Comparative Safety of Long-Acting vs. Short-Acting Erythropoiesis-Stimulating Agents Among Patients Undergoing Hemodialysis.

Both short-acting (epoetin alfa or beta) and long-acting (darbepoetin alfa or PEG-epoetin) erythropoiesis-stimulating agents (ESAs) are commonly prescribed for patients with kidney failure undergoing maintenance hemodialysis. We compared the risks of major adverse cardiovascular events (MACE) and of all-cause mortality associated with receipt of short- vs. long-acting ESAs. This retrospective cohort analysis included Medicare hemodialysis beneficiaries aged ≥ 18 years in the United States Renal Data System from January 2015 to December 2017. We included adults who survived > 90 days after initiating hemodialysis and received either short- or long-acting ESAs. Outcomes were MACE (first occurrence of stroke, acute myocardial infarction, or cardiovascular-related mortality) and all-cause mortality. After stabilized inverse probability of treatment weighting, Cox proportional hazards regression models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for each outcome. Of 68,607 patients (mean age: 65 years, 45% females), 33,658 (49%) received long-acting ESAs and 34,949 (51%) received short-acting ESAs. There was no difference in the risk of MACE associated with receipt of short- vs. long-acting ESAs (HR: 1.02 (95% CI: 0.98-1.08)). However, long-acting (vs. short-acting) ESA receipt was associated with a lower risk of all-cause mortality (HR: 0.91 (95% CI: 0.87-0.96)). Compared with short-acting ESAs, long-acting ESAs were associated with a lower risk of all-cause mortality, with no difference in the risk of MACE. Future studies with a longer follow-up are needed to confirm these findings.

Weight-based vs fixed dosing of darbepoetin alfa for anemia following kidney transplantation.

PURPOSE: Post-transplantation anemia (PTA) is common in kidney transplant recipients, with patients frequently treated with erythropoietin-stimulating agents such as darbepoetin alfa. The optimal dosing for darbepoetin alfa remains controversial. METHODS: This retrospective cohort study involved kidney transplant recipients who received darbepoetin alfa at 2 clinics. Patients were stratified into 2 groups: those who received a fixed dose of 200 µg and those who received a weight-based dose of 0.45 µg/kg. The dosing interval varied depending on clinical response, clinic visit timing, and frequency allowed by insurance. The primary outcome was achieving a hemoglobin concentration of at least 10 g/dL without blood transfusion by 12 weeks after darbepoetin alfa initiation. RESULTS: Of the 110 patients in the study, 45% received weight-based dosing and 55% received fixed dosing. Darbepoetin alfa was initiated significantly earlier after transplantation in the fixed-dose group (median of 14 vs 20 days; P = 0.003). The weight-based group received more doses of darbepoetin alfa (median of 4 vs 2 doses; P = 0.002) and had a significantly lower cumulative exposure to darbepoetin alfa (125 vs 590 µg; P < 0.001). The median time between doses was 9 days (interquartile range, 7-14 days) in the weight-based group and 12 days (7-32 days) in the fixed-dose group (P = 0.04). Patients in the weight-based group more frequently achieved the primary outcome (67.3% vs 47.5%; P = 0.059). There was no significant difference in secondary or safety outcomes between the groups. CONCLUSION: Weight-based and fixed dosing approaches for darbepoetin alfa were not different in the achievement of a hemoglobin concentration of at least 10 g/dL without blood transfusion at 12 weeks after darbepoetin alfa initiation, with significantly lower cumulative darbepoetin alfa utilization in the weight-based group. Weight-based dosing of darbepoetin alfa in PTA appears to be safe and effective, with the potential for significant patient and health-system cost savings.

Epoetin-alfa induced pruritic maculopapular eruption: Case report and literature review.

BACKGROUND: Erythropoiesis-stimulating agents (ESA) are commonly used in clinical practice to improve anaemia. Despite a number of patients successfully treated without adverse events, the complications have been previously reported. OBJECTIVE: To report and review the characteristics and management of ESA hypersensitivities. METHODS: Case reports and related articles associated with ESA use, published between January 1999 and December 2018, were retrieved through Electronic databases (MEDLINE® and PubMed®). RESULTS: Forty-seven ESA patients with various immediate and delayed hypersensitivity reactions caused by epoetin and pharmaceutical excipients were identified from nineteen studies and one case report in this paper. Fatal hypersensitivity to ESA and ESA-allergic cross-reactivities have been documented. Desensitization or change of EPO molecular structure has been reported as successful methods of re-introducing the drug. CONCLUSIONS: ESA hypersensitivity in the various allergic reactions and cross-reactivity have been documented. Desensitization and Epoetin structural changes could be successful methods to re-introduce the drug.

Analysis of on-treatment cancer safety events with daprodustat versus conventional erythropoiesis-stimulating agents-post hoc analyses of the ASCEND-ND and ASCEND-D trials.

BACKGROUND: The prespecified on-treatment analysis of ASCEND-ND (NCT02876835) raised concerns about a higher relative risk of cancer-related adverse events (AEs) with daprodustat vs darbepoetin in patients with anaemia of CKD. This concern was not observed in dialysis patients in ASCEND-D (NCT02879305). METHODS: ASCEND-ND randomized 3872 patients to daprodustat or darbepoetin. ASCEND-D randomized 2964 patients to daprodustat or conventional erythropoiesis-stimulating agents (ESAs). In both studies ESA comparators used different dosing intervals (3/week, 1/week, every 2 or every 4 weeks). The prespecified on-treatment approach examined relative risks for cancer AEs up to the last dose date + 1 day. In these analyses, owing to different dosing intervals between arms, Cox models were used to estimate the daprodustat effect by various follow-up periods (censoring at last dose date, last dose date + dosing intervals, or end of study). RESULTS: In ASCEND-ND, the safety of daprodustat vs darbepoetin on cancer-related AEs depended on the duration of follow-up after last dose date: hazard ratio (HR) 1.04 [95% confidence interval (CI) 0.77, 1.40] at end of study [HR 1.12 (95% CI 0.81, 1.56) for last dose date + dosing interval; HR 1.50 (95% CI 1.04, 2.15) for last dose date + 1 day]. In ASCEND-D, no excess risk of cancer-related AEs was observed with any model examined. CONCLUSIONS: Prespecified on-treatment analyses for cancer-related AEs appeared to result in biased risk estimates in ASCEND-ND by preferentially under-counting events from patients assigned to darbepoetin. Analyses accounting for longer darbepoetin dosing intervals, or extending follow-up, resulted in attenuation of effect estimates towards neutrality, similar to ASCEND-D, where ESA comparator dosing intervals are closer to daprodustat. TRIAL REGISTRATION: The ASCEND-ND trial is registered with ClinicalTrials.gov (NCT02876835); the ASCEND-D trial is registered with ClinicalTrials.gov (NCT02879305).

Comparison of darbepoetin alpha and recombinant human erythropoietin for treatment of anemia in pediatric chronic kidney disease: a non-inferiority trial from India.

To determine whether or not Darbepoetin alpha (DA) was non-inferior to recombinant human erythropoietin (rHuEPO) in the treatment of anemia in children with chronic kidney disease (CKD) stage 3-5 (on or not on dialysis). This was a randomized, open-label, two-arm, parallel group, active-controlled, non-inferiority trial conducted at a tertiary care center in New Delhi, India. Fifty patients of either gender (aged 1-18 years) with CKD stage 3-5 (on or not on dialysis) who had baseline hemoglobin (Hb) between 9 and 12 g/dL and were on stable erythropoietin therapy for at least 8 weeks were randomized (1:1) to either continue rHuEPO or switch to DA therapy for a period of 28 weeks. Doses were titrated in the initial 23 weeks to maintain the Hb between 11 and 12 g/dL, and efficacy was assessed between weeks 24 and 28. The primary efficacy outcome was the mean change in Hb between baseline and the evaluation period. In the intention-to-treat population (n = 50), the adjusted between-group difference in mean Hb change between the baseline and the evaluation period was 0.131 g/dL (95% CI: - 0.439 to 0.719, p = 0.629). The lower limit of the two-sided 95% CI for the difference in the mean change in Hb between the two treatment groups was well above the pre-specified non-inferiority margin of - 1.0 g/dL. Similar pattern of non-inferiority was seen for per protocol population. The safety profile of DA and rHuEPO was also comparable (injection site pain:rHuEPO-3, DA-7; p-0.296).   Conclusion: DA is non-inferior to rHuEPO for the treatment of anemia of CKD (stage 3-5) in pediatric population with a comparable safety profile.   Trial registration: ClinicalTrials.gov Identifier: NCT04959578 (retrospectively registered), Date: July 13, 2021. What is Known: • Limited studies showing darbepoetin alpha is effective in children as an erythropoiesis stimulating agent. • No RCT from Indian subcontinent addressing this topic. What is New: • Darbepoetin alpha is non inferior to recombinant human erythropoietin for treatment of anemia in children with CKD stage 3-5 (on or not on dialysis) with safety comparable to recombinant human erythropoietin. • A cost reduction of approximately 8.6% per patient by shifting to darbepoetin alpha.

Efficacy and safety of vadadustat compared to darbepoetin alfa on anemia in patients with chronic kidney disease: a meta-analysis.

OBJECTIVE: As a novel oral agent in treating anemia of chronic kidney disease (CKD), several clinical trials of vadadustat have been conducted to compare with darbepoetin alfa. This study systematically reviews and investigates the efficacy and safety of vadadustat in the anemia treatment with different duration in both nondialysis-dependent CKD (NDD-CKD) and dialysis-dependent CKD (DD-CKD). METHODS: Several main databases were searched for randomized controlled trials (RCTs) reporting vadadustat vs darbepoetin alfa for anemia patients with CKD. The outcome indicators were focused on hemoglobin (Hb), the percentage of patients within the target Hb, the need for RBC (Red Blood Cell) transfusions, and serious adverse events (SAEs). RESULTS: Four eligible studies with 8,026 participants were included. The changes of Hb levels from the baseline in the darbepoetin alfa group were significantly higher than that in the vadadustat group with DD-CKD (mean difference (MD) - 0.19, [95% confidence interval (CI), - 0.21 to - 0.17], p < 0.0001). In NDD-CKD patients, the changes of Hb levels in the two groups are not significantly different (MD = - 0.06, [95% CI, - 0.18 to 0.05], p = 0.006), especially, during the treatment duration of 20-36 weeks (MD = 0.02, [95% CI, - 0.04 to 0.08], p = 0.51). The percentage of patients within the target Hb was significantly lower in the vadadustat group than that in the darbepoetin alfa group in DD-CKD patients (MD = 0.9, [95% CI, 0.86 to 0.94], p < 0.00001), while in NDD-CKD patients, there was no significant difference (MD = 1.05, [95% CI, 0.99 to 1.12], p < 0.00001). In terms of safety, the two agents had no significant difference in the incidence of RBC transfusions and SAEs (RR = 1.26 [95% CI, 0.99 to 1.61], p = 0.52; RR = 0.97, [95% CI, 0.94 to 1.01], p = 0.19; respectively). CONCLUSION: Compared to darbepoetin alfa, vadadustat had the same effect in raising the hemoglobin level in NDD-CKD patients in the short term. Vadadustat may become an effective and safe alternative for the treatment of patients with anemia and CKD, especially in NDD-CKD patients. As the application of vadadustat is still under exploration, future research should compensate for the limitations of our study to estimate the vadadustat's value.

Overall Adverse Event Profile of Vadadustat versus Darbepoetin Alfa for the Treatment of Anemia Associated with Chronic Kidney Disease in Phase 3 Trials.

INTRODUCTION: Anemia frequently occurs in chronic kidney disease (CKD), is associated with poor quality of life and cardiovascular outcomes, and its treatment represents a considerable economic burden to the healthcare system. Although effective, the current standard of care for the treatment of anemia in chronic kidney disease patients with erythropoiesis-stimulating agents requires chronic/ongoing injections, making the treatment less accessible or desirable to patients not treated by in-center maintenance hemodialysis. Furthermore, safety concerns, including an increased risk of cardiovascular events and mortality, have emerged from their use in studies targeting hemoglobin concentrations in the normal or near-normal range. The orally active hypoxia-inducible factor prolyl hydroxylase inhibitor vadadustat may offer advantages over erythropoiesis-stimulating agents by correcting anemia via pathways activating endogenous erythropoietin production. METHODS: To comprehensively analyze the safety profile of vadadustat in patients with dialysis-dependent and non-dialysis-dependent CKD-related anemia, we pooled the safety populations from each of the four trials in the phase 3 clinical program (n = 7,373) and compared the risk of treatment-emergent adverse events (TEAEs) for each treatment arm. RESULTS: In patients randomized to vadadustat versus darbepoetin alfa, rates of TEAEs (88.9% vs. 89.3%), treatment-emergent serious adverse events (58.0% vs. 59.3%), and TEAEs leading to death (16.1% vs. 16.2%) were similar, as were rates of adverse events of special interest, including cardiovascular-, hepatic-, and neoplasm-related adverse events. DISCUSSION/CONCLUSION: Among patients with CKD-related anemia treated with vadadustat, we observed similar rates of adverse events relative to those treated with darbepoetin alfa.

Comparative Efficacy and Safety Study of Darbepoetin Alfa versus Epoetin Alfa in Management of Anemia Associated with ESRD in Egyptian Hemodialysis Patients.

BACKGROUND: Anemia is one of the most common complications of Chronic Kidney Disease (CKD). The vast majority of Egyptian CKD patients are interchangeably treated with Darbepoetin Alfa (DPA) and Epoetin Alfa (EPA) to achieve and maintain target hemoglobin levels. Our study aimed to compare the efficacy and safety of DPA versus EPA for managing anemia amongst Egyptian patients with CKD undergoing dialysis. METHODS: A multicenter, open label, randomized, prospective, parallel study was conducted. Patients with CKD undergoing dialysis with Hb level < 10 g/dl were enrolled. The primary efficacy endpoint was the change in hemoglobin concentration at the evaluation period (weeks 20-24). Prespecified adverse events of interest following administration, including blood transfusions requirement, blood pressure and hemoglobin excursions, the relationship between C - Reactive Protein (CRP) and hemoglobin, were assessed. RESULTS: Only 98 of 104 enrolled patients completed the study, fifty patients received EPA, and 48 patients received DPA. Our results showed that a significantly higher percentage of patients who achieved target Hb level ≥ 11 g/dL in DPA treated group vs. EPA as well as the meantime to achieve Hb level ≥ 10 g/dL was shorter in DPA treated group. Safety profiles of both treatments were similar. A negative correlation was observed between serum CRP and hemoglobin level in hemodialysis patients. CONCLUSION: Our study showed that DPA was more effective and well tolerated in achieving and maintaining Hb levels with lower dosing frequency compared to EPA. Furthermore, CRP is recommended to be routinely measured where patients with higher CRP require high ESA doses.

Daprodustat for the Treatment of Anemia in Patients Undergoing Dialysis.

BACKGROUND: Among patients with chronic kidney disease (CKD), the use of recombinant human erythropoietin and its derivatives for the treatment of anemia has been linked to a possibly increased risk of stroke, myocardial infarction, and other adverse events. Several trials have suggested that hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors (PHIs) are as effective as erythropoiesis-stimulating agents (ESAs) in increasing hemoglobin levels. METHODS: In this randomized, open-label, phase 3 trial, we assigned patients with CKD who were undergoing dialysis and who had a hemoglobin level of 8.0 to 11.5 g per deciliter to receive an oral HIF-PHI (daprodustat) or an injectable ESA (epoetin alfa if they were receiving hemodialysis or darbepoetin alfa if they were receiving peritoneal dialysis). The two primary outcomes were the mean change in the hemoglobin level from baseline to weeks 28 through 52 (noninferiority margin, -0.75 g per deciliter) and the first occurrence of a major adverse cardiovascular event (a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), with a noninferiority margin of 1.25. RESULTS: A total of 2964 patients underwent randomization. The mean (±SD) baseline hemoglobin level was 10.4±1.0 g per deciliter overall. The mean (±SE) change in the hemoglobin level from baseline to weeks 28 through 52 was 0.28±0.02 g per deciliter in the daprodustat group and 0.10±0.02 g per deciliter in the ESA group (difference, 0.18 g per deciliter; 95% confidence interval [CI], 0.12 to 0.24), which met the prespecified noninferiority margin of -0.75 g per deciliter. During a median follow-up of 2.5 years, a major adverse cardiovascular event occurred in 374 of 1487 patients (25.2%) in the daprodustat group and in 394 of 1477 (26.7%) in the ESA group (hazard ratio, 0.93; 95% CI, 0.81 to 1.07), which also met the prespecified noninferiority margin for daprodustat. The percentages of patients with other adverse events were similar in the two groups. CONCLUSIONS: Among patients with CKD undergoing dialysis, daprodustat was noninferior to ESAs regarding the change in the hemoglobin level from baseline and cardiovascular outcomes. (Funded by GlaxoSmithKline; ASCEND-D ClinicalTrials.gov number, NCT02879305.).

Daprodustat for the Treatment of Anemia in Patients Not Undergoing Dialysis.

BACKGROUND: Daprodustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor. In patients with chronic kidney disease (CKD) who are not undergoing dialysis, the efficacy and safety of daprodustat, as compared with the conventional erythropoiesis-stimulating agent darbepoetin alfa, are unknown. METHODS: In this randomized, open-label, phase 3 trial with blinded adjudication of cardiovascular outcomes, we compared daprodustat with darbepoetin alfa for the treatment of anemia in patients with CKD who were not undergoing dialysis. The primary outcomes were the mean change in the hemoglobin level from baseline to weeks 28 through 52 and the first occurrence of a major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke). RESULTS: Overall, 3872 patients were randomly assigned to receive daprodustat or darbepoetin alfa. The mean (±SD) baseline hemoglobin levels were similar in the two groups. The mean (±SE) change in the hemoglobin level from baseline to weeks 28 through 52 was 0.74±0.02 g per deciliter in the daprodustat group and 0.66±0.02 g per deciliter in the darbepoetin alfa group (difference, 0.08 g per deciliter; 95% confidence interval [CI], 0.03 to 0.13), which met the prespecified noninferiority margin of -0.75 g per deciliter. During a median follow-up of 1.9 years, a first MACE occurred in 378 of 1937 patients (19.5%) in the daprodustat group and in 371 of 1935 patients (19.2%) in the darbepoetin alfa group (hazard ratio, 1.03; 95% CI, 0.89 to 1.19), which met the prespecified noninferiority margin of 1.25. The percentages of patients with adverse events were similar in the two groups. CONCLUSIONS: Among patients with CKD and anemia who were not undergoing dialysis, daprodustat was noninferior to darbepoetin alfa with respect to the change in the hemoglobin level from baseline and with respect to cardiovascular outcomes. (Funded by GlaxoSmithKline; ASCEND-ND ClinicalTrials.gov number, NCT02876835.).

Safety and Efficacy of Vadadustat for Anemia in Patients Undergoing Dialysis.

BACKGROUND: Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, a class of compounds that stimulate endogenous erythropoietin production. METHODS: We conducted two randomized, open-label, noninferiority phase 3 trials to evaluate the safety and efficacy of vadadustat, as compared with darbepoetin alfa, in patients with anemia and incident or prevalent dialysis-dependent chronic kidney disease (DD-CKD). The primary safety end point, assessed in a time-to-event analysis, was the first occurrence of a major adverse cardiovascular event (MACE, a composite of death from any cause, a nonfatal myocardial infarction, or a nonfatal stroke), pooled across the trials (noninferiority margin, 1.25). A key secondary safety end point was the first occurrence of a MACE plus hospitalization for either heart failure or a thromboembolic event. The primary and key secondary efficacy end points were the mean change in hemoglobin from baseline to weeks 24 to 36 and from baseline to weeks 40 to 52, respectively, in each trial (noninferiority margin, -0.75 g per deciliter). RESULTS: A total of 3923 patients were randomly assigned in a 1:1 ratio to receive vadadustat or darbepoetin alfa: 369 in the incident DD-CKD trial and 3554 in the prevalent DD-CKD trial. In the pooled analysis, a first MACE occurred in 355 patients (18.2%) in the vadadustat group and in 377 patients (19.3%) in the darbepoetin alfa group (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.11). The mean differences between the groups in the change in hemoglobin concentration were -0.31 g per deciliter (95% CI, -0.53 to -0.10) at weeks 24 to 36 and -0.07 g per deciliter (95% CI, -0.34 to 0.19) at weeks 40 to 52 in the incident DD-CKD trial and -0.17 g per deciliter (95% CI, -0.23 to -0.10) and -0.18 g per deciliter (95% CI, -0.25 to -0.12), respectively, in the prevalent DD-CKD trial. The incidence of serious adverse events in the vadadustat group was 49.7% in the incident DD-CKD trial and 55.0% in the prevalent DD-CKD trial, and the incidences in the darbepoetin alfa group were 56.5% and 58.3%, respectively. CONCLUSIONS: Among patients with anemia and CKD who were undergoing dialysis, vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and correction and maintenance of hemoglobin concentrations. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; INNO2VATE ClinicalTrials.gov numbers, NCT02865850 and NCT02892149.).

Vadadustat in Patients with Anemia and Non-Dialysis-Dependent CKD.

BACKGROUND: Vadadustat is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, a class of drugs that stabilize HIF and stimulate erythropoietin and red-cell production. METHODS: In two phase 3, randomized, open-label, active-controlled, noninferiority trials, we compared vadadustat with the erythropoiesis-stimulating agent (ESA) darbepoetin alfa in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) not previously treated with an ESA who had a hemoglobin concentration of less than 10 g per deciliter and in patients with ESA-treated NDD-CKD and a hemoglobin concentration of 8 to 11 g per deciliter (in the United States) or 9 to 12 g per deciliter (in other countries). The primary safety end point, assessed in a time-to-event analysis, was the first major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), pooled across the two trials. Secondary safety end points included expanded MACE (MACE plus hospitalization for either heart failure or a thromboembolic event). The primary and key secondary efficacy end points in each trial were the mean change in hemoglobin concentration from baseline during two evaluation periods: weeks 24 through 36 and weeks 40 through 52. RESULTS: A total of 1751 patients with ESA-untreated NDD-CKD and 1725 with ESA-treated NDD-CKD underwent randomization in the two trials. In the pooled analysis, in which 1739 patients received vadadustat and 1732 received darbepoetin alfa, the hazard ratio for MACE was 1.17 (95% confidence interval [CI], 1.01 to 1.36), which did not meet the prespecified noninferiority margin of 1.25. The mean between-group differences in the change in the hemoglobin concentration at weeks 24 through 36 were 0.05 g per deciliter (95% CI, -0.04 to 0.15) in the trial involving ESA-untreated patients and -0.01 g per deciliter (95% CI, -0.09 to 0.07) in the trial involving ESA-treated patients, which met the prespecified noninferiority margin of -0.75 g per deciliter. CONCLUSIONS: Vadadustat, as compared with darbepoetin alfa, met the prespecified noninferiority criterion for hematologic efficacy but not the prespecified noninferiority criterion for cardiovascular safety in patients with NDD-CKD. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; PRO2TECT ClinicalTrials.gov numbers, NCT02648347 and NCT02680574.).

Changes in Erythropoiesis Stimulating Agent Use Under a Risk Evaluation and Mitigation Strategy (REMS) Program.

INTRODUCTION: Risk evaluation and mitigation strategy (REMS) programs are intended to improve safe use of US Food and Drug Administration-approved drugs. However, controversy exists over whether they consistently accomplish this goal. OBJECTIVE: We aimed to assess how initiation of the erythropoiesis stimulating agents (ESAs) darbepoetin alfa and epoetin alfa changed following implementation and enforcement (following a 1-year post-implementation grace period) of a prominent REMS program warning physicians against use in cancer patients with hemoglobin above 10 g/dL. METHODS: Using claims data from a large US commercial insurance company, we conducted interrupted time-series analyses of darbepoetin alfa and epoetin alfa initiation among adult cancer patients in the 12 months before REMS program implementation, after REMS program implementation, and after REMS program enforcement. We also evaluated differences in inappropriate initiation (hemoglobin tests all above 10 g/dL in the prior month) between the periods. RESULTS: In total, we identified 3456 darbepoetin alfa initiators and 2632 epoetin alfa initiators. Over the study period, the monthly number of initiators per 100,000 patients with cancer fell from 119 to 32 for darbepoetin alfa and from 82 to 34 for epoetin alfa. However, non-significant post-REMS program implementation level and slope changes per 100,000 adult patients with cancer were observed for darbepoetin alfa (level 0.03 [95% confidence interval (CI) -14.98 to 15.05]; slope 1.94 [95% CI -0.22 to 4.10]) and epoetin alfa (level -4.10 [95% CI -16.85 to 8.65]; slope -0.52 [95% CI -2.35 to 1.32]). Non-significant post-REMS program enforcement level and slope changes were also seen for both drugs (darbepoetin alfa level 1.58 [95% CI -0.58 to 3.74, slope -0.28 [95% CI -15.29 to 14.73]; epoetin alfa level 1.58 (95% CI -0.26 to 3.42], slope 5.74 [95% CI -7.01 to 18.49]). Finally, non-significant changes in inappropriate darbepoetin alfa (60% vs. 53% vs. 57%, p = 0.68) and epoetin alfa (53% vs. 53% vs. 46%, p = 0.41) initiation were observed between the three study periods. CONCLUSION: REMS program implementation and enforcement were not associated with significant changes in ESA initiation, adding to concerns over the degree to which certain REMS programs enhance patient safety.

Efficacy and Safety of Daprodustat Compared with Darbepoetin Alfa in Japanese Hemodialysis Patients with Anemia: A Randomized, Double-Blind, Phase 3 Trial.

BACKGROUND AND OBJECTIVES: Daprodustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and regulates genes related to iron metabolism. The efficacy (noninferiority) and safety of daprodustat compared with standard therapy (darbepoetin alfa) was evaluated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a randomized, phase 3, double-blind, active-control study in Japanese patients receiving hemodialysis with anemia of CKD. Participants' treatment was switched from current erythropoiesis-stimulating agents (ESAs) to daprodustat 4 mg once daily or darbepoetin alfa 10-60 µg once weekly (on the basis of the prestudy ESA dose). Dose was adjusted every 4 weeks for daprodustat or every 2 weeks for darbepoetin alfa, according to a protocol-specified algorithm. The primary end point was mean hemoglobin during weeks 40-52 in the intent-to-treat population. RESULTS: Of 332 participants screened, 271 participants were randomized (safety evaluation: 271 participants; efficacy evaluation: 267 intent-to-treat population). The mean hemoglobin during weeks 40-52 were maintained within the target range in both groups (10.9 g/dl [95% confidence interval (95% CI), 10.8 to 11.0] for daprodustat, and 10.8 g/dl [95% CI, 10.7 to 11.0] for darbepoetin alfa). Daprodustat was noninferior to darbepoetin alfa, as the lower bound of the confidence interval for the treatment difference (0.1 g/dl; 95% CI, -0.1 to 0.2 g/dl) was greater than the noninferiority criterion of -1.0 g/dl. For most participants, hemoglobin was maintained within the target range (10.0-12.0 g/dl) during weeks 40-52 (88% daprodustat; 90% darbepoetin alfa). Geometric mean hepcidin levels decreased more at week 52 with daprodustat (-37%; 95% CI, -49 to -23) than with darbepoetin alfa (-20%; 95% CI, -36 to -1), and an increase in total iron-binding capacity was observed in the daprodustat group. Frequency of adverse events were generally similar between daprodustat and darbepoetin alfa. CONCLUSIONS: Oral daprodustat was noninferior to darbepoetin alfa as measured by mean hemoglobin over weeks 40-52 in Japanese patients receiving hemodialysis switched from ESAs. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: 201754, Clinicaltrials.gov, NCT02969655.

Efficacy and safety of HIF prolyl-hydroxylase inhibitor vs epoetin and darbepoetin for anemia in chronic kidney disease patients not undergoing dialysis: A network meta-analysis.

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are a new class of oral medicines being developed for the treatment of anemia in chronic kidney disease (CKD) patients. This study aimed to compare the efficacy and safety of HIF-PHI vs epoetin and darbepoetin in CKD patients with anemia not undergoing dialysis. The PubMed, Embase, Cochrane Library, Web of Science, and clinicaltrials.gov databases were searched from inception to October 2019 for randomized controlled trials investigating different agents (six HIF-PHIs, epoetin, darbepoetin, and placebo) for treating CKD patients with anemia that did not undergo dialysis. The outcomes included a change in hemoglobin (Hb) levels and all-cause mortality. A total of 19 studies were included. Compared with the placebo, except for vadadustat (mean differences: 1.12, 95 % confidence interval [CI]: ‒0.11-2.35), the other drugs significantly increased Hb levels, with mean differences of 2.46 (95 % CI: 0.93-3.99) for desidustat, 1.81 (0.87-2.75) for enarodustat, 1.68 (0.64-2.72) for molidustat, 1.66 (0.89-2.44) for epoetin, 1.63 (0.69-2.56) for darbepoetin, 1.61 (0.99-2.22) for roxadustat, and 1.55 (0.74-2.36) for daprodustat. No differences were found in the Hb level elevations among these eight drugs. Compared with the placebo, there also was no significant association between the drugs and all-cause mortality (molidustat of RR, 0.39 [95 % CI, 0.06-2.59]; roxadustat, 0.40 (0.06-2.84); enarodustat, 0.33 (0.01-16.25); desidustat, 0.34 (0.01-17.00); epoetin, 0.50 (0.18-1.42); daprodustat, 0.54 (0.09-3.31); darbepoetin, 1.03 (0.65-1.65); and vadadustat, 1.43 (0.15-13.27)). No differences were observed in the all-cause mortality among the drugs. In conclusion, these HIF-PHIs are effective and relatively tolerant for treating anemia patients with CKD not undergoing dialysis. Further research should consider the limitations of our study to evaluate the value of these HIF-PHIs in clinical settings.

Darbepoetin Alfa in Patients with Advanced CKD without Diabetes: Randomized, Controlled Trial.

BACKGROUND AND OBJECTIVES: Large, randomized, controlled trials targeting higher hemoglobin level with erythropoiesis-stimulating agents for Western patients with CKD showed harm. However, the effect of anemia correction using erythropoiesis-stimulating agents may differ between CKD subpopulations. The Prevention of ESKD by Darbepoetin Alfa in CKD Patients with Non-diabetic Kidney Disease study, a multicenter, randomized, open-label, parallel-group study, aimed to examine the effect of targeting hemoglobin levels of 11-13 g/dl using darbepoetin alfa with reference to a low-hemoglobin target of 9-11 g/dl on kidney outcome in patients with advanced CKD without diabetes in Japan. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We enrolled 491 patients with CKD without diabetes, and an eGFR of 8-20 ml/min per 1.73 m2. Of these 491 patients, 239 and 240 were ultimately assigned to the high- and low-hemoglobin groups, respectively (12 patients were excluded). The primary outcome was a kidney composite end point (starting maintenance dialysis, kidney transplantation, eGFR≤6 ml/min per 1.73 m2, and 50% reduction in eGFR). RESULTS: Mean hemoglobin levels were 11.2±1.1 and 10.0±0.9 g/dl in the high- and low-hemoglobin groups, respectively, during the mean study period of 73.5±29.7 weeks. The kidney composite end point occurred in 105 (44%) and 116 (48%) patients in the high- and low-hemoglobin groups, respectively (log-rank test; P=0.32). The adjusted Cox proportional hazards model showed that the hazard ratio for the high- versus low-hemoglobin group was 0.78 (95% confidence interval, 0.60 to 1.03; P=0.08). Cardiovascular events occurred in 19 (8%) and 16 (7%) patients in each group, respectively, with no significant between-group difference (log-rank test; P=0.66). CONCLUSIONS: Targeting a higher hemoglobin level (11-13 g/dl) with darbepoetin alfa did not improve kidney outcome compared with targeting a lower hemoglobin level (9-11 g/dl) in patients with advanced CKD without diabetes. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Prevention of ESKD by Darbepoetin Alfa in CKD Patients with Non-diabetic Kidney Disease (PREDICT), NCT01581073.

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.

Efficacy and Safety of CKD-11101 (Proposed Biosimilar of Darbepoetin-Alfa) Compared with Darbepoetin-Alfa in Patients on Hemodialysis: A Randomized, Double-Blinded, Parallel-Group Phase III Study.

BACKGROUND: Darbepoetin-alfa is an erythropoiesis-stimulating agent (ESA) with a long elimination half-life that achieves better hemoglobin (Hb) stability than short-acting ESAs. OBJECTIVE: We aimed to evaluate the efficacy and safety of intravenous CKD-11101 (a biosimilar of darbepoetin-alfa) compared with those of darbepoetin-alfa in hemodialysis patients. METHODS: The study was performed in 24 centers in Korea between June 2015 and June 2017. The study subjects were randomized in a double-blind manner. The follow-up duration was 24 weeks, which consisted of 20 weeks of maintenance and 4 weeks of evaluation period. All patients underwent a stabilization period to achieve a target baseline Hb of 10-12 g/dL before randomization. Following randomization, patients received darbepoetin-alfa or CKD-11101 weekly or biweekly. RESULTS: A total of 403 patients were randomized into two groups, and a total of 325 patients (80.6%) completed the investigation. The differences between the two groups in terms of change in the average Hb level from baseline to evaluation were not significant. The average administered dose of ESA was similar between the groups. There was no difference in the proportion of patients who maintained the target Hb during the evaluation period [60.4% vs. 66.2% in the CKD-11101 and darbepoetin-alfa groups, respectively (p = 0.3038)]. In addition, the safety analysis, consisting of adverse events and adverse drug reactions, showed comparable results between the two groups. CONCLUSION: The changes in the level of Hb, dose of erythropoietin, and achievement rate of the target Hb during the study period were comparable between the groups. CKD-11101 has an equivalent efficacy and safety compared with darbepoetin-alfa in patients undergoing hemodialysis.

Types of Erythropoietin-Stimulating Agents and Mortality among Patients Undergoing Hemodialysis.

BACKGROUND: Despite the widespread use of erythropoietin-stimulating agents (ESAs) to treat anemia in patients undergoing hemodialysis, the relative mortality risks associated with use of different types of ESAs are unknown. METHODS: To compare the mortality risk associated with use of short-acting ESAs versus long-acting ESAs, we conducted a nationwide cohort study of 194,698 hemodialysis patients in Japan who received either a short-acting (epoetin α/ß or epoetin κ) or a long-acting (darbepoetin or epoetin ß pegol) ESA. Study outcomes were 2-year all-cause and cause-specific mortality. In addition to Cox proportional hazards models, we performed an instrumental variable analysis in which facility-level long-acting ESA prescription rates were taken as the instrumental variable. RESULTS: During the 2-year follow-up period, 31,557 deaths occurred. In a multivariable Cox model, long-acting ESA users had a 13% higher rate of deaths compared with short-acting ESA users, a significant difference (P<0.001). Similar results were obtained in other analyses. This difference in risk was pronounced among patients receiving high doses of ESA (for whom the adjusted 2-year number needed to harm for death was 30.8). Long-acting ESA use was associated with an increased rate of death from cardiovascular diseases, infection, and malignancies. In the instrumental variable analysis, long-acting ESA users remained at a significantly higher risk of death. Compared with anemic (hemoglobin 9.0-9.9 g/dl) short-acting ESA users, long-acting ESA users who achieved more optimal hemoglobin levels (10.0-10.9 g/dl) showed a higher mortality rate. CONCLUSIONS: Among patients undergoing hemodialysis, use of long-acting ESAs might be associated with a higher risk of death than use of short-acting ESAs.