Early hemoglobin response and alternative metrics of efficacy with erythropoietic agents for chemotherapy-related anemia

OBJECTIVE: To examine associations between early hemoglobin response and alternative measures of efficacy following treatment with an erythropoietic agent for chemotherapy-related anemia. RESEARCH DESIGN AND METHODS: Preliminary data from an ongoing randomized, multicenter, 16-week, open-label clinical trial of epoetin alfa versus darbepoetin alfa were used to dichotomize patients based on attainment of early hemoglobin response (> or = 1 g/dL increase in hemoglobin level within 4 weeks of treatment initiation). Measures of efficacy were compared between patients with early hemoglobin response and those without. Sensitivity analyses were then performed to evaluate the impact of various methods for handling censored data and hemoglobin values following blood transfusion. MAIN OUTCOME MEASURES: Efficacy measures included: the proportion of patients with a > or = 1 g/dL increase in hemoglobin by 4 weeks or a > or = 2 g/dL increase by 8 weeks; mean hemoglobin levels at 4, 8, 12, and 16 weeks; area under the curve for change in hemoglobin level; proportion of patients who required a blood transfusion after 4 weeks; proportion of follow-up days on which patients had hemoglobin levels within the therapeutic range of 11 g/dL to 13 g/dL; and proportion of patients who never had a hemoglobin level within this range. RESULTS: A total of 274 patients were included (66.1% female, mean age 62.4), of whom 48.9% had an early hemoglobin response and 51.1% did not. Mean duration of follow-up was 10.1 +/- 5.05 weeks. All metrics indicated superior longer-term response among patients with early hemoglobin response compared to patients without early response. The findings were robust across sensitivity analyses. Although the analysis establishes a significant relationship between early hemoglobin response and alternative efficacy metrics, causality cannot be inferred. CONCLUSIONS: Early hemoglobin response is significantly associated with various metrics of clinical response to erythropoietic agents and is an appropriate measure for evaluating treatment effects.     

Randomized,double-blind,placebo-controlled trial of every-3-week darbepoetin alfa 300 micrograms for treatment of chemotherapy-induced anemia

ABSTRACT

Objective: Darbepoetin alfa is effective in treating chemotherapy-induced anemia (CIA). Administration of subcutaneous darbepoetin alfa every 3 weeks (Q3W) could simplify treatment through synchronization with common Q3W chemotherapy regimens. We report results from a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial evaluating the efficacy and safety of fixed-dose Q3W darbepoetin alfa in patients with a wide variety of tumor types who experienced CIA.

Research design and methods: Patients aged?≥?18 years with anemia (hemoglobin <11?g/dL) being treated for nonmyeloid malignancy were randomized 1:1 to receive darbepoetin alfa 300?μg (n?=?193) or placebo (n?=?193) subcutaneously Q3W from weeks 1 to 13 in this 16-week study. Doses could be adjusted per prespecified rules.

Main outcome measures: The primary endpoint was the proportion of patients who received ≥1 red blood cell (RBC) transfusion between week 5 and the end of the treatment period (EOTP). The study also analyzed the proportions of patients achieving a hemoglobin concentration ≥11?g/dL and subsequently maintaining hemoglobin levels above 11?g/dL, and the change in hemoglobin concentration over time.

Results: The proportion of patients requiring RBC transfusions between week 5 and EOTP was significantly lower in the darbepoetin alfa-treated group than in the placebo-treated group (24 vs. 41% of patients, a 16.3% difference, p?<?0.001). There were no differences between the two treatment arms in quality-of-life measures. Cardiovascular/thromboembolic adverse events were uncommon and were not associated with increases in hemoglobin levels. Study limitations suggest caution in the interpretation of these results: transfusions, the primary endpoint, were recommended but not required if hemoglobin concentrations were ≤8.0?g/dL, and protocol deviations (primarily dosing errors) occurred in approximately one-half of the patients in both treatment groups.

Conclusions: In this study, fixed-dose Q3W darbepoetin alfa appeared to be well-tolerated and effective for the treatment of CIA.

Trial registration: ClinicalTrials.gov identifier: NCT00110955.     

Anemia treatment with Q2W darbepoetin alfa in patients with chronic kidney disease naïve to erythropoiesis-stimulating agents*

ABSTRACT

Objective: To evaluate the efficacy and safety of darbepoetin alfa dosed every-other-week (Q2W) to treat anemia in subjects with chronic kidney disease (CKD), not receiving dialysis, who were naïve to erythropoiesis-stimulating agent (ESA) therapy.

Research design and methods: This was an open-label, multicenter, single-arm study enrolling ESA-naïve CKD subjects with baseline hemoglobin (Hb)?<?11.0?g/dL. Q2W darbepoetin alfa treatment was initiated at a dose of 0.75?µg/kg and titrated to achieve and maintain Hb levels at 11.0–13.0?g/dL. Treatment was administered from week 1 to week 19.

Main outcome measures: The primary endpoint was the proportion of subjects who achieved Hb?≥?11?g/dL at any study visit, except in week 1. Hb levels, darbepoetin alfa dose, and safety were also assessed.

Results: Of the 128 subjects who received at least one dose of darbepoetin alfa and of the subjects who completed the study, 118 (92%) and 112 (97%), respectively, achieved a Hb?≥?11?g/dL in a median time of 5 weeks. Median darbepoetin alfa dose at week 1 and at the time of achieving a Hb?≥?11?g/dL were 60 and 80?µg, respectively. Darbepoetin alfa was well-tolerated, and short-term adverse events were consistent with those expected in CKD subjects.

Conclusions: This study demonstrates that de novo Q2W darbepoetin alfa was effective in correcting and maintaining Hb levels in ESA-naïve subjects with CKD who were not receiving dialysis. Study limitations, including lack of a control arm for the study and multiple race information for subjects, must be considered in interpreting the results.

Trial registration: ClinicalTrials.gov identifier: NCT00112008.     

Comparison of the therapeutic effects of epoetin zeta to epoetin alfa in the maintenance phase of renal anaemia treatment

ABSTRACT

Objective: To evaluate the therapeutic efficacy and safety of epoetin zeta, compared with epoetin alfa, in maintaining target haemoglobin (Hb) concentrations in patients with anaemia and chronic kidney disease (CKD) maintained on haemodialysis.

Methods: Patients received epoetin zeta or epoetin alfa intravenously, 1–3 times/week for 12 weeks, then the alternative treatment for 12 weeks, in this double-blind, crossover, phase III trial. Eligible patients were 18–75 years old with CKD stage 5 maintained on haemodialysis. Patients had received epoetin for ≥ 3 months upon study entry and had achieved a target Hb level of 10.5–12.5?g/dL with a stable epoetin dose.

Main outcome measures: Primary efficacy endpoints were intra-individual differences (test–reference) in mean Hb levels and mean weekly dose/kg of body weight. Safety endpoints included occurrence of neutralizing anti-erythro­poietin antibodies, tolerability, and adverse events (AEs).

Results: In total, 313 patients were randomized to receive epoetin zeta (n = 155) or epoetin alfa (n = 158); 146 and 145 patients (respectively) switched treatment after 12 weeks. Mean (range) Hb levels were 11.35 (8.96–14.22) g/dL and 11.54 (8.74–13.84) g/dL for patients receiving epoetin zeta and epoetin alfa, respectively (95% confidence interval [CI] [test–reference]: 0.09–0.28?g/dL, within the predefined equivalence range of ±?0.6?g/dL). Mean (range) weekly doses were 92.68 (12.74–398.41) IU/kg/wk and 92.58 (10.53–393.07) IU/kg/wk for patients receiving epoetin zeta and epoetin alfa, respectively (95% CI [test–reference]: –4.67 and 4.29 IU/kg/wk, within the equivalence range of ±?45.00?IU/kg/wk). Patients underwent minor nominal dose adjustments during treatment crossover. AE profile was similar for both products; the most commonly reported AEs were infections and infestations (in 26.5% of patients receiving epoetin zeta and 23.6% receiving epoetin alfa). No patients developed neutralizing anti-erythropoietin antibodies.

Conclusions: Epoetin zeta is therapeutically equivalent to epoetin alfa in the maintenance of target Hb levels in patients with renal anaemia. No unexpected AEs were seen.     

A randomized,controlled trial comparing darbepoetin alfa correction/maintenance dosing with weekly dosing for treating chemotherapy-induced anemia

ABSTRACT

Objective: To evaluate if a darbepoetin alfa correction/maintenance dosing regimen is non-inferior to a weekly regimen with respect to red blood cell trans­fusion requirements in patients with chemotherapy-induced anemia (CIA).

Research design and methods: In this randomized, active-controlled, double-blind phase 3 trial, CIA patients were randomized 1?:?1 to receive darbepoetin alfa in either a correction/maintenance schedule (4.5?μg/kg weekly for 4 weeks followed by 4.5?μg/kg every 3 weeks (Q3W)) or a weekly schedule (2.25?μg/kg weekly). The primary endpoint was the transfusion incidence during weeks 1–16. Non-inferiority was to be concluded if the upper limit of the 95% confidence interval (CI) of the difference in transfusion incidence between treatment groups was below 12.5%. Hematologic responses and safety profiles were also compared.

Results: Transfusion incidence (95% CI) during weeks 1–16 was 37% (32–42) and 38% (32–43) in the weekly and correction/maintenance groups, respectively. The difference (95% CI) in transfusions was 0.4% (–7.0 to 7.8), demonstrating non-inferiority between treatment groups. Similar percentages in both groups achieved and maintained hemoglobin in a target range of 11–13?g/dL and had clinically meaningful FACT?F score improvements. The median (range) time to hemoglobin response was 10 (1–17) weeks and 12 (2–17) weeks in the weekly and correction/maintenance groups, respectively. Both groups had similar safety profiles.

Conclusions: A correction/maintenance schedule with its initial two-fold higher weekly dosing and subsequent Q3W dosing yielded outcomes similar to those observed with a weekly schedule. Although correction/maintenance dosing provided no incremental clinical benefit, Q3W dosing could provide benefits of convenience and facilitate patient compliance.     

Therapeutic effects of epoetin zeta in the treatment of chemotherapy-induced anaemia

ABSTRACT

Objective: To perform an open, non-controlled, multiple-dose, international, multicentre, phase III study to evaluate epoetin zeta, a biosimilar epoetin referenced to epoetin alfa, for the treatment of chemotherapy-induced anaemia in patients with cancer.

Methods: Safety, tolerability and efficacy of subcutaneously administered epoetin zeta were assessed in 216 patients with solid tumours or non-myeloid haematological malignancies receiving chemotherapy and at risk of transfusion.

Results: A significant (p?<?0.0001) increase in mean haemoglobin (Hb) level (1.8?g/dL) was observed between baseline and week 12 (intent-to-treat population); 176/216 (81.5%) patients achieved a response (increase in Hb?≥?1?g/dL or reticulocyte count ≥40?000 cells/μL) by week 8. Over the treatment period, 231 treatment-emergent adverse events were experienced by 91 patients; 9/216 (4.2%) experienced a clinically significant thrombotic event within the first 12 weeks of epoetin zeta treatment, significantly lower than the assumed 18% baseline incidence (p?<?0.0001) based on historical data from epoetin trials. No transfusion was necessary for 175/216 patients (81.0%) and quality of life improved over the study. No patients developed anti-erythropoietin antibodies. Sponsor trial no: CT-830-05-0009.

Conclusion: This study demonstrates that subcutaneously administered epoetin zeta is well-tolerated and has efficacy in the treatment of anaemia in patients with cancer receiving chemotherapy and at risk of transfusion.     

Randomized,open-label comparison of epoetin alfa extended dosing (80 000 U Q2W) vs weekly dosing (40 000 U QW) in patients with chemotherapy-induced anemia

ABSTRACT

Objective: This randomized, open-label, multicenter study compared the efficacy and safety of epoetin alfa (EPO) 80 000 U every 2 weeks (Q2W) to the FDA-approved regimen of 40 000 U weekly (QW) in patients with chemotherapy-induced anemia.

Research design and methods: A total of 310 patients with nonmyeloid malignancy and baseline hemoglobin (Hb) < 11?g/dL who were scheduled to receive chemotherapy for a minimum of 12 weeks were randomized to EPO Q2W or QW for up to 12 weeks, with dose modification to maintain Hb at approximately 12?g/dL. Efficacy analyses used the per-protocol population (patients who completed the study with a value for Hb change) for the primary endpoint only and the modified intent-to-treat (mITT) population (patients who received study drug and had at least one postbaseline Hb value) for the primary and secondary endpoints.

Results: Analysis of the primary endpoint revealed that the mean change in Hb from baseline to study end was comparable between the Q2W and QW groups in the per-protocol population (1.6?g/dL vs 1.8?g/dL, respectively; treatment difference, ?0.2?g/dL; one-sided 95% confidence interval [‐0.56, ‐]); similar results were observed in the mITT population. Among patients on study at Day 29, 9.6% (13/135) and 11.1% (14/126) of patients in the Q2W and QW groups, respectively, received a transfusion between Day 29 and the end of the study (p = 0.709). Dose withholds (21% vs 42%, p < 0.001) and dose reductions (41% vs 59%, p = 0.003) were less common for Q2W than QW. Safety profiles were similar between groups; clinically relevant thrombotic vascular events occurred in 8% of patients in each group. The open-label dosing and the patient attrition rate did not appear to influence overall study results.

Conclusions: Extended dosing (80 000 U Q2W) and once-weekly dosing (40 000 U QW) of EPO provided comparable safety and efficacy for chemotherapy-induced anemia.     

Epoetin delta is effective for the management of anaemia associated with chronic kidney disease

ABSTRACT

Objective: To demonstrate the efficacy and safety of epoetin delta for the treatment of anaemia in dialysis patients with chronic kidney disease (CKD).

Research design and methods: This was a 12‐week, randomized, double-blind, active-comparator study. CKD patients who were naïve to epoetin treatment and had haemoglobin < 10?g/dL were randomized to epoetin delta 15, 50, 150, or 300 IU/kg or epoetin alfa 50 IU/kg. Patients initially entered a correction phase until they recorded haemoglobin of ≥ 11.5?g/dL for two consecutive weekly measurements or one haemoglobin measurement of ≥ 13?g/dL (correction success). A maintenance phase followed where the dose was adjusted to maintain haemoglobin ≥ 10.5?g/dL. Maintenance success was defined as haemoglobin > 10.5?g/dL at Week 12. Total success was defined as achieving maintenance and correction success.

Main outcome measures: The primary objective was to demonstrate that the proportion of patients achieving total success was greater in the pooled 150?IU/kg and 300?IU/kg groups compared with the 15?IU/kg dose group.

Results: Total success was achieved in 55.6% of patients in the pooled highest epoetin delta group compared with 4.5% in the lowest dose group. There was no significant difference in total success for the epoetin delta and epoetin alfa 50?IU/kg groups. Significant increases in haemoglobin and haematocrit levels were observed in the 150 and 300?IU/kg dose groups. Adverse events occurred at frequencies expected for this patient group.

Conclusions: Epoetin delta was effective in increasing haemoglobin levels in patients with baseline haemoglobin of < 10?g/dL.     

Preference for monthly darbepoetin alfa dosing in patients with chronic kidney disease not receiving dialysis

ABSTRACT

Objective: To determine patient preference for once-weekly Epoetin alfa versus once-monthly (QM) darbepoetin alfa in patients with chronic kidney disease (CKD) not receiving dialysis.

Methods: AMPS (Aranesp Monthly Preference Study) consisted of two studies of similar design, each with a 2-week screening/baseline period, a 20-week QM darbepoetin alfa dosing period, and an 8-week follow-up period. Patients aged ≥18 years had a nephrologist-reported diagnosis of CKD but were not receiving dialysis, and were required to have at least two hemoglobin levels within 10–12?g/dL and to have been receiving a stable dose (< 25% change) of once-weekly or once- every-other-weekly Epoetin alfa for at least 8 weeks. At week 21, patients could continue on QM darbepoetin alfa or revert back to their previous Epoetin alfa regimen. The primary analysis assessed patient preference at week 21 for QM darbepoetin alfa versus previous onceweekly Epoetin alfa.

Results: AMPS enrolled 442 patients: 54% were female, 67% were Caucasian, and mean (SD) age was 68.3 (13.5) years. At week 21, 346 patients remained on study. Of the patients converted from once-weekly Epoetin alfa, 86% (138/161) preferred darbepoetin alfa QM, and of all patients who expressed a preference, regardless of previous Epoetin alfa dosing frequency, 96% (305/319) preferred QM darbepoetin alfa. Mean (SD) hemoglobin at week 29 of the study was similar to mean hemoglobin at baseline (for those who completed the study and were receiving QM darbepoetin alfa at week 29: 11.2 [1.1]?g/dL at week 29 versus 11.4 [0.7]?g/dL at baseline). QM darbepoetin alfa was well tolerated.

Conclusion: These data show that the majority of study patients preferred QM darbepoetin alfa to more frequent Epoetin alfa, and that QM darbepoetin alfa maintained hemoglobin levels at week 29 and was well tolerated over the study period. The single-item questionnaire could be a potential limitation of this study and further investigation with a multi-question instrument may be helpful in confirming these results.     

A prospective observational study of the effectiveness,safety, and effect on fatigue of darbepoetin alfa for the treatment of chemotherapy-induced anaemia

ABSTRACT

Objective: Anaemia is common in cancer patients treated with chemotherapy. Darbepoetin alfa (DA) is the only erythropoiesis-stimulating protein approved for administration at weekly and every-three-week intervals in cancer patients receiving chemotherapy. This article investigates the effectiveness, tolerability and effect on fatigue of DA.

Methods: Prospective, observational study performed in 30 Spanish centres. Eligible patients were ≥?18?years of age, anaemic (haemoglobin [Hb] ≤?11?g/dL), with non-myeloid malignancies, receiving chemotherapy. DA (150?μg) was administered weekly for a maximum of 16?weeks (dosage doubled if Hb increased <?1?g/dL after 4?weeks).

Main outcome measures: Haematopoietic response (Hb increase ≥?2?g/dL or Hb ≥?12?g/dL in the absence of transfusions in the previous 28?days), transfusion required between Weeks 5 and 16 and fatigue measured by the Fatigue subscale of the Functional Assessment of Cancer Therapy.

Results: 293 adults were recruited (56.4% women), with lymphoproliferative malignancies (44.3%) or solid tumours (55.7%). Baseline Hb was 9–11?g/dL in 83.7% of patients. Sixty-four per cent (95% CI: 58.1–69.4%) had a haematopoietic response and 12% required transfusions. After adjusting for performance status, concomitant diseases and chemotherapy type, an increase in Hb level was significantly associated with an improvement in Fatigue subscale (+1.9 points per 1?g/dL). Only 2% of patients had treatment-related adverse events: thromboembolic pulmonary disease (0.3%); hypersensitivity reaction (0.3%); local pain following DA administration (0.3%); insomnia (0.3%); thrombocytosis (0.3%) and deep vein thrombosis (0.3%).

Conclusions: Fixed-dose DA administered once weekly seems to be an effective, well-tolerated treatment for chemotherapy-induced anaemia in patients with non-myeloid malignancies, and there is an indication of a possible benefit on fatigue in the clinical practice.     

Comparison of the therapeutic effects of epoetin zeta and epoetin alfa in the correction of renal anaemia

ABSTRACT

Objective: To assess the therapeutic equivalence of epoetin zeta and epoetin alfa for correction of haemoglobin (Hb) concentration in patients with anaemia and chronic kidney disease (CKD) stage 5 maintained on haemodialysis.

Study design: In total, 609 patients with CKD and anaemia (Hb?<?9?g/dL) were randomly assigned to receive either epoetin zeta or epoetin alfa intravenously, one to three times per week for 24 weeks. Dosing was titrated individually to achieve a stable, target Hb concentration of 11–12?g/dL. Primary endpoints were the mean weekly dose of epoetin per kilogram of body weight and mean Hb concentration during the last 4 weeks of treatment. Safety endpoints were the occurrence of anti-erythropoietin antibodies, ratings of tolerability and adverse events (AEs).

Results: Mean (± standard deviation [SD]) Hb concentration over the last 4 weeks of treatment was 11.61?±?1.27?g/dL for patients receiving epoetin zeta, compared with 11.63?±?1.37?g/dL for patients receiving epoetin alfa (95% confidence interval [CI]: –0.25 to 0.20?g/dL). Mean (± SD) epoetin zeta weekly dose over the last 4 weeks of treatment was 182.20?±?118.11?IU/kg/wk, compared with 166.14?±?109.85?IU/kg/wk for epoetin alfa (95% CI: –3.21 to 35.34?IU/kg/wk). The most commonly reported AEs (> 5% of patients) were infections and infestations (12.5% and 12.8% of patients treated with epoetin zeta and epoetin alfa, respectively) and vascular disorders (8.5% and 8.9%, respectively). No patients developed neutralizing anti-erythropoietin antibodies.

Conclusions: Epoetin zeta, administered intravenously, is therapeutically equivalent to epoetin alfa in the correction of low Hb concentration in patients with CKD undergoing haemodialysis. No unexpected AEs were seen and both epoetin zeta and epoetin alfa were well tolerated.     

Hemoglobin levels that trigger erythropoiesis-stimulating agent treatment decisions for cancer-associated anemia – examination of practice in Germany

ABSTRACT

Objective: Given the safety concerns regarding off-label use of erythropoiesis-stimulating agents (ESAs) in the treatment of cancer-associated anemia, data from the German Cancer Anemia Registry (CAR) were analyzed to examine whether current practice in Germany adheres to treatment guidelines.

Research design and methods: CAR was a web-based registry gathering patient data for 12 weeks following anemia diagnosis or until the primary treatment objective was achieved.

Results: Of over 2000 patients surveyed, 783 were treated with ESAs. Treatment was primarily aimed at improvement of quality of life (37.3%), hemoglobin correction (32.7%), and prevention of transfusions (24.4%). The average hemoglobin level triggering ESA treatment was 9.7?g/dL (6.0?mmol/L), however, starting levels varied with cancer type. For 67.8% of patients, transfusions could be avoided. ESA treatment was stopped at 11.2?g/dL (7.0?mmol/L) and maximum hemoglobin levels during the study averaged 11.8?g/dL (7.3?mmol/L). In 4.8% of the women and 6.0% of the men, maximum hemoglobin levels were >14?g/dL (8.7?mmol/L); in 15.6% and 9.1%, respectively, levels were between 13 and 14?g/dL. The median hemoglobin level triggering transfusion was 8.3?g/dL (5.2?mmol/L), irrespective of the malignant disease.

Conclusion: Current use of ESAs for the treatment of cancer-associated anemia in Germany appears to be in good compliance with treatment guidelines. Similar results obtained from other studies in Europe and the US indicate this to be true beyond Germany.     

The prevalence of anemia in patients with chronic kidney disease

SUMMARY

Objective: Anemia is a complication of chronic kidney disease and may contribute to adverse clinical outcomes. Early identification and treatment of anemia may improve cardiovascular morbidity and mortality. No large-scale population data are available specifically for patients with chronic kidney disease regarding prevalence of anemia, subpopulations at risk, and relationships between anemia and kidney function. This study was undertaken to address these questions in patients with chronic kidney disease, and investigate the relationship between anemia and glomerular filtration rate.

Research design and methods: Large-scale, cross-sectional, US multicenter survey; 5222 patients (mean age, 68.2?years; 46.6% male); 237 physician practices. Eligible patients: ≥ 18?years of age; serum creatinine: 1.5?mg/dL–6.0?mg/dL (females), 2.0?mg/dL–6.0?mg/dL (males).

Main outcome measures: Primary study end point: prevalence and severity of anemia (hemoglobin ≤ 12?g/dL). Data further stratified by hemoglobin (≤ 12?g/dL, ≤ 10?g/dL).

Results: Primary etiologies of chronic kidney disease (5222 evaluable patients): diabetes (49.5%); hypertension (33.0%). Glomerular filtration rate: < 60?mL/min/1.73?m² for 97.7% of evaluable patients. Mean ± SD serum creatinine level: 2.2?mg/dL ± 0.9?mg/dL; 2.5?mg/dL ± 1.0?mg/dL for males, 2.0?mg/dL ± 0.8?mg/dL for females. Mean ± SD hemoglobin: 12.2?g/dL ± 1.6?g/dL (47.7% had hemoglobin ≤ 12?g/dL; 8.9% had hemoglobin ≤ 10?g/dL). Prevalence of anemia was strongly associated with declining glomerular filtration rate. Percentage of patients with hemoglobin ≤ 12?g/dL increased from 26.7% to 75.5% when glomerular filtration rate decreased from ≥ 60?mL/min/1.73?m² to < 15?mL/min/1.73?m². Prevalence of hemoglobin ≤ 10?g/dL increased substantially from 5.2% to 27.2% when glomerular filtration rate diminished from ≥ 60?mL/min/1.73?m² to < 15?mL/min/1.73?m². After controlling for other patient characteristics associated with increased prevalence of anemia, the prevalence odds ratio for hemoglobin ≤ 10?g/dL was 0.54 (0.49–0.60) and for hemoglobin ≤ 12?g/dL was 0.68 (0.65–0.72), with each 10-mL/min/1.73?m² increase in glomerular filtration rate. Predictors of anemia: diabetes, female sex, and race/ethnicity.

Conclusions: Anemia was present in 47.7% of 5222 predialysis patients with chronic kidney disease. Prevalence of anemia increased as kidney function decreased. Certain subgroups are at increased risk for anemia.     

Retrospective observational study of patients with chemotherapy-related anemia receiving erythropoietic agents

OBJECTIVE: Epoetin alfa (EPO) and darbepoetin alfa (DARB) are approved for the treatment of chemotherapy-related anemia (CRA) in patients with nonmyeloid malignancies. This study examined dosing and hematologic outcomes with these agents in community oncology clinics. METHODS: Medical charts were abstracted retrospectively for 1005 patients (527 EPO, 478 DARB) with CRA (hemoglobin [Hb] < or = 11 g/dL) who received EPO or DARB at 10 U.S. oncology clinics between January 2002 and March 2003. MAIN OUTCOME MEASURES: Outcome measures included dose and frequency of erythropoietic therapy, change in Hb at 4, 8, and 12 weeks after initiation of therapy, and transfusion of packed red blood cells. RESULTS: Baseline characteristics were generally similar between groups. Most EPO-treated patients received EPO once weekly, but 25% received EPO every 2-3 weeks, with 40,000 U the predominant dose. DARB was usually given every 1-2 weeks in doses ranging from 200-400 mcg/injection. Mean treatment duration was relatively short (< 8 weeks) in both groups, with a similar number of Hb determinations and similar incidence of red blood transfusion between groups. Hb increased from baseline in the EPO and DARB groups at 4 weeks (0.99 vs. 0.69 g/dL, p = 0.003), 8 weeks (1.39 vs. 1.06 g/dL, p = 0.011), and 12 weeks (1.43 vs. 1.11 g/dL, p = 0.055). Early Hb response (> or = 1 g/dL increase by 4 weeks) was more common with EPO than DARB (48% vs. 38%, p = 0.008). CONCLUSIONS: EPO was superior to DARB for early hematologic outcomes in patients with CRA in community oncology clinics. Retrospective data collection and relative inexperience with DARB at the time of the study may limit the generalization of these results. Randomized, controlled trials comparing EPO and DARB are warranted.     

The association of darbepoetin alfa with hemoglobin and health-related quality of life in patients with chronic kidney disease not receiving dialysis

ABSTRACT

Objective: Anemia of chronic kidney disease (CKD) decreases patients’ health-related quality of life (HRQoL). The objective of this subanalysis was to determine the effect of every-other-week (Q2W) darbepoetin alfa on hemoglobin (Hb) levels and HRQoL measures in subjects with CKD who are naïve to erythropoiesis-stimulating agents (ESAs).

Methods: STAAR was a 52-week, multicenter, single-arm study. Subject inclusion criteria included: ≥?18?years of age and creatinine clearance ≤?70?mL/min or estimated glomerular filtration rate ≤?60?mL/min/1.73 m² but not receiving dialysis. Subjects included in this subanalysis were previously naïve to ESAs, had Hb <?11?g/dL, were initiated on subcutaneous Q2W darbepoetin alfa to achieve a Hb level not to exceed 12?g/dL, and had responses to at least one question on the KDQOL-CRI forms administered at baseline, week 12, and week 52.

Results: Of 911 ESA-naïve subjects enrolled in the study, 277 (30.4%) were included in this subanalysis. The majority of subanalysis subjects were Caucasian (63.2%) and/or women (54.5%). Mean Hb concentrations and all KDQOL-CRI scores improved significantly between baseline and week 12 (?p < 0.0001), and were maintained until week 52. Darbepoetin alfa was well tolerated.

Conclusions: Darbepoetin alfa initiated Q2W achieved and maintained Hb targets, and significantly improved and maintained HRQoL in study subjects with CKD. Limitations of the study must be considered when extrapolating these results to assess the benefits of treatment on HRQoL in the general CKD population.     

Reengineering clinical operations in a medical practice to optimize the management of anemia of chronic kidney disease

OBJECTIVES: To describe the clinic design, clinical evaluations, and treatment approaches used in a multidisciplinary clinic for management of anemia of chronic kidney disease (CKD), and to evaluate several selected clinical outcomes associated with this approach to anemia management. SETTING: University-affiliated, division of nephrology, outpatient multidisciplinary model CKD clinic headed by a clinical pharmacist. PATIENTS: One hundred sixty-six patients with anemia of CKD who were referred by nephrologists and primary care providers to the multidisciplinary clinic from March 1, 2002-July 31, 2004. MEASUREMENTS AND MAIN RESULTS: Patients received darbepoetin alfa dosed on an every-other-week basis. If patients were already receiving once-weekly recombinant human erythropoietin (r-HuEPO), the darbepoetin alfa dose was calculated by using the darbepoetin alfa package insert conversion table. If patients were na?ve to previous erythropoietic therapy, the darbepoetin alfa dose was either 60 microg or 0.7 microg/kg. The dose and frequency of darbepoetin alfa and oral iron supplements were adjusted to achieve the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) targets for hemoglobin levels and iron measures. The primary outcome analyzed was the proportion of patients with at least 30 days of treatment who achieved a target hemoglobin level of 11.0 g/dl or greater. Of 128 patients who received at least 30 days of treatment, 100 (78%) attained the hemoglobin level (mean +/- SD 11.7 +/- 7 g/dl). Ninety-nine of 128 patients were originally na?ve to erythropoietic therapy; 77 (78%) of these 99 patients achieved the hemoglobin target in a mean +/- SD of 7.9 +/- 7.5 weeks. These data contrast with the data of 29 patients seen in the year previous to the reengineered clinic process, whereby only 12 (41%) of these comparable patients reached hemoglobin target with r-HuEPO therapy. Of the 77 previously erythropoietic-na?ve patients, 82% were receiving darbepoetin alfa every other week, 14% every 3 weeks, and 4% every 4 weeks at the time the hemoglobin target was achieved. Oral iron administration significantly increased the chance of achieving the K/DOQI targets for hemoglobin and iron. CONCLUSION: Redefining roles and practices of members of a clinical practice and reengineering processes for anemia management were effective in achieving and maintaining target hemoglobin and iron levels.     

Dosing patterns,hematologic outcomes,and costs of erythropoietic agents in predialysis chronic kidney disease patients with anemia

ABSTRACT

Objective: Few observational studies have evaluated the use of epoetin alfa (EPO) and darbepoetin alfa (DARB) in chronic kidney disease (CKD) patients with anemia. The objective of this study was to investigate dosing patterns, hematologic outcomes, and intervention costs with EPO and DARB in anemic CKD patients treated in an ambulatory care setting.

Methods: This was a multicenter, retrospective, chart review of predialysis CKD patients with anemia treated with EPO or DARB. Charts were sequentially selected from 435 EPO and 432 DARB patients naive to erythropoietic therapy and treated for ≥ 24 weeks. Hemoglobin (Hb) levels, dates, and EPO/DARB doses were recorded. Drug costs using 2005 wholesale acquisition costs (WAC) and Federal Supply Schedule (FSS) pricing were based on the mean cumulative drug dose over the 24‐week study period.

Results: A total of 393 EPO and 396 DARB charts met all criteria with predominantly male subjects (EPO: 94%; DARB: 96%). Mean baseline GFR and Hb levels were similar. Once-weekly and extended dosing (≥ Q2W) was common in both groups. At Weeks 4, 8, and 12 following initiation of therapy, a greater proportion of EPO than DARB patients reached target Hb levels (≥ 11?g/dL) (?p < 0.0001); at Week 24, all patients reached target Hb levels. Mean 24‐week cumulative doses were EPO 279?336 ± 68?302 units and DARB 1084 ± 246?µg. Drug cost was higher for DARB independent of pricing utilized (WAC: EPO = $3400, DARB = $4726; FSS: EPO = $1528, DARB = $2379).

Conclusions: Extended dosing (≥ Q2W) was common in EPO- and DARB-treated patients with CKD-related anemia, with EPO-treated patients experiencing a significantly greater hematologic response (at Weeks 4, 8, and 12). In addition, drug cost was 39–56% higher in the DARB group. The male predominance may limit generalizability, warranting further research in other populations.     

Identification,diagnosis, and management of anemia in adult ambulatory patients treated by primary care physicians: evidence-based and consensus recommendations

ABSTRACT

Objective: Provide recommendations for the identification, diagnosis, and management of ambulatory patients with anemia.

Materials and methods: The RAND/UCLA Appropriateness Method was used to develop the recommendations. A literature review of anemia prevalence (based on a search of PubMed for the period 1990 to 2003), etiology, and treatment outcomes was reviewed by a panel comprised of nine physicians (six primary care, three specialists) who then rated 336 clinical scenarios and grouped them into three categories: ‘appropriate’, ‘uncertain’, or ‘inappropriate’.

Results: Performing a complete blood count on a yearly basis was rated ‘appropriate’ for patients with an underlying chronic condition, for men ≥ 50 years old, and for all women with no chronic condition on an every-5‐years basis. Specific recommendations were made for five anemia management options (observation, referral, empiric trial of iron, transfusion, and erythropoietic growth factors). Recommendations for observation alone were based on age, gender, and hemoglobin level. Immediate referral to a gastroenterologist or hematologist for a work-up was rated ‘inappropriate’ in all cases. An empiric trial of iron was rated ‘inappropriate’ for women over age 40 and for all men. Recommendations on the use of erythropoietic growth factors were based on hemoglobin level and anemia symptoms (‘appropriate’ if Hb < 9.5?g/dL, or if Hb = 9.5–11.0?g/dL and anemia symptoms were present). Finally, recommendations about transfusion were based on the severity of anemia and the presence of cardiovascular disease (‘appropriate’ in patients ≥ 70 years old and in those presenting with either symptoms of anemia or underlying cardiovascular disease). The recommendations did not address anemia related to nutritional deficiencies, cancer/chemotherapy, or chronic renal failure.

Conclusion: Primary care physicians should obtain screening blood counts, perform diagnoses, and manage anemia in patient groups known to be at risk. These recommendations on the identification, diagnosis, and management of anemia represent an opportunity to improve outcomes in ambulatory patients with anemia.     

Relationship between hemoglobin level and quality of life in anemic patients with chronic kidney disease receiving epoetin alfa

ABSTRACT

Objectives: To evaluate the relationship between hemoglobin (Hb) level and quality of life (QOL) in anemic patients with non-dialysis chronic kidney disease receiving epoetin alfa.

Patients and methods: A post-hoc analysis using data from a multicenter, open-label, prospective study of epoetin alfa for anemia in patients with chronic kidney disease not on dialysis was conducted. The relationship between Hb and QOL was analyzed using correlation and longitudinal analyses, the latter adjusting for sample selection bias. The Linear Analog Scale Assessment (LASA) and the Kidney Disease Questionnaire (KDQ) subscales were used to measure QOL. The impact of an incremental 1?g/dL increase in Hb level on LASA and KDQ scores was determined using an incremental analysis.

Results: A total of 1183 and 1044 patients formed the study populations for the LASA and KDQ analyses, respectively. There was a positive and significant relationship between Hb levels and QOL (?p < 0.05). Using non-linear regression analysis, we characterized the sigmoid-shape of the relationship between Hb levels and QOL scores. Hemoglobin change was a statistically significant determinant of QOL improvement for both LASA and KDQ scales (?p < 0.05). The model predicted that, based on a 2?unit change in Hb, the greatest incremental QOL improvement per unit of Hb increase occurred when Hb was in the range of 11 to 12?g/dL.

Conclusions: This study demonstrates that, beyond the well-known relationship between Hb increases and QOL improvements, the maximal incremental gain in QOL occurred when Hb reached 11 to 12?g/dL. This suggests that treating anemic patients with non-dialysis chronic kidney disease until their Hb level reaches 12?g/dL will result in the greatest QOL improvement per Hb unit increase. The analyses were conducted based on an open-label study of epoetin alfa and could be further validated using a randomized, controlled trial, comparing incremental gains in QOL associated with treatment initiation at varying levels of Hb across arms.     

Dosing patterns,drug costs,and hematologic outcome in anemic patients with chronic kidney disease switching from darbepoetin alfa to epoetin alfa

ABSTRACT

Objective: To compare real-world dosing patterns, drug costs, and hematologic outcome in anemic chronic kidney disease (CKD) patients, not receiving dialysis, who switched from darbepoetin alfa (DARB) to epoetin alfa (EPO) in a community practice setting.

Research design and methods: This retrospective observational chart review from a US nephrology clinic included 153 anemic CKD patients ≥ 18 years of age who did not receive dialysis during the study period, switched from DARB to EPO between 8/2003 and 8/2005, and received ≥ 2 doses of both agents. Paired t-test and McNemar's chi-square were performed comparing pre-switch and post-switch outcomes.

Results: Mean interval between doses increased from 24.3 ± 11.1 days with DARB to 28.8 ± 19.8 days with EPO (?p = 0.001). Weighted mean pre-switch weekly dose for DARB was 25?µg, while weighted mean post-switch weekly dose for EPO was 7090 Units, resulting in a dose ratio (Units EPO:µg DARB) of 287:1. These doses resulted in mean weekly costs of $110 (DARB) and $86 (EPO). Mean hemoglobin (Hb) levels increased over time from 10.8?g/dL at 6 months pre-switch to 11.1?g/dL 6 months after EPO initiation (?p = 0.0132). Mean Hb levels were > 11?g/dL, but below 12?g/dL, while patients received EPO.

Conclusions: Patients switching from DARB to EPO had a greater mean interval between doses, lower drug costs, and consistently maintained recommended Hb levels over time.

Limitations: The reverse direction (EPO to DARB) was not investigated. Although treatment outcomes were not assessed in a randomized, controlled setting, the study's observational nature provided actual evidence in a real-world setting.