Darbepoetin alfa: a new approach to the treatment of chemotherapy-induced anaemia

Chemotherapy-induced anaemia has important consequences on the quality of life and social function of cancer patients. The finding of erythropoietin (EPO) deficiency in these patients led to the therapeutic development of erythropoietic proteins. Darbepoetin alfa (Aranesp), Amgen Inc, Thousand Oaks, California), a new erythropoietic growth factor, has eight more sialic acids than epoetin alfa. The increased sialic acid content confers a three-fold longer half-life and allows the drug to be administered less frequently than epoetin alfa. Darbepoetin alfa affects the same early haematopoietic cells as epoetin alfa and the endogenous hormone EPO. Preclinical pharmacokinetic studies suggest that the intrinsic pharmacological properties of darbepoetin alfa are comparable to those of epoetin alfa, but that the increased sialic acid content allows for less-frequent administration with superior performance. Darbepoetin alfa has been shown to have safe clinical efficacy in a variety of tumour settings and with several types of chemotherapy.     

Darbepoetin alfa: a new therapy for the management of anaemia associated with chronic kidney disease

Darbepoetin alfa (Aranesp^®, Amgen, Inc., Thousand Oaks, California) is a new erythropoietic protein that corrects anaemia associated with chronic kidney disease (CKD) in the majority of patients. Darbepoetin alfa contains five N-linked carbohydrate chains compared with three in recombinant human erythropoietin (rHuEPO). The two additional sialic acid-containing carbohydrate chains prolong the serum half-life of darbepoetin alfa, resulting in greater biological activity and a reduced dosing frequency compared with rHuEPO. Clinical studies in patients with CKD have demonstrated that darbepoetin alfa is effective in correcting anaemia in rHuEPO-naive patients and in patients who have been converted from rHuEPO therapy. Darbepoetin alfa provides long-term maintenance of haemoglobin levels when administered once weekly or once every other week, with the possibility of once-monthly dosing in some patients. Darbepoetin alfa is well tolerated and has a safety profile similar to that of rHuEPO. Owing to its half-life being three times longer than rHuEPO, darbepoetin alfa can be administered at an extended dosing interval, without compromising efficacy. Lessfrequent dosing has potential benefits for both patients with CKD and healthcare providers. These benefits include reduced visits to the clinic, fewer injections and a reduced demand on staff and treatment facilities.     

Comparison of effects of darbepoetin alfa and epoetin alfa on serum endothelin level and blood pressure

It is well known that epoetin alfa increases serum endothelin (ET)-1 and blood pressure. No data are available, however, on the effects of darbepoetin alfa on serum ET-1 and blood pressure. This study was conducted to compare the effects of darbepoetin alfa and epoetin alfa on serum ET-1 and blood pressure in patients on hemodialysis (HD). A total of 42 patients on HD were included in the study. Serum samples for measuring levels of ET-1 were taken 30 min after administration of epoetin alfa. After blood samples had been taken from all patients, epoetin alfa was changed to darbepoetin alfa. Three months after the start of darbepoetin alfa treatment, blood samples were taken to measure the same parameters. Mean arterial blood pressure was measured before recombinant human erythropoietin (EPO) administration and 30 min after EPO administration while patients were taking epoetin alfa or darbepoetin alfa. Injection of epoetin alfa or darbepoetin alfa significantly increased serum ET-1 levels compared with levels in those patients who were not on EPO therapy (P < .05). When the effects of epoetin alfa on serum ET-1 level were compared with those of darbepoetin alfa, the 2 types of EPO were found to increase serum ET-1 levels similarly (P > .05). Administration of epoetin alfa or darbepoetin alfa increased systolic and diastolic blood pressures significantly over values in the control group (P < .05). Serum systolic and diastolic blood pressures increased similarly after injection of epoetin alfa or darbepoetin alfa. Administration of darbepoetin alfa increased blood pressure in patients on HD in a way that was positively correlated with enhanced ET-1 release; a similar correlation was noted with epoetin alfa.     

A multicenter retrospective cohort study of practice patterns and clinical outcomes of the use of darbepoetin alfa and epoetin alfa for chemotherapy-induced anemia

BACKGROUND: Darbepoetin alfa is the second erythropoietic protein to be approved for the treatment of chemotherapy-induced anemia (CIA). In the clinical setting, darbepoetin alfa can be administered less frequently than epoetin alfa with similar efficacy. Practice patterns and outcomes associated with the use of darbepoetin alfa and epoetin alfa in the clinical setting have not been reported. OBJECTIVE: This study compared practice patterns and clinical outcomes of the use of darbepoetin alfa and epoetin alfa for CIA at oncology practices in the United States. METHODS: This was a multicenter retrospective cohort study. Data were abstracted from the medical charts of consecutive patients who began darbepoetin alfa treatment between August 1 and October 4, 2002, or epoetin alfa treatment between April 1 and July 31, 2002, and were receiving concurrent chemotherapy. These data were used to determine the initial dose and dosing schedule, dose changes, and changes in hemoglobin concentrations after 4, 8, and 12 weeks of treatment, adjusted for red blood cell (RBC) transfusions, and the incidence of RBC transfusions over time. To minimize potential bias, the study protocol defined specific end points and prespecified analytic techniques for assessing clinical outcomes with the 2 agents. RESULTS: The records of 1391 patients from 16 community and hospital outpatient oncology clinics were abstracted. Of these, 1293 patients (93.0%) received only 1 erythropoietic agent (darbepoetin alfa, 735 [56.8%]; epoetin alfa, 558 [43.2%]); the remainder received both agents. In the patients who received darbepoetin alfa, most (553 [75.2%]) received an initial dosage of 200 microg q2wk. A similar proportion (414 [74.2%]) received epoetin alfa at an initial dosage of 40,000 U qwk. As these were the regimens for the majority of patients whose records were abstracted, the results reported here are for these patients. The dose was increased in 63 darbepoetin alfa recipients (11.4%) and 58 epoetin alfa recipients (14.0%) at a median of 7 weeks. After 12 weeks, the 2 groups had an identical mean imputed change from baseline in hemoglobin concentration (1.0 g/dL), and the incidence of RBC transfusions during treatment was also similar between groups (darbepoetin alfa, 44553 [8.0%]; epoetin alfa, 39414 [9.4%]). CONCLUSIONS: Darbepoetin alfa 200 microg q2wk was used as a standard regimen for CIA at the 16 US oncology practices participating in this study. It appeared to be as effective as epoetin alfa 40,000 U qwk, with a reduced frequency of dosing.     

Darbepoetin alfa: a new therapy for the management of anaemia associated with chronic kidney disease

Darbepoetin alfa (Aranesp, Amgen, Inc., Thousand Oaks, California) is a new erythropoietic protein that corrects anaemia associated with chronic kidney disease (CKD) in the majority of patients. Darbepoetin alfa contains five N-linked carbohydrate chains compared with three in recombinant human erythropoietin (rHuEPO). The two additional sialic acid-containing carbohydrate chains prolong the serum half-life of darbepoetin alfa, resulting in greater biological activity and a reduced dosing frequency compared with rHuEPO. Clinical studies in patients with CKD have demonstrated that darbepoetin alfa is effective in correcting anaemia in rHuEPO-naive patients and in patients who have been converted from rHuEPO therapy. Darbepoetin alfa provides long-term maintenance of haemoglobin levels when administered once weekly or once every other week, with the possibility of once-monthly dosing in some patients. Darbepoetin alfa is well tolerated and has a safety profile similar to that of rHuEPO. Owing to its half-life being three times longer than rHuEPO, darbepoetin alfa can be administered at an extended dosing interval, without compromising efficacy. Lessfrequent dosing has potential benefits for both patients with CKD and healthcare providers. These benefits include reduced visits to the clinic, fewer injections and a reduced demand on staff and treatment facilities.     

Speed of haemoglobin response in patients with cancer: a review of the erythropoietic proteins

Background Patients with cancer-related anaemia generally have a poor prognosis. Evidence suggests that an effective erythropoietic protein (epoetin)-mediated haemoglobin (Hb) response provides marked improvement in quality of life (QoL). An early Hb response to erythropoietic protein therapy in these patients would appear ideal but few studies have compared the speed of response to different erythropoietic proteins, or the potential benefits associated with an early Hb response. Results and discussion The pharmacokinetic/pharmacodynamic profiles of commercially available erythropoietic proteins are reviewed along with available clinical data to examine Hb response and associated clinical outcomes for each of these agents. Randomised, head-to-head trials comparing epoetin alfa and darbepoetin alfa suggest that patients administered with epoetin alfa achieve a satisfactory Hb response significantly earlier than those given darbepoetin alfa, and with consistently lower monthly transfusion rates. Non-comparative studies support this, suggesting also that epoetin beta may provide a relatively faster Hb response in a greater number of patients than either epoetin alfa or darbepoetin alfa, irrespective of malignancy or chemotherapy type. Moreover, studies suggest consistently that a ‘front-loading’ dosing regimen with epoetin alfa does not convey improved speed of Hb response over epoetin beta administered according to current clinical practice guidelines. Conclusions Given the poor prognosis of anaemic patients with cancer, the use of an agent which provides clinical benefits quickly but with minimal thromboembolic risk, should be considered an essential component of anaemia management in these patients. However, more head-to-head studies are required to confirm the relative efficacy of currently available erythropoietic proteins.     

Epoetin alfa and darbepoetin alfa for the treatment of chemotherapy-related anemia in cancer patients in Sweden: Comparative analysis of drug utilization, costs, and hematologic response

A retrospective chart review was performed at 3 Swedish hospitals to evaluate the utilization, outcomes, and cost of using epoetin alfa or darbepoetin alfa to treat cancer patients with chemotherapy-related anemia. Data on dosage, duration of treatment, hematologic response, red blood cell transfusions, and healthcare resource consumption were collected and analyzed at various time points following the initiation of drug therapy. A significantly faster hematologic response and increase in hemoglobin were observed in patients treated with epoetin alfa. Dosages used in clinical practice appeared to be lower than those recommended by Swedish treatment guidelines. There were no significant differences in resource utilization or healthcare costs between the 2 treatment groups. By day 112, the mean treatment cost per patient, in Swedish kronors (SEK), was SEK74,701 (~US$9800 or E8300) with epoetin alfa and SEK85,285 (~US$11,000 or E9500) with darbepoetin alfa. Drug acquisition and administration accounted for 81 % and 67% of the total cost of epoetin alfa and darbepoetin alfa therapy, respectively; the remainder of the total cost was for hospitalization and transfusions.     

Darbepoetin alfa in lung cancer patients on chemotherapy: a retrospective comparison of outcomes in patients with mild versus moderate-to-severe anaemia at baseline

Goals Currently, there is some debate concerning the haemoglobin level at which treatment of anaemia with erythropoiesis-stimulating agents should be initiated in cancer patients on chemotherapy. We report several analyses of data from a phase III trial of darbepoetin alfa versus placebo, comparing outcomes for patients with mild and moderate-to-severe anaemia.Patients and methods Data were obtained from a phase III trial of darbepoetin alfa versus placebo in anaemic patients with lung cancer receiving chemotherapy (n=314). Outcomes were compared for patients with baseline haemoglobin 10–11 g/dl and <10 g/dl.Results Darbepoetin alfa significantly reduced transfusions compared with placebo, irrespective of haemoglobin level at treatment initiation. For patients with baseline haemoglobin <10 g/dl, 31% and 59% of those receiving darbepoetin alfa and placebo, respectively, required a transfusion from week 5 to the end of the treatment phase (P<0.038). For patients with baseline haemoglobin 10 g/dl, the proportions were 15% and 41%, respectively (P<0.001). Darbepoetin alfa also improved fatigue compared with placebo in both haemoglobin categories.Conclusions These findings show that initiating treatment at haemoglobin levels both <10 g/dl and 10–11 g/dl results in substantial clinical benefits, supporting the use of erythropoietic therapy also in patients with mild anaemia.J. Vansteenkiste is the beneficiary of the Amgen Fund in Supportive Cancer Care at the Catholic University, Leuven, Belgium.This work was supported by Amgen Inc., Thousand Oaks, California, USA     

The effectiveness and tolerability of epoetin alfa in patients with multiple myeloma refractory to chemotherapy

Anemia is a frequent complication of multiple myeloma, becoming chronic in patients who are resistant to chemotherapy. This randomized, parallel, controlled multicenter study (71 patients receiving concomitant chemotherapy) evaluated the efficacy and safety of epoetin alfa in improving anemia and eliminating the need for transfusions in multiple myeloma patients refractory to conventional first- or second-line chemotherapy. Forty patients were treated with subcutaneous epoetin alfa (150 IU/kg per dose, increasing to 300 IU/kg per dose, every 3 weeks) for 6 months, and 31 entered a control group. The epoetin alfa group had a significantly (P≤0.001) greater percentage of patients (75% vs. 21%) with increases in hemoglobin levels and/or reduced transfusion requirements. In 44 non pre-transfused patients (20 controls, 24 in the epoetin alfa group), the mean increase in hemoglobin was significantly (P≤0.0001) greater in the epoetin alfa group (+2.1 vs. −0.2 g/dl). Increases in hematocrit and red blood cells were also significantly (P≤0.0001) greater in epoetin alfa-treated patients, with corresponding reductions in transfusion requirement. In the 27 pre-transfused patients (11 controls, 16 in the epoetin alfa group), there was a trend towards reduced transfusional need in epoetin alfa-treated patients. Thus, in patients with multiple myeloma refractory to chemotherapy epoetin alfa is a well-tolerated treatment which improves anemia in non pre-transfused patients and appears to reduce transfusion need in those previously transfused.     

Role of oral versus IV iron supplementation in the erythropoietic response to rHuEPO: a randomized, placebo-controlled trial

BACKGROUND: Preoperative treatment with rHuEPO (epoetin alfa: EPREX, Janssen-Cilag; or PROCRIT, Ortho Biotech) in conjunction with iron supplementation increases the erythropoietic response in elective orthopedic surgery patients, but it is not known whether the magnitude of this response is dependent on the route of iron administration. STUDY DESIGN and METHODS: Non-iron-deficient patients undergoing elective orthopedic surgery (N = 110) with baseline Hb > or =10 to < or =13 g per dL were randomly assigned to receive either epoetin alfa (600 IU/kg) plus IV iron (n = 29) or oral iron (n = 29) or placebo plus IV iron (n = 25) or oral iron (n = 27) in this 14-day study. RBC production, Hb, Hct, reticulocytes, iron status, and adverse events were monitored throughout the study. RESULTS: Epoetin alfa treatment plus either oral or IV iron supplementation significantly increased total RBC production, Hb, Hct, and reticulocytes over the values seen with the respective placebo treatments (p = 0.0001). There were no differences between the epoetin alfa treatment groups. Placebo treatment plus oral or IV iron supplementation was not associated with increases in hematologic values. There were no differences in the incidence of adverse events among the treatment groups. CONCLUSION: There was a comparable erythropoietic response to epoetin alfa, irrespective of the route of iron administration. The route of iron administration, therefore, does not modulate the erythropoietic response to epoetin alfa in patients who are not iron deficient. Safety and convenience benefits may be gained by adopting oral iron supplementation in this patient subset.     

Response of erythropoiesis and iron metabolism to recombinant human erythropoietin in intensive care unit patients

OBJECTIVES: Critically ill patients often are anemic, which may impair oxygen delivery. Transfusion of red cells and supplementation with vitamins or iron are the usual therapeutic strategies, whereas only sporadic data are available on the use of epoetin alfa in these patients. We investigated endogenous erythropoietin (EPO) production and the response to epoetin alfa in anemic intensive care unit (ICU) patients. DESIGN: Randomized, open trial. SETTING: Multidisciplinary ICU in a single secondary care center. PATIENTS: Thirty-six critically ill patients admitted to the ICU who became anemic (hemoglobin concentration, <11.2 g/dL or <12.1 g/dL in case of cardiac disease) were randomized to one of three study groups. INTERVENTIONS: All patients received folic acid (1 mg) daily. The control group received no additional therapy, the iron group received 20 mg of iron saccharate intravenously (iv) daily for 14 days. The EPO group received iv iron and epoetin alfa (300 IU/kg) subcutaneously on days 1, 3, 5, 7, and 9. MEASUREMENTS AND MAIN RESULTS: Blood and reticulocyte counts were measured daily for 22 days. Serum EPO, C-reactive protein, serum transferrin receptor, and iron variables were measured on days 0, 2, 6, 10, and 21. Blood loss and red cell transfusions were recorded. Serum EPO concentrations were inappropriately low for the degree of anemia at baseline, with no difference between patients with and without renal failure. Exogenous administration of EPO increased EPO concentrations from 23+/-13 to a maximum of 166+/-98 units/L on day 10 (p < .05). Reticulocyte count increased exclusively in the EPO group from 56+/-33 x 10(9)/L to a maximum of 189+/-97 on day 13 (p < .05). Serum transferrin receptor rose only in the EPO group from 3.7+/-1.4 to 8.6+/-3.1 mg/L on day 10 (p < .05) and remained elevated on day 21, indicating an increase in erythropoiesis. Hemoglobin concentration and platelet count remained identical in the three study groups. CONCLUSION: Endogenous EPO concentrations are low in critically ill patients. The bone marrow of these patients is able to respond to exogenous epoetin alfa, as shown by elevated concentrations of reticulocytes and serum transferrin receptors.     

Darbepoetin alfa in the treatment of chemotherapy-induced anaemia

Background: Darbepoetin alfa is an erythropoiesis-stimulating agent (ESA), with a longer half-life than previous recombinant human erythropoietins. After its initial development for anaemia due to renal insufficiency, an extensive clinical trial program has defined its role in cancer patients. Objective/methods: Review of the initial registration studies, further development and recent progress, guidelines for use in clinical practice (EORTC, ASCO/ASH), and specific focus on recent safety concerns. Results: Darbepoetin alfa significantly decreases the number of red blood cell transfusions in patients with chemotherapy-induced anaemia, and has been shown to improve health-related quality of life in several studies. The prolonged half-life allows a prolonged dosing interval. Administration every three weeks, a suitable schedule to synchronise with day 1 of many chemotherapy regimens, is as efficient as the initially registered weekly administration. Recent data strongly suggest that the addition of intravenous iron improves haemoglobin response rates. The use of these agents in clinical practice has to be according to the guidelines. Recent safety data reported a negative effect on survival when ESAs were used to treat anaemia that was either not chemotherapy related, or when used to maintain high levels of haemoglobin and prevent anaemia. All of these studies were not in accordance with existing guidelines, while safety data from clinical trials using ESAs according to the guidelines remain reassuring. Conclusion: Darbepoetin alfa has a well defined place in the treatment of chemotherapy-induced anaemia, and is safe when used in line with existing guidelines. Recent safety signals on cancer outcomes in studies not in accordance with these guidelines illustrate the need for further research into the complex interaction between anaemia and tumour hypoxia in cancer patients.     

Epoetin alfa reduces blood transfusion requirements in patients with intertrochanteric fracture

Purpose

The purpose of this study is to identify the potential benefits or complications from the use of epoetin alfa in patients with intertrochanteric fracture.

Materials and Methods

Seventy-nine patients who sustained an intertrochanteric fracture were divided into 2 groups. One group received 10 daily doses of 20?000 IU of epoetin alfa beginning from the day of trauma, whereas the control group received placebo.

Results

We found a statistically significant difference in the required units of allogenic blood used between the 2 groups (P = .034). The group that received epoetin alfa also showed an elevation of hematocrit and hemoglobin values, which was statistically significant at the seventh postoperative day (P = .019 and .015, respectively) compared to the control group. No complications were evident during our study.

Conclusions

Patients with intertrochanteric fractures seem to benefit from the use of epoetin alfa because it is safe and reduces the need for blood transfusions.     

Epoetin alfa versus darbepoetin alfa in chemotherapy-related anemia

OBJECTIVE: To review and compare the data concerning the clinical activity of epoetin alfa versus darbepoetin alfa when administered to patients with cancer who are experiencing treatment-related anemia. DATA SOURCES: English-language publications from the MEDLINE database (1990-June 2005), published articles, and meeting abstracts were reviewed. STUDY SELECTION AND DATA EXTRACTION: Relevant data were extracted from published reports and abstracts on studies of humans with cancer who developed treatment-related anemia and were treated with epoetin alfa or darbepoetin alfa. DATA SYNTHESIS: Epoetin alfa and darbepoetin alfa are similar agents with identical indications for treatment of anemia in patients with cancer. Clinical trials have demonstrated that both agents can significantly improve hemoglobin levels, reduce transfusion requirements, and improve quality of life. Epoetin alfa is approved for administration at a dose of 150 units/kg subcutaneously 3 times per week, and darbepoetin alfa is approved for administration at a dose of 2.25 units/kg once a week. Clinical studies have demonstrated that epoetin alfa may be administered at 40,000 units once a week and that darbepoetin alfa may be administered at 200 microg every 2 weeks without loss of efficacy. Cost analysis, based on the average wholesale price of each drug alone administered for 12 weeks at Food and Drug Administration-approved doses, revealed that epoetin alfa is less expensive than darbepoetin alfa. When they are administered in the extended schedules, the cost of darbepoetin alfa is slightly less than that of epoetin alfa. However, the total expense associated with the extended schedule of either agent is further reduced by a reduction in other costs associated with drug administration. CONCLUSIONS: Epoetin alfa and darbepoetin alfa have identical indications for treatment of anemia in patients receiving cancer chemotherapy. Clinical trials have demonstrated similar activities with both agents. Darbepoetin alfa, with a longer half-life, can be administered less frequently, saving costs as well as reducing patient office visits.     

Epoetin alfa increases hemoglobin levels and improves quality of life in anemic geriatric cancer patients receiving chemotherapy

Goal To evaluate epoetin alfa (EPO) treatment of anemia in geriatric cancer patients receiving chemotherapy, a retrospective subgroup analysis was conducted of anemic cancer patients ≥65 years of age from three 16-week community-based studies of thrice-weekly (TIW) or once-weekly (QW) EPO for chemotherapy-related anemia (CRA).Patients and methods Analyses were conducted on the overall geriatric population (≥65 years) and by age subgroup (65–74, 75–84, and ≥85 years), and compared with younger patients (<65 years) for each individual study and for pooled data.Main results Some 3,634 geriatric patients were compared with 3,467 younger patients. From baseline to final measurement, EPO therapy significantly increased Hb by 2.0 g/dl in patients ≥65 years and 1.9 g/dl in patients <65 years (P<0.0001) and reduced transfusion utilization in both groups (P<0.006). Both age groups also had significant improvements in quality of life (QOL), measured by the 100-mm Linear Analog Assessment Scale (LASA). In younger patients, mean LASA changes were significantly greater than those in geriatric patients (P<0.05); however, QOL improvements in both age groups were clinically meaningful. There were no significant differences across geriatric age subgroups or between TIW and QW regimens for Hb change or QOL improvement. Overall hematopoietic response rate to EPO was 65.4% for patients ≥65 years and 64.7% for patients <65 years. Predictors of greater hematopoietic response (based on a pooled analysis) included lower body weight, baseline Hb, and baseline serum erythropoietin levels; better tumor response; and history of EPO dose reduction and longer time on study.Conclusions Anemic geriatric patients receiving EPO for CRA responded comparably to younger patients <65 years and should be treated similarly.     

Advances in erythropoietic growth factor therapy for myelodysplastic syndromes

Refractory anaemia associated with excessive intramedullary erythroid apoptosis and dysplasia is a major feature of myelodysplastic syndromes (MDS). Recombinant human erythropoietin (specifically, epoetin alfa [EPO]) has been used in the therapy of MDS for many years. Initially, the erythroid response rates were modest, as EPO was used in all subgroups of MDS patients without discretion. However, with increased sophistication in patient selection and response evaluation criteria, there has been a significant improvement in the response rates to EPO therapy. This review discusses the evolution of therapeutic strategies incorporating EPO for the treatment of MDS.     

Drug administration frequency and provider office visit patterns for oncology patients during treatment with erythropoietic agents: an analysis of four observational studies

BACKGROUND: Several drug administration regimens of epoetin alfa (EPO) and darbepoetin alfa (DARB) are used for the management of anemia in cancer patients in the clinical practice setting. OBJECTIVE: The purpose of the present analysis was to assess whether drug administration regimens were associated with differences in the number of provider office visits and hemoglobin assessments during treatment with these agents. METHODS: Data from 4 observational studies that examined treatment patterns of EPO and DARE and health care resource utilization were analyzed. These studies, selected based on the availability of office visit and/or hemoglobin determination data during the course of treatment, included a retrospective chart review, 2 retrospective claims analyses, and an ongoing prospective patient registry. The treatment patterns and oncology-related provider visits and/or the frequency of hemoglobin evaluations among the studies were reported. RESULTS: Data from 15,845 cancer patients were included in the analysis. The patient demographic and baseline characteristics were similar across all 4 studies; patients were predominantly women (62%-71%) with a mean age range of 56 to 63 years. Mean treatment duration ranged from 7.1 to 8.4 weeks without significant differences between EPO and DARE in any study. Weekly and extended (at least every 2 weeks [> or =Q2W]) drug administration frequencies were observed in both treatment groups. The most frequent drug administration schedule for EPO was once weekly (53%-75% of patients), and for DARE Q2W (67%-73%). Despite the difference in erythropoietic agent administration frequency, no significant differences were observed between EPO and DARB for either the number of oncology-related provider visits or the number of hemoglobin assessments. CONCLUSIONS: The frequency of oncology-related provider visits and hemoglobin assessments appears to be independent of the EPO and DARB administration frequency. These findings might provide useful information for health care providers and oncology patients in understanding patterns of care during treatment with erythropoietic agents.     

Advances in erythropoietic growth factor therapy for myelodysplastic syndromes

Refractory anaemia associated with excessive intramedullary erythroid apoptosis and dysplasia is a major feature of myelodysplastic syndromes (MDS). Recombinant human erythropoietin (specifically, epoetin alfa [EPO]) has been used in the therapy of MDS for many years. Initially, the erythroid response rates were modest, as EPO was used in all subgroups of MDS patients without discretion. However, with increased sophistication in patient selection and response evaluation criteria, there has been a significant improvement in the response rates to EPO therapy. This review discusses the evolution of therapeutic strategies incorporating EPO for the treatment of MDS.     

Pharmacokinetics and pharmacodynamics of once-weekly subcutaneous epoetin alfa in critically ill patients: results of a randomized, double-blind, placebo-controlled trial

OBJECTIVE: To describe the erythropoietin pharmacokinetic profile after once-weekly epoetin alfa treatment in critically ill patients. Secondary objectives were to compare pharmacodynamic and safety profiles between active treatment and placebo in these patients. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Medical, surgical, or mixed medical/surgical intensive care units. PATIENTS: A total of 73 anemic critically ill adults with an expected stay of >3 days and a hematocrit value of <38%. INTERVENTIONS: Patients were randomized 2:1 to epoetin alfa, 40,000 IU, administered subcutaneously once weekly (n=48) or matching placebo (n=25) for up to 4 wks. MEASUREMENTS AND MAIN RESULTS: Serum erythropoietin concentration and hematologic variables (percentage reticulocytes [RETI], hemoglobin [Hb], and total red blood cell [RBC] counts) were measured, and area under the serum concentration-time curve from time 0 to the last blood sampling time at time t (t: 120, 144, or 168 hrs) postdose (AUC0-Tlast) for these three variables was determined. Mean serum erythropoietin concentrations in placebo patients were slightly higher than typical physiologic levels of erythropoietin in healthy subjects, although not appropriate for the degree of anemia in these patients. Overall, exposure of endogenous erythropoietin in the placebo group (in terms of AUC0-Tlast) was only about 20% of exposure to exogenous erythropoietin in the epoetin alfa group. Baseline hemoglobin levels were the same in both groups (9.9 g/dL). Mean change in hemoglobin level from baseline through day 29 was 1.9 g/dL and 1.6 g/dL in the epoetin alfa and placebo groups, respectively. Mean AUC(RETI)0-Tlast was higher with epoetin alfa than with placebo and was related to the AUC of erythropoietin. There were no apparent differences in AUC(Hb)0-Tlast and AUC(RBC)0-Tlast between epoetin alfa and placebo groups, which was most likely due to bleeding and transfusion events. Epoetin alfa was safe and well tolerated, with a rate of treatment-emergent complications similar to that seen with placebo. CONCLUSION: Epoetin alfa, once weekly, augmented the erythropoietic response in critically ill patients as indicated by the increased erythropoietin levels and larger AUC(RETI)0-Tlast in treated patients.     

Use of epoetin alfa in critically ill patients

OBJECTIVE: To discuss the controversies regarding the use of epoetin alfa (EPO) for reducing red blood cell (RBC) transfusions in critically ill patients with anemia. DATA SOURCES: A MEDLINE search (1966-July 2003) was conducted using the search terms anemia; critical illness; erythropoietin; epoetin alfa; and erythropoietin, recombinant. References of selected articles were reviewed for studies that may have been missed by the computerized search. STUDY SELECTION AND DATA EXTRACTION: Studies pertaining to the use of EPO for anemia of critical illness with an emphasis on data obtained from controlled trials. DATA SYNTHESIS: Anemia is a common complication in patients admitted to the intensive care unit (ICU). Two prospective, randomized studies have demonstrated decreased transfusion requirements associated with EPO administration in medical/surgical patients who were in the ICU for at least 3 days and had hematocrit concentrations <38%. No differences were found in length of stay or mortality. A multicenter trial found that a restrictive strategy of RBC transfusion (hemoglobin goal 7-9 g/dL) was associated with in-hospital mortality lower than that with a more liberal approach, which calls into question the 38% hematocrit goal in the EPO trials. Furthermore, preliminary results from an economic analysis of EPO use in the ICU setting have demonstrated that EPO is not cost-effective. CONCLUSIONS: Given the controversies surrounding EPO administration in critically ill patients, institutions are encouraged to develop EPO guidelines to help ensure the most appropriate use of this expensive product. Additional studies regarding patients most likely to benefit from EPO therapy, the most effective dosing regimen, and use of adjunctive therapies are needed.