Darbepoetin Alfa Dose Research Articles

Cost-effectiveness analysis of patients in peritoneal dialysis with methoxy polyethylene glycol-epoetin β versus darbepoetin α in Santiago De Compostela University Hospital Complex, Spain

BackgroundCosts related to anaemia treatment in chronic kidney disease (CKD) patients are still under discussion. Near 80% of CKD patients included in a peritoneal dialysis program receive erythropoietin stimulating agents...

Stroke in Patients With Type 2 Diabetes Mellitus, Chronic Kidney Disease, and Anemia Treated With Darbepoetin Alfa

Background— More strokes were observed in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) among patients assigned to darbepoetin alfa. We sought to identify baseline characteristics and postrandomization factors that might explain this association. Methods and Results— A multivariate logistic regression model was used to identify baseline predictors of stroke in 4038 patients with diabetes mellitus, chronic kidney disease, and anemia randomized to receive darbepoetin alfa or placebo. To determine whether postrandomization blood pressure, hemoglobin level, platelet count, or treatment dose were responsible for the increased risk related to darbepoetin alfa, we performed a nested case-control analysis (1:10 matching) identifying nonstroke controls with propensity matching. The risk of stroke was doubled with darbepoetin alfa. Overall, 154 patients had a stroke, 101/2012 (5.0%) in the darbepoetin alfa arm and 53/2026 (2.6%) in the placebo arm (hazard ratio 1.9; 95% confidence interval, 1.4–2.7). Independent predictors of stroke included assignment to darbepoetin alfa (odds ratio 2.1; 95% confidence interval, 1.5–2.9), history of stroke (odds ratio 2.0; 95% confidence interval, 1.4–2.9), more proteinuria, and known cardiovascular disease. In patients assigned to darbepoetin alfa, postrandomization systolic and diastolic blood pressure, hemoglobin level, platelet count, and darbepoetin alfa dose did not differ between those with and without stroke. Additional sensitivity analyses using maximal values, latest values, or changes over varying periods of exposure yielded similar results. Conclusions— The 2-fold increase in stroke with darbepoetin alfa in TREAT could not be attributed to any baseline characteristic or to postrandomization blood pressure, hemoglobin, platelet count, or dose of treatment. These readily identifiable factors could not be used to mitigate the risk of darbepoetin alfa–related stroke. Clinical Trial Registration— http://www.clinicaltrials.gov . Unique identifier: NCT00093015.

Faisabilité de la stratégie d’administration de la darbepoetin alfa tous les 15 jours : expérience 2005–2007 d’un centre de dialyse

Darbepoetin alfa is a recombinant erythropoiesis-stimulating agent, with a longer half-life leaving the possibility to extending dosing administration in haemodialysis patients. A protocol of injection every 2 weeks was initiated in the dialysis unit. From 2005 to 2007, 176 dialysis patients were studied with a target haemoglobin level between 11 and 12.5 g/dL: the median haemoglobin level was ranged from 11.32 and 11.72 g/dL during the study with a median darbepoetin alfa dose injected between 60 and 64 μg per injection (0.46 to 0.47 μg/kg per week). The mean number of dose changes was three per year per patient. The diabetic population did not differ from the general population in terms of haemoglobin levels and doses of darbepoetin alfa. Ten percent of the patients had to resume one injection per week for medical reasons: the profile of these patients was carefully studied. Hospitalisations resulted in a decrease in haemoglobin level and an increase in the darbepoetin alfa doses. Patients who died showed during the last 3 months, a particular profile. Hyporesponsiveness has been explored. Time saving with this protocol was important for all the nursing staff. Although numerous factors of variability have been studied, there still a room for improvement of anemia management in haemodialysis patient.

The relationship between serum hepcidin levels and clinical outcomes in patients with chemotherapy-associated anemia treated in a controlled trial.

9031 Background: The Mayo Clinic Cancer Research Consortium recently published results from a phase III, randomized study (MC04CC) of darbepoetin alfa (DA) combined with intravenous (IV) ferric gluconate 187.5 mg q3wks x 5 doses, oral ferrous sulfate, or no iron supplementation for patients (pts) with chemotherapy-associated anemia (CAA) (Steensma et al, J Clin Oncol 2011;29:97-105). There was no benefit from IV iron in the MC04CC trial, possibly due to iron parameters of enrolled pts. The peptide hepcidin is a major regulator of systemic iron homeostasis, but the relationship between hepcidin and response to erythropoiesis-stimulating agents (ESAs) or IV iron therapy has not been systematically studied in pts with CAA. Methods: Serum hepcidin concentration was measured in pre-treatment samples from 405/489 eligible pts enrolled in the MC04CC study, using a sensitive quantitative mass spectrometry-based method. Hemoglobin and transfusion endpoints were analyzed, stratified by hepcidin tertiles and treatment group. Results: See table. Conclusions: Pts with serum hepcidin levels in the lower two tertiles appeared to have a better clinical response to DA plus higher doses of IV iron than either pts with higher hepcidin levels, or pts with lower hepcidin levels who did not receive higher dose IV iron. Hepcidin measurements may help predict response to ESAs and supplemental iron. DA + placebo DA + oral iron DA + IV iron (pts receiving <4 doses IV iron) DA + IV iron (pts receiving 4 or 5 doses IV iron) Hemoglobin response Total 106/163 (65%) 109/163 (67%) 40/71 (56%) 74/92 (80%) Hepcidin 1st tertile (≤20.2 ng/mL) 30/47 (64%) 26/41 (63%) 12/20 (60%) 24/26 (92%) Hepcidin 2nd tertile (>20.2-64.3 ng/mL) 36/53 (68%) 32/53 (60%) 6/11 (55%) 20/21 (95%) Hepcidin 3rd tertile (>64.3 ng/mL) 23/36 (64%) 29/37 (78%) 14/24 (58%) 25/36 (69%) Hepcidin missing 17/27 (63%) 22/32 (69%) 8/16 (50%) 5/9 (56%) RBC transfusion Total 22/163 (13%) 21/163 (13%) 12/71 (17%) 8/92 (9%) Hepcidin 1st tertile 6/47 (13%) 4/41 (10%) 2/20 (10%) 0/26 (0%) Hepcidin 2nd tertile 8/53 (15%) 9/53 (17%) 2/11 (18%) 0/21 (0%) Hepcidin 3rd tertile 6/36 (17%) 5/37 (14%) 4/24 (17%) 6/35 (17%) Hepcidin missing 2/27 (7%) 3/32 (9%) 4/16 (25%) 2/9 (22%)

Macrocytosis may be associated with mortality in chronic hemodialysis patients: a prospective study.

BackgroundMacrocytosis occurs in chronic hemodialysis (CHD) patients; however, its significance is unknown. The purpose of this study was to establish the prevalence and distribution of macrocytosis, to identify its clinical associations and to determine if macrocytosis is associated with mortality in stable, chronic hemodialysis patients.MethodsWe conducted a single-centre prospective cohort study of 150 stable, adult CHD patients followed for nine months. Macrocytosis was defined as a mean corpuscular volume (MCV) > 97 fl. We analyzed MCV as a continuous variable, in tertiles and using a cutoff point of 102 fl.ResultsThe mean MCV was 99.1 ± 6.4 fl, (range 66-120 fl). MCV was normally distributed. 92 (61%) of patients had an MCV > 97 fl and 45 (30%) > 102 fl. Patients were not B12 or folate deficient in those with available data and three patients with an MCV > 102 fl had hypothyroidism. In a logistic regression analysis, an MCV > 102 fl was associated with a higher Charlson-Age Comorbidity Index (CACI) and higher ratios of darbepoetin alfa to hemoglobin (Hb), [(weekly darbepoetin alfa dose in micrograms per kg body weight / Hb in g/L)*1000]. There were 23 deaths at nine months in this study. Unadjusted MCV > 102 fl was associated with mortality (HR 3.24, 95% CI 1.42-7.39, P = 0.005). Adjusting for the CACI, an MCV > 102 fl was still associated with mortality (HR 2.47, 95% CI 1.07-5.71, P = 0.035).ConclusionsMacrocytosis may be associated with mortality in stable, chronic hemodialysis patients. Future studies will need to be conducted to confirm this finding.

Erythropoietic response to erythropoiesis-stimulating agents and outcome: should we give up the haemoglobin target approach?

The hypothesis that complete anaemia correction with erythropoiesis-stimulating agents (ESA) would reduce the risk of death and cardiovascular and renal endpoints among patients with chronic kidney disease (CKD) has been largely tested in the last 15 years. Despite expectations, no study has demonstrated any clinical benefit except some improvement in quality of life by targeting at high haemoglobin (Hb) levels in comparison to partial anaemia correction. Some of these studies even found a trend towards increased risk of cardiovascular endpoints (i.e. death, stroke, acute myocardial infarction and hospitalization for congestive heart failure in different combinations) at primary or secondary analyses [1–4]. A lively debate has developed focussing on possible explanations why clinical trials have not confirmed what has been shown by observational studies: the higher the Hb the better the outcome. The Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) study randomized 4038 patients with Type 2 diabetes and CKD Stages III–IV to darbepoetin alfa (Hb of 13 g/dL) or to placebo (with rescue darbepoetin alfa for Hb <9.0 g/dL) [5]. Results were neutral on primary composite cardiovascular and renal outcomes, but a higher risk of stroke, death for cancer in patients with previous history of malignancies and thromboembolic events were found at secondary analyses in those randomized to complete anaemia correction. This parallelled a reduction in cardiac revascularization procedures, transfusion rates and improvement in quality of life in this group [6]. Possible implications of these findings have already been discussed [7]. In this editorial, we would like to examine carefully and comment on the recent secondary analysis of the TREAT data by Solomon et al. [8], which investigated the relationship between initial response to darbepoetin alfa, patient characteristics and outcomes. For this purpose, patients in the darbepoetin-alfa group having a Hb change <2% in the first month after the initial weight-based two doses of darbepoetin alfa were defined as having a poor response and compared with the remaining ones (upper three quartiles of Hb changes). After adjusting for outcome-related covariates, this subgroup had a higher risk of reaching the cardiovascular composite endpoint or death from any cause than the better Hb responders who had an event rate similar to the placebo group. Conversely, both subgroups had similar stroke rates that were higher than the placebo group. This post hoc analysis suggests that after just two doses of darbepoetin alfa, it is possible to classify the patients in good and bad responders and this may translate into a different outcome risk. This may be an easy method to identify high-risk patients and tailor ESA treatment accordingly, avoiding excessive doses. However, as admitted by the authors, these findings cannot identify the culprit of increased cardiovascular risk following ESA treatment. Is this a consequence of too high ESA doses especially in those who are hyporesponsive to treatment or does this merely reflect patient characteristics?

Treatment of Renal Anemia in Saudi Dialysis Patients: Between Darbepoetin Alfa and Recombinant Human Eryhthrpoietin (rHuEPO)

Background: Darbepoetin alfa is an erythopoietic agent with a 3-fold longer elimination half-life than recombinant human erythropoietin (rHuEPO), which allows less frequent dosing, and hence it maintains an effective hemoglobin control at extended dose intervals compared with rHuEPO. This study assessed the efficacy and safety of unit doses of darbepoetin alfa for the treatment of renal anemia in hemodialysis (HD) and peritoneal dialysis (PD) patients. Methods: In this prospective study, 143 dialysis patients (68 HD and 75 PD patients) maintained on stable rHuEpo treatment were switched to darbepoetin alfa at extended dose intervals by the same route of administration as previous rHuEpo therapy [intravenous (i.v.), n=78 or subcutaneous (s.c.), n= 65]. Patients receiving rHuEpo two or three times a week were switched to darbepoetin alfa once a week and those receiving rHuEpo once a week were switched to darbepoetin alfa once every two weeks. The unit doses of darbepoetin alfa (10-150 ug) were titrated to maintain hemoglobin concentrations of 10-12 g/dl for 24 weeks. Results: Hemoglobin (Hgb) concentrations were maintained effectively in our patients regardless of the dose interval of darbepoetin alfa. The overall mean change in Hgb concentration from baseline to evaluation period was an increase of 0.18 g/dl (95% CI ± 0.16). Regardless of route of administration, darbepoetin alfa effectively maintained mean Hgb concentration above 11 g/dl throughout the entire study period. Darbepoetin alfa administered by both the i.v. and s.c. routes resulted in stable mean Hgb concentrations during the evaluation period. Subjects with baseline Hgb concentrations < 11 g/dl experienced significant mean increase in Hgb concentration from baseline to evaluation, which was more pronounced following i.v. than s.c. administration (0.79 vs o.55 g/dl respectively). Relative to baseline, i.v. and s.c. darbepoetin alfa dosage requirements decreased in subjects with baseline Hgb ≥11g/dl (21.64 to 15.86 ug/week and 21.95 to 18.52 ug/week respectively p =0.0214), while there was a little increase in darbepoetin alfa dosage in subjects with baseline Hgb < 11 g/dl (25.22 to 26.76 ug/week and 22.74 to 24.81 ug/week in the i.v. and s.c. groups respectively p=0.0581). The percentage change in dose requirements from baseline to evaluation period in all patients, regardless of route of administration was not significant (2.28%, 95% CI -3.64, 7.89). Hemoglobin concentrations were also effectively maintained in patients who received darbepoetin alfa once weekly and once every other week. Darbepoetin alfa was well tolerated in all HD and PD patients, and the safety profile was consistent with previous trials with darbepoetin alfa in dialysis patients. Conclusion: The treatment of renal anemia in dialysis patients (both HD and PD) with unit doses of darbepoetin alfa is both effective and well tolerated. Moreover, administration of darbepoetin alfa by both i.v. and s.c. route is associated with stable Hgb concentration. Darbepoetin alfa administered i.v. or s.c once weekly or once every other week is an effective and safe treatment regimen for hemodialysis and peritoneal dialysis patients with renal anemia.

A Prospective Protocol-Based Trial of Darbepoetin Alfa Therapy to Correct the Early Anemia Following Renal Transplantation

Anemia is a common complication accompanying renal transplantation. The evaluation and therapy for posttransplant anemia (PTA) are not standardized and remain controversial. This was a prospective, protocol-driven attempt at early PTA evaluation and management by transplant nurse coordinators. Between 1 and 2 months posttransplantation, 75 consecutive recipients were evaluated for the presence and causes of anemia. Anemic patients were given standard doses of darbepoetin alfa (DA) for 3 months. Response to therapy and patient outcomes were evaluated over 15 months. Twenty-five (33%) of all patients were anemic, including 32% who were erythropoietin (EPO)-deficient and 68% with relative EPO resistance. No patient with early PTA showed an elevated EPO level or increased reticulocytes. Predisposing factors for early PTA included increased numbers of perioperative transfusions, deceased kidney donor, decrease reticulocyte count, and renal insufficiency. DA therapy corrected anemia in 20% of patients at 1 month and in 60% at 3 months. Patients unresponsive to standard DA doses were observed to display reduced renal function and new onset iron deficiency. Patients with prolonged PTA may represent a high-risk population requiring more intensive medical supervision. Nurses were able to efficiently direct DA therapy with only 1.7% protocol violations.

Comparison of darbepoetin alfa dosed weekly (QW) vs. extended dosing schedule (EDS) in the treatment of anemia in patients receiving multicycle chemotherapy in a randomized, phase 2, open-label trial

BackgroundChemotherapy-induced anemia (CIA) is responsive to treatment with erythropoiesis-stimulating agents (ESAs) such as darbepoetin alfa. Administration of ESAs on a synchronous schedule with chemotherapy administration could benefit patients by reducing clinic visits and potentially enhancing on-time chemotherapy delivery.MethodsThis phase 2, 25-week, open-label study evaluated the noninferiority of darbepoetin alfa administered weekly vs. as an extended dosing schedule (every 2 or 3 weeks) in patients with CIA. Patients were randomized 1:1 to an extended dosing schedule (EDS: darbepoetin alfa 300 μg Q2W if chemotherapy was QW, Q2W, or Q4W or darbepoetin alfa 500 μg Q3W if chemotherapy was Q3W) or weekly (150 μg QW regardless of chemotherapy schedule). Stratification factors included chemotherapy cycle length, screening hemoglobin (<10 g/dL vs. ≥10 g/dL), and tumor type (lung/gynecological vs. other nonmyeloid malignancies). The primary endpoint was change in hemoglobin from baseline to Week 13.ResultsSeven hundred fifty-two patients (374 QW patients; 378 EDS patients) received ≥1 dose of darbepoetin alfa and were included in the analysis. Demographics and disease state were similar between groups. Seventy-one percent of patients in the EDS group and 76% in the QW group achieved the target hemoglobin of ≥11.0 g/dL. There was a minimal difference in the primary endpoint of mean change in hemoglobin (baseline to Week 13) between the QW and the EDS groups (-0.04 g/dL; 95% confidence interval: -0.26, 0.17 g/dL). The upper limit of the 95% confidence interval was less than the prespecified limit of <0.75 g/dL, supporting noninferiority of the EDS dosing schedule. Reported adverse events were similar between groups. A slight increase in transfusions was reported in the QW group.ConclusionDarbepoetin alfa, when administered synchronously with chemotherapy, on an EDS appears to be similarly efficacious to darbepoetin alfa weekly dosing with no unexpected adverse events. This study provides prospective data on how multiple dosing regimens available with darbepoetin alfa can be synchronized with chemotherapy administered across a range of dosing schedules.Trial registrationClinicalTrials.gov Identifier NCT00144131.

Estimate of maintenance EPO to darbepoetin alfa dose conversion ratio in a hospital-based dialysis patient population

Background:Epoetin alfa (EPO) and darbepoetin alfa are erythropoiesis-stimulating agents (ESAs) used to treat anemia in patients with chronic kidney disease. EPO and darbepoetin alfa have a non-proportional dose conversion relationship across the dosing spectrum. However, reports comparing the dose relationship between the two ESAs do not adjust for the non-proportional dose relationship or for population differences. Because drug cost is directly related to dosage, appropriate methods to assess the dose relationship between the two ESAs are important to understand the economic implications of converting patient populations from one ESA treatment to another.Objective:To describe dose conversion methods that take into account the non-proportional dose relationship between EPO and darbepoetin alfa, and calculate the dose conversion ratio (DCR) between the two ESAs in a hospital-based dialysis patient population.Methods:This was a retrospective observational study where longitudinal data from medical charts were collected for chronic hemodialysis patients being treated at hospital-based dialysis centers. Mean maintenance DCRs were calculated at the population level for hemodialysis patients converted from EPO to darbepoetin alfa treatment and subsequently maintained on darbepoetin alfa. Two methods were used to determine the DCRs: a regression-based method using ordinary least squares regression, and ratio-based method using an arithmetic mean.Results:The estimated population mean maintenance DCR for the population in this analysis was 320:1 (Units EPO:µg darbepoetin alfa) using the regression-based method, and 350:1 using the ratio-based method. Sensitivity analysis yielded DCRs ranging from 311 to 333:1.Conclusions:The two methods in estimating the DCR presented here provide payers with an empirical way of comparing ESA utilization for pharmacoeconomic evaluation. DCR results may vary according to patient characteristics; however, mean DCRs of greater than 300:1 were obtained in this analysis. Exclusion of other patient-related factors that may influence ESA dose is a possible limitation of the study.

Effects of CERA (continuous erythropoietin receptor activator) in patients with advanced non-small-cell lung cancer (NSCLC) receiving chemotherapy: results of a phase II study

Background: Continuous erythropoietin receptor activator (CERA; methoxy polyethylene glycol-epoetin beta) is a new erythropoiesis-stimulating agent with a prolonged half-life. The objective of this study was to select a starting dose of CERA for the treatment of anemia in non-small-cell lung cancer (NSCLC) patients.Patients and methods: The study was an open-label randomized phase II trial containing four treatment groups of patients with anemia and stage IIIB or IV NSCLC. The fourth treatment group was a reference group of patients treated with darbepoetin alfa administered at either 6.75 μg/kg s.c. every 3 weeks or 2.25 μg/kg weekly. Due to observed imbalances in death across treatment arms, this study was prematurely terminated.Results: The primary efficacy parameter of the mean hemoglobin (Hb) change from baseline during weeks 5–13 was +0.03 g/dl, +0.50 g/dl, and -0.02 g/dl in the CERA 6.3, 9, and 12 μg/kg dose groups, respectively, and +0.26 g/dl in the darbepoetin alfa dose group (P value not significant for all three study arms). Eight (21%), 12 (32%), 9 (24%), and 4 (10%) patients in the CERA 6.3, 9, and 12 μg/kg and darbepoetin groups, respectively, died.Conclusion: In this phase II study in patients with stage IIIB or IV NSCLC receiving chemotherapy, none of the four treatment arms showed an adequate increase in mean Hb level.

Anemia Management With Darbepoetin-Alfa in Outpatient Hemodialysis Patients Switched From Epoetin-Alfa: A Community Hospital Experience

Epoetin-alfa (EA) and darbepoetin-alfa (DA) are agents for treating anemia in dialysis patients. In September 2005, our free-standing outpatient hemodialysis center (community-hospital based) implemented an interchange from EA to DA. Since then, all hemodialysis patients receive DA as the preferred agent. We performed this observational study to compare effectiveness of DA with EA in anemia management in a cohort of hemodialysis outpatients. We studied 98 hemodialysis outpatients who received twice to thrice weekly EA from January to August 2005. These patients were switched to DA in September 2005, and baseline DA dose was calculated from the conversion table in the package insert. After a 4 month titration phase, the same cohort of patients, now on once weekly DA, was followed from January to September 2006. Dose of EA or DA was adjusted to maintain hemoglobin at 11 to 13 g/dL. Hematologic and dialysis parameters were collected on a monthly basis, and inpatient data were excluded. Mean ± standard deviation age was 65.8 ± 14.2 years, with 42 (42.9%) women. Mean ± standard deviation hemoglobin level was 12.5 ± 1.6 g/dL during EA and 12.5 ± 1.6 g/dL during DA therapy (P = 0.23). Proportion of patients achieving hemoglobin (11-13 g/dL) was 44.5% ± 28.9% with EA and 49.8% ± 25.8% with DA (P = 0.09). Average intrapatient absolute hemoglobin variability was 1.0 ± 0.5 g/dL on EA and 1.1 ± 0.5 g/dL on DA (P = 0.29). Median (and interquartile range) EA dose used was 11,400 (7,050-22,800) IU/week, and median DA dose was 59.8 (40-91.6) mcg/week with an EA:DA dose conversion ratio of 191:1. Patients on EA or DA had similar dialysis adequacy, albumin, and iron parameters. DA is as effective as EA in treating anemia in hemodialysis outpatients. Dose requirement of DA is greater than 200:1 of the amount of EA and may not translate into cost savings.

Exposure‐Response Modeling of Darbepoetin Alfa in Anemic Patients With Chronic Kidney Disease Not Receiving Dialysis

A population pharmacokinetic and pharmacodynamic model (PK/PD) of darbepoetin alfa following intravenous (IV) or subcutaneous (SC) administration in participants with chronic kidney disease (CKD) was developed. Darbepoetin alfa concentrations from 96 CKD participants, who received IV or SC darbepoetin alfa, and Hgb concentration from 332 CKD participants not on dialysis, who received SC doses of darbepoetin alfa, were used to develop the PK/PD model. An open 2-compartment model with sequential zero- and first-order absorption was used to characterize darbepoetin alfa pharmacokinetics. Darbepoetin alfa was assumed to trigger concentration-dependent stimulation of production of progenitor cells of red blood cells (RBCs) in bone marrow, which become red blood cells and died after life span expiration. Model evaluation was performed through nonparametric bootstrap and posterior predictive checks. Absolute bioavailability, total mean absorption time, clearance, and volume of distribution were estimated to be 44%, 52 h, 3.4 L/d/70 kg, and 5.9 L/70 kg, respectively. The estimates of drug potency, efficacy, and RBC life span were 0.41 ng/mL, 64%, and 77 days, respectively. Pharmacokinetic or pharmacodynamic parameters of darbepoetin alfa were not affected by age and sex. The qualified model supports the use of darbepoetin alfa administered biweekly (SC) in CKD patients for anemia correction and monthly (SC) for hemoglobin maintenance. In addition, the model is deemed appropriate to conduct simulations to support dose selection for additional clinical studies.

Darbepoetin alfa 300 or 500 μg once every 3 weeks with or without intravenous Iron in patients with chemotherapy‐induced anemia

This study evaluated efficacy and safety of darbepoetin alfa administered every 3 weeks (Q3W) at fixed doses of 300 or 500 μg with or without intravenous (IV) iron in treating anemia in patients receiving multicycle chemotherapy. This Phase 2, double-blind, 2 × 2 factorial study randomized patients to one of four treatment arms; darbepoetin alfa 300 μg (n = 62), darbepoetin alfa 300 μg plus IV iron (n = 60), darbepoetin alfa 500 μg (n = 60), or darbepoetin alfa 500 μg plus IV iron (n = 60). Patients had nonmyeloid malignancies, hemoglobin levels ≤10 g dL(-1), and no iron deficiency. Primary endpoint was achievement of target hemoglobin (≥11 g dL(-1)). Secondary endpoints included incidence of transfusions and change in Functional Assessment of Cancer Therapy Fatigue (FACT-F) score from baseline to end of study. Safety was evaluated by incidence of adverse events. No evidence of a statistically significant interaction between darbepoetin alfa dose received and IV iron usage was observed, therefore, results are provided separately comparing darbepoetin alfa doses and comparing IV iron usage groups. Similar proportions of patients receiving darbepoetin alfa 300 or 500 μg achieved target hemoglobin (75 and 78%, respectively); Kaplan-Meier median time to target hemoglobin was 10 and 8 weeks, respectively. More patients receiving IV iron (82%) than not receiving IV iron (72%) achieved hemoglobin target. Adverse events profiles were similar for darbepoetin alfa treatment groups. Transient anaphylactoid reactions were reported in two patients receiving IV iron. Darbepoetin alfa at 300 μg Q3W and 500 μg Q3W showed similar benefit, while added IV iron improved treatment response in these patients.

2008 Japanese Society for Dialysis Therapy: Guidelines for Renal Anemia in Chronic Kidney Disease

2008 Japanese Society for Dialysis Therapy: Guidelines for Renal Anemia in Chronic Kidney Disease

Intravenously administered darbepoetin alfa once a week could maintain hemoglobin level more efficiently than once every 2 weeks in patients on hemodialysis

Darbepoetin alfa, which has a much longer half-life than recombinant human erythropoietin, is used to treat renal anemia. However, there are few reports investigating the efficacy of darbepoetin alfa administered every 2 weeks (Q2W). We performed the single-center, prospective, and randomized study in chronic hemodialysis patients. Clinically stable patients on hemodialysis were recruited, and darbepoetin alfa 15-40 microg/week was administered intravenously once a week (QW) to achieve a hemoglobin (Hb) level of 10.5-12.0 g/dl for 8 weeks prior to randomization. The patients were randomly assigned to 2 different dosing frequency groups: once a week (QW) or every 2 weeks (Q2W). We switched to a double dose in the Q2W group. We measured Hb level every 2 weeks and administered darbepoetin alfa to achieve an Hb level of 10.5-11.5 g/dl. The primary endpoints were the weekly dose of darbepoetin alfa administered at week 24. We assigned 19 and 20 patients into QW and Q2W, respectively. There were no significant differences between the groups in Hb, transferrin saturation, ferritin, and weekly dose of darbepoetin alfa at end of the baseline period. There was no significant difference in Hb level at week 24, at which time the weekly dose requirement and dose per dry body weight were much higher in the Q2W than in the QW group. Administration of darbepoetin alfa Q2W could maintain Hb level similarly to to that obtained QW, but we did not confirm efficiency at a higher dose requirement or blood pressure elevation.

A Phase III, Randomized Study of the Effects of Parenteral Iron, Oral Iron, or No Iron Supplementation On the Erythropoietic Response to Darbepoetin Alfa for Patients with Chemotherapy-Associated Anemia: A Study of the Mayo Clinic Cancer Research Consortium (MCCRC).

Abstract 630 Introduction:Erythropoiesis stimulating agents (ESAs) improve hemoglobin (Hb) levels and reduce red blood cell (RBC) transfusion requirements in patients (pts) with chemotherapy-associated anemia (CAA), but many pts with CAA do not respond to ESAs. Functional iron deficiency due to inflammation-related hepcidin production and pathological sequestration of bioavailable iron may be an important reason for lack of ESA response in iron-replete pts. The common clinical practice of co-administering oral iron with ESAs does not appear to alter the disordered iron processing in CAA. We conducted a prospective trial to evaluate whether parenteral iron might overcome functional iron deficiency and benefit iron-replete pts with CAA undergoing ESA treatment. Patients and Methods:Eligible pts were receiving chemotherapy for a non-myeloid neoplasm and had Hb level <11.0 g/dL, ferritin >20 ng/mL, transferrin saturation <60%, and ECOG performance score ≤2. All pts received darbepoetin alfa (DA) 500 mcg subcutaneously q3wks until Hb reached >11 g/dL, and thereafter DA 300 mcg q3wks; DA was held for Hb >13 g/dL until Hb fell to <12 g/dL, then restarted with 25% dose reduction. Pts were randomized 1:1:1 to receive either sodium ferric gluconate complex in sucrose (Ferrlecit) 187.5 mg intravenously q3wks (total dose 1,125 mg), oral ferrous sulfate 325 mg once daily, or oral placebo. Quality of life (QOL) was measured using the Symptom Distress Scale, Brief Fatigue Inventory, FACT-An, and LASA instruments. The primary endpoint was the proportion of patients achieving Hb ≥12.0 g/dL or ≥2.0 g/dL Hb increment from baseline by the end of the 16-week study. Secondary endpoints included transfusion requirements. changes in QOL, changes in iron parameters, and adverse events (AEs). Results:Planned enrollment was 582 pts, but the study met an early stopping rule due to an excess of serious AEs in the IV iron arm; 502 pts enrolled at 14 MCCRC sites between February 2006 and December 2008. The median age of the 490 evaluable pts was 64 years; 65% were female and 94% white; 6% had hematological neoplasms (lymphoma or multiple myeloma), 25% had severe anemia (Hb <9.5 g/dL), 48% received platinum-containing therapy, and 66% completed all 16 weeks of the study. Baseline characteristics were comparable between groups. With respect to the primary endpoint, 69.5% of IV iron-treated pts achieved a Hb response (median Hb increase from baseline to end of study, 2.7 g/dl), compared to 66.9% with oral iron (median increase, 2.4 g/dL) and 65.0% with placebo (median increase 2.3 g/dl) (p=0.73). There were no significant differences in the proportion of patients requiring RBC transfusion (12.8% for IV iron, 12.9% for oral iron, 13.5% for placebo; p=0.87) or QOL changes. A total of 17 pts (3%) died on study–8 in the IV iron arm, 6 oral iron, 3 placebo (p=0.22). Grade 3 or higher AEs occurred in 54% of IV iron pts compared to 43% for oral iron and 45% placebo (p=0.03). The end-of-study ferritin level was higher in the IV iron arm (median 501 ng/mL) compared to the oral iron (229 ng/mL) and placebo (193 ng/mL) arms (p=0.0022). The median total DA dose administered was similar between arms (p=0.71). Conclusions:Co-administration of DA with intravenous ferrous gluconate q3wks did not result in improvement in Hb levels, reduce transfusions, improve QOL endpoints, or allow lower doses of DA, compared with DA + oral iron or DA + placebo. IV iron increased AEs. The reason for discordant results with 5 previous smaller studies is unclear. Disclosure:The study was supported by a grant from Amgen (Thousand Oaks, CA) to the MCCRC. Disclosures:Off Label Use: Ferrlecit, chemotherapy-associated anemia.

CHOICE, an international, observational study to examine current practice use of darbepoetin alfa in the management of chemotherapy-induced anaemia

Introduction In February 2008, the European product label for darbepoetin alfa (DA) in the treatment of chemotherapy-induced anaemia (CIA) was changed to stipulate target haemoglobin (Hb) values between 10 and 12 g/dL. EORTC guidelines on ESA use state similar Hb target levels. The primary aim of this study is to assess adherence to the recommended Hb target range in patients (pts) receiving DA in routine clinical practice. Methods This prospective, multicenter, observational study evaluated the routine clinical practice use of DA in 11 European countries in pts with various non-myeloid malignancies (breast, colorectal, ovarian and lung cancer) at any time during chemotherapy treatment. Key outcome measures were Hb levels and the requirement for red blood cell (RBC) transfusions. Results 336 (mean±SD age 61.8±10.9 years) out of 1300 pts were included in this interim analysis. 80 pts had breast, 57 colorectal, 131 lung (33 small cell lung and 98 non-small cell lung cancer) and 68 ovarian cancer. 25% and 61% of pts had stage 3 and 4 disease at baseline, respectively. At baseline, 60% of all pts (53% of breast cancer and 62% of lung cancer pts) had a baseline Hb value of At week 9, Hb values for 243 pts (72%) were available. Of these, 136 pts (56%) had Hb levels between 10 and 12 g/dL, 59 pts (24%) had a Hb value > 12 g/dL and for 48 pts (20%), a Hb value below 10 g/dL was reported. The Kaplan-Meier percentage of pts with Hb levels ⩾10 g/dL was 89% (see table). The Kaplan-Meier percentage of pts requiring RBC transfusions from week 5 to end of treatment period was 17% (see table). A median DA dose of 500 μg was administered 3 times (median). Additional efficacy outcomes are presented in the table below. A treatment related non-serious adverse drug reaction (back pain) was reported for one patient only. Table 1Efficacy outcomes Total Breast cancer Lung cancer n (%) 336 (100) 80 (24) 131 (39) Hb (g/dL )at baseline, mean (SD) 9.8 (0.8) 9.9 (0.7) 9.7 (0.9) Hb (g/dL)at EOTP, mean (SD) 10.8 (1.6) 11.2 (1.4) 10.5 (1.7) K-M Hb⩾10 (g/dL) from wk 1 to EOTP, % (95% CI), na 89 (84, 95), 202 91 (82,101), 42 94 (85,102), 81 K-M RBC transfusions from wk 1 to EOTP, % (95% CI), n 26 (20, 31), 336 19 (8, 29), 80 37 (27, 46), 131 K-M RBC transfusions from wk 5 to EOTP, % (95% CI), nb 17 (12, 23), 208 12 (2, 22), 50 24 (14, 35), 72 CI, confidence interval; Hb, haemoglobin; EOTP, end of treatment period; K-M, Kaplan-Meier; RBC, red blood cell; wk, week.aOnly patients with Hb Conclusions This interim analysis suggests that the majority of pts were treated according to the European product label for DA and EORTC guidelines and did not surpass Hb levels of 12 g/dL. Furthermore, only 17% needed RBC transfusions from week 5 to end of treatment period. These data further support the effectiveness of DA for the treatment of pts with CIA. Sponsored by Amgen GmbH.

A meta-analysis of the relative doses of erythropoiesis-stimulating agents in patients undergoing dialysis.

Background. Erythropoiesis-stimulating agents (ESAs) such as epoetin alfa and beta, and darbepoetin alfa have improved the management of anaemia secondary to chronic kidney disease. Numerous studies have reported a dose reduction when patients receiving dialysis were converted from epoetin to darbepoetin alfa using the starting dose conversion of 200:1 as indicated on the prescribing label by the European Medicines Agency. The objective of this meta-analysis was to summarize the existing body of scientific evidence to evaluate the potential dose savings when comparing epoetin alfa or beta to darbepoetin alfa.Method. Medline and EmBase were searched to identify all published trials investigating ESA treatment in anaemic patients receiving dialysis and converted from epoetins to darbepoetin alfa. We selected prospective randomized controlled, non-randomized and observational studies involving patients on dialysis that compared epoetin and darbepoetin alfa dosing.Results. Of 573 articles identified, 9 studies met the eligibility criteria and were included in our analysis. The overall percentage dose savings attained when dialysis patients were converted from epoetin to darbepoetin alfa was 30% (range: 4%–44%). Greater dose savings were noted with intravenous administration (33%) compared with subcutaneous (27%) and between switch-over studies (31%) and RCTs (27%). In all studies, target haemoglobin levels were maintained before and after conversion.Conclusion. This meta-analysis demonstrates that when using an initial 200:1 conversion ratio, as indicated on the European label, from epoetin to darbepoetin, a subsequent reduction in dose was observed and an average 30% dose savings could be achieved.

Every-Other-Week Darbepoetin Alfa in the Correction and Maintenance of Haemoglobin Levels in Elderly Patients with Chronic Kidney Disease

Anaemia is a common complication of chronic kidney disease (CKD) and is associated with increased rates of mortality and diminished quality of life in patients with CKD. Although extended dosing with darbepoetin alfa, an erythropoiesis-stimulating agent (ESA), has been shown to be effective in maintaining haemoglobin (Hb) levels in CKD patients, little information is published on the use of darbepoetin alfa in the correction and maintenance of Hb levels in elderly CKD patients naive to ESA therapy. This post hoc subanalysis of data from two clinical trials was conducted to investigate the efficacy and safety profile of de novo every-other-week (q2w) darbepoetin alfa in elderly patients with CKD-associated anaemia (not on dialysis), as compared with that of a younger (aged <65 years) patient cohort. This analysis was based on data obtained from two open-label, single-arm, multicentre studies of similar design. Patients were aged >or=18 years and naive to previous ESA therapy. Darbepoetin alfa administration was initiated at 0.75 microg/kg and titrated according to individual patient requirements to achieve and maintain Hb levels between 11.0 and 13.0 g/dL. The proportion of patients who achieved the primary endpoint, Hb >or=11.0 g/dL (study 1), and an Hb level between 11.0 and 13.0 g/dL (study 2) at weeks 4, 8 and 12 weeks and at the end of the study were determined. The results of this subanalysis were stratified by age (<65, 65-74 and >or=75 years). A total of 203 patients were enrolled in the two studies; 60% were female, 84 (41%) were aged <65 years, 57 (28%) were aged 65-74 years and 62 (31%) were aged >or=75 years. The proportion of patients who achieved Hb levels of >or=11.0 g/dL in study 1 and 11.0-13.0 g/dL in study 2 at week 20 were 93%, 96% and 92%, respectively, for the three age groups. Weight-adjusted q2w darbepoetin alfa doses were similar between the age groups and stable throughout the study period. The mean (standard deviation) Hb levels at week 21 were 12.0 (1.2), 12.7 (1.1) and 12.6 (1.0) g/dL in subjects aged <65, 65-74 and >or=75 years, respectively. The median (standard error) time to reach the primary endpoint was 5.0 (4.7), 5.0 (5.7) and 5.0 (5.7) weeks for subjects aged <65 years, 65-74 years and >or=75 years, respectively. The safety profiles of q2w darbepoetin alfa in both the older and younger age-groups were consistent with those expected for patients with CKD not receiving dialysis. The results of this study suggest that ESA-naive subjects aged <65, 65-74 and >or=75 years of age with CKD (not receiving dialysis) who received q2w darbepoetin alfa were able to achieve and maintain Hb levels at 11.0-13.0 g/dL. The de novo q2w treatment regimen with darbepoetin alfa described in the present report may help optimize anaemia management in CKD-associated anaemia patients, including those in the older adult population.