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    Clinical Trial Results:
    Cost-effectiveness of CYP2C19 guided treatment with antiplatelet drugs in patients with ST-segment-elevation myocardial infarction undergoing immediate percutaneous coronary intervention with stent implantation

    Summary
    EudraCT number
    		 2010-024667-40
    Trial protocol
    		 NL  
    Global end of trial date
    04 Apr 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 May 2021
    First version publication date
    06 May 2021
    Other versions
    Summary report(s)
    		 Trial results

    Trial information

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    Trial identification
    Sponsor protocol code
    PGxSTEMI08
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01761786
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 NTR: NTR3017
    Sponsors
    Sponsor organisation name
    St Antonius hospital
    Sponsor organisation address
    Koekoekslaan 1, Nieuwegein, Netherlands,
    Public contact
    Jurrien M ten Berg, St. Antonius Hospital, 31 883201232, j.ten.berg@antoniusziekenhuis.nl
    Scientific contact
    Jurrien M ten Berg, St. Antonius Hospital, 31 883201232, j.ten.berg@antoniusziekenhuis.nl
    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
    04 Apr 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Apr 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine whether the CYP2C19 genotype guided antiplatelet treatment strategy is not inferior to a treatment strategy with the newer antiplatelet drugs i.e. ticagrelor and prasugrel (control group) in terms of the composite of death, recurrent MI, definite stent thrombosis, stroke and PLATO major bleeding at 1 year, in patients undergoing primary PCI for STEMI. If non-inferiority is proven, analysis will be performed for superiority. To determine whether the genotype guided treatment strategy is superior to a treatment of the control group in terms of a composite endpoint of PLATO major and minor bleeding. To assess the quality of life of patients and health-care resource use in both treatment groups to calculate Quality Adjusted Life Years (QALY’s) and net costs per life-year and QALY.
    Protection of trial subjects
    Blood samples were collected at the same time as other blood samples. Thus not requiring additional vena punctures.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jun 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 84
    Country: Number of subjects enrolled
    Netherlands: 2523
    Country: Number of subjects enrolled
    Italy: 144
    Worldwide total number of subjects
    2751
    EEA total number of subjects
    2751
    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)
    1627
    From 65 to 84 years
    1074
    85 years and over
    50

    Subject disposition

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    Recruitment
    Recruitment details
    		 Inclusion between june 2011 and april 2018

    Pre-assignment
    Screening details
    		 Inclusion criteria 1) more than 21 years of age with symptoms of acute myocardial infarction of more than 30 minutes but less than 12 hours 2) performed primary PCI with stenting for STEMI

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Assessor [1]
    Blinding implementation details
    Outcome assessor was blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Genotype-guided
    Arm description
    		 Carriers of CYP2C19*2 or *3 loss-of-function alleles were treated with ticagrelor/prasugrel while noncarriers were treated with clopidogrel
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    75mg once daily

    Investigational medicinal product name
    Ticagrelor
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    90mg twice daily

    Investigational medicinal product name
    Prasugrel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10mg once daily or 5mg once daily according to the guideline

    Arm title
    		 Standard treatment
    Arm description
    		 Ticagrelor or prasugrel according to guideline instructions
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ticagrelor
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    90mg twice daily

    Investigational medicinal product name
    Prasugrel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10mg once daily or 5mg once daily according to the guideline

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: The members of the clinical event committee were blinded for the treatment allocation of the trial subjects.
    Number of subjects in period 1
    		Genotype-guided Standard treatment
    Started
    1370
    1381
    Completed
    1240
    1245
    Not completed
    130
    136
         Consent withdrawn by subject
    33
    38
         Duplicate randomization
    6
    7
         Included under older protocol
    89
    90
         Lost to follow-up
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Genotype-guided
    Reporting group description
    		 Carriers of CYP2C19*2 or *3 loss-of-function alleles were treated with ticagrelor/prasugrel while noncarriers were treated with clopidogrel

    Reporting group title
    Standard treatment
    Reporting group description
    		 Ticagrelor or prasugrel according to guideline instructions

    Reporting group values
    		 Genotype-guided Standard treatment Total
    Number of subjects
    		 1370 1381 2751
    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
        arithmetic mean (standard deviation)
    		 61.9 ± 11.1 61.4 ± 11.5 -
    Gender categorical
    Units: Subjects
        Female
    		 317 309 626
        Male
    		 1053 1072 2125

    End points

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    End points reporting groups
    Reporting group title
    Genotype-guided
    Reporting group description
    		 Carriers of CYP2C19*2 or *3 loss-of-function alleles were treated with ticagrelor/prasugrel while noncarriers were treated with clopidogrel

    Reporting group title
    Standard treatment
    Reporting group description
    		 Ticagrelor or prasugrel according to guideline instructions

    Primary: Primary outcome

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    End point title
    		 Primary outcome
    End point description
    All-cause death, recurrent myocardial infarction, stent thrombosis, stroke, PLATO major bleeding
    End point type
    Primary
    End point timeframe
    12 months after primary PCI
    End point values
    		 Genotype-guided Standard treatment
    Number of subjects analysed
    1242
    1246
    Units: 136
        number (not applicable)
    63
    73
    Statistical analysis title
    		 Primary outcome non-inferiority
    Comparison groups
    Genotype-guided v Standard treatment
    Number of subjects included in analysis
    2488
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.001
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Primary outcome superiority analysis
    Comparison groups
    Genotype-guided v Standard treatment
    Number of subjects included in analysis
    2488
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.21

    Primary: Primary bleeding outcome

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    End point title
    		 Primary bleeding outcome
    End point description
    End point type
    Primary
    End point timeframe
    12 months after primary PCI
    End point values
    		 Genotype-guided Standard treatment
    Number of subjects analysed
    1242
    1248
    Units: 278
        number (not applicable)
    122
    156
    Statistical analysis title
    		 Primary bleeding outcome
    Comparison groups
    Genotype-guided v Standard treatment
    Number of subjects included in analysis
    2490
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.04
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 0.98

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    12 months
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 No dictionary
    Dictionary version
    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: As per the trial protocol non-serious adverse events were not systematically collected, since the trial included only approved drugs.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Feb 2012
    The standard treatment group switched from using clopidogrel as standard treatment to using ticagrelor or prasugrel as standard treatment due to a change in the guidelines.

    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.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31479209
    http://www.ncbi.nlm.nih.gov/pubmed/32139231
    http://www.ncbi.nlm.nih.gov/pubmed/33722066
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    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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