The Cochrane database of systematic reviewsAug 14, 2020

Erythropoietin with iron compared to placebo or iron alone before surgery in adults with anemia

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 20, 2026

Abstract

Preoperative treatment with rHuEPO and iron is associated with a 55% reduction in the need for red blood cell transfusions in anaemic adults undergoing non-cardiac surgery.

The combination of rHuEPO and iron therapy may lead to 231 fewer transfusions required per 1000 anaemic patients compared to control.
High-dose rHuEPO plus iron therapy significantly increases preoperative haemoglobin levels by an average of 1.87 g/dL.
Low-dose rHuEPO plus iron therapy does not significantly affect haemoglobin levels.
There is probably little or no difference in the total number of red blood cell units transfused per patient.
The risk of mortality within 30 days post-surgery and the incidence of adverse events do not significantly differ between treatment and control groups.
The treatment does not appear to shorten the length of hospital stay for patients.

Simplified

BACKGROUND: Approximately 30% of adults undergoing non-cardiac surgery suffer from preoperative anaemia. Preoperative anaemia is a risk factor for mortality and adverse outcomes in different surgical specialties and is frequently the reason for blood transfusion. The most common causes are renal, chronic diseases, and iron deficiency. International guidelines recommend that the cause of anaemia guide preoperative anaemia treatment. Recombinant human erythropoietin (rHuEPO) with iron supplementation has frequently been used to increase preoperative haemoglobin concentrations in patients in order to avoid the need for perioperative allogeneic red blood cell (RBC) transfusion.

OBJECTIVES: To evaluate the efficacy of preoperative rHuEPO therapy (subcutaneous or parenteral) with iron (enteral or parenteral) in reducing the need for allogeneic RBC transfusions in preoperatively anaemic adults undergoing non-cardiac surgery.

SEARCH METHODS: We searched CENTRAL, Ovid MEDLINE(R), Ovid Embase, ISI Web of Science: SCI-EXPANDED and CPCI-S, and clinical trial registries WHO ICTRP and ClinicalTrials.gov on 29 August 2019.

SELECTION CRITERIA: We included all randomized controlled trials (RCTs) that compared preoperative rHuEPO + iron therapy to control treatment (placebo, no treatment, or standard of care with or without iron) for preoperatively anaemic adults undergoing non-cardiac surgery. We used the World Health Organization (WHO) definition of anaemia: haemoglobin concentration (g/dL) less than 13 g/dL for males, and 12 g/dL for non-pregnant females (decision of inclusion based on mean haemoglobin concentration). We defined two subgroups of rHuEPO dosage: 'low' for 150 to 300 international units (IU)/kg body weight, and 'high' for 500 to 600 IU/kg body weight.

DATA COLLECTION AND ANALYSIS: Two review authors collected data from the included studies. Our primary outcome was the need for RBC transfusion (no autologous transfusion, fresh frozen plasma or platelets), measured in transfused participants during surgery (intraoperative) and up to five days after surgery. Secondary outcomes of interest were: haemoglobin concentration (directly before surgery), number of RBC units (where one unit contains 250 to 450 mL) transfused per participant (intraoperative and up to five days after surgery), mortality (within 30 days after surgery), length of hospital stay, and adverse events (e.g. renal dysfunction, thromboembolism, hypertension, allergic reaction, headache, fever, constipation).

MAIN RESULTS: Most of the included trials were in orthopaedic, gastrointestinal, and gynaecological surgery and included participants with mild and moderate preoperative anaemia (haemoglobin from 10 to 12 g/dL). The duration of preoperative rHuEPO treatment varied across the trials, ranging from once a week to daily or a 5-to-10-day period, and in one trial preoperative rHuEPO was given on the morning of surgery and for five days postoperatively. We included 12 trials (participants = 1880) in the quantitative analysis of the need for RBC transfusion following preoperative treatment with rHuEPO + iron to correct preoperative anaemia in non-cardiac surgery; two studies were multiarmed trials with two different dose regimens. Preoperative rHuEPO + iron given to anaemic adults reduced the need RBC transfusion (risk ratio (RR) 0.55, 95% confidence interval (CI) 0.38 to 0.80; participants = 1880; studies = 12; I= 84%; moderate-quality evidence due to inconsistency). This analysis suggests that on average, the combined administration of rHuEPO + iron will mean 231 fewer individuals will need transfusion for every 1000 individuals compared to the control group. Preoperative high-dose rHuEPO + iron given to anaemic adults increased the haemoglobin concentration (mean difference (MD) 1.87 g/dL, 95% CI 1.26 to 2.49; participants = 852; studies = 3; I= 89%; low-quality evidence due to inconsistency and risk of bias) but not low-dose rHuEPO + iron (MD 0.11 g/dL, 95% CI -0.46 to 0.69; participants = 334; studies = 4; I= 69%; low-quality evidence due to inconsistency and risk of bias). There was probably little or no difference in the number of RBC units when rHuEPO + iron was given preoperatively (MD -0.09, 95% CI -0.23 to 0.05; participants = 1420; studies = 6; I= 2%; moderate-quality evidence due to imprecision). There was probably little or no difference in the risk of mortality within 30 days of surgery (RR 1.19, 95% CI 0.39 to 3.63; participants = 230; studies = 2; I= 0%; moderate-quality evidence due to imprecision) or of adverse events including local rash, fever, constipation, or transient hypertension (RR 0.93, 95% CI 0.68 to 1.28; participants = 1722; studies = 10; I= 0%; moderate-quality evidence due to imprecision). The administration of rHuEPO + iron before non-cardiac surgery did not clearly reduce the length of hospital stay of preoperative anaemic adults (MD -1.07, 95% CI -4.12 to 1.98; participants = 293; studies = 3; I= 87%; low-quality evidence due to inconsistency and imprecision). 2 2 2 2 2 2 2

AUTHORS' CONCLUSIONS: Moderate-quality evidence suggests that preoperative rHuEPO + iron therapy for anaemic adults prior to non-cardiac surgery reduces the need for RBC transfusion and, when given at higher doses, increases the haemoglobin concentration preoperatively. The administration of rHuEPO + iron treatment did not decrease the mean number of units of RBC transfused per patient. There were no important differences in the risk of adverse events or mortality within 30 days, nor in length of hospital stay. Further, well-designed, adequately powered RCTs are required to estimate the impact of this combined treatment more precisely.

Funding

Competing interests

1. Lutz Kaufner is employed as a clinical and academic anaesthesiologist with a clinical and research focus on preoperative anaemia and haemostasis. He has no conflicts of interest relating to this review or any products that are the subject of this review. He received a personal honorarium for a lecture and travel cost reimbursement from Daiichi Sankyo in 2015. He has not received any honoraria from Daiichi Sankyo in relation to ferricarboxymaltose. Additionallly, Lutz Kaufner received personal honoraria for the development of educational presentations from HICC GbR (2015, 2016, 2017, 2018, 2019), CSL Behring (2015), and NovoNordisk (2015, 2016, 2017, 2018, 2019), none of which is relevant to this review. His institution received a one‐time honoraria from Bristol‐Myers Squibb in 2015 for an advisory board membership concerning new oral anticoagulants (NOAC). None of the mentioned companies produces any products relevant to the scope of this review. All received honoraria for lectures and travel cost reimbursements were unrelated to the topic of this review. 2. Ravi Gill is a consultant cardiac anaesthetist. He received a payment from Octapharma for helping to organize and chair a lunchtime symposia on the management of bleeding after cardiac surgery at the Joint European Association of Cardiothoracic Anaestheiologists/Association for Cardiothoracic Anaesthesia and Critical Care (EACTA/ACTACC) meeting in Manchester in September 2018. This honoraria and travel cost reimbursement was unrelated to the topic of this review. This is the only commercial work he has undertaken since April 2016. 3. Stephanie Weibel is an academic researcher. She has no conflicts of interest. 4. Nathan Pace is a non‐practicing anaesthesiologist and statistician faculty member of the University of Utah. He provides statistical consulting (research design, sample size planning) to Elute, Inc (Salt Lake City, Utah, USA), which develops polymer‐based, antibiotic drug delivery orthopaedic bone cements. 5. Peter Kranke is employed as a Professor of Anaesthesia. In this position, he is Principal Investigator for the site in Würzburg in the LIBERAL‐Trials, investigating transfusion strategies in elderly patients (LIBERAL 2017). He has received payment for consultancies up to 2019 from Ratiopharm, B. Braun; grants/grants pending from B. Braun; and payments for lectures up to 2019 from FreseniusKabi, Ratiopharm, CSL Behring, Medtronic, Grünenthal and Pajunk. All received honoraria were unrelated to the topic of this review. He has no conflict of interest relating to the topic of this review. 6. Joerg Meerpohl is Director of Cochrane Germany and a trained paediatrician, paediatric haematologist, and oncologist. He has no conflicts of interest. 7. Christian von Heymann is employed as a clinical and academic anaesthesiologist and intensive care physician with a clinical and research focus on perioperative blood conservation, anaemia, and haemostasis at a tertiary care and teaching hospital in Berlin, Germany. He has participated in a clinical trial (EMIT‐AF/VTE‐study) on the perioperative management of edoxaban (an oral anticoagulant), and his department received case payments for this participation from Daiichi Sankyo Germany. Furthermore, he is member of the steering committee of this study and has received honoraria for this work from Daiichi Sankyo Germany. He states that he has not received any honoraria from Daiichi Sankyo in relation to ferricarboxymaltose (see statement from Dr Kaufner). Furthermore, Christian von Heymann has received personal payments for consultancies or lecture fees and/or travel reimbursements within the last three years after publication of the protocol (December 2016) from: Bayer AG (last paid speaker activity May 2019); AstraZeneca (last paid speaker activity June 2018); Haemonetics (last paid activity in November 2017); Daiichi Sankyo (last paid speaker activity September 2019); Bristol‐Myers Squibb (last paid speaker activity December 2017); NovoNordisk GmbH (last paid speaker activity November 2018); CSL Behring (last paid speaker activity October 2019); Biotest GmbH (last paid speaker activity April 2019); Leo Pharma GmbH (last paid speaker activity in September 2018); Ferring GmbH (last paid speaker activity September 2016); Boehringer Ingelheim (last paid consultancy activity September 2016); and Baxter/Shire (now Takeda) GmbH (last paid speaker activity in September 2017), none of which are relevant to this review, as these payments relate to lectures and consultancy work on the use of anticoagulants, clotting factor concentrates, or point‐of‐care coagulation devices that are produced by these companies. Christian von Heymann received payments for the development of educational presentations from HICC GbR, CSL Behring, and NovoNordisk, none of which are relevant to this review. Christian von Heymann has been delegated by the European Association of Cardiothoracic Anaesthesiologists (EACTA) to take part in the European Guideline on Patient Blood Management in Cardiac Surgery, which is a joint venture from EACTA and the European Association of Cardiothoracic Surgeons (EACTS). This activity is unpaid. Christian von Heymann has been nominated to take part in the update of the German haemotherapy guidelines (chapters on therapeutic plasma and procoagulants), which are issued by the German Medical Chamber. This activity is unpaid. Christian von Heymann is currently chair of the scientific subcommittee on Transfusion, Haemostasis and Thrombosis of the European Society of Anaesthesiology (ESA) and has been nominated to take part in the development of the guideline on the management of anticoagulants in regional anaesthesia. This activity is unpaid. Christian von Heymann states that he has not received any payment from companies related to the use of any products, interventions, or comparators that are of interest to this review for the last three years and longer. 8. Anne Henkelmann is a pharmacist and is working as a research associate at the Department of Anesthesiology at Charité‐Universitätsmedizin Berlin. She has no conflicts of interest. Acknowledgement of potential conflict of interest policy breach: The authors allude to a potential breach of the Cochrane conflict of interest policy relating to payments received from Daiichi Sankyo. Daiichi Sankyo is one of the distributors of ferricarboxymaltose in the US (Injectafer is manufactured under license from Vifor International, Inc, Switzerland), which could potentially be a part of the intervention in some of the analysed randomized controlled trials in the review. This review will be updated in the future with an author team free of said potential conflicts.

PubMed

Erythropoietin with iron compared to placebo or iron alone before surgery in adults with anemia

Abstract

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