Factors Affecting Doses of Roxadustat Versus Darbepoetin Alfa for Anemia in Nondialysis Patients.

INTRODUCTION: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for treating anemia of chronic kidney disease (CKD). This post hoc analysis of a Japanese, open-label, partially randomized, phase 3 study in nondialysis-dependent (NDD) CKD patients treated with traditional erythropoiesis-stimulating agents (ESAs) evaluated dosing trends of roxadustat and darbepoetin alfa (DA) required to maintain target hemoglobin concentrations in patients with risk factors associated with ESA hyporesponsiveness. METHODS: Patients enrolled in the 1517-CL-0310 study (NCT02988973) that demonstrated noninferiority of roxadustat to DA for change in average hemoglobin levels of week 18-24 from baseline who had used human recombinant erythropoietin or DA before conversion and who were randomized to either roxadustat or DA were included. The endpoints were the average allocated dose of roxadustat and DA per administration in the last 6 weeks (AAD/6W), assessed by subgroups known to be associated with ESA hyporesponsiveness. The analysis of variance was performed by the treatment group to test the influence of subgroup factors on the AAD/6W of study drug. The ratios between the mean AAD/6W in each subgroup category and the within-arm mean AAD/6W were calculated. RESULTS: Two hundred and sixty-two patients were randomized to either the roxadustat or DA comparative group and received treatment (roxadustat, n = 131; DA, n = 131). Higher mean (standard deviation) doses of both roxadustat (63.15 [24.84] mg) and DA (47.33 [29.79] µg) were required in the highest ESA resistance index (≥6.8) quartile (p = 0.003 and p < 0.001, respectively). Patients with adequate iron repletion had the lowest doses for both roxadustat (45.54 [18.01] mg) and DA (28.13 [20.98] µg). High-sensitivity C-reactive protein ≥28.57 nmol/L and the estimated glomerular filtration rate <15 mL/min/1.73 m2 were associated with requiring higher DA but not roxadustat doses. DISCUSSION/CONCLUSION: The roxadustat dose required to maintain target hemoglobin in NDD patients in Japan with anemia of CKD relative to DA dose may not be impacted by low-grade inflammation. Roxadustat may be beneficial for ESA-hyporesponsive NDD CKD patients.

Comparison of Pharmacokinetic, Pharmacodynamic and Tolerability Profiles of CKD-11101, Darbepoetin Alfa (NESP®) Biosimilar, to Those of NESP® After a Single Subcutaneous or Intravenous Administration to Healthy Subjects.

INTRODUCTION: Darbepoetin alfa (NESP® and ARANESP®) has a sustained erythropoietic activity with a longer half-life than conventional recombinant human erythropoietin. CKD-11101 is under clinical development as a biosimilar of darbepoetin alfa. The purpose of this study was to compare the pharmacokinetic (PK), pharmacodynamic (PD), and tolerability profiles of CKD-11101 with those of reference drug in healthy subjects. METHODS: This study was performed in two parts for healthy subjects. In each period, CKD-11101 and reference, both at 60 µg, were administered via intravenous (IV) or subcutaneous (SC) route of administration. RESULTS: After both IV or SC dose, the geometric mean ratio (GMR) of CKD-11101 to reference drug and its 90% confidence intervals (CIs) for Cmax, AUC0-last and AUC0-∞ were all within 0.8-1.25. No statistically significant differences were noted in the maximum baseline adjusted reticulocyte count or the area under the baseline adjusted reticulocyte count-time between the CKD-11101 and reference drug after IV or SC dose (all p-value>0.05). Both CKD-11101 and reference drug were generally well tolerated. DISCUSSION: After a single IV or SC dose, the CKD-11101 was well tolerated and showed comparable PK and PD characteristics with reference drug.

Conversion from Aranesp® to NESP® in dialysis patients-Exploration of dosing strategies and the feasibility of extending the dosing interval.

AIM: Darbepoetin alpha is available as Aranesp® and NESP®, which differ in the inactive component and maximum dose-strength of prefilled syringes. We conducted an observational cohort study to investigate optimal conversion strategies and the feasibility of extending dosing intervals with higher-dose preparations in dialysis patients converting from Aranesp® to NESP®. METHODS: Adult dialysis patients on Aranesp® with stable haemoglobin of 9-12 g/dL were converted to NESP® at the same monthly total dose according to one of three conversion regimens. Group A included patients on ≤80 mcg/month of Aranesp® who converted with dosing regimen unchanged. Group B patients converted to NESP® with extended dosing intervals using higher individual dose preparations. Group C were patients on 100 mcg Aranesp® who converted to NESP® 120 mcg with extended dosing intervals. Patients were observed for 6 months. RESULTS: Fifty patients were included. All 24 Group A patients maintained stable haemoglobin. In Group B, 10 patients (50%) maintained stable haemoglobin with extension of dosing interval from 1.04 ± 0.14 to 3.03 ± 1.28 weeks. Factors associated with success in extending dosing interval included a lower prevalence of cardiovascular disease and a higher Kt/Vurea in peritoneal dialysis patients. Four patients (80%) in Group C maintained stable haemoglobin after conversion to NESP® 120 mcg with extended dosing interval. The use of NESP® 120 mcg was well tolerated, and was associated with reduced patient-reported pain score and 38% reduction of drug cost. CONCLUSION: Dialysis patients on Aranesp® can be successfully converted to NESP® and the dosing interval can be extended successfully in a significant proportion of patients, which could reduce discomfort and drug cost.

A Randomized Trial of Strategies Using Darbepoetin Alfa To Avoid Transfusions in CKD.

BACKGROUND: Exposure to high doses or a high cumulative dose of erythropoiesis-stimulating agents (ESAs) may contribute to cardiovascular events in patients with CKD and anemia. Whether using a low fixed ESA dose versus dosing based on a hemoglobin-based, titration-dose algorithm in such patients might reduce risks associated with high ESA doses and decrease the cumulative exposure-while reducing the need for red blood cell transfusions-is unknown. METHODS: In this phase-3, randomized trial involving 756 adults with stage-3 to -5 CKD and anemia, we evaluated incidence of red blood cell transfusions for participants randomized to receive darbepoetin given as a fixed dose (0.45 µg/kg every 4 weeks) versus administered according to a hemoglobin-based, titration-dose algorithm, for up to 2 years. Participants received transfusions as deemed necessary by the treating physician. RESULTS: There were 379 patients randomized to the fixed-dose group, and 377 to the titration-dose group. The percentage of participants transfused did not differ (24.1% and 24.4% for the fixed-dose and titration-dose group, respectively), with similar time to first transfusion. The titration-dose group achieved significantly higher median hemoglobin (9.9 g/dl) compared with the fixed-dose group (9.4 g/dl). The fixed-dose group had a significantly lower median cumulative dose of darbepoetin (median monthly dose of 30.9 µg) compared with the titration-dose group (53.6 µg median monthly dose). The FD and TD group received a median (Q1, Q3) cumulative dose per 4 weeks of darbepoetin of 30.9 (21.8, 40.0) µg and 53.6 (31.1, 89.9) µg, respectively; the median of the difference between treatment groups was -22.1 (95% CI, -26.1 to -18.1) µg. CONCLUSIONS: These findings indicate no evidence of difference in incidence of red blood cell transfusion for a titration-dose strategy versus a fixed-dose strategy for darbepoetin. This suggests that a low fixed dose of darbepoetin may be used as an alternative to a dose-titration approach to minimize transfusions, with less cumulative dosing.

A pharmacist-managed dosing algorithm for darbepoetin alfa and iron sucrose in hemodialysis patients: A randomized, controlled trial.

The attainment of target hemoglobin levels in hemodialysis patients is low. Several factors play a role, such as hyporesponsiveness to erythropoiesis-stimulating agents (ESA), but also suboptimal prescribing of ESA and iron. The goal of this study was to investigate if a pharmacist-managed dosing algorithm for darbepoetin alfa (DA) and iron sucrose improves the attainment of target hemoglobin levels. In this randomized controlled trial, 200 hemodialysis patients from a Dutch teaching hospital were included. In the intervention group (n = 100), a pharmacist monthly provided dose recommendations for DA and iron sucrose based on dosing algorithms. The control group (n = 100) received usual care. In the intervention group, the percentage per patient within the target range (PTR) for hemoglobin (target range 6.8-7.4 mmol/L) and iron status was higher than in the control group (for hemoglobin median 38.5% vs 23.1%, P = .001 and for iron status median 21.1% vs 8.3%, P = .003). The percentage of high hemoglobin levels (>8.1 mmol/L) was lower in the intervention group (median 0.0% vs 7.7%, P = .034). The weekly dose of DA was lower in the intervention group (median 34.0 vs 46.9 mcg, P = .020), whereas iron dose was higher (median 75 vs 0 mg). No difference was found for the percentage of hemoglobin levels below the target range. In conclusion, a pharmacist-managed dosing algorithm for DA and iron sucrose increased the attainment of target levels for hemoglobin and iron status, reduced the percentage of high hemoglobin levels, and was associated with a lower DA and a higher iron sucrose dose.

A fully human anti-BMP6 antibody reduces the need for erythropoietin in rodent models of the anemia of chronic disease.

Recombinant erythropoietin (EPO) and iron substitution are a standard of care for treatment of anemias associated with chronic inflammation, including anemia of chronic kidney disease. A black box warning for EPO therapy and concerns about negative side effects related to high-dose iron supplementation as well as the significant proportion of patients becoming EPO resistant over time explains the medical need to define novel strategies to ameliorate anemia of chronic disease (ACD). As hepcidin is central to the iron-restrictive phenotype in ACD, therapeutic approaches targeting hepcidin were recently developed. We herein report the therapeutic effects of a fully human anti-BMP6 antibody (KY1070) either as monotherapy or in combination with Darbepoetin alfa on iron metabolism and anemia resolution in 2 different, well-established, and clinically relevant rodent models of ACD. In addition to counteracting hepcidin-driven iron limitation for erythropoiesis, we found that the combination of KY1070 and recombinant human EPO improved the erythroid response compared with either monotherapy in a qualitative and quantitative manner. Consequently, the combination of KY1070 and Darbepoetin alfa resulted in an EPO-sparing effect. Moreover, we found that suppression of hepcidin via KY1070 modulates ferroportin expression on erythroid precursor cells, thereby lowering potentially toxic-free intracellular iron levels and by accelerating erythroid output as reflected by increased maturation of erythrocyte progenitors. In summary, we conclude that treatment of ACD, as a highly complex disease, becomes more effective by a multifactorial therapeutic approach upon mobilization of endogenous iron deposits and stimulation of erythropoiesis.

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.

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.

Usefulness of mid-week hemoglobin measurement for anemia management in patients undergoing hemodialysis: a retrospective cohort study.

BACKGROUND: Short-term hemoglobin (Hb) variability related to volume status is observed in chronic kidney disease (CKD) patients receiving hemodialysis (HD). Given the lack of studies regarding outcomes according to the day of Hb sampling, the existing guidelines do not strongly recommend regarding measurement timing. Pre-dialysis mid-week sampling (Wednesday and Thursday) is preferable to minimize short-term Hb variability, although numerous HD centers perform early-week sampling (Monday and Tuesday). The different measurement days may influence the prescribed dose of erythropoiesis-stimulating agent (ESA) and related patient outcomes. We investigated changes in Hb levels and ESA doses according to the Hb measurement day among HD patients. METHODS: Starting September 2013, the day for pre-dialysis Hb measurement at the Asan Medical Center was changed from early-week days to mid-week days. This single-center retrospective study evaluated medical records of 92 patients who received maintenance HD between September 2012 and August 2014. RESULTS: There was no significant difference in the mean Hb levels between early-week days and mid-week days (10.71 ± 0.06 g/dL vs. 10.78 ± 0.47 g/dL, p = 0.105). However, the mean doses of darbepoetin-α on early-week days were higher than those on mid-week days (175.4 ± 72.5 µg/month vs. 163.7 ± 83.6 µg/month, p = 0.022). The mean doses of intravenous iron hydroxide sucrose for early-week measurements were also higher than those for mid-week measurements (623.0 ± 489.0 mg/year vs. 447.0 ± 505.2 mg/year, p = 0.001). The mean interdialytic weight gains were 2.81 ± 0.82 kg on early-week days and 1.99 ± 0.61 kg on mid-week days (p < 0.001). CONCLUSIONS: Compared with early-week measurements, mid-week pre-dialysis Hb measurements were significantly associated with lower ESA doses without a change in Hb levels.

Long-Term Efficacy and Safety of Molidustat for Anemia in Chronic Kidney Disease: DIALOGUE Extension Studies.

BACKGROUND: Molidustat, a novel hypoxia-inducible factor-prolyl hydroxylase inhibitor, is being investigated for the treatment of anemia associated with chronic kidney disease (CKD). The efficacy and safety of molidustat were recently evaluated in three 16-week phase 2b studies. Here, we report the results of two long-term extension studies of molidustat. METHODS: Both studies were parallel-group, open-label, multicenter studies of ≤36 months' duration, in patients with anemia due to CKD, and included an erythropoiesis-stimulating agent as active control. One study enrolled patients not receiving dialysis (n = 164), and the other enrolled patients receiving hemodialysis (n = 88). The primary efficacy variable for both studies was change in blood hemoglobin (Hb) level from baseline to each post-baseline visit, and safety outcomes included adverse events (AEs). RESULTS: In patients not on dialysis, the mean ± SD Hb concentrations at baseline were 11.28 ± 0.55 g/dL for molidustat and 11.08 ± 0.51 g/dL for darbepoetin. The mean ± SD blood Hb concentrations throughout the study (defined as mean of each patient's overall study Hb levels) were 11.10 ± 0.508 and 10.98 ± 0.571 g/dL in patients treated with molidustat and darbepoetin, respectively. Similar proportions of patients reported at least one AE in the molidustat (85.6%) and darbepoetin (85.7%) groups. In patients on dialysis, mean ± SD Hb levels at baseline were 10.40 ± 0.70 and 10.52 ± 0.53 g/dL in the molidustat and epoetin groups, respectively. The mean ± SD blood Hb concentrations during the study were 10.37 ± 0.56 g/dL in the molidustat group and 10.52 ± 0.47 g/dL in the epoetin group. Proportions of patients who reported at least one AE were 91.2% in the molidustat group and 93.3% in the epoetin group. CONCLUSIONS: Molidustat was well tolerated for up to 36 months and appears to be an effective alternative to darbepoetin and epoetin in the long-term management of anemia associated with CKD.

Efficacy, tolerability and safety of darbepoetin alfa injection for the treatment of anemia associated with chronic kidney disease (CKD) undergoing dialysis: a randomized, phase-III trial.

BACKGROUND: Darbepoetin alfa (DA-α) is a long-acting erythropoiesis-stimulating glycoprotein which has half-life three-fold longer than that of Erythropoietin alfa (EPO). The objective of this study was to compare the efficacy and safety of DA-α injection versus EPO for treating renal anemia amongst Indian patients with end-stage renal disease (ESRD) undergoing dialysis. METHODS: Patients of either gender (aged 18-65 years) with ESRD undergoing dialysis who had hemoglobin (Hb) levels < 10 g/dL after receiving EPO were switched to DA-α (0.45 µg/kg) once weekly subcutaneously or EPO 50 IU/kg thrice weekly subcutaneously (centrally randomized 1:1) for 12-24 weeks (correction phase) followed by 12 weeks maintenance phase (for Hb levels ≥10 g/dL). The primary efficacy endpoint was mean change in Hb level from baseline to end of correction phase. RESULTS: In the intention-to-treat population (n = 126), the between group difference in mean Hb change was - 0.01 g/dL (95% CI - 0.68 to - 0.66, p = 0.97). After adjusting for covariates, the difference was - 0.2878 g/dL (95% CI -0.936 to0.360). The lower limit of the two-sided 95% CI of primary endpoint was above the pre-specified non-inferiority margin of - 1.0 g/dL. Similar trend of non-inferiority was observed for per-protocol population. Safety profile of DA-α and EPO were observed to be similar. CONCLUSION: Our study results demonstrated that for patients with ESRD undergoing dialysis, administering DA-α at lower dose frequency, is equally effective and well tolerated as EPO for treating renal anemia. TRIAL REGISTRATION: CTRI/2012/07/002835 [Registered on: 27/07/2012]; Trial Registered Prospectively.

Efficacy of IntraCoronary Erythropoietin Delivery BEfore Reperfusion-Gauging Infarct Size in Patients with Acute ST-segment Elevation Myocardial Infarction (ICEBERG).

Previous clinical studies have shown inconsistent results regarding the effect of erythropoietin in ST-segment elevation myocardial infarction (STEMI). This study investigated whether directed intracoronary infusion of darbepoetin-α into ischemic myocardium before reperfusion would reduce infarct size or post-infarct remodeling in STEMI patients.Eighty STEMI patients received one of the following treatments simultaneously with the first balloon inflation: intracoronary darbepoetin-α 300 µg (n = 40) or saline (n = 40), administered via the over-the-wire balloon system. The primary endpoint was infarct size estimated by serial cardiac enzyme levels after procedure. The secondary endpoints were (1) infarct size and proportion of salvaged myocardium measured with cardiac magnetic resonance (CMR) at baseline; (2) post-infarct remodeling (PIR), defined as an increase in left ventricular end-diastolic volume more than 20% at 4 months compared to the baseline on CMR; and (3) composite cardiovascular endpoints assessed at 4 months.The peak CK-MB [median 270.0 (interquartile range 139.8-356.3) versus 231.5 (131.0-408.5) ng/mL, P = 0.55] and troponin-I [128.5 (63.5-227.8) versus 109.0 (43.8-220.0) ng/mL, P = 0.52) ] did not differ between the darbepoetin-α and control group. Fifty-seven patients completed the baseline and 4-month follow-up CMR. There were no differences in infarct size [30.6 (18.1-49.8) versus 31.5 (22.5-47.3) cm3, P = 0.91), proportion of salvaged myocardium [26.7% (15.9-42.6%) versus 35.8% (22.4-48.8%), P = 0.12) or PIR (8.0% versus 6.7%, P = 0.62) between the two groups. Composite cardiovascular outcomes did not differ between the two groups.In conclusion, administration of intracoronary darbepoetin-α before reperfusion did not reduce infarct size or post-infarct remodeling in STEMI patients.

T cell and monocyte/macrophage activation markers associate with adverse outcome, but give limited prognostic value in anemic patients with heart failure: results from RED-HF.

BACKGROUND: Activated leukocytes may contribute to the development and progression of heart failure (HF). We investigated the predictive value of circulating levels of stable and readily detectable markers reflecting both monocyte/macrophage and T-cell activity, on clinical outcomes in HF patients with reduced ejection fraction (HFrEF). METHODS: The association between baseline plasma levels of soluble CD163 (sCD163), macrophage migration inhibitory factor (MIF), granulysin, soluble interleukin-2 receptor (sIL-2R), and activated leukocyte cell adhesion molecule (ALCAM) and the primary endpoint of death from any cause or first hospitalization for worsening of HF was evaluated using multivariable Cox proportional hazard models in 1541 patients with systolic HF and mild to moderate anemia, enrolled in the Reduction of Events by darbepoetin alfa in Heart Failure (RED-HF) trial. Modifying effects and interaction with darbepoetin alfa treatment were also assessed. RESULTS: All leukocyte markers, except granulysin, were associated with the primary outcome and all-cause death in univariate analysis (all p < 0.01) and remained significantly associated in multivariable analysis adjusting for conventional clinical variables (e.g. age, gender, BMI, NYHA class, creatinine, LVEF, etiology) and CRP. However, after final adjustment for TnT and NT-proBNP no associations were found with outcomes. No interaction with darbepoetin alpha treatment was observed for any marker. CONCLUSIONS: Leukocyte activation markers sCD163, MIF, sIL-2R, and ALCAM were associated with adverse outcome in patients with HFrEF, but add little as prognostic markers on top of established biochemical risk markers. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT00358215 .

Elimination of hepatitis C virus infection from a hemodialysis unit and impact of treatment on the control of anemia.

INTRODUCTION: In the interferon era, the treatment of hepatitis C virus (HCV) infection in patients on haemodialysis (HD) was limited due to the significant number of treatment-related adverse events (AEs). Direct-acting antivirals (DAAs) have demonstrated their efficacy and safety in the treatment of HCV in patients with advanced chronic kidney disease on haemodialysis. The objective of the study was to evaluate the success in eliminating HCV infection from our dialysis unit using DAAs, and to assess the impact of HCV elimination on clinical and analytical outcomes. PATIENTS AND METHODS: This is a prospective, interventional, single-center study at Hospital Clínic de Barcelona. All HCV-RNA positive patients who received antiviral therapy with DAAs within a 3-year period (2014-2017) were analyzed (n=20). Data on virologic response, adverse events, and biochemical and hematological parameters during and after DAA therapy were analyzed. RESULTS: All patients achieved sustained virologic response (SVR) and only 40% of patients presented with mild AEs. None of the patients presented with HCV reinfection after a 1-year follow-up period, and thus HCV was eliminated from our HD unit. SVR was associated with a significant increase in hemoglobin and hematocrit, and a tendency toward the need for lower doses of iron supplementation with no changes in darbepoetin dose. CONCLUSION: HCV infection can be safely eliminated from HD units with the use of DAAs, preventing new infections in patients and healthcare staff. In the short term, the achievement of SVR is associated with an improvement in the control of anemia.

Safety and effectiveness of long-term use of darbepoetin alfa in non-dialysis patients with chronic kidney disease: a post-marketing surveillance study in Japan.

BACKGROUND: This post-marketing surveillance (PMS) study evaluated the safety and effectiveness of long-term darbepoetin alfa (darbepoetin) for the treatment of renal anemia in Japanese non-dialysis chronic kidney disease patients. METHODS: Patients were treated with darbepoetin and followed up for 3 years. Adverse events (AEs), adverse drug reactions (ADRs), hemoglobin (Hb) levels, and renal function were assessed. Patients were stratified by Hb level at the time of occurrence of cardiovascular-related AEs. Statistical analyses were performed to explore factors affecting the occurrence of AEs, cardiovascular-related AEs, and composite renal endpoints. RESULTS: In the safety analysis set (5547 patients), AEs and ADRs occurred in 44.4 and 7.1% of patients, respectively. Cardiovascular-related AEs were observed in 12.6% of the overall population. The proportion of patients who presented cardiovascular-related AEs was lower among those with a higher Hb level at the time of occurrence. In the effectiveness analysis set (5024 patients), mean Hb levels remained between 10.0 and 10.6 g/dL (Weeks 4-156). Three months after darbepoetin administration, patients with Hb ≥ 11 g/dL presented fewer composite renal endpoints than those with Hb < 11 g/dL (p = 0.0013), and the cumulative proportion of renal survival was higher in those with Hb ≥ 11 g/dL vs. Hb < 11 g/dL (p < 0.0001). CONCLUSIONS: This PMS study showed the safety and effectiveness of long-term use of darbepoetin in a large number of patients. Patients with Hb ≥ 11 g/dL presented fewer composite renal endpoints than those with Hb < 11 g/dL, without an increase in the incidence of cardiovascular-related AEs.

Real-world utilization of darbepoetin alfa in cancer chemotherapy patients.

OBJECTIVES: To provide an understanding of darbepoetin alfa dose patterns in cancer patients undergoing myelosuppressive chemotherapy starting from 2011. STUDY DESIGN: This is a retrospective cohort study using a proprietary outpatient oncology database. METHODS: Metastatic, solid tumor cancer patients receiving concomitant myelosuppressive chemotherapy and darbepoetin alfa with an associated hemoglobin <10 g/dL during 2011-2015 were identified. The analysis was restricted to the first continuous exposure to chemotherapy agents (maximum allowable gap of 90 days between consecutive exposures) with darbepoetin alfa for each eligible patient. Initial, maintenance, weekly, and cumulative doses of darbepoetin alfa were examined across all darbepoetin alfa users. Subgroup analyses were conducted by chemotherapy type, baseline hemoglobin level, year of chemotherapy, solid tumor type, and initial dosing schedule. Differences in weekly doses across subgroups were evaluated using Wilcoxon rank-sum tests. RESULTS: Among 835 eligible patients, over 90% were 50 years or older. Mean chemotherapy course duration was 248 days, and mean duration of darbepoetin alfa treatment was 106 days. The mean weekly darbepoetin alfa dose was 110 µg. Patients received a mean of 4.3 darbepoetin alfa injections in the first chemotherapy course. There were no statistically significant differences (all P values > .05) in weekly dose by chemotherapy type, baseline hemoglobin level, year of chemotherapy, or solid tumor type. CONCLUSION: The average weekly darbepoetin alfa dose among metastatic cancer patients with chemotherapy-induced anemia from this study was 110 µg, which was lower than the labeled dosage for most adults. This estimate did not differ over time, across chemotherapy regimens, baseline hemoglobin levels, or solid tumor types.

Trends in anemia care in non-dialysis-dependent chronic kidney disease (CKD) patients in the United States (2006-2015).

BACKGROUND: The objective of the study was to examine overall anemia management trends in non-dialysis patients with chronic kidney disease (CKD) from 2006 to 2015, and to evaluate the impact of Trial to Reduced Cardiovascular Events with Ananesp Therapy (TREAT)'s study results (October 2009) and the US Food and Drug Administration (FDA)'s (June 2011) safety warnings and guidelines on the use of ESA therapy in the current treatment of anemia. METHODS: A retrospective cohort analysis of anemia management in CKD patients using Truven MarketScan Commercial and Medicare Supplemental databases was conducted. Monthly rates and types of anemia treatment for post-TREAT and post-FDA safety warning periods were compared to pre-TREAT period. Anemia management included ESA, intravenous iron, and blood transfusion. A time-series analysis using Autoregressive Integrated Moving Average (ARIMA) model and a Generalized Estimating Equation (GEE) model were used. RESULTS: Between 2006 and 2015, CKD patients were increasingly less likely to be treated with ESAs, more likely to receive intravenous iron supplementation, and blood transfusions. The adjusted probabilities of prescribing ESAs were 31% (odds ratio (OR) = 0.69, 95% confidence interval (CI): 0.67-0.71) and 59% (OR = 0.41, 95% CI: 0.40, 0.42) lower in the post-TREAT and post-FDA warning periods compared to pre-TREAT period. The probability of prescribing intravenous iron was increased in the post-FDA warning period (OR = 1.11, 95% CI: 1.03-1.19) although the increase was not statistically significant in the post-TREAT period (OR = 1.03, 95% CI: 0.94-1.12). The probabilities of prescribing blood transfusion during the post-TREAT and post-FDA warning periods increased by 14% (OR = 1.14, 95% CI: 1.06-1.23) and 31% (OR = 1.31, 95% CI: 1.22-1.39), respectively. Similar trends of prescribing ESAs and iron supplementations were observed in commercially insured CKD patients but the use of blood transfusions did not increase. CONCLUSIONS: After the 2011 FDA safety warnings, the use of ESA continued to decrease while the use of iron supplementation continued to increase. The use of blood transfusions increased significantly in Medicare patients while it remained stable in commercially insured patients. Results suggest the TREAT publication had effected treatment of anemia prior to the FDA warning but the FDA warning solidified TREAT's recommendations for anemia treatment for non- dialysis dependent CKD patients.

Protective effects of Tadalafil and darbepoetin against ischemia - reperfusion injury in a rat testicular torsion model

ABSTRACT Objectives: To evaluate protective effects of darbepoetin and tadalafil against ischemia-reperfusion injury in ipsilateral and contralateral testicle. Materials and Methods: Thirty 3-month-old adult male Wistar-Albino rats were randomly divided into 5 groups (A-E). Sham operation was performed in the first group. In Group B, rats did not received any medication after creating 720 degrees torsion of the left testis. The rats in Group C, D and E received darbepoetin, tadalafil, and darbepoetin/tadalafil combination 30 minutes after creating 720 degrees torsion of the left testis, respectively. The testes of rats in these three groups were detorsioned at 90 minutes after drug administration. Both testes were removed at 30 minutes after detorsion. Results: There were significant differences between the groups in terms of the degree of histopathological damage, Johnsen score, fibrosis score and caspase-3 immunoreactivity in the torsioned testes (p: 0.000). The results for each parameter in the left testes were significantly better in the darbepoetin / tadalafil combination group. Similarly, there were also significant differences in the contralateral testes (p: 0.000). Conclusion: The active substances darbepoetin and tadalafil that were used as a combination had protective effects on both testes and produced out better results in preserving testicular histology. Especially in cases where it is not possible to rescue the torsioned testis, this result was more noticeable in the contralateral testis.

El modelo de control de anemia: ¿ayuda al nefrólogo en la decisión terapéutica para el manejo de la anemia? / The anaemia control model: Does it help nephrologists in therapeutic decision-making in the management of anaemia?

INTRODUCCIÓN: La anemia es frecuente en los pacientes en hemodiálisis, y su tratamiento con estimulantes de la eritropoyesis (AEE) resulta complejo debido a múltiples factores. OBJETIVOS: Valorar la utilidad del modelo de control de anemia (MCA) en el tratamiento de la anemia en hemodiálisis. MÉTODOS: El MCA es un software que predice la dosis óptima de darbepoetina y hierro sacarosa para alcanzar niveles de hemoglobina (Hb) y ferritina deseados, emitiendo sugerencias de prescripción. Estudio realizado en clínicas de diálisis de 18 meses de duración en dos fases de intervención (FI) con MCA (FI1, n: 213; FI2, n: 218) separadas por una fase de control (FC, n: 219). El resultado primario fue el porcentaje de Hb en rango y la mediana de dosis de AEE y los resultados secundarios fueron las transfusiones, las hospitalizaciones o los acontecimientos cardiovasculares. Análisis a nivel de clínica y de pacientes valorando la variabilidad de la Hb mediante la desviación estándar (DE) de esta. También se analizaron pacientes con la mayoría de sugerencias confirmadas (grupo MCA cumplidores) RESULTADOS: El MCA aumentó el porcentaje de Hb en rango: 80,9% FI2 frente a 72,7% en FC, y redujo el consumo de darbepoetina (FI1: 20 [70]; FC 30 [80] μg, p = 0,032) con menor fluctuación de la Hb (0,91 ± 0,49 en FC a 0,82 ± 0,37g/dl en FI2; p < 0,05) mejorando en el grupo MCA cumplidores. En cuanto a los resultados secundarios, descendieron con el uso del MCA. CONCLUSIONES: El MCA ayuda a obtener mejores resultados de anemia en los pacientes en hemodiálisis, minimizando los riesgos del tratamiento con AEE y reduciendo costes

INTRODUCTION: Anaemia is common in haemodialysis patients and treating it with erythropoiesis-stimulating agents (ESAs) is complex due to many factors. OBJECTIVES: To assess the usefulness of the Anaemia Control Model (ACM) in the treatment of anaemia in haemodialysis. METHODS: ACM is a software that predicts the optimal dose of darbepoetin and iron sucrose to achieve target haemoglobin (Hb) and ferritin levels, and makes prescription suggestions. Study conducted in dialysis clinics lasting 18months with two intervention phases (IPs) with ACM (IP1, n:213; IP2, n:218) separated by a control phase (CP, n:219). The primary outcome was the percentage of Hb in range and the median dose of ESAs, and the secondary outcomes were transfusion, hospitalisation and cardiovascular events. Clinical and patient analyses were performed. Hb variability was assessed by the standard deviation (SD) of the Hb. We also analysed the patients with most of the suggestions confirmed (ACM compliant group). RESULTS: ACM increased the percentage of Hb in range: 80.9% in IP2, compared with 72.7% in the CP and reduced the intake of darbepoetin (IP1: 20 [70]; CP 30 [80] μg P = 0.032) with less Hb fluctuation (0.91 ± 0.49 in the CP to 0.82 ± 0.37 g/dl in IP2, P < 0.05), improving in the ACM compliant group. The secondary outcomes decreased with the use of ACM. CONCLUSIONS: ACM helps to obtain better anaemia results in haemodialysis patients, minimising the risks of treatment with ESAs and red