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Maternal Fatigue after Postpartum Anemia Treatment with Intravenous Ferric Carboxymaltose vs. Intravenous Ferric Derisomaltose vs. Oral Ferrous Sulphate: A Randomized Controlled Trial
Bombač Tavčar, L., Hrobat, H., Gornik, L., Preložnik Zupan, I., Vidmar Šimic, M., Pečlin, P., Kavšek, G., Lučovnik, M.
Journal of clinical medicine. 2024;13(3)
Abstract
(1) Background: Postpartum anemia is a common maternal complication and is recognized as a cause of impaired quality of life, reduced cognitive abilities, and fatigue. Efficient iron supplementation for the treatment of postpartum anemia is an essential component of high-quality maternal care. The optimal mode of iron supplementation has not been determined yet, whether oral or intravenous. The objective of this study was to compare postpartum anemia treatment with intravenous ferric carboxymaltose, intravenous ferric derisomaltose, and oral ferrous sulfate. (2) Methods: A single-center, open-label, randomized controlled trial. Women with hemoglobin < 100 g/L within 48 h postpartum were randomly allocated to receive intravenous ferric carboxymaltose, intravenous ferric derisomaltose, or oral ferrous sulfate. Intravenous iron was given in one or two doses, while ferrous sulfate was given as two 80 mg tablets once daily. The primary outcome was maternal fatigue measured by the Multidimensional Fatigue Inventory (MFI) six weeks postpartum. Hemoglobin, ferritin, and transferrin saturation levels were analyzed as secondary outcomes. A Kruskal-Wallis test was used for group comparison (p < 0.05 significant). (3) Results: Three hundred women were included. The MFI score at six weeks postpartum did not differ between groups (median 38 (inter-quartile range (IQR) 29-47) in the ferric carboxymaltose group, median 34 (IQR 26-42) in the ferric derisomaltose group, and median 36 (IQR 25-47) in the ferrous sulfate group; p = 0.26). Participants receiving oral iron had lower levels of hemoglobin (135 (131-139) vs. 134 (129-139) vs. 131 (125-137) g/L; p = 0.008), ferritin (273 (198-377) vs. 187 (155-246) vs. 24 (17-37) µg/L; p < 0.001) and transferrin saturation (34 (28-38) vs. 30 (23-37) vs. 24 (17-37) %; p < 0.001) than those receiving ferric carboxymaltose or ferric derisomaltose. (4) Conclusions: Intravenous ferric carboxymaltose, intravenous ferric derisomaltose, and oral ferrous sulfate had similar impacts on maternal fatigue at six weeks postpartum despite improved laboratory parameters in the intravenous groups.
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Roxadustat and Oral Iron Absorption in Chinese Patients with Anemia of Chronic Kidney Disease: A Randomized, Open-Label, Phase 4 Study (ALTAI)
Wu, H., Cheng, H., Wang, C., Yao, L., Qin, S., Zuo, L., Hu, Z., Zhang, C., Wu, Y., Hofherr, A., et al
Advances in therapy. 2024
Abstract
INTRODUCTION Anemia of chronic kidney disease (CKD) has a high incidence and is associated with many disease conditions. Iron dysmetabolism is an important contributor to anemia in CKD patients. METHODS ALTAI, a randomized, active-controlled, phase 4 trial, investigated the efficacy of roxadustat versus recombinant human erythropoietin (rHuEPO) on gastrointestinal iron absorption in patients with anemia of CKD (stage 4/5). The primary endpoint was change from baseline to day 15 in gastrointestinal iron absorption (serum iron area under the concentration-time curve; AUC(0-3h)) following single-dose oral iron. RESULTS Twenty-five patients with a mean age of 55.1 years were randomized 1:1 to roxadustat (n = 13) or rHuEPO (n = 12). Baseline iron profiles were similar between treatment groups. Change from baseline to day 15 in serum iron AUC(0-3h) was not statistically significantly different between the roxadustat and rHuEPO groups. Mean (SD) change from baseline in serum iron AUC(0-3h) was 11.3 (28.2) g × 3 h/dl in the roxadustat group and - 0.3 (9.7) g × 3 h/dl in the rHuEPO group. Roxadustat treatment was associated with decreased hepcidin and also increased transferrin, soluble transferrin receptor, and total iron-binding capacity (TIBC), with nominal significance. The proportion of patients experiencing one or more adverse events was 38.5% when treated with roxadustat and 16.7% with rHuEPO. CONCLUSIONS The study showed no significant difference between roxadustat and rHuEPO in iron absorption but was underpowered because of recruitment challenges. TRIAL REGISTRATION ClinicalTrials.gov Identifier NCT04655027.
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Predicting response to iron supplementation in patients with active inflammatory bowel disease (PRIme): a randomised trial protocol
Loveikyte, R., Duijvestein, M., Mujagic, Z., Goetgebuer, R. L., Dijkstra, G., van der Meulen-de Jong, A. E.
BMJ open. 2024;14(1):e077511
Abstract
INTRODUCTION Iron deficiency anaemia (IDA) is the most common systemic manifestation of inflammatory bowel disease (IBD) that has detrimental effects on quality of life (QoL) and disease outcomes. Iron deficiency (ID), with or without anaemia, poses a diagnostic and therapeutic challenge in patients with IBD due to the multifactorial nature of ID(A) and its frequent recurrence. Elevated hepcidin-a systemic iron regulator that modulates systemic iron availability and intestinal iron absorption-has been associated with oral iron malabsorption in IBD. Therefore, hepcidin could assist in therapeutic decision-making. In this study, we investigate whether hepcidin can predict response to oral and intravenous iron supplementation in patients with active IBD undergoing anti-inflammatory treatment. METHODS AND ANALYSIS PRIme is an exploratory, multicentre, open-label and randomised trial. All adult patients with active IBD and ID(A) will be assessed for eligibility. The participants (n=90) will be recruited at five academic hospitals within the Netherlands and randomised into three groups (1:1:1): oral ferrous fumarate, oral ferric maltol or intravenous iron. Clinical and biochemical data will be collected at the baseline and after 6, 14 and 24 weeks. Blood samples will be collected to measure hepcidin and other biomarkers related to iron status. In addition, patient-reported outcomes regarding QoL and disease burden will be evaluated. The primary outcome is the utility of hepcidin as a predictive biomarker for response to iron therapy, which will be assessed using receiver operating curve analysis. ETHICS AND DISSEMINATION The study has been approved by the Institutional Review Board at the Leiden University Medical Center (IRB No. P21.109) and other study sites. All participants will provide written informed consent to enrol in the study. The findings will be published in a peer-reviewed journal and disseminated at scientific conferences; the dataset will be available on reasonable request. TRIAL REGISTRATION Prospectively registered in the https://clinicaltrials.gov/ and the Eudra registries. First submitted on 10 May 2022 to the ClinicalTrials.gov (ID: NCT05456932) and on 3 March 2022 to the European Union Drug Regulating Authorities Clinical Trials Database (ID: 2022-000894-16).
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Efficacy and cost-effectiveness of darbepoetin alfa once every 4 weeks versus continuous erythropoietin receptor activator once every 4 weeks for anemia correction in patients with chronic kidney disease not on dialysis
Park, G. N., Lee, K. H., Moon, J. E., Choi, S. J., Park, M. Y., Kim, J. K., Yu, B. C.
Kidney research and clinical practice. 2024
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Editor's Choice
Abstract
BACKGROUND For anemia management in patients with chronic kidney disease not on dialysis, darbepoetin alfa (DA), which has a shorter half-life but is more inexpensive than continuous erythropoietin receptor activator (CERA), is preferred in Korea. This study evaluated the efficacy, safety, and cost-effectiveness of once-in-4-weeks DA compared with once-in-4-weeks CERA in patients with chronic kidney disease not on dialysis. METHODS In this randomized, prospective, non-inferiority study, 40 erythropoiesis-stimulating agent-naïve patients with chronic kidney disease not on dialysis were randomized 1:1 to the DA group and CERA group. They received the study drug once in 4 weeks during 10- or 12-week correction period and 24-week efficacy evaluation period. The primary outcomes were the mean difference in the changes in hemoglobin levels between baseline and efficacy evaluation period and hemoglobin response rates during the correction period. The secondary outcomes included differences in adverse events and costs. RESULTS DA was non-inferior to CERA for anemia correction; the mean difference in the change in hemoglobin levels between the groups was -0.070 g/dL (95% confidence interval, -0.730 to 0.590 g/dL). Hemoglobin response rates were 100% with DA and 94.1% with CERA. Adverse events were comparable. The mean cost of DA was approximately one-third that of CERA (34,100 ± 7,600 Korean won/4 weeks vs. 115,500 ± 23,600 Korean won/4 weeks; p < 0.001). CONCLUSION Once-in-4-weeks DA safely corrects anemia in erythropoiesis-stimulating agent-naïve patients with chronic kidney disease not on dialysis and is more cost-effective than once-in-4-weeks CERA.
PICO Summary
Population
Patients with chronic kidney disease not on dialysis (n= 40).
Intervention
Darbepoetin alfa (DA), (n= 20).
Comparison
Continuous erythropoietin receptor activator (CERA), (n= 20).
Outcome
The patients received the study drug once in 4 weeks during 10- or 12-week correction period and 24-week efficacy evaluation period. The primary outcomes were the mean difference in the changes in haemoglobin levels between baseline and efficacy evaluation period and haemoglobin response rates during the correction period. DA was non-inferior to CERA for anaemia correction; the mean difference in the change in haemoglobin levels between the groups was -0.070 g/dL (95% confidence interval [-0.730, 0.590 g/dL]). Haemoglobin response rates were 100% with DA and 94.1% with CERA. Adverse events were comparable. The mean cost of DA was approximately one-third that of CERA (34,100 ± 7,600 Korean won/4 weeks vs. 115,500 ± 23,600 Korean won/4 weeks).
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The differential effect of modern intravenous iron on fibroblast growth factor 23 and phosphate in non-dialysis dependent CKD - the exploratory randomized controlled double-blind ExplorIRON-CKD study
Kassianides, X., Bhandari, S.
BMC nephrology. 2024;25(1):54
Abstract
BACKGROUND Intravenous iron is commonly used in patients with non-dialysis-dependent chronic kidney disease (CKD). Modern intravenous iron compounds (e.g. ferric derisomaltose (FDI), ferric carboxymaltose (FCM)) are increasingly utilized with similar efficacy. A differential effect in terms of hypophosphatemia has been noted following administration of FCM, which may be related to fibroblast growth factor 23 (FGF23). This study was designed to examine the comparative effects of FDI and FCM on FGF23, phosphate and other markers of bone turnover. METHODS The single-center double-blind randomized controlled trial "Iron and Phosphaturia - ExplorIRON-CKD" primarily assessed the effects of FCM and FDI on intact FGF23 and phosphate, whilst also studying the impact on vitamin D, parathyroid hormone and phosphaturia. Bone markers including alkaline phosphatase, bone-specific alkaline phosphatase, procollagen type 1 N-terminal propeptide and carboxy-terminal collagen cross-linked telopeptide were monitored. Non-dialysis-dependent CKD patients (stage 3a-5) with iron deficiency with/without anemia (serum ferritin < 200 µg/L or transferrin saturation = 20% and serum ferritin 200-299 µg/L) were randomized to receive FDI or FCM in a 1:1 ratio. At baseline 1000 mg of intravenous iron was administered followed by 500-1000 mg at 1 month to achieve replenishment. Measurements were performed at baseline, 1-2 days following iron administration, 2 weeks, 1 month (second iron administration), 1-2 days following second administration, 2 months and 3 months following initial infusion. RESULTS Twenty-six patients participated in the trial; 14 randomized to FDI and 12 to FCM. Intact FGF23 increased following administration of iron, and the increase was significantly higher with FCM compared to FDI (Baseline to 1-2 days following 1st administration: FDI: 3.0 (IQR: - 15.1 - 13.8) % vs. FCM: 146.1 (IQR: 108.1-203.1) %; p < 0.001 and Baseline to 1-2 days following 2nd administration: FDI: 3.2 (IQR: - 3.5 - 25.4) % vs. FCM: 235.1 (138.5-434.6) %; p = 0.001). Phosphate levels decreased in the FCM group, causing a significant difference versus FDI 2 weeks following administration of the first dose. A significantly greater decrease in 1,25 (OH)(2) Vitamin D was noted with FCM. Several markers of bone turnover significantly changed following administration of FCM but not FDI. CONCLUSIONS The study suggests a differential effect on FGF23 following administration of FCM compared to FDI in non-dialysis-dependent CKD patients, similar to other patient groups. This may lead to changes consistent with hypovitaminosis D and alterations in bone turnover with potential clinical consequences. Further definitive studies are required to understand these differences of intravenous iron compounds. TRIAL REGISTRATION European Union Drug Regulating Authorities Clinical Trials Database (EudraCT) number: 2019-004370-26 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004370-26/GB ) (First date of trial registration: 03/12/2019).
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Full Correction of Posttransplant Anemia Is Associated With Stabilized Cardiac Dimensions Among Kidney Transplant Recipients: A Prospective Randomized Controlled Trial
Al-Otaibi, T., Nagib, A. M., Halim, M. A., Abo-Atya, H., Mahmoud, T., Nair, P., Adel, H., Mosaad, A., Fathy, A., Abdul-Hameed, M., et al
Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation. 2024;22(Suppl 1):323-331
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Editor's Choice
Abstract
OBJECTIVES Posttransplant anemia might be associated with cardiovascular morbidity and increased mortality. To our knowledge, the debate on anemia correction has neither been revisited nor decided definitively. We aimed to assess the effects of full correction of posttransplant anemia on the cardiovascular system and quality of life among renal transplant recipients with stable graft function who were using erythropoietin-stimulating agents. MATERIALS AND METHODS We enrolled 247 kidney recipients with stable graft function to be assessed for anemia. Eligible patients were randomized to achieve targeted hemoglobin of 11 to 12 g/dL (group 1, n = 183) or of 13 to 15 g/dL (group 2, n = 64) with the use of erythropoietin-stimulating agents. Patients underwent monthly clinical and laboratory evaluations of kidney graft function. Quality of life and echocardiography were assessed at study start and at 12 months. RESULTS The 2 groups were comparable regarding pretransplant characteristics. In group 2, we observed comparable posttransplant complications (P > .05) but better graft function at 6 months and better cardiac indexes at 1 year of the study (P < .05). At 12 months, quality of life had improved after full correction of posttransplant anemia in the renal transplant recipients who received erythropoietinstimulating agents. CONCLUSIONS Full correction of posttransplant anemia in renal transplant recipients was associated with improved quality of life and cardiac indexes without an effect on cardiovascular comorbidity.
PICO Summary
Population
Adult kidney transplant recipients with stable graft function (n= 247).
Intervention
Targeted haemoglobin of 11 to 12 g/dL with the use of erythropoietin-stimulating agents (ESA) (group 1, n= 183)
Comparison
Targeted haemoglobin of 13 to 15 g/dL with ESA (group 2, n= 64)
Outcome
Patients underwent monthly clinical and laboratory evaluations of kidney graft function. Quality of life and echocardiography were assessed at study start and at 12 months. In group 2, there were comparable post-transplant complications, but better graft function at 6 months and better cardiac indexes at 1 year of the study. At 12 months, quality of life had improved after full correction of post-transplant anaemia in the renal transplant recipients who received erythropoietin-stimulating agents.
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Incidence of postpartum depression after treatment of postpartum anaemia with intravenous ferric carboxymaltose, intravenous ferric derisomaltose or oral ferrous sulphate: A randomized clinical trial
Bombač Tavčar, L., Hrobat, H., Gornik, L., Globevnik Velikonja, V., Lučovnik, M.
European journal of obstetrics & gynecology and reproductive biology: X. 2023;20:100247
Abstract
OBJECTIVES This study aimed to explore whether the type of iron preparation used to treat postpartum anaemia affects the incidence of postpartum depression and whether the risk of postpartum depression is higher in postpartum patients with anaemia who were adequately treated compared to the general postpartum population. STUDY DESIGN Single-center, open-label, randomized trial. Women were allocated to receive intravenous ferric carboxymaltose, intravenous ferric derisomaltose or oral ferrous sulphate. Intravenous iron was given in one or two doses, while ferrous sulphate as two 80 mg tablets once daily. Primary outcome was postpartum depression measured by Edinburgh Postnatal Depression Scale (EPDS) six weeks postpartum. Haematological parameters were analyzed as secondary outcomes. Kruskal-Wallis test was used for group comparison (p < 0.05 significant). The chi-square test was applied to compare categorical variables as well as the group of all subjects treated for anaemia in the study with the historical data for the Slovenian postpartum population. RESULTS Three-hundred women with postpartum anemia (hemoglobin < 100 g/L within 48-hours postpartum) were included between September 2020 and March 2022 in tertiary perinatal center. Most characteristics were similar across groups. EPDS score at six weeks postpartum did not differ between groups. The treatment modality of postpartum anaemia did not have a statistically significant effect on the EPDS score six weeks after treatment (p = 0.10), nor did it have a statistically significant effect on the difference in EPDS scores before and after treatment (p = 0.68). The proportions of participants who scored 10 or more points on the EPDS scores at six weeks postpartum were not statistically different between the groups (p = 0.79). The proportion of participants with an EPDS score of 10 or more at six weeks postpartum in the total study population did not differ significantly from previously reported proportion of postpartum women with EPDS score of 10 or more in the general population (12 % vs. 21 %; p < 0.001). CONCLUSIONS Maternal depression at 6 weeks postpartum did not differ in women treated for postpartum anemia with intravenous ferric carboxymaltose, intravenous ferric derisomaltose or oral ferrous sulphate. Participants with postpartum anaemia who are adequately treated with either oral or intravenous iron preparations are not at a higher risk of postpartum depression than the general population at six weeks postpartum.
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Intravenous ferric carboxymaltose for iron repletion following acute heart failure in patients with and without diabetes: a subgroup analysis of the randomized AFFIRM-AHF trial
Rosano, G., Ponikowski, P., Vitale, C., Anker, S. D., Butler, J., Fabien, V., Filippatos, G., Kirwan, B. A., Macdougall, I. C., Metra, M., et al
Cardiovascular diabetology. 2023;22(1):215
Abstract
BACKGROUND In AFFIRM-AHF, treatment of iron deficiency with intravenous ferric carboxymaltose (FCM) reduced the risk of heart failure (HF) hospitalization and improved quality of life (QoL) vs placebo in patients stabilized following an acute HF (AHF) episode, with no effect on cardiovascular (CV) death. Diabetes and iron deficiency frequently accompany AHF. This post hoc analysis explored the effects of diabetes on outcomes in AFFIRM-AHF patients. METHODS Patients were stratified by diabetes yes/no at baseline. The effects of FCM vs placebo on primary (total HF hospitalizations and CV death) and secondary (total CV hospitalizations and CV death; CV death; total HF hospitalizations; time to first HF hospitalization or CV death; and days lost due to HF hospitalizations or CV death) endpoints at Week 52 and change vs baseline in disease-specific QoL (12-item Kansas City Cardiomyopathy Questionnaire [KCCQ-12]) at Week 24 were assessed by subgroup. For each endpoint, the interaction between diabetes status and treatment outcome was explored. RESULTS Of 1108 AFFIRM-AHF patients, 475 (FCM: 231; placebo: 244) had diabetes and 633 (FCM: 327; placebo: 306) did not have diabetes. Patients with diabetes were more commonly male (61.5% vs 50.9%), with a higher frequency of ischemic HF etiology (57.9% vs 39.0%), prior HF history (77.7% vs 66.5%), and comorbidities (including previous myocardial infarction [49.3% vs 32.9%] and chronic kidney disease [51.4% vs 32.4%]) than those without diabetes. The annualized event rate/100 patient-years with FCM vs placebo for the primary endpoint was 66.9 vs 80.9 in patients with diabetes (rate ratio [RR]: 0.83, 95% CI 0.58-1.81) and 51.3 vs 66.9 in patients without diabetes (RR: 0.77, 95% CI 0.55-1.07), with no significant interaction between diabetes status and treatment effect (p(interaction) = 0.76). Similar findings were observed for secondary outcomes. Change from baseline in KCCQ-12 overall summary score was numerically greater with FCM vs placebo at almost all time points in both subgroups, with no interaction between diabetes and treatment effect at Week 24. CONCLUSIONS The clinical and QoL benefits observed with intravenous FCM in patients with iron deficiency following stabilization from an AHF episode are independent of diabetes status. Trial registration Clinicaltrials.gov, NCT02937454 (registered 10.18.2016).
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Association Between Hemoglobin Levels and Efficacy of Intravenous Ferric Carboxymaltose in Patients With Acute Heart Failure and Iron Deficiency: An AFFIRM-AHF Subgroup Analysis
Filippatos G, Ponikowski P, Farmakis D, Anker SD, Butler J, Fabien V, Kirwan BA, Macdougall IC, Metra M, Rosano G, et al
Circulation. 2023
Abstract
BACKGROUND Iron deficiency, with or without anemia, is an adverse prognostic factor in heart failure (HF). In AFFIRM-AHF (a randomized, double-blind placebo-controlled trial comparing the effect of intravenous ferric carboxymaltose on hospitalizations and mortality in iron-deficient subjects admitted for acute heart failure), intravenous ferric carboxymaltose (FCM), although having no significant effect on the primary end point, reduced the risk of HF hospitalization (hHF) and improved quality of life versus placebo in iron-deficient patients stabilized after an acute HF (AHF) episode. These prespecified AFFIRM-AHF subanalyses explored the association between hemoglobin levels and FCM treatment effects. METHODS AFFIRM-AHF was a multicenter, double-blind, randomized, placebo-controlled trial of FCM in hospitalized AHF patients with iron deficiency. Patients were stratified by baseline hemoglobin level (<12 versus ≥12 g/dL). In each subgroup, the primary composite (total hHF and cardiovascular death) and secondary (total hHF; total cardiovascular hospitalizations and cardiovascular death; time to cardiovascular death, and time to first/days lost due to hHF or cardiovascular death) outcomes were assessed with FCM versus placebo at week 52. Sensitivity analyses using the World Health Organization anemia definition (hemoglobin level <12 g/dL [women] or <13 g/dL [men]) were performed, among others. RESULTS Of 1108 AFFIRM-AHF patients, 1107 were included in these subanalyses: 464 (FCM group, 228; placebo group, 236) had a hemoglobin level <12 g/dL, and 643 (FCM, 329; placebo, 314) had a hemoglobin level ≥12 g/dL. Patients with a hemoglobin level <12 g/dL were older (mean, 73.7 versus 69.1 years), with more frequent previous HF (75.0% versus 68.7%), serum ferritin <100 μg/L (75.4% versus 68.1%), and transferrin saturation <20% (87.9% versus 81.4%). For the primary outcome, annualized event rates per 100 patient-years with FCM versus placebo were 71.1 and 73.6 (rate ratio, 0.97 [95% CI, 0.66-1.41]), respectively, and 48.5 versus 72.9 (RR, 0.67 [95% CI, 0.48-0.93]) in the hemoglobin levels <12 and ≥12 g/dL subgroups, respectively. No significant interactions between hemoglobin subgroup and treatment effect were observed for primary (P(interaction)=0.15) or secondary outcomes. Changes from baseline in hemoglobin, serum ferritin and transferrin saturation were significantly greater with FCM versus placebo in both subgroups between weeks 6 and 52. Findings were similar using the World Health Organization definition for anemia. CONCLUSIONS The effects of intravenous FCM on outcomes in iron-deficient patients stabilized after an AHF episode, including improvements in iron parameters over time, did not differ between patients with hemoglobin levels <12 and ≥12 g/dL. REGISTRATION URL: https://www. CLINICALTRIALS gov; Unique identifier: NCT02937454.
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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).