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1.
Regional Variation of Erythropoiesis-Stimulating Agent Hyporesponsiveness in the Global Daprodustat Dialysis Study (ASCEND-D)
Macdougall IC, Meadowcroft AM, Blackorby A, Cizman B, Cobitz AR, Godoy S, Jha V, Johansen KL, McMahon G, Obrador GT, et al
American journal of nephrology. 2023
Abstract
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 2964 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 pre-specified 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.
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2.
Safety of Roxadustat Versus Erythropoiesis-Stimulating Agents in Patients with Anemia of Non-dialysis-Dependent or Incident-to-Dialysis Chronic Kidney Disease: Pooled Analysis of Four Phase 3 Studies
Barratt J, Dellanna F, Portoles J, Choukroun G, De Nicola L, Young J, Dimković N, Reusch M
Advances in therapy. 2023
Abstract
INTRODUCTION This study was conducted to elucidate the safety of roxadustat, an oral medication, in patients with non-dialysis-dependent (NDD) or incident dialysis dialysis-dependent (ID-DD) chronic kidney disease (CKD). METHODS Safety results from four phase 3, randomized, open-label studies comparing roxadustat to an erythropoiesis-stimulating agent (ESA) in men and women with NDD or ID-DD CKD with anemia were pooled and evaluated. Endpoints were time to major adverse cardiovascular event (MACE; myocardial infarction, stroke, and all-cause mortality) and MACE+ (MACE plus congestive heart failure or unstable angina requiring hospitalization), all-cause mortality, and treatment-emergent adverse events (TEAEs). MACE and MACE+ were evaluated for non-inferiority at 1.8- and 1.3-margins using hazard ratios (HRs) and 95% confidence intervals (CIs). TEAEs were descriptively summarized. RESULTS In total, 2142 patients were evaluated (1083 roxadustat; 1059 ESA). Roxadustat was comparable to ESA for risk of MACE (HR 0.79, 95% CI 0.61-1.02), MACE+ (HR 0.78, 95% CI 0.62-0.98), and all-cause mortality (HR 0.78, 95% CI 0.57-1.05). TEAEs were comparable between roxadustat and ESA groups, including any TEAE [incidence rate per 100 (IR/100) patient-exposure years 56.1 vs. 53.5], TEAEs leading to study drug discontinuation (IR/100 patient-exposure years 6.7 vs. 5.1), and TEAEs leading to death (IR/100 patient-exposure years 6.9 vs. 7.4). CONCLUSION There was no evidence of increased risk of cardiovascular events or mortality with roxadustat compared with ESA in patients with anemia who have NDD or ID-DD CKD. Although TEAEs occurred commonly in both the roxadustat and ESA groups, patients infrequently discontinued the study drug because of an adverse event. CLINICAL TRIAL REGISTRATION NUMBERS DOLOMITES, 1517-CL-0610 [NCT02021318]; HIMALAYAS, FGCL-4592-063 [NCT02052310]; SIERRAS, FGCL-4592-064 [NCT02273726]; and ROCKIES, D5740C00002 [NCT02174731].
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3.
Maintenance intravenous iron in hemodialysis patients to minimize erythropoietin doses: a double-blinded, randomized controlled trial (the MAINTAIN IRON trial)
Anumas, S., Chatkrailert, A., Tantiyavarong, P.
Scientific Reports. 2023;13(1):1287
Abstract
In patients on chronic hemodialysis, there is no standard protocol for maintenance iron supplementation. This study aimed to compare two fixed-dose intravenous (IV) iron protocols to reduce erythropoiesis-stimulating agents (ESA). We conducted a double-blinded, randomized controlled study on hemodialysis patients having ferritin levels between 200 and 700 ng/dl and transferrin saturation values between 20 and 40%. Patients were assigned to receive either 100 or 200 mg of IV iron each month. ESA was adjusted every month to keep Hb between 10 and 12 g/dl. ESA dose at 12 months was the primary outcome. The secondary outcomes were all-cause mortality, cardiovascular events, absolute iron deficiency anemia (IDA), blood transfusion, adverse events, and iron withholding rate. Of the 79 eligible patients, 40 received 100 mg of IV iron, while 39 received 200 mg. At month 12, the mean monthly ESA dose in the 100-mg IV iron group was 35,706 ± 21,637 IU, compared to 26,382 ± 14,983 IU in the 200-mg group (P = 0.03). IDA was found in twelve patients (30%) in the 100-mg group and four patients (10.5%) in the 200-mg group (P = 0.05). In each group, three patients died (P = 0.9). Hospitalization, venous access thrombosis, and infection rates were similar in both groups. The withholding rate of IV iron was higher in 200-mg group (25% vs. 64.1%), but the protocol compliance was found more in 100-mg group (50% vs. 28.2%) (P = 0.001). In conclusion, monthly 200-mg IV iron infusions significantly reduce ESA doses but have a higher withholding rate. (Funded by the Kidney Foundation of Thailand and the Research Group in Nephrology and Renal Replacement Therapy from the Faculty of Medicine, Thammasat University).Thai Clinical Trials Registry number, TCTR20190707001.
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4.
Vadadustat for treatment of anemia in patients with dialysis-dependent chronic kidney disease receiving peritoneal dialysis
Sarnak MJ, Agarwal R, Boudville N, Chowdhury PCP, Eckardt KU, Gonzalez CR, Kooienga LA, Koury MJ, Ntoso KA, Luo W, et al
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2023
Abstract
BACKGROUND Hypoxia-inducible factor prolyl hydroxylase inhibitors such as vadadustat may provide an oral alternative to injectable erythropoiesis-stimulating agents for treating anemia in patients receiving peritoneal dialysis. In two randomized (1:1), global, phase 3, open-label, sponsor-blind, parallel-group, active-controlled noninferiority trials in patients with dialysis-dependent chronic kidney disease (INNO2VATE), vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and hematological efficacy. Vadadustat's effects in patients receiving only peritoneal dialysis is unclear. METHODS We conducted a post hoc analysis of patients in the INNO2VATE trials receiving peritoneal dialysis at baseline. The prespecified primary safety endpoint was time to first major cardiovascular event (MACE; defined as all-cause mortality or nonfatal myocardial infarction or stroke). The primary efficacy endpoint was mean change in hemoglobin from baseline to the primary efficacy period (weeks 24-36). RESULTS Of the 3923 patients randomized in the two INNO2VATE trials, 309 were receiving peritoneal dialysis (vadadustat, n = 152; darbepoetin alfa, n = 157) at baseline. Time to first MACE was similar in the vadadustat and darbepoetin alfa groups (hazard ratio 1.10; 95% CI 0.62, 1.93). In patients receiving peritoneal dialysis, the difference in mean change in hemoglobin concentrations was -0.10 g/dL (95% CI -0.33, 0.12) in the primary efficacy period. The incidence of treatment-emergent adverse events (TEAEs) was 88.2% versus 95.5%, and serious TEAEs was 52.6% versus 73.2% in the vadadustat and darbepoetin alfa groups, respectively. CONCLUSIONS In the subgroup of patients receiving peritoneal dialysis in the phase 3 INNO2VATE trials, safety and efficacy of vadadustat were similar to darbepoetin alfa.
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5.
Treatment satisfaction with molidustat in CKD-related anemia in non-dialysis patients: a post-hoc analysis of two clinical trials
Yamamoto H, Yamada T, Miyazaki K, Yamashita T, Kato T, Ohara K, Nakamura Y, Akizawa T
Clinical and experimental nephrology. 2023
Abstract
BACKGROUND Erythropoiesis-stimulating agents (ESAs) are the standard treatment for patients with renal anemia to increase hemoglobin (Hb) levels and reduce the need for blood transfusions. However, treatments targeting high Hb levels require high doses of ESAs administered intravenously, which is associated with an elevated risk of adverse cardiovascular events. Furthermore, there have been some problems such as hemoglobin variability and low achievement of target hemoglobin due to the shorter half-lives of ESAs. Consequently, erythropoietin-promoting medications, such as hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors, have been developed. This study aimed to evaluate changes in the Treatment Satisfaction Questionnaire for Medicine version II (TSQM-II) domain scores relative to baseline in each trial, to assess patient satisfaction with molidustat versus darbepoetin alfa. METHODS This post-hoc analysis of two clinical trials compared treatment satisfaction with an HIF-PH inhibitor, molidustat, versus a standard ESA, darbepoetin alfa, as part of therapy in patients with non-dialysis chronic kidney disease (CKD) and renal anemia. RESULTS Exploratory outcome data using the TSQM-II showed that both arms in both trials had enhanced treatment satisfaction over the course of the study period, as well as improvements in most TSQM-II domains at week 24 of treatment. Molidustat was associated with convenience domain scores at multiple time points depending on the trial. More patients were highly satisfied with the convenience of molidustat than that of darbepoetin alfa. Patients treated with molidustat had increased global satisfaction domain scores compared with those treated with darbepoetin alfa; however, the differences in global satisfaction domain scores were not significant. CONCLUSION These patient-reported satisfaction outcomes support the use of molidustat as a patient-centered treatment option for CKD-related anemia. REGISTRATION OF CLINICAL TRIALS ClinicalTrials.gov Identifier: NCT03350321 (November 22, 2017). CLINICALTRIALS gov Identifier: NCT03350347 (November 22, 2017).
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6.
Effects of hypoxia-inducible factor-prolyl hydroxylase inhibitors vs. erythropoiesis-stimulating agents on iron metabolism in non-dialysis-dependent anemic patients with CKD: A network meta-analysis
Yang, J., Xing, J., Zhu, X., Xie, X., Wang, L., Zhang, X.
Frontiers in Endocrinology. 2023;14:1131516
Abstract
OBJECTIVE To compare the effects of five hypoxia-inducible factor-prolyl hydroxylase domain inhibitors (HIF-PHIs), two erythropoiesis-stimulating agents (ESAs), and placebo on iron metabolism in renal anemia patients with non-dialysis-dependent chronic kidney disease (NDD-CKD). METHOD Five electronic databases were searched for studies. Randomized controlled clinical trials comparing HIF-PHIs, ESAs, and placebo in NDD-CKD patients were selected. The statistical program used for network meta-analysis was Stata/SE 15.1. The main outcomes were the change in hepcidin and hemoglobin (Hb) levels. The merits of intervention measures were predicted by the surface under the cumulative ranking curve method. RESULTS Of 1,589 original titles screened, data were extracted from 15 trials (3,228 participants). All HIF-PHIs and ESAs showed greater Hb level-raising ability than placebo. Among them, desidustat demonstrated the highest probability of increasing Hb (95.6%). Hepcidin [mean deviation (MD) = -43.42, 95%CI: -47.08 to -39.76], ferritin (MD= -48.56, 95%CI: -55.21 to -41.96), and transferrin saturation (MD = -4.73, 95%CI: -5.52 to -3.94) were decreased, while transferrin (MD = 0.09, 95%CI: 0.01 to 0.18) and total iron-binding capacity (MD = 6.34, 95%CI: 5.71 to 6.96) was increased in HIF-PHIs versus those in ESAs. In addition, this study observed heterogeneity in the ability of HIF-PHIs to decrease hepcidin. Compared with darbepoetin, only daprodustat (MD = -49.09, 95% CI: -98.13 to -0.05) could significantly reduce hepcidin levels. Meanwhile, daprodustat also showed the highest hepcidin-lowering efficacy (84.0%), while placebo was the lowest (8.2%). CONCLUSION For NDD-CKD patients, HIF-PHIs could ameliorate functional iron deficiency by promoting iron transport and utilization, which may be achieved by decreasing hepcidin levels. Interestingly, HIF-PHIs had heterogeneous effects on iron metabolism. SYSTEMATIC REVIEW REGISTRATION https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=242777, Identifier CRD42021242777.
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7.
The treatment effects and cardiovascular events of high-dose intravenous iron for hemodialysis patients with renal anemia: A systematic review and meta-analysis
Zhang, S., Ouyang, M., Liu, L.
Chronic illness. 2023;:17423953231180453
Abstract
BACKGROUND Hemodialysis patients are common to have renal anemia in the nephrology practice. For the renal anemia, the high-dose iron from the intravenous route is an important treatment option. We can understand the treatment effects and cardiovascular events of high-dose intravenous iron reviewing the randomized clinical trials. METHODS We compared the high-dose and low-dose iron treatments to find if the high-dose intravenous iron can influence the hematological parameters more significantly than the low-dose iron. The cardiovascular events were also analyzed for the high-dose iron treatment. Six studies with a total of 2422 renal anemia patients under hemodialysis were enrolled. We focused the outcomes of hemoglobin, transferrin saturation percentage, ferritin, erythropoietin dose, and cardiovascular events. RESULTS The high-dose intravenous iron might be associated with a greater number of ferritin, transferrin saturation percentage, and hemoglobin. In addition, the erythropoietin dose was less needed to maintain the ideal hemoglobin range in the high-dose intravenous iron group. CONCLUSIONS In current meta-analysis, the high-dose intravenous iron might show the superior effects on the ferritin, transferrin saturation percentage, and hemoglobin levels and needed dose of erythropoietin when compared to low-dose iron treatment.
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8.
Comparative Study of Recombinant Human Erythropoietin (rhEPO) Products on CKD (Chronic Kidney Disease) Patients
Dwitanto K, Angginy N, Sutandar W
Drug research. 2023
Abstract
PURPOSE This study was conducted to evaluate whether the efficacy and safety profile of recombinant human erythropoietin (rhEPO) manufactured by Daewoong Pharmaceutical Co., Ltd was similar to biological products approved by the drug safety regulatory authority. PATIENTS AND METHODS It was an open-label, randomized, comparative, parallel, multi-center study in hemodialysis patients with anemia. The reference product at an individualized dose 3 times a week was given in 4-8 weeks of titration period and hemoglobin (Hb) level was controlled to reach the range of 10-12 g/dL. Then, the subjects were randomly administered with reference or test product with the same dose regimen. The primary endpoints were to demonstrate the Hb level change between baseline and evaluation period in both treatment groups, while the secondary endpoints were the mean change in weekly dosage per kg body weight and the instability rate of Hb level during maintenance and evaluation period. The safety was evaluated based on the adverse events incidence. RESULTS There was no statistical difference in the change of Hb between test and reference (0.14 g/dL and 0.75 g/dL respectively, with p>0.05), also for the mean changes of weekly dosage between groups (1091.40 IU and 570.15 IU respectively, with p>0.05). The instability rate of Hb in both test and reference was not statistically significantly different as well (26 and 15% respectively, with p>0.05). CONCLUSION This study proves that the efficacy indicated by the change instability of Hb and safety indicated by adverse event incidence of Epodion and the reference product on chronic kidney disease were similar.
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9.
Higher hemoglobin levels using darbepoetin alfa and kidney outcomes in advanced chronic kidney disease without diabetes: a prespecified secondary analysis of the PREDICT trial
Maruyama, S., Kurasawa, S., Hayashi, T., Nangaku, M., Narita, I., Hirakata, H., Tanabe, K., Morita, S., Tsubakihara, Y., Imai, E., et al
Clinical and experimental nephrology. 2023
Abstract
BACKGROUND In the primary analysis of the PREDICT trial, a higher hemoglobin target (11-13 g/dl) with darbepoetin alfa did not improve renal outcomes compared with a lower hemoglobin target (9-11 g/dl) in advanced chronic kidney disease (CKD) without diabetes. Prespecified secondary analyses were performed to further study the effects of targeting higher hemoglobin levels on renal outcomes. METHODS Patients with an estimated glomerular filtration rate (eGFR) 8-20 ml/min/1.73 m(2) without diabetes were randomly assigned 1:1 to the high- and low-hemoglobin groups. The differences between the groups were evaluated for the following endpoints and cohort sets: eGFR and proteinuria slopes, assessed using a mixed-effects model in the full analysis set and the per-protocol set that excluded patients with off-target hemoglobin levels; the primary endpoint of composite renal outcome, evaluated in the per-protocol set using the Cox model. RESULTS In the full analysis set (high hemoglobin, n = 239; low hemoglobin, n = 240), eGFR and proteinuria slopes were not significantly different between the groups. In the per-protocol set (high hemoglobin, n = 136; low hemoglobin, n = 171), the high-hemoglobin group was associated with reduced composite renal outcome (adjusted hazard ratio: 0.64; 95% confidence interval: 0.43-0.96) and an improved eGFR slope (coefficient: + 1.00 ml/min/1.73 m(2)/year; 95% confidence interval: 0.38-1.63), while the proteinuria slope did not differ between the groups. CONCLUSIONS In the per-protocol set, the high-hemoglobin group demonstrated better kidney outcomes than the low-hemoglobin group, suggesting a potential benefit of maintaining higher hemoglobin levels in patients with advanced CKD without diabetes. CLINICAL TRIAL REGISTRATION Clinicaltrials.gov (identifier: NCT01581073).
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10.
Safety Endpoints With Vadadustat Versus Darbepoetin Alfa in Patients With Non-Dialysis-Dependent CKD: A Post Hoc Regional Analysis of the PRO(2)TECT Randomized Clinical Trial of ESA-Naïve Patients
Winkelmayer, W. C., Arnold, S., Burke, S. K., Chertow, G. M., Eckardt, K. U., Jardine, A. G., Lewis, E. F., Luo, W., Matsushita, K., McCullough, P. A., et al
Kidney medicine. 2023;5(7):100666
Abstract
RATIONALE & OBJECTIVE Prespecified analyses of the PRO(2)TECT trials comparing the safety of the oral hypoxia-inducible factor prolyl hydroxylase inhibitor vadadustat with darbepoetin alfa in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) found no difference in major adverse cardiovascular events (MACE; death from any cause or nonfatal myocardial infarction or stroke) among US patients and a higher risk among patients treated with vadadustat outside the United States. We investigated regional differences in MACE in the PRO(2)TECT trial that enrolled 1,751 patients previously untreated with erythropoiesis-stimulating agents. STUDY DESIGN Phase 3, global, open-label, randomized, active-controlled clinical trial. SETTING AND PARTICIPANTS Erythropoiesis-stimulating agent-untreated patients with anemia and NDD-CKD. INTERVENTION Eligible patients were randomized 1:1 to receive vadadustat or darbepoetin alfa. OUTCOMES The primary safety end point was time to first MACE. Secondary safety end points included time to first expanded MACE (MACE plus hospitalization for heart failure or thromboembolic event, excluding vascular access thrombosis). RESULTS In the non-US/non-Europe region, there was a higher proportion of patients with baseline estimated glomerular filtration rate (eGFR) level of ≤10 mL/min/1.73 m(2) in the vadadustat group [96 (34.7%)] than in the darbepoetin alfa group [66 (24.0%)]. In this region, there were 21 excess MACEs reported in the vadadustat group [78 events (n=276)] versus the darbepoetin alfa [57 events (n=275)], including 13 excess noncardiovascular deaths, largely from kidney failure. Noncardiovascular deaths were concentrated in Brazil and South Africa, which enrolled higher proportions of patients with an eGFR of ≤10 mL/min/1.73 m(2) and who may not have had access to dialysis. LIMITATIONS Different regional treatment patterns of patients with NDD-CKD. CONCLUSIONS The higher MACE rate in the non-US/non-Europe vadadustat group may have been partly because of imbalances in the baseline eGFR level in countries where dialysis was not uniformly available resulting in many kidney-related deaths.
