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NCT Number: NCT04608539

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

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.

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Key information

Conditions

Anemia Postoperative Anemia Hematologic Diseases Hemic and Lymphatic Diseases Iron Deficiencies Iron Metabolism Disorders Metabolic Diseases Nutritional and Metabolic Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

Aarhus University Hospital

Aarhus, 8200, Denmark

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Ferric derisomaltose

Drug

Single-dose intravenous infusion, 20 mg/kg body weight, postoperative day 1

Other names: MonoFer, iron isomaltoside 1000

Ferrous Sulfate

Drug

Oral therapy, 100 mg twice daily, from postoperative day 4 until 4-week follow-up

Other names: Ferro Duretter

normal saline

Drug

Single-dose infusion (placebo), postoperative day 1

Other names: 0.9% natriumchloride

Primary outcomes

  1. The proportion of participants who are neither anemic nor have received allogeneic red blood cells since randomisation

    Time frame: 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 outcomes

  1. Mean change in hemoglobin level

    Time frame: From baseline to 4-week follow-up

    Unit: g/dl

  2. Proportion of participants with a haemoglobin increase ≥ 1.3 mmol/l (≥ 2 g/dL)

    Time frame: From baseline to 4-week follow-up

    Unit: %

  3. Mean haemoglobin level

    Time frame: 4-week follow-up

    Unit: g/dl

  4. Mean reticulocyte count

    Time frame: 4-week follow-up

    Unit: 10^9/l

  5. Mean plasma iron

    Time frame: 4-week follow-up

    μmol/l

  6. Mean plasma ferritin

    Time frame: 4-week follow-up

    µg/l

  7. Mean transferrin saturation

    Time frame: 4-week follow-up

    Unit: %

  8. Mean change in haemoglobin level

    Time frame: From the day before surgery to 4-week follow-up

    Unit: g/dl

  9. Mean change in reticulocyte count

    Time frame: From the day before surgery to 4-week follow-up

    Unit: 10^9/l

  10. Mean change in plasma iron

    Time frame: From the day before surgery to 4-week follow-up

    μmol/l

  11. Mean change in plasma ferritin

    Time frame: From the day before surgery to 4-week follow-up

    µg/l

  12. Mean change in transferrin saturation

    Time frame: From the day before surgery to 4-week follow-up

    Unit: %

  13. Proportion of participants transfused with allogeneic red blood cells

    Time frame: From the time of randomisation to 4-week follow-up

    Units: %

  14. Six-minute walk distance

    Time frame: 4-week follow-up

    Units: meter

  15. Health-related quality of life

    Time frame: 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".

  16. Fatique

    Time frame: 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.

  17. New York Heart Association (NYHA) functional class

    Time frame: 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.

Other outcomes

  1. Gastrointestinal symptoms

    Time frame: 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.

  2. Treatment adherence to oral iron therapy

    Time frame: 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.

  3. Cost-effectiveness analysis

    Time frame: 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.

  4. Quality of Recovery Score (QoR9-questionnaire)

    Time frame: 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.

Sponsors and collaborators

Lead sponsor

Michael Kremke

Other

Collaborators

  • Aarhus University Hospital
  • Pharmacosmos A/S
  • University of Aarhus

Registry information

Official study title

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

Acronym: PICS

Important dates

Study start
2021
Primary completion
2023
Study completion
2023
First posted
Oct 29, 2020
Registry last updated
Jun 28, 2023

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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