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Frontiers in Pharmacology 2023: The comparative benefits and acceptability of HIF-PHIs for treating anemia have not been well researched to date. We sought to compare the effectiveness of 6 HIF-PHIs...
Comparative effectiveness and acceptability of HIF prolyl-hydroxylase inhibitors for anemia patients with chronic kidney disease undergoing dialysis: a systematic review and network meta-analysis.
: The comparative benefits and acceptability of HIF-PHIs for treating anemia have not been well researched to date. We sought to compare the effectiveness of 6 HIF-PHIs and 3 ESAs for the treatment of renal anemia patients undergoing dialysis. Cochrane Central Register of Controlled Trials, PubMed, Embase, Cochrane Library, MEDLINE, Web of Science, and clinicaltrials.gov databases. Twenty-five RCTs (involving 17,204 participants) were included, all of which were designed to achieve target Hb levels by adjusting thee dose of HIF-PHIs. Regarding the efficacy in achieving target Hb levels, no significant differences were found between HIF-PHIs and ESAs in Hb response at the dose-adjusted designed RCTs selected for comparison. Intervention with roxadustat showed a significantly lower risk of RBC transfusion than rhEPO, with an OR and 95% CI of 0.76 (0.56-0.93). Roxadustat and vadadustat had higher risks of increasing the discontinuation rate than ESAs; the former had ORs and 95% CIs of 1.58 (95% CI: 1.21-2.06) for rhEPO, 1.66 (1.16-2.38) for DPO (darbepoetin alfa), and 1.76 (1.70-4.49) for MPG-EPO, and the latter had ORs and 95% CIs of 1.71 (1.09-2.67) for rhEPO, 1.79 (1.29-2.49) for DPO, and 2.97 (1.62-5.46) for MPG-EPO. No differences were observed in the AEs and SAEs among patients who received the studied drugs. Results of a meta-analysis of gastrointestinal disorders among AEs revealed that vadadustat was less effect on causing diarrea than DPO, with an OR of 0.97 (95% CI, 0.9-0.99). Included HIF-PHIs, were proven to be more effective than ESAs in reducing hepcidin levels and increasing TIBC and serum iron level with OR of -0.17 (95% CI, -0.21 to -0.12), OR of 0.79 (95% CI, 0.63-0.95), and OR of 0.39 (95% CI, 0.33-0.45), respectively. HIF-PHIs and ESAs have their characteristics and advantages in treating anemia undergoing dialysis. With the selected dose-adjusted mode, some HIF-PHIs appeared to be a potential treatment for DD-CKD patients when ompared with rhEPO, due to its effectiveness in decreasing the risk of RBC transfusion rate or regulating iron or lipid metabolism while achieving target Hb levels. https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=306511; Identifier: CRD42022306511.
PubMed: 37521459
DOI: 10.3389/fphar.2023.1050412 -
Journal of Pharmaceutical and... Sep 2023Glycosylation is a crucial attribute for biotherapeutics with significant impacts on quality, stability, safety, immunogenicity, pharmacokinetics, and efficacy.... (Review)
Review
Glycosylation is a crucial attribute for biotherapeutics with significant impacts on quality, stability, safety, immunogenicity, pharmacokinetics, and efficacy. Therefore, to ensure consistent glycosylation, a systematic review of biotherapeutics is absolutely required including the variable glycan structure (micro-heterogeneity) and different occupancy at individual site (macro-heterogeneity) from drug design to upstream and downstream bioprocesses. Various methods have been used for glyco-characterization of biotherapeutics at the glycan, glycopeptide, and intact protein levels. In particular, intact protein analysis is considered a facile and rapid glycoform monitoring approach used throughout the product development lifecycle to determine suitable glycosylation lead candidates and reproducible product quality. However, intact glycoform characterization of diverse and complex biotherapeutics with multiple N- and O-glycosylation sites can be very challenging. To address this, a robust analytical platform that enables rapid and accurate characterization of a biotherapeutics with highly complex multiple glycosylation using two-step intact glycoform mass spectrometry has been developed. We used darbepoetin alfa, a second-generation EPO bearing multiple N- and O-glycosylation sites, as a model biotherapeutics to obtain integrated information on glycan heterogeneity and site occupancy through step-by-step MS of intact protein and enzyme-treated protein. In addition, we performed a comparative assessment of the heterogeneity from different products, confirming that our new method can efficiently evaluate glycosylation equivalence. This new strategy provides rapid and accurate information on the degree of glycosylation of a therapeutic glycoprotein with multiple glycosylation, which can be used to assess glycosylation similarity between batches and between biosimilar and reference during development and production.
Topics: Glycosylation; Darbepoetin alfa; Mass Spectrometry; Proteins; Polysaccharides
PubMed: 37393692
DOI: 10.1016/j.jpba.2023.115558 -
Indian Journal of Pediatrics Mar 2024Neonatal hypoxic-ischemic encephalopathy is a major cause of perinatal death and neurodevelopmental impairment (NDI). Hypothermia (HT) is the standard of care; however,... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
Neonatal hypoxic-ischemic encephalopathy is a major cause of perinatal death and neurodevelopmental impairment (NDI). Hypothermia (HT) is the standard of care; however, additional neuroprotective agents are required to improve prognosis. The authors searched for all drugs in combination with HT and compared their effects using a network meta-analysis.
METHODS
The authors searched PubMed, Embase, and Cochrane Library until September 24, 2022 for articles assessing mortality, NDI, seizures, and abnormal brain imaging findings in neonates with hypoxic-ischemic encephalopathy. Direct pairwise comparisons and a network meta-analysis was performed under random effects.
RESULTS
Thirteen randomized clinical trials enroled 902 newborns treated with six combination therapies: erythropoietin magnesium sulfate, melatonin (MT), topiramate, xenon, and darbepoetin alfa. The results of all comparisons were not statistically significant, except for NDI, HT vs. MT+HT: odds ratio = 6.67, 95% confidence interval = 1.14-38.83; however, the overall evidence quality was low for the small sample size.
CONCLUSIONS
Currently, no combination therapy can reduce mortality, seizures, or abnormal brain imaging findings in neonatal hypoxic-ischemic encephalopathy. According to low quality evidence, HT combined with MT may reduce NDI.
Topics: Infant, Newborn; Humans; Hypoxia-Ischemia, Brain; Hypothermia; Network Meta-Analysis; Hypothermia, Induced; Seizures
PubMed: 37199820
DOI: 10.1007/s12098-023-04563-3 -
The Cochrane Database of Systematic... Feb 2023Erythropoiesis-stimulating agents (ESAs) are commonly used to treat anaemia in people with chronic kidney disease (CKD). However, their use has been associated with... (Meta-Analysis)
Meta-Analysis Review
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.
Topics: Adult; Humans; Hematinics; Epoetin Alfa; Darbepoetin alfa; Biosimilar Pharmaceuticals; Network Meta-Analysis; Erythropoiesis; Anemia; Renal Insufficiency, Chronic; Hypertension; Thrombosis; Dyspnea; Myocardial Infarction
PubMed: 36791280
DOI: 10.1002/14651858.CD010590.pub3 -
Frontiers in Pharmacology 2021Vadadustat is a novel drug for treating anemia patients with chronic kidney disease (CKD), but its effect and safety remain uncertain. This study aimed to summarize the... (Review)
Review
Vadadustat is a novel drug for treating anemia patients with chronic kidney disease (CKD), but its effect and safety remain uncertain. This study aimed to summarize the evidence for vadadustat in the treatment of CKD patients with anemia. PubMed, Ovid Medline, Embase, Cochrane CENTRAL, Wanfang Data, China National Knowledge Infrastructure and an international trial register were searched from their inception to June 2021 for randomized controlled trials (RCTs) comparing the efficacy and safety of vadadustat to those of placebo or erythropoiesis-stimulating agents (ESAs) in treating anemia in CKD patients. Data were pooled in a meta-analysis, with results expressed as the mean difference for continuous outcomes and relative risk for categorical outcomes with 95% confidence intervals (95% CIs). The certainty of evidence was rated according to Cochrane methods and the GRADE approach. Ten RCTs comparing vadadustat with placebo (4 RCTs) or darbepoetin alfa (6 RCTs) were included ( = 8,438 participants). Compared with placebo, vadadustat increased the hemoglobin (Hb) response rate (risk ratio 5.27; 95% CI: 2.69 to 10.31; < 0.001; high certainty of evidence) and Hb level from baseline (∆Hb) (mean difference (MD) 1.28; 95% CI: 0.83 to 1.73; < 0.001; low certainty of evidence). Compared with placebo or darbepoetin alfa, vadadustat decreased hepcidin (MD -36.62; 95% CI: -54.95 to -18.30; < 0.001) and ferritin (MD -56.24; 95% CI: -77.37 to -35.11; < 0.001) levels and increased iron-binding capacity (MD 24.38; 95% CI: 13.69 to 35.07; < 0.001), with a low to moderate certainty of evidence. Moderate to high certainty evidence suggested that compared with placebo or darbepoetin alfa, vadadustat significantly increased the risk of nausea and diarrhea but did not significantly increase the risk of serious adverse events, especially all-cause mortality, cardiac events and nonfatal stroke. Vadadustat may safely improve Hb levels and promote iron utilization in CKD patients with anemia without increasing the incidence of serious adverse events.
PubMed: 35115942
DOI: 10.3389/fphar.2021.795214 -
Frontiers in Pharmacology 2021Roxadustat is a new oral drug for anemia in chronic kidney disease (CKD). This study aimed to synthesize the evidence from randomized controlled trial (RCT)-based...
Roxadustat is a new oral drug for anemia in chronic kidney disease (CKD). This study aimed to synthesize the evidence from randomized controlled trial (RCT)-based studies that estimated the efficacy and safety of roxadustat in anemia patients with non-dialysis-dependent (NDD) and dialysis-dependent (DD) CKD. We searched the PubMed, Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL) databases for related published studies. Moreover, we manually searched relevant pharmaceutical company websites and two international clinical trial registers to search for published and unpublished RCTs comparing roxadustat with erythropoietin-stimulating agents (ESAs) or placebo. Fifteen RCTs (seven for DD-CKD patients, eight for NDD-CKD patients) were included in the meta-analysis, with 10,189 patients, 4,810 DD-CKD patients, and 5,379 NDD-CKD patients enrolled. Compared with ESAs (epoetin alfa or darbepoetin alfa) and placebo, roxadustat raised the hemoglobin level [weighted mean difference (WMD): 0.82 g/dL; 95% confidence interval (CI): 0.43-1.21], transferrin level (WMD: 0.5 g/L; 95% CI: 0.34-0.65), and TIBC level (WMD: 41.79 μg/dL; 95% CI: 38.67-44.92) and lowered the hepcidin level (WMD: -37.38 ng/ml; 95% CI: -46.63- -28.12) in both the DD-CKD and NDD-CKD patients with renal anemia. Roxadustat improved hemoglobin response and lowered the ferritin and TAST levels in the NDD-CKD patients but not in the DD-CKD patients. Furthermore, there was no difference between the treatment-emergent adverse events (TEAEs) of roxadustat and that of ESAs or placebo. But the incidence of serious TEAEs in the roxadustat group was significantly higher with NDD-CKD patients (OR: 1.15; 95% CI: 1.02-1.29). This study confirmed that roxadustat therapy could alleviate the anemia of DD-CKD and NDD-CKD patients by raising the hemoglobin level and regulating iron metabolism, but increased serious incidences of treatment-emergent adverse events (TEAEs) in NDD-CKD patients.
PubMed: 34276361
DOI: 10.3389/fphar.2021.658079 -
Journal of the College of Physicians... Mar 2020The impact of erythropoiesis stimulating agents (ESAs) on clinical outcomes among breast cancer patients is debatable. Current review is aimed to ascertain the efficacy...
The impact of erythropoiesis stimulating agents (ESAs) on clinical outcomes among breast cancer patients is debatable. Current review is aimed to ascertain the efficacy of ESAs among breast cancer patients. Randomised controlled trials (RCTs) were electronically searched. Primary outcomes were mortality, blood transfusion requirements and thromboembolic events (TEEs); whereas, secondary outcomes were safety, tumor progression, anemia treatment, hemoglobin levels and quality of life (QOL). Out of 11 RCTs including 6,849 participants, 9 RCTs reported 2,312 deaths with overall mortality of 33.7%. Mortality reported for epoetin alfa (EA), epoetin beta (EB) and darbepoetin alfa (DA) was 41.24%, 73.1% and 8.99% respectively. TEEs reported for EA, EB and DA were 5.88%, 9.28% and 2.85%, respectively. Serious adverse events were 39.04%, 36.29%, 1.53% for EA, EB and DA, respectively. Tumor progression for EA and EB was 37.53% and 95.46%, respectively. No tumor progression was reported with DA. Erythropoietin reported no mortality, TEEs, serious ADRs and tumor progression. About 9% patients required transfusions during ESA therapy. Current evidence suggests that use of ESA reduces transfusion need but increases mortality and risks of TEEs.
Topics: Breast Neoplasms; Female; Hematinics; Humans; Outcome Assessment, Health Care
PubMed: 32169139
DOI: 10.29271/jcpsp.2020.03.292 -
British Journal of Haematology Jan 2019Many patients with lower-risk myelodysplastic syndrome (MDS) experience anaemia, which has negative consequences. Erythropoiesis-stimulating agents (ESAs) and their... (Review)
Review
Clinical effectiveness and safety of erythropoietin-stimulating agents for the treatment of low- and intermediate-1-risk myelodysplastic syndrome: a systematic literature review.
Many patients with lower-risk myelodysplastic syndrome (MDS) experience anaemia, which has negative consequences. Erythropoiesis-stimulating agents (ESAs) and their biosimilars are used to treat anaemia in MDS and, currently, epoetin alfa and darbepoetin alfa are commonly used and recommended by clinical guidelines. To better understand the evidence available on the use of ESAs for anaemia in lower-risk MDS, we conducted a systematic literature review to identify randomized and nonrandomized prospective studies reporting on clinical efficacy/effectiveness, patient-reported quality of life (QoL), and safety. We extended our review to include retrospective studies for darbepoetin alfa specifically and to ascertain the feasibility of completing an indirect network meta-analysis comparing epoetin and darbepoetin alfa. Overall, 53 articles reporting on 35 studies were included. The studies indicated a clinical benefit of ESAs, with benefits observed across key clinical outcomes. ESAs showed consistent improvement in erythroid response rates (ESA-naïve, 45-73%; previous ESA exposure, 25-75%) and duration of response. Comparative studies demonstrated similar progression to acute myeloid leukaemia and several showed improved overall survival and QoL. Limited safety concerns were identified. This analysis confirmed ESA therapy should be the foremost first-line treatment of anaemia in most patients with lower-risk MDS who lack the 5q deletion.
Topics: Biosimilar Pharmaceuticals; Darbepoetin alfa; Epoetin Alfa; Hematinics; Humans; Myelodysplastic Syndromes; Prospective Studies; Quality of Life; Randomized Controlled Trials as Topic
PubMed: 30549002
DOI: 10.1111/bjh.15707 -
The Cochrane Database of Systematic... Nov 2017Preterm infants have low plasma levels of erythropoietin (EPO), providing a rationale for the use of erythropoiesis-stimulating agents (ESAs) to prevent or treat anaemia... (Meta-Analysis)
Meta-Analysis Review
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; I = 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; I = 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. I = 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; I = 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; I = 0% (no heterogeneity) for RR; I = 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 darepoetin requires further study.
Topics: Anemia, Neonatal; Darbepoetin alfa; Enterocolitis, Necrotizing; Erythrocyte Transfusion; Erythropoietin; Hematinics; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Retinopathy of Prematurity
PubMed: 29145693
DOI: 10.1002/14651858.CD004863.pub5 -
The Cochrane Database of Systematic... Aug 2017Continuous erythropoiesis receptor activator (CERA) is a newer, longer acting ESA which might be preferred to other ESAs (epoetin or darbepoetin) based on its lower... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Continuous erythropoiesis receptor activator (CERA) is a newer, longer acting ESA which might be preferred to other ESAs (epoetin or darbepoetin) based on its lower frequency of administration. Different dosing requirements and molecular characteristics of CERA compared with other ESAs may lead to different health outcomes (mortality, cardiovascular events, quality of life) in people with anaemia and chronic kidney disease (CKD).
OBJECTIVES
To assess benefits and harms of CERA compared with other epoetins (darbepoetin alfa and epoetin alfa or beta) or placebo/no treatment or CERA with differing strategy of administration for anaemia in individuals with CKD.
SEARCH METHODS
We searched the Cochrane Kidney and Transplant Specialised Register to 13 June 2017 through contact with the Information Specialist using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE, and EMBASE; handsearching conference proceedings; and searching the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) of at least three months' duration, comparing CERA with a different ESA (darbepoetin alfa or epoetin alfa or beta) or placebo or standard care or versus CERA with different strategies for administration in people with any stage of CKD.
DATA COLLECTION AND ANALYSIS
Data were extracted by two independent investigators. We summarised patient-centred outcomes (all-cause and cardiovascular mortality, major adverse cardiovascular events, red cell blood transfusion, iron therapy, cancer, hypertension, seizures, dialysis vascular access thrombosis, drug injection-related events, hyperkalaemia and health-related quality of life and haemoglobin levels) using random effects meta-analysis. Treatment estimates were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean differences or standardized mean difference with 95% CI for continuous outcomes.
MAIN RESULTS
We included 27 studies involving 5410 adults with CKD. Seven studies (1273 participants) involved people not requiring dialysis, 19 studies (4209 participants) involved people treated with dialysis and one study (71 participants) evaluated treatment in recipients of a kidney transplant. Treatment was given for 24 weeks on average. No data were available for children with CKD. Studies were generally at high or unclear risk of bias from allocation concealment and blinding of outcomes. Only two studies masked participants and investigators to treatment allocation. One study compared CERA with placebo, nine studies CERA with epoetin alfa or beta, nine studies CERA with darbepoetin alfa, and two studies compared CERA with epoetin alfa or beta and darbepoetin alfa. Three studies assessed the effects of differing frequencies of CERA administration and five assessed differing CERA doses.There was low certainty evidence that CERA had little or no effects on mortality (RR 1.07, 95% CI 0.73 to 1.57; RR 1.11, 95% CI 0.75 to 1.65), major adverse cardiovascular events (RR 5.09, 95% CI 0.25 to 105.23; RR 5.56, 95% CI 0.99 to 31.30), hypertension (RR 1.01, 95% CI 0.75 to 1.37; RR 1.00, 95% CI 0.79 to 1.28), need for blood transfusion (RR 1.02, 95% CI 0.72 to 1.46; RR 0.94, 95% CI 0.55 to 1.61), or additional iron therapy (RR 1.03, 95% CI 0.91 to 1.15; RR 0.99, 95% CI 0.95 to 1.03) compared to epoetin alfa/beta or darbepoetin alfa respectively. There was insufficient evidence to compare the effect of CERA to placebo on clinical outcomes. Only one low quality study reported that CERA compared to placebo might lead to little or no difference in the risk of major cardiovascular events (RR 2.97, 95% CI 0.31 to 28.18) and hypertension ((RR 0.73, 95% CI 0.35 to 1.52). There was low certainty evidence that different doses (higher versus lower) or frequency (twice versus once monthly) of CERA administration had little or no different effect on all-cause mortality (RR 3.95, 95% CI 0.17 to 91.61; RR 0.97, 95% CI 0.56 to 1.66), hypertension (RR 0.45, 95% CI 0.08 to 2.52; RR 0.85, 95% CI 0.60 to 1.21), and blood cell transfusions (RR 4.16, 95% CI 0.89 to 19.53; RR 0.91, 95% CI 0.51 to 1.62). No studies reported comparative treatment effects of different ESAs on health-related quality of life.
AUTHORS' CONCLUSIONS
There is low certainty evidence that CERA has little or no effects on patient-centred outcomes compared with placebo, epoetin alfa or beta or darbepoetin alfa for adults with CKD. The effects of CERA among children who have CKD have not studied in RCTs.
Topics: Adult; Aged; Anemia; Cardiovascular Diseases; Cause of Death; Darbepoetin alfa; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Humans; Hypertension; Middle Aged; Polyethylene Glycols; Publication Bias; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Thrombosis
PubMed: 28782299
DOI: 10.1002/14651858.CD009904.pub2