Elsevier

The Lancet

Volume 393, Issue 10187, 1–7 June 2019, Pages 2201-2212
The Lancet

Articles
Effect of ultra-short-term treatment of patients with iron deficiency or anaemia undergoing cardiac surgery: a prospective randomised trial

https://doi.org/10.1016/S0140-6736(18)32555-8Get rights and content

Summary

Background

Anaemia and iron deficiency are frequent in patients scheduled for cardiac surgery. This study assessed whether immediate preoperative treatment could result in reduced perioperative red blood cell (RBC) transfusions and improved outcome.

Methods

In this single-centre, randomised, double-blind, parallel-group controlled study, patients undergoing elective cardiac surgery with anaemia (n=253; haemoglobin concentration (Hb) <120 g/L in women and Hb <130 g/L in men) or isolated iron deficiency (n=252; ferritin <100 mcg/L, no anaemia) were enrolled. Participants were randomly assigned (1:1) with the use of a computer-generated range minimisation (allocation probability 0·8) to receive either placebo or combination treatment consisting of a slow infusion of 20 mg/kg ferric carboxymaltose, 40 000 U subcutaneous erythropoietin alpha, 1 mg subcutaneous vitamin B12, and 5 mg oral folic acid or placebo on the day before surgery. Primary outcome was the number of RBC transfusions during the first 7 days. This trial is registered with ClinicalTrials.gov, number NCT02031289.

Findings

Between Jan 9, 2014, and July 19, 2017, 1006 patients were enrolled; 505 with anaemia or isolated iron deficiency and 501 in the registry. The combination treatment significantly reduced RBC transfusions from a median of one unit in the placebo group (IQR 0–3) to zero units in the treatment group (0–2, during the first 7 days (odds ratio 0·70 [95% CI 0·50–0·98] for each threshold of number of RBC transfusions, p=0·036) and until postoperative day 90 (p=0·018). Despite fewer RBC units transfused, patients in the treatment group had a higher haemoglobin concentration, higher reticulocyte count, and a higher reticulocyte haemoglobin content during the first 7 days (p≤0·001). Combined allogeneic transfusions were less in the treatment group (0 [IQR 0–2]) versus the placebo group (1 [0–3]) during the first 7 days (p=0·038) and until postoperative day 90 (p=0·019). 73 (30%) serious adverse events were reported in the treatment group group versus 79 (33%) in the placebo group.

Interpretation

An ultra-short-term combination treatment with intravenous iron, subcutaneous erythropoietin alpha, vitamin B12, and oral folic acid reduced RBC and total allogeneic blood product transfusions in patients with preoperative anaemia or isolated iron deficiency undergoing elective cardiac surgery.

Funding

Vifor Pharma and Swiss Foundation for Anaesthesia Research.

Introduction

Anaemia is frequent in patients scheduled for elective cardiac surgery and is associated with an increased number of red blood cell (RBC) transfusions and adverse clinical outcomes, including mortality.1, 2 Iron deficiency is of prime importance in many forms of anaemia.3 In addition, iron plays a pivotal part in many processes involved in energy production and efficient organ function such as myocardial function.4, 5 Several expert groups therefore recommend treatment of iron deficiency preoperatively even if not yet associated with anaemia.5, 6 This could be of particular relevance in patients with impaired left ventricular function undergoing cardiac surgery because treatment of iron deficiency in patients with congestive heart failure has been shown to improve functional status within 4 weeks and to reduce the need for hospital admission and mortality.7, 8 Previous studies have shown that up to 37% of patients undergoing cardiac surgery were reported to be iron deficient, two-thirds of them without anaemia, and they received more RBC transfusions perioperatively than patients without iron deficiency.9 A systematic assessment and treatment of anaemia and iron deficiency before cardiac surgery is currently lacking and not an integral part of the preoperative standard work-up in most health-care systems. This study addressed the hypothesis that an immediate preoperative treatment of anaemia or isolated iron deficiency could result in reduced perioperative RBC transfusions and in an improved perioperative outcome.

Research in context

Evidence before this study

Anaemia and iron deficiency are frequent in patients scheduled for elective cardiac surgery and preoperative anaemia is associated with an increased rate of red blood cell (RBC) transfusions and adverse clinical outcomes. Iron deficiency is of prime importance in many forms of anaemia and iron plays a pivotal part in efficient organ function such as myocardial function. We searched MEDLINE from inception until May 30, 2018, including the search terms “anaemia”, “preoperative”, “iron deficiency”, “cardiac”, “surgery”, “transfusion”, “erythropoietin”, and “iron” to identify studies assessing the effect of preoperative treatment of anaemia and iron deficiency in cardiac surgery. We identified one previous randomised trial in patients undergoing cardiac valve surgery in which a combination treatment with subcutaneous erythropoietin and intravenous iron the day prior to surgery resulted in a decrease in RBC transfusions.

Added value of this study

Our trial found that ultra-short-term (usually the day before surgery but on Friday in patients operated the next Monday) combination treatment with intravenous iron, subcutaneous erythropoietin alpha, vitamin B12, and oral folic acid reduced the need for RBC and total allogeneic blood product transfusions in patients with preoperative anaemia or isolated iron deficiency undergoing elective cardiac surgery.

Implications of all the available evidence

Physicians should routinely measure haemoglobin and iron parameters in patients undergoing cardiac surgery and consider combination treatment of preoperative anaemia or iron deficiency even the day prior to surgery. This is of particular relevance since a growing percentage of elective cardiac surgery is done within a few days after an acute cardiac event.

Section snippets

Study design and participants

This was a single-centre, randomised, double-blind, parallel-group controlled study in patients undergoing elective cardiac surgery. Patients with anaemia (n=253; haemoglobin concentration (Hb) <120 g/L in women and Hb <130 g/L in men) or isolated iron deficiency (n=252; ferritin <100 mcg/L, no anaemia) were enrolled from University Hospital of Zürich (Zürich, Switzerland). Patients with anaemia and iron deficiency were stratified to the anaemia subgroup. In parallel, data from eligible

Results

Between Jan 9, 2014, and July 19, 2017, 1006 patients were enrolled; 505 with anaemia or isolated iron deficiency and 501 in the registry. From 505 patients with anaemia or isolated iron deficiency, three were not randomly assigned, four were not operated, in three patients more complex surgery rendered patients ineligible, two required emergency surgery, two were resuscitated between enrolment and the planned surgery, two required intraoperative extra-corporeal membrane oxygenation, two

Discussion

To the best of our knowledge, this is the first large scale prospective randomised controlled trial showing that an ultra-short-term combination treatment with intravenous iron, subcutaneous erythropoietin alpha, vitamin B12, and oral folic acid reduces RBC and total allogeneic blood product transfusions in patients with preoperative anaemia or isolated iron deficiency undergoing elective cardiac surgery.

Ideally, erythropoietin is given days before a planned intervention since the earliest

Data sharing statement

For original deidentified individual patient data please contact [email protected]. Data will be made available for a period of 5 years after the publication date.

Declaration of interests

DRS's academic department is receiving grant support from the Swiss National Science Foundation, Berne, Switzerland, the Ministry of Health (Gesundheitsdirektion) of the Canton of Zurich, Switzerland for Highly Specialized Medicine, the Swiss Society of Anesthesiology and Reanimation (SGAR), Berne,

References (34)

  • EA Jankowska et al.

    Effects of intravenous iron therapy in iron-deficient patients with systolic heart failure: a meta-analysis of randomized controlled trials

    Eur J Heart Fail

    (2016)
  • P Piednoir et al.

    Preoperative iron deficiency increases transfusion requirements and fatigue in cardiac surgery patients: a prospective observational study

    Eur J Anaesthesiol

    (2011)
  • OM Theusinger et al.

    Patient blood management in orthopaedic surgery: a four-year follow-up of transfusion requirements and blood loss from 2008 to 2011 at the Balgrist University Hospital in Zurich, Switzerland

    Blood Transfus

    (2014)
  • LT Goodnough et al.

    Current concepts: erythropoietin therapy

    N Engl J Med

    (1997)
  • S Yoon et al.

    Comparable pharmacokinetics and pharmacodynamics of two epoetin alfa formulations Eporon((R)) and Eprex((R)) following a single subcutaneous administration in healthy male volunteers

    Drug Des Devel Ther

    (2017)
  • SJ Head et al.

    Adverse events while awaiting myocardial revascularization: a systematic review and meta–analysis

    Eur J Cardiothorac Surg

    (2017)
  • OM Theusinger et al.

    Treatment of iron deficiency anemia in orthopedic surgery with intravenous iron: efficacy and limits: a prospective study

    Anesthesiology

    (2007)
  • Cited by (0)

    Contributed equally

    View full text