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    Clinical Trial Results:
    Evaluation of the Safety and Efficacy of an Edoxaban-based Compared to a Vitamin K Antagonist-based Antithrombotic Regimen in Subjects with Atrial Fibrillation Following Successful Percutaneous Coronary Intervention (PCI) With Stent Placement (ENTRUST AF-PCI)

    Summary
    EudraCT number
    		 2016-002683-14
    Trial protocol
    		 FR   IE   GB   NL   DE   LT   ES   AT   HU   PT   BE   IT  
    Global end of trial date
    06 Jun 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 May 2020
    First version publication date
    27 May 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    DSE-EDO-01-15-EU
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02866175
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Daiichi Sankyo Europe, GmbH, a Daiichi Sankyo Company
    Sponsor organisation address
    Zielstattstrasse 48, Munich, Germany, 81379
    Public contact
    Late Phase Clinical Operations, Daiichi Sankyo Europe GmbH, +49 89 7808 614, Petra.laeis@daiichi-sankyo.eu
    Scientific contact
    Late Phase Clinical Operations, Daiichi Sankyo Europe GmbH, +49 89 7808 614, Petra.laeis@daiichi-sankyo.eu
    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
    07 Jan 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jun 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to compare a 12-month antithrombotic regimen of edoxaban in combination with clopidogrel or another P2Y12 antagonist against a regimen of a vitamin K antagonist (VKA) in combination with clopidogrel or another P2Y12 antagonist and at least 1 month acetylsalicylic acid (ASA) in subjects with atrial fibrillation (AF) following successful PCI with stent placement in terms of the incidence of major or clinically relevant non-major International Society on Thrombosis and Hemostasis (ISTH)-defined bleeding (MCRB).
    Protection of trial subjects
    The study protocol, amendments, informed consent forms, and information sheets were approved by the appropriate and applicable Independent Ethics Committees or Institutional Review Boards. The study was conducted in compliance with the protocol, the ethical principles that have their origin in the Declaration of Helsinki, the International Council for Harmonisation (ICH) consolidated Guideline E6(R2) for Good Clinical Practice (GCP) (EMA/CHMP/ICH/135/1995) and applicable regulatory requirements including the following: European Commission Directive (2001/20/EC Apr 2001), and /or European Commission Directive (2005/28/EC Apr 2005), and/or European Data Protection Directive (94/46/EC), and/or General Data Protection Regulation (European Union 2016/679), and/or other applicable local regulations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Feb 2017
    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
    Spain: 115
    Country: Number of subjects enrolled
    Switzerland: 7
    Country: Number of subjects enrolled
    Taiwan: 78
    Country: Number of subjects enrolled
    Ukraine: 344
    Country: Number of subjects enrolled
    United Kingdom: 15
    Country: Number of subjects enrolled
    Austria: 26
    Country: Number of subjects enrolled
    Belgium: 80
    Country: Number of subjects enrolled
    France: 41
    Country: Number of subjects enrolled
    Germany: 167
    Country: Number of subjects enrolled
    Hungary: 103
    Country: Number of subjects enrolled
    Italy: 153
    Country: Number of subjects enrolled
    Korea, Republic of: 91
    Country: Number of subjects enrolled
    Lithuania: 45
    Country: Number of subjects enrolled
    Netherlands: 10
    Country: Number of subjects enrolled
    Poland: 140
    Country: Number of subjects enrolled
    Portugal: 24
    Country: Number of subjects enrolled
    Romania: 39
    Country: Number of subjects enrolled
    Serbia: 28
    Worldwide total number of subjects
    1506
    EEA total number of subjects
    958
    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)
    428
    From 65 to 84 years
    1007
    85 years and over
    71

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 1506 subjects who met all inclusion criteria and no exclusion criteria were enrolled in the study; 1486 subjects received treatment. A total of 20 subjects (5 Edoxaban and 15 Vitamin K antagonist) did not receive treatment.

    Pre-assignment
    Screening details
    		 The screening period started after a percutaneous coronary intervention (PCI) with stent placement. Subjects were randomized 1:1 to either a Edoxaban-based or VKA-based regimen within 4 hours and 5 days after a successful PCI.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-label study with blinded endpoint evaluation.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Edoxaban Regimen
    Arm description
    		 Subjects who were randomized to Edoxaban 60 mg once-daily or 30 mg once-daily and clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel [5 mg or 10 mg once-daily] or ticagrelor [90 mg twice-daily] may be used).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Edoxaban
    Investigational medicinal product code
    Other name
    Savaysa
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    60 mg once-daily or 30 mg once-daily, oral administration

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    Other name
    Plavix
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Clopidogrel 75 mg once daily

    Investigational medicinal product name
    Prasugrel
    Investigational medicinal product code
    Other name
    Effient
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prasugrel 5 mg or 10 mg once daily

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

    Arm title
    		 Vitamin K Antagonist Regimen
    Arm description
    		 Subjects who were randomized to VKA in combination with clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel [5 mg or 10 mg once-daily] or ticagrelor [90 mg twice-daily] may be used) and aspirin (100 mg once-daily, for a minimum of 1 month and up to 12 months duration.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Vitamin K antagonist
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    VKA once daily dosing for target international normalized ratio between 2.0 and 3.0, inclusive

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    Other name
    Plavix
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Clopidogrel 75 mg once daily

    Investigational medicinal product name
    Prasugrel
    Investigational medicinal product code
    Other name
    Effient
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prasugrel 5 mg or 10 mg once daily

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

    Number of subjects in period 1
    		Edoxaban Regimen Vitamin K Antagonist Regimen
    Started
    751
    755
    Completed
    616
    580
    Not completed
    135
    175
         Consent withdrawn by subject
    31
    52
         Physician decision
    3
    15
         Adverse event, non-fatal
    56
    54
         Death
    30
    23
         Not specified
    7
    14
         Did not receive treatment
    5
    15
         Progressive disease
    1
    1
         Lost to follow-up
    2
    -
         Lack of efficacy
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Edoxaban Regimen
    Reporting group description
    		 Subjects who were randomized to Edoxaban 60 mg once-daily or 30 mg once-daily and clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel [5 mg or 10 mg once-daily] or ticagrelor [90 mg twice-daily] may be used).

    Reporting group title
    Vitamin K Antagonist Regimen
    Reporting group description
    		 Subjects who were randomized to VKA in combination with clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel [5 mg or 10 mg once-daily] or ticagrelor [90 mg twice-daily] may be used) and aspirin (100 mg once-daily, for a minimum of 1 month and up to 12 months duration.

    Reporting group values
    		 Edoxaban Regimen Vitamin K Antagonist Regimen Total
    Number of subjects
    		 751 755 1506
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 226 202 428
        From 65-84 years
    		 489 518 1007
        85 years and over
    		 36 35 71
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 69.4 ± 9.74 70.1 ± 9.51 -
    Gender categorical
    Units: Subjects
        Female
    		 194 192 386
        Male
    		 557 563 1120
    Region of Enrollment
    Units: Subjects
        Romania
    		 17 22 39
        Hungary
    		 49 54 103
        Ukraine
    		 169 175 344
        United Kingdom
    		 6 9 15
        Portugal
    		 12 12 24
        Switzerland
    		 2 5 7
        Spain
    		 58 57 115
        Austria
    		 18 8 26
        Netherlands
    		 3 7 10
        South Korea
    		 50 41 91
        Belgium
    		 43 37 80
        Taiwan
    		 32 46 78
        Poland
    		 74 66 140
        Italy
    		 69 84 153
        France
    		 21 20 41
        Lithuania
    		 24 21 45
        Serbia
    		 17 11 28
        Germany
    		 87 80 167

    End points

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    End points reporting groups
    Reporting group title
    Edoxaban Regimen
    Reporting group description
    		 Subjects who were randomized to Edoxaban 60 mg once-daily or 30 mg once-daily and clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel [5 mg or 10 mg once-daily] or ticagrelor [90 mg twice-daily] may be used).

    Reporting group title
    Vitamin K Antagonist Regimen
    Reporting group description
    		 Subjects who were randomized to VKA in combination with clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel [5 mg or 10 mg once-daily] or ticagrelor [90 mg twice-daily] may be used) and aspirin (100 mg once-daily, for a minimum of 1 month and up to 12 months duration.

    Primary: Number of Participants With Adjudicated Major or Clinically Relevant Non-major Bleeding As First Event Defined by International Society on Thrombosis and Haemostasis Following Edoxaban-based Regimen Compared With Vitamin K Antagonist (VKA)-Based Regimen

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    End point title
    		 Number of Participants With Adjudicated Major or Clinically Relevant Non-major Bleeding As First Event Defined by International Society on Thrombosis and Haemostasis Following Edoxaban-based Regimen Compared With Vitamin K Antagonist (VKA)-Based Regimen [1]
    End point description
    Subjects' first major or clinically relevant non-major bleeding (MCRB) events were reported. International Society on Thrombosis and Hemostasis (ISTH) defined bleeding events included: MCRB, major bleeding, including fatal bleeding (intracranial and non-intracranial), symptomatic intracranial hemorrhage, symptomatic bleeding in a critical area or organ, and clinically overt and causing ≥2.0 g/dL adjusted hemoglobin loss, clinically relevant non-major (CRNM) bleeding, minor bleedings, any bleeding (defined as the composite of major, CRNM, and minor bleeding), life-threatening bleeding, provoked (spontaneous, instrumental/traumatic, unknown) bleeding, and spontaneous bleeding.
    End point type
    Primary
    End point timeframe
    Day 1 to 12 months postdose
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and the study drugs administered for this outcome.
    End point values
    		 Edoxaban Regimen Vitamin K Antagonist Regimen
    Number of subjects analysed
    751
    755
    Units: participants
    number (not applicable)
        Composite MCRB
    128
    152
        Major bleeding
    39
    44
        Clinically relevant non-major bleeding
    89
    108
    No statistical analyses for this end point

    Secondary: Number of Participants With Adjudicated Major, Clinically Relevant Non-major and Minor Bleeding (All Events) Defined by International Society on Thrombosis and Haemostasis Following Edoxaban-based Regimen Compared With Vitamin K Antagonist-Based Regimen

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    End point title
    		 Number of Participants With Adjudicated Major, Clinically Relevant Non-major and Minor Bleeding (All Events) Defined by International Society on Thrombosis and Haemostasis Following Edoxaban-based Regimen Compared With Vitamin K Antagonist-Based Regimen
    End point description
    All major, clinically relevant non-major and minor bleeding are reported for the secondary outcome. Subjects may have experiences more than 1 bleeding event, all occurrences are reported. Subjects with International Society on Thrombosis and Hemostasis (ISTH) defined bleeding events included: major or clinically relevant non-major bleeding (MCRB), major bleeding, including fatal bleeding (intracranial and non-intracranial), symptomatic intracranial hemorrhage, symptomatic bleeding in a critical area or organ, and clinically overt and causing ≥2.0 g/dL adjusted hemoglobin loss, clinically relevant non-major (CRNM) bleeding, minor bleedings, any bleeding (defined as the composite of major, CRNM, and minor bleeding), life-threatening bleeding, provoked (spontaneous, instrumental/traumatic, unknown) bleeding, and spontaneous bleeding.
    End point type
    Secondary
    End point timeframe
    Day 1 to 12 months postdose
    End point values
    		 Edoxaban Regimen Vitamin K Antagonist Regimen
    Number of subjects analysed
    751
    755
    Units: participants
    number (not applicable)
        Major bleeding
    45
    48
        Clinically relevant non-major bleeding
    97
    114
        Minor bleeding
    116
    125
        Symptomatic intracranial hemorrhage
    4
    9
        Fatal major bleeding
    1
    7
        Fatal intracranial hemorrhage
    0
    4
        Life-threatening bleeding
    5
    8
        Spontaneous bleeding
    184
    210
    No statistical analyses for this end point

    Secondary: Number of Participants With Adjudicated Major, Minor, and Minimal Bleeding by Thrombolysis in Myocardial Infarction (TIMI) Definition Following Edoxaban-based Regimen Compared With Vitamin K Antagonist (VKA)-Based Regimen

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    End point title
    		 Number of Participants With Adjudicated Major, Minor, and Minimal Bleeding by Thrombolysis in Myocardial Infarction (TIMI) Definition Following Edoxaban-based Regimen Compared With Vitamin K Antagonist (VKA)-Based Regimen
    End point description
    Thrombolysis in Myocardial Infarction (TIMI) defined bleeding events included: Major bleeding (including fatal bleeding and non-fatal bleeding [fulfilling the TIMI major bleeding definition], major or minor bleeding, minor bleeding, minimal bleeding, and any bleeding (defined as composite of major, minor, and minimal bleeding)
    End point type
    Secondary
    End point timeframe
    Day 1 to 12 months postdose
    End point values
    		 Edoxaban Regimen Vitamin K Antagonist Regimen
    Number of subjects analysed
    751
    755
    Units: participants
    number (not applicable)
        Major bleeding
    15
    24
        Fatal bleeding
    1
    4
        Major or minor bleeding
    124
    144
        Minor bleeding
    113
    126
        Minimal bleeding
    117
    131
    No statistical analyses for this end point

    Secondary: Number of Participants With Bleeding Academic Research Consortium (BARC) Type 1, 2, 3, and 5 Bleeding According to the BARC Definitions Following Edoxaban-based Regimen Compared With Vitamin K Antagonist (VKA)- Based Regimen

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    End point title
    		 Number of Participants With Bleeding Academic Research Consortium (BARC) Type 1, 2, 3, and 5 Bleeding According to the BARC Definitions Following Edoxaban-based Regimen Compared With Vitamin K Antagonist (VKA)- Based Regimen
    End point description
    Bleeding Academic Research Consortium (BARC) bleeding events included: Bleeding (defined by BARC type 3 or 5), bleeding (defined by BARC type 2, 3, or 5), and any bleeding (defined as the composite of BARC type 1, 2, 3, or 5), where increases in BARC type indicate worse outcome. Type 1: bleeding that is not actionable and does not cause the patient to seek unscheduled performance of studies, hospitalization, or treatment by a healthcare professional; may include episodes leading to self-discontinuation of medical therapy by the patient without consultation; Type 2: any overt, actionable sign of hemorrhage that does not fit the criteria for type 3, 4, or 5 but does meet at least one of the following criteria: (1) requiring nonsurgical, medical intervention, (2) leading to hospitalization or increased level of care, or (3) prompting evaluation; Type 3: Overt bleeding plus hemoglobin drop of 3 to ≤5 g/dL (3a), ≥5 g/dl (3b), and intracranial hemorrhage (3c) Type 5: Fatal bleeding
    End point type
    Secondary
    End point timeframe
    Day 1 to 12 months postdose
    End point values
    		 Edoxaban Regimen Vitamin K Antagonist Regimen
    Number of subjects analysed
    751
    755
    Units: participants
    number (not applicable)
        Bleeding (BARC Type 3 or 5)
    36
    42
        Bleeding (BARC Type 2, 3 or 5)
    124
    144
        Bleeding (BARC Type 1, 2, 3, or 5)
    207
    242
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) Following Edoxaban-based Regimen Compared With Vitamin K Antagonist (VKA)-Based Regimen

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    End point title
    		 Number of Subjects With Treatment-emergent Adverse Events (TEAEs) Following Edoxaban-based Regimen Compared With Vitamin K Antagonist (VKA)-Based Regimen
    End point description
    Treatment-emergent adverse events (TEAEs) in >1.0% of subjects were defined as events which started on or after first dose of the assigned study drug (edoxaban and VKA) or started prior to but then worsened after the first dose of the assigned study drug.
    End point type
    Secondary
    End point timeframe
    Day 1 to 30 days after the last dose
    End point values
    		 Edoxaban Regimen Vitamin K Antagonist Regimen
    Number of subjects analysed
    746
    740
    Units: participants
    number (not applicable)
        Any TEAE
    457
    447
        Infections and Infestations
    145
    140
        Nasopharyngitis
    25
    22
        Pneumonia
    20
    22
        Bronchitis
    19
    20
        Urinary tract infection
    14
    19
        Respiratory tract infection
    12
    15
        Influenza
    10
    7
        Cardiac Disorders
    136
    134
        Cardiac failure
    40
    47
        Atrial fibrillation
    39
    41
        Bradycardia
    10
    7
        Cardiac failure congestive
    8
    8
        Ventricular extrasystoles
    7
    8
        Tachycardia
    11
    3
        General Disorders & Administration Site Condition
    113
    98
        Non-cardiac chest pain
    30
    24
        Oedema peripheral
    31
    22
        Asthenia
    21
    14
        Chest pain
    7
    11
        Fatigue
    11
    6
        Gastrointestinal Disorders
    110
    83
        Diarrhea
    23
    19
        Constipation
    11
    7
        Abdominal pain upper
    6
    10
        Gastritis
    9
    5
        Nausea
    8
    5
        Dyspepsia
    8
    3
        Respiratory, Thoracic, and Mediastinal Disorders
    87
    72
        Dyspnoea
    22
    26
        Cough
    21
    11
        Dyspnoea exertional
    18
    5
        Chronic obstructive pulmonary disease
    6
    10
        Musculoskeletal and Connective Tissue Disorders
    69
    83
        Back pain
    14
    14
        Arthralgia
    11
    12
        Pain in extremity
    5
    13
        Myalgia
    8
    8
        Osteoarthritis
    9
    5
        Investigations
    70
    79
        Blood creatinine increased
    15
    13
        Alanine aminotransferase increased
    8
    13
        Blood pressure increased
    12
    8
        Creatinine renal clearance decreased
    12
    7
        Aspartate aminotransferase increased
    7
    11
        International normalized ratio increased
    0
    12
        Nervous System Disorders
    83
    65
        Dizziness
    30
    22
        Headache
    19
    12
        Syncope
    8
    6
        Vascular Disorders
    55
    62
        Hypertension
    23
    23
        Hypotension
    14
    14
        Hypertensive crisis
    11
    8
        Renal and Urinary Disorders
    49
    55
        Renal failure
    11
    12
        Acute kidney injury
    8
    13
        Renal impairment
    7
    8
        Injury, Poisoning, and Procedural Complications
    44
    44
        Fall
    8
    12
        Skin and Subcutaneous Tissue Disorders
    55
    33
        Pruritus
    12
    7
        Rash
    10
    9
        Metabolism and Nutrition Disorders
    42
    42
        Gout
    11
    4
        Blood and Lymphatic System Disorders
    41
    35
        Anaemia
    19
    20
        Psychiatric Disorder
    23
    20
        Insomnia
    8
    8
        Ear and Labyrinth Disorders
    12
    16
        Vertigo
    8
    5
    No statistical analyses for this end point

    Secondary: Number of Subjects With Study Drug-related Treatment-emergent Adverse Events (TEAEs) Experienced by 2 or More Subjects Following Edoxaban-based Regimen Compared With Vitamin K Antagonist (VKA)-Based Regimen

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    End point title
    		 Number of Subjects With Study Drug-related Treatment-emergent Adverse Events (TEAEs) Experienced by 2 or More Subjects Following Edoxaban-based Regimen Compared With Vitamin K Antagonist (VKA)-Based Regimen
    End point description
    Study drug-related treatment-emergent adverse events (TEAEs) (experienced by 2 or more subjects) were defined as events which started on or after first dose of the assigned study drug (edoxaban and VKA) or started prior to but then worsened after the first dose of the assigned study drug and were found to be related to treatment by the Investigator.
    End point type
    Secondary
    End point timeframe
    Day 1 to 30 days after the last dose
    End point values
    		 Edoxaban Regimen Vitamin K Antagonist Regimen
    Number of subjects analysed
    746
    740
    Units: participants
    number (not applicable)
        Any Related TEAE
    57
    48
        Blood and Lymphatic System Disorders
    12
    11
        Anaemia
    9
    7
        Haemorrhagic anaemia
    0
    2
        Normochromic normocytic anaemia
    2
    0
        Investigations
    7
    16
        International normalised ratio increased
    0
    12
        Blood creatinine increased
    3
    1
        Creatinine renal clearance decreased
    2
    2
        Haemoglobin decreased
    2
    0
        Gastrointestinal Disorders
    12
    4
        Abdominal pain upper
    3
    1
        Dyspepsia
    3
    1
        Nausea
    2
    0
        Skin and Subcutaneous Tissue Disorders
    6
    5
        Pruritus
    2
    1
        Rash
    1
    2
        Injury, Poisoning, and Procedural Complications
    1
    7
        Overdose
    0
    4
        Contusion
    1
    1
        General Disorders & Administration Site Conditions
    6
    1
        Death
    3
    0
        Renal and Urinary Disorders
    2
    2
        Chronic kidney disease
    1
    1
        Renal failure
    1
    1
        Nervous System Disorders
    3
    0
        Dizziness
    2
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Main Efficacy Endpoints For the Overall Study Period Following Edoxaban-based Regimen Compared With Vitamin K Antagonist (VKA)-Based Regimen

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    End point title
    		 Number of Participants With Main Efficacy Endpoints For the Overall Study Period Following Edoxaban-based Regimen Compared With Vitamin K Antagonist (VKA)-Based Regimen
    End point description
    The main efficacy endpoints were defined as the composite of CV death (ARC), stroke (protocol defined), systemic embolic event (SEE), myocardial infarction (MI), or definite stent thrombosis.
    End point type
    Secondary
    End point timeframe
    Day 1 to 12 months postdose
    End point values
    		 Edoxaban Regimen Vitamin K Antagonist Regimen
    Number of subjects analysed
    751
    755
    Units: participants
    number (not applicable)
        Composite MEE event
    49
    46
        Cardiovascular death (ARC)
    10
    12
        Stroke (Protocol definition)
    10
    11
        Systemic embolic event
    0
    0
        Myocardial infarction
    22
    18
        Definite stent thrombosis
    7
    5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from Day 1 to 30 days after last dose, up to 2 years, 4 months.
    Adverse event reporting additional description
    Adverse events were reported from the Safety Analysis Set (746 Edoxaban regimen; 740 Vitamin K Antagonist regimen).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Edoxaban Regimen
    Reporting group description
    		 Subjects who were randomized to Edoxaban 60 mg once-daily or 30 mg once-daily and clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel [5 mg or 10 mg once-daily] or ticagrelor [90 mg twice-daily] may be used).

    Reporting group title
    Vitamin K Antagonist Regimen
    Reporting group description
    		 Subjects who were randomized to VKA in combination with clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel [5 mg or 10 mg once-daily] or ticagrelor [90 mg twice-daily] may be used) and aspirin (100 mg once-daily, for a minimum of 1 month and up to 12 months duration.

    Serious adverse events
    		 Edoxaban Regimen Vitamin K Antagonist Regimen
    Total subjects affected by serious adverse events
         subjects affected / exposed
    176 / 746 (23.59%)
    175 / 740 (23.65%)
         number of deaths (all causes)
    46
    37
         number of deaths resulting from adverse events
    29
    24
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma gastric
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical fibroxanthoma
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 746 (0.00%)
    2 / 740 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder neoplasm
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    2 / 746 (0.27%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibrosarcoma
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic neoplasm
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectosigmoid cancer
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tongue neoplasm malignant stage unspecified
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic dissection
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extremity necrosis
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 746 (0.27%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    4 / 746 (0.54%)
    3 / 740 (0.41%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 746 (0.00%)
    2 / 740 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 746 (0.13%)
    2 / 740 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Coronary revascularisation
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 746 (0.27%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    2 / 746 (0.27%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    4 / 746 (0.54%)
    3 / 740 (0.41%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 3
         deaths causally related to treatment / all
    2 / 4
    0 / 3
    Drowning
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernia
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    6 / 746 (0.80%)
    3 / 740 (0.41%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 746 (0.13%)
    3 / 740 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Vascular stent restenosis
         subjects affected / exposed
    2 / 746 (0.27%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular stent thrombosis
         subjects affected / exposed
    2 / 746 (0.27%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Immune system disorders
    Amyloidosis
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    3 / 746 (0.40%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical dysplasia
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    2 / 746 (0.27%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    2 / 746 (0.27%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spermatocele
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary edema
         subjects affected / exposed
    2 / 746 (0.27%)
    3 / 740 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 746 (0.00%)
    3 / 740 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    5 / 746 (0.67%)
    9 / 740 (1.22%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dyspnoea
         subjects affected / exposed
    2 / 746 (0.27%)
    2 / 740 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea at rest
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 746 (0.13%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 746 (0.00%)
    2 / 740 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    3 / 746 (0.40%)
    2 / 740 (0.27%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 746 (0.00%)
    2 / 740 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 746 (0.13%)
    2 / 740 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 746 (0.00%)
    2 / 740 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device capturing issue
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    International normalised ratio increased
         subjects affected / exposed
    0 / 746 (0.00%)
    3 / 740 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Arterial restenosis
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Compression fracture
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Costal cartilage fracture
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 746 (0.00%)
    2 / 740 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 746 (0.13%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 746 (0.13%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 746 (0.00%)
    2 / 740 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product use issue
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound necrosis
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Phimosis
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute left ventricular failure
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adams-Stokes syndrome
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    2 / 746 (0.27%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    20 / 746 (2.68%)
    14 / 740 (1.89%)
         occurrences causally related to treatment / all
    0 / 20
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    3 / 746 (0.40%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    2 / 746 (0.27%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 746 (0.00%)
    2 / 740 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    2 / 746 (0.27%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 746 (0.27%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    29 / 746 (3.89%)
    35 / 740 (4.73%)
         occurrences causally related to treatment / all
    0 / 29
    4 / 35
         deaths causally related to treatment / all
    0 / 1
    0 / 4
    Cardiac failure acute
         subjects affected / exposed
    2 / 746 (0.27%)
    4 / 740 (0.54%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiac failure chronic
         subjects affected / exposed
    3 / 746 (0.40%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    6 / 746 (0.80%)
    5 / 740 (0.68%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac ventricular thrombosis
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    2 / 746 (0.27%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    2 / 746 (0.27%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Cardiovascular insufficiency
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coronary artery disease
         subjects affected / exposed
    2 / 746 (0.27%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 746 (0.13%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 746 (0.13%)
    3 / 740 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulseless electrical activity
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus arrest
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    2 / 746 (0.27%)
    3 / 740 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    2 / 746 (0.27%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    2 / 746 (0.27%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    3 / 746 (0.40%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Carotid artery stenosis
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervicogenic headache
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic neuropathy
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Monoparesis
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 746 (0.13%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    3 / 746 (0.40%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertebrobasilar insufficiency
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 746 (0.54%)
    3 / 740 (0.41%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypochromic anaemia
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune thrombocytopenic purpura
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrogenic anaemia
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Normochromic normocytic anaemia
         subjects affected / exposed
    2 / 746 (0.27%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 746 (0.13%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iridocyclitis
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis chronic
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 746 (0.27%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 746 (0.13%)
    2 / 740 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute abdomen
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal stenosis
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dental cyst
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 746 (0.27%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 746 (0.00%)
    2 / 740 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 746 (0.00%)
    2 / 740 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal polyp
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary fistula
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    3 / 746 (0.40%)
    4 / 740 (0.54%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    2 / 746 (0.27%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatorenal syndrome
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Cold sweat
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cutaneous lupus erythematosus
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic foot
         subjects affected / exposed
    2 / 746 (0.27%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pemphigoid
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psoriasis
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 746 (0.40%)
    7 / 740 (0.95%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Calculus urethral
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    End stage renal disease
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nephrolithiasis
         subjects affected / exposed
    1 / 746 (0.13%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prerenal failure
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal artery stenosis
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    5 / 746 (0.67%)
    2 / 740 (0.27%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    2 / 746 (0.27%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chondropathy
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 746 (0.00%)
    3 / 740 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint swelling
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Monarthritis
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal discomfort
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathic arthropathy
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    2 / 746 (0.27%)
    2 / 740 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rheumatic disorder
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Aeromonas infection
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 746 (0.13%)
    2 / 740 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 746 (0.13%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    3 / 746 (0.40%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device-related infection
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 746 (0.13%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Implant site infection
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious colitis
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    1 / 746 (0.13%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis cryptococcal
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal abscess
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    14 / 746 (1.88%)
    13 / 740 (1.76%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 13
         deaths causally related to treatment / all
    0 / 3
    0 / 3
    Postoperative wound infection
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 746 (0.00%)
    2 / 740 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 746 (0.27%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Septic shock
         subjects affected / exposed
    3 / 746 (0.40%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Sialoadenitis
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 746 (0.40%)
    2 / 740 (0.27%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 746 (0.13%)
    0 / 740 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    2 / 746 (0.27%)
    2 / 740 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic metabolic decompensation
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 746 (0.00%)
    1 / 740 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Edoxaban Regimen Vitamin K Antagonist Regimen
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    457 / 746 (61.26%)
    447 / 740 (60.41%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    23 / 746 (3.08%)
    23 / 740 (3.11%)
         occurrences all number
    23
    23
    Hypertensive crisis
         subjects affected / exposed
    11 / 746 (1.47%)
    8 / 740 (1.08%)
         occurrences all number
    11
    8
    Hypotension
         subjects affected / exposed
    14 / 746 (1.88%)
    14 / 740 (1.89%)
         occurrences all number
    14
    14
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    21 / 746 (2.82%)
    14 / 740 (1.89%)
         occurrences all number
    21
    14
    Chest pain
         subjects affected / exposed
    7 / 746 (0.94%)
    11 / 740 (1.49%)
         occurrences all number
    7
    11
    Fatigue
         subjects affected / exposed
    11 / 746 (1.47%)
    6 / 740 (0.81%)
         occurrences all number
    11
    6
    Non-cardiac chest pain
         subjects affected / exposed
    30 / 746 (4.02%)
    24 / 740 (3.24%)
         occurrences all number
    30
    24
    Oedema peripheral
         subjects affected / exposed
    31 / 746 (4.16%)
    22 / 740 (2.97%)
         occurrences all number
    31
    22
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    6 / 746 (0.80%)
    10 / 740 (1.35%)
         occurrences all number
    6
    10
    Cough
         subjects affected / exposed
    21 / 746 (2.82%)
    11 / 740 (1.49%)
         occurrences all number
    21
    11
    Dyspnoea
         subjects affected / exposed
    22 / 746 (2.95%)
    26 / 740 (3.51%)
         occurrences all number
    22
    26
    Dyspnoea exertional
         subjects affected / exposed
    18 / 746 (2.41%)
    5 / 740 (0.68%)
         occurrences all number
    18
    5
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    8 / 746 (1.07%)
    8 / 740 (1.08%)
         occurrences all number
    8
    8
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    8 / 746 (1.07%)
    13 / 740 (1.76%)
         occurrences all number
    8
    13
    Aspartate aminotransferase increased
         subjects affected / exposed
    7 / 746 (0.94%)
    11 / 740 (1.49%)
         occurrences all number
    7
    11
    Blood creatinine increased
         subjects affected / exposed
    15 / 746 (2.01%)
    13 / 740 (1.76%)
         occurrences all number
    15
    13
    Blood pressure increased
         subjects affected / exposed
    12 / 746 (1.61%)
    8 / 740 (1.08%)
         occurrences all number
    12
    8
    Creatinine renal clearance increased
         subjects affected / exposed
    12 / 746 (1.61%)
    7 / 740 (0.95%)
         occurrences all number
    12
    7
    International normalised ratio increased
         subjects affected / exposed
    0 / 746 (0.00%)
    12 / 740 (1.62%)
         occurrences all number
    0
    12
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    8 / 746 (1.07%)
    12 / 740 (1.62%)
         occurrences all number
    8
    12
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    39 / 746 (5.23%)
    41 / 740 (5.54%)
         occurrences all number
    39
    41
    Bradycardia
         subjects affected / exposed
    10 / 746 (1.34%)
    7 / 740 (0.95%)
         occurrences all number
    10
    7
    Cardiac failure
         subjects affected / exposed
    40 / 746 (5.36%)
    47 / 740 (6.35%)
         occurrences all number
    40
    47
    Cardiac failure congestive
         subjects affected / exposed
    8 / 746 (1.07%)
    8 / 740 (1.08%)
         occurrences all number
    8
    8
    Tachycardia
         subjects affected / exposed
    11 / 746 (1.47%)
    3 / 740 (0.41%)
         occurrences all number
    11
    3
    Ventricular extrasystoles
         subjects affected / exposed
    7 / 746 (0.94%)
    8 / 740 (1.08%)
         occurrences all number
    7
    8
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    30 / 746 (4.02%)
    22 / 740 (2.97%)
         occurrences all number
    30
    22
    Headache
         subjects affected / exposed
    19 / 746 (2.55%)
    12 / 740 (1.62%)
         occurrences all number
    19
    12
    Syncope
         subjects affected / exposed
    8 / 746 (1.07%)
    6 / 740 (0.81%)
         occurrences all number
    8
    6
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    19 / 746 (2.55%)
    20 / 740 (2.70%)
         occurrences all number
    19
    20
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    8 / 746 (1.07%)
    5 / 740 (0.68%)
         occurrences all number
    8
    5
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    6 / 746 (0.80%)
    10 / 740 (1.35%)
         occurrences all number
    6
    10
    Constipation
         subjects affected / exposed
    11 / 746 (1.47%)
    7 / 740 (0.95%)
         occurrences all number
    11
    7
    Diarrhoea
         subjects affected / exposed
    23 / 746 (3.08%)
    19 / 740 (2.57%)
         occurrences all number
    23
    19
    Dyspepsia
         subjects affected / exposed
    8 / 746 (1.07%)
    3 / 740 (0.41%)
         occurrences all number
    8
    3
    Gastritis
         subjects affected / exposed
    9 / 746 (1.21%)
    5 / 740 (0.68%)
         occurrences all number
    9
    5
    Nausea
         subjects affected / exposed
    8 / 746 (1.07%)
    5 / 740 (0.68%)
         occurrences all number
    8
    5
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    12 / 746 (1.61%)
    7 / 740 (0.95%)
         occurrences all number
    12
    7
    Rash
         subjects affected / exposed
    10 / 746 (1.34%)
    9 / 740 (1.22%)
         occurrences all number
    10
    9
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    8 / 746 (1.07%)
    13 / 740 (1.76%)
         occurrences all number
    8
    13
    Renal failure
         subjects affected / exposed
    11 / 746 (1.47%)
    12 / 740 (1.62%)
         occurrences all number
    11
    12
    Renal impairment
         subjects affected / exposed
    7 / 746 (0.94%)
    8 / 740 (1.08%)
         occurrences all number
    7
    8
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    11 / 746 (1.47%)
    12 / 740 (1.62%)
         occurrences all number
    11
    12
    Back pain
         subjects affected / exposed
    14 / 746 (1.88%)
    14 / 740 (1.89%)
         occurrences all number
    14
    14
    Myalgia
         subjects affected / exposed
    8 / 746 (1.07%)
    8 / 740 (1.08%)
         occurrences all number
    8
    8
    Osteoarthritis
         subjects affected / exposed
    9 / 746 (1.21%)
    5 / 740 (0.68%)
         occurrences all number
    9
    5
    Pain in extremity
         subjects affected / exposed
    5 / 746 (0.67%)
    13 / 740 (1.76%)
         occurrences all number
    5
    13
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    19 / 746 (2.55%)
    20 / 740 (2.70%)
         occurrences all number
    19
    20
    Influenza
         subjects affected / exposed
    10 / 746 (1.34%)
    7 / 740 (0.95%)
         occurrences all number
    10
    7
    Nasopharyngitis
         subjects affected / exposed
    25 / 746 (3.35%)
    22 / 740 (2.97%)
         occurrences all number
    25
    22
    Pneumonia
         subjects affected / exposed
    20 / 746 (2.68%)
    22 / 740 (2.97%)
         occurrences all number
    20
    22
    Respiratory tract infection
         subjects affected / exposed
    12 / 746 (1.61%)
    15 / 740 (2.03%)
         occurrences all number
    12
    15
    Urinary tract infection
         subjects affected / exposed
    14 / 746 (1.88%)
    19 / 740 (2.57%)
         occurrences all number
    14
    19
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    11 / 746 (1.47%)
    4 / 740 (0.54%)
         occurrences all number
    11
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Jan 2017
    Updated secondary exploratory objectives, study design, and subject eligibility criteria; amended the procedure for removing subjects from therapy; revised procedures prior to and following randomization; clarified assessments to be performed at each site; and included a definition of unexpected adverse events.
    28 Feb 2017
    Updated exclusion criteria for subjects with renal impairment and end stage renal disease.

    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
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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
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