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    Clinical Trial Results:
    A multicenter, randomized, open label, parallel group study comparing pre-discharge and posT-discharge tReatment initiation with LCZ696 in heArt failure patieNtS with reduced ejectIon-fracTion hospItalized for an acute decOmpensation eveNt (ADHF) (the TRANSITION study)

    Summary
    EudraCT number
    		 2015-003266-87
    Trial protocol
    		 DE   GB   SK   PT   SE   ES   CZ   FR   BE   PL   HU   IT  
    Global end of trial date
    20 Jun 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    19 Jul 2020
    First version publication date
    06 Jul 2019
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    CLCZ696B2401
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02661217
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.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
    20 Jun 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jun 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate the proportion of subjects in the pre-discharge and post-discharge treatment initiation groups achieving the target dose of 200 mg LCZ696 bid at the end of the Week 10 after randomization (treatment epoch), regardless of previous temporary dose interruption or down-titration.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Feb 2016
    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
    Lebanon: 33
    Country: Number of subjects enrolled
    Saudi Arabia: 7
    Country: Number of subjects enrolled
    Turkey: 43
    Country: Number of subjects enrolled
    Belgium: 29
    Country: Number of subjects enrolled
    France: 20
    Country: Number of subjects enrolled
    Germany: 129
    Country: Number of subjects enrolled
    Italy: 30
    Country: Number of subjects enrolled
    Norway: 30
    Country: Number of subjects enrolled
    Portugal: 51
    Country: Number of subjects enrolled
    Spain: 147
    Country: Number of subjects enrolled
    Sweden: 5
    Country: Number of subjects enrolled
    Switzerland: 21
    Country: Number of subjects enrolled
    United Kingdom: 88
    Country: Number of subjects enrolled
    Czech Republic: 78
    Country: Number of subjects enrolled
    Poland: 104
    Country: Number of subjects enrolled
    Russian Federation: 74
    Country: Number of subjects enrolled
    Slovakia: 57
    Country: Number of subjects enrolled
    Argentina: 37
    Country: Number of subjects enrolled
    Canada: 19
    Worldwide total number of subjects
    1002
    EEA total number of subjects
    768
    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)
    392
    From 65 to 84 years
    570
    85 years and over
    40

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 1002 patients were randomized, including 2 screen failure patients (1 in each group) and 2 patients who were randomized in error. A total of 998 patients entered the 10 week treatment epoch: 497 patients in pre-discharge group and 501 patients in post-discharged group.

    Pre-assignment
    Screening details
    		 The study consisted of 3 Epochs: the Screening Epoch (from signing of informed consent form to randomization), the treatment epoch (10 weeks following randomization), and a 16 weeks Follow-up Epoch following treatment epoch.

    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
    		 LCZ696 Pre-discharge treatment initiation
    Arm description
    		 Patients received first dose at any point after Randomization but no later than 12 h before discharge.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LCZ696
    Investigational medicinal product code
    LCZ696
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were required to take the study medication bid in addition to their daily therapies, possibly at 12 hour interval (i.e., at 7:00 am in the morning and 7:00 pm in the evening). Tablets were taken with a glass of water, and were administered with or without food.

    Arm title
    		 LCZ696 Post-discharge treatment initiation
    Arm description
    		 Patients received first dose after discharge and up to 14 days thereafter.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LCZ696
    Investigational medicinal product code
    LCZ696
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were required to take the study medication bid in addition to their daily therapies, possibly at 12 hour interval (i.e., at 7:00 am in the morning and 7:00 pm in the evening). Tablets were taken with a glass of water, and were administered with or without food.

    Number of subjects in period 1
    		LCZ696 Pre-discharge treatment initiation LCZ696 Post-discharge treatment initiation
    Started
    500
    502
    10 weeks treatment epoch
    460
    455
    Completed
    425
    419
    Not completed
    75
    83
         Adverse event, serious fatal
    22
    17
         Physician decision
    12
    15
         Consent withdrawn by subject
    15
    19
         Adverse event, non-fatal
    10
    8
         Protocol Deviation
    -
    4
         Non-compliance with study treatment
    5
    5
         Did not enter follow-up epoch
    7
    10
         Mis-randomized and not treated
    3
    1
         Lost to follow-up
    1
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LCZ696 Pre-discharge treatment initiation
    Reporting group description
    		 Patients received first dose at any point after Randomization but no later than 12 h before discharge.

    Reporting group title
    LCZ696 Post-discharge treatment initiation
    Reporting group description
    		 Patients received first dose after discharge and up to 14 days thereafter.

    Reporting group values
    		 LCZ696 Pre-discharge treatment initiation LCZ696 Post-discharge treatment initiation Total
    Number of subjects
    		 500 502 1002
    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)
    		 206 186 392
        From 65-84 years
    		 275 295 570
        85 years and over
    		 19 21 40
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 66.7 ± 12.27 67.0 ± 11.67 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 126 125 251
        Male
    		 374 377 751
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 488 486 974
        Black
    		 5 8 13
        Asian
    		 7 3 10
        Native American
    		 0 1 1
        Pacific Islander
    		 0 1 1
        Other
    		 0 1 1
        Unknown
    		 0 2 2

    End points

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    End points reporting groups
    Reporting group title
    LCZ696 Pre-discharge treatment initiation
    Reporting group description
    		 Patients received first dose at any point after Randomization but no later than 12 h before discharge.

    Reporting group title
    LCZ696 Post-discharge treatment initiation
    Reporting group description
    		 Patients received first dose after discharge and up to 14 days thereafter.

    Primary: Percentage of patients achieving the target dose of LCZ696 200 mg bid at 10 weeks post randomization

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    End point title
    		 Percentage of patients achieving the target dose of LCZ696 200 mg bid at 10 weeks post randomization
    End point description
    Percentage of patients achieving and maintaining LCZ696 200 mg bid for at least 2 weeks leading to Week 10
    End point type
    Primary
    End point timeframe
    10 weeks after Randomization
    End point values
    		 LCZ696 Pre-discharge treatment initiation LCZ696 Post-discharge treatment initiation
    Number of subjects analysed
    493
    489
    Units: Percentage of patients
        number (not applicable)
    45.44
    50.72
    Statistical analysis title
    		 Analysis of subjects achieving 200 mg at 10 weeks
    Comparison groups
    LCZ696 Pre-discharge treatment initiation v LCZ696 Post-discharge treatment initiation
    Number of subjects included in analysis
    982
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.099
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.896
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.786
         upper limit
    		 1.021

    Secondary: Percentage of patients achieving and maintaining either LCZ696 100 mg and/or 200 mg bid

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    End point title
    		 Percentage of patients achieving and maintaining either LCZ696 100 mg and/or 200 mg bid
    End point description
    Percentage of patients achieving and maintaining either LCZ696 100 mg and/or 200 mg bid for at least 2 weeks leading to Week 10
    End point type
    Secondary
    End point timeframe
    10 weeks after Randomization
    End point values
    		 LCZ696 Pre-discharge treatment initiation LCZ696 Post-discharge treatment initiation
    Number of subjects analysed
    493
    489
    Units: Percentage of patients
        number (not applicable)
    62.07
    68.51
    Statistical analysis title
    		 Subjects maintaining 100 and/or 200 mg
    Comparison groups
    LCZ696 Pre-discharge treatment initiation v LCZ696 Post-discharge treatment initiation
    Number of subjects included in analysis
    982
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.034
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.906
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.827
         upper limit
    		 0.993

    Secondary: Percentage of patients achieving and maintaining any dose of LCZ696

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    End point title
    		 Percentage of patients achieving and maintaining any dose of LCZ696
    End point description
    Percentage of patients achieving any dose of LCZ696 for at least 2 weeks leading to 10 weeks of treatment
    End point type
    Secondary
    End point timeframe
    10 weeks after Randomization
    End point values
    		 LCZ696 Pre-discharge treatment initiation LCZ696 Post-discharge treatment initiation
    Number of subjects analysed
    493
    489
    Units: Percentage of patients
        number (not applicable)
    86.00
    89.57
    Statistical analysis title
    		 Subjects maintaining any dose
    Comparison groups
    LCZ696 Pre-discharge treatment initiation v LCZ696 Post-discharge treatment initiation
    Number of subjects included in analysis
    982
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.089
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.916
         upper limit
    		 1.006

    Secondary: Percentage of patients permanently discontinued from treatment

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    End point title
    		 Percentage of patients permanently discontinued from treatment
    End point description
    Percentage of patients permanently discontinued from LCZ696 (1) up to week 10 due to AEs, and (2) up to week 26 due to any reasons
    End point type
    Secondary
    End point timeframe
    10 weeks after Randomization AND 26 weeks after randomization
    End point values
    		 LCZ696 Pre-discharge treatment initiation LCZ696 Post-discharge treatment initiation
    Number of subjects analysed
    493
    489
    Units: Percentage of patients
    number (not applicable)
        up to week 10 due to AEs
    7.3
    4.91
        up to week 26 due to any reasons
    16.84
    15.95
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    26 weeks after randomization
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    LCZ696 Pre-discharge treatment initiation
    Reporting group description
    		 Patients received first dose at any point after Randomization but no later than 12 h before discharge.

    Reporting group title
    LCZ696 Post-discharge treatment
    Reporting group description
    		 Patients received first dose after discharge and up to 14 days thereafter.

    Reporting group title
    All patients
    Reporting group description
    		 All patients

    Serious adverse events
    		 LCZ696 Pre-discharge treatment initiation LCZ696 Post-discharge treatment All patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    159 / 493 (32.25%)
    134 / 489 (27.40%)
    293 / 982 (29.84%)
         number of deaths (all causes)
    23
    13
    36
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma gastric
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain neoplasm
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    2 / 493 (0.41%)
    0 / 489 (0.00%)
    2 / 982 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm of ampulla of Vater
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant peritoneal neoplasm
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    6 / 493 (1.22%)
    2 / 489 (0.41%)
    8 / 982 (0.81%)
         occurrences causally related to treatment / all
    2 / 5
    2 / 2
    4 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    2 / 493 (0.41%)
    0 / 489 (0.00%)
    2 / 982 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 493 (0.20%)
    1 / 489 (0.20%)
    2 / 982 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 493 (0.41%)
    5 / 489 (1.02%)
    7 / 982 (0.71%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 493 (0.20%)
    3 / 489 (0.61%)
    4 / 982 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Sudden death
         subjects affected / exposed
    2 / 493 (0.41%)
    0 / 489 (0.00%)
    2 / 982 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 493 (0.20%)
    1 / 489 (0.20%)
    2 / 982 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 493 (0.20%)
    1 / 489 (0.20%)
    2 / 982 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    3 / 493 (0.61%)
    4 / 489 (0.82%)
    7 / 982 (0.71%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 493 (0.20%)
    1 / 489 (0.20%)
    2 / 982 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    6 / 493 (1.22%)
    5 / 489 (1.02%)
    11 / 982 (1.12%)
         occurrences causally related to treatment / all
    1 / 6
    2 / 8
    3 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mediastinal haematoma
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orthopnoea
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary congestion
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    3 / 493 (0.61%)
    7 / 489 (1.43%)
    10 / 982 (1.02%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
    0 / 10
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device battery issue
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    2 / 493 (0.41%)
    0 / 489 (0.00%)
    2 / 982 (0.20%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac output decreased
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ejection fraction abnormal
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 493 (0.00%)
    2 / 489 (0.41%)
    2 / 982 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Heart rate abnormal
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme abnormal
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weight increased
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 493 (0.20%)
    1 / 489 (0.20%)
    2 / 982 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 493 (0.20%)
    1 / 489 (0.20%)
    2 / 982 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 493 (0.20%)
    2 / 489 (0.41%)
    3 / 982 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transplant failure
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Tracheo-oesophageal fistula
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 493 (0.20%)
    2 / 489 (0.41%)
    3 / 982 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 493 (0.20%)
    3 / 489 (0.61%)
    4 / 982 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    2 / 493 (0.41%)
    1 / 489 (0.20%)
    3 / 982 (0.31%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Angina unstable
         subjects affected / exposed
    3 / 493 (0.61%)
    0 / 489 (0.00%)
    3 / 982 (0.31%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    2 / 493 (0.41%)
    1 / 489 (0.20%)
    3 / 982 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Arteriosclerosis coronary artery
         subjects affected / exposed
    2 / 493 (0.41%)
    0 / 489 (0.00%)
    2 / 982 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    4 / 493 (0.81%)
    5 / 489 (1.02%)
    9 / 982 (0.92%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 493 (0.20%)
    1 / 489 (0.20%)
    2 / 982 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    2 / 493 (0.41%)
    2 / 489 (0.41%)
    4 / 982 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    2 / 493 (0.41%)
    1 / 489 (0.20%)
    3 / 982 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    4 / 493 (0.81%)
    1 / 489 (0.20%)
    5 / 982 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    0 / 4
    Cardiac failure
         subjects affected / exposed
    46 / 493 (9.33%)
    45 / 489 (9.20%)
    91 / 982 (9.27%)
         occurrences causally related to treatment / all
    0 / 59
    2 / 41
    2 / 100
         deaths causally related to treatment / all
    0 / 4
    0 / 2
    0 / 6
    Cardiac failure acute
         subjects affected / exposed
    11 / 493 (2.23%)
    9 / 489 (1.84%)
    20 / 982 (2.04%)
         occurrences causally related to treatment / all
    0 / 13
    1 / 7
    1 / 20
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Cardiac failure chronic
         subjects affected / exposed
    3 / 493 (0.61%)
    2 / 489 (0.41%)
    5 / 982 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    1 / 493 (0.20%)
    4 / 489 (0.82%)
    5 / 982 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 493 (0.20%)
    2 / 489 (0.41%)
    3 / 982 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    Cardiogenic shock
         subjects affected / exposed
    1 / 493 (0.20%)
    5 / 489 (1.02%)
    6 / 982 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    Cardiomyopathy
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congestive cardiomyopathy
         subjects affected / exposed
    0 / 493 (0.00%)
    2 / 489 (0.41%)
    2 / 982 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic cardiomyopathy
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    1 / 493 (0.20%)
    1 / 489 (0.20%)
    2 / 982 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Low cardiac output syndrome
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Mitral valve incompetence
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial fibrosis
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 493 (0.20%)
    1 / 489 (0.20%)
    2 / 982 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Myocardial ischaemia
         subjects affected / exposed
    2 / 493 (0.41%)
    0 / 489 (0.00%)
    2 / 982 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus arrest
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    1 / 493 (0.20%)
    2 / 489 (0.41%)
    3 / 982 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    1 / 493 (0.20%)
    2 / 489 (0.41%)
    3 / 982 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 493 (0.20%)
    1 / 489 (0.20%)
    2 / 982 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    3 / 493 (0.61%)
    2 / 489 (0.41%)
    5 / 982 (0.51%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Autonomic nervous system imbalance
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain injury
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral arteriosclerosis
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 493 (0.20%)
    2 / 489 (0.41%)
    3 / 982 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    Cognitive disorder
         subjects affected / exposed
    1 / 493 (0.20%)
    1 / 489 (0.20%)
    2 / 982 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Extrapyramidal disorder
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 493 (0.20%)
    1 / 489 (0.20%)
    2 / 982 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 493 (0.00%)
    2 / 489 (0.41%)
    2 / 982 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    3 / 493 (0.61%)
    3 / 489 (0.61%)
    6 / 982 (0.61%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 3
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 493 (0.61%)
    2 / 489 (0.41%)
    5 / 982 (0.51%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypocoagulable state
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Splenic haemorrhage
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 493 (0.00%)
    3 / 489 (0.61%)
    3 / 982 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea haemorrhagic
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 493 (0.20%)
    1 / 489 (0.20%)
    2 / 982 (0.20%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lip swelling
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 493 (0.20%)
    1 / 489 (0.20%)
    2 / 982 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Cholecystitis acute
         subjects affected / exposed
    2 / 493 (0.41%)
    0 / 489 (0.00%)
    2 / 982 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Hepatic function abnormal
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    1 / 493 (0.20%)
    2 / 489 (0.41%)
    3 / 982 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Skin ulcer
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    12 / 493 (2.43%)
    7 / 489 (1.43%)
    19 / 982 (1.93%)
         occurrences causally related to treatment / all
    4 / 10
    1 / 5
    5 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Chronic kidney disease
         subjects affected / exposed
    3 / 493 (0.61%)
    2 / 489 (0.41%)
    5 / 982 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 493 (0.00%)
    2 / 489 (0.41%)
    2 / 982 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    3 / 493 (0.61%)
    4 / 489 (0.82%)
    7 / 982 (0.71%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 2
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 493 (0.00%)
    4 / 489 (0.82%)
    4 / 982 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bursitis
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fistula
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacterial sepsis
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Biliary sepsis
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 493 (0.20%)
    4 / 489 (0.82%)
    5 / 982 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Catheter site abscess
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 493 (0.20%)
    1 / 489 (0.20%)
    2 / 982 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 493 (0.20%)
    3 / 489 (0.61%)
    4 / 982 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 493 (0.20%)
    1 / 489 (0.20%)
    2 / 982 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 493 (0.20%)
    3 / 489 (0.61%)
    4 / 982 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection viral
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    7 / 493 (1.42%)
    8 / 489 (1.64%)
    15 / 982 (1.53%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 5
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Q fever
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 493 (0.00%)
    4 / 489 (0.82%)
    4 / 982 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 493 (0.41%)
    1 / 489 (0.20%)
    3 / 982 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Septic phlebitis
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 493 (0.20%)
    2 / 489 (0.41%)
    3 / 982 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Tuberculosis
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    4 / 493 (0.81%)
    2 / 489 (0.41%)
    6 / 982 (0.61%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 489 (0.00%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    3 / 493 (0.61%)
    6 / 489 (1.23%)
    9 / 982 (0.92%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 6
    6 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 489 (0.20%)
    1 / 982 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 493 (0.20%)
    2 / 489 (0.41%)
    3 / 982 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 LCZ696 Pre-discharge treatment initiation LCZ696 Post-discharge treatment All patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    200 / 493 (40.57%)
    201 / 489 (41.10%)
    401 / 982 (40.84%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    71 / 493 (14.40%)
    67 / 489 (13.70%)
    138 / 982 (14.05%)
         occurrences all number
    74
    71
    145
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    32 / 493 (6.49%)
    30 / 489 (6.13%)
    62 / 982 (6.31%)
         occurrences all number
    32
    31
    63
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    20 / 493 (4.06%)
    26 / 489 (5.32%)
    46 / 982 (4.68%)
         occurrences all number
    19
    29
    48
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    17 / 493 (3.45%)
    29 / 489 (5.93%)
    46 / 982 (4.68%)
         occurrences all number
    18
    29
    47
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    36 / 493 (7.30%)
    24 / 489 (4.91%)
    60 / 982 (6.11%)
         occurrences all number
    44
    24
    68
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    29 / 493 (5.88%)
    19 / 489 (3.89%)
    48 / 982 (4.89%)
         occurrences all number
    35
    14
    49
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    67 / 493 (13.59%)
    59 / 489 (12.07%)
    126 / 982 (12.83%)
         occurrences all number
    80
    73
    153

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Feb 2016
    The purpose of this amendment was to address the inquiry by the Health Authorities from Germany. This change applied to Germany only referring to the eligibility of subjects.
    18 Jul 2016
    Wording changes + clarifications

    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
    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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