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

Sponsor

Michael Kremke (Other)

Overall Status

Enrolling by invitation

CT.gov ID

NCT04608539

Collaborator

Aarhus University Hospital (Other), University of Aarhus (Other), Pharmacosmos A/S (Industry)

110

Enrollment

Location

Arms

14.3

Anticipated Duration (Months)

7.7

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Anemia Postoperative	Drug: Ferric Derisomaltose Drug: Ferrous sulfate Drug: normal saline	Phase 4

Study Design

Study Type:

Interventional

Anticipated Enrollment :

110 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

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.

Primary Purpose:

Treatment

Official 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

Actual Study Start Date :

May 21, 2021

Anticipated Primary Completion Date :

Jun 30, 2022

Anticipated Study Completion Date :

Jul 31, 2022

Arms and Interventions

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

Arm

Intervention/Treatment

Experimental: Intravenous iron group

Single-dose intravenous infusion of 20 mg/kg body weight ferric derisomaltose/iron isomaltoside 1000 (MonoFer®)

Drug: Ferric Derisomaltose

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

Other Names:

MonoFer, iron isomaltoside 1000

Active Comparator: Oral iron group

Oral therapy with 100 mg oral ferrous sulfate twice daily

Drug: Ferrous sulfate

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

Other Names:

Ferro Duretter

Drug: normal saline

Single-dose infusion (placebo), postoperative day 1

Other Names:

0.9% natriumchloride

Outcome Measures

Primary Outcome Measures

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 Outcome Measures

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 haemoglobin level [From the day before surgery to 4-week follow-up]
Unit: g/dl
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: %
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.

Other Outcome Measures

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.
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.
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.