Intravenous Iron for Treatment of Anaemia Before Cardiac Surgery
Intravenous Iron for Treatment of Anaemia Before Cardiac Surgery
This randomised double-blind, controlled phase IV trial will compare the efficacy, safety and
 cost-effectiveness of preoperative IV iron with placebo in patients with anaemia before
 elective cardiac surgery.
Preoperative anaemia is common (≈30%) in patients awaiting cardiac surgery, and is associated
 with increased complications, ICU and hospital stay, and mortality. The extent of anaemia is
 worsened by haemodilution occurring with cardiopulmonary bypass and surgical bleeding
 (average blood loss 0.5-1.5 litres), which in turn impair end-organ blood flow and tissue
 oxygen delivery. Further, the need for blood transfusion is greatly increased in anaemic
 patients, and is associated with poor outcomes. In addition, blood transfusions are costly
 (>$700 per unit), with around 50% of all transfusions used in surgery being for cardiac
 surgery. The investigators have identified high rates of bleeding complications and
 transfusion requirements in Australian cardiac surgery; and in another international
 collaboration, it was found that anaemia, transfusion and kidney injury are inter-related
 after cardiac surgery. After risk-adjustment, the combination of these three risk factors was
 associated with a 3.5-fold (95% CI 2.3-5.2) increased odds of kidney injury.

 Both anaemia and red cell transfusion are independent risk factors in major surgery. Some of
 the investigators reviewed Australian cardiac surgery patients from six Victorian hospitals,
 2005-2011. We linked the ANZ Society of Cardiothoracic Surgeons cardiac surgery database to
 laboratory data, including preoperative haemoglobin and all issued blood products (manuscript
 in preparation). Anaemia was defined according to the WHO definition (Hb <130 g/L for males
 and <120 g/L for females). There were 15,948 cardiac surgery patients available for inclusion
 in the analysis, of which 28% were anaemic. Anaemic patients were more likely to receive a
 red cell transfusion (71% vs. 40%, p<0.001), more transfused units of blood (median 4 [IQR
 2-8] vs. 3 [2-5], p<0.001), and had higher 30-day mortality (5.4% vs. 1.9%, p<0.001), new
 renal failure (43% vs. 26%, p<0.001), and longer hospital stay in survivors (13 days [8-23]
 vs. 8 days [6-14], p<0.001). After multivariable adjustment, preoperative anaemia was an
 independent predictor of mortality (adj. OR 1.46, 95% CI 1.14-1.88, p=0.003). Similar results
 were obtained when restricted to elective surgery, but with hospital stay 9 days (7-17) vs. 7
 days (6-11), p<0.001. Other large studies are consistent with this.

 The investigators have also analysed data for patients undergoing major non-cardiac surgery
 from the American College of Surgeons' National Surgical Quality Improvement Program database
 (a validated outcomes registry from 211 hospitals worldwide). In 227,425 patients undergoing
 noncardiac surgery, and found that preoperative anaemia was associated with increased 30-day
 mortality (adj. OR 1.42, 95% CI 1.31-1.54) and morbidity (adj. OR 1.35, 1.30-1.40).

 Alfred hospital (Melbourne) transfusion data for 2012-14 (n=2,091) show that anaemic (27% of
 cohort) and non-anaemic cardiac surgical patients had intraoperative red cell transfusion
 rates of 31% and 14%, respectively; p<0.01.

 Iron deficiency is the commonest cause of anaemia worldwide, and iron deficiency per se
 independently worsens outcomes after surgery. The traditional textbook definition of iron
 deficiency anaemia refers to depletion of the body's iron stores due to dietary deficiency or
 chronic blood loss - an absolute iron deficiency. Chronic disease and inflammation have a
 direct effect in the pathway of iron absorption and metabolism leading to a state of
 functional iron deficiency and anaemia. Specifically, the iron regulatory protein hepcidin is
 upregulated, blocking pathways of iron transport. This prevents iron absorption from the gut,
 further uptake by the reticuloendothelial system increases stores (ferritin), but
 distribution and transfer to the bone marrow is blocked. Consequently, despite normal or even
 increased body iron stores (with normal ferritin levels), these are artifactual, and a state
 of 'functional iron deficiency' exists. This is commonly seen in renal and cardiac disease
 and increasingly recognised as a cause for anaemia in the surgical patient. Importantly, IV
 iron has been shown to overcome this functional deficiency and correct anaemia.

 IV iron therapy is effective in treating anaemia in medical (heart failure, kidney disease),
 post-partum, and preoperative settings (orthopaedic surgery, colon cancer resection,
 hysterectomy, hip/knee joint replacement. Earlier IV iron preparations using high molecular
 weight dextran were associated with anaphylaxis due to pre-formed antibodies, but newer
 preparations are safer, enabling delivery of a full treatment dose in 15 mins, so iron can be
 administered safely and quickly in outpatients. It is now readily available in Australia and
 is PBS-listed. This gives patients the equivalent dose of 12 months of tablets in only 15
 mins.

 Iron deficiency is very common in patients having coronary artery surgery. It is highly
 plausible that anaemia correction will improve patient outcome following cardiac
 surgery.However, some data suggest that free iron mediates free radical production associated
 with organ damage or infection in surgery and this balance between effective anaemia
 correction and potential risk needs further research. A definitive large trial is needed to
 determine if IV iron safely, effectively, and promptly corrects preoperative anaemia, and
 thus reduces risk in cardiac surgery.

 The investigators undertook a Cochrane review of iron therapy to treat anaemia in adults
 including 4,745 participants in 21 trials. This found a trend for better haemoglobin levels
 with IV iron (MD 0.50 g/dL, 95% CI 0.73-0.27; six studies, N=769) but with considerable,
 unexplained heterogeneity. Differences in the proportion of participants requiring
 transfusion were imprecise (RR 0.84, 95% CI 0.66-1.06; 8 studies, N=1,315). Thus the current
 evidence base is sparse; few randomised trials have been done and these were too small -
 there remains considerable equipoise.

 Review of the literature on anaemia and iron therapy in cardiac surgery, which included 4
 small trials of IV iron. Overall, half of all cardiac surgery patients were anaemic before
 surgery. Preoperative anaemia was found to be independently associated with higher mortality
 and blood transfusion rate, as well as longer ICU and hospital stay. As also shown by others,
 preoperative haematocrit was a powerful independent predictor of mortality, renal failure and
 deep sternal wound infection. In adjusted analyses each 5 point decrease in preoperative
 haematocrit was associated with an 8% increased risk of death (OR, 1.08; p<0.0003), a 22%
 increased risk of postoperative renal failure (OR, 1.22; p<0.0001), and a 10% increased risk
 of deep sternal wound infection (OR, 1.10; p<0.01). There is a need for a well-designed,
 pragmatic trial to assess the role of preoperative anaemia treatment using IV iron in
 patients undergoing cardiac surgery.
Inclusion Criteria:

 -  Patients with anaemia (males Hb <130 g/L, females <120 g/L) undergoing elective
 cardiac surgery, and available to receive trial drug 1- 10 weeks prior to surgery

 Exclusion Criteria:

 -  Pregnancy

 -  Known hypersensitivity to study drug (ferric carboxymaltose or equivalent) or its
 excipients

 -  Known or suspected haemoglobinopathy/thalassaemia

 -  Bone marrow disease

 -  Haemochromatosis

 -  Renal dialysis

 -  Erythropoietin or IV iron in the previous 4 weeks