Anemia Postoperative
Conditions
Keywords
Anemia, Iron deficiency, Transfusion, Postoperative period, Rehabilitation
Brief summary
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.
Interventions
Single-dose intravenous infusion, 20 mg/kg body weight, postoperative day 1
DRUGFerrous sulfate
Oral therapy, 100 mg twice daily, from postoperative day 4 until 4-week follow-up
DRUGnormal saline
Single-dose infusion (placebo), postoperative day 1
Sponsors
Aarhus University Hospital
University of Aarhus
Pharmacosmos A/S
Michael Kremke
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
The study is primarily open label. It includes, however, a short period (from the 1. to the 4. postoperative day) of participant, care provider and investigator masking. The aim is to reduce differences in transfusion practices.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The proportion of participants who are neither anemic nor have received allogeneic red blood cells since randomisation | 4-week follow-up | Unit: percentage; anemia according to WHO criteria defined as hemoglobin \< 12 g/dl in women and \< 13 g/dl in men. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean change in haemoglobin level | From the day before surgery to 4-week follow-up | Unit: g/dl |
| Six-minute walk distance | 4-week follow-up | Units: meter |
| Health-related quality of life | 4-week follow-up | 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. |
| Fatique | 4-week follow-up | 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. |
| New York Heart Association (NYHA) functional class | 4-week follow-up | 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. |
| Mean change in hemoglobin level | From baseline to 4-week follow-up | Unit: g/dl |
| Proportion of participants with a haemoglobin increase ≥ 1.3 mmol/l (≥ 2 g/dL) | From baseline to 4-week follow-up | Unit: % |
| Mean haemoglobin level | 4-week follow-up | Unit: g/dl |
| Mean reticulocyte count | 4-week follow-up | Unit: 10\^9/l |
| Mean plasma iron | 4-week follow-up | μmol/l |
| Mean plasma ferritin | 4-week follow-up | µg/l |
| Mean transferrin saturation | 4-week follow-up | Unit: % |
| Mean change in reticulocyte count | From the day before surgery to 4-week follow-up | Unit: 10\^9/l |
| Mean change in plasma iron | From the day before surgery to 4-week follow-up | μmol/l |
| Mean change in plasma ferritin | From the day before surgery to 4-week follow-up | µg/l |
| Mean change in transferrin saturation | From the day before surgery to 4-week follow-up | Unit: % |
| Proportion of participants transfused with allogeneic red blood cells | From the time of randomisation to 4-week follow-up | Units: % |
Other
| Measure | Time frame | Description |
|---|---|---|
| Cost-effectiveness analysis | 4-week follow-up | Patient-specific data for resource usage are collected. Hospital resources are recorded for each individual patient from the time of randomisation until follow-up visit four weeks postoperatively: * study drug costs * units of allogeneic red blood cell transfused * length of hospital stay (in days) * length of stay in the intensive care unit (in days) * readmission to hospital (in days) * visits to outpatient clinic Costs associated with health care utilization are calculated by multiplying volumes of resources used by unit costs of that item. |
| Quality of Recovery Score (QoR9-questionnaire) | 4-week follow-up | Quality of recovery (QoR) is assessed with the QoR-9 questionnaire. The QoR-9 is a patient rated score developed and validated to measure the quality of recovery after surgery and anaesthesia. This nine item instrument can be completed by patients in less than two minutes, has a maximum score of 18 and a minimum score of 0. Lesser scores indicate worse outcome. |
| Treatment adherence to oral iron therapy | 4-week follow-up | Units: %. Treatment adherence is measured as the proportion of oral iron tablets that the participant actually has taken in relation to the total number of tablets prescribed. |
| Gastrointestinal symptoms | 4-week follow-up | Participants are asked to report the gastrointestinal symptoms the week prior to follow-up. We developed a simple scoring system with the five dimensions nausea, constipation, diarrhea, abdominal pain and bloating. Participants are asked to rate the presence and severity of each symptom on a scale from 0 to 3, where 0 indicates 'symptom has not been present', 1 'the symptom was present and resulted in mild discomfort', 2 '... moderate discomfort' and 3 '... severe discomfort'. A final score is calculated by adding each item, 15 is the worst, 0 the best outcome. |
Countries
Denmark
Outcome results
None listed