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Roxadustat reduces left ventricular mass index compared to rHuEPO in haemodialysis patients in a randomized controlled trial
Tan, W., Wang, X., Sun, Y., Wang, X., He, J., Zhong, L., Jiang, X., Sun, Y., Tian, E., Li, Z., et al
Journal of internal medicine. 2024
Abstract
BACKGROUND Left ventricular hypertrophy (LVH) is highly prevalent in haemodialysis (HD) patients and is associated with an increased risk of death. Roxadustat and recombinant human erythropoietin (rHuEPO, abbreviated as EPO) are the main treatment strategies for renal anaemia in HD patients, but it has not been clear whether there is a difference in their effect on LVH. METHODS In this multi-centre, prospective, randomized trial of 12-month duration, study participants were randomized in a 1:1 ratio to the roxadustat group or the EPO group. The doses of both treatment regimens were adjusted so that the patients had a haemoglobin level of 10.0-12.0 g per dL. The primary study endpoint was the change from baseline to 12 months in the left ventricular mass index (LVMI, g/m(2) ) measured by echocardiography. RESULTS In total, 114 patients were enrolled. The mean age was 50 years, and the median dialysis duration was 33 months. Sixty-one patients were men, and 24 were diabetic. LVMI decreased from 116.18 ± 27.84 to 110.70 ± 25.74 g/m(2) in the roxadustat group. However, it increased from 109.35 ± 23.41 to 114.99 ± 28.46 g/m(2) in the EPO group, with a significant difference in the change in LVMI between the two groups [-5.48 (-11.60 to 0.65) vs. 5.65 (0.74 to 10.55), p < 0.05]. Changes in left ventricular mass, end-diastolic volume and 6-min walk test seemed superior in the roxadustat group. There were no significant differences in other cardiac geometry, biochemical parameters and major adverse cardiovascular events between the two groups. CONCLUSIONS Compared to EPO, roxadustat is more helpful in the regression of LVH in HD patients.
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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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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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Impact of C-reactive protein on the effect of Roxadustat for the treatment of anemia in chronic kidney disease: a systematic review of randomized controlled trials
Luo, X., Li, G., Yang, H., Chen, L., Gao, Y., Cong, J., Luo, H., Zhang, W.
BMC nephrology. 2024;25(1):47
Abstract
BACKGROUND Chronic inflammation, reflected by an increased blood C-reactive protein (CRP) level, is common in patients with chronic kidney disease (CKD) and is involved in the development of renal anemia. This systematic review aims to investigate the impacts of CRP on the efficacy of hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) in the treatment of renal anemia in patients with CKD. METHODS We conducted a comprehensive search of electronic databases including Pubmed, Web of Science, Embase, Cochrane Library, CNKI, Wanfang, and the International Clinical Trials Registry Platform (ICTRP), from their inception to May 19, 2022. We systematically reviewed evidence from randomized controlled trials using HIF-PHIs for renal anemia treatment. The mean difference (MD) in changes in hemoglobin concentration (∆Hb) before and after treatment served as the meta-analysis outcome, utilizing a random-effects model. We compared groups with CRP levels greater than or equal to the upper limit of normal (ULN) and less than the ULN. Additionally, further analysis was conducted in the CRP ≥ ULN group comparing HIF-PHIs and erythropoiesis-stimulating agents (ESA). RESULTS A total of 7 studies from 6 publications were included in the analysis. In the comparison between the CRP ≥ ULN group and the CRP < ULN group, 524 patients from 4 studies were incorporated into the analysis. All patients received roxadustat as the primary intervention. The pooled results revealed no significant difference in ΔHb between patients with CRP ≥ ULN and CRP < ULN at baseline (Mean Difference: 0.00, 95% Confidence Interval: -0.32 to 0.33, P = 0.99). Moreover, within the CRP ≥ ULN group, three studies involving 1399 patients compared the efficacy of roxadustat and erythropoiesis-stimulating agents (ESAs). The results indicated no significant difference in ΔHb between patients treated with ESAs and HIF-PHIs (Mean Difference: 0.24, 95% Confidence Interval: -0.08 to 0.56, P = 0.14). In terms of medication dosage, an increase in ESA dose over time was observed across various studies, particularly evident in the CRP ≥ ULN group, while the dose of roxadustat remains constant over time and is not influenced by the baseline levels of CRP. CONCLUSIONS Our systematic review demonstrates that roxadustat exhibits similar efficacy across different CRP levels. Moreover, within the CRP ≥ ULN group, roxadustat can maintain efficacy comparable to ESA without the necessity for dose escalation. TRIAL REGISTRATION CRD42023396704.
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Investigating the relationship between erythropoiesis-stimulating agents and mortality in hemodialysis patients: A systematic review and meta-analysis
Karimi, Z., Raeisi Shahraki, H., Mohammadian-Hafshejani, A.
PloS one. 2023;18(11):e0293980
Abstract
BACKGROUND In recent years, various studies have been conducted to investigate the relationship between erythropoiesis-stimulating agents (ESAs) and mortality in hemodialysis patients, who showed contradictory results. Therefore, this study aimed to investigate the relationship between ESAs and mortality in hemodialysis patients. METHODS The current study is a systematic review and meta-analysis based on observational and interventional studies published in the Web of Science, Cochrane Library, Science Direct, PubMed, Scopus, and Google Scholar databases between 1980 and the end of 2022. Jadad scale checklist and Newcastle Ottawa scale were used to evaluate the quality of articles. The study data were analyzed using Stata 15 software. RESULTS In the initial search, 3933 articles were extracted, and by screening and considering the research criteria, 68 studies were finally included in the meta-analysis. According to the meta-analysis results, the risk ratio (RR) of overall mortality in hemodialysis patients receiving ESAs was equal to 1.19 (95% CI: 1.16-1.23, P ≤ 0.001). The RR of mortality in patients aged 60 years and under was equal to 1.33 (1.15-1.55, P ≤ 0.001), in the age group over 60 years was equal to 1.13 (1.10-1.16, P ≤ 0.001), in randomized clinical trial studies was equal to 1.06 (0.80-1.40, P = 0.701), in cohort studies was equal to 1.20 (1.16-1.25, P ≤ 0.001), in American countries was equal to 1.19 (1.10-1.29, P ≤ 0.001), in Asian countries was equal to 1.15 (1.10-1.19, P ≤ 0.001), and in European countries was equal to 1.18 (1.05-1.34, P = 0.007). CONCLUSION The results of the study show that receiving ESAs is associated with a 19% increase in the risk of overall mortality in hemodialysis patients.
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Erythropoiesis-stimulating agents and cardiovascular mortality: A systematic review and meta-analysis of 17 studies and 372,156 hemodialysis patients
Karimi, Z., Raeisi Shahraki, H., Mohammadian-Hafshejani, A.
International journal of cardiology. Cardiovascular risk and prevention. 2023;19:200220
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Editor's Choice
Abstract
INTRODUCTION Prior studies on the association between erythropoiesis-stimulating agents (ESAs) and cardiovascular mortality in hemodialysis patients have yielded conflicting findings. We aimed to clarify this relationship through a systematic review and meta-analysis of current evidence. METHODS We comprehensively searched major databases for observational and interventional studies on ESA use and cardiovascular mortality in hemodialysis patients published from 1980 to September 2023. Pooled risk ratios (RR) with 95 % confidence intervals (CI) were calculated using random-effects models. Sources of heterogeneity were explored through subgroup analyses and meta-regression. The study data were analyzed using Stata 15 software. FINDINGS Upon conducting the initial search, we extracted 792 articles and, after screening and considering the research criteria, 17 studies with 372,156 participants were included in the meta-analysis. Overall, ESA use was associated with a 27 % increased risk of cardiovascular mortality (RR 1.27, 95 % CI: 1.15-1.40, p < 0.001). This risk varied by geographical location, with RRs of 1.27 (95 % CI: 1.14-1.41; p-value≤0.001) for America, 1.33 (95 % CI: 1.12-1.58; p-value = 0.001) for Asia, and 1.23 (95 % CI: 1.02-1.49; p-value = 0.028) for Europe. Importantly, a gender disparity was revealed, with studies involving a higher proportion of males showing greater risks (RR 1.51, 95 % CI: 1.25-1.83, p < 0.001) than female-predominant studies (RR 1.08, 95 % CI: 0.86-1.36, p < 0.001). CONCLUSION Our meta-analysis indicates ESA use is associated with heightened cardiovascular mortality in hemodialysis patients, especially in males. These findings have implications for optimizing dosing strategies while balancing efficacy and safety. Further research is warranted, particularly randomized controlled trials, to establish definitive ESA dosing guidelines.
PICO Summary
Population
Haemodialysis patients (17 studies, n= 372,156).
Intervention
Systematic review and meta-analysis evaluating the relationship between erythropoiesis-stimulating agents (ESAs) use and cardiovascular mortality.
Comparison
Outcome
Overall, ESA use was associated with a 27% increased risk of cardiovascular mortality (RR, 1.27; 95% CI [1.15, 1.40]). This risk varied by geographical location, with RRs of 1.27; 95% CI [1.14, 1.41] for America, 1.33; 95% CI [1.12, 1.58] for Asia, and 1.23; 95% CI [1.02, 1.49] for Europe. A gender disparity was revealed, with studies involving a higher proportion of males showing greater risks RR, 1.51; 95% CI [1.25, 1.83] than female-predominant studies RR, 1.08; 95% CI [0.86, 1.36].
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Predictors of hyporesponsiveness to erythropoiesis-stimulating agents in patients with non-dialysis-dependent chronic kidney disease (RADIANCE-CKD Study)
Mase, K., Yamagata, K., Yamamoto, H., Tsuruya, K., Hase, H., Nishi, S., Nangaku, M., Wada, T., Hayashi, T., Uemura, Y., et al
American journal of nephrology. 2023
Abstract
INTRODUCTION Hyporesponsiveness to erythropoiesis-stimulating agents (ESA) has been associated with increased mortality and cardiovascular events in patients with chronic kidney disease. We hypothesized that the prediction of ESA resistance when ESA administration would be very useful in deciding on a treatment plan. METHODS Patients enrolled in a randomized controlled trial to evaluate renal prognosis in anemic patients with non-dialysis-dependent chronic kidney disease with hyporesponsiveness to ESA were included; the patients had different target hemoglobin levels. A landmark analysis was performed at 3 months into the study. To construct a predictive model for the severe ESA hypo-responder group, in which there was no increase in hemoglobin even with active treatment, background factors and serum test items that affect anemia at study entry were included in a logistic regression model, the area under the curve (AUC) and 95% confidence intervals (CI) were estimated, and sensitivity and specificity were calculated. This study was a post-hoc sub-analysis of a randomized controlled trial. RESULTS The AUC for the 19 existing risk factors as predictors was 0.783 (95% CI; 0.711-0.855). Among the 19 risk factors, the combination of six factors (hemoglobin level, systolic blood pressure, weight, gender, smoking status and hypertensive retinopathy) with the largest χ-square statistics were selected by multiple logistics regression. The AUC for these 6 predictors was 0.716 (95% CI: 0.634-0.799). To the six existing risk factors, five serum test items that affecting anemia (vitamin B12, vitamin B6, folic acid, parathyroid hormone, and 25-hydroxyvitamin D) were added, for a total of 11 risk factors, with a similar AUC of 0.736 (95% CI; 0.655-0.817), sufficient to predict ESA resistance. CONCLUSIONS Our results suggest that existing risk factors and serum test items can be used to predict ESA resistance in patients with non-dialysis-dependent chronic kidney disease on ESA.
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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).
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Erythropoiesis-stimulating agents for anaemia in adults with chronic kidney disease: a network meta-analysis
Chung, E. Y., Palmer, S. C., Saglimbene, V. M., Craig, J. C., Tonelli, M., Strippoli, G. F.
The Cochrane Database of Systematic Reviews. 2023;2(2):Cd010590
Abstract
BACKGROUND Erythropoiesis-stimulating agents (ESAs) are commonly used to treat anaemia in people with chronic kidney disease (CKD). However, their use has been associated with cardiovascular events. This is an update of a Cochrane review first published in 2014. OBJECTIVES To compare the efficacy and safety of ESAs (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta, and biosimilar ESAs against each other, placebo, or no treatment) to treat anaemia in adults with CKD. SEARCH METHODS In this update, we searched the Cochrane Kidney and Transplant Register of Studies up to 29 April 2022 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA Randomised controlled trials (RCTs) that included a comparison of an ESA (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta, a biosimilar epoetin or a biosimilar darbepoetin alfa) with another ESA, placebo or no treatment in adults with CKD were considered for inclusion. DATA COLLECTION AND ANALYSIS Two independent authors screened the search results and extracted data. Data synthesis was performed using random-effects pairwise meta-analysis (expressed as odds ratios (OR) and their 95% confidence intervals (CI)) and network meta-analysis. We assessed for heterogeneity and inconsistency within meta-analyses using standard techniques and planned subgroup and meta-regression to explore sources of heterogeneity or inconsistency. We assessed certainty in treatment estimates for the primary outcomes (preventing blood transfusions and death (any cause)) using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS Sixty-two new studies (9237 participants) were included in this update, so the review now includes 117 studies with 25,237 participants. Most studies were at high or unclear risk of bias in most methodological domains. Overall, results remain similar in this update compared to our previous review in 2014. For preventing blood transfusion, epoetin alfa (OR 0.28, 95% CI 0.13 to 0.61; low certainty evidence) and epoetin beta (OR 0.19, 95% CI 0.08 to 0.47; low certainty evidence) may be superior to placebo, and darbepoetin alfa was probably superior to placebo (OR 0.27, 95% CI 0.11 to 0.67; moderate certainty evidence). Methoxy polyethylene glycol-epoetin beta (OR 0.33, 95% CI 0.11 to 1.02; very low certainty evidence), a biosimilar epoetin (OR 0.34, 95% CI 0.11 to 1.03; very low certainty evidence) and a biosimilar darbepoetin alfa (OR 0.37, 95% CI 0.07 to 1.91; very low certainty evidence) had uncertain effects on preventing blood transfusion compared to placebo. The comparative effects of ESAs compared with another ESA on preventing blood transfusions were uncertain, in low to very low certainty evidence. Effects on death (any cause) were uncertain for epoetin alfa (OR 0.79, 95% CI 0.51 to 1.22; low certainty evidence), epoetin beta (OR 0.69, 95% CI 0.40 to 1.20; low certainty evidence), methoxy polyethylene glycol-epoetin beta (OR 1.07, 95% CI 0.67 to 1.71; very low certainty evidence), a biosimilar epoetin (OR 0.80, 95% CI 0.47 to 1.36; low certainty evidence) and a biosimilar darbepoetin alfa (OR 1.63, 95% CI 0.51 to 5.23; very low certainty evidence) compared to placebo. There was probably no difference between darbepoetin alfa and placebo on the odds of death (any cause) (OR 0.99, 95% CI 0.81 to 1.21; moderate certainty evidence). The comparative effects of ESAs compared with another ESA on death (any cause) were uncertain in low to very low certainty evidence. Epoetin beta probably increased the odds of hypertension when compared to placebo (OR 2.17, 95% CI 1.17 to 4.00; moderate certainty evidence). Compared to placebo, epoetin alfa (OR 2.10, 95% CI 1.22 to 3.59; very low certainty evidence), darbepoetin alfa (OR 1.88, 95% CI 1.12 to 3.14; low certainty evidence) and methoxy polyethylene glycol-epoetin beta (OR 1.98, 95% CI 1.05 to 3.74; low certainty evidence) may increase the odds of hypertension, but a biosimilar epoetin (OR 1.88, 95% CI 0.96 to 3.67; low certainty evidence) and biosimilar darbepoetin alfa (OR 1.98, 95% CI 0.84 to 4.66; low certainty evidence) had uncertain effects on hypertension. The comparative effects of all ESAs compared with another ESA, placebo or no treatment on cardiovascular death, myocardial infarction, stroke, vascular access thrombosis, kidney failure, and breathlessness were uncertain. Network analysis for fatigue was not possible due to sparse data. AUTHORS' CONCLUSIONS The comparative effects of different ESAs on blood transfusions, death (any cause and cardiovascular), major cardiovascular events, myocardial infarction, stroke, vascular access thrombosis, kidney failure, fatigue and breathlessness were uncertain.