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    Clinical Trial Results:
    Adenosine in initial cardioplegia

    Summary
    EudraCT number
    		 2014-001382-26
    Trial protocol
    		 FI  
    Global end of trial date
    31 May 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Apr 2022
    First version publication date
    25 Apr 2022
    Other versions
    Summary report(s)
    		 Preliminary results of CABG

    Trial information

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    Trial identification
    Sponsor protocol code
    HCS-2014-2
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Tampere University Hospital Heart Center
    Sponsor organisation address
    Elämänaukio 1, Tampere, Finland, 33520
    Public contact
    Prof Jari Laurikka, Tays Sydänsairaala, +358 (0)3311 67669, jari.laurikka@sydansairaala.fi
    Scientific contact
    Prof Jari Laurikka, Tays Sydänsairaala, +358 (0)3311 67669, jari.laurikka@sydansairaala.fi
    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
    Interim
    Date of interim/final analysis
    07 Apr 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 May 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    31 May 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    myocardial function after cardiac surgery
    Protection of trial subjects
    Trial patients in both study comparison groups received high-quality medical procedures to alleviate any surgical pain or discomfort prior, during and after the procedures. Close monitoring of health (medical parameters e.g. hemodynamic, metabolic and respiratory function measurements) were used. The surgical procedures for their medical conditions (aortic, stenosis and/or coronary artery disease) were used based on a multidisciplinary team evaluation and were performed by experienced surgeons and anesthesiologists.
    Background therapy
    		 Aortic valve replacement (AVR) in extracorporeal circulation (1st study group, 45 patients). Coronary artery bypass grafting (CABG) in extracorporeal circulation (2nd study group, 43 patients).
    Evidence for comparator
    		 Adenosine 20 mg i.a. in the study medication group, same volume of saline i.a. in the control group in both procedure types (AVR, CABG) applied right after aortic cross-clamping (beginning of the shut off of the heart circulation) and followed by routine administration of potassium enriched blood cardioplegia (to stop and protect the heart).
    Actual start date of recruitment
    04 Nov 2015
    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
    Finland: 88
    Worldwide total number of subjects
    88
    EEA total number of subjects
    88
    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
    61
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment time: 3.11.2015- 2.1.2018

    Pre-assignment
    Screening details
    		 Inclusion criteria check, exclusion criteria check prior to individual study presentation (for informed consent) to the patient

    Pre-assignment period milestones
    Number of subjects started
    		 88
    Number of subjects completed
    		 88

    Period 1
    Period 1 title
    Baseline (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Independent pharmacist provided adenosine and saline, independent anesthesia nurse provided the operative team with the drug in no-name sterile syringe

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Adenosine group
    Arm description
    		 Individuals receiving active drug based on a randomization code during either AVR or CABG procedure
    Arm type
    		 Experimental

    Investigational medicinal product name
    Adenosine
    Investigational medicinal product code
    C01EB10
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intraarterial use
    Dosage and administration details
    20 mg given intra-arterial to asc. aorta after aortic cross-clamping and followed by routine potassium enriched blood cardioplegia

    Arm title
    		 Placebo
    Arm description
    		 Equal amount 4 ml of saline given intra-arterial to asc. aorta after aortic cross-clamping and followed by routine potassium enriched blood cardioplegia
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intraarterial use
    Dosage and administration details
    4 ml given intra-arterial to asc. aorta after aortic cross-clamping and followed by routine potassium enriched blood cardioplegia

    Number of subjects in period 1
    		Adenosine group Placebo
    Started
    44
    44
    Completed
    44
    44

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Adenosine group
    Reporting group description
    		 Individuals receiving active drug based on a randomization code during either AVR or CABG procedure

    Reporting group title
    Placebo
    Reporting group description
    		 Equal amount 4 ml of saline given intra-arterial to asc. aorta after aortic cross-clamping and followed by routine potassium enriched blood cardioplegia

    Reporting group values
    		 Adenosine group Placebo Total
    Number of subjects
    		 44 44 88
    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
    Age at operation
    Units: years
        arithmetic mean (standard deviation)
    		 67.36 ± 7.32 68.25 ± 9.43 -
    Gender categorical
    Units: Subjects
        Female
    		 13 9 22
        Male
    		 31 35 66
    Subject analysis sets

    Subject analysis set title
    CABG
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Recruited CABG patients

    Subject analysis set title
    AVR
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Recruited AVR patients

    Subject analysis sets values
    		 CABG AVR
    Number of subjects
    43
    45
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Age at operation
    Units: years
        arithmetic mean (standard deviation)
    68.5 ± 9.1
    67.1 ± 7.7
    Gender categorical
    Units: Subjects
        Female
    2
    20
        Male
    41
    25

    End points

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    End points reporting groups
    Reporting group title
    Adenosine group
    Reporting group description
    		 Individuals receiving active drug based on a randomization code during either AVR or CABG procedure

    Reporting group title
    Placebo
    Reporting group description
    		 Equal amount 4 ml of saline given intra-arterial to asc. aorta after aortic cross-clamping and followed by routine potassium enriched blood cardioplegia

    Subject analysis set title
    CABG
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Recruited CABG patients

    Subject analysis set title
    AVR
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Recruited AVR patients

    Primary: Time to asystole

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    End point title
    		 Time to asystole
    End point description
    myocardial electrical contraction cessation after active drug or placebo injection
    End point type
    Primary
    End point timeframe
    At induction of cardioplegia
    End point values
    		 Adenosine group Placebo CABG AVR
    Number of subjects analysed
    44
    44
    43
    45
    Units: seconds
        arithmetic mean (standard deviation)
    29.7 ± 66.7
    121.0 ± 75.5
    70.3 ± 87.5
    80.2 ± 81.9
    Statistical analysis title
    		 t-test
    Statistical analysis description
    t-test
    Comparison groups
    Adenosine group v Placebo v AVR v CABG
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -91.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -121
         upper limit
    		 -61
    Variability estimate
    Standard deviation
    Dispersion value
    15.2

    Primary: Myocardial performance, cardiac indices

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    End point title
    		 Myocardial performance, cardiac indices
    End point description
    Cardiac index and Stroke work indices (SWI) from baseline to post-CPB and at @19 (post operatively), @06 (next morning) in the ICU. Here we report Cardiac Index @ post-CPB.
    End point type
    Primary
    End point timeframe
    from baseline to post-CPB and at @19, @06 ICU stay
    End point values
    		 Adenosine group Placebo CABG AVR
    Number of subjects analysed
    42 [1]
    40 [2]
    38 [3]
    44 [4]
    Units: l/min/m2, and SWI units
        arithmetic mean (confidence interval 95%)
    2.44 (2.23 to 2.65)
    2.62 (2.41 to 2.84)
    2.42 (2.20 to 2.65)
    2.62 (2.42 to 2.83)
    Notes
    [1] - n in repeated measures anova for 4 time points
    [2] - n in repeated measures anova for 4 time points
    [3] - n in repeated measures anova for 4 time points
    [4] - n in repeated measures anova for 4 time points
    Statistical analysis title
    		 Repeated measures analysis of CI at 4 time points
    Statistical analysis description
    Repeated measures analysis of CI at 4 time points by Adenosine/Placebo
    Comparison groups
    Adenosine group v Placebo
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.186
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.491
         upper limit
    		 0.119
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.153

    Primary: Myocardial performance, echographic

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    End point title
    		 Myocardial performance, echographic
    End point description
    transesophageal echo was recorded into file in all patients and prespecified time points were used to collect data from left and right ventricular contractive activity. Data under analysis.
    End point type
    Primary
    End point timeframe
    from baseline to the end of surgical procedure
    End point values
    		 Adenosine group Placebo CABG AVR
    Number of subjects analysed
    44
    44
    43
    45
    Units: change from baseline
        arithmetic mean (standard deviation)
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    Statistical analysis title
    		 Analysis undergoing
    Statistical analysis description
    Analysis undergoing
    Comparison groups
    Placebo v Adenosine group
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.05
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk ratio (RR)
    Confidence interval
    Notes
    [5] - Analysis undergoing

    Secondary: Markers of inflammation and injury in the myocardium

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    End point title
    		 Markers of inflammation and injury in the myocardium
    End point description
    Myocardial markers (CK,CK-MBm,Troponin-T ) are measured from baseline to 1st postoperative day. Here reported CK-MB at 1st PODay.
    End point type
    Secondary
    End point timeframe
    from baseline to 1st postoperative day
    End point values
    		 Adenosine group Placebo CABG AVR
    Number of subjects analysed
    44
    44
    43
    45
    Units: mg/l
        arithmetic mean (standard deviation)
    36.1 ± 30.9
    38.3 ± 26.1
    38.6 ± 36.5
    35.9 ± 18.2
    Statistical analysis title
    		 Comparison between medication groups
    Statistical analysis description
    Analysis in all CABG and AVR patients combined, comparing adenosine and placebo groups
    Comparison groups
    Placebo v Adenosine group
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.4
         upper limit
    		 10.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.2

    Other pre-specified: Intra- and postoperative ECG data

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    End point title
    		 Intra- and postoperative ECG data
    End point description
    ECG was recorded from baseline to the 3rd postoperative day into a computer (mostly 1 channel data)
    End point type
    Other pre-specified
    End point timeframe
    from baseline to the 3rd postoperative day
    End point values
    		 Adenosine group Placebo CABG AVR
    Number of subjects analysed
    44
    44
    43
    45
    Units: deviations from baseline
    0
    0
    0
    0
    No statistical analyses for this end point

    Other pre-specified: Metabolic changes in the right atrial myocardial tissue

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    End point title
    		 Metabolic changes in the right atrial myocardial tissue
    End point description
    right atrial tissue was harvested prior and post-CPB during the RA cannulation procedure
    End point type
    Other pre-specified
    End point timeframe
    right atrial tissue harvesting prior and post-CPB
    End point values
    		 Adenosine group Placebo CABG AVR
    Number of subjects analysed
    44
    44
    43
    45
    Units: percentage change from baseline
        arithmetic mean (standard deviation)
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    No statistical analyses for this end point

    Other pre-specified: Postoperative major complications

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    End point title
    		 Postoperative major complications
    End point description
    Recording all major surgical and medical complications (SAE, AE ) from time of induction of anesthesia to time of discharge from hospital.
    End point type
    Other pre-specified
    End point timeframe
    from time of induction of anesthesia to time of discharge from hospital.
    End point values
    		 Adenosine group Placebo CABG AVR
    Number of subjects analysed
    44
    44
    43
    45
    Units: frequency
    0
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    from operation to discharge from hospital
    Adverse event reporting additional description
    All major surgical adverse cardiovascular and cerebral complications
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Frequency threshold for reporting non-serious adverse events: 5%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: 1 SAE (stroke w/later death) in the CABG Adenosine group on postop.day 3 but unrelated to study medication

    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 results are in the process of being published, 1st CABG (mid 2022) and then AVR related results (end 2022).
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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