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    Clinical Trial Results:
    A prospective, randomized, open-label, parallel-group, active-controlled, multicenter study exploring the efficacy and safety of once-daily oral rivaroxaban (BAY59-7939) compared with that of dose-adjusted oral vitamin K antagonist (VKA) for the prevention of stroke and non-central nervous system systemic embolism in subjects with non-valvular atrial fibrillation scheduled for cardioversion

    Summary
    EudraCT number
    		 2011-002234-39
    Trial protocol
    		 FI   PT   ES   NL   DE   GR   BE   GB   IT   DK  
    Global end of trial date
    24 Jan 2014

    Results information
    Results version number
    		 v3(current)
    This version publication date
    17 Feb 2019
    First version publication date
    26 Apr 2015
    Other versions
    		 v1 , v2
    Version creation reason
    • Correction of full data set
    Control of data.

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY59-7939/15693
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01674647
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, Leverkusen, D-51368, Germany,
    Public contact
    Clinical Trials Contact, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Clinical Trials Contact, Bayer AG, clinical-trials-contact@bayer.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
    11 Apr 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jan 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary efficacy and safety objectives were to explore the efficacy of rivaroxaban compared with that of dose-adjusted VKA in the prevention of the events with regard to the combined efficacy endpoint of all stroke or transient ischemic attack (TIA), non-central nervous system (CNS) systemic embolism, myocardial infarction (MI), and cardiovascular death in subjects with atrial fibrillation (AF) scheduled for cardioversion; and to explore the safety of rivaroxaban compared with dose-adjusted VKA with regard to the safety endpoint of major bleeding events in subjects with AF scheduled for cardioversion.
    Protection of trial subjects
    All clinical work conducted in this study was subjected to the rules of Good Clinical Practice and under the guidelines of Declaration of Helsinki. Participating subjects or their legally authorized representative signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Oct 2012
    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
    Portugal: 62
    Country: Number of subjects enrolled
    Spain: 84
    Country: Number of subjects enrolled
    United Kingdom: 117
    Country: Number of subjects enrolled
    Netherlands: 82
    Country: Number of subjects enrolled
    Belgium: 108
    Country: Number of subjects enrolled
    Denmark: 160
    Country: Number of subjects enrolled
    Finland: 84
    Country: Number of subjects enrolled
    France: 46
    Country: Number of subjects enrolled
    Germany: 120
    Country: Number of subjects enrolled
    Greece: 23
    Country: Number of subjects enrolled
    Italy: 156
    Country: Number of subjects enrolled
    United States: 290
    Country: Number of subjects enrolled
    South Africa: 93
    Country: Number of subjects enrolled
    Singapore: 20
    Country: Number of subjects enrolled
    Canada: 74
    Country: Number of subjects enrolled
    China: 65
    Worldwide total number of subjects
    1584
    EEA total number of subjects
    1042
    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)
    696
    From 65 to 84 years
    858
    85 years and over
    30

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 141 centers (involving 144 investigators) in Europe, South Africa, North America, and Asia Pacific.

    Pre-assignment
    Screening details
    		 Overall, 1584 subjects were screened and 80 subjects did not complete or pass screening. 1504 subjects were randomized; 1002 were assigned to rivaroxaban and 502 to Vitamin K antagonist (VKA).

    Pre-assignment period milestones
    Number of subjects started
    		 1584
    Number of subjects completed
    		 1504

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 7
    Reason: Number of subjects
    		 Screening failure: 71
    Reason: Number of subjects
    		 Adverse event: 2
    Period 1
    Period 1 title
    Treatment period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Rivaroxaban (Xarelto; BAY59-7939)
    Arm description
    		 Subjects randomized to treatment with rivaroxaban received rivaroxaban 20 milligram (mg) orally once daily. Subjects with moderate renal impairment [i.e., Creatinine clearance (CrCl) of 30 to 49 milliliter per minute (mL/min), inclusive] at screening received the adjusted dose of 15 mg once daily. The duration of the treatment period for a given subject depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, the cardioversion procedure was performed within 1-5 days after randomization. Rivaroxaban was given for 1-5 days before planned direct cardioversion and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received rivaroxaban for 21 (+4) to 56 (+4) days prior to cardioversion and for 42 days thereafter.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rivaroxaban
    Investigational medicinal product code
    BAY59-7939
    Other name
    Xarelto
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Rivaroxaban 20 mg orally once daily; subjects with moderate renal impairment [i.e., CrCl of 30 to 49 mL/min, inclusive] received the adjusted dose of 15 mg orally once daily.

    Arm title
    		 Vitamin K antagonist (VKA)
    Arm description
    		 Subjects assigned to treatment with VKA received VKA orally once daily titrated to a target INR of 2.5 (range 2.0-3.0, inclusive). The specific VKA was assigned by the investigator according to the local standard of practice. For subjects randomized to receive VKA, the investigator assessed if a parenteral anticoagulant drug, particularly prior to cardioversion, was needed as bridging therapy with VKA as standard of care (until target INR was achieved). The duration depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, the cardioversion procedure was performed within 1-5 days after randomization. VKA was given for 1-5 days before cardioversion and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received VKA for 21 (+4) to 56 (+4) days before cardioversion and for 42 days thereafter.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Vitamin K antagonist
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects assigned to treatment with VKA received VKA orally once daily titrated to a target INR of 2.5 (range 2.0-3.0, inclusive). The specific VKA (eg, warfarin) was assigned by the investigator according to the local standard of practice.

    Number of subjects in period 1 [1]
    		Rivaroxaban (Xarelto; BAY59-7939) Vitamin K antagonist (VKA)
    Started
    1002
    502
    subjects received treatment
    988
    499
    Completed
    846
    400
    Not completed
    156
    102
         Consent withdrawn by subject
    19
    16
         Physician decision
    3
    1
         Logistical difficulties
    5
    8
         Treatment failure
    -
    14
         Protocol violation
    56
    36
         Death
    4
    1
         Switching to other therapy
    5
    2
         Non-compliance with study drug
    3
    -
         Adverse event
    60
    22
         Efficacy outcome reached
    -
    1
         Lost to follow-up
    1
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Due to screen failure, not all enrolled subjects were randomized and treated with study drugs
    Period 2
    Period 2 title
    30-day safety follow-up period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Rivaroxaban (Xarelto; BAY59-7939)
    Arm description
    		 After the 42 day treatment period subsequent to cardioversion, the investigator assessed whether or not long-term anticoagulation was warranted and treated the subject according to standard of care. The subject then entered the 30-day follow-up period.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Vitamin K antagonist (VKA)
    Arm description
    		 After the 42 day treatment period subsequent to cardioversion, the investigator assessed whether or not long-term anticoagulation was warranted and treated the subject according to standard of care. The subject then entered the 30-day follow-up period.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Rivaroxaban (Xarelto; BAY59-7939) Vitamin K antagonist (VKA)
    Started
    982
    487
    Completed
    924
    446
    Not completed
    58
    41
         Consent withdrawn by subject
    7
    8
         Logistical difficulties
    1
    3
         Protocol violation
    39
    22
         Death
    3
    2
         Non-compliance with study drug
    -
    1
         Lost to follow-up
    8
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Rivaroxaban (Xarelto; BAY59-7939)
    Reporting group description
    		 Subjects randomized to treatment with rivaroxaban received rivaroxaban 20 milligram (mg) orally once daily. Subjects with moderate renal impairment [i.e., Creatinine clearance (CrCl) of 30 to 49 milliliter per minute (mL/min), inclusive] at screening received the adjusted dose of 15 mg once daily. The duration of the treatment period for a given subject depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, the cardioversion procedure was performed within 1-5 days after randomization. Rivaroxaban was given for 1-5 days before planned direct cardioversion and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received rivaroxaban for 21 (+4) to 56 (+4) days prior to cardioversion and for 42 days thereafter.

    Reporting group title
    Vitamin K antagonist (VKA)
    Reporting group description
    		 Subjects assigned to treatment with VKA received VKA orally once daily titrated to a target INR of 2.5 (range 2.0-3.0, inclusive). The specific VKA was assigned by the investigator according to the local standard of practice. For subjects randomized to receive VKA, the investigator assessed if a parenteral anticoagulant drug, particularly prior to cardioversion, was needed as bridging therapy with VKA as standard of care (until target INR was achieved). The duration depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, the cardioversion procedure was performed within 1-5 days after randomization. VKA was given for 1-5 days before cardioversion and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received VKA for 21 (+4) to 56 (+4) days before cardioversion and for 42 days thereafter.

    Reporting group values
    		 Rivaroxaban (Xarelto; BAY59-7939) Vitamin K antagonist (VKA) Total
    Number of subjects
    		 1002 502 1504
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.9 ( 10.6 ) 64.7 ( 10.5 ) -
    Gender categorical
    Units: Subjects
        Female
    		 275 135 410
        Male
    		 727 367 1094
    CHADS 2 score
    Predicts clinical risk of stroke and thromboembolism in atrial fibrillation incorporating these risk factors: Congestive heart failure, Hypertension, Age [greater than or equal to (>=)75 years], Diabetes mellitus, Stroke/transient ischemic attack. Total score ranged from 0 to 6, with "0"= low risk, "1"= moderate risk and ">=2"= high risk.
    Units: units on scale
        arithmetic mean (standard deviation)
    		 1.3 ( 1.1 ) 1.4 ( 1.1 ) -
    CHA 2 DS 2 VASc score
    Predicts clinical risk of stroke and thromboembolism in atrial fibrillation incorporating these risk factors: Congestive heart failure/left ventricular dysfunction, Hypertension, Age >= 75 years, Diabetes mellitus, Stroke/transient ischemic attack/thromboembolism, Vascular disease (prior myocardial infarction, peripheral artery disease, or aortic plaque), Age 65 - 74 years, Sex category (i.e., female). Total score ranged from 0 to 8, with "0" (or 1 if female only)= Low risk ; "1" (except for female gender alone)= moderate risk and ">=2"=high risk.
    Units: units on scale
        arithmetic mean (standard deviation)
    		 2.3 ( 1.6 ) 2.3 ( 1.6 ) -

    End points

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    End points reporting groups
    Reporting group title
    Rivaroxaban (Xarelto; BAY59-7939)
    Reporting group description
    		 Subjects randomized to treatment with rivaroxaban received rivaroxaban 20 milligram (mg) orally once daily. Subjects with moderate renal impairment [i.e., Creatinine clearance (CrCl) of 30 to 49 milliliter per minute (mL/min), inclusive] at screening received the adjusted dose of 15 mg once daily. The duration of the treatment period for a given subject depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, the cardioversion procedure was performed within 1-5 days after randomization. Rivaroxaban was given for 1-5 days before planned direct cardioversion and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received rivaroxaban for 21 (+4) to 56 (+4) days prior to cardioversion and for 42 days thereafter.

    Reporting group title
    Vitamin K antagonist (VKA)
    Reporting group description
    		 Subjects assigned to treatment with VKA received VKA orally once daily titrated to a target INR of 2.5 (range 2.0-3.0, inclusive). The specific VKA was assigned by the investigator according to the local standard of practice. For subjects randomized to receive VKA, the investigator assessed if a parenteral anticoagulant drug, particularly prior to cardioversion, was needed as bridging therapy with VKA as standard of care (until target INR was achieved). The duration depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, the cardioversion procedure was performed within 1-5 days after randomization. VKA was given for 1-5 days before cardioversion and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received VKA for 21 (+4) to 56 (+4) days before cardioversion and for 42 days thereafter.
    Reporting group title
    Rivaroxaban (Xarelto; BAY59-7939)
    Reporting group description
    		 After the 42 day treatment period subsequent to cardioversion, the investigator assessed whether or not long-term anticoagulation was warranted and treated the subject according to standard of care. The subject then entered the 30-day follow-up period.

    Reporting group title
    Vitamin K antagonist (VKA)
    Reporting group description
    		 After the 42 day treatment period subsequent to cardioversion, the investigator assessed whether or not long-term anticoagulation was warranted and treated the subject according to standard of care. The subject then entered the 30-day follow-up period.

    Subject analysis set title
    Intention-to-treat (ITT) population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized unique subjects. Subjects were analyzed as randomized.

    Subject analysis set title
    modified ITT (mITT) population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects in the ITT population in whom a left atrial/left atrial appendage (LA/LAA) thrombus was not diagnosed during a transesophageal echocardiogram (TEE) performed before the first planned cardioversion in the study. Subjects were analyzed as randomized. A total of 34 subjects were excluded from the ITT population based upon confirmation of LA/LAA thrombus; thus, the mITT population comprised 1470 subjects, including 978 subjects randomized to rivaroxaban and 492 subjects randomized to VKA.

    Subject analysis set title
    Safety analysis set (SAF) population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    SAF population included all randomized subjects who received at least 1 dose of study medication after randomization during the treatment period. Subjects were analyzed as treated. The SAF population comprised 1487 subjects, including 988 subjects randomized to rivaroxaban and 499 subjects randomized to VKA.

    Primary: Number of subjects with composite of the following events, adjudicated centrally: stroke, transient ischemic attack, non-central nervous system systemic embolism, myocardial infarction and cardiovascular death

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    End point title
    		 Number of subjects with composite of the following events, adjudicated centrally: stroke, transient ischemic attack, non-central nervous system systemic embolism, myocardial infarction and cardiovascular death
    End point description
    Stroke, TIA, Non-CNS Embolism, MI and cardiovascular death were adjudicated and confirmed by Clinical Endpoints Committee (CEC). Stroke included hemorrhagic and ischemic infarction. TIA including information if with or without matching lesion. Non CNS systemic embolism included emboli in peripheral arterial of the upper and lower extremities, ocular and retinal (pulmonary embolism and MI were excluded from the category). MI was assessed based on either cardiac biomarkers, new abnormal Q waves appeared on electrocardiogram for >= 2 leads, or autopsy confirmation. Cardiovascular death included death in subjects with non-valvular atrial fibrillation (AF). Number of subjects with composite events were reported.
    End point type
    Primary
    End point timeframe
    From randomization to the date of last dose of study drug +2 days for subjects who completed planned treatment or the earlier date [last planned dose, follow-up visit at the end of 30-day follow-up period] for subjects who prematurely stopped treatment
    End point values
    		 Rivaroxaban (Xarelto; BAY59-7939) Vitamin K antagonist (VKA)
    Number of subjects analysed
    978 [1]
    492 [2]
    Units: subjects
    5
    5
    Notes
    [1] - The primary population for the efficacy analysis was the mITT population.
    [2] - The primary population for the efficacy analysis was the mITT population.
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    No statistical test performed; Descriptive comparison of crude estimates of the cumulative incidence and estimation of risk ratio, all with 95% confidence intervals.
    Comparison groups
    Rivaroxaban (Xarelto; BAY59-7939) v Vitamin K antagonist (VKA)
    Number of subjects included in analysis
    1470
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.15
         upper limit
    		 1.73
    Notes
    [3] - Crude estimate of the cumulative incidence for rivaroxaban (Xarelto, BAY59-7939): 0.51% (0.20% - 1.17%). Crude estimate of the cumulative incidence for Vitamin K antagonist (VKA): 1.02% (0.40% - 2.34%).

    Primary: Number of Subjects with Major Bleedings as per Central Adjudication

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    End point title
    		 Number of Subjects with Major Bleedings as per Central Adjudication
    End point description
    Bleeding events were adjudicated and confirmed by CEC blinded to treatment. The CEC categorized the bleeding events as major or non-major. The bleeding events were defined per the International Society on Thrombosis and Hemostasis (ISTH) criteria. Major bleeding was clinically overt bleeding associated with a fall in hemoglobin of 2 gram per deciliter (g/dL) or higher, leading to a transfusion of 2 or more units of packed red blood cells or whole blood, occurring in a critical site or contributing to death. Number of subjects with confirmed adjudicated bleeding events occurring in greater than (>)1 total subjects were reported.
    End point type
    Primary
    End point timeframe
    From randomization up to the date of the last dose of study drug + 2 days
    End point values
    		 Rivaroxaban (Xarelto; BAY59-7939) Vitamin K antagonist (VKA)
    Number of subjects analysed
    988 [4]
    499 [5]
    Units: subjects
    6
    4
    Notes
    [4] - SAF population included all randomized subjects who received at least 1 dose of study medication.
    [5] - SAF population included all randomized subjects who received at least 1 dose of study medication.
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    No test performed; Descriptive comparison of crude estimates of the cumulative incidence and estimation of risk ratio, all with 95% confidence intervals
    Comparison groups
    Rivaroxaban (Xarelto; BAY59-7939) v Vitamin K antagonist (VKA)
    Number of subjects included in analysis
    1487
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.21
         upper limit
    		 2.67
    Notes
    [6] - Crude estimate of the cumulative incidence for rivaroxaban (Xarelto, BAY59-7939): 0.61% (0.26% - 1.27%). Crude estimate of the cumulative incidence for Vitamin K antagonist (VKA): 0.80% (0.27% - 2.00%).

    Secondary: Number of Subjects with Composite of Strokes and Non-central Nervous System Systemic Embolisms

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    End point title
    		 Number of Subjects with Composite of Strokes and Non-central Nervous System Systemic Embolisms
    End point description
    Stroke and Non-CNS Embolism were adjudicated and confirmed by CEC. Stroke included hemorrhagic and ischemic infarction. Non CNS systemic embolism included emboli in peripheral arterial of the upper and lower extremities, ocular and retinal (pulmonary embolism and MI were excluded from the category). Number of subjects with composite events were reported.
    End point type
    Secondary
    End point timeframe
    From randomization to the date of last dose of study drug +2 days for subjects who completed planned treatment or the earlier date [last planned dose, follow-up visit at the end of 30-day follow-up period] for subjects who prematurely stopped treatment
    End point values
    		 Rivaroxaban (Xarelto; BAY59-7939) Vitamin K antagonist (VKA)
    Number of subjects analysed
    978 [7]
    492 [8]
    Units: subjects
    2
    3
    Notes
    [7] - The primary population for the efficacy analysis was the mITT population.
    [8] - The primary population for the efficacy analysis was the mITT population.
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    No statistical test performed; Descriptive comparison of crude estimates of the cumulative incidence and estimation of risk ratio, all with 95% confidence intervals.
    Comparison groups
    Rivaroxaban (Xarelto; BAY59-7939) v Vitamin K antagonist (VKA)
    Number of subjects included in analysis
    1470
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.06
         upper limit
    		 2
    Notes
    [9] - Crude estimate of the cumulative incidence for rivaroxaban (Xarelto, BAY59-7939): 0.20% (0.04% - 0.71%). Crude estimate of the cumulative incidence for Vitamin K antagonist (VKA): 0.61% (0.17% - 1.72%).

    Secondary: Number of subjects with Composite of Strokes, Transient Ischemic Attacks, Non-central Nervous System Systemic Embolisms, Myocardial Infarctions and All-cause Mortality

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    End point title
    		 Number of subjects with Composite of Strokes, Transient Ischemic Attacks, Non-central Nervous System Systemic Embolisms, Myocardial Infarctions and All-cause Mortality
    End point description
    Stroke, TIA, Non- CNS systemic embolism, MI and all-cause mortality were adjudicated and confirmed by CEC. Stroke included hemorrhagic and ischemic infarction. TIA including information if with or without matching lesion. Non CNS systemic embolism included emboli in peripheral arterial of the upper and lower extremities, ocular and retinal (pulmonary embolism and MI were excluded from the category). MI was assessed based on either cardiac biomarkers, new abnormal Q waves appeared on electrocardiogram for >= 2 leads, or autopsy confirmation. All-cause mortality included vascular death and non-vascular death. Number of subjects with composite events were reported.
    End point type
    Secondary
    End point timeframe
    From randomization to the date of last dose of study drug +2 days for subjects who completed planned treatment or the earlier date [last planned dose, follow-up visit at the end of 30-day follow-up period] for subjects who prematurely stopped treatment
    End point values
    		 Rivaroxaban (Xarelto; BAY59-7939) Vitamin K antagonist (VKA)
    Number of subjects analysed
    978 [10]
    492 [11]
    Units: subjects
    6
    6
    Notes
    [10] - The primary population for the efficacy analysis was the mITT population.
    [11] - The primary population for the efficacy analysis was the mITT population.
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    No statistical test performed; Descriptive comparison of crude estimates of the cumulative incidence and estimation of risk ratio, all with 95% confidence intervals
    Comparison groups
    Rivaroxaban (Xarelto; BAY59-7939) v Vitamin K antagonist (VKA)
    Number of subjects included in analysis
    1470
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.16
         upper limit
    		 1.55
    Notes
    [12] - Crude estimate of the cumulative incidence for rivaroxaban (Xarelto, BAY59-7939): 0.61% (0.27% - 1.29%). Crude estimate of the cumulative incidence for Vitamin K antagonist (VKA): 1.22% (0.53% - 2.51%).

    Secondary: Number of subjects with Strokes

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    End point title
    		 Number of subjects with Strokes
    End point description
    All events were adjudicated and confirmed by a CEC blinded to treatment. Stroke included hemorrhagic (Stroke with local collections of intraparenchymal blood. Subarachnoid hemorrhage, subdural hemorrhage, and epidural hemorrhage were excluded), ischemic infarction (Stroke without focal collection of intracranial blood) and unknown (No imaging data and anatomic findings were available). Number of subjects with strokes were reported.
    End point type
    Secondary
    End point timeframe
    From randomization to the date of last dose of study drug +2 days for subjects who completed planned treatment or the earlier date [last planned dose, follow-up visit at the end of 30-day follow-up period] for subjects who prematurely stopped treatment
    End point values
    		 Rivaroxaban (Xarelto; BAY59-7939) Vitamin K antagonist (VKA)
    Number of subjects analysed
    978 [13]
    492 [14]
    Units: subjects
    2
    2
    Notes
    [13] - The primary population for the efficacy analysis was the mITT population.
    [14] - The primary population for the efficacy analysis was the mITT population.
    No statistical analyses for this end point

    Secondary: Number of subjects with Transient Ischemic Attacks

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    End point title
    		 Number of subjects with Transient Ischemic Attacks
    End point description
    All events were adjudicated and confirmed by a CEC blinded to treatment. Number of subjects with TIA were reported.
    End point type
    Secondary
    End point timeframe
    From randomization to the date of last dose of study drug +2 days for subjects who completed planned treatment or the earlier date [last planned dose, follow-up visit at the end of 30-day follow-up period] for subjects who prematurely stopped treatment
    End point values
    		 Rivaroxaban (Xarelto; BAY59-7939) Vitamin K antagonist (VKA)
    Number of subjects analysed
    978 [15]
    492 [16]
    Units: subjects
    0
    0
    Notes
    [15] - The primary population for the efficacy analysis was the mITT population.
    [16] - The primary population for the efficacy analysis was the mITT population.
    No statistical analyses for this end point

    Secondary: Number of subjects with Non-Central Nervous System Systemic Embolisms

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    End point title
    		 Number of subjects with Non-Central Nervous System Systemic Embolisms
    End point description
    All events were adjudicated and confirmed by a CEC blinded to treatment. Non CNS systemic embolism included emboli in peripheral arterial of the upper and lower extremities, ocular and retinal (pulmonary embolism and MI were excluded from the category). Number of subjects with non-CNS embolism were reported.
    End point type
    Secondary
    End point timeframe
    From randomization to the date of last dose of study drug +2 days for subjects who completed planned treatment or the earlier date [last planned dose, follow-up visit at the end of 30-day follow-up period] for subjects who prematurely stopped treatment
    End point values
    		 Rivaroxaban (Xarelto; BAY59-7939) Vitamin K antagonist (VKA)
    Number of subjects analysed
    978 [17]
    492 [18]
    Units: subjects
    0
    1
    Notes
    [17] - The primary population for the efficacy analysis was the mITT population.
    [18] - The primary population for the efficacy analysis was the mITT population.
    No statistical analyses for this end point

    Secondary: Number of subjects with Myocardial Infarctions

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    End point title
    		 Number of subjects with Myocardial Infarctions
    End point description
    All events were adjudicated and confirmed by a CEC blinded to treatment. MI was assessed based on either cardiac biomarkers, new abnormal Q waves appeared on electrocardiogram for >= 2 leads, or autopsy confirmation. Number of subjects with MI were reported.
    End point type
    Secondary
    End point timeframe
    From randomization to the date of last dose of study drug +2 days for subjects who completed planned treatment or the earlier date [last planned dose, follow-up visit at the end of 30-day follow-up period] for subjects who prematurely stopped treatment
    End point values
    		 Rivaroxaban (Xarelto; BAY59-7939) Vitamin K antagonist (VKA)
    Number of subjects analysed
    978 [19]
    492 [20]
    Units: subjects
    1
    1
    Notes
    [19] - The primary population for the efficacy analysis was the mITT population.
    [20] - The primary population for the efficacy analysis was the mITT population.
    No statistical analyses for this end point

    Secondary: Number of subjects with Cardiovascular Deaths

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    End point title
    		 Number of subjects with Cardiovascular Deaths
    End point description
    All events were adjudicated and confirmed by a CEC blinded to treatment. Any death that was not clearly non-vascular (e.g., deaths due to spontaneous bleeding, myocardial infarction, stroke, cardiac failure, and arrhythmia). Number of subjects with cardiovascular deaths were reported.
    End point type
    Secondary
    End point timeframe
    From randomization to the date of last dose of study drug +2 days for subjects who completed planned treatment or the earlier date [last planned dose, follow-up visit at the end of 30-day follow-up period] for subjects who prematurely stopped treatment
    End point values
    		 Rivaroxaban (Xarelto; BAY59-7939) Vitamin K antagonist (VKA)
    Number of subjects analysed
    978 [21]
    492 [22]
    Units: subjects
    4
    2
    Notes
    [21] - The primary population for the efficacy analysis was the mITT population.
    [22] - The primary population for the efficacy analysis was the mITT population.
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    No statistical test performed; Descriptive comparison of crude estimates of the cumulative incidence and estimation of risk ratio, all with 95% confidence intervals.
    Comparison groups
    Rivaroxaban (Xarelto; BAY59-7939) v Vitamin K antagonist (VKA)
    Number of subjects included in analysis
    1470
    Analysis specification
    Pre-specified
    Analysis type
    		 other [23]
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.18
         upper limit
    		 5.47
    Notes
    [23] - Crude estimate of the cumulative incidence for rivaroxaban (Xarelto, BAY59-7939): 0.41% (0.14% - 1.02%). Crude estimate of the cumulative incidence for Vitamin K antagonist (VKA): 0.41% (0.07% - 1.41%).

    Secondary: Number of subjects with All-cause Mortality

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    End point title
    		 Number of subjects with All-cause Mortality
    End point description
    All events were adjudicated and confirmed by a CEC blinded to treatment. All-cause mortality included vascular death and non-vascular death. Number of subjects with all-cause mortality were reported.
    End point type
    Secondary
    End point timeframe
    From randomization to the date of last dose of study drug +2 days for subjects who completed planned treatment or the earlier date [last planned dose, follow-up visit at the end of 30-day follow-up period] for subjects who prematurely stopped treatment
    End point values
    		 Rivaroxaban (Xarelto; BAY59-7939) Vitamin K antagonist (VKA)
    Number of subjects analysed
    978 [24]
    492 [25]
    Units: subjects
    5
    3
    Notes
    [24] - The primary population for the efficacy analysis was the mITT population.
    [25] - The primary population for the efficacy analysis was the mITT population.
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    No statistical test performed; Descriptive comparison of crude estimates of the cumulative incidence and estimation of risk ratio, all with 95% confidence intervals.
    Comparison groups
    Rivaroxaban (Xarelto; BAY59-7939) v Vitamin K antagonist (VKA)
    Number of subjects included in analysis
    1470
    Analysis specification
    Pre-specified
    Analysis type
    		 other [26]
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 3.49
    Notes
    [26] - Crude estimate of the cumulative incidence for rivaroxaban (Xarelto, BAY59-7939): 0.51% (0.20% - 1.17%). Crude estimate of the cumulative incidence for Vitamin K antagonist (VKA): 0.61% (0.17% - 1.72%).

    Secondary: Number of subjects with Composite of Major and Non-major Bleeding Events

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    End point title
    		 Number of subjects with Composite of Major and Non-major Bleeding Events
    End point description
    All events were adjudicated and confirmed by a CEC blinded to treatment. The CEC categorized the bleeding events as major or non-major. The bleeding events were defined per the ISTH criteria. Clinically relevant bleeding included major bleeding (overt bleeding associated with 2 g/dL or greater fall in hemoglobin, leading to a transfusion of 2 or more units of packed red blood cells or whole blood, occurring in a critical site or contributing to death) and non-major bleeding associated with medical intervention, unscheduled physician contact, (temporary) cessation of study treatment, discomfort for the participants such as pain, or impairment of activities of daily life. Number of subjects with clinically relevant major and non-major bleeding events were reported.
    End point type
    Secondary
    End point timeframe
    From randomization up to the date of the last dose of study drug + 2 days
    End point values
    		 Rivaroxaban (Xarelto; BAY59-7939) Vitamin K antagonist (VKA)
    Number of subjects analysed
    988 [27]
    499 [28]
    Units: subjects
    33
    14
    Notes
    [27] - SAF population included all randomized subjects who received at least 1 dose of study medication.
    [28] - SAF population included all randomized subjects who received at least 1 dose of study medication.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first administration of study drug to date of last study drug + 2 days
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Rivaroxaban (Xarelto; BAY59-7939)
    Reporting group description
    		 Subjects randomized to treatment with rivaroxaban received rivaroxaban 20 milligram (mg) orally... more once daily. Subjects with moderate renal impairment [i.e., Creatinine clearance (CrCl) of 30 to 49 milliliter per minute (mL/min), inclusive] at screening received the adjusted dose of 15 mg once daily. The duration of the treatment period for a given subject depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, the cardioversion procedure was performed within 1-5 days after randomization. Rivaroxaban was given for 1-5 days before planned direct cardioversion and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received rivaroxaban for 21 (+4) to 56 (+4) days prior to cardioversion and for 42 days thereafter.

    Reporting group title
    Vitamin K Antagonist (VKA)
    Reporting group description
    		 Subjects assigned to treatment with VKA received VKA orally once daily titrated to a target INR of 2.5 (range 2.0-3.0, inclusive). The specific VKA was assigned by the investigator according to the local standard of practice. For subjects randomized to receive VKA, the investigator assessed if a parenteral anticoagulant drug, particularly prior to cardioversion, was needed as bridging therapy with VKA as standard of care (until target INR was achieved). The duration depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, the cardioversion procedure was performed within 1-5 days after randomization. VKA was given for 1-5 days before cardioversion and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received VKA for 21 (+4) to 56 (+4) days before cardioversion and for 42 days thereafter.

    Serious adverse events
    		 Rivaroxaban (Xarelto; BAY59-7939) Vitamin K Antagonist (VKA)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    93 / 988 (9.41%)
    38 / 499 (7.62%)
         number of deaths (all causes)
    8
    3
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder neoplasm
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (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 / 988 (0.10%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 988 (0.20%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Bladder catheterisation
         subjects affected / exposed
    0 / 988 (0.00%)
    1 / 499 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac ablation
         subjects affected / exposed
    3 / 988 (0.30%)
    1 / 499 (0.20%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Implantable defibrillator insertion
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plastic surgery
         subjects affected / exposed
    0 / 988 (0.00%)
    1 / 499 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shoulder arthroplasty
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (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
    Chest discomfort
         subjects affected / exposed
    1 / 988 (0.10%)
    1 / 499 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    5 / 988 (0.51%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical device site reaction
         subjects affected / exposed
    0 / 988 (0.00%)
    1 / 499 (0.20%)
         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
    1 / 988 (0.10%)
    0 / 499 (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
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 988 (0.00%)
    1 / 499 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    4 / 988 (0.40%)
    1 / 499 (0.20%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary alveolar haemorrhage
         subjects affected / exposed
    0 / 988 (0.00%)
    1 / 499 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary congestion
         subjects affected / exposed
    0 / 988 (0.00%)
    1 / 499 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (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 / 988 (0.10%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory disorder
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Arteriogram coronary
         subjects affected / exposed
    0 / 988 (0.00%)
    1 / 499 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram PR prolongation
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram T wave abnormal
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Subdural haematoma
         subjects affected / exposed
    0 / 988 (0.00%)
    1 / 499 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound haemorrhage
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    2 / 988 (0.20%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Arrhythmia supraventricular
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (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
    8 / 988 (0.81%)
    4 / 499 (0.80%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    4 / 988 (0.40%)
    1 / 499 (0.20%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradyarrhythmia
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial thrombosis
         subjects affected / exposed
    4 / 988 (0.40%)
    3 / 499 (0.60%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    3 / 988 (0.30%)
    3 / 499 (0.60%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    3 / 988 (0.30%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    8 / 988 (0.81%)
    2 / 499 (0.40%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    10 / 988 (1.01%)
    2 / 499 (0.40%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 988 (0.00%)
    1 / 499 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 988 (0.00%)
    1 / 499 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 988 (0.00%)
    1 / 499 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracardiac thrombus
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    3 / 988 (0.30%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhythm idioventricular
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sick sinus syndrome
         subjects affected / exposed
    0 / 988 (0.00%)
    2 / 499 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 988 (0.00%)
    2 / 499 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia induced cardiomyopathy
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (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
    Carotid artery stenosis
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (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 / 988 (0.00%)
    1 / 499 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 988 (0.20%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thalamus haemorrhage
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Blindness transient
         subjects affected / exposed
    0 / 988 (0.00%)
    1 / 499 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 988 (0.40%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 988 (0.10%)
    1 / 499 (0.20%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Nausea
         subjects affected / exposed
    2 / 988 (0.20%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 988 (0.00%)
    1 / 499 (0.20%)
         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
    2 / 988 (0.20%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 988 (0.10%)
    2 / 499 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Vomiting
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (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
    Haematuria
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 988 (0.00%)
    2 / 499 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urogenital haemorrhage
         subjects affected / exposed
    0 / 988 (0.00%)
    1 / 499 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis reactive
         subjects affected / exposed
    0 / 988 (0.00%)
    1 / 499 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 988 (0.00%)
    1 / 499 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 988 (0.10%)
    1 / 499 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis viral
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 988 (0.00%)
    1 / 499 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 988 (0.20%)
    1 / 499 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 988 (0.00%)
    1 / 499 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (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
    2 / 988 (0.20%)
    3 / 499 (0.60%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pseudomembranous colitis
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (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
    0 / 988 (0.00%)
    1 / 499 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 988 (0.10%)
    0 / 499 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Rivaroxaban (Xarelto; BAY59-7939) Vitamin K Antagonist (VKA)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    272 / 988 (27.53%)
    126 / 499 (25.25%)
    Investigations
    International normalised ratio increased
         subjects affected / exposed
    1 / 988 (0.10%)
    9 / 499 (1.80%)
         occurrences all number
    1
    10
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    3 / 988 (0.30%)
    5 / 499 (1.00%)
         occurrences all number
    5
    5
    Vascular disorders
    Hypertension
         subjects affected / exposed
    22 / 988 (2.23%)
    4 / 499 (0.80%)
         occurrences all number
    22
    4
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 988 (0.20%)
    7 / 499 (1.40%)
         occurrences all number
    2
    7
    Atrial thrombosis
         subjects affected / exposed
    16 / 988 (1.62%)
    6 / 499 (1.20%)
         occurrences all number
    16
    6
    Atrioventricular block first degree
         subjects affected / exposed
    40 / 988 (4.05%)
    25 / 499 (5.01%)
         occurrences all number
    40
    25
    Bradycardia
         subjects affected / exposed
    30 / 988 (3.04%)
    13 / 499 (2.61%)
         occurrences all number
    30
    15
    Sinus bradycardia
         subjects affected / exposed
    25 / 988 (2.53%)
    12 / 499 (2.40%)
         occurrences all number
    25
    12
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    25 / 988 (2.53%)
    9 / 499 (1.80%)
         occurrences all number
    28
    9
    Headache
         subjects affected / exposed
    25 / 988 (2.53%)
    7 / 499 (1.40%)
         occurrences all number
    25
    7
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    14 / 988 (1.42%)
    9 / 499 (1.80%)
         occurrences all number
    15
    9
    Oedema peripheral
         subjects affected / exposed
    20 / 988 (2.02%)
    5 / 499 (1.00%)
         occurrences all number
    20
    5
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    10 / 988 (1.01%)
    3 / 499 (0.60%)
         occurrences all number
    11
    3
    Diarrhoea
         subjects affected / exposed
    18 / 988 (1.82%)
    3 / 499 (0.60%)
         occurrences all number
    18
    3
    Nausea
         subjects affected / exposed
    17 / 988 (1.72%)
    1 / 499 (0.20%)
         occurrences all number
    17
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    13 / 988 (1.32%)
    3 / 499 (0.60%)
         occurrences all number
    13
    3
    Dyspnoea
         subjects affected / exposed
    16 / 988 (1.62%)
    12 / 499 (2.40%)
         occurrences all number
    18
    12
    Epistaxis
         subjects affected / exposed
    30 / 988 (3.04%)
    9 / 499 (1.80%)
         occurrences all number
    36
    9
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    12 / 988 (1.21%)
    5 / 499 (1.00%)
         occurrences all number
    12
    5
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    12 / 988 (1.21%)
    5 / 499 (1.00%)
         occurrences all number
    12
    6
    Influenza
         subjects affected / exposed
    3 / 988 (0.30%)
    5 / 499 (1.00%)
         occurrences all number
    3
    5
    Urinary tract infection
         subjects affected / exposed
    7 / 988 (0.71%)
    5 / 499 (1.00%)
         occurrences all number
    9
    5

    More information

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

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/25182247
    http://www.ncbi.nlm.nih.gov/pubmed/24944325
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    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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