Efficacy and safety of erythropoietin and iron therapy to reduce red blood cell transfusion in surgical patients: a systematic review and meta-analysis

  • Tiffanie Kei
  • Nikhil Mistry
  • Gerard Curley
  • Katerina Pavenski
  • Nadine Shehata
  • Rosa Maria Tanzini
  • Marie-France Gauthier
  • Kevin Thorpe
  • Tom A. Schweizer
  • Sarah Ward
  • C. David Mazer
  • Gregory M. T. HareEmail author
Review Article/Brief Review



Iron restricted anemia is prevalent in surgical patients and is associated with an increased risk of allogeneic red blood cell (RBC) transfusion and adverse events. Treatment of anemia includes oral and intravenous iron and erythropoiesis stimulating agents (ESAs). More recent studies have focused on the use of intravenous iron as the primary approach to treating anemia. Nevertheless, the optimal treatment strategy for anemia remains to be established. Our primary objective was to evaluate the efficacy and safety of ESA and iron therapy relative to iron therapy alone in reducing RBC transfusion in surgical patients.


We searched the Cochrane Library, MEDLINE, EMBASE, and from inception to May 2018. We included randomized-controlled trials in which adult surgical patients received an ESA and iron, vs iron alone, prior to cardiac and non-cardiac surgery. Our primary outcome was RBC transfusion rate. Secondary outcomes included hemoglobin concentration (post-treatment and postoperatively), number of RBC units transfused, mortality, stroke, myocardial infarction (MI), renal dysfunction, pulmonary embolism (PE), and deep vein thrombosis (DVT).

Principal findings

In total, 25 studies (4,719 participants) were included. Erythropoiesis stimulating agents and iron therapy reduced RBC transfusion relative to iron therapy (relative risk [RR] 0.57; 95% confidence interval [CI], 0.46 to 0.71) without any change in mortality (RR 1.31; 95% CI, 0.80 to 2.16), stroke (RR 1.91; 95% CI, 0.63 to 5.76), MI (RR 1.12; 95% CI, 0.50 to 2.50), renal dysfunction (RR 0.96; 95% CI, 0.72 to 1.26), PE (RR 0.92; 95% CI, 0.15 to 5.83), or DVT (RR 1.48; 95% CI, 0.95 to 2.31).


Administration of ESA and iron therapy reduced the risk for RBC transfusion compared with iron therapy alone in patients undergoing cardiac and non-cardiac surgery. Nevertheless, publication bias and heterogeneity reduces the confidence of the finding. Although the analysis was probably under-powered for some outcomes, no difference in the incidence of serious adverse events was observed with ESA and iron compared with iron alone. Further large prospective trials are required to confirm these findings.

Efficacité et innocuité d’un traitement d’érythropoïétine et de fer pour réduire la transfusion de culots sanguins chez les patients chirurgicaux: une revue systématique et méta-analyse



L’anémie ferriprive est prévalente chez les patients chirurgicaux et est associée à un risque accru de transfusion de culots sanguins allogènes et d’événements indésirables. Le traitement de l’anémie comprend la prise orale et intraveineuse de fer et d’agents stimulant l’érythropoïèse (ASE). Les études plus récentes se sont concentrées sur l’utilisation de fer intraveineux en tant que thérapie principale pour traiter l’anémie. Toutefois, la stratégie thérapeutique optimale pour l’anémie demeure inconnue. Notre objectif principal était d’évaluer l’efficacité et l’innocuité des ASE et du traitement de fer par rapport à un traitement à base de fer seulement afin de réduire les transfusions de culots sanguins chez les patients chirurgicaux.


Nous avons effectué des recherches dans les bases de données suivantes : Cochrane Library, MEDLINE, EMBASE et, de leur création au mois de mai 2018. Nous avons inclus les études randomisées contrôlées dans lesquelles des patients chirurgicaux adultes ont reçu des ASE et du fer vs du fer seulement, avant une chirurgie cardiaque ou non cardiaque. Notre critère d’évaluation principal était le taux de transfusion de culots sanguins. Nos critères secondaires comprenaient la concentration d’hémoglobine (post-traitement et en postopératoire), le nombre d’unités de culots sanguins transfusées, la mortalité, les accidents vasculaires cérébraux (AVC), les infarctus du myocarde (IM), le dysfonctionnement rénal, l’embolie pulmonaire (EP) et la thrombose veineuse profonde (TVP).

Constatations principales

Au total, 25 études (4719 participants) ont été retenues. Le traitement à base d’agents stimulant l’érythropoïèse et de fer a réduit les transfusions de culots sanguins par rapport au traitement à base de fer seul (risque relatif [RR] 0,57; intervalle de confiance [IC] 95 %, 0,46 à 0,71), sans changement au niveau de la mortalité (RR 1,31; IC 95 %, 0,80 à 2,16), des AVC (RR 1,91; IC 95 %, 0,63 à 5,76), des IM (RR 1,12; IC 95 %, 0,50 à 2,50), du dysfonctionnement rénal (RR 0,96; IC 95 %, 0,72 à 1,26), de l’EP (RR 0,92; IC 95 %, 0,15 à 5,83), ou de la TVP (RR 1,48; IC 95 %, 0,95 à 2,31).


L’administration d’un traitement d’ASE et de fer a réduit le risque de transfusion de culots sanguins par rapport à un traitement à base de fer uniquement chez les patients subissant une chirurgie cardiaque ou non cardiaque. Toutefois, le biais de publication et l’hétérogénéité des études réduisent la fiabilité de cette conclusion. Bien que notre analyse manquait probablement de puissance quant à certains critères d’évaluation, aucune différence dans l’incidence d’événements indésirables graves n’a été observée avec l’administration d’ASE et de fer par rapport à une administration de fer seul. D’autres études prospectives d’envergure sont nécessaires afin de confirmer ces résultats.


Conflicts of interest

None declared.

Editorial responsibility

This submission was handled by Dr. Philip M. Jones, Associate Editor, Canadian Journal of Anesthesia.

Author contributions

Tiffanie Kei, Nikhil Mistry, Gerard Curley, Katerina Pavenski, Nadine Shehata, Kevin Thorpe, Tom A. Schweizer, Sarah Ward, C. David Mazer, and Gregory M.T. Hare contributed substantially to the conception and design of the study. Tiffanie Kei, Nikhil Mistry, Gerard Curley, C. David Mazer, and Gregory M.T. Hare contributed substantially to the acquisition of data. Tiffanie Kei, Nikhil Mistry, Gerard Curley, Katerina Pavenski, Nadine Shehata, Rosa Maria Tanzini, Marie-France Gauthier, Kevin Thorpe, Tom A. Schweizer, Sarah Ward, C. David Mazer, and Gregory M.T. Hare contributed to the analysis of data. Tiffanie Kei, Nikhil Mistry, Gerard Curley, Katerina Pavenski, Nadine Shehata, Rosa Maria Tanzini, Marie-France Gauthier, Kevin Thorpe, Tom A. Schweizer, Sarah Ward, C. David Mazer, and Gregory M.T. Hare contributed substantially to the interpretation of data. All authors contributed to drafting, revising, and adding important intellectual content to the manuscript.

Funding support

Dr. Hare and Dr. Mazer are supported by University of Toronto, Department of Anesthesia Merit Awards. Dr. Hare received support from the Academic Health Science Centre Alternative Funding Plan (SMH-15-012). Dr. Curley has received Innovation Fund support from Royal College of Surgeons in Ireland. Dr. Shehata is supported by a Canadian Institute of Health Research/Canadian Blood Services New Investigator Award. The authors would like to acknowledge Mr. David Lightfoot for his assistance with the formal literature search.

Supplementary material

12630_2019_1351_MOESM1_ESM.pdf (3.2 mb)
Supplementary material 1 (PDF 3239 kb)


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Copyright information

© Canadian Anesthesiologists' Society 2019

Authors and Affiliations

  • Tiffanie Kei
    • 1
  • Nikhil Mistry
    • 1
  • Gerard Curley
    • 2
  • Katerina Pavenski
    • 4
    • 5
  • Nadine Shehata
    • 6
  • Rosa Maria Tanzini
    • 7
  • Marie-France Gauthier
    • 8
  • Kevin Thorpe
    • 9
  • Tom A. Schweizer
    • 3
  • Sarah Ward
    • 10
  • C. David Mazer
    • 1
    • 3
    • 11
  • Gregory M. T. Hare
    • 1
    • 3
    • 5
    • 11
    Email author
  1. 1.Department of Anesthesia, St. Michael’s HospitalUniversity of TorontoTorontoCanada
  2. 2.Department of Anesthesia and Critical Care MedicineRoyal College of Surgeons in IrelandDublinIreland
  3. 3.Keenan Research Centre for Biomedical Science in the Li Ka Shing Knowledge Institute of St. Michael’s HospitalTorontoCanada
  4. 4.Department of Laboratory Medicine and Pathobiology, St. Michael’s HospitalUniversity of TorontoTorontoCanada
  5. 5.St. Michael’s Hospital, Centre of Excellence in Patient Blood ManagementTorontoCanada
  6. 6.Departments of Medicine and Laboratory Medicine and Pathobiology, Institute of Health Policy Management and EvaluationMount Sinai HospitalTorontoCanada
  7. 7.Department of PharmacySt. Michael’s HospitalTorontoCanada
  8. 8.Department of PharmacyMontfort HospitalOttawaCanada
  9. 9.Applied Health Research Centre, St. Michael’s Hospital, Dalla Lana School of Public HealthUniversity of TorontoTorontoCanada
  10. 10.Division of Orthopedic surgery, Department of Surgery, St. Michael’s HospitalUniversity of TorontoTorontoCanada
  11. 11.Department of PhysiologyUniversity of TorontoTorontoCanada

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