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Introduction: Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) affects 10-15% of the chronic dialysis population. We explored baseline characteristics and predictors of ESA hyporesponsiveness in a global randomized cardiovascular outcomes study comparing an investigational hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), daprodustat, with conventional ESA treatment., Methods: ASCEND-D (NCT02879305) recruited 2,964 chronic dialysis patients receiving ESA treatment (standardized to weekly intravenous [IV] epoetin) who were iron replete at baseline. The primary ESA hyporesponsiveness definition was an ESA Resistance Index (ERI, ESA units/kg/week/hemoglobin g/L) ≥2 or IV standardized ESA dose ≥450 units/kg/week. Predictors of ESA hyporesponsiveness were determined using a multivariable regression model. Alternative hyporesponder definitions were explored., Results: Using the primary definition, 354 (12%) patients were ESA hyporesponsive. Geographic region, notably Latin America, lower baseline body mass index and transferrin saturation, younger age, lower albumin concentration, and a higher baseline IV iron dose were identified as strongly associated (p < 0.001) with ESA hyporesponsiveness. Additional predictors of ESA hyporesponsiveness included female sex (p = 0.010), history of heart failure (p = 0.035), longer dialysis vintage (p = 0.077), smoking status (p = 0.247), aspirin use (p = 0.121), and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use (p = 0.214)., Conclusion: This is the first global HIF-PHI study to report prespecified definitions and predictors of ESA hyporesponsiveness. While most of the predictors identified in our study have been previously reported, geographic region stands out as an unexpected finding, meriting further investigation., (The Author(s). Published by S. Karger AG, Basel.)

Background: Anaemia is common in chronic kidney disease (CKD) and assessment of the risks and benefits of new therapies is important., Methods: The Anaemia Study in CKD: Erythropoiesis via a Novel prolyl hydroxylase inhibitor Daprodustat-Non-Dialysis (ASCEND-ND) trial includes adult patients with CKD Stages 3-5, not using erythropoiesis-stimulating agents (ESAs) with screening haemoglobin (Hb) 8-10 g/dL or receiving ESAs with screening Hb of 8-12 g/dL. Participants were randomized to daprodustat or darbepoetin alfa (1:1) in an open-label trial (steering committee- and sponsor-blinded), with blinded endpoint assessment. The co-primary endpoints are mean change in Hb between baseline and evaluation period (average over Weeks 28-52) and time to first adjudicated major adverse cardiovascular (CV) event. Baseline characteristics were compared with those of participants in similar anaemia trials., Results: Overall, 3872 patients were randomized from 39 countries (median age 67 years, 56% female, 56% White, 27% Asian and 10% Black). The median baseline Hb was 9.9 g/dL, blood pressure was 135/74 mmHg and estimated glomerular filtration rate was 18 mL/min/1.73 m2. Among randomized patients, 53% were ESA non-users, 57% had diabetes and 37% had a history of CV disease. At baseline, 61% of participants were using renin-angiotensin system blockers, 55% were taking statins and 49% were taking oral iron. Baseline demographics were similar to those in other large non-dialysis anaemia trials., Conclusion: ASCEND-ND will define the efficacy and safety of daprodustat compared with darbepoetin alfa in the treatment of patients with anaemia associated with CKD not on dialysis., (© The Author(s) 2021. Published by Oxford University Press on behalf of the ERA.)

Background and Objectives: Daprodustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) being investigated for the treatment of anemia of CKD. In this noninferiority trial, we compared daprodustat administered three times weekly with epoetin alfa (epoetin) in patients on prevalent hemodialysis switching from a prior erythropoiesis-stimulating agent (ESA)., Design, Setting, Participants, & Measurements: Patients on hemodialysis with a baseline hemoglobin of 8-11.5 g/dl receiving an ESA were randomized 2:1 to daprodustat three times weekly ( n =270) or conventional epoetin ( n =137) for 52 weeks. Dosing algorithms aimed to maintain hemoglobin between 10 and 11 g/dl. The primary end point was mean change in hemoglobin from baseline to the average during the evaluation period (weeks 28-52). The principal secondary end point was average monthly intravenous iron dose. Other secondary end points included BP and hemoglobin variability., Results: Daprodustat three times weekly was noninferior to epoetin for mean change in hemoglobin (model-adjusted mean treatment difference [daprodustat-epoetin], -0.05; 95% confidence interval, -0.21 to 0.10). During the evaluation period, mean (SD) hemoglobin values were 10.45 (0.55) and 10.51 (0.85) g/dl for daprodustat and epoetin groups, respectively. Responders (defined as mean hemoglobin during the evaluation period in the analysis range of 10 to 11.5 g/dl) were 80% in the daprodustat group versus 64% in the epoetin group. Proportionately fewer participants in the daprodustat group versus the epoetin group had hemoglobin values either below 10 g/dl or above 11.5 g/dl during the evaluation period. Mean monthly intravenous iron use was not significantly lower with daprodustat versus epoetin. The effect on BP was similar between groups. The percentage of treatment-emergent adverse events was similar between daprodustat (75%) and epoetin (79%)., Conclusions: Daprodustat was noninferior to epoetin in hemoglobin response and was generally well tolerated., Clinical Trial Registry Name and Registration Number: Anemia Studies in Chronic Kidney Disease: Erythropoiesis via a Novel Prolyl Hydroxylase Inhibitor Daprodustat-Three Times Weekly Dosing in Dialysis (ASCEND-TD), NCT03400033., (Copyright © 2022 by the American Society of Nephrology.)

Importance: Daprodustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, is being evaluated as an oral alternative to conventional erythropoiesis-stimulating agent (ESA) therapy. Few studies of anemia treatment in an incident dialysis (ID) population have been reported., Objective: To evaluate the efficacy and safety of daprodustat vs darbepoetin alfa in treating anemia of chronic kidney disease in ID patients., Design, Setting, and Participants: This prospective, randomized, open-label clinical trial was conducted from May 11, 2017, through September 24, 2020, in 90 centers across 14 countries. Patients with advanced CKD were eligible if they planned to start dialysis within 6 weeks from screening or had started and received hemodialysis (HD) or peritoneal dialysis (PD) within 90 days before randomization, had a screening hemoglobin (Hb) concentration of 8.0 to 10.5 g/dL (to convert to grams per liter, multiply by 10) and a randomization Hb of 8.0 to 11.0 g/dL, were ESA-naive or had received limited ESA treatment, and were iron-replete., Interventions: Randomized 1:1 to daprodustat or darbepoetin alfa., Main Outcomes and Measures: The primary analysis in the intent-to-treat population evaluated the mean change in Hb concentration from baseline to evaluation period (weeks 28-52) to assess noninferiority of daprodustat vs darbepoetin alfa (noninferiority margin, -0.75 g/dL). The mean monthly intravenous (IV) iron dose from baseline to week 52 was the principal secondary end point. Rates of treatment-emergent and serious adverse events (AEs) were also compared between treatment groups to assess safety and tolerability., Results: A total of 312 patients (median [IQR] age, 55 [45-65] years; 194 [62%] male) were randomized to either daprodustat (157 patients; median [IQR] age, 52.0 [45-63] years; 96 [61%] male) or darbepoetin alfa (155 patients; median [IQR] age, 56.0 [45-67] years; 98 [63%] male); 306 patients (98%) completed the trial. The mean (SD) Hb concentration during the evaluation period was 10.5 (1.0) g/dL for the daprodustat and 10.6 (0.9) g/dL for the darbepoetin alfa group, with an adjusted mean treatment difference of -0.10 g/dL (95% CI, -0.34 to 0.14 g/dL), indicating noninferiority. There was a reduction in mean monthly IV iron use from baseline to week 52 in both treatment groups; however, daprodustat was not superior compared with darbepoetin alfa in reducing monthly IV iron use (adjusted mean treatment difference, 19.4 mg [95% CI, -11.0 to 49.9 mg]). Adverse event rates were 76% for daprodustat vs 72% for darbepoetin alfa., Conclusions and Relevance: This randomized clinical trial found that daprodustat was noninferior to darbepoetin alfa in treating anemia of CKD and may represent a potential oral alternative to a conventional ESA in the ID population., Trial Registration: ClinicalTrials.gov Identifier: NCT03029208.

Background: The Anemia Studies in chronic kidney disease (CKD): Erythropoiesis via a Novel prolyl hydroxylase inhibitor Daprodustat-Dialysis (ASCEND-D) trial will test the hypothesis that daprodustat is noninferior to comparator epoetin alfa or darbepoetin alfa for two co-primary endpoints: hemoglobin (Hb) efficacy and cardiovascular (CV) safety., Methods: We report the trial design, key demographic, clinical and laboratory findings, and baseline therapies of 2964 patients randomized in the open-label (sponsor-blinded) active-controlled, parallel-group, randomized ASCEND-D clinical trial. We also compare baseline characteristics of ASCEND-D patients with patients who are on dialysis (CKD G5D) enrolled in other large CV outcome trials (CVOTs) and in the most relevant registries., Results: The median age of patients was 58 years, 43% were female; 67% were White and 16% were Black. The median Hb at baseline was 10.4 g/dL. Among randomized patients, 89% were receiving hemodialysis and 11% peritoneal dialysis. Among key comorbidities, 42% reported a history of diabetes mellitus and 45% a history of CV disease. Median blood pressure was 134/74 mmHg. The median weekly dose of epoetin was 5751 units. Intravenous and oral iron uses were noted in 64 and 11% of patients, respectively. Baseline demographics were similar to patients with CKD G5D enrolled in other CVOTs and renal patient registries., Conclusions: ASCEND-D will evaluate the efficacy and safety of daprodustat compared with epoetin alfa or darbepoetin alfa in the treatment of patients with anemia with CKD G5D.This trial is registered with ClinicalTrials.gov: NCT02879305. EudraCT Number: 2016-000541-31; Sponsor Protocol Number: 200807., (© The Author(s) 2021. Published by Oxford University Press on behalf of the ERA-EDTA.)

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.)., (Copyright © 2021 Massachusetts Medical Society.)

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.)., (Copyright © 2021 Massachusetts Medical Society.)

Purpose of Review: Prolyl-hydroxylase inhibitors are a novel class of orally administered drugs that are under development for the treatment of anemia in patients with chronic kidney disease. This review discusses the biology of these drugs and their target - hypoxia-inducible factor and potential advantages and disadvantages of these therapies. Finally, we will discuss current trials in patients with both chronic kidney disease and end-stage renal disease., Recent Findings: Recent smaller studies have found that prolyl-hydroxylase are as effective as erythropoietin in treating anemia of chronic kidney disease. We do not yet know if they have the same cardiovascular and cancer-related risk profile and these questions will be answered by large phase III trials that are ongoing., Summary: Although prolyl hydroxylase inhibitors have much potential, questions remain regarding their efficacy and safety. Should these concerns prove to be unfounded, the treatment of anemia in chronic kidney disease will likely be transformed over the next decade.

Rationale & Objective: Evidence from clinical trials to guide patient preparation for maintenance dialysis therapy is limited. Although anemia is associated with mortality and cardiovascular (CV) disease in individuals initiating maintenance dialysis therapy, it is not known if treatment of anemia before dialysis therapy initiation with erythropoiesis-stimulating agents alters outcomes., Study Design: Post hoc analysis of a randomized controlled trial., Setting & Participants: Participants with type 2 diabetes and chronic kidney disease who progressed to dialysis therapy (n=590) in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT)., Exposure: Randomized treatment assignment (darbepoetin vs placebo)., Outcomes: All-cause mortality, CV mortality, nonfatal myocardial infarction, heart failure, and stroke within the first 180 days of dialysis therapy initiation., Analytical Approach: Proportional hazards regression., Results: Overall, 590 of 4,038 (14.6%) participants initiated dialysis therapy during the trial (n=298 and 292 in the darbepoetin and placebo groups, respectively). Corresponding hemoglobin levels were 11.3±1.6 and 9.5±1.5g/dL (P<0.001). Death from any cause occurred in 31 (10.4%) participants assigned to darbepoetin and 28 (9.6%) assigned to placebo (HR, 1.16; 95% CI, 0.69-1.93), while death from CV causes occurred in 15 (5.0%) and 13 (4.5%) participants, respectively (HR, 1.21; 95% CI, 0.58-1.93). There were no differences in risk for nonfatal myocardial infarction or heart failure. Stroke occurred in 8 (2.8%) participants assigned to darbepoetin and 1 (0.3%) assigned to placebo (HR, 8.6; 95% CI, 1.1-68.7)., Limitations: Post hoc analyses of a subgroup of study participants., Conclusions: Despite initiating dialysis therapy with a higher hemoglobin level, prior treatment with darbepoetin was not associated with a reduction in mortality, myocardial infarction, or heart failure in the first 180 days, but a higher frequency of stroke was observed. In the absence of more definitive data, this may inform decisions regarding the use of erythropoiesis-stimulating agents to treat mild to moderate anemia in patients with type 2 diabetes and chronic kidney disease nearing dialysis therapy initiation., (Copyright © 2018. Published by Elsevier Inc.)

Background: HX575 (biosimilar epoetin alfa) was approved in Europe in 2007 for the treatment of chronic kidney disease (CKD)-related anemia. This study assessed the clinical equivalence of HX575 with the US-licensed reference epoetin alfa (Epogen®/Procrit®, Amgen/Janssen) following subcutaneous (SC) administration in dialysis patients with CKD-related anemia., Methods: This randomized, double-blind, parallel-group, multicenter study (NCT01693029) was conducted at 49 US clinical sites. Eligible patients were aged ≥18 years, had end-stage renal disease, were on hemodialysis or peritoneal dialysis for ≥6 months (or ≥12 months in the case of a failed kidney transplant), and were receiving treatment with stable SC doses of epoetin alfa. Eligible patients also had mean hemoglobin (Hb) concentration between 9.0 and 11.5 g/dL during the screening period. The primary endpoint was the mean absolute change in Hb concentration between the screening/baseline period (week-4 to week-1) and the evaluation period (weeks 21 to 28)., Results: Hb values at the end of the evaluation period and the Hb change from baseline to evaluation period were similar between treatment groups. The estimated difference between groups in mean absolute change in Hb concentration was -0.093 g/dL, with 90% CI (-0.23 to 0.04) entirely within the pre-specified equivalence limits (-0.5 to 0.5 g/dL). The safety profile of each medicine was similar and as expected in dialysis patients, and neither method of treatment led to the development of neutralizing, clinically relevant antibodies., Conclusions: SC HX575 in dialysis patients with renal anemia was therapeutically equivalent to the reference medicine in terms of maintaining stable Hb levels and safety., (© 2017 S. Karger AG, Basel.)

Background: The pathogenesis of chronic kidney disease associated anemia is multifactorial and includes decreased production of erythropoietin (EPO), iron deficiency, inflammation, and EPO resistance. To better understand the trajectory of these parameters, we described temporal trends in hemoglobin (Hb), ferritin, transferrin saturation, C-reactive protein (CRP), and darbepoetin dosing in the Trial to Reduce cardiovascular Events with Aranesp Therapy (TREAT)., Methods: We performed a post hoc analysis of 4,038 participants in TREAT. Mixed effects linear regression models were used to determine the trajectory of parameters of interest prior to end-stage renal disease (ESRD). Likelihood ratio tests were used to determine the overall differences in biomarker values and differences in trajectories between those who did and did not develop ESRD., Results: Hb declined precipitously in the year prior to the development of ESRD (irrespective of treatment assignment), and was on average 1.15 g/dL (95% CI -1.26 to -1.04) lower in those who developed ESRD versus those who did not, at the time of ESRD/end of follow-up. Simultaneously, the mean darbepoetin dose and CRP concentration increased, while serum ferritin and transferrin saturations were >140 μg/L and 20%, respectively., Conclusions: Our analyses provide descriptive insights regarding the temporal changes of Hb, darbepoetin dose, and related parameters as ESRD approaches in participants of TREAT. Hb declined as much as 1-2 years prior to the development of ESRD, without biochemical evidence of iron deficiency. The most precipitous decline occurred in the months immediately prior to ESRD, despite administration of escalating doses of darbepoetin and in parallel with an increase in CRP., (© 2017 S. Karger AG, Basel.)

Background: Sparse data are available about the natural history of hemoglobin (Hb) level trends in contemporary patients with anemia, chronic kidney disease (CKD), and type 2 diabetes mellitus. We intended to describe Hb level trends over time with no or minimal administration of erythropoiesis-stimulating agents., Study Design: Prospective clinical trial cohort., Setting & Participants: 2,019 individuals with type 2 diabetes, moderate anemia, and CKD from the placebo arm of the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) followed up for 2.3 years with an average of 32 monthly Hb level determinations per patient. Darbepoetin alfa was administered only if Hb level decreased to <9 g/dL., Outcomes & Measurements: Number of protocol-directed doses of darbepoetin alfa received due to an Hb level decrease to <9 g/dL., Results: 1,106 (55%) placebo patients consistently maintained an Hb level ≥9 g/dL and received no protocol-directed darbepoetin alfa. The other patients received 1 (16%), 2-4 (16%), or 5 or more (13%) doses of darbepoetin alfa. Those who received no darbepoetin alfa doses had higher baseline Hb levels, higher estimated glomerular filtration rates (eGFRs), less proteinuria, and lower ferritin and transferrin saturation values. On average, Hb levels were stable or increased in all groups. Compared with individuals who received no darbepoetin alfa, those who received 5 or more doses were more likely to receive intravenous iron therapy and blood transfusions and progress to renal replacement therapy, but were not at higher risk of death. The strongest predictors of requiring 5 or more doses of darbepoetin alfa were lower baseline Hb level, lower eGFR, and higher proteinuria level., Limitations: Post hoc analysis of a clinical trial of a specific population with diabetes, anemia, and non-dialysis-dependent CKD., Conclusions: In the TREAT placebo arm, Hb levels were stable with no or minimal protocol-directed darbepoetin alfa during 2.3 years of follow-up. Most patients with moderate anemia, non-dialysis-dependent CKD, and type 2 diabetes are able to maintain a stable Hb level without implementing long-term erythropoiesis-stimulating agent therapy., (Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Recombinant erythropoietin has become a routine component of care of patients with chronic kidney disease reducing the need for blood transfusions but raising the risks for cardiovascular events. We undertook this secondary analysis of subjects enrolled in the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial to examine the interrelationships between epoetin-alfa maintenance doses utilized and achieved hemoglobin (Hb) irrespective of treatment target and randomized allocation., Methods: We performed a post hoc analysis from the CHOIR trial. Inclusion criteria were Hb <11.0 g/dl and estimated glomerular filtration rates of 15-50 ml/min/1.73 m(2). To be included in the present analysis, subjects needed to be free of the composite event at 4 months, receive epoetin-alfa, and have ≥1 postbaseline Hb measurement. The mean weekly dose of epoetin-alfa received up to the time of first event or censure was the main exposure variable, while the achieved Hb at month 4 was the confounder representing the subject's underlying response to treatment. The primary outcome was the composite of death, heart failure hospitalization, stroke, or myocardial infarction. A Cox proportional hazard regression model was used in time-to-event analysis., Results: Among 1,244 subjects with complete data, the average weekly dose of epoetin-alfa ranged 143.3-fold from 133 to 19,106 units/week at the time of first event or censure. Cox proportional hazard analysis found that those in the middle tertile of Hb achieved (>11.5 to <12.7 g/dl) and the lowest tertile of epoetin-alfa dose exposure level (<5,164 units/week) had the lowest risk. Irrespective of Hb achieved, the relative risk in the highest tertile (>10,095 units/week) of epoetin-alfa dose exposure level was significantly escalated (hazard ratios ranged from 2.536 to 3.572, p < 0.05, when compared to the group of middle Hb tertile and lowered dose tertile). In a multivariable model that adjusted for achieved Hb, albumin, cholesterol, age, prior heart failure, prior stroke, prior deep venous thrombosis, atrial fibrillation or malignancy, the average weekly dose had a significant (p = 0.005) relative risk of 1.067 per 1,000 units of epoetin-alfa for the primary end point., Conclusions: In the CHOIR trial, average epoetin-alfa doses >10,095 units/week were associated with increased risks for cardiovascular events irrespective of the Hb achieved within the first 4 months of treatment. These data suggest the weekly epoetin-alfa dose and not the Hb achieved was a principal determinant in the primary outcome observed implicating a cardiovascular toxicity of this erythrocyte-stimulating agent., (Copyright © 2013 S. Karger AG, Basel.)

Background: Conflicting relationships have been described between anemia correction using erythropoiesis-stimulating agents and progression of chronic kidney disease (CKD). This study was undertaken to examine the impact of target hemoglobin level on progression of kidney disease in the CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency) trial., Study Design: Secondary analysis of a randomized controlled trial., Setting & Participants: 1,432 participants with CKD and anemia., Intervention: Participants were randomly assigned to target hemoglobin levels of 13.5 versus 11.3 g/dL with the use of epoetin alfa., Outcomes & Measurements: Cox regression was used to estimate HRs for progression of CKD (a composite of doubling of creatinine level, initiation of renal replacement therapy, or death). Interactions between hemoglobin target and select baseline variables (estimated glomerular filtration rate, proteinuria, diabetes, heart failure, and smoking history) also were examined., Results: Participants randomly assigned to higher hemoglobin targets experienced shorter time to progression of kidney disease in both univariate (HR, 1.25; 95% CI, 1.03-1.52; P = 0.02) and multivariable models (HR, 1.22; 95% CI, 1.00-1.48; P = 0.05). These differences were attributable to higher rates of renal replacement therapy and death for participants in the high hemoglobin arm. Hemoglobin target did not interact with estimated glomerular filtration rate, proteinuria, diabetes, or heart failure (P > 0.05 for all). In the multivariable model, hemoglobin target interacted with tobacco use (P = 0.04) such that the higher target had a greater risk of CKD progression for participants who currently smoked (HR, 2.50; 95% CI, 1.23-5.09; P = 0.01), which was not present for those who did not currently smoke (HR, 1.15; 95% CI, 0.93-1.41; P = 0.2)., Limitations: A post hoc analysis; thus, cause and effect cannot be determined., Conclusions: These results suggest that a high hemoglobin target is associated with a greater risk of progression of CKD. This risk may be augmented by concurrent smoking. Further defining the mechanism of injury may provide insight into methods to optimize outcomes in anemia management., (Copyright © 2012 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: More strokes were observed in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) among patients assigned to darbepoetin alfa. We sought to identify baseline characteristics and postrandomization factors that might explain this association., Methods and Results: A multivariate logistic regression model was used to identify baseline predictors of stroke in 4038 patients with diabetes mellitus, chronic kidney disease, and anemia randomized to receive darbepoetin alfa or placebo. To determine whether postrandomization blood pressure, hemoglobin level, platelet count, or treatment dose were responsible for the increased risk related to darbepoetin alfa, we performed a nested case-control analysis (1:10 matching) identifying nonstroke controls with propensity matching. The risk of stroke was doubled with darbepoetin alfa. Overall, 154 patients had a stroke, 101/2012 (5.0%) in the darbepoetin alfa arm and 53/2026 (2.6%) in the placebo arm (hazard ratio 1.9; 95% confidence interval, 1.4-2.7). Independent predictors of stroke included assignment to darbepoetin alfa (odds ratio 2.1; 95% confidence interval, 1.5-2.9), history of stroke (odds ratio 2.0; 95% confidence interval, 1.4-2.9), more proteinuria, and known cardiovascular disease. In patients assigned to darbepoetin alfa, postrandomization systolic and diastolic blood pressure, hemoglobin level, platelet count, and darbepoetin alfa dose did not differ between those with and without stroke. Additional sensitivity analyses using maximal values, latest values, or changes over varying periods of exposure yielded similar results., Conclusions: The 2-fold increase in stroke with darbepoetin alfa in TREAT could not be attributed to any baseline characteristic or to postrandomization blood pressure, hemoglobin, platelet count, or dose of treatment. These readily identifiable factors could not be used to mitigate the risk of darbepoetin alfa-related stroke., Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT00093015.

Background: Non–placebo-controlled trials of erythropoiesis-stimulating agents (ESAs) comparing lower and higher hemoglobin targets in patients with chronic kidney disease indicate that targeting of a lower hemoglobin range may avoid ESA-associated risks. However, target-based strategies are confounded by each patient's individual hematopoietic response., Methods: We assessed the relationship among the initial hemoglobin response to darbepoetin alfa after two weight-based doses, the hemoglobin level achieved after 4 weeks, the subsequent darbepoetin alfa dose, and outcomes in 1872 patients with chronic kidney disease and type 2 diabetes mellitus who were not receiving dialysis. We defined a poor initial response to darbepoetin alfa (which occurred in 471 patients) as the lowest quartile of percent change in hemoglobin level (<2%) after the first two standardized doses of the drug., Results: Patients who had a poor initial response to darbepoetin alfa had a lower average hemoglobin level at 12 weeks and during follow-up than did patients with a better hemoglobin response (a change in hemoglobin level ranging from 2 to 15% or more) (P<0.001 for both comparisons), despite receiving higher doses of darbepoetin alfa (median dose, 232 μg vs. 167 μg; P<0.001). Patients with a poor response, as compared with those with a better response, had higher rates of the composite cardiovascular end point (adjusted hazard ratio, 1.31; 95% confidence interval [CI], 1.09 to 1.59) or death (adjusted hazard ratio, 1.41; 95% CI, 1.12 to 1.78)., Conclusions: A poor initial hematopoietic response to darbepoetin alfa was associated with an increased subsequent risk of death or cardiovascular events as doses were escalated to meet target hemoglobin levels. Although the mechanism of this differential effect is not known, these findings raise concern about current target-based strategies for treating anemia in patients with chronic kidney disease. (Funded by Amgen; ClinicalTrials.gov number, NCT00093015.)

Purpose of Review: This article examines the potential mechanisms underlying adverse risk observed in four randomized controlled trials of anemia correction in chronic kidney disease (CKD) patients., Recent Findings: The Normal Hematocrit Study, Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin-beta, Correction of Hemoglobin and Outcomes in Renal Insufficiency, and Trial to Reduce Cardiovascular Events with Aranesp Therapy demonstrate increased risk of mortality and/or cardiovascular complications with targeting of a higher hemoglobin (Hb) in CKD patients. Although a higher Hb level was targeted in these trials, erythropoiesis-stimulating agent (ESA) exposure itself might account for the observed increased risk. This is because, in these trials, achieving a normal or near normal Hb was associated with improved survival and reduced cardiovascular risk. Indeed, it was the 'targeting' of a higher Hb with ESA that seemed to be the problem. Observational data, although conflicting, on the whole provide support for high dosage of ESA being harmful but cannot, by their very nature, prove causality., Summary: After 20 years of ESA use, is it plausible that ESAs could be toxic? How does one reconcile conflicting observational data with a hypothesis that postulates ESA toxicity? Does the biology of erythropoietin provide a mechanistic explanation? The answers to these questions, among others, will be important in charting a future role for ESAs in treating CKD anemia.

The triad of diabetes mellitus, anemia, and chronic kidney disease (CKD) define a group of patients at high risk for death and cardiovascular complications. The approval of epoetin alfa in 1989 transformed the treatment of anemia in patients with CKD. However, evidence has emerged from randomized controlled trials that correcting anemia with erythropoiesis-stimulating agents in CKD patients is associated with increased risk. Most recently, the TREAT (Trial to Reduce Cardiovascular Events With Aranesp Therapy) study of anemic type 2 diabetic patients with CKD reported that treatment with darbepoetin conferred no benefit in mortality or in attenuating cardiovascular or renal events. Instead, there was a twofold higher rate of stroke and thromboembolic complications and a higher rate of cancer deaths in patients randomized to treatment with darbepoetin. Furthermore, there was an inconsistent and modest improvement in health-related quality of life. TREAT raises questions about whether anemia in type 2 diabetic patients should be treated and under what circumstances.

The effect of erythropoiesis-stimulating agents (ESAs) on renal and cardiovascular outcomes in patients with chronic kidney disease (CKD) and heart failure (HF) is uncertain. Observational data indicate a strong relationship between the severity of anemia and poor outcome. On the other hand, randomized controlled trials on patients with CKD indicate that ESAs used in targeting a higher hemoglobin concentration result in increased risk. This article reviews the observational data as well as the recent information from randomized trials that point to increased risk in CKD and HF settings, and whether these disparate results can be explained by exposure to ESAs in this setting., (Copyright 2010 Elsevier Inc. All rights reserved.)

The CHOIR trial in anemic patients with chronic kidney disease compared epoetin-alfa treatment with low (11.3 g/l) and high (13.5 g/l) hemoglobin targets on the composite end point of death, hospitalization for heart failure, stroke, and myocardial infarction. However, other anemia management trials in patients with chronic kidney disease found there was increased risk when hemoglobin is targeted above 13 g/dl. In this secondary analysis of the CHOIR trial, we compared outcomes among the subgroups of patients with diabetes and heart failure to describe the comparative relationship of treatment to these two different hemoglobin goals. By Cox regression analysis, there was no increased risk associated with the higher hemoglobin target among patients with heart failure. In patients without heart failure, however, the hazard ratio (1.86) associated with the higher target was significant. Comparing survival curves in an unadjusted model, patients with diabetes did not have a greater hazard associated with the higher target. Subjects without diabetes had a significantly greater hazard in the high as compared to the low target, but the interaction between diabetes and the target was not significant. We suggest that the increased risks associated with higher hemoglobin targets are not clinically apparent among subgroups with greater mortality risk. These differential outcomes underscore the need for dedicated trials in these subpopulations.

Background: Anemia is associated with an increased risk of cardiovascular and renal events among patients with type 2 diabetes and chronic kidney disease. Although darbepoetin alfa can effectively increase hemoglobin levels, its effect on clinical outcomes in these patients has not been adequately tested., Methods: In this study involving 4038 patients with diabetes, chronic kidney disease, and anemia, we randomly assigned 2012 patients to darbepoetin alfa to achieve a hemoglobin level of approximately 13 g per deciliter and 2026 patients to placebo, with rescue darbepoetin alfa when the hemoglobin level was less than 9.0 g per deciliter. The primary end points were the composite outcomes of death or a cardiovascular event (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia) and of death or end-stage renal disease., Results: Death or a cardiovascular event occurred in 632 patients assigned to darbepoetin alfa and 602 patients assigned to placebo (hazard ratio for darbepoetin alfa vs. placebo, 1.05; 95% confidence interval [CI], 0.94 to 1.17; P=0.41). Death or end-stage renal disease occurred in 652 patients assigned to darbepoetin alfa and 618 patients assigned to placebo (hazard ratio, 1.06; 95% CI, 0.95 to 1.19; P=0.29). Fatal or nonfatal stroke occurred in 101 patients assigned to darbepoetin alfa and 53 patients assigned to placebo (hazard ratio, 1.92; 95% CI, 1.38 to 2.68; P<0.001). Red-cell transfusions were administered to 297 patients assigned to darbepoetin alfa and 496 patients assigned to placebo (P<0.001). There was only a modest improvement in patient-reported fatigue in the darbepoetin alfa group as compared with the placebo group., Conclusions: The use of darbepoetin alfa in patients with diabetes, chronic kidney disease, and moderate anemia who were not undergoing dialysis did not reduce the risk of either of the two primary composite outcomes (either death or a cardiovascular event or death or a renal event) and was associated with an increased risk of stroke. For many persons involved in clinical decision making, this risk will outweigh the potential benefits. (ClinicalTrials.gov number, NCT00093015.), (2009 Massachusetts Medical Society)

Background: The optimal hemoglobin target and possible toxicity of epoetin therapy in hemodialysis patients are controversial. Previous studies suggest that African American patients use higher doses of epoetin and have better survival compared with white hemodialysis patients., Study Design: Retrospective longitudinal cohort., Setting & Participants: Epoetin-exposed incident hemodialysis patients (N = 12,733; African Americans, n = 4,801; white, n = 7,386) treated in Dialysis Clinic Inc facilities during 2000 to 2006., Predictors: Hemoglobin, epoetin, iron., Outcomes: Mortality, hospitalization., Measurements: Proportional hazards models with time-varying covariates., Results: Hemoglobin concentrations less than 10 g/dL in whites and less than 11 g/dL in African Americans were associated with increased mortality and hospitalization versus the referent hemoglobin level of 11 to 11.9 g/dL. Hemoglobin levels of 13 g/dL or greater in whites were associated with decreased noncardiovascular mortality. Six-month cumulative epoetin doses of 20,000 U/wk or greater were associated with increased mortality and hospitalization versus the referent group (8,000 to 12,499 U/wk). Epoetin doses less than 8,000 U/wk were associated with decreased risk. Higher epoetin doses were associated with increased mortality at hemoglobin concentrations of 10 to 12.9 g/dL and with increased hospitalization at all hemoglobin concentrations of 10 g/dL or greater. Higher epoetin doses were associated with increased mortality and hospitalization within each tertile of serum albumin concentration. These patterns did not differ by race., Limitations: Treatment-by-indication bias and unidentified confounders cannot be excluded. Small sample sizes in the highest and lowest hemoglobin strata decrease statistical power., Conclusions: Relationships between hemoglobin concentration and mortality differed between African Americans and whites. Additionally, the relationship of lower mortality with greater achieved hemoglobin concentration seen in white patients was observed for all-cause, but not cardiovascular, mortality. A higher cumulative epoetin dose was associated with worse outcomes, even in patients with albumin levels greater than 4 g/dL. There were no statistically significant interactions between race and epoetin dose. Further studies are needed to confirm and to define the mechanism of these findings.

Posttransplant anemia is a common problem that may hinder patients' quality of life. It occurs in 12 to 76% of patients, and is most common in the immediate posttransplant period. A variety of factors have been identified that increase the risk of posttransplant anemia, of which the level of renal function is most important. Sirolimus, a mammalian target of rapamycin inhibitor, has been implicated as playing a special role in posttransplant anemia. This review considers anemia associated with sirolimus, including its presentation, mechanisms, and management.

Background: Anemia augments the already high rates of fatal and major nonfatal cardiovascular and renal events in individuals with type 2 diabetes. In 2004, we initiated the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT). This report presents the baseline characteristics and therapies of TREAT participants and subgroups defined by the presence or absence of overt proteinuria and history of cardiovascular disease. The design of TREAT and baseline characteristics also are compared with 2 recent trials of nondialysis patients with chronic kidney disease (CKD) in which treatment with another erythropoiesis-stimulating agent targeting greater hemoglobin levels had either a neutral or adverse effect on clinical outcomes., Study Design: Randomized trial., Setting & Participants: 4,044 participants with type 2 diabetes, CKD (defined as estimated glomerular filtration rate of 20 to 60 mL/min/1.73 m(2)), and anemia (hemoglobin < or = 11 g/dL) from 24 countries., Intervention: Darbepoetin alfa to attempt to increase hemoglobin levels to 13 g/dL compared with placebo., Outcomes: TREAT is an event-driven design to continue until approximately 1,203 patients experience a primary event: the composite end point of death or cardiovascular morbidity (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia). The composite end point of death or need for long-term renal replacement therapy also is a primary end point., Conclusions: With several-fold more patient-years and a placebo arm, TREAT will provide a robust estimate of the safety and efficacy of darbepoetin alfa and generate prospective data regarding the risks of major cardiovascular and renal events in a contemporarily managed cohort of patients with type 2 diabetes, CKD, and anemia.

Some time has passed since the torrent of discussion surrounding the cardiovascular risk of pushing up hemoglobin concentrations in dialysis patients with erythropoietin. The debate here reflects a look back on the tension produced by confusing data and outcomes. Is it the target hemoglobin per se or the high doses of erythropoietin in subsets of resistant patients that is the problem? You decide.

A subgroup of hemodialysis patients experience high serum ferritin and low tansferrin saturation for reasons not clearly understood. Here we determined the economic impact of administering sodium ferric gluconate complex to patients with serum ferritin levels higher than 500 ng/ml and a transferrin saturation less than 25% based on the Dialysis Patients Response to IV Iron with Elevated Ferritin (DRIVE) study and its extension, DRIVE II. A cost effectiveness model was developed, consistent with the DRIVE studies, using decision analysis with a 12-week time horizon. The primary effectiveness measure was the mean hemoglobin increase in the intent to treat patient groups comparing epoetin with or without sodium ferric gluconate complex. Costs were computed using projected 2007 US Medicare reimbursements for the treatments and for serious adverse events, with the effectiveness factored by the increase in hemoglobin. The net savings for sodium ferric gluconate complex plus epoetin treatment was $1390 compared to epoetin alone for each g/dl hemoglobin increase over 12 weeks of study. Sensitivity analyses were performed to test the impact of change in the variables (using medians or means and actual 2005 or projected 2007 Medicare reimbursements) and these affirmed the robustness of the model. Our study shows that treatment of patients with high ferritin and low transferrin saturation levels, as defined in DRIVE, with sodium ferric gluconate complex and epoetin resulted in significant savings compared to epoetin alone.

Treatment of the anemia of chronic kidney disease (CKD) with erythropoiesis-stimulating agents (ESAs) has been intensely debated during the past 2 years. Treatment with ESAs has transformed the lives of millions of patients with CKD, with fewer blood transfusions and improved quality of life. However, randomized trials have suggested that targeting greater hematocrits/hemoglobin levels and/or exposure to high doses of ESAs is associated with a greater risk of cardiovascular complications and mortality. The US Food and Drug Administration has inserted a boxed warning for ESAs and, along with the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (KDOQI), decreased recommended target hemoglobin ranges for ESA therapy. The Centers for Medicare & Medicaid Services has decreased ESA dosing recommendations in the Medicare claims policy for ESAs. Managing the anemia of CKD in the era of the hemoglobin level and ESA controversy has required aiming for appropriate hemoglobin levels, using the lowest effective ESA dose, and better managing the problem of ESA hyporesponsiveness.

Inflammatory cytokines are important predictors of cardiovascular mortality especially in patients with chronic kidney disease. Here we explored the relationship of anemia and epoetin treatment to inflammatory cytokine levels in patients with chronic kidney disease. One hundred non-dialysis patients with chronic kidney disease over 18 years of age were evenly split into anemic and non-anemic cohorts. Of the 50 anemic patients, 23 were receiving erythropoiesis stimulating agents treatments. Levels of tumor necrosis factor (TNF)-alpha were found to be significantly higher and serum albumin was significantly lower with trends towards higher interleukin (IL)-6 and IL-8 in anemic compared to non-anemic patients. Further analysis by multiple logistic regression found that anemic patients treated with erythropoiesis stimulating agents had significantly higher odds for the upper two quartiles for IL-6, IL-8 and TNF-alpha compared to non-anemic patients. Our study found that the anemia of chronic kidney disease was associated with up regulation of TNF-alpha, and possibly IL-6 and IL-8 along with increased levels of these proinflammatory cytokines in patients treated with epoetin.

Trials of anemia correction in chronic kidney disease have found either no benefit or detrimental outcomes of higher targets. We did a secondary analysis of patients with chronic kidney disease enrolled in the Correction of Hemoglobin in the Outcomes in Renal Insufficiency trial to measure the potential for competing benefit and harm from achieved hemoglobin and epoetin dose trials. In the 4 month analysis, significantly more patients in the high-hemoglobin compared to the low-hemoglobin arm were unable to achieve target hemoglobin and required high-dose epoetin-alpha. In unadjusted analyses, the inability to achieve a target hemoglobin and high-dose epoetin-alpha were each significantly associated with increased risk of a primary endpoint (death, myocardial infarction, congestive heart failure or stroke). In adjusted models, high-dose epoetin-alpha was associated with a significant increased hazard of a primary endpoint but the risk associated with randomization to the high hemoglobin arm did not suggest a possible mediating effect of higher target via dose. Similar results were seen in the 9 month analysis. Our study demonstrates that patients achieving their target had better outcomes than those who did not; and among subjects who achieved their randomized target, no increased risk associated with the higher hemoglobin goal was detected. Prospective studies are needed to confirm this relationship and determine safe dosing algorithms for patients unable to achieve target hemoglobin.

The Dialysis Patients Response to IV Iron with Elevated Ferritin (DRIVE) study demonstrated the efficacy of intravenous ferric gluconate to improve hemoglobin levels in anemic hemodialysis patients who were receiving adequate epoetin doses and who had ferritin levels between 500 and 1200 ng/ml and transferrin saturation (TSAT) < or = 25%. The DRIVE-II study reported here was a 6-wk observational extension designed to investigate how ferric gluconate impacted epoetin dosage after DRIVE. During DRIVE-II, treating nephrologists and anemia managers adjusted doses of epoetin and intravenous iron as clinically indicated. By the end of observation, patients in the ferric gluconate group required significantly less epoetin than their DRIVE dose (mean change of -7527 +/- 18,021 IU/wk, P = 0.003), whereas the epoetin dose essentially did not change for patients in the control group (mean change of 649 +/- 19,987 IU/wk, P = 0.809). Mean hemoglobin, TSAT, and serum ferritin levels remained higher in the ferric gluconate group than in the control group (P = 0.062, P < 0.001, and P = 0.014, respectively). Over the entire 12-wk study period (DRIVE plus DRIVE-II), the control group experienced significantly more serious adverse events than the ferric gluconate group (incidence rate ratio = 1.73, P = 0.041). In conclusion, ferric gluconate maintains hemoglobin and allows lower epoetin doses in anemic hemodialysis patients with low TSAT and ferritin levels up to 1200 ng/ml.

Background/aims: Anemia in chronic kidney disease is an independent predictor of cardiovascular disease (CVD). We explored the relationship between anemia and markers of inflammation and endothelial activation in non-dialysis chronic kidney disease (ND-CKD) patients to understand this mechanism., Methods: Cross-sectional analysis was performed on 30 adult ND-CKD patients for markers of inflammation and endothelial activation using a multiplexed immunoassay. Data were analyzed according to the anemic status defined by the modified World Health Organization criteria., Results: Seventeen patients were classified as anemic. Baseline characteristics by anemic status were similar except that anemic patients were older (p = 0.006), had lower estimated glomerular filtration rate (eGFR; p = 0.01) and higher prevalence of CVD (p = 0.02). Compared to non-anemic patients, log-transformed values of fibrinogen (p = 0.012); von Willebrand factor (vWF, p = 0.008), vascular cell adhesion molecule-1 (VCAM-1, p = 0.025) and C-reactive protein (p = 0.043) were elevated in anemic patients. Serum ferritin (p = 0.93) and serum albumin (p = 0.06) were not different. Age and eGFR-adjusted logistic regression analysis showed that anemic patients had increased odds for a composite of higher median values of fibrinogen, vWF and VCAM-1 (p = 0.01, odds ratio 8.1, 95% CI 1.08-111.0)., Conclusion: We report the association of anemia with elevated markers of endothelial activation in ND-CKD patients. Longitudinal studies are needed to confirm our findings., ((c) 2008 S. Karger AG, Basel.)

Anemia treatment in nondialysis chronic kidney disease (ND-CKD) and dialysis CKD patients (D-CKD) has been recently scrutinized in the literature and by the lay press. New evidence suggests that patients receiving epoetin and achieving higher hemoglobin have a higher risk of death and cardiovascular complications. Data from the Centers for Medicare & Medicaid Services demonstrate upward spiraling costs of injectables, especially epoetin, in the care of CKD patients. There is considerable literature favoring the use of subcutaneous administration of epoetin compared to intravenous route in hemodialysis patients. Evidence clearly shows that the subcutaneous route achieves the target hemoglobin level at a lower administered dose. Thus, the same clinical effect can be achieved at a lower cost. Despite the economic and evidentiary justifications for subcutaneous administration of epoetin, adoption of this strategy has been limited, especially in the United States. Reasons include: inflexibility by dialysis providers because of reduced profitability, claims that patients oppose the subcutaneous route because of pain at the site of injection, concerns regarding pure red cell aplasia associated with subcutaneous administration, and greater hemoglobin cycling with the subcutaneous route. In this article, the advantages and disadvantages of the subcutaneous route are reviewed.

Objective: To compare the efficacy of extended epoetin alfa dosing in maintaining hemoglobin (Hb) concentrations in patients with and without diabetes as the primary cause of chronic kidney disease., Methods: We undertook a post hoc analysis of the Clinical Evaluation of PROCRIT(R) for Maintenance Phase Treatment of Patients With Anemia Due to Chronic Kidney Disease (PROMPT) study. The study patients had chronic kidney disease but were not receiving dialysis, had stable Hb levels of >or= 11.0 g/dL, and had been receiving epoetin alfa for >or= 2 months. Patients received 1 of 4 epoetin alfa dosing regimens administered subcutaneously for up to 16 weeks: 10,000 U once weekly (QW), 20,000 U every 2 weeks (Q2W), 30,000 U every 3 weeks (Q3W), or 40,000 U every 4 weeks (Q4W). The primary end point was the percentage of patients able to achieve Hb maintenance, defined as a mean Hb level of >or= 11.0 g/dL from week 2 to final measurement., Results: Among 445 evaluable patients, 201 had diabetes and 244 did not have diabetes. Mean baseline Hb was 11.9 g/dL in both groups. The percentage of patients achieving Hb maintenance, stratified by epoetin alfa dosing regimen, was similar in patients with and those without diabetes: QW (90.2% versus 96.5%), Q2W (91.1% versus 87.9%), Q3W (80.0% versus 75.7%), or Q4W (79.2% versus 72.5%). The incidence of adverse events was low and comparable between patients with and those without diabetes., Conclusion: Approximately 90% of patients with and without diabetes in the QW and Q2W groups and more than 70% in the Q3W and Q4W groups maintained mean Hb levels of >or= 11.0 g/dL from week 2 to final measurement. These results demonstrated that patients with diabetes responded in a similar manner as patients without diabetes to extended dosing of epoetin alfa up to Q4W.

Few data exist to guide treatment of anemic hemodialysis patients with high ferritin and low transferrin saturation (TSAT). The Dialysis Patients' Response to IV Iron with Elevated Ferritin (DRIVE) trial was designed to evaluate the efficacy of intravenous ferric gluconate in such patients. Inclusion criteria were hemoglobin or=225 IU/kg per wk or >or=22,500 IU/wk. Patients with known infections or recent significant blood loss were excluded. Participants (n=134) were randomly assigned to no iron (control) or to ferric gluconate 125 mg intravenously with eight consecutive hemodialysis sessions (intravenous iron). At randomization, epoetin was increased 25% in both groups; further dosage changes were prohibited. At 6 wk, hemoglobin increased significantly more (P=0.028) in the intravenous iron group (1.6 +/- 1.3 g/dl) than in the control group (1.1 +/- 1.4 g/dl). Hemoglobin response occurred faster (P=0.035) and more patients responded after intravenous iron than in the control group (P=0.041). Ferritin 800 ng/ml had no relationship to the magnitude or likelihood of responsiveness to intravenous iron relative to the control group. Similarly, the superiority of intravenous iron compared with no iron was similar whether baseline TSAT was above or below the study median of 19%. Ferritin decreased in control subjects (-174 +/- 225 ng/ml) and increased after intravenous iron (173 +/- 272 ng/ml; P<0.001). Intravenous iron resulted in a greater increase in TSAT than in control subjects (7.5 +/- 7.4 versus 1.8 +/- 5.2%; P<0.001). Reticulocyte hemoglobin content fell only in control subjects, suggesting worsening iron deficiency. Administration of ferric gluconate (125 mg for eight treatments) is superior to no iron therapy in anemic dialysis patients receiving adequate epoetin dosages and have a ferritin 500 to 1200 ng/ml and TSAT