Erythropoietin stimulating agents as replacement therapy for blood transfusions in critically ill patients with anaemia: A systematic review with meta-analysis
Transfusion medicine (Oxford, England). 2020
OBJECTIVES The primary objectives of this meta-analysis in critically ill adult patients admitted to the intensive care unit (ICU) were to analyse whether erythropoiesis-stimulating agents (ESAs) reduced the number of patients receiving red blood cell (RBC) transfusion and resulted in a change in haemoglobin (Hb) concentration. Our secondary objectives were adverse events and mortality. BACKGROUND Anaemia is common in ICU patients, and currently, the standard therapy is RBC transfusion, which is known to be associated with adverse events. ESA could potentially reduce the need for RBC transfusion. METHODS EMBASE, Cochrane and PubMed were searched up to January 2020. RESULTS A total of 1357 articles were identified, of which 18 articles met the inclusion criteria for the qualitative synthesis. Eight of these studies were used in the meta-analyses. Comparing ESA vs control group, there was a small reduction in the proportion of patients who received one or more RBC transfusions (relative risk [RR] 0.88; confidence interval [CI] 0.78-1.00, moderate certainty). The change in Hb concentration was trivial (mean difference -0.31 g/dL; CI -0.51 to -0.05, high certainty). The number of serious adverse events (RR 1.02; 0.90-1.15, low certainty) and the overall short-term mortality were similar (RR 0.80; CI 0.61-1.05, low certainty) between the groups. CONCLUSION ESA resulted in a small reduction in the proportion of patients transfused and a trivial increase in haemoglobin concentration, both of questionable clinical relevance, without impacting adverse events or mortality. These results do not support the routine use of ESA to treat anaemia in critically ill adults.
Management and prevention of anemia (acute bleeding excluded) in adult critical care patients
Ann Intensive Care. 2020;10(1):97
OBJECTIVE Anemia is very common in critical care patients, on admission (affecting about two-thirds of patients), but also during and after their stay, due to repeated blood loss, the effects of inflammation on erythropoiesis, a decreased red blood cell life span, and haemodilution. Anemia is associated with severity of illness and length of stay. METHODS A committee composed of 16 experts from four scientific societies, SFAR, SRLF, SFTS and SFVTT, evaluated three fields: (1) anemia prevention, (2) transfusion strategies and (3) non-transfusion treatment of anemia. Population, Intervention, Comparison, and Outcome (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Analysis of the literature and formulation of recommendations were then conducted according to the GRADE(®) methodology. RESULTS The SFAR-SRLF guideline panel provided ten statements concerning the management of anemia in adult critical care patients. Acute haemorrhage and chronic anemia were excluded from the scope of these recommendations. After two rounds of discussion and various amendments, a strong consensus was reached for ten recommendations. Three of these recommendations had a high level of evidence (GRADE 1±) and four had a low level of evidence (GRADE 2±). No GRADE recommendation could be provided for two questions in the absence of strong consensus. CONCLUSIONS The experts reached a substantial consensus for several strong recommendations for optimal patient management. The experts recommended phlebotomy reduction strategies, restrictive red blood cell transfusion and a single-unit transfusion policy, the use of red blood cells regardless of storage time, treatment of anaemic patients with erythropoietin, especially after trauma, in the absence of contraindications and avoidance of iron therapy (except in the context of erythropoietin therapy).
Safety and efficacy of erythropoiesis-stimulating agents in critically ill patients admitted to the intensive care unit: a systematic review and meta-analysis
Intensive care medicine. 2019
PURPOSE Severe immune dysregulation is common in patients admitted to the intensive care unit (ICU) and is associated with adverse outcomes. Erythropoietin-stimulating agents (ESAs) have immune-modulating and anti-apoptotic effects. However, their safety and efficacy in critically ill patients remain uncertain. We evaluated whether ESAs, administered to critically unwell adult patients admitted to the ICU, reduced mortality at hospital discharge. METHODS The search strategy was conducted according to a predetermined protocol and included OVID MEDLINE, OVID EMBASE and The Cochrane Central Register of Controlled Trials from inception until 20 May 2019. Publications were eligible for inclusion if they were randomized controlled trials (RCTs) including adult patients admitted to an ICU, that identified and reported a group receiving ESA therapy compared to a group not receiving ESA therapy and reported mortality. There were no language restrictions. RESULTS The systematic review included 21 studies with 5452 participants. In-hospital mortality, reported in 16 studies of which only one was at low risk of bias, was lower in the ESA group (276 of 2187 patients, 12.6%) than the comparator group (339 out of 2204 patients, 15.4%), [relative risk (RR) 0.82, 95% CI 0.71-0.94, P = 0.006, I(2) = 0.0%]. The RR of SAEs and thromboembolic events for the ESA and comparator groups were similar, RR 1.11 (95% CI 0.94-1.31, P = 0.228, I(2) 66%) and 1.22 (95% CI 0.95-1.58, P = 0.086, I(2) 47%), respectively. CONCLUSIONS In heterogenous populations of critically ill adults, evidence from RCTs of mainly low or unclear quality, suggests that ESA therapy may decrease mortality.
Clinical outcomes related to the gastrointestinal trophic effects of erythropoietin in preterm neonates: a systematic review and meta-analysis
Advances in Nutrition (Bethesda, Md.). 2018;9((3)):238-246.
Erythropoietin (EPO) plays an important role in the development and maturation of the gastrointestinal tract. Recombinant EPO (rEPO) has been used to prevent anemia of prematurity. The gastrointestinal trophic effects of EPO may reduce feeding intolerance and necrotizing enterocolitis (NEC) in preterm neonates. The aim of this systematic review of randomized controlled trials (RCTs) was to evaluate the effects of rEPO on clinical outcomes such as feeding intolerance, stage II or higher NEC, any stage NEC, sepsis, retinopathy of prematurity, and bronchopulmonary dysplasia in preterm neonates. Twenty-five RCTs (intravenous: 13; subcutaneous: 10; enteral: 2; n = 4025) were eligible for inclusion. Meta-analysis of data from 17 RCTs (rEPO compared with placebo) with the use of a fixed-effects model showed no significant effect of rEPO on stage II or higher NEC (RR: 0.87; 95% CI: 0.64, 1.19; P = 0.39). Meta-analysis of data from 25 RCTs (rEPO compared with placebo) showed that rEPO significantly decreased the risk of any stage NEC [cases/total sample: 120/2058 (5.83%) compared with 146/1967 (7.42%); RR: 0.77; 95% CI: 0.61, 0.97; P = 0.03]. Only one RCT reported on time to full feedings. Meta-analysis of data from 15 RCTs showed a significant reduction in late-onset sepsis after rEPO administration (RR: 0.81; 95% CI: 0.71, 0.94; P = 0.004). Meta-analysis of 13 RCTs showed no significant effect of rEPO on mortality, retinopathy of prematurity, and bronchopulmonary dysplasia. Prophylactic rEPO had no effect on stage II or higher NEC, but it reduced any stage NEC, probably by reducing feeding intolerance, which is often labeled as stage I NEC. Adequately powered RCTs are required to confirm these findings.
Early erythropoiesis-stimulating agents in preterm or low birth weight infants
The Cochrane Database of Systematic Reviews. 2017;((11)):CD004863.
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 E
Recombinant human erythropoietin in neonates: guidelines for clinical practice from the French Society of Neonatology . French
Archives de Pediatrie. 2015;22((10)):1092-7.
OBJECTIVE 1/To assess the effectiveness and safety of EPO in reducing red blood cell (RBC) transfusions in preterm infants. 2/To provide guidelines for clinical practice in France. METHODS 1/This systematic evidence review is based on PubMed search, Cochrane library. 2/Using French National Authority for Health methods concerning guidelines for clinical practice. RESULTS Early EPO reduced the risk of RBC transfusions, donor exposure, and the number of transfusions in very preterm infants (LE2). Late EPO reduced the risk of RBC transfusions and the number of transfusions in very preterm infants (LE2). There is no difference between the effectiveness of early and late EPO (LE2). There is no difference between high-dose and low-dose EPO (LE2). The level of evidence is too low to recommend the intravenous route. EPO has no impact on the rate of bronchopulmonary dysplasia, necrotizing enterocolitis (LE3), and retinopathy of prematurity (LE2). The level of evidence is too low to recommend EPO for neuroprotection in very preterm or term infants. CONCLUSIONS EPO to reduce RBC transfusion in very preterm infants is recommended (Level A). The optimal time to start therapy is unknown (Level B). The recommended dose is 750IU/kg/week via three subcutaneous injections for 6weeks (Level B).Copyright © 2015 Elsevier Masson SAS. All rights reserved.
Safety of off-label erythropoiesis stimulating agents in critically ill patients: a meta-analysis
Intensive Care Medicine. 2013;39((11):):1896-908.
PURPOSE Erythropoiesis stimulating agents (ESAs) are used to treat anemia in critically ill patients. This indication is off-label, because it is not licensed by regulatory authorities. Recently ESAs were suspected to harm critically ill patients. Our objective was to assess the safety of ESAs in off-label indications in critically ill patients. METHODS Eleven databases were searched up to April 2012. We considered randomized controlled trials (RCTs) and controlled observational studies in any language that compared off-label ESAs treatment with other effective interventions, placebo or no treatment in critically ill patients. Two authors independently screened and evaluated retrieved records, extracted data and assessed risk of bias and quality of reporting. RESULTS We used frequentist and Bayesian models to combine studies, and performed sensitivity and subgroup analyses. From 12,888 citations, we included 48 studies (34 RCTs; 14 observational), involving 944,856 participants. Harm reporting was of medium to low quality. There was no statistically significant increased risk of adverse events in general, serious adverse events, the most frequently reported adverse events, and death in critically ill patients treated with ESAs. These results were robust against risk of bias and analysis methods. There is evidence that ESAs increase the risk of clinically relevant thrombotic vascular events, and there is some less certain evidence that ESAs might increase the risk for venous thromboembolism. CONCLUSIONS In critically ill patients, administration of ESAs is associated with a significant increase in clinically relevant thrombotic vascular events but not with other frequently reported adverse events and death.
A meta-analysis of randomized controlled trials in critically ill patients to evaluate the dose-response effect of erythropoietin
Journal of Intensive Care Medicine. 2007;22((5):):270-82.
The use of erythropoietin in critically ill patients has been investigated in multiple randomized clinical trials and its role in decreasing the number of units of blood transfused has been demonstrated in some trials. A meta-analysis was conducted to determine the pooled estimate of the decrease in number of units of blood transfused with the use of erythropoietin and investigated its dose-response effect. A systematic search was performed of the MEDLINE, EMBASE, and the Current Controlled Trials Register to identify randomized clinical trials investigating the role of erythropoietin in critically ill patients. Of 664 studies identified in the search, 5 randomized clinical trials met the inclusion criteria. The pooled estimate of the decrease of number of units of blood transfused was -1.64 (95% CI -2.6 to -0.67). Sensitivity analysis to establish the influence of temporal bias, quality of the study and comorbidities such as age and Acute Physiology and Chronic Health Evaluation (APACHE) II score were undertaken and did not reveal a significant difference. The inclusion of studies with higher doses of erythropoietin revealed a greater decrease in the number of units of blood transfused (-2.15; 95% CI -3.06 to -1.24). Despite the limitations of a meta-analysis we believe that the use of erythropoietin significantly decreases the number of units of blood transfused per patient. Our study also reveals the possibility of a dose-response effect of erythropoietin in decreasing the number of units of blood transfused.
Recombinant human erythropoietin use in intensive care
Annals of Pharmacotherapy. 2002;36((6):):1068-74.
OBJECTIVE To review the literature concerning the role of recombinant human erythropoietin (rHuEPO) in reducing the need for transfusion in critically ill patients. DATA SOURCES Articles were obtained through searches of the MEDLINE database (from 1990 to June 2001) using the key words erythropoietin, epoetin alfa, anemia, reticulocytes, hemoglobin, critical care, intensive care, critical illness, and blood transfusion. Additional references were found in the bibliographies of the articles cited. The Cochrane library was also consulted. STUDY SELECTION AND DATA EXTRACTION Controlled, prospective, and randomized studies on the use of rHuEPO in critically ill adults were selected. DATA SYNTHESIS Anemia is a common complication in patients requiring intensive care. It is caused, in part, by abnormally low concentrations of endogenous erythropoietin and is mainly seen in patients with sepsis and multiple organ dysfunction syndrome, in whom inflammation mediator concentrations are often elevated. High doses of rHuEPO produce a rapid response in these patients, despite elevated cytokine concentrations. There have been 3 studies on rHuEPO administration in intensive care and 1 trial in acutely burned patients. Only 2 of these studies looked at the impact of rHuEPO administration on the need for transfusion. CONCLUSIONS Few randomized, controlled trials explore the role of rHuEPO in critical care. Only 1 was a large, randomized clinical trial, but it presents many limitations. Future outcome and safety studies comparing rHuEPO with placebo must include clinical endpoints such as end-organ morbidity, mortality, transfusion criteria, and pharmacoeconomic analysis. rHuEPO appears to provide an erythropoietic response. Optimal dosage and the real impact of rHuEPO on the need for transfusion in intensive care remain to be determined. Currently, based on the evidence available from the literature, rHuEPO cannot be recommended to reduce the need for red blood cell transfusions in anemic, critically ill patients.