Dose-finding study of peginesatide for anemia correction in chronic kidney disease patients

Summary

Background and objectives

Peginesatide is a synthetic, PEGylated, investigational, peptide-based erythropoiesis-stimulating agent. We report the first assessment of its efficacy and safety in correcting renal anemia in a population of 139 nondialysis chronic kidney disease patients.

Design, setting, participants, & measurements

Chronic kidney disease patients who were not on dialysis and not receiving treatment with erythropoiesis-stimulating agents in the 12 weeks before study drug administration were sequentially assigned to one of 10 cohorts; cohorts differed in starting peginesatide dose (different body weight-based or absolute doses), route of administration (intravenous or subcutaneous), and frequency of administration (every 4 or 2 weeks).

Results

Across all cohorts, 96% of patients achieved a hemoglobin response. A dose-response relationship was evident for hemoglobin increase. Comparable subcutaneous and intravenous peginesatide doses produced similar hemoglobin responses. Rapid rates of hemoglobin rise and hemoglobin excursions >13 g/dl tended to occur more frequently with every-2-weeks dosing than they did with every-4-weeks dosing. The range of final median doses in the every-4-weeks dosing groups was 0.019 to 0.043 mg/kg. Across all cohorts, 20% of patients reported serious adverse events (one patient had a possibly drug-related serious event) and 81% reported adverse events (11.5% reported possibly drug-related events); these events were consistent with those routinely observed in this patient population.

Conclusions

This study suggests that peginesatide administered every 4 weeks can increase and maintain hemoglobin in nondialysis chronic kidney disease patients. Additional long-term data in larger groups of patients are required to further elucidate the efficacy and safety of this peptide-based erythropoiesis-stimulating agent.     

Epoetin alfa maintains ribavirin dose in HCV-infected patients: a prospective, double-blind, randomized controlled study

BACKGROUND & AIMS: Combination therapy with interferon alpha (IFN-alpha) and ribavirin (RBV) or pegylated IFN-alpha (PEG-IFN-alpha)/RBV for chronic hepatitis C virus (HCV) infection often causes anemia, prompting RBV dose reduction/discontinuation. This study assessed whether epoetin alfa could maintain RBV dose, improve quality of life (QOL), and increase hemoglobin (Hb) in anemic HCV-infected patients. METHODS: HCV-infected patients (n = 185) on combination therapy who developed anemia (Hb < or = 12 g/dL) were randomized into a U. S. multicenter, placebo-controlled, clinical trial of epoetin alfa, 40,000 U subcutaneously, once weekly vs. matching placebo. The study design used an 8-week, double-blind phase (DBP) followed by an 8-week, open-label phase (OLP), in which placebo patients were crossed over to epoetin alfa. RESULTS: At the end of the DBP, RBV doses were maintained in 88% of patients receiving epoetin alfa vs. 60% of patients receiving placebo (P < 0.001). Mean QOL scores at the end of the DBP improved significantly on all domains of the Linear Analog Scale Assessment (LASA) and on 7 of the 8 domains of the Short Form-36, version 2 (SF-36v2). Mean Hb increased by 2.2 +/- 1.3 g/dL (epoetin alfa) and by 0.1 +/- 1.0 g/dL (placebo) in the DBP (P < 0.001). Similar results were demonstrated in patients who switched from placebo to epoetin alfa in the OLP. Epoetin alfa was well tolerated; the most common adverse effects were headache and nausea. CONCLUSIONS: Epoetin alfa maintained RBV dose and improved QOL and Hb in anemic HCV-infected patients receiving combination therapy.     

The added-up albumin enhances the diuretic effect of furosemide in patients with hypoalbuminemic chronic kidney disease: a randomized controlled study

ABSTRACT: BACKGROUND: Chronic kidney disease (CKD) with edema is a common clinical problem resulting from defects in water and solute excretion. Furosemide is the drug of choice for treatment. In theory, good perfusion and albumin are required for the furosemide to be secreted at the tubular lumen. Thus, in the situation of low glomerular filtration rate (GFR) and hypoalbuminemia, the efficacy of furosemide alone might be limited. There has been no study to validate the effectiveness of the combination of furosemide and albumin in this condition. METHODS: We conducted a randomized controlled crossover study to compare the efficacy of diuretics between furosemide alone and the combination of furosemide plus albumin in stable hypoalbuminemic CKD patients by measuring urine output and sodium. The baseline urine output/sodium at 6 and 24 hours were recorded. The increment of urine output/sodium after treatment at 6 and 24 hours were calculated by using post-treatment minus baseline urine output/sodium at the corresponding period. RESULTS: Twenty-four CKD patients (GFR = 31.0 [PLUS-MINUS SIGN] 13.8 mL/min) with hypoalbuminemia (2.98 [PLUS-MINUS SIGN] 0.30 g/dL) were enrolled. At 6 hours, there were significant differences in the increment of urine volume (0.47 [PLUS-MINUS SIGN] 0.40 vs 0.67 [PLUS-MINUS SIGN] 0.31 L, P < 0.02) and urine sodium (37.5 [PLUS-MINUS SIGN] 29.3 vs 55.0 [PLUS-MINUS SIGN] 26.7 mEq, P < 0.01) between treatment with furosemide alone and with furosemide plus albumin. However, at 24 hours, there were no significant differences in the increment of urine volume (0.49 [PLUS-MINUS SIGN] 0.47 vs 0.59 [PLUS-MINUS SIGN] 0.50 L, P = 0.46) and urine sodium (65.3 [PLUS-MINUS SIGN] 47.5 vs 76.1 [PLUS-MINUS SIGN] 50.1 mEq, P = 0.32) between the two groups. CONCLUSION: The combination of furosemide and albumin has a superior short-term efficacy over furosemide alone in enhancing water and sodium diuresis in hypoalbuminemic CKD patients.Trial registrationThe Australian New Zealand Clinical Trials Registration (ANZCTR12611000480987).     

Treatment of renal anemia with darbepoetin alfa administered once every other week in predialysis patients with chronic kidney disease and previously treated with epoetin alfa

Darbepoetin alfa is an erythropoiesis-stimulating glycoprotein with up to 3 times longer half-life than recombinant human erythropoietin (rHuEPO) in humans. The aim of this study was to assess the efficacy and safety of darbepoetin alfa given once every other week as treatment of anemia in predialysis patients with chronic renal failure (CRF) previously treated with once-weekly epoetin alfa. A total of 42 CRF patients were included, all of whom had previously been treated with epoetin alfa and showed stable hemoglobin (Hb) levels without dose changes during the last 8 weeks prior to enrolment in this study. All patients received s.c. darbepoetin alfa once every other week at doses calculated from the protein mass equivalence between rHuEPO and darbepoetin alfa. Follow-up lasted for 24 weeks. Dose adjustments were conducted to preserve target Hb levels between 11 and 13 g/dl. Thirty-nine patients completed the 24 weeks of study. Hb levels increased during follow-up [mean values of 0.39 (p < 0.002), 0.58) (p < 0.001), and 0.83 g/dl (p < 0.001) at 8, 16 and 24 weeks, respectively] despite reducing the darbepoetin alfa dose up to 15% at 24 weeks [from 0.192 microg/kg body weight to 0.185, 0.178 and 0.163 at 8, 16, and 24 weeks, respectively (p < 0.001)]. No adverse events related to darbepoetin alfa were reported. In conclusion, these results show s.c. administration of darbepoetin alfa once every other week was superior to weekly epoetin alfa as a maintenance treatment for anemia in predialysis CRF patients, since the former provided higher Hb levels. Moreover, darbepoetin alfa administration was safe in these patients.     

Chronic anemia and fatigue in elderly patients: results of a randomized, double-blind, placebo-controlled, crossover exploratory study with epoetin alfa

OBJECTIVES: To evaluate the effect of epoetin alfa treatment on hemoglobin (Hb), fatigue, quality of life (QOL), and mobility in elderly patients with chronic anemia. DESIGN: An exploratory, 32 week, randomized, double-blind, crossover treatment trial. PARTICIPANTS: Sixty-two community-dwelling individuals aged 65 and older with chronic anemia (Hb < or =11.5 g/dL). INTERVENTION: Subcutaneous epoetin alfa or placebo weekly for 16 weeks (Phase I) with crossover to the opposite treatment (Phase II). MEASUREMENTS: Hb and QOL scores from the Functional Assessment of Chronic Illness Therapy (FACIT) measurement system. Mobility was assessed as a secondary outcome using the Timed Up and Go (TUG) test. RESULTS: Of the 62 subjects enrolled, complete data were analyzed for 58 in Phase I and 54 participants in Phase II. Of those enrolled, most were African American (95%) and female (85%) and had multiple comorbidities and a mean age+/-standard deviation of 76.1+/-7.2. Mean baseline Hb was 10.5+/-0.9 g/dL (7.3-11.5). In Phase I, 67% of those taking epoetin alfa, and in Phase II, 69% of those taking epoetin alfa had an increase in Hb of more than 2 g/dL, significantly more than those taking placebo (P<.001). Similarly, elderly participants significantly improved on the fatigue and anemia subscales of the FACIT across phases (all P<.05). No significant differences were found between treatment and placebo on TUG scores. Epoetin alfa was well tolerated. CONCLUSION: In this trial involving predominantly older African-American women with anemia, a direct relationship existed between increases in Hb during epoetin alfa therapy and improvements in fatigue and QOL.     

Epoetin alfa improves quality of life in anemic HCV-infected patients receiving combination therapy

Anemia and decreased health-related quality of life (HRQL) are common in patients receiving combination therapy of interferon alfa (IFN) and ribavirin (RBV) for chronic hepatitis C virus (HCV) infection. In a randomized, prospective study evaluating the effectiveness of epoetin alfa in maintaining RBV dose, alleviating anemia, and improving HRQL in anemic (Hb < or = 12 g/dL) HCV-infected patients receiving combination therapy, patients receiving epoetin alfa had significant improvements in HRQL compared with placebo. In this study, 185 patients were randomized to 40,000 units of epoetin alfa subcutaneously weekly or placebo for an 8-week double-blind phase (DBP), followed by an 8-week open-label phase during which all patients received epoetin alfa. To further assess the impact of epoetin alfa on HRQL, post hoc analyses were conducted in the same patient population to compare the HRQL of these patients at randomization with norms of other populations, and to determine the critical relationship between hemoglobin (Hb) levels and HRQL. Mean HRQL scores of anemic HCV-infected patients receiving combination therapy at randomization were significantly lower than those of both the general population and patients who had other chronic conditions. Patients receiving epoetin alfa who had the greatest Hb increases from randomization to the end of the DBP also had the largest improvements in HRQL. Hb improvement was an independent predictor of HRQL improvement in these patients. In conclusion, epoetin alfa provided clinically significant HRQL improvement in HCV-infected patients receiving IFN/RBV therapy.     

Erythropoietin with iron supplementation to prevent allogeneic blood transfusion in total hip joint arthroplasty. A randomized, controlled trial

BACKGROUND: The optimum regimen of epoetin alfa for prevention of allogeneic blood transfusion is unknown. OBJECTIVE: To determine whether a modified regimen of epoetin alfa reduces allogeneic blood transfusion in patients undergoing hip arthroplasty. DESIGN: Randomized, double-blind, multicenter trial comparing two modified dose regimens of epoetin alfa with placebo. SETTING: 13 teaching hospitals and 4 community hospitals in Canada. PATIENTS: 201 patients undergoing primary hip arthroplasty who had a hemoglobin concentration of 98 to 137 g/L and did not predonate blood. INTERVENTION: Patients were assigned in a 3:5:5 ratio to receive four weekly doses of epoetin alfa, 40 000 U (high-dose; n = 44) or 20 000 U (low-dose; n = 79), or placebo (n = 78), starting 4 weeks before surgery. All patients received oral iron supplementation, 450 mg/d, for 42 or more days before surgery. MEASUREMENTS: The primary end point was allogeneic transfusion. Secondary end points were thromboembolic events and change in reticulocyte count and hemoglobin concentration. RESULTS: Both modified epoetin alfa regimens significantly reduced the need for allogeneic transfusion: Five (11.4%) patients in the high-dose group (P = 0.001) and 18 (22. 8%) patients in the low-dose group (P = 0.003) had transfusion, compared with 35 (44.9%) patients in the placebo group. The hematologic response was substantial in patients who received epoetin alfa. In the high-dose group, low-dose group, and placebo group, the preoperative increase in reticulocyte count was 58.8, 37. 0 and 1.8 x 10(9) cells/L (P < 0.001), respectively, and the increase in hemoglobin concentration was 19.5, 17.2, and 1.2 g/L (P < 0.001). The incidence of thromboembolic events did not differ among groups. CONCLUSIONS: Both modified epoetin alfa regimens were effective compared with placebo in reducing allogeneic transfusion in patients undergoing hip arthroplasty. Patients who received high-dose epoetin alfa had the lowest transfusion rate.     

Evaluating the Effectiveness of Epoetin Alfa in Community Oncology Practices

Purpose: This retrospective case-series review studied the effectiveness of epoetin alfa in community oncology practices, which until now has not been well documented.

Methods: We reviewed the medical records of 118 cancer patients treated between 1999 and 2001 with cyclic chemotherapy plus epoetin alfa in 27 US community-based oncology practices. Two analysis sets were examined: one including all patients (n=118) and one including only those patients with no concurrent events impacting hemoglobin data interpretation (n=73). Efficacy of epoetin alfa was evaluated by hemoglobin response (a≥2 g/dl increase in hemoglobin from baseline) at weeks 12 and 16, the time to hemoglobin response, and change in hemoglobin concentrations from baseline at specific time points.

Results: After 12 weeks of treatment, 43% (95% confidence interval [CI], 33-54%) of patients had a hemoglobin response, and the proportion of responders further rose to 61% (95% CI, 49-72%) after 16 weeks. The median time to response was 92 days (lower 95% confidence limit, 74 days; upper bound not estimable). Hemoglobin increased from baseline at all time points evaluated during epoetin alfa treatment, with a mean increase of 1.1 g/dl (95% CI, 0.77-1.4 g/dl) by the last observation.

Conclusion: These results indicate that epoetin alfa is effective in community practice, but most patients take longer than 3 months to respond. Because slow responses may negatively impact on the quality of life in these patients, alternative treatment approaches providing faster and perhaps better responses may provide greater clinical benefit.     

Long‐Term Safety and Efficacy of JR‐131, a Biosimilar of Darbepoetin Alfa,in Japanese Patients With Renal Anemia Undergoing Hemodialysis: Phase 3 Prospective Study

The objective of this study was to evaluate the safety and efficacy of JR‐131, a biosimilar of darbepoetin alfa, for long‐term treatment of renal anemia patients undergoing hemodialysis. In this multicenter, single‐arm, phase 3 study, 159 patients with renal anemia who had been receiving darbepoetin alfa or recombinant human erythropoietins were treated with intravenous JR‐131 for 52 weeks. In patients receiving darbepoetin alfa, JR‐131 was administered at the same dose, while in patients receiving recombinant human erythropoietin the dose was determined based on the 1:200 conversion ratio following the Japanese darbepoetin alfa package insert. No notable adverse drug reactions were reported, and no anti‐JR‐131 antibodies were detected. The hemoglobin levels were maintained in the range of 10.0–12.0 g/dL throughout the study. JR‐131 proved to be a useful and lower‐cost alternative to darbepoetin alfa in the management of renal anemia in patients undergoing hemodialysis.     

JR‐131, a Biosimilar of Darbepoetin Alfa,for the Treatment of Hemodialysis Patients With Renal Anemia: A Randomized,Double‐Blinded,Parallel‐Group Phase 3 Study

The aim of this study was to compare the efficacy and safety of intravenous JR‐131, a darbepoetin alfa biosimilar, to darbepoetin alfa in hemodialysis patients with renal anemia. In this 24‐week, multicenter, randomized, double‐blinded, parallel‐group phase 3 study, 334 hemodialysis patients with renal anemia who had been receiving darbepoetin alfa were randomized to either JR‐131 or darbepoetin alfa group. The initial dose was set based on the darbepoetin alfa dose during the observation period. The primary endpoint was change in hemoglobin level from baseline to end of treatment. The 95% confidence interval of the difference in the change in hemoglobin level between the groups was ?0.19 to ?0.20 g/dL, within the equivalent margin of ?0.5 to 0.5 g/dL. No notable treatment‐emergent adverse events were observed in either group. JR‐131 was therapeutically equivalent to darbepoetin alfa, and the safety profile of JR‐131 was similar to that of darbepoetin alfa.     

A phase 3, open-label,single-arm study of vadadustat for anemia in chronic kidney disease for Japanese patients on hemodialysis not receiving erythropoiesis-stimulating agents

Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved in Japan for the treatment of anemia in patients with chronic kidney disease (CKD). This phase 3, open-label, single-arm study evaluated the efficacy and safety of vadadustat in 24 Japanese patients with CKD-associated anemia on hemodialysis who were not receiving erythropoiesis-stimulating agents (ESAs). Patients received vadadustat for 24 weeks; the starting dose was 300 mg/day and doses were adjusted to achieve the target hemoglobin (Hb) range of 10.0–12.0 g/dL. The least squares mean of average Hb at Weeks 20 and 24 (95% confidence interval) was 10.75 g/dL (10.35, 11.14). The most common adverse event was shunt stenosis (25.0%). Adverse drug reactions (diarrhea and vomiting) occurred in two patients (8.3%) and the severity was mild. Vadadustat increased and maintained Hb levels within the target range and was generally well-tolerated in Japanese patients with anemia on hemodialysis not receiving ESAs.     

Once-weekly epoetin alfa improves anemia and facilitates maintenance of ribavirin dosing in hepatitis C virus-infected patients receiving ribavirin plus interferon alfa

OBJECTIVE: The aim of this study was to determine the efficacy of epoetin alfa in alleviating anemia and minimizing ribavirin (RBV) dose reductions in patients with chronic hepatitis C virus (HCV) infection receiving combination RBV/interferon alfa (IFN) therapy. METHODS: HCV-infected patients who had Hb levels of 12 g/dl or less during the first 24 wk of combination RBV/IFN therapy (n=64) were randomized to treatment with epoetin alfa (40,000 units) s.c. q.w. or to standard of care (SOC) for anemia management (RBV dose reduction or discontinuation, transfusions). Primary and secondary efficacy endpoints were changes in Hb level and RBV dosage, respectively, from baseline to week 16 of epoetin alfa therapy.Based on intent-to-treat analysis, the mean changes from baseline Hb levels at week 16 were +2.8 g/dl for epoetin alfa versus +0.4 g/dl for SOC (p<0.0001), and the mean changes in RBV dosage were -34 mg/day for epoetin alfa versus -146 mg/day (p=0.060) for SOC. The mean Hb level at week 16 in the epoetin alfa group (13.8 g/dl) was significantly (p<0.0001) higher than that of the SOC group (11.4 g/dl). At week 4 and subsequently, significantly more patients in the epoetin alfa group did not have RBV dosage reductions (p<0.011). At study end, 83% of epoetin alfa-treated patients maintained RBV dosages of at least 800 mg/day, compared with 54% of patients receiving SOC (p=0.022). Epoetin alfa was well tolerated. CONCLUSIONS: In anemic HCV-infected patients treated with RBV/IFN, epoetin alfa increases Hb levels and maintains RBV dosing. Based on these results, epoetin alfa seems to be promising in the treatment of HCV treatment-related anemia. Further research is warranted to determine the potential impact on outcomes, including quality of life and sustained viral response rate.     

Once-weekly epoetin alfa improves quality of life and increases hemoglobin in anemic HIV+ patients

This prospective, open-label, multicenter trial evaluated the effects of once-weekly (qw) epoetin alfa on quality of life (QOL) and hemoglobin (Hb) levels in anemic human immunodeficiency virus (HIV)-infected adult receiving antiretroviral therapy. A total of 650 patients with Hb < or = 11 g/dl received epoetin alfa 40,000 U qw subcutaneously, with dose escalation to 60,000 qw if Hb increase was <1 g/dl after 4 weeks. The linear Analog Scale Assessment (LASA) overall QOL score, LASA energy score, and LASA activity score each significantly improved from baseline to final measurement (p < 0.0001 for each parameter). Improvements in the Medical Outcomes Study (MOS)-HIV physical and mental health summary scores were also significant (p < 0.0001), and coincided with Hb increases. Mean Hb increased from baseline to final measurement by 2.5 g/dl (95% CI: 2.3, 2.6 g/dl; p < 0.0001). Objective hematological response rate, defined as a > or = 1 g/dl Hb increase from baseline to week 8, was 86%. Hemoglobin increased significantly in all subgroups of race, zidovudine use, CD4+ cell count, and viral load. Once-weekly epoetin alfa was well tolerated. Once-weekly epoetin alfa is effective in improving QOL and Hb measures.     

Antibody-mediated pure red cell aplasia due to epoetin alfa during antiviral therapy of chronic hepatitis C

Anemia frequently complicates the treatment of chronic hepatitis C with interferon and ribavirin (RVN), requiring dose reduction and jeopardizing sustained virologic response. Increasingly, epoetin alfa is used to prevent anemia in this setting. Below, we report the first case of pure red cell aplasia (PRCA) in a patient with chronic hepatitis C who received epoetin alfa (Procrit) to manage anti-viral treatment-induced anemia. Red blood cell transfusion-dependence developed 16 wk after the patient was started on peginterferon alfa-2b and RVN for chronic hepatitis C despite the simultaneous administration of epoetin alfa and subsequent discontinuation of the antiviral medications. Bone marrow biopsy was consistent with PRCA. High-titer erythropoietin antibodies, assayed by two methods, appeared shortly after epoetin alfa was administered, and were associated with a decline in serum erythropoietin to undetectable levels. Erythropoietin antibodies directed toward epoetin alfa were shown to cross react with darbepoetin alfa (Aranesp), and a neutralization assay confirmed that they inhibited cell growth in the presence of erythropoietin. Transfusion-dependence resolved approximately 16 wk after discontinuing epoetin alfa, and 6 wk after starting danazol. PRCA caused by the development of erythropoietin antibodies is a potentially life-threatening complication of administering epoetin alfa to prevent the anemia associated with antiviral therapy in patients with chronic hepatitis C.     

Predictor of poor coronary collaterals in chronic kidney disease population with significant coronary artery disease

ABSTRACT: BACKGROUND: Coronary collateral circulation plays an important role to protect myocardium from ischemia, preserve myocardial contractility and reduce cardiovascular events. Chronic kidney disease (CKD) is associated with poor coronary collateral development and cardiovascular outcome. However, limited research investigates the predictors for collateral development in the CKD population. METHODS: We evaluated 970 consecutive patients undergoing coronary angiography and 202 patients with CKD, defined as a glomerular filtration rate less than 60 ml/min/1.73 m2, were finally analyzed. The collateral scoring system developed by Rentrop was used to classify patients into poor (grades 0 and 1) or good (grades 2 and 3) collateral group. RESULTS: The patients with poor collateral (n = 122) had a higher incidence of hypertension (82 % vs 63.8 %, p = 0.005), fewer diseased vessels numbers (2.1 [PLUS-MINUS SIGN] 0.9 vs 2.6 [PLUS-MINUS SIGN] 0.6, p < 0.001) and a trend to be diabetic (56.6 % vs. 43.8 %, p = 0.085) or female sex (37.7 % vs. 25.0 %, p = 0.067). Multivariate analysis showed hypertension (odd ratio (OR) 2.672, p = 0.006), diabetes (OR 1.956, p = 0.039) and diseased vessels numbers (OR 0.402, p < 0.001) were significant predictors of poor coronary collaterals development. Furthermore, hypertension and diabetes have a negative synergistic effect on collateral development (p = 0.004 for interaction). CONCLUSIONS: In the CKD population hypertension and diabetes might negatively influence the coronary collaterals development.     

Use of epoetin in patients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology

Anemia resulting from cancer or its treatment is an important clinical problem increasingly treated with the recombinant hematopoietic growth factor erythropoietin. To address uncertainties regarding indications and efficacy, the American Society of Clinical Oncology and the American Society of Hematology developed an evidence-based clinical practice guideline for the use of epoetin in patients with cancer. The guideline panel found good evidence to recommend use of epoetin as a treatment option for patients with chemotherapy-associated anemia with a hemoglobin (Hgb) concentration below 10 g/dL. Use of epoetin for patients with less severe anemia (Hgb level below 12 g/dL but never below 10 g/dL) should be determined by clinical circumstances. Good evidence from clinical trials supports the use of subcutaneous epoetin thrice weekly (150 U/kg) for a minimum of 4 weeks. Less strong evidence supports an alternative weekly (40 000 U/wk) dosing regimen, based on common clinical practice. With either administration schedule, dose escalation should be considered for those not responding to the initial dose. In the absence of response, continuing epoetin beyond 6-8 weeks does not appear to be beneficial. Epoetin should be titrated once the hemoglobin concentration reaches 12 g/dL. Evidence from one randomized controlled trial supports use of epoetin for patients with anemia associated with low-risk myelodysplasia not receiving chemotherapy; however, there are no published high-quality studies to support its use for anemia in other hematologic malignancies in the absence of chemotherapy. Therefore, for anemic patients with hematologic malignancies it is recommended that physicians initiate conventional therapy and observe hematologic response before considering use of epoetin.     

Critical appraisal of scientific posters comparing anemia treatments for cancer patients: applying ISPOR Task Force guidelines on methodological quality of retrospective studies

Two independent reviewers used the methodological criteria published by the ISPOR Task Force on Retrospective Data to assess the quality of four posters presenting the results of retrospective database studies on the use of erythropoiesis-stimulating agents (epoetin alfa, epoetin beta, or darbepoetin alfa) for treating patients with cancer. A third reviewer consolidated the results. Overall, from the information reported in the four posters, their methodological quality ranged from poor to very poor; only a few of the criteria were satisfactorily addressed. The quality of the data sources and the research design received very poor scores. Key elements such as selection bias were not considered. These findings caution against the use of posters without appropriate assessment of their methodological quality. The ISPOR guidelines for the evaluation of retrospective analyses are a useful tool for assessing the quality of scientific posters.     

A pharmacoepidemiological study of the multi-level determinants, predictors, and clinical outcomes of biosimilar epoetin alfa for renal anaemia in haemodialysis patients: background and methodology of the MONITOR-CKD5 study

Prior longitudinal observational studies have examined the practice patterns and outcomes of anaemia management, including the use of erythropoiesis-stimulating agents (ESAs). Several dimensions of effectiveness remain unaddressed; especially considering the revised ESA label (target Hb levels between 10 and 12 g/dL), the recently published TREAT study, and the European approval of the first ESA biosimilar (HX575). Anecdotal evidence suggests that patient outcomes are influenced by physician-related variables and whether anaemia management is congruent with practice guidelines, but this has not been studied systematically. MONITOR-CKD5 is an international, prospective, observational, pharmacoepidemiological study evaluating the multi-level factors and outcomes of treatment with HX575 for renal anaemia in haemodialysis patients. Driven by a novel, integrated, multi-focal framework for post-approval observational studies, it examines determinants of response at both the patient and the physician level; integrates an advocated statistical methodology here to fore used mainly in the social and behavioural sciences; assesses factors potentially predictive of a poor treatment response; and evaluates the extent to which treatment is congruent with evidence-based guidelines, good practice evidence, and the revised ESA label. This pan-European study will recruit at least 1,000 patients from a minimum of 75 centres, and follow them for up to 24 months following initiation of anaemia management with biosimilar epoetin alfa. MONITOR-CKD5 will not only study the core issues addressed by prior observational studies but also aims to take knowledge discovery a step further by assessing outcomes across varying cohorts of patients, and examining the impact of evidence-based practice on clinical outcomes, differentiating, in the process, between physician-level and patient-level determinants.     

Randomized,dose-finding study of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies

Darbepoetin alfa is a novel erythropoiesis-stimulating protein with a prolonged serum half-life. This randomized, double-blind, placebo-controlled, dose-finding study investigated the efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies who were receiving chemotherapy. Patients were randomized in a 1:2:2:1 ratio to receive darbepoetin alfa 1.0 microg/kg (n = 11), 2.25 microg/kg (n = 22), 4.5 microg/kg (n = 22) or placebo (n = 11), administered subcutaneously once weekly for 12 weeks. No dose increases were allowed during the study. A higher proportion of patients achieved a haemoglobin response (defined as a >/= 2.0 g/dl increase from baseline) in the darbepoetin alfa 1.0 microg/kg (45%), 2.25 microg/kg (55%) and 4.5 microg/kg (62%) groups than in the placebo group (10%; P < 0.01). The mean change in haemoglobin from baseline to week 13 was 1.56 g/dl in the 1.0 microg/kg group, 1.64 g/dl in the 2.25 microg/kg group and 2.46 g/dl in the 4.5 microg/kg group, compared with a mean change of 1.00 g/dl in the placebo group. The overall safety profile of darbepoetin alfa in this study was similar to that of placebo. These results show that darbepoetin alfa effectively and safely increased haemoglobin concentrations in patients with lymphoproliferative malignancies. Confirmative studies at doses of 2.25 and/or 4.5 microg/kg/week in this population are warranted.