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.     

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.     

Epoetin Beta: a review of its clinical use in the treatment of anaemia in patients with cancer

Epoetin beta (NeoRecormon) is a recombinant form of erythropoietin. It increases reticulocyte counts, haemoglobin (Hb) levels and haematocrit. Epoetin beta administered subcutaneously once weekly corrected anaemia and had equivalent efficacy to that of epoetin beta administered three times weekly in patients with haematological malignancies. Subcutaneous epoetin beta reduced transfusion requirements and increased Hb levels versus no treatment in patients with solid tumours and chemotherapy-induced anaemia in nonblind, randomised trials. Anaemia and quality of life were also improved, and blood transfusion requirements were reduced to a significantly greater extent than placebo or no treatment (with supportive blood transfusion) in patients with haematological malignancies. Most patients were receiving chemotherapy. Subcutaneous epoetin beta was well tolerated by patients with cancer; adverse events with the drug occurred with a similar incidence to those with placebo or no treatment (with supportive blood transfusion). Hypertension was relatively uncommon with epoetin beta in clinical trials. Patients with haematological malignancies and a baseline platelet count > or =100 x 10(9)/L, Hb levels of > or =9 g/dL or lower erythropoietin levels have demonstrated better responses to epoetin beta than other patients in clinical trials. However, neither baseline erythropoietin level nor the observed to predicted ratio of erythropoietin levels correlated with the response to epoetin beta in patients with solid tumours and chemotherapy-induced anaemia. A decrease of <1 g/dL or an increase in Hb with epoetin beta during the first chemotherapy cycle indicated a low transfusion need in subsequent cycles in patients with ovarian carcinoma. In general, the efficacy of epoetin beta is not limited by tumour type. Response to the drug occurred irrespective of the nature (platinum- or nonplatinum-based) or presence of chemotherapy treatment in randomised trials. CONCLUSION: Epoetin beta has shown efficacy in the management of cancer-related anaemia in patients with haematological malignancies and of chemotherapy-induced anaemia in patients with solid tumours. Once-weekly administration provides added convenience for patients and may be cost saving, although additional research into the potential pharmacoeconomic benefits of this regimen are required. The drug is well tolerated in patients with cancer and is associated with little injection-site pain when administered subcutaneously. Epoetin beta is an important option in the prevention of chemotherapy-induced anaemia, and a valid and valuable alternative to blood transfusion therapy for the treatment of cancer-related or chemotherapy-induced anaemia.     

Effectiveness and safety of recombinant human erythropoietin beta in maintaining common haemoglobin targets in routine clinical practice in Europe: the GAIN study

ABSTRACT

Objective: The Gain effectiveness in Anaemia treatment wIth NeoRecormon^* (epoetin beta) study (GAIN) evaluated the effectiveness and safety of recombinant human erythropoietin beta in correcting and/or maintaining common haemoglobin (Hb) targets in routine clinical practice in Europe.

Research design and methods: European 18-month observational, prospective clinical practice study across 217 centres from 13 countries. During a 3-month retrospective period, patients received any erythropoiesis stimulating agent (ESA). For the subsequent 18-month study phase, patients receiving intravenous (IV) epoetin beta or any other ESA were recommended to be switched to subcutaneous (SC) epoetin beta. Presence of anti-erythropoietin antibodies (AEAB) and related outcomes was investigated before and during the study.

Clinical trial registration: ClinicalTrials.gov number: NCT00551603.

Main outcome measures: Correction and maintenance of Hb levels within recommended target range and mean dose requirement to correct and maintain target Hb levels.

Results: A total of 4264 patients on haemodialysis received an ESA for treatment of renal anaemia. During the study period, the number of patients who maintained Hb levels in the recommended target range of 10–12?g/dL increased from 57% to 62%. Administration of SC epoetin beta resulted in a 24% lower mean dose requirement to maintain target Hb levels compared to IV administration (p?<?0.001). Considerable differences were observed between countries in the study. No patients developed pure red cell aplasia associated with AEAB during observation.

Conclusion: This observational study suggests that haemodialysis patients who are receiving any ESA via SC or IV administration for treatment of their renal anaemia can be safely and effectively switched to SC epoetin beta to achieve or maintain the currently recommended Hb targets. SC required a lower dose than IV administration to maintain similar efficacy, thereby potentially lowering the drug costs.

Trial registration: ClinicalTrials.gov identifier: NCT00551603.     

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.     

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.     

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.     

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.     

Utilization of darbepoetin alfa in relation to cancer patients’ hemoglobin levels

ABSTRACT

Objective: Previous labeling and guidelines recommended initiating erythropoiesis agents (ESAs) for chemotherapy-induced anemia (CIA) at hemoglobin (Hb) levels <?11?g/dL, maintaining near 12?g/dL, and withholding at ≥?13?g/dL. This study analyzed adherence with recommendations in administration of darbepoetin (DA) to cancer patients.

Design, setting, and participants: Retrospective analysis of Hb levels at which DA was administered using Varian electronic medical records (EMRs). The dataset comprises 141?694 cancer patients from 82 sites across 13 states. The study evaluated DA administrations with respect to recorded Hb for 8988 patients from 1/1/05 to 5/31/07.

Main outcome measures: Proportion of DA admin­istrations at Hb ≥?12 and Hb ≥?13?g/dL. Hb level was analyzed for all administrations, stratified by year and anemia type (CIA, anemia-of-cancer, and myelodysplastic syndrome).

Results: There were 51?111 DA administrations with Hb results. The proportion of administrations at Hb ≥?12?g/dL was 7.2% and at Hb ≥?13?g/dL was 0.6%, and for CIA 6.9%/0.6%, anemia of cancer (AOC) 8.8%/0.8%, and myelodysplastic syndrome (MDS) 6.5%/0.6%. The propor­tion of all DA administrations at Hb ≥?12?g/dL and ≥?13?g/dL declined from 8.6% to 5.3% (?p < 0.0001) and from 0.7% to 0.4% (?p < 0.0007), respectively during 1/1/05–5/31/07.

Conclusions: In this population, DA administration at Hb ≥?12?g/dL and Hb ≥?13?g/dL occurred in 7.2% and 0.6% of administrations, respectively, a ≈?93% adherence rate with recommendations. Further research is required to under­stand dose titrations at Hb 12–13?g/dL, and whether similar patterns are observed for other ESAs, and in other practice settings. This study provides context for the debate regarding the utilization, benefits and risks of ESAs in cancer patients.     

Epoetin delta,erythropoietin produced in a human cell line,in the management of anaemia in predialysis chronic kidney disease patients

ABSTRACT

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

Research design and methods: This was a multicentre, open-label, uncontrolled study with predialysis CKD patients who had previously received subcutaneous epoetin therapy. Patients were switched to epoetin delta from their previous therapy, at an identical dose. Dose was subsequently titrated to maintain haemoglobin at 10.0–12.0?g/dL. Study duration was 52 weeks.

Main outcome measures: The primary endpoint was average haemoglobin levels over Weeks 12, 16, 20 and 24. Secondary analyses were performed on the proportion of patients with haemoglobin and haematocrit levels over preset target levels, haemoglobin and haematocrit levels through to study end and dosing levels.

Results: Haemoglobin levels were maintained at 11.3 ± 1.2?g/dL over Weeks 12–24. Over 80% of the haemoglobin measurements and 95% of the haematocrit measurements were above the predefined target level (haemoglobin ≥ 10?g/dL; haematocrit ≥ 30%). Weekly dose levels did not change significantly over the course of the trial. Epoetin delta was well tolerated, with adverse events occurring at frequencies expected for this patient population; no patient developed neutralizing anti-erythropoietin antibodies.

Conclusions: Epoetin delta was an effective and well-tolerated agent for the management of anaemia in a subgroup of predialysis CKD patients.     

Effect of a continuous erythropoietin receptor activator (C.E.R.A.) on stable haemoglobin in patients with CKD on dialysis: once monthly administration*

ABSTRACT

Aims: This Phase II study aimed to determine the optimal dose and administration schedule of continuous erythropoietin receptor activator (C.E.R.A.) given subcutaneously (SC) in patients receiving dialysis converting directly from SC epoetin therapy 1–3 times/week. An extension phase examined long-term safety and efficacy.

Methods: Patients were assigned to one of three C.E.R.A. dose groups determined by multiplying the previous weekly dose of epoetin by one of three ratios (0.4/150, 0.8/150, 1.2/150 for groups A, B and C, respectively). Within each group, patients were randomized to once weekly (QW), once every 3 weeks (Q3W) and once monthly (Q4W) schedules. Dose adjustments were not permitted for the first 6 weeks. The core study period was 19 weeks (21 weeks in the Q4W cohorts). Patients could enter a 12?month extension period at the same schedule, aiming to maintain haemoglobin (Hb) at 11–12?g/dL.

Results: 137 patients entered the core period, and 62 continued into the extension period. A dose-dependent relationship was seen in the primary efficacy variable, change in Hb standardized to a 6 week period (?p < 0.0001), but effect was independent of schedule. Hb levels were maintained throughout the study, with few dose changes. C.E.R.A. was generally well tolerated and the most frequent adverse event was hypotension.

Conclusion: The results suggest that SC C.E.R.A. at up to once monthly intervals provides stable maintenance of Hb levels in dialysis patients converting directly from epoetin 1–3 times/week. Achieving tight Hb control with few dose adjustments at extended administration intervals may offer health benefits and improvements in resource management.

Trial registration: ClinicalTrials.gov identifier: NCT00364832.     

A randomised,cross-over study comparing injection site pain with subcutaneous epoetin beta and subcutaneous darbepoetin alfa in patients with chronic kidney disease*

ABSTRACT

Objective: To compare injection site pain of subcutaneous (sc) epoetin beta and darbepoetin alfa in adult patients with chronic kidney disease.

Research design and methods: This was a multi-centre, randomised, two-arm, single-blind, cross-over study. Patients were randomised to receive weekly sc darbepoetin alfa 30?μg or weekly sc epoetin beta 6000?IU for 2 weeks and were then crossed over to the alternative treatment for 2 weeks. Injection site pain was assessed using a 10?cm ungraduated visual analogue scale (0?=?no pain, 10?=?worst pain) and a six-point verbal rating scale. Patient preference for treatment was also assessed.

Trial registration: http://clinicaltrials.gov/(NCT00377481).

Results: All randomised patients (N?=?48) completed the study. The sample comprised 29 chronic kidney disease patients (Stage 3 or Stage 4), 11 peritoneal dialysis patients and 8 renal transplant patients. Patients perceived significantly less pain with epoetin beta than darbepoetin alfa, using the visual analogue scale (relative pain score?=?2.75, darbepoetin alfa:epoetin beta, 95% CI: 1.85, 4.07; p?<?0.0001) and the verbal rating scale (median: 0.5, 95% CI: 0.5, 1.0 vs. median: 1.5, 95% CI: 1.0, 2.0; p?<?0.0001). Epoetin beta was preferred by significantly more patients (65%) than darbepoetin alfa (10%) (p?<?0.001); 25% of patients reported no preference.

Conclusions: Limitations included lack of an epoetin alfa comparator and limited blinding (patients were blinded to treatment, however, an unblinded nurse administered treatment). We show that sc injection of epoetin beta is significantly less painful than darbepoetin alfa and patient preference for epoetin beta confirms that the difference is clinically meaningful.     

Haematopoietic effects of Angelica sinensis root cap polysaccharides against lisinopril-induced anaemia in albino rats

Context: Angelica sinensis L. (Umbelliferae) has medicinal properties.

Objectives: The present study evaluates the haematopoietic effects of A. sinensis polysaccharides (ASP) against lisinopril-induced anaemia.

Materials and methods: Thirty healthy adult male albino rats were randomly divided into five groups (n?=?6). Group I was control group. Group II was treated with angiotensin-converting enzyme inhibitor (ACEI, 20?mg/kg/day) to induce anaemia. In group III, erythropoietin (EPO, 100?IU/kg/each) was administered in combination with ACEI. Group IV was treated with ASP (1?g/kg/day), extracted from A. sinensis root caps. In Group V, ASP (1?g/kg/day) was treated with ACEI. After 28 days, blood and tissue samples were collected for haematological and histopathological analysis, respectively.

Results: The results showed that ACEI significantly reduced the haemoglobin (Hb, 10.0?g/dL), packed cell volume (PCV, 39.5%), red blood cells (RBCs, 6.2 million/mm³), mean corpuscular volume (MCV, 53.5 fL) and mean corpuscular haemoglobin (MCH, 16.2?pg/cell) values. In the group treated with ASP, the Hb (13.7?g/dL) and RBCs (7.8 million/mm³) increased significantly (p?p?3), MCV (54.42 fL) and MCH (16.44?pg/cell) values. While histopathological examination of the liver and kidney cells showed a mild degree of toxicity in the ASP-treated group.

Conclusion: ASP has a potentiating effect on haematological parameters when given alone. However, when administered simultaneously with lisinopril, it showed an unfavourable effect with more complicated anaemia so it should not be used with ACEIs.     

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

ABSTRACT

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 (≥ 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 ≥ 1?g/dL increase in hemoglobin by 4 weeks or a ≥ 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.     

Prevalence of anemia and correlation with biomarkers and specific antiretroviral regimens in 9690 human immunodeficiency virus-infected patients: findings of the Anemia Prevalence Study*

ABSTRACT

Objective: To describe anemia prevalence and correlates with biomarkers and antiretroviral therapy (ART) in HIV/AIDS.

Methods: Multicenter, cross-sectional study; clinical laboratory data collected at single visits, including hemoglobin (Hb), CD4⁺ count, HIV?1 RNA. Patients receiving care at US physician offices during the year 2000. Main outcome measure was anemia (Hb < 14?g/dL [men]; < 12?g/dL [women]) and marked anemia (Hb < 11?g/dL [men]; < 10?g/dL [women]) prevalence. Multivariable models examined association of anemia prevalence with HIV?1 biomarkers and ART.

Results: Among 9690 patients, prevalence of anemia and marked anemia was 36% and 5%, respectively. Among 1721 patients receiving no ART, 39.7% were anemic; among 7252 receiving highly active antiretroviral therapy (HAART), 35.5% were anemic (?p = 0.001). Anemia was most prevalent among men (37.3 vs. 32.3%; p?= 0.0008), blacks (49 vs. 26% [whites]; p < 0.0001), patients with CD4⁺ < 200 cells/mm³ (57 vs. 23% [≥ 500 CD4⁺]; p?< 0.00001), and HIV?1 RNA > 30?000 copies/ml (53 vs. 30% [< 500 copies/ml]; p?< 0.00001). Marked anemia was more common in women (6.8 vs. 4.3%; p?< 0.0001). Among treated patients, logistic regression analysis controlling for CD4⁺, HIV?1 RNA, sex, and ethnicity, zidovudine (ZDV)-containing regimens (except combination with saquinavir/ZDV/lamivudine) were associated with increased overall anemia risk (odds ratio, 1.39 : 1.74). No regimen was associated with increased risk for marked anemia. Multivariable logistic regression showed CD4⁺, sex, and ethnicity more strongly associated with anemia than any ART regimen.

Conclusion: This large, single-visit, cross-sectional, US-based study shows that anemia remains highly prevalent in HIV-infected patients. Data from this analysis suggest low CD4⁺ count, black ethnicity, and male sex are consistently strongest correlates of overall anemia; women are significantly more likely to have marked anemia.     

The cost of treating ribavirin-induced anemia in hepatitis C:the impact of using recombinant human erythropoietin

ABSTRACT

Objective: Ribavirin-induced anemia (RIA) is a common adverse effect of chronic hepatitis C treatment. Studies have shown that the use of epoetin decreases the need for ribavirin dose reduction or discontinuation. The primary objective was to calculate the incremental cost of treating hepatitis C in those without versus with RIA, using either the strategy of ribavirin dose reduction/discontinua­tion or epoetin. The secondary objective was to calculate the incremental cost of using epoetin versus no epoetin to treat RIA, per ribavirin dose reduction/discontinuation averted.

Methods: Estimates from the literature and decision-analytic techniques were used to model treatment patterns and estimate the cost of managing RIA in genotype 1, 2, and 3 subjects. Sensitivity analyses were used to address uncertainty.

Results: Clinically significant RIA, a reduction in hemoglobin of ≥ 2?g/dL (1.2?mmol/L), developed in 72% of patients in observational studies. The incremental cost of treating chronic hepatitis C decreased when employing the strategy of ribavirin-dose reduction/discontinuation to treat RIA, and increased by 5.7% (genotype 1) or 34.4% (genotype 2 or 3), when using epoetin. Using one-way sensitivity analyses, the cost of using epoetin per ribavirin dose reduction/discontinuation averted was $39?579–$52?023. Generalizability may be limited to settings in which a similar proportion of patients develop RIA.

Conclusions: The proportional cost of treating hepatitis C when using epoetin to treat RIA is significant in genotype 2 or 3 patients. The cost of using epoetin per ribavirin dose reduction/discontinuation averted is substantial in patients with genotypes 1, 2, or 3; and varies with the probability of response to epoetin. These findings suggest that additional studies are warranted that will determine the effect of epoetin on treatment outcomes and its role as supportive therapy in patients with RIA.     

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.     

Effect of saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes

ABSTRACT

Objective: To evaluate the efficacy and safety of once-daily saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes (T2D) and inadequate glycemic control.

Research design and methods: This study included a main treatment cohort (MTC) with 401 patients (HbA_1c?≥?7% and ≤10%) randomized and treated with oral saxagliptin 2.5, 5, or 10?mg once daily or placebo for 24 weeks and a separate open-label cohort (OLC) with 66 patients (HbA_1c?>?10% and ≤12%) who received saxagliptin 10?mg once daily for 24 weeks. Primary endpoint was HbA_1c change from baseline to week 24. Secondary endpoints included change from baseline to week 24?in fasting plasma glucose (FPG), proportion of patients achieving HbA_1c?<?7%, and changes in postprandial glucose area-under-the-curve (PPG-AUC). Efficacy analyses for continuous variables were performed using an ANCOVA model with last-observation-carried-forward methodology.

Results: In the MTC, saxagliptin demonstrated statistically significant decreases in adjusted mean HbA_1c changes from baseline (mean, 7.9%) to week 24 (?0.43%, ?0.46%, ?0.54%) for saxagliptin 2.5, 5, and 10?mg, respectively, vs. +0.19% for placebo (all p?<?0.0001). Adjusted mean FPG was significantly reduced from baseline (?15, ?9, ?17?mg/dL) for saxagliptin 2.5, 5, and 10?mg, respectively, vs. +6?mg/dL for placebo (p?=?0.0002, p?=?0.0074, p?<?0.0001, respectively). More saxagliptin-treated patients achieved HbA_1c?<?7% at week 24 (35% [p?=?NS], 38% [p?=?0.0443], 41% [p?=?0.0133]) for saxagliptin 2.5, 5, and 10?mg, respectively, than placebo (24%). PPG-AUC was reduced for saxagliptin 2.5, 5, and 10?mg (?6868, ?6896, ?8084?mg·min/dL, respectively) vs. placebo (?647?mg·min/dL) with statistical significance demonstrated for saxagliptin 5?mg (p?=?0.0002) and 10?mg (p?<?0.0001). HbA_1c, FPG, and PPG-AUC reductions were also observed in the OLC at 24 weeks. In the MTC, adverse event frequency was similar across all study arms. No cases of confirmed hypoglycemia (symptoms, with fingerstick glucose ≤50?mg/dL) were observed in either cohort. Saxagliptin was not associated with weight gain. Study limitations included the lack of a control group for the OLC and the use of prespecified rescue criteria, which limited the exposure time during which patients could remain on their originally randomized medication without the introduction of additional antihyperglycemic rescue treatment.

Conclusions: Once-daily saxagliptin monotherapy for 24 weeks was generally well tolerated and demonstrated clinically meaningful reductions in key parameters of glycemic control vs. placebo.

Trial Registration: Clinical Trials NCT00121641     

Guidelines and recommendations for the management of anaemia in patients with lymphoid malignancies

Patients with lymphoid malignancies frequently require repetitive and intensive anticancer treatments to induce and maintain disease remission. Anaemia (haemoglobin [Hb] <12 g/dL) is a common and debilitating problem associated with both the malignancy itself and its treatment burden. Anaemia negatively impacts on all aspects of patient quality of life (QOL) and treatment outcomes and survival, particularly in this disease setting.Widely acknowledged goals of anaemia treatment include Hb correction to approximately 12 g/dL, reduction in transfusion requirements and optimisation of patient QOL. Since the introduction of recombinant human erythropoietic therapy, transfusion (once the only anaemia treatment option available) is now primarily reserved for non-responders or those with severe or life-threatening anaemia. Data from randomised, double-blind, placebo-controlled studies, and large, non-randomised, open-label, community-based studies, along with almost 15 years of practical experience, support the assertion that epoetin alfa administered at a dosage of 150-300 U/kg three times weekly or 40,000-60,000U once weekly, both of which are US FDA-approved dose administration schedules, can effectively and safely achieve anaemia treatment goals for the majority of patients with lymphoid malignancies. Data and practical experience collected over the last 5 years on another erythropoietic agent with a slightly longer half-life but lower binding affinity, darbepoetin alfa, show that this agent when administered according to the FDA-approved dose administration schedules (2.25-4.5 microg/kg once weekly or 500microg once every 3 weeks) or according to a commonly-administered dose in clinical practice (3.0-5.0 microg/kg once every 2 weeks) can also effectively and safely correct anaemia, reduce transfusion requirements and improve QOL in many patients with lymphoid malignancies. One comparative head-to-head trial suggested that epoetin alfa might be superior to darbepoetin alfa in anaemic cancer patients receiving chemotherapy with respect to timing and magnitude of Hb correction, although further study is necessary, especially concerning optimal dose administration. Alternative dose administration schedules, such as epoetin alfa 80,000U every 2 weeks from initiation or 80,000U every 3 weeks following initiation with once weekly administration and darbepoetin alfa 4.5 microg/kg every 3 weeks following initiation with once weekly administration, are being actively investigated with the goal of increased flexibility for patients and healthcare providers.The treatment of anaemia in patients with lymphoid malignancies is an important part of overall disease management, as evidenced by continuous investigation of existing erythropoietic agents and new agents. Although treatment guidelines issued by organisations such as the National Comprehensive Cancer Network (NCCN) and American Society of Hematology (ASH)/American Society of Clinical Oncology (ASCO) suggest intervention with erythropoietic therapy when Hb falls below 10-11 g/dL or based on clinical symptoms, data suggest that anaemia is vastly under-recognised and under-treated. Clearly, an update on the definition, identification and optimal management of anaemia in patients with lymphoid malignancies is warranted.     

Effects of exenatide versus sitagliptin on postprandial glucose,insulin and glucagon secretion,gastric emptying,and caloric intake: a randomized,cross-over study

ABSTRACT

Background: This study evaluated the effects of exenatide, a GLP-1 receptor agonist, and sitagliptin, a DPP-4 inhibitor, on 2-h postprandial glucose (PPG), insulin and glucagon secretion, gastric emptying, and caloric intake in T2D patients.

Methods: This double-blind, randomized cross-over, multi-center study was conducted in metformin-treated T2D patients: 54% female; BMI: 33?±?5?kg/m²; HbA_1c: 8.5?±?1.2%; 2-h PPG: 245?±?65?mg/dL. Patients received exenatide (5?µg BID for 1 week, then 10?µg BID for 1 week) or sitagliptin (100?mg QAM) for 2 weeks. After 2 weeks, patients crossed-over to the alternate therapy. Postprandial glycemic measures were assessed via standard meal test; caloric intake assessed by ad libitum dinner (subset of patients). Gastric emptying was assessed by acetaminophen absorption (Clinicaltrials.gov Registry Number: NCT00477581).

Results: After 2 weeks of therapy, 2-h PPG was lower with exenatide versus sitagliptin: 133?±?6?mg/dL versus 208?±?6?mg/dL, p?<?0.0001 (evaluable, N?=?61). Switching from exenatide to sitagliptin increased 2-h PPG by +73?±?11?mg/dL, while switching from sitagliptin to exenatide further reduced 2-h PPG by ?76?±?10?mg/dL. Postprandial glucose parameters (AUC, C_ave, C_max) were lower with exenatide than sitagliptin (p?<?0.0001). Reduction in fasting glucose was similar with exenatide and sitagliptin (?15?±?4?mg/dL vs. ?19?±?4?mg/dL, p?=?0.3234). Compared to sitagliptin, exenatide improved the insulinogenic index of insulin secretion (ratio exenatide to sitagliptin: 1.50?±?0.26, p?=?0.0239), reduced postprandial glucagon (AUC ratio exenatide to sitagliptin: 0.88?±?0.03, p?=?0.0011), reduced postprandial triglycerides (AUC ratio exenatide to sitagliptin: 0.90?±?0.04, p?=?0.0118), and slowed gastric emptying (acetaminophen AUC ratio exenatide to sitagliptin: 0.56?±?0.05, p?<?0.0001). Exenatide reduced total caloric intake compared to sitagliptin (?134?±?97?kcal vs. +130?±?97?kcal, p?=?0.0227, N?=?25). Common adverse events with both treatments were mild to moderate in intensity and gastrointestinal in nature.

Conclusions: Although this study was limited by a 2-week duration of exposure, these data demonstrate that, exenatide had: (i) a greater effect than sitagliptin to lower postprandial glucose and (ii) a more potent effect to increase insulin secretion and reduce postprandial glucagon secretion in T2D patients. In contrast to sitagliptin, exenatide slowed gastric emptying and reduced caloric intake. These key findings differentiate the therapeutic actions of the two incretin-based approaches, and may have meaningful clinical implications.