as adjuncts to transfusions in maintaining red cell mass in preterm infants.

Keywords: anemia; erythropoietin; prematurity; transfusions.

FIGURE 1

Hematologic indices during the study curves were generated for ARC (A), hematocrit (B), absolute neutrophil count (C), and platelet count (D) using nonparametric Lowess (locally weighted scatterplot smoothing) regression smoothers calculated for each treatment arm separately. Data were fit with linear mixed models where each subject was allowed a separate quadratic trajectory (random coefficient regression), with interaction allowed between time and treatment arm, and P values reported are for the fixed effects contrasts comparing groups. A, Changes in ARC. Infants treated with Darbe (dotted line) or Epo (hatched line) had significantly higher ARCs than infants in the placebo group (solid line; P = .001). Similarly, hematocrits were significantly greater in the ESA groups compared with placebo (P = .001; B). There were no differences in absolute neutrophil counts (C) or platelet counts (D) among groups during the study.