Intravenous Iron for Treatment of Anaemia Before Cardiac Surgery (ITACS)
Primary Purpose
Anaemia
Status
Recruiting
Phase
Phase 4
Locations
Australia
Study Type
Interventional
Intervention
Ferric carboxymaltose
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Anaemia
Eligibility Criteria
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
Sites / Locations
- Alfred HealthRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Placebo Comparator
Arm Label
ferric carboxymaltose
Placebo
Arm Description
ferric carboxymaltose 1000 mg or Iron isomaltoside 1000 mg given Intravenously
Placebo intravenous infusion
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
Intensive care stay
Total days in hospital and Intensive care from induction of anaesthesia for cardiac surgery up until 30 days post operation
hospital stay
Total days in hospital from induction of anaesthesia for cardiac surgery up until 30 days post operation
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
90-day survival
mortality within 90 days from induction of anaesthesia for cardiac surgery
units of allogeneic blood transfused
number of blood products transfused
Quality of life
Quality of life after cardiac surgery
Cost-effectiveness
comparative cost analysis for the use of iron v's placebo
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.
Full Information
NCT ID
NCT02632760
First Posted
December 7, 2015
Last Updated
January 9, 2023
Sponsor
Bayside Health
Collaborators
National Health and Medical Research Council, Australia, Monash University
1. Study Identification
Unique Protocol Identification Number
NCT02632760
Brief Title
Intravenous Iron for Treatment of Anaemia Before Cardiac Surgery
Acronym
ITACS
Official Title
Intravenous Iron for Treatment of Anaemia Before Cardiac Surgery
Study Type
Interventional
2. Study Status
Record Verification Date
January 2023
Overall Recruitment Status
Recruiting
Study Start Date
July 15, 2016 (undefined)
Primary Completion Date
December 2023 (Anticipated)
Study Completion Date
June 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Bayside Health
Collaborators
National Health and Medical Research Council, Australia, Monash University
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Anaemia
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
1000 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
ferric carboxymaltose
Arm Type
Active Comparator
Arm Description
ferric carboxymaltose 1000 mg or Iron isomaltoside 1000 mg given Intravenously
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo intravenous infusion
Intervention Type
Drug
Intervention Name(s)
Ferric carboxymaltose
Other Intervention Name(s)
ferinject, Iron isomaltoside
Intervention Description
treatment for Iron deficient anaemia
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
No active drug
Intervention Description
placebo - no active drug
Primary Outcome Measure Information:
Title
Days alive and out of hospital.
Description
90 days post surgery. the number of days the patient was not in hospital or care facility during the 90 day period from surgery.
Time Frame
induction of anaesthesia for cardiac surgery up to 90 days post operatively
Secondary Outcome Measure Information:
Title
Correction of anemia following administration of trial drug to day of surgery measure by hemoglobin
Description
following administration of trial drug to day of surgery. Analysis of the Haemoglobin changes.
Time Frame
from administration of trial drug up to induction of anaesthesia for cardiac surgery up to 10 weeks
Title
Intensive care stay
Description
Total days in hospital and Intensive care from induction of anaesthesia for cardiac surgery up until 30 days post operation
Time Frame
induction of anaesthesia for cardiac surgery to 30 days post operatively
Title
hospital stay
Description
Total days in hospital from induction of anaesthesia for cardiac surgery up until 30 days post operation
Time Frame
induction of anaesthesia for cardiac surgery to 30 days post operatively
Title
Disability-free survival
Description
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
Time Frame
180 days from induction of anaesthesia for cardiac surgery
Title
90-day survival
Description
mortality within 90 days from induction of anaesthesia for cardiac surgery
Time Frame
induction of anaesthesia for cardiac surgery up to 90 days post operatively
Title
units of allogeneic blood transfused
Description
number of blood products transfused
Time Frame
induction of anaesthesia for cardiac surgery to discharge from hospital up to 30 days
Title
Quality of life
Description
Quality of life after cardiac surgery
Time Frame
induction of anaesthesia for cardiac surgery up to 180 days post operatively
Title
Cost-effectiveness
Description
comparative cost analysis for the use of iron v's placebo
Time Frame
From trial drug administration to 180 days from induction of anaesthesia for cardiac surgery
Title
Days alive and out of hospital.
Description
30 days post surgery. the number of days the patient was not in hospital or care facility during the 30 day period from surgery.
Time Frame
induction of anaesthesia for cardiac surgery up to 30 days post operatively
Other Pre-specified Outcome Measures:
Title
Anaphylaxis
Description
drug or transfusion reaction
Time Frame
during administration of the trial drug (up to 1 hour)
Title
Infection
Description
Surgical site infection rate following induction of anaesthesia for cardiac surgery to 30 days post operative
Time Frame
induction of anaesthesia for cardiac surgery to 30 days post operatively
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Paul S Myles, MD
Phone
+61390762000
Ext
3176
Email
p.myles@alfred.org.au
First Name & Middle Initial & Last Name or Official Title & Degree
Sophie k Wallace, MPH
Phone
+61390762000
Ext
2651
Email
s.wallace@alfred.org.au
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Paul S Myles, MD
Organizational Affiliation
Bayside Health
Official's Role
Study Chair
Facility Information:
Facility Name
Alfred Health
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3181
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Paul s Myles, MD
Phone
+61390763176
Ext
63176
Email
p.myles@alfred.org.au
First Name & Middle Initial & Last Name & Degree
Sophie K Wallace, MPH
Phone
+61 390762651
Ext
62651
Email
s.wallace@alfred.org.au
12. IPD Sharing Statement
Plan to Share IPD
Undecided
Citations:
PubMed Identifier
34088733
Citation
Cameron MJ, Al Kharusi L, Gosselin A, Baradari PG, Chirico A, Amar-Zifkin A, Yang SS. Iron supplementation for patients undergoing cardiac surgery: a protocol for a systematic review and meta-analysis of randomized controlled trials. CMAJ Open. 2021 Jun 4;9(2):E623-E626. doi: 10.9778/cmajo.20200204. Print 2021 Apr-Jun.
Results Reference
derived
Links:
URL
http://www.itacs.org.au
Description
ITACS web site
Learn more about this trial
Intravenous Iron for Treatment of Anaemia Before Cardiac Surgery
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