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    Clinical Trial Results:
    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.

    Summary
    EudraCT number
    		 2020-001389-12
    Trial protocol
    		 DK  
    Global end of trial date
    26 Jun 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Dec 2024
    First version publication date
    05 Dec 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    PICS1.0
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04608539
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Aarhus University Hospital
    Sponsor organisation address
    Palle Juul-Jensens Boulevard 99, Aarhus N, Denmark, 8200
    Public contact
    Department of Cardiothoracic and Vascular Surgery, Aarhus University Hospital, +45 30911059, michhinr@rm.dk
    Scientific contact
    Department of Cardiothoracic and Vascular Surgery, Aarhus University Hospital, +45 30911059, michhinr@rm.dk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Jul 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Jun 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jun 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effectiveness of single-, high-dose intravenous iron infusion versus oral iron supplementation for the treatment of anaemia following cardiac surgery.
    Protection of trial subjects
    1. Baseline blood samples were taken in the operating room from preexisting arterial katheters, therefore not inflicting unnecessary pain on participants. 2. During the first 5 minutes of study drug infusion, infusion speed was reduced to half speed to monitor for potential infusion reactions. Participants were monitored during infusion with standard monitoring of postoperative cardiac surgery patients, i.e. ECG, invasive arterial blood pressure and pulsoxymetry.
    Background therapy
    		 Participants underwent standard cardiac surgery and received perioperative care in accordance with institutional protocols. Routine interventions to optimize hemoglobin levels before surgery, such as intravenous iron therapy or treatment with erythropoiesis-stimulating agents (ESA), were not performed. Throughout the hospital stay, red blood cell transfusions were considered for hemoglobin levels below 7.5 g/dL, with discretion for higher levels in specific cases such as unstable or actively bleeding patients, or those experiencing symptoms of anemia. Following cardiac surgery, participants were transferred to the cardiac surgery ICU. In the absence of active bleeding or severe anemia, fluid therapy consisted of crystalloid solutions (e.g., Ringer's acetate) or colloid fluids (e.g., 5% or 20% albumin solution). Stable patients were discharged to the cardiothoracic ward on the first postoperative day.
    Evidence for comparator
    		 Oral iron supplementation is the standard treatment for mild or moderate anemia following cardiac surgery (i.e. anemia not requiring blood transfusion). In our trial, oral iron supplementation with ferrous sulfate (Ferro Duretter®, ACO, Upplands Väsby, Sweden) was started on postoperative day 4, in line with our department’s standard practice.
    Actual start date of recruitment
    01 Jan 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 110
    Worldwide total number of subjects
    110
    EEA total number of subjects
    110
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    27
    From 65 to 84 years
    83
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were approached for participation by a cardiac surgeon or anesthesiologist during their preoperative visit, usually held on the last working day before their scheduled surgery.

    Pre-assignment
    Screening details
    		 We screened adult patients aged 18 years or older who were scheduled for non-emergent cardiac surgery with cardiopulmonary bypass. This included isolated coronary artery bypass grafting, valve surgery, or a combination of both.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    The trial had a double-blind design until POD4 and changed to open-label format after initiation of oral iron could, as this caused black an tarry stools and could not be concealed. The distinctive dark brown color of ferric derisomaltose made it easily distinguishable from the placebo. To maintain blinding, non-transparent bags, black infusion lines (B. Braun Medical, Melsungen, Germany), and aluminum foil sheaths covering the central venous line were used during the infusion.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 IV iron (intervention)
    Arm description
    		 Study participants in the IV iron group received a single, high-dose infusion of 20 mg/kg ferric derisomaltose on the morning of the first postoperative day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ferric derisomaltose
    Investigational medicinal product code
    B03AC
    Other name
    MonoFer
    Pharmaceutical forms
    Solution for injection/infusion, Sterile concentrate
    Routes of administration
    Infusion , Intravenous use
    Dosage and administration details
    20 mg/kg body weight via central venouse line, infused in 30 minutes

    Arm title
    		 Oral iron (control)
    Arm description
    		 Participants in the oral iron group received treatment with oral ferrous sulfate 100 mg x 2 from postoperative day 4 until 4 weeks after randiomization
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ferrous sulfate
    Investigational medicinal product code
    B03AA07
    Other name
    Ferro Duretter
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg twice daily from postoperative day 4 until 4-week follow-up

    Number of subjects in period 1
    		IV iron (intervention) Oral iron (control)
    Started
    57
    53
    Completed
    53
    51
    Not completed
    4
    2
         Lost to follow-up
    4
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    IV iron (intervention)
    Reporting group description
    		 Study participants in the IV iron group received a single, high-dose infusion of 20 mg/kg ferric derisomaltose on the morning of the first postoperative day.

    Reporting group title
    Oral iron (control)
    Reporting group description
    		 Participants in the oral iron group received treatment with oral ferrous sulfate 100 mg x 2 from postoperative day 4 until 4 weeks after randiomization

    Reporting group values
    		 IV iron (intervention) Oral iron (control) Total
    Number of subjects
    		 57 53 110
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 71 (42 to 84) 70 (28 to 77) -
    Gender categorical
    Units: Subjects
        Female
    		 20 17 37
        Male
    		 37 36 73
    Risk profile: urgent surgery
    Proportion of participants undergoing urgent surgery
    Units: Subjects
        Urgent surgery
    		 2 4 6
        Elective surgery
    		 55 49 104
        Not recorded
    		 0 0 0
    Type of surgery
    The type of cardiac surgery participants underwent before randomization
    Units: Subjects
        CABG
    		 20 17 37
        Aortic valve only
    		 22 17 39
        Mitral valve only
    		 6 9 15
        Combined / other procedures
    		 9 10 19
    Preoperative anemia
    Preoperative anemia (according to the WHO definition: hemoglobin < 13 g/dl in men, < 12 g/dl in women)
    Units: Subjects
        Anemic (WHO definition)
    		 10 9 19
        Non-anemic (WHO definition)
    		 47 44 91
        Not recorded
    		 0 0 0
    Preoperative iron deficiency (ferritin <30 µg/l)
    Preoperative iron deficiency (defined as ferritin level <30 µg/l)
    Units: Subjects
        Ferritin <30 µg/l
    		 13 9 22
        Ferritin >= 30 µg/
    		 44 44 88
        Not recorded
    		 0 0 0
    Preoperative iron deficiency (ferritin <100 µg/l)
    Preoperative iron deficiency (defined as ferritin level <100 µg/l)
    Units: Subjects
        Ferritin <100 µg/l
    		 31 34 65
        Ferritin >=100 µg/l
    		 26 19 45
        Not recorded
    		 0 0 0
    Preoperative iron deficiency (TSAT <20%)
    Preoperative iron deficiency (defined as transferrin saturation <20%)
    Units: Subjects
        TSAT <20%
    		 21 15 36
        TSAT >= 20%
    		 36 38 74
        Not recorded
    		 0 0 0
    Risk profile: recent myocardial infarction (MI)
    Units: Subjects
        Recent MI
    		 5 4 9
        No recent MI
    		 52 49 101
        Not recorded
    		 0 0 0
    Risk profile: reduced LVEF
    Risk profile: reduced LVEF
    Units: Subjects
        Reduced LVEF
    		 6 7 13
        Normal LVEF
    		 51 46 97
        Not recorded
    		 0 0 0
    Risk profile: diabetes mellitus
    Risk profile: patients medically treated for diabetes mellitus
    Units: Subjects
        Diabetes
    		 7 9 16
        No diabetes
    		 50 44 94
        Not recorded
    		 0 0 0
    Risk profile: chronic lung disease
    Proportion of patients medically treated for chronic lung disease
    Units: Subjects
        Chronic lung disease
    		 9 2 11
        No chronic lung disease
    		 48 51 99
        Not recorded
    		 0 0 0
    Risk profile: chronic kidney disease
    Participants with estimated glomerular filtration rate ≤50 mL/min/1.73 m²
    Units: Subjects
        Chronic kidney disease
    		 1 5 6
        No chronic kidney disease
    		 56 48 104
        Not recorded
    		 0 0 0
    Risk profile: preoperative oral iron therapy
    Units: Subjects
        Preoperative oral iron
    		 2 1 3
        No preoperative oral iron
    		 55 52 107
        Not recorded
    		 0 0 0
    BMI
    Body Mass Index
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 27.1 ( 4.0 ) 26.2 ( 3.6 ) -
    EuroSCORE
    Perioperative mortality risk assesment via EuroSCORE calculation
    Units: percent
        arithmetic mean (standard deviation)
    		 2.0 ( 1.5 ) 1.5 ( 1.1 ) -
    Preoperative hemoglobin
    Preoperative hemoglobin
    Units: gram(s)/decilitre
        arithmetic mean (standard deviation)
    		 13.3 ( 1.1 ) 13.5 ( 1.0 ) -
    Preoperative reticulocytes
    Preoperative reticulocytes
    Units: 10^9/L
        arithmetic mean (standard deviation)
    		 71 ( 19 ) 70 ( 19 ) -
    Preoperative ferritin level
    Preoperative ferritin level
    Units: mikrogram/litre
        median (inter-quartile range (Q1-Q3))
    		 82 (34 to 158) 72 (38 to 162) -
    Preoperative transferrin saturation
    Preoperative transferrin saturation
    Units: percent
        arithmetic mean (standard deviation)
    		 23 ( 10 ) 25 ( 11 ) -
    Preoperative creatinine
    Units: micromole(s)/litre
        arithmetic mean (standard deviation)
    		 84 ( 18 ) 82 ( 23 ) -
    Preoperative estimated glomerular filtration rate (eGFR)
    Preoperative estimated glomerular filtration rate (eGFR)
    Units: mL/min/1.73 m²)
        arithmetic mean (standard deviation)
    		 74 ( 12 ) 78 ( 15 ) -
    Preoperative vitamin B12 level
    Preoperative vitamin B12 level
    Units: pikomol/l
        arithmetic mean (standard deviation)
    		 376 ( 148 ) 358 ( 148 ) -
    Preoperative folate level
    Preoperative folate level
    Units: nmol/L
        arithmetic mean (standard deviation)
    		 32 ( 13 ) 32 ( 13 ) -

    End points

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    End points reporting groups
    Reporting group title
    IV iron (intervention)
    Reporting group description
    		 Study participants in the IV iron group received a single, high-dose infusion of 20 mg/kg ferric derisomaltose on the morning of the first postoperative day.

    Reporting group title
    Oral iron (control)
    Reporting group description
    		 Participants in the oral iron group received treatment with oral ferrous sulfate 100 mg x 2 from postoperative day 4 until 4 weeks after randiomization

    Primary: Treatment success (no anemia at 4 weeks, no postoperative blood transfusion)

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    End point title
    		 Treatment success (no anemia at 4 weeks, no postoperative blood transfusion)
    End point description
    The proportion of participants who were a) no longer anemic and b) had not received allogeneic RBC transfusions after randomization. Anemia was defined according to World Health Organization (WHO) criteria as hemoglobin levels <13 g/dL in men and <12 g/dL in women.
    End point type
    Primary
    End point timeframe
    Evaluated at a follow-up visit four weeks after randomization.
    End point values
    		 IV iron (intervention) Oral iron (control)
    Number of subjects analysed
    53
    51
    Units: Percentage
    15
    8
    Statistical analysis title
    		 Pearson's two-tailed chi-squared test
    Comparison groups
    IV iron (intervention) v Oral iron (control)
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.121
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.03
         upper limit
    		 0.28

    Secondary: Prevalence of anemia

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    End point title
    		 Prevalence of anemia
    End point description
    The proportion of participants with anemia at 4-weeks after randomization. Anemia was defined according to World Health Organization (WHO) criteria as hemoglobin levels <13 g/dL in men and <12 g/dL in women.
    End point type
    Secondary
    End point timeframe
    Evaluated at a follow-up visit four weeks after randomization.
    End point values
    		 IV iron (intervention) Oral iron (control)
    Number of subjects analysed
    53
    51
    Units: Proportion of participants
    35
    42
    Statistical analysis title
    		 Pearson's two-tailed chi-squared test
    Comparison groups
    IV iron (intervention) v Oral iron (control)
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.058
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.33
         upper limit
    		 0

    Secondary: Postoperative allogeneic red blood cells transfusion

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    End point title
    		 Postoperative allogeneic red blood cells transfusion
    End point description
    The proportion of participants receiving any allogeneic RBC transfusion in the period from randomization to the 4-week follow-up visit.
    End point type
    Secondary
    End point timeframe
    Evaluated at a follow-up visit four weeks after randomization.
    End point values
    		 IV iron (intervention) Oral iron (control)
    Number of subjects analysed
    53
    51
    Units: RBC units
    9
    17
    Statistical analysis title
    		 Pearson's two-tailed chi-squared test
    Comparison groups
    IV iron (intervention) v Oral iron (control)
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.054
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.33
         upper limit
    		 0

    Secondary: Mean change in haemoglobin (baseline / 4 weeks)

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    End point title
    		 Mean change in haemoglobin (baseline / 4 weeks)
    End point description
    The increase in hemoglobin level from the time of randomization until 4-week follow-up visit.
    End point type
    Secondary
    End point timeframe
    Evaluated at a follow-up visit four weeks after randomization.
    End point values
    		 IV iron (intervention) Oral iron (control)
    Number of subjects analysed
    53
    51
    Units: g/dl
        arithmetic mean (confidence interval 95%)
    2.3 (2.0 to 2.7)
    1.8 (1.5 to 2.3)
    Statistical analysis title
    		 Two-tailed t-test
    Comparison groups
    IV iron (intervention) v Oral iron (control)
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.053
    Method
    		 t-test, 2-sided
    Parameter type
    		 Median difference (final values)
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 1

    Secondary: Mean hemoglobin level at 4 weeks

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    End point title
    		 Mean hemoglobin level at 4 weeks
    End point description
    The difference in hemoglobin level between groups
    End point type
    Secondary
    End point timeframe
    Evaluated at a follow-up visit four weeks after randomization.
    End point values
    		 IV iron (intervention) Oral iron (control)
    Number of subjects analysed
    53
    51
    Units: g/dl
        arithmetic mean (standard deviation)
    12.0 ( 1.1 )
    11.4 ( 1.3 )
    Statistical analysis title
    		 Two-tailed t-test
    Comparison groups
    IV iron (intervention) v Oral iron (control)
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.013
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 1.1

    Secondary: Ferritin < 100 µg/l at 4 weeks

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    End point title
    		 Ferritin < 100 µg/l at 4 weeks
    End point description
    The proportion of participants with ferritin levels below 100 µg/l
    End point type
    Secondary
    End point timeframe
    Measured at 4-weeks after randomization
    End point values
    		 IV iron (intervention) Oral iron (control)
    Number of subjects analysed
    53
    51
    Units: Proportion of participants
    0
    13
    Statistical analysis title
    		 Pearson's two-tailed chi-squared test
    Comparison groups
    IV iron (intervention) v Oral iron (control)
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.38
         upper limit
    		 -0.14

    Secondary: Transferrin saturation < 20% at 4 weeks

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    End point title
    		 Transferrin saturation < 20% at 4 weeks
    End point description
    The proportion of participants with transferrin saturation below 20%
    End point type
    Secondary
    End point timeframe
    Evaluated 4 weeks after randomization
    End point values
    		 IV iron (intervention) Oral iron (control)
    Number of subjects analysed
    53
    51
    Units: Proportion of participants
    25
    37
    Statistical analysis title
    		 Pearson's two-tailed chi-squared test
    Comparison groups
    Oral iron (control) v IV iron (intervention)
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.006
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.45
         upper limit
    		 -0.08

    Secondary: Mean reticulocyte count at 4 weeks

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    End point title
    		 Mean reticulocyte count at 4 weeks
    End point description
    Mean reticulocyte count 4 weeks after randomization
    End point type
    Secondary
    End point timeframe
    4 weeks after randomization
    End point values
    		 IV iron (intervention) Oral iron (control)
    Number of subjects analysed
    52
    49
    Units: number/l
        number (not applicable)
    52
    49
    Statistical analysis title
    		 two-tailed t-test
    Statistical analysis description
    two-tailed t-test
    Comparison groups
    IV iron (intervention) v Oral iron (control)
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.917
    Method
    		 t-test, 2-sided
    Parameter type
    		 Median difference (final values)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.9
         upper limit
    		 13.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.3

    Secondary: Mean ferritin level at 4 weeks

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    End point title
    		 Mean ferritin level at 4 weeks
    End point description
    Mean ferritin level at 4 weeks
    End point type
    Secondary
    End point timeframe
    Measured at 4-weeks after randomization
    End point values
    		 IV iron (intervention) Oral iron (control)
    Number of subjects analysed
    52
    50
    Units: µg/l
        arithmetic mean (standard deviation)
    699 ( 596 )
    219 ( 180 )
    No statistical analyses for this end point

    Secondary: Mean transferrin saturation at 4 weeks

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    End point title
    		 Mean transferrin saturation at 4 weeks
    End point description
    Mean transferrin saturation at 4 weeks
    End point type
    Secondary
    End point timeframe
    Measured at a 4-week follow-up meeting
    End point values
    		 IV iron (intervention) Oral iron (control)
    Number of subjects analysed
    51
    49
    Units: %
        arithmetic mean (standard deviation)
    20.6 ( 7.4 )
    16.3 ( 8.6 )
    Statistical analysis title
    		 two-tailed t-test
    Comparison groups
    IV iron (intervention) v Oral iron (control)
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.009
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    4.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.1
         upper limit
    		 7.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.6

    Secondary: 6-minute walk distance

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    End point title
    		 6-minute walk distance
    End point description
    6-minute walk distance
    End point type
    Secondary
    End point timeframe
    Measured at 4 weeks after randomization
    End point values
    		 IV iron (intervention) Oral iron (control)
    Number of subjects analysed
    46
    41
    Units: m
        arithmetic mean (standard deviation)
    400 ( 96 )
    423 ( 79 )
    Statistical analysis title
    		 two-tailed t-test
    Comparison groups
    IV iron (intervention) v Oral iron (control)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.208
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -61
         upper limit
    		 14
    Variability estimate
    Standard error of the mean
    Dispersion value
    19

    Secondary: New York Heart Association (NYHA) functional class I

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    End point title
    		 New York Heart Association (NYHA) functional class I
    End point description
    The NYHA classification is a valid tool for assessing functional status in patients with heart failure [44]. A trained trial nurse describes the participant's functional status with one of four NYHA classes at follow-up: I. No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnoea. II. Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnoea. III. Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation, or dyspnoea. IV. Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If any physical activity is undertaken, discomfort increases. The outcome of interest is the proportion of participants with a NYHA functional class of I.
    End point type
    Secondary
    End point timeframe
    At 4 week after randomization
    End point values
    		 IV iron (intervention) Oral iron (control)
    Number of subjects analysed
    48
    43
    Units: participants
    23
    14
    Statistical analysis title
    		 Pearson chi2
    Comparison groups
    Oral iron (control) v IV iron (intervention)
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.136
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.35

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time of randomization on the morning of the first postoperative day until follow-up at 4 weeks after randomization
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.1
    Reporting groups
    Reporting group title
    IV iron group
    Reporting group description
    		 The participants who were randomized to treatment with 20 mg/kg ferric derisomaltose on postoperative day 1

    Reporting group title
    Oral iron group
    Reporting group description
    		 -

    Serious adverse events
    		 IV iron group Oral iron group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    37 / 57 (64.91%)
    33 / 53 (62.26%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Pulmonary embolism
    Additional description: Pulmonary embolism
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    19 / 57 (33.33%)
    16 / 53 (30.19%)
         occurrences causally related to treatment / all
    0 / 19
    0 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
    Additional description: Clinically relevant pericardial effusion
         subjects affected / exposed
    6 / 57 (10.53%)
    3 / 53 (5.66%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block
    Additional description: AV-blok
         subjects affected / exposed
    3 / 57 (5.26%)
    3 / 53 (5.66%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Embolic stroke
    Additional description: Embolic stroke
         subjects affected / exposed
    4 / 57 (7.02%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
    Additional description: Gastrointestinal bleeding
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal ischaemia
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
    Additional description: Severe constipation
         subjects affected / exposed
    0 / 57 (0.00%)
    3 / 53 (5.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
    Additional description: Pleural effusion requiring pleurocentesis
         subjects affected / exposed
    8 / 57 (14.04%)
    9 / 53 (16.98%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
    Additional description: Participants with acute kidney injury
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Wound infection
    Additional description: Wound infection
         subjects affected / exposed
    3 / 57 (5.26%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 IV iron group Oral iron group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 57 (8.77%)
    2 / 53 (3.77%)
    Cardiac disorders
    Ventricular arrhythmia
         subjects affected / exposed
    2 / 57 (3.51%)
    0 / 53 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    Nausea
    Additional description: Nausea during study drug infusion
         subjects affected / exposed
    1 / 57 (1.75%)
    2 / 53 (3.77%)
         occurrences all number
    1
    2
    Taste disorder
    Additional description: Metal taste during study drug infusion
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 53 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Pruritus
    Additional description: Itching during study drug infusion
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 53 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The main limitation of our study is that it was likely underpowered to demonstrate a significant difference in the primary outcome. The choice of a composite primary outcome may have contributed to this.
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