A Clinical Trial Assessing the Efficacy of Intravenous Iron for the Treatment of Anemia Following Cardiac Surgery

Study Overview
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Brief Summary
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BACKGROUND Anemia and iron deficiency are highly prevalent in cardiac surgery patients. Both conditions may adversely affect postoperative rehabilitation. At hospital discharge, anemia is almost invariably present due to perioperative blood loss and frequent blood sampling. Two previous analyses demonstrated a prevalence of anemia early after coronary artery bypass grafting (CABG) of 94% and 98%, respectively. Almost half of CABG patients had persistent anemia two months after surgery. Postoperative anemia may result in debilitating symptoms, like dyspnoea, fatigue and poor exercise tolerance, and is associated with an increased likelihood of cardiovascular events and death after cardiac surgery. Mild to moderate anemia is commonly corrected with oral iron supplements. Oral iron is however poorly absorbed in patients with chronic diseases, and about 40% of patients suffer from debilitating gastrointestinal side-effects. As iron stores are frequently reduced or depleted after cardiac surgery, treatment with oral iron supplements may take several months. In patients with chronic heart failure (CHF), iron deficiency is associated with reduced exercise capacity, quality of life and survival even in the absence of anemia. Several large randomised trials demonstrated that treatment with intravenous iron improved clinical symptoms, exercise capacity and quality of life of CHF patients. RATIONALE It is desirable to replenish body iron stores rapidly after cardiac surgery with the aim to effectively correct anemia, optimize exercise tolerance and improve patient wellbeing. Modern intravenous iron formulations permit fast replenishment of body iron stores and have emerged as potential alternatives to oral iron. These formulations are well-tolerated and have become an established therapeutic option in anemic patients with reduced intestinal iron absorption. Several studies have demonstrated the efficacy of intravenous iron for the treatment of anemia following major non-cardiac surgery. Data regarding the efficacy of intravenous iron in cardiac surgery, however, are conflicting. HYPOTHESIS Single-dose intravenous iron therapy with ferric derisomaltose/iron isomaltoside is superior to oral iron supplementation for the correction of anemia following cardiac surgery. Moreover, single-dose intravenous iron therapy with ferric derisomaltose/iron isomaltoside results in a greater postoperative exercise capacity, an improved quality of life and less fatigue.

Official Title
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The Postoperative Iron in Cardiac Surgery (PICS-) Trial: A Randomised Clinical Trial Comparing the Efficacy of Single-, High-dose Intravenous Iron and Oral Iron for the Treatment of Anaemia Following Cardiac Surgery

Conditions
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Anemia Postoperative

Intervention / Treatment
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* Drug: Ferric Derisomaltose
* Drug: Ferrous sulfate
* Drug: normal saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients 18 years of age or older undergoing first-time, non-emergent cardiac surgery with cardiopulmonary bypass. Eligible procedures are A: isolated CABG surgery (+/- arrhythmia surgery), B: isolated cardiac valve surgery (+/- arrhythmia surgery), C: a combination of CABG and cardiac valve surgery (+/- arrhythmia surgery) Moderate anaemia on the first postoperative day. According to World Health Organization-criteria defined as a haemoglobin concentration of equal to or greater than 5.0 mmol/l (8 g/dl) and less than 6.8 mmol/l (11 g/dl). Exclusion Criteria: Known hypersensitivity to any iron formulation Multiple drug allergies or history of previous anaphylaxis Severe asthma, eczema or another atopic allergy Rheumatoid arthritis or systemic lupus erythematosus History of iron overload or disturbances in iron utilisation (e.g. haemochromatosis, hemosiderosis) History of liver disease (e.g. cirrhosis) Severe active infection or inflammation (e.g. endocarditis) Porphyria cutanea tarda Treatment with intravenous iron within 4 weeks prior to surgery. Untreated vitamin B12 or folate deficiency. Anticipated inability to perform a six-minute walk test. Women of childbearing potential, pregnant and nursing women. Anticipated postoperative length of stay in the intensive care unit (ICU) > 48 hours. Patients incapable of giving consent personally. Significantly increased risk of non-adherence or loss to follow-up. Active participation in another interventional trial with potential impact on postoperative anaemia or exercise capacity.

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intravenous iron group<br>Single-dose intravenous infusion of 20 mg/kg body weight ferric derisomaltose/iron isomaltoside 1000 (MonoFer®) | Drug: Ferric Derisomaltose<br>* Single-dose intravenous infusion, 20 mg/kg body weight, postoperative day 1<br>* Other names: MonoFer, iron isomaltoside 1000;|
| Active Comparator: Oral iron group<br>Oral therapy with 100 mg oral ferrous sulfate twice daily | Drug: Ferrous sulfate<br>* Oral therapy, 100 mg twice daily, from postoperative day 4 until 4-week follow-up<br>* Other names: Ferro Duretter;Drug: normal saline<br>* Single-dose infusion (placebo), postoperative day 1<br>* Other names: 0.9% natriumchloride;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of participants who are neither anemic nor have received allogeneic red blood cells since randomisation | Unit: percentage; anemia according to WHO criteria defined as hemoglobin < 12 g/dl in women and < 13 g/dl in men. | 4-week follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change in hemoglobin level | Unit: g/dl | From baseline to 4-week follow-up | 
| Proportion of participants with a haemoglobin increase ≥ 1.3 mmol/l (≥ 2 g/dL) | Unit: % | From baseline to 4-week follow-up | 
| Mean haemoglobin level | Unit: g/dl | 4-week follow-up | 
| Mean reticulocyte count | Unit: 10^9/l | 4-week follow-up | 
| Mean plasma iron | μmol/l | 4-week follow-up | 
| Mean plasma ferritin | µg/l | 4-week follow-up | 
| Mean transferrin saturation | Unit: % | 4-week follow-up | 
| Mean change in haemoglobin level | Unit: g/dl | From the day before surgery to 4-week follow-up | 
| Mean change in reticulocyte count | Unit: 10^9/l | From the day before surgery to 4-week follow-up | 
| Mean change in plasma iron | μmol/l | From the day before surgery to 4-week follow-up | 
| Mean change in plasma ferritin | µg/l | From the day before surgery to 4-week follow-up | 
| Mean change in transferrin saturation | Unit: % | From the day before surgery to 4-week follow-up | 
| Proportion of participants transfused with allogeneic red blood cells | Units: % | From the time of randomisation to 4-week follow-up | 
| Six-minute walk distance | Units: meter | 4-week follow-up | 
| Health-related quality of life | Health-related quality of life is assessed with the standardized European Quality of Life (EuroQol) Group five dimensions questionnaire (EQ-5D). The outcome of interest is the visual analogue scale (EQ VAS). The 5-level EQ-5D (EQ-5D-5L) consists of a descriptive system and the EQ VAS. The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The EQ VAS records the patient's self-rated health on a vertical visual analogue scale, where the best endpoint is 100 and the worst 0. | 4-week follow-up | 
| Fatique | Fatigue is assessed using the validated Multidimensional Fatigue Inventory (MFI-20). The outcome of interest is physical fatigue. The MFI-20 consists of 20 items for the assessment of fatigue in five different dimensions: general fatigue, physical fatigue, reduced activity, reduced motivation, and mental fatigue. Each dimension contains four items for which participants have to indicate on a five-point scale how the particular statement suited their experience. An equal number of items are worded in a positive and a negative way to counteract for response tendencies. A score of four indicates no presence of fatigue, while a score of 20 indicates the highest level of fatigue. | 4-week follow-up | 
| New York Heart Association (NYHA) functional class | Assessing symptoms (i.e. angina and dyspnea) and the resulting limitations during ordinary physical activity. Class I-IV. I=no symptoms, higher classes are associated with more severe symptoms and limitations. IV=severe symptoms and limitations. The outcome of interest is the proportion of participants with a NYHA functional class of I. | 4-week follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anemia, Iron deficiency, Transfusion, Postoperative period, Rehabilitation