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Early erythropoiesis-stimulating agents in preterm or low birth weight infants.
Ohlsson, A, Aher, SM
The Cochrane database of systematic reviews. 2020;(2):CD004863
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Abstract
BACKGROUND Preterm infants have low plasma levels of erythropoietin (EPO), providing a rationale for the use of erythropoiesis-stimulating agents (ESAs) to prevent or treat anaemia and to provide neuro protection and protection against necrotising enterocolitis (NEC). Darbepoetin (Darbe) and EPO are currently available ESAs. OBJECTIVES To assess the effectiveness and safety of ESAs (erythropoietin (EPO) and/or Darbe) initiated early (before eight days after birth) compared with placebo or no intervention in reducing red blood cell (RBC) transfusions, adverse neurological outcomes, and feeding intolerance including necrotising enterocolitis (NEC) in preterm and/or low birth weight infants. Primary objective for studies that primarily investigate the effectiveness and safety of ESAs administered early in reducing red blood cell transfusions: To assess the effectiveness and safety of ESAs initiated early in reducing red blood cell transfusions in preterm infants. Secondary objectives: Review authors performed subgroup analyses of low (≤ 500 IU/kg/week) and high (> 500 IU/kg/week) doses of EPO and the amount of iron supplementation provided: none, low (≤ 5 mg/kg/d), and high (> 5 mg/kg/d). Primary objective for studies that primarily investigate the neuro protective effectiveness of ESAs: To assess the effectiveness and safety of ESAs initiated early in reducing adverse neurological outcomes in preterm infants. Primary objective for studies that primarily investigate the effectiveness of EPO or Darbe administered early in reducing feeding intolerance: To assess the effectiveness and safety of ESAs administered early in reducing feeding intolerance (and NEC) in preterm infants. Other secondary objectives: To compare the effectiveness of ESAs in reducing the incidence of adverse events and improving long-term neurodevelopmental outcomes. SEARCH METHODS We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2), MEDLINE via PubMed (1966 to 10 March 2017), Embase (1980 to 10 March 2017), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 10 March 2017). We searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomised and quasi-randomised controlled trials. SELECTION CRITERIA Randomised and quasi-randomised controlled trials of early initiation of EAS treatment versus placebo or no intervention in preterm or low birth weight infants. DATA COLLECTION AND ANALYSIS We used the methods described in the Cochrane Handbook for Systematic Reviews of Interventions and the GRADE approach to assess the quality of evidence. MAIN RESULTS This updated review includes 34 studies enrolling 3643 infants. All analyses compared ESAs versus a control consisting of placebo or no treatment. Early ESAs reduced the risk of 'use of one or more [red blood cell] RBC transfusions' (typical risk ratio (RR) 0.79, 95% confidence interval (CI) 0.74 to 0.85; typical risk difference (RD) -0.14, 95% CI -0.18 to -0.10; I2 = 69% for RR and 62% for RD (moderate heterogeneity); number needed to treat for an additional beneficial outcome (NNTB) 7, 95% CI 6 to 10; 19 studies, 1750 infants). The quality of the evidence was low. Necrotising enterocolitis was significantly reduced in the ESA group compared with the placebo group (typical RR 0.69, 95% CI 0.52 to 0.91; typical RD -0.03, 95% CI -0.05 to -0.01; I2 = 0% for RR and 22% for RD (low heterogeneity); NNTB 33, 95% CI 20 to 100; 15 studies, 2639 infants). The quality of the evidence was moderate. Data show a reduction in 'Any neurodevelopmental impairment at 18 to 22 months' corrected age in the ESA group (typical RR 0.62, 95% CI 0.48 to 0.80; typical RD -0.08, 95% CI -0.12 to -0.04; NNTB 13, 95% CI 8 to 25. I2 = 76% for RR (high heterogeneity) and 66% for RD (moderate); 4 studies, 1130 infants). The quality of the evidence was low. Results reveal increased scores on the Bayley-II Mental Development Index (MDI) at 18 to 24 months in the ESA group (weighted mean difference (WMD) 8.22, 95% CI 6.52 to 9.92; I2 = 97% (high heterogeneity); 3 studies, 981 children). The quality of the evidence was low. The total volume of RBCs transfused per infant was reduced by 7 mL/kg. The number of RBC transfusions per infant was minimally reduced, but the number of donors to whom infants who were transfused were exposed was not significantly reduced. Data show no significant difference in risk of stage ≥ 3 retinopathy of prematurity (ROP) with early EPO (typical RR 1.24, 95% CI 0.81 to 1.90; typical RD 0.01, 95% CI -0.02 to 0.04; I2 = 0% (no heterogeneity) for RR; I2 = 34% (low heterogeneity) for RD; 8 studies, 1283 infants). Mortality was not affected, but results show significant reductions in the incidence of intraventricular haemorrhage (IVH) and periventricular leukomalacia (PVL). AUTHORS' CONCLUSIONS Early administration of ESAs reduces the use of red blood cell (RBC) transfusions, the volume of RBCs transfused, and donor exposure after study entry. Small reductions are likely to be of limited clinical importance. Donor exposure probably is not avoided, given that all but one study included infants who had received RBC transfusions before trial entry. This update found no significant difference in the rate of ROP (stage ≥ 3) for studies that initiated EPO treatment at less than eight days of age, which has been a topic of concern in earlier versions of this review. Early EPO treatment significantly decreased rates of IVH, PVL, and NEC. Neurodevelopmental outcomes at 18 to 22 months and later varied in published studies. Ongoing research should evaluate current clinical practices that will limit donor exposure. Promising but conflicting results related to the neuro protective effect of early EPO require further study. Very different results from the two largest published trials and high heterogeneity in the analyses indicate that we should wait for the results of two ongoing large trials before drawing firm conclusions. Administration of EPO is not currently recommended because limited benefits have been identified to date. Use of darbepoetin requires further study.
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Iron deficiency markers in patients undergoing iron replacement therapy: a 9-year retrospective real-world evidence study using healthcare databases.
Cacoub, P, Nicolas, G, Peoc'h, K
Scientific reports. 2020;(1):14983
Abstract
The diagnosis and treatment of iron deficiency is a primary public health goal. This study aimed to make an inventory of the use of biomarkers to assess the iron supply in patients given iron replacement therapy. A retrospective longitudinal real-world study of a cohort of patients receiving iron replacement therapy was conducted using data from healthcare coverage databases between January 2006 and December 2015 in France. The frequency of oral or intravenous iron treatment episodes preceded and/or followed by a biological assessment of iron deficiency was described. We then differentiate patients with or without chronic inflammatory diseases, which could impact the prescription. The evolution between 2006 and 2015 was also studied. The 96,724 patients received an average of 4.9 administrations of iron per patient, corresponding to 1.7 treatment episodes. In one-third of treatment episodes (34.6%), patients had a pre-treatment biological assessment, 15.5% a post-treatment assessment, and 7.3% both. The post-treatment measure of iron supply markers (i.e., Ferritin and transferrin saturation) was more frequent in patients suffering from chronic inflammatory diseases than in those without underlying chronic condition (22.6% to 41.0% vs. 3.1%; p < 0.0001). Serum ferritin was measured 30 times more than transferrin saturation measurements. The use of both tests increased steadily during the study period, although remaining low. Despite the recommendations, biological assessments of iron status are seldom prescribed and/or performed in the context of a pre- or post-treatment assessment, although more frequently realized in patients with chronic inflammatory diseases.
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Are prolyl-hydroxylase inhibitors potential alternative treatments for anaemia in patients with chronic kidney disease?
Locatelli, F, Del Vecchio, L
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2020;(6):926-932
Abstract
Prolyl-hydroxylase (PHD) inhibitors (PHD-I) are the most appealing drugs undergoing clinical development for the treatment of anaemia in patients with chronic kidney disease. PHD inhibition mimics the exposure of the body to hypoxia and activates the hypoxia-inducible factor system. Among many other pathways, this activation promotes the production of endogenous erythropoietin (EPO) and the absorption and mobilization of iron. PHD-I are given orally and, differing from erythropoiesis-stimulating agents (ESAs), they correct and maintain haemoglobin levels by stimulating endogenous EPO production. Their efficacy and safety are supported by several Phases I and II studies with relatively short follow-up. This class of drugs has the potential to have a better safety profile than ESAs and there may be additional advantages for cardiovascular disease (CVD), osteoporosis and metabolism. However, possible adverse outcomes are feared. These span from the worsening or occurrence of new cancer, to eye complications or pulmonary hypertension. The data from the ongoing Phase III studies are awaited to better clarify the long-term safety and possible advantages of PHD-I.
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Effect of Ferric Citrate versus Ferrous Sulfate on Iron and Phosphate Parameters in Patients with Iron Deficiency and CKD: A Randomized Trial.
Womack, R, Berru, F, Panwar, B, Gutiérrez, OM
Clinical journal of the American Society of Nephrology : CJASN. 2020;(9):1251-1258
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BACKGROUND AND OBJECTIVES Ferric citrate is an oral medication approved for treatment of iron deficiency anemia in patients with CKD not requiring dialysis. The relative efficacy of ferric citrate versus ferrous sulfate in treating iron deficiency in patients with CKD is unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We randomized 60 adults with moderate to severe CKD (eGFR 15-45 ml/min per 1.73 m2) and iron deficiency (transferrin saturation [TSAT] ≤30% and ferritin ≤300 ng/ml) to ferric citrate (2 g three times a day with meals, n=30) or ferrous sulfate (325 mg three times a day, n=30) for 12 weeks. Primary outcomes were change in TSAT and ferritin from baseline to 12 weeks. Secondary outcomes were change in hemoglobin, fibroblast growth factor 23 (FGF23), and hepcidin. RESULTS Baseline characteristics were well balanced between study arms. There was a greater increase in TSAT (between-group difference in mean change, 8%; 95% confidence interval [95% CI], 1 to 15; P=0.02) and ferritin (between-group difference in mean change, 37 ng/ml; 95% CI, 10 to 64; P=0.009) from baseline to 12 weeks in participants randomized to ferric citrate as compared with ferrous sulfate. Similarly, as compared with ferrous sulfate, treatment with ferric citrate resulted in a greater increase in hepcidin from baseline to 12 weeks (between-group difference, 69 pg/ml; 95% CI, 8 to 130). There were no between-group differences in mean change for hemoglobin (0.3 g/dl; 95% CI, -0.2 to 0.8), intact FGF23 (-29 pg/ml; 95% CI, -59 to 0.1), or C-terminal FGF23 (61 RU/ml; 95% CI, -181 to 58). The incidence of adverse events did not differ between treatment arms. CONCLUSIONS As compared with ferrous sulfate, treatment with ferric citrate for 12 weeks resulted in a greater mean increase in TSAT and ferritin concentrations in individuals with moderate to severe CKD and iron deficiency. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER Impact of Ferric Citrate vs Ferrous Sulfate on Iron Parameters and Hemoglobin in Individuals With Moderate to Severe Chronic Kidney Disease (CKD) With Iron Deficiency, NCT02888171.
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Effect of iron chelation therapy on EPO-STAT5 signalling pathway and EPO resistance in iron-overloaded low-risk myelodysplastic syndrome patients.
Zhang, Y
Hematology (Amsterdam, Netherlands). 2020;(1):1-10
Abstract
Objectives: Background/aims: We aim to explore low-risk MDS patients' ESA response and the difference between iron-overloaded (IO) group and the control group in the expression of SOCS1, STAT5 and BCL2L1 which play a key role to EPO-STAT5 signal pathway.Methods: 56 low-risk MDS patients were divided into experimental group, IO patients; control group, non-IO patients. Among experimental group, 28 IO patients were treated with iron chelation therapy (ICT). SOCS1, phosphorylated STAT5 (p-STAT5) and BCL2L1 protein concentration in bone marrow supernatant have been analyzed by ELISA, STAT5a+b protein concentration in bone marrow mononuclear cells (BMMC) have been analyzed by Western blot, and mRNA expression of them have been detected in BMMC by RQ-PCR. The percentage of CD71+ cells in BMMC, apoptotic rate of CD71+ cells and ROS expression in CD71+ cells were detected by Flow cytometry.Results: Compared with the control group, the sEPO concentration, the efficacy of ESA and the expression of SOCS1, apoptotic rates of CD71+ cells and ROS expression in CD71+ cells in IO group were increased, the expression of STAT5 and BCL2L1 was reduced. Interestingly, after receiving ICT, some patients with EPO resistance have responded again to ESA treatment, with the decrease of the expression of SOCS1, apoptotic rates of CD71+ cells, ROS expression in CD71+ cells and the increase of the expression of STAT5 and BCL2L1.Conclusion: Iron overload can increase EPO resistance and the expression of SOCS1, inhibit the expression of STAT5 and BCL2L1. ICT could allivation of EPO resistance.
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Effect of hypoxia-inducible factor-prolyl hydroxylase inhibitors on anemia in patients with CKD: a meta-analysis of randomized controlled trials including 2804 patients.
Wang, B, Yin, Q, Han, YC, Wu, M, Li, ZL, Tu, Y, Zhou, LT, Wei, Q, Liu, H, Tang, RN, et al
Renal failure. 2020;(1):912-925
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Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) are orally active first-in-class new generation drugs for renal anemia. This extensive meta-analysis of randomized controlled trials (RCTs) was designed to provide clear information on the efficacy and safety of HIF-PHIs on anemia in chronic kidney disease (CKD) patients. Searches included PubMed, Web of Science, Ovid MEDLINE, and Cochrane Library database up to October 2019. RCTs of patients with CKD comparing HIF-PHIs with erythropoiesis-stimulating agents (ESAs) or placebo in the treatment of anemia. The primary outcome was hemoglobin change from baseline (Hb CFB); the secondary outcomes included iron-related parameters and the occurrence of each adverse event. 26 trials in 17 articles were included, with a total of 2804 dialysis or patients with CKD. HIF-PHIs treatment produced a significant beneficial effect on Hb CFB compared with the placebo group (MD, 0.69; 95% CI, 0.36 to 1.02). However, this favored effect of HIF-PHIs treatment was not observed in subgroup analysis among trials compared with ESAs (MD, 0.06; 95% CI, -0.20 to 0.31). The significant reduction in hepcidin by HIF-PHIs was observed in all subgroups when compared with the placebo group, whereas this effect was observed only in NDD-CKD patients when compared with ESAs. HIF-PHIs increased the risk of nausea (RR, 2.20; 95% CI, 1.06 to 4.53) and diarrhea (RR, 1.75; 95% CI, 1.06 to 2.92). We conclude that orally given HIF-PHIs are at least as efficacious as ESAs treatment to correct anemia short term in patients with CKD. In addition, HIF-PHIs improved iron metabolism and utilization in patients with CKD.
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Evolution of Treatment for Anemia in Chronic Kidney Disease.
Vaught, K, Kerber, S
Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation. 2020;(5):e67-e70
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Iron Sucrose: A Wealth of Experience in Treating Iron Deficiency.
Macdougall, IC, Comin-Colet, J, Breymann, C, Spahn, DR, Koutroubakis, IE
Advances in therapy. 2020;(5):1960-2002
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Iron deficiency and iron-deficiency anemia are associated with increased morbidity and mortality in a wide range of conditions. In many patient populations, this can be treated effectively with oral iron supplementation; but in patients who are unable to take or who do not respond to oral iron therapy, intravenous iron administration is recommended. Furthermore, in certain conditions, such as end-stage kidney disease, chronic heart failure, and inflammatory bowel disease, intravenous iron administration has become first-line treatment. One of the first available intravenous iron preparations is iron sucrose (Venofer®), a nanomedicine that has been used clinically since 1949. Treatment with iron sucrose is particularly beneficial owing to its ability to rapidly increase hemoglobin, ferritin, and transferrin saturation levels, with an acceptable safety profile. Recently, important new data relating to the use of iron sucrose, including the findings from the landmark PIVOTAL trial in patients with end-stage kidney disease, have been reported. Several years ago, a number of iron sucrose similars became available, although there have been concerns about the clinical appropriateness of substituting the original iron sucrose with an iron sucrose similar because of differences in efficacy and safety. This is a result of the complex and unique physicochemical properties of nanomedicines such as iron sucrose, which make copying the molecule difficult and problematic. In this review, we summarize the evidence accumulated during 70 years of clinical experience with iron sucrose in terms of efficacy, safety, and cost-effectiveness.
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In Search of Predictors of Switching Between Erythropoiesis-Stimulating Agents in Clinical Practice: A Multi-Regional Cohort Study.
Ingrasciotta, Y, Belleudi, V, Trotta, F, Addis, A, Fontana, A, Chinellato, A, Ientile, V, Tari, DU, Roberto, G, Pastorello, M, et al
BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy. 2020;(1):55-64
Abstract
BACKGROUND AND OBJECTIVES Switching between different erythropoiesis-stimulating agents (ESAs) during the first year of therapy is frequent (15-20%), much more so toward reference products than biosimilars. The objectives of this study were to investigate the frequency and identify the potential predictors of switching between biosimilar and originator ESAs during the first year of treatment in patients with chronic kidney disease (CKD), or chemotherapy-related anemia from six large Italian geographic areas in the years 2009-2015. METHODS A retrospective cohort study was conducted using six Italian regional claims databases (≥ 13 million inhabitants) during 2009-2015. Among incident epoetin users, the frequency of single, multiple, and backward switch during the first year of treatment was evaluated. Using frailty Cox models, potential predictors of first switch were identified. All analyses were stratified by the main indications for use. RESULTS Among 102,240 incident epoetin users, 15,853 (15.5%) switched to another epoetin during the first year of therapy; only 18% of these switched to biosimilars. Single switch was more common (62.2% of the switchers) than multiple (23.5%) or backward switch (14.3%). In cancer, the cumulative number of transfusions and iron preparations dispensed, as well as hyperparathyroidism, were predictors of switching. In CKD, the cumulative number of transfusions, number of vitamin A/D preparations dispensed, and CKD severity increased the probability of switching. CONCLUSIONS Switching between ESAs was frequent in both CKD and cancer patients. The number of cumulative transfusions and severity of disease seemed to affect the switch.
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Medium cut-off dialyzer improves erythropoiesis stimulating agent resistance in a hepcidin-independent manner in maintenance hemodialysis patients: results from a randomized controlled trial.
Lim, JH, Jeon, Y, Yook, JM, Choi, SY, Jung, HY, Choi, JY, Park, SH, Kim, CD, Kim, YL, Cho, JH
Scientific reports. 2020;(1):16062
Abstract
The response to erythropoiesis stimulating agents (ESAs) is affected by inflammation linked to middle molecules in hemodialysis (HD) patients. We evaluated the effect of a medium cut-off (MCO) dialyzer on ESA resistance in maintenance HD patients. Forty-nine patients who underwent high-flux HD were randomly allocated to the MCO or high-flux group. The primary outcome was the changes of erythropoietin resistance index (ERI; U/kg/wk/g/dL) between baseline and 12 weeks. The MCO group showed significant decrease in the ESA dose, weight-adjusted ESA dose, and ERI compared to the high-flux group at 12 weeks (p < 0.05). The generalized estimating equation models revealed significant interactions between groups and time for the ESA dose, weight-adjusted ESA dose, and ERI (p < 0.05). Serum iron and transferrin saturation were higher in the MCO group at 12 weeks (p < 0.05). The MCO group showed a greater reduction in TNF-α and lower serum TNF-α level at 12 weeks compared to the high-flux group (p < 0.05), whereas no differences were found in the reduction ratio of hepcidin and serum levels of erythropoietin, erythroferrone, soluble transferrin receptor and hepcidin between groups. HD with MCO dialyzer improves ESA resistance over time compared to high-flux HD in maintenance HD patients. The MCO dialyzer provides superior removal of the inflammatory cytokine and thus improves iron metabolism in a hepcidin-independent manner.