Intravenous Iron for Treatment of Anaemia Before Cardiac Surgery

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Intravenous Iron for Treatment of Anaemia Before Cardiac Surgery

Conditions
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Anaemia

Intervention / Treatment
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* Drug: Ferric carboxymaltose
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ferric carboxymaltose<br>ferric carboxymaltose 1000 mg or Iron isomaltoside 1000 mg given Intravenously | Drug: Ferric carboxymaltose<br>* treatment for Iron deficient anaemia<br>* Other names: Iron isomaltoside;|
| Placebo Comparator: Placebo<br>Placebo intravenous infusion | Drug: Placebo<br>* placebo - no active drug<br>* Other names: No active drug;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Days alive and out of hospital. | 90 days post surgery. the number of days the patient was not in hospital or care facility during the 90 day period from surgery. | induction of anaesthesia for cardiac surgery up to 90 days post operatively | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correction of anemia following administration of trial drug to day of surgery measure by hemoglobin | following administration of trial drug to day of surgery. Analysis of the Haemoglobin changes. | from administration of trial drug up to induction of anaesthesia for cardiac surgery up to 10 weeks | 
| Intensive care stay | Total days in hospital and Intensive care from induction of anaesthesia for cardiac surgery up until 30 days post operation | induction of anaesthesia for cardiac surgery to 30 days post operatively | 
| hospital stay | Total days in hospital from induction of anaesthesia for cardiac surgery up until 30 days post operation | induction of anaesthesia for cardiac surgery to 30 days post operatively | 
| Disability-free survival | Using the WHODAS to measure disability post operatively up to180 days from surgery. disability will be measured as an increased score of ≥4 for a period of ≥ 3months | 180 days from induction of anaesthesia for cardiac surgery | 
| 90-day survival | mortality within 90 days from induction of anaesthesia for cardiac surgery | induction of anaesthesia for cardiac surgery up to 90 days post operatively | 
| units of allogeneic blood transfused | number of blood products transfused | induction of anaesthesia for cardiac surgery to discharge from hospital up to 30 days | 
| Quality of life | Quality of life after cardiac surgery | induction of anaesthesia for cardiac surgery up to 180 days post operatively | 
| Cost-effectiveness | comparative cost analysis for the use of iron v's placebo | From trial drug administration to 180 days from induction of anaesthesia for cardiac surgery | 
| Days alive and out of hospital. | 30 days post surgery. the number of days the patient was not in hospital or care facility during the 30 day period from surgery. | induction of anaesthesia for cardiac surgery up to 30 days post operatively |