Effect of administering recombinant erythropoietin to women with postpartum anemia: a meta-analysis.

OBJECTIVES: Recombinant erythropoietin (rEpo) has been administered to women with postpartum anemia in an attempt to accelerate their increase in hemoglobin concentration and reduce postpartum transfusions. However, it is not clear whether such an approach can be supported by evidence and should be generally recommended. STUDY DESIGN AND METHODS: Medical and scientific literature from January 1990 to December 2002 was searched and studies that reported the administration of rEpo to women with postpartum anemia were evaluated. RESULTS: Eight evaluated studies reported an aggregate of 480 women; 300 rEpo recipients and 180 controls. Significant diversity in design was observed in rEpo dose, route of rEpo administration, iron supplementation, and baseline hemoglobin. No significant safety concerns were reported. In all five studies where it was reported, 4 to 7 days after beginning treatment, greater increases in hemoglobin concentration were observed among the rEpo recipients than among the controls. However, heterogeneity of results (Q-test statistic, p<0.01) indicated that it was not appropriate to apply summary statistics. The effect of rEpo on postpartum transfusion rate was not measurable by summary statistics because of the limited number of transfusions given (no transfusions among the 300 rEpo recipients vs two transfusions among the 180 controls). CONCLUSION: Administration of rEpo to women with postpartum anemia appears to be safe, and is associated with a trend toward a faster increase in hemoglobin concentration. However, its efficacy in terms of diminishing postpartum transfusions is unproven.

Effect of beginning recombinant erythropoietin treatment within the first week of life, among very-low-birth-weight neonates, on "early" and "late" erythrocyte transfusions: a meta-analysis.

OBJECTIVES: Erythrocyte transfusions to neonates can be categorized as "early" if given during the first 3 weeks of life and "late" if given thereafter. We used a meta-analysis to determine whether recombinant erythropoietin (rEpo) administration to very-low-birth-weight (VLBW, <1500 g) neonates, beginning in the first week of life, reduces either "early" or "late" transfusions. STUDY DESIGN AND METHODS: Studies that used a randomized, placebo-controlled, double-masked design were deemed acceptable. We identified 12 acceptable, relevant, clinical trials. Additional data not provided in the publications were obtained from two of the authors. RESULTS: The acceptable studies involved an aggregate of 561 rEpo and 529 placebo recipients. If rEpo was begun in the first week of life, the summary odds ratio (OR) for receiving any transfusion ("early" or "late") was 0.52, 95% confidence interval (CI): 0.34 to 0.79 (p=0.001). The OR for receiving an "early" transfusion was 0.54 (95% CI: 0.25 to 1.15; p=0.055), and the OR for receiving a "late" transfusion was 0.56 (95% CI: 0.37 to 0.83; p=0.036). Heterogeneity among studies was too great to estimate the effect of rEpo on the number of transfusions received or the volume of blood transfused (p<0.001 for the Q-test statistic). Subgroup analysis suggested that when rEpo is begun in the first week of life, neonates 1000 to 1500 g and >29 weeks are more likely to completely avoid transfusion than are extremely low-birth-weight (ELBW, <1000 g) neonates. No dose-response relationship was apparent between rEpo dose or iron dose and transfusion. No difference was apparent depending on whether the rEpo was given subcutaneously vs intravenously. CONCLUSION: If rEpo is begun in the first week of life, a moderate reduction can be expected (p=0.001) in the proportion of VLBW neonates transfused. Reduction is less significant in "early" transfusion (p=0.055) than in "late" transfusion (p=0.036). Such treatment is not likely to eliminate transfusions among ELBW neonates completely.

Evidence that the granulocyte colony-stimulating factor (G-CSF) receptor plays a role in the pharmacokinetics of G-CSF and PegG-CSF using a G-CSF-R KO model.

The covalent attachment of polyethylene glycol to filgrastim results in a new molecule pegfilgrastim, which has a significantly longer half-life than filgrastim. It is likely that the clearance of both filgrastim and pegfilgrastim involves granulocyte colony simulating factor (G-CSF) receptor binding, but the pharmacokinetics of these drugs have not been compared in mice with and without a functional G-CSF receptor. We sought to clarify the role of receptor-mediated clearance of filgrastim and pegfilgrastim using wild-type (WT) mice or mice with a non-functional G-CSF-R (knockout, KO). We administered single doses of filgrastim or pegfilgrastim (10 or 100 microg kg(-1)) intravenously to WT and KO mice. Plasma levels of protein were measured by enzyme-linked immunosorbent assay (ELISA) at preset time points, and AUC, MRT, CL, V(d), and T(1/2) were calculated. When compared with WT mice, the G-CSF-R KO mice had significantly greater AUC, longer MRT, longer T(1/2), and lower clearance. This was the case whether animals received 10 or 100 microg kg(-1) and whether they received filgrastim or pegfilgrastim. The volume of protein distribution was identical among WT and KO mice. However, the V(d) was larger after pegfilgrastim dosing than after filgrastim dosing. In both WT and KO mice, increasing the dose of figrastim or pegfilgrastim resulted in a proportional increase in the AUC. A functional G-CSF-R is an important mechanism in the plasma clearance of both filgrastim and pegfilgrastim.