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    Clinical Trial Results:
    A Phase 4 Trial to Assess the Effectiveness of Apixaban Compared With Usual Care Anticoagulation in Subjects With Nonvalvular Atrial Fibrillation Undergoing Cardioversion

    Summary
    EudraCT number
    		 2014-001231-36
    Trial protocol
    		 DK   ES   BE   SE   DE  
    Global end of trial date
    08 Feb 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Feb 2018
    First version publication date
    02 Feb 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    B0661025/CV185-267
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02100228
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    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 Jul 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Feb 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the occurrence of clinical endpoints in nonvalvular atrial fibrillation subjects (i.e., without rheumatic mitral valve disease, a prosthetic heart valve, or valve repair) indicated for cardioversion and treated with apixaban or usual care (parenteral heparin and/or oral anticoagulation with vitamin K antagonist, excluding other novel oral anticoagulant).
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Jul 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 135
    Country: Number of subjects enrolled
    Canada: 38
    Country: Number of subjects enrolled
    Denmark: 70
    Country: Number of subjects enrolled
    Germany: 320
    Country: Number of subjects enrolled
    Israel: 295
    Country: Number of subjects enrolled
    Italy: 55
    Country: Number of subjects enrolled
    Japan: 49
    Country: Number of subjects enrolled
    Korea, Republic of: 102
    Country: Number of subjects enrolled
    Romania: 79
    Country: Number of subjects enrolled
    Spain: 57
    Country: Number of subjects enrolled
    Sweden: 84
    Country: Number of subjects enrolled
    United States: 216
    Worldwide total number of subjects
    1500
    EEA total number of subjects
    800
    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)
    679
    From 65 to 84 years
    774
    85 years and over
    47

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Fifteen hundred subjects were enrolled at 134 centers. The study was conducted from 14 July 2014 to 08 Feb 2017.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Apixaban
    Arm description
    		 Subjects with non-valvular atrial fibrillation undergoing cardioversion, received Apixaban orally for 30 days after cardioversion or 90 days after randomization if cardioversion was not performed. The dosing of Apixaban was based on investigator’s judgement as per local label for the prevention of stroke and systemic embolism in subjects.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Apixaban
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered orally with 2.5 or 5 milligram (mg) of Apixaban twice daily for 30 days following cardioversion or 90 days post randomization if cardioversion was not performed within that timeframe.

    Arm title
    		 Parenteral heparin/Oral Vitamin K Antagonist (Usual Care)
    Arm description
    		 Subjects with non-valvular atrial fibrillation undergoing cardioversion, received parenteral heparin and/or oral Vitamin K antagonist as usual care, orally for 30 days after cardioversion or 90 days after randomization if cardioversion was not performed. The dosing of the parenteral heparin and Vitamin K antagonist was based on individual subject’s sensitivity to the drug according to the investigators usual practice.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Vitamin K
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered orally with Vitamin K (dosing was based on individual subject’s sensitivity to the drug according to the investigators usual practice) for 30 days following cardioversion or 90 days post randomization if cardioversion was not performed within that timeframe.

    Investigational medicinal product name
    Heparin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered intravenously with Heparin (dosing was based on individual subject’s sensitivity to the drug according to the investigators usual practice) for 30 days following cardioversion or 90 days post randomization if cardioversion was not performed within that timeframe.

    Number of subjects in period 1
    		Apixaban Parenteral heparin/Oral Vitamin K Antagonist (Usual Care)
    Started
    753
    747
    Completed
    678
    657
    Not completed
    75
    90
         Adverse event, serious fatal
    1
    1
         Inclusion/Exclusion criteria not met
    12
    16
         Consent withdrawn by subject
    27
    37
         Adverse event, non-fatal
    16
    12
         Non-compliance
    -
    3
         Unspecified
    19
    19
         Lost to follow-up
    -
    1
         Administrative reason
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Apixaban
    Reporting group description
    		 Subjects with non-valvular atrial fibrillation undergoing cardioversion, received Apixaban orally for 30 days after cardioversion or 90 days after randomization if cardioversion was not performed. The dosing of Apixaban was based on investigator’s judgement as per local label for the prevention of stroke and systemic embolism in subjects.

    Reporting group title
    Parenteral heparin/Oral Vitamin K Antagonist (Usual Care)
    Reporting group description
    		 Subjects with non-valvular atrial fibrillation undergoing cardioversion, received parenteral heparin and/or oral Vitamin K antagonist as usual care, orally for 30 days after cardioversion or 90 days after randomization if cardioversion was not performed. The dosing of the parenteral heparin and Vitamin K antagonist was based on individual subject’s sensitivity to the drug according to the investigators usual practice.

    Reporting group values
    		 Apixaban Parenteral heparin/Oral Vitamin K Antagonist (Usual Care) Total
    Number of subjects
    		 753 747 1500
    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)
    		 342 337 679
        From 65-84 years
    		 388 386 774
        85 years and over
    		 23 24 47
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.7 ( 12.19 ) 64.5 ( 12.76 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    		 248 250 498
        Male
    		 505 497 1002
    Race/Ethnicity, Customized
    Units: Subjects
        Race: White
    		 654 648 1302
        Race: Black or African American
    		 21 20 41
        Race: Asian
    		 78 76 154
        Race: Other
    		 0 3 3
    Race/Ethnicity, Customized
    Units: Subjects
        Ethnicity: Hispanic or Latino
    		 8 9 17
        Ethnicity: Not Hispanic or Latino
    		 100 99 199
        Ethnicity: Unknown or Not Reported
    		 645 639 1284

    End points

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    End points reporting groups
    Reporting group title
    Apixaban
    Reporting group description
    		 Subjects with non-valvular atrial fibrillation undergoing cardioversion, received Apixaban orally for 30 days after cardioversion or 90 days after randomization if cardioversion was not performed. The dosing of Apixaban was based on investigator’s judgement as per local label for the prevention of stroke and systemic embolism in subjects.

    Reporting group title
    Parenteral heparin/Oral Vitamin K Antagonist (Usual Care)
    Reporting group description
    		 Subjects with non-valvular atrial fibrillation undergoing cardioversion, received parenteral heparin and/or oral Vitamin K antagonist as usual care, orally for 30 days after cardioversion or 90 days after randomization if cardioversion was not performed. The dosing of the parenteral heparin and Vitamin K antagonist was based on individual subject’s sensitivity to the drug according to the investigators usual practice.

    Primary: Number of Subjects With Acute Stroke Event

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    End point title
    		 Number of Subjects With Acute Stroke Event
    End point description
    An acute stroke was defined as a new, important neurological insufficiency of rapid onset that lasted for at least 24 hours and that was not due to a readily identifiable non-vascular cause (like brain tumor or trauma). Full analysis set included all randomized subjects.
    End point type
    Primary
    End point timeframe
    Baseline up to 30 days post cardio version (or up to 90 days after randomization, if cardio version was not performed within that time frame)
    End point values
    		 Apixaban Parenteral heparin/Oral Vitamin K Antagonist (Usual Care)
    Number of subjects analysed
    753
    747
    Units: subjects
    0
    6
    Statistical analysis title
    		 Comparison of Apixaban and Usual Care
    Statistical analysis description
    This was a descriptive study, and there was no formal pre-defined hypothesis testing.
    Comparison groups
    Apixaban v Parenteral heparin/Oral Vitamin K Antagonist (Usual Care)
    Number of subjects included in analysis
    1500
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.0151
    Method
    		 Fisher exact
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.6425
    Notes
    [1] - Display exact confidence limits for relative risk and Fisher’s exact test for comparisons of two proportions.

    Primary: Number of Subjects With Systemic Embolism Event

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    End point title
    		 Number of Subjects With Systemic Embolism Event [2]
    End point description
    Systemic embolism occurred in subject when there was a clinical history consistent with an acute loss of blood flow to a peripheral artery (or arteries), which was supported by evidence of embolism from surgical specimens, autopsy, angiography, or other objective testing. Full analysis set included all randomized subjects.
    End point type
    Primary
    End point timeframe
    Baseline up to 30 days post cardioversion (or up to 90 days after randomization, if cardioversion was not performed within that time frame)
    Notes
    [2] - 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: No statistical analyses was done for this endpoint since there were no subjects with systemic embolism event.
    End point values
    		 Apixaban Parenteral heparin/Oral Vitamin K Antagonist (Usual Care)
    Number of subjects analysed
    753
    747
    Units: subjects
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Major Bleeding Event

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    End point title
    		 Number of Subjects With Major Bleeding Event
    End point description
    Major bleeding was defined as clinically evident bleeding that was accompanied by one or more of the following: a decrease in hemoglobin of 2 gram per deciliter or more, a transfusion of 2 or more units of packed red blood cells, bleeding that was fatal or bleeding that occurred in at least one of the following critical sites: intracranial, intra-spinal, intraocular (within the corpus of the eye; thus, a conjunctival bleed was not an intraocular bleed), pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal. Full analysis set included all randomized subjects.
    End point type
    Primary
    End point timeframe
    Baseline up to 30 days post cardioversion (or up to 90 days after randomization, if cardioversion was not performed within that time frame)
    End point values
    		 Apixaban Parenteral heparin/Oral Vitamin K Antagonist (Usual Care)
    Number of subjects analysed
    735
    721
    Units: subjects
        number (not applicable)
    3
    6
    Statistical analysis title
    		 Comparison of Apixaban and Usual Care
    Statistical analysis description
    This was a descriptive study, and there was no formal pre-defined hypothesis testing.
    Comparison groups
    Apixaban v Parenteral heparin/Oral Vitamin K Antagonist (Usual Care)
    Number of subjects included in analysis
    1456
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.3378
    Method
    		 Fisher exact
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.4905
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1046
         upper limit
    		 2.0678
    Notes
    [3] - Display exact confidence limits for relative risk and Fisher’s exact test for comparisons of two proportions.

    Primary: Number of Subjects With Clinically Relevant Non-Major Bleeding Events

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    End point title
    		 Number of Subjects With Clinically Relevant Non-Major Bleeding Events
    End point description
    Clinically relevant non-major bleeding was defined as the clinically evident bleeding consisted of any bleeding that compromised hemodynamics, led to hospitalization, subcutaneous hematoma larger than 25/100 centimeter square if there was a traumatic cause, intramuscular hematoma, epistaxis, gingival bleeding, hematuria, macroscopic gastrointestinal hemorrhage with at least one episode of melena or hematemesis, rectal blood loss, hemoptysis or any other bleeding type with clinical consequences for a subject, such as medical intervention, the need for unscheduled contact with a physician, temporary cessation of a study drug, or associated with pain or impairment of activities of daily life. Full analysis set included all randomized subjects.
    End point type
    Primary
    End point timeframe
    Baseline up to 30 days post cardioversion (or up to 90 days after randomization, if cardioversion was not performed within that time frame)
    End point values
    		 Apixaban Parenteral heparin/Oral Vitamin K Antagonist (Usual Care)
    Number of subjects analysed
    735
    721
    Units: subjects
        number (not applicable)
    11
    13
    Statistical analysis title
    		 Comparison of Apixaban and Usual Care
    Statistical analysis description
    This was a descriptive study, and there was no formal pre-defined hypothesis testing.
    Comparison groups
    Apixaban v Parenteral heparin/Oral Vitamin K Antagonist (Usual Care)
    Number of subjects included in analysis
    1456
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.6851
    Method
    		 Fisher exact
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3433
         upper limit
    		 1.8916
    Notes
    [4] - Display exact confidence limits for relative risk and Fisher’s exact test for comparisons of two proportions.

    Primary: Number of Subjects With All Cause Death

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    End point title
    		 Number of Subjects With All Cause Death
    End point description
    Full analysis set included all randomized subjects.
    End point type
    Primary
    End point timeframe
    Baseline up to 30 days post cardioversion (or up to 90 days after randomization, if cardioversion was not performed within that time frame)
    End point values
    		 Apixaban Parenteral heparin/Oral Vitamin K Antagonist (Usual Care)
    Number of subjects analysed
    753
    747
    Units: subjects
        number (not applicable)
    2
    1
    Statistical analysis title
    		 Comparison of Apixaban and Usual Care
    Statistical analysis description
    This was a descriptive study, and there was no formal pre-defined hypothesis testing.
    Comparison groups
    Apixaban v Parenteral heparin/Oral Vitamin K Antagonist (Usual Care)
    Number of subjects included in analysis
    1500
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 > 0.9999
    Method
    		 Fisher exact
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.9841
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1866
         upper limit
    		 53.9968
    Notes
    [5] - Display exact confidence limits for relative risk and Fisher’s exact test for comparisons of two proportions.

    Secondary: Time to First Attempt of Cardioversion

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    End point title
    		 Time to First Attempt of Cardioversion
    End point description
    Cardioversion was an effective method of converting an abnormally fast heart rate (tachycardia) or other cardiac arrhythmia to normal rhythm using electricity or drugs. First attempt of cardioversion was defined as the first time the subject was admitted for the cardioversion procedure. Full analysis set included all randomized subjects. Here "N" signifies number of subjects evaluable for the specified outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day of first attempt of cardioversion procedure (Visit 2, up to 130 days)
    End point values
    		 Apixaban Parenteral heparin/Oral Vitamin K Antagonist (Usual Care)
    Number of subjects analysed
    510
    511
    Units: days
        median (full range (min-max))
    2.0 (1 to 93)
    2.0 (1 to 126)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Different Type of Cardioversion Events

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    End point title
    		 Number of Subjects With Different Type of Cardioversion Events
    End point description
    Cardioversion was an effective method of converting an abnormally fast heart rate (tachycardia) or other cardiac arrhythmia to normal rhythm using different type of cardioversion events i.e. electrical and pharmacologic. Electrical cardioversion was a procedure in which an electric current was used to reset the heart's rhythm back to its regular pattern (normal sinus rhythm). Pharmacologic cardioversion, also called chemical cardioversion, used antiarrhythmia medication instead of an electrical shock. Full analysis set included all randomized subjects. Here "N" signifies number of subjects evaluable for the specified outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day of first attempt of cardioversion procedure (Visit 2, up to 130 days)
    End point values
    		 Apixaban Parenteral heparin/Oral Vitamin K Antagonist (Usual Care)
    Number of subjects analysed
    496
    494
    Units: subjects
        Electrical
    461
    464
        Pharmacologic
    35
    30
    No statistical analyses for this end point

    Secondary: Number of Cardioversion Attempt of Subjects

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    End point title
    		 Number of Cardioversion Attempt of Subjects
    End point description
    Cardioversion attempts were defined as the number of times the subject was admitted to hospital for the cardioversion procedure and not the number of attempts during a single hospital admission. Full analysis set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day of first attempt of cardioversion procedure (Visit 2, up to 130 days)
    End point values
    		 Apixaban Parenteral heparin/Oral Vitamin K Antagonist (Usual Care)
    Number of subjects analysed
    753
    747
    Units: subjects
        No Cardioversion Attempt
    234
    224
        1 Cardioversion Attempt
    488
    496
        More than 2 Cardioversion Attempts
    31
    27
    No statistical analyses for this end point

    Secondary: Number of Subjects With Their Rhythm Status

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    End point title
    		 Number of Subjects With Their Rhythm Status
    End point description
    Rhythm status was further distinguished into sinus rhythm, atrial fibrillation and atrial flutter. Sinus rhythm was defined as a normal heartbeat. Atrial fibrillation was an irregular heartbeat (arrhythmia) that can lead to blood clots, stroke, heart failure and other heart-related complications and atrial flutter was a common abnormal heart rhythm that was usually associated with a fast heart rate (100 or more heart beats per minute). Safety data set included all treated subjects (randomized subjects who received at least one dose of study drug). Here "N" signifies number of subjects evaluable for the specified outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day of first attempt of cardioversion procedure (Visit 2, up to 130 days)
    End point values
    		 Apixaban Parenteral heparin/Oral Vitamin K Antagonist (Usual Care)
    Number of subjects analysed
    719
    712
    Units: subjects
        Normal Sinus
    1
    2
        Atrial Fibrillation
    715
    704
        Atrial Flutter
    3
    6
    No statistical analyses for this end point

    Secondary: Duration of Hospital Stay of Subjects

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    End point title
    		 Duration of Hospital Stay of Subjects
    End point description
    Duration of hospital stay was defined as the number of hours from hospital admission to hospital discharge followed by early cardioversion. Full analysis set included all randomized subjects. Here "N" signifies number of subjects evaluable for the specified outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day of first attempt of cardioversion procedure (Visit 2, up to 130 days)
    End point values
    		 Apixaban Parenteral heparin/Oral Vitamin K Antagonist (Usual Care)
    Number of subjects analysed
    330
    346
    Units: hours
        median (full range (min-max))
    45.36 (0.4 to 747.0)
    49.47 (0.6 to 709.6)
    No statistical analyses for this end point

    Secondary: Number of Subjects Who Used Image Guidance Approach

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    End point title
    		 Number of Subjects Who Used Image Guidance Approach
    End point description
    An image-guided approach helped cardioversion earlier than the conventional minimum of 3 weeks of anticoagulation that would normally be required prior to cardioversion. Transesophageal echocardiography (TEE or TOE) and computed tomography (CT) were 2 image-guided approaches that were used in this study. Full analysis set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day of first attempt of cardioversion procedure (Visit 2, up to 130 days)
    End point values
    		 Apixaban Parenteral heparin/Oral Vitamin K Antagonist (Usual Care)
    Number of subjects analysed
    753
    747
    Units: subjects
    383
    399
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline up to 30 days after cardioversion or 90 days after randomization, if cardioversion was not performed
    Adverse event reporting additional description
    Same event may appear as adverse event (AE) and serious adverse event (SAE), what is presented are distinct events. Event may be categorized as serious in 1 subject and as non-serious in another subject or 1 subject may have experienced both serious and non-serious event during study. Safety data set included all treated subjects.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Apixaban
    Reporting group description
    		 Subjects with non-valvular atrial fibrillation undergoing cardioversion, received Apixaban orally for 30 days after cardioversion or 90 days after randomization if cardioversion was not performed. The dosing of Apixaban was based on investigator’s judgement as per local label for the prevention of stroke and systemic embolism in subjects.

    Reporting group title
    Parenteral heparin/Oral Vitamin K Antagonist (Usual Care)
    Reporting group description
    		 Subjects with non-valvular atrial fibrillation undergoing cardioversion, received parenteral heparin and/or oral Vitamin K antagonist as usual care, orally for 30 days after cardioversion or 90 days after randomization if cardioversion was not performed. The dosing of the parenteral heparin and Vitamin K antagonist was based on individual subject’s sensitivity to the drug according to the investigators usual practice.

    Serious adverse events
    		 Apixaban Parenteral heparin/Oral Vitamin K Antagonist (Usual Care)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    100 / 735 (13.61%)
    112 / 721 (15.53%)
         number of deaths (all causes)
    1
    3
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    ACUTE LEUKAEMIA
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ADENOCARCINOMA
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BREAST CANCER
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ENDOMETRIAL CANCER
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    METASTASES TO BONE
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PROSTATE CANCER
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SQUAMOUS CELL CARCINOMA OF SKIN
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    ARTERIAL HAEMORRHAGE
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ARTERIOVENOUS FISTULA
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMATOMA
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERTENSION
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERTENSIVE CRISIS
         subjects affected / exposed
    0 / 735 (0.00%)
    2 / 721 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOTENSION
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHEST PAIN
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (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
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MUCOSAL HAEMORRHAGE
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MULTIPLE ORGAN DYSFUNCTION SYNDROME
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    3 / 735 (0.41%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUDDEN DEATH
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Immune system disorders
    DRUG HYPERSENSITIVITY
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    VAGINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ACUTE PULMONARY OEDEMA
         subjects affected / exposed
    1 / 735 (0.14%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATELECTASIS
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSPNOEA
         subjects affected / exposed
    3 / 735 (0.41%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EPISTAXIS
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MEDIASTINAL CYST
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MEDIASTINAL HAEMATOMA
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PLEURAL EFFUSION
         subjects affected / exposed
    2 / 735 (0.27%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMOTHORAX
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY CONGESTION
         subjects affected / exposed
    3 / 735 (0.41%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY HYPERTENSION
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (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
    1 / 735 (0.14%)
    2 / 721 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY SARCOIDOSIS
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY FAILURE
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    DEPRESSION
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    COMPUTERISED TOMOGRAM CORONARY ARTERY ABNORMAL
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FUNCTIONAL RESIDUAL CAPACITY DECREASED
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATIC ENZYME INCREASED
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTERNATIONAL NORMALISED RATIO ABNORMAL
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTERNATIONAL NORMALISED RATIO INCREASED
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WEIGHT DECREASED
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    ARTERIAL BYPASS THROMBOSIS
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EYE INJURY
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FALL
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEMUR FRACTURE
         subjects affected / exposed
    2 / 735 (0.27%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEAD INJURY
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (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 / 735 (0.00%)
    3 / 721 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RADIUS FRACTURE
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TOXICITY TO VARIOUS AGENTS
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRAUMATIC INTRACRANIAL HAEMORRHAGE
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VASCULAR PSEUDOANEURYSM
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (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
    ADENOMATOUS POLYPOSIS COLI
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERTROPHIC CARDIOMYOPATHY
         subjects affected / exposed
    1 / 735 (0.14%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    ACUTE MYOCARDIAL INFARCTION
         subjects affected / exposed
    2 / 735 (0.27%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANGINA PECTORIS
         subjects affected / exposed
    2 / 735 (0.27%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ARTERIOSCLEROSIS CORONARY ARTERY
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIAL FIBRILLATION
         subjects affected / exposed
    27 / 735 (3.67%)
    40 / 721 (5.55%)
         occurrences causally related to treatment / all
    0 / 30
    0 / 48
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIAL FLUTTER
         subjects affected / exposed
    3 / 735 (0.41%)
    6 / 721 (0.83%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIAL THROMBOSIS
         subjects affected / exposed
    0 / 735 (0.00%)
    3 / 721 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIOVENTRICULAR BLOCK COMPLETE
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIOVENTRICULAR DISSOCIATION
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRADYCARDIA
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC FAILURE
         subjects affected / exposed
    5 / 735 (0.68%)
    7 / 721 (0.97%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC FAILURE ACUTE
         subjects affected / exposed
    1 / 735 (0.14%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC FAILURE CONGESTIVE
         subjects affected / exposed
    9 / 735 (1.22%)
    7 / 721 (0.97%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIO-RESPIRATORY ARREST
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    CARDIOGENIC SHOCK
         subjects affected / exposed
    2 / 735 (0.27%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CONGESTIVE CARDIOMYOPATHY
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CORONARY ARTERY DISEASE
         subjects affected / exposed
    2 / 735 (0.27%)
    6 / 721 (0.83%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CORONARY ARTERY STENOSIS
         subjects affected / exposed
    1 / 735 (0.14%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ISCHAEMIC CARDIOMYOPATHY
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (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 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MITRAL VALVE PROLAPSE
         subjects affected / exposed
    0 / 735 (0.00%)
    3 / 721 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYOCARDIAL ISCHAEMIA
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PALPITATIONS
         subjects affected / exposed
    1 / 735 (0.14%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERICARDIAL EFFUSION
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERICARDITIS CONSTRICTIVE
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (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
    2 / 735 (0.27%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SINUS NODE DYSFUNCTION
         subjects affected / exposed
    2 / 735 (0.27%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TACHYARRHYTHMIA
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (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
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TACHYCARDIA INDUCED CARDIOMYOPATHY
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRICUSPID VALVE INCOMPETENCE
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    BRAIN INJURY
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBRAL HAEMORRHAGE
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBRAL INFARCTION
         subjects affected / exposed
    1 / 735 (0.14%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    1 / 735 (0.14%)
    3 / 721 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEMENTIA
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIZZINESS
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PRESYNCOPE
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEIZURE
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (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
    0 / 735 (0.00%)
    2 / 721 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRANSIENT ISCHAEMIC ATTACK
         subjects affected / exposed
    0 / 735 (0.00%)
    2 / 721 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    HAEMORRHAGIC ANAEMIA
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DUODENAL ULCER HAEMORRHAGE
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ENTEROCOLITIS
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEMORAL HERNIA INCARCERATED
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTRIC ULCER
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTRITIS
         subjects affected / exposed
    2 / 735 (0.27%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    2 / 735 (0.27%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMATEMESIS
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMATOCHEZIA
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LARGE INTESTINE PERFORATION
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    MELAENA
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MESENTERIC PANNICULITIS
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OEDEMATOUS PANCREATITIS
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OESOPHAGITIS
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PEPTIC ULCER
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PEPTIC ULCER HAEMORRHAGE
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RECTAL HAEMORRHAGE
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SMALL INTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    DRUG-INDUCED LIVER INJURY
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATIC CONGESTION
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (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
    DECUBITUS ULCER
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (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
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PETECHIAE
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUBCUTANEOUS EMPHYSEMA
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    1 / 735 (0.14%)
    5 / 721 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMATURIA
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POSTRENAL FAILURE
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL HAEMORRHAGE
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    ADRENAL HAEMORRHAGE
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TOXIC NODULAR GOITRE
         subjects affected / exposed
    2 / 735 (0.27%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    FLANK PAIN
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    ABSCESS LIMB
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRONCHITIS
         subjects affected / exposed
    2 / 735 (0.27%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CELLULITIS
         subjects affected / exposed
    1 / 735 (0.14%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ESCHERICHIA URINARY TRACT INFECTION
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFECTION
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFECTIVE EXACERBATION OF CHRONIC OBSTRUCTIVE AIRWAYS DISEASE
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFLUENZA
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTESTINAL SEPSIS
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUNG INFECTION
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    3 / 735 (0.41%)
    5 / 721 (0.69%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPTIC SHOCK
         subjects affected / exposed
    1 / 735 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    1 / 735 (0.14%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UROSEPSIS
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
         subjects affected / exposed
    1 / 735 (0.14%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOKALAEMIA
         subjects affected / exposed
    0 / 735 (0.00%)
    1 / 721 (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: 2%
    Non-serious adverse events
    		 Apixaban Parenteral heparin/Oral Vitamin K Antagonist (Usual Care)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    70 / 735 (9.52%)
    101 / 721 (14.01%)
    Investigations
    INTERNATIONAL NORMALISED RATIO ABNORMAL
         subjects affected / exposed
    0 / 735 (0.00%)
    19 / 721 (2.64%)
         occurrences all number
    0
    41
    INTERNATIONAL NORMALISED RATIO INCREASED
         subjects affected / exposed
    0 / 735 (0.00%)
    27 / 721 (3.74%)
         occurrences all number
    0
    30
    Cardiac disorders
    ATRIAL FIBRILLATION
         subjects affected / exposed
    43 / 735 (5.85%)
    46 / 721 (6.38%)
         occurrences all number
    43
    48
    ATRIAL THROMBOSIS
         subjects affected / exposed
    17 / 735 (2.31%)
    13 / 721 (1.80%)
         occurrences all number
    17
    13
    Respiratory, thoracic and mediastinal disorders
    DYSPNOEA
         subjects affected / exposed
    15 / 735 (2.04%)
    8 / 721 (1.11%)
         occurrences all number
    15
    8

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Feb 2016
    Simultaneous treatment with both aspirin and a thienopyridine (eg, clopidogrel, ticlopidine, prasugrel) or simultaneous treatment with both aspirin and ticagrelor.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The prioritization of outcome measures is not mentioned in the study documents (Statistical Analysis Plan and Protocol). The prioritization of outcome measures is based on team’s discretion.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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