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    Clinical Trial Results:
    A multicenter, randomized, double-blind, active controlled study to evaluate the effects of LCZ696 compared to valsartan on cognitive function in patients with chronic heart failure and preserved ejection fraction

    Summary
    EudraCT number
    		 2016-001254-17
    Trial protocol
    		 GB   LT   DE   ES   BG   NL   PL   BE   HR   IT  
    Global end of trial date
    16 May 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 May 2023
    First version publication date
    18 May 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLCZ696B2320
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02884206
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    : Novartis Pharma AG
    Sponsor organisation address
    Novartis Campus, 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
    16 May 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 May 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the effects of LCZ696 compared to valsartan on cognitive function over 3 years in patients with heart failure and preserved ejection fraction (HFpEF) as assessed by the CogState cognitive assessment battery (Global Cognitive Composite Score (GCCS)).
    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
    23 Nov 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
    Argentina: 25
    Country: Number of subjects enrolled
    Australia: 7
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Bulgaria: 17
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    Croatia: 7
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Germany: 71
    Country: Number of subjects enrolled
    United Kingdom: 27
    Country: Number of subjects enrolled
    Italy: 39
    Country: Number of subjects enrolled
    Korea, Republic of: 10
    Country: Number of subjects enrolled
    Lithuania: 6
    Country: Number of subjects enrolled
    Netherlands: 17
    Country: Number of subjects enrolled
    Poland: 68
    Country: Number of subjects enrolled
    Russian Federation: 39
    Country: Number of subjects enrolled
    Spain: 23
    Country: Number of subjects enrolled
    Switzerland: 12
    Country: Number of subjects enrolled
    Taiwan: 9
    Country: Number of subjects enrolled
    Turkey: 7
    Country: Number of subjects enrolled
    United States: 197
    Worldwide total number of subjects
    592
    EEA total number of subjects
    252
    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)
    86
    From 65 to 84 years
    482
    85 years and over
    24

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 1200 patients were screened, of which 494 patients discontinued prior to completing the screening epoch. All 706 patients who completed the screening epoch were included in the Enrolled set. A total of 659 patients completed the valsartan run-in epoch and entered the LCZ696 run-in epoch. Overall, 592 patients completed the treatment run-in epoch.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LCZ696 200 mg bid
    Arm description
    		 Patients who were able to tolerate the treatment during the single-blind treatment run-in epoch. Following the run-in period, patients randomized in this arm were given LCZ696 at 200 mg twice daily for three years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sacubitril/valsartan
    Investigational medicinal product code
    LCZ696
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    LCZ696 200 mg bid

    Arm title
    		 Valsartan 160 mg bid
    Arm description
    		 Patients who were able to tolerate the treatment during the single-blind treatment run-in epoch. Following the run-in period, patients randomized in this arm were given valsartan at 160 mg twice daily for three years.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Valsartan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Valsartan 160 mg bid

    Number of subjects in period 1
    		LCZ696 200 mg bid Valsartan 160 mg bid
    Started
    295
    297
    Safety set
    295
    297
    PET substudy set
    244 [1]
    247
    Completed
    251
    237
    Not completed
    44
    60
         Adverse event, serious fatal
    28
    39
         Physician decision
    2
    -
         Adverse event, non-fatal
    -
    3
         Non-compliance with study treatment
    -
    1
         Patient/guardian decision
    10
    13
         Lost to follow-up
    4
    4
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Subset of the SAF patients who participated in the PET substudy and had non-missing baseline assessment.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LCZ696 200 mg bid
    Reporting group description
    		 Patients who were able to tolerate the treatment during the single-blind treatment run-in epoch. Following the run-in period, patients randomized in this arm were given LCZ696 at 200 mg twice daily for three years.

    Reporting group title
    Valsartan 160 mg bid
    Reporting group description
    		 Patients who were able to tolerate the treatment during the single-blind treatment run-in epoch. Following the run-in period, patients randomized in this arm were given valsartan at 160 mg twice daily for three years.

    Reporting group values
    		 LCZ696 200 mg bid Valsartan 160 mg bid Total
    Number of subjects
    		 295 297 592
    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)
    		 41 45 86
        From 65-84 years
    		 243 239 482
        85 years and over
    		 11 13 24
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 72.27 ( 6.749 ) 72.61 ( 7.043 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 134 143 277
        Male
    		 161 154 315
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 273 271 544
        Asian
    		 11 12 23
        Black
    		 6 9 15
        Native American
    		 2 0 2
        Unknown
    		 1 2 3
        Other
    		 2 3 5

    End points

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    End points reporting groups
    Reporting group title
    LCZ696 200 mg bid
    Reporting group description
    		 Patients who were able to tolerate the treatment during the single-blind treatment run-in epoch. Following the run-in period, patients randomized in this arm were given LCZ696 at 200 mg twice daily for three years.

    Reporting group title
    Valsartan 160 mg bid
    Reporting group description
    		 Patients who were able to tolerate the treatment during the single-blind treatment run-in epoch. Following the run-in period, patients randomized in this arm were given valsartan at 160 mg twice daily for three years.

    Primary: Change from baseline in the CogState Global Cognitive Composite Score (GCCS)

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    End point title
    		 Change from baseline in the CogState Global Cognitive Composite Score (GCCS)
    End point description
    The CogState cognitive battery was composed of 7 tests, which were administered electronically by the patients at scheduled visits. For each test, a standardized z-score was calculated. The GCCS was the average of the non-missing individual test z-scores. A higher score indicated better cognitive function. CogState GCCS changes from baseline (randomization) were analyzed using a repeated measures ANCOVA in which treatment, age stratification factor, Mini mental state examination stratification factor, education level, Apolipoprotein E ε4 allele status, cerebrovascular disease burden at screening, visit and treatment-by-visit interaction are included as fixed-effect factor, and baseline (randomization) GCCS and visit-by- baseline GCCS as covariates with a common unstructured covariance matrix among visits between treatment groups. The analysis was based on a direct likelihood method with an assumption of Missing at random.
    End point type
    Primary
    End point timeframe
    Baseline, month 36
    End point values
    		 LCZ696 200 mg bid Valsartan 160 mg bid
    Number of subjects analysed
    195
    183
    Units: Global Cognitive Composite Score
        least squares mean (standard error)
    -0.0902 ( 0.0372 )
    -0.0722 ( 0.0383 )
    Statistical analysis title
    		 LCZ696 vs. Valsartan
    Statistical analysis description
    Repeated measure ANCOVA
    Comparison groups
    LCZ696 200 mg bid v Valsartan 160 mg bid
    Number of subjects included in analysis
    378
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 = 0.7363
    Method
    		 ANCOVA
    Parameter type
    		 LSM
    Point estimate
    -0.018
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.123
         upper limit
    		 0.087
    Notes
    [1] - To demonstrate non-inferiority that LCZ696 does not lead to a relevant decrease in cognition compared to valsartan at year 3, the lower bound of 95% CI does not include the pre-specified non-inferiority (NI) boundary (Cohen’s D) of -0.3. An effect size of 0.3 in Cohen’s D is generally considered as small.

    Secondary: Change from baseline in cortical composite standardized uptake value ratio (SUVr)

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    End point title
    		 Change from baseline in cortical composite standardized uptake value ratio (SUVr)
    End point description
    The effects of LCZ696 compared to valsartan on Aβ deposition in the brain over 3 years were evaluated in a subset of patients using amyloid positron emission tomography (PET) imaging by assessing the change from baseline in cortical composite SUVr. PET imaging was performed at selected PET-capable centers on all eligible patients participating in the substudy. Sites with patients performing the PET scan were a subset of the overall patient population and overall sites for the study. Change from baseline to 3 years was analyzed based on an ANCOVA model with treatment, age, MMSE, amyloid status (+ve/−ve) stratification factors, region, APOE4 status and cerebrovascular disease burden as fixed effects, with baseline SUVr and treatment-by-baseline SUVr interaction as covariates for each of these imputed datasets. Results were obtained by applying Rubin’s rules on the estimates from the imputed datasets.
    End point type
    Secondary
    End point timeframe
    Baseline, month 36
    End point values
    		 LCZ696 200 mg bid Valsartan 160 mg bid
    Number of subjects analysed
    147
    134
    Units: value ratio (SUVr)
    least squares mean (standard error)
        Global cortical composite
    0.0273 ( 0.0114 )
    0.0564 ( 0.0101 )
        Cingulum posterior composite
    0.0416 ( 0.0113 )
    0.0876 ( 0.0109 )
        Frontal lobe composite
    0.0218 ( 0.0117 )
    0.0434 ( 0.0104 )
        Parietal lobe composite
    0.0231 ( 0.0119 )
    0.0532 ( 0.0104 )
        Temporal lobe composite
    0.0249 ( 0.0110 )
    0.0418 ( 0.0097 )
        White matter composite
    0.0061 ( 0.0094 )
    -0.0072 ( 0.0083 )
    Statistical analysis title
    		 LCZ696 vs. Valsartan
    Statistical analysis description
    Multiple Imputation ANCOVA in Global cortical composite
    Comparison groups
    LCZ696 200 mg bid v Valsartan 160 mg bid
    Number of subjects included in analysis
    281
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    P-value
    		 = 0.0579
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean
    Point estimate
    -0.0292
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.0593
         upper limit
    		 0.001
    Notes
    [2] - To show that the point estimate of SUVr difference in mean change over 3 years is in favor of LCZ696 and the non-inferiority is demonstrated, with the upper bound of the 95% CI excluding the NI boundary of 0.01.

    Secondary: Change from baseline in individual cognitive domains

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    End point title
    		 Change from baseline in individual cognitive domains
    End point description
    The effects of LCZ696 compared to valsartan on the individual cognitive domains (memory, executive function, and attention) over 3 years were evaluated by assessing the individual components of the CogState cognitive battery. Composite scores for the 3 individual cognitive domains were generated by combining the standardized z-scores of selected tests from the CogState cognitive battery. Each composite score was the average of the non-missing individual test z-scores. A higher score indicated better cognitive function.
    End point type
    Secondary
    End point timeframe
    Baseline, month 36
    End point values
    		 LCZ696 200 mg bid Valsartan 160 mg bid
    Number of subjects analysed
    197
    185
    Units: Z-scores
    least squares mean (standard error)
        Memory domain (n= 197, 185)
    -0.0573 ( 0.0477 )
    -0.0580 ( 0.0490 )
        Executive function domain (n= 196, 184)
    -0.0375 ( 0.0480 )
    -0.0702 ( 0.0493 )
        Attention domain (n= 197, 184)
    -0.1836 ( 0.0614 )
    -0.0794 ( 0.0634 )
    Statistical analysis title
    		 LCZ696 vs. Valsartan for memory domain
    Statistical analysis description
    Repeated measure ANCOVA for memory domain
    Comparison groups
    LCZ696 200 mg bid v Valsartan 160 mg bid
    Number of subjects included in analysis
    382
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.9916
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean
    Point estimate
    0.0007
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1339
         upper limit
    		 0.1353
    Statistical analysis title
    		 LCZ696 vs. Valsartan for attention domain
    Statistical analysis description
    Repeated measure ANCOVA for attention domain
    Comparison groups
    LCZ696 200 mg bid v Valsartan 160 mg bid
    Number of subjects included in analysis
    382
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2403
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean
    Point estimate
    -0.1042
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2783
         upper limit
    		 0.07
    Statistical analysis title
    		 LCZ696 vs. Valsartan for executive function domain
    Statistical analysis description
    Repeated measure ANCOVA for executive function domain
    Comparison groups
    LCZ696 200 mg bid v Valsartan 160 mg bid
    Number of subjects included in analysis
    382
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6348
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean
    Point estimate
    0.0327
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1024
         upper limit
    		 0.1677

    Secondary: Change from baseline in the summary score of the instrumental activities of daily living (IADL)

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    End point title
    		 Change from baseline in the summary score of the instrumental activities of daily living (IADL)
    End point description
    The effects of LCZ696 compared to valsartan on the changes in IADL over 3 years were evaluated by as assessing the Functional activities questionnaire (FAQ) summary scores. The FAQ is a 30-point questionnaire that is made up of 10 questions that reflect a patient’s ability to perform activities of daily living and to function independently. A score of 0 represents no impairment and a score of 30 represents severe impairment.
    End point type
    Secondary
    End point timeframe
    Baseline, month 36
    End point values
    		 LCZ696 200 mg bid Valsartan 160 mg bid
    Number of subjects analysed
    197
    186
    Units: FAQ scores
        least squares mean (standard error)
    0.5983 ( 0.2064 )
    0.7089 ( 0.2115 )
    Statistical analysis title
    		 LCZ696 vs. Valsartan
    Statistical analysis description
    Repeated measure ANCOVA
    Comparison groups
    LCZ696 200 mg bid v Valsartan 160 mg bid
    Number of subjects included in analysis
    383
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.7081
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean
    Point estimate
    -0.1105
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6906
         upper limit
    		 0.4696

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of 37 months.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    LCZ696
    Reporting group description
    		 LCZ696

    Reporting group title
    Total
    Reporting group description
    		 Total

    Reporting group title
    Valsartan
    Reporting group description
    		 Valsartan

    Serious adverse events
    		 LCZ696 Total Valsartan
    Total subjects affected by serious adverse events
         subjects affected / exposed
    145 / 295 (49.15%)
    306 / 592 (51.69%)
    161 / 297 (54.21%)
         number of deaths (all causes)
    28
    67
    39
         number of deaths resulting from adverse events
    0
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B-cell lymphoma
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 295 (0.34%)
    7 / 592 (1.18%)
    6 / 297 (2.02%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 8
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Benign hepatobiliary neoplasm
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder neoplasm
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cancer recurrent
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchial carcinoma
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Carcinoid tumour in the large intestine
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colorectal adenoma
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Invasive breast carcinoma
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung cancer metastatic
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometrial stromal sarcoma
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Follicular lymphoma
         subjects affected / exposed
    1 / 295 (0.34%)
    2 / 592 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic neoplasm
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    2 / 295 (0.68%)
    3 / 592 (0.51%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to peritoneum
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Metastases to liver
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphocytic leukaemia
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 295 (0.34%)
    2 / 592 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostatic adenoma
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    2 / 295 (0.68%)
    4 / 592 (0.68%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian cancer
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-Hodgkin's lymphoma
         subjects affected / exposed
    1 / 295 (0.34%)
    2 / 592 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasm prostate
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Refractory cytopenia with unilineage dysplasia
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tonsil cancer
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         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 cell carcinoma
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         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
    Aneurysm
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic aneurysm
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    2 / 295 (0.68%)
    2 / 592 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    0 / 295 (0.00%)
    2 / 592 (0.34%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Deep vein thrombosis
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Extremity necrosis
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         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
    0 / 295 (0.00%)
    5 / 592 (0.84%)
    5 / 297 (1.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 295 (0.34%)
    2 / 592 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive urgency
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    3 / 295 (1.02%)
    8 / 592 (1.35%)
    5 / 297 (1.68%)
         occurrences causally related to treatment / all
    1 / 3
    4 / 9
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intermittent claudication
         subjects affected / exposed
    1 / 295 (0.34%)
    2 / 592 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 295 (0.34%)
    4 / 592 (0.68%)
    3 / 297 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    1 / 295 (0.34%)
    2 / 592 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Vasculitis
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subclavian artery stenosis
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    2 / 295 (0.68%)
    2 / 592 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac death
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Asthenia
         subjects affected / exposed
    0 / 295 (0.00%)
    2 / 592 (0.34%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    5 / 295 (1.69%)
    8 / 592 (1.35%)
    3 / 297 (1.01%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 8
    0 / 3
         deaths causally related to treatment / all
    0 / 5
    0 / 8
    0 / 3
    Impaired healing
         subjects affected / exposed
    0 / 295 (0.00%)
    2 / 592 (0.34%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    8 / 295 (2.71%)
    10 / 592 (1.69%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 10
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 295 (0.00%)
    2 / 592 (0.34%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Vascular stent stenosis
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 295 (0.00%)
    2 / 592 (0.34%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    2 / 295 (0.68%)
    2 / 592 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    Immune system disorders
    Allergy to arthropod bite
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Endometrial hyperplasia
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Testicular swelling
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Testicular pain
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchiectasis
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         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
    5 / 295 (1.69%)
    10 / 592 (1.69%)
    5 / 297 (1.68%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 11
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    Central sleep apnoea syndrome
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    9 / 295 (3.05%)
    13 / 592 (2.20%)
    4 / 297 (1.35%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 19
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Cough
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 295 (0.34%)
    4 / 592 (0.68%)
    3 / 297 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 295 (0.34%)
    3 / 592 (0.51%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 295 (1.02%)
    10 / 592 (1.69%)
    7 / 297 (2.36%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 12
    0 / 9
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    Hiccups
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    3 / 295 (1.02%)
    4 / 592 (0.68%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Hypercapnia
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Pulmonary alveolar haemorrhage
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 295 (0.34%)
    4 / 592 (0.68%)
    3 / 297 (1.01%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    Pulmonary toxicity
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 295 (0.34%)
    5 / 592 (0.84%)
    4 / 297 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    1 / 295 (0.34%)
    2 / 592 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angiocardiogram
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         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 creatinine increased
         subjects affected / exposed
    2 / 295 (0.68%)
    2 / 592 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood glucose increased
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Catheterisation cardiac abnormal
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronavirus test positive
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral test positive
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SARS-CoV-2 test positive
         subjects affected / exposed
    0 / 295 (0.00%)
    3 / 592 (0.51%)
    3 / 297 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procalcitonin increased
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 295 (0.34%)
    2 / 592 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weight increased
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 295 (0.34%)
    3 / 592 (0.51%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 295 (0.34%)
    3 / 592 (0.51%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    2 / 295 (0.68%)
    9 / 592 (1.52%)
    7 / 297 (2.36%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 9
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    Craniocerebral injury
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain contusion
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epicondylitis
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 295 (0.34%)
    2 / 592 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria traumatic
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fractured sacrum
         subjects affected / exposed
    1 / 295 (0.34%)
    2 / 592 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    2 / 295 (0.68%)
    7 / 592 (1.18%)
    5 / 297 (1.68%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 7
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 295 (0.00%)
    2 / 592 (0.34%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural complication
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural pulmonary embolism
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Periprosthetic fracture
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 295 (0.00%)
    2 / 592 (0.34%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Humerus fracture
         subjects affected / exposed
    2 / 295 (0.68%)
    3 / 592 (0.51%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 295 (0.00%)
    2 / 592 (0.34%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sternal fracture
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         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
    2 / 295 (0.68%)
    2 / 592 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transfusion reaction
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Traumatic fracture
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 295 (0.00%)
    2 / 592 (0.34%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Acute myocardial infarction
         subjects affected / exposed
    8 / 295 (2.71%)
    20 / 592 (3.38%)
    12 / 297 (4.04%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 21
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
    Acute left ventricular failure
         subjects affected / exposed
    3 / 295 (1.02%)
    4 / 592 (0.68%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Acute right ventricular failure
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 295 (0.00%)
    3 / 592 (0.51%)
    3 / 297 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Aortic valve stenosis
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Angina unstable
         subjects affected / exposed
    3 / 295 (1.02%)
    8 / 592 (1.35%)
    5 / 297 (1.68%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 8
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    2 / 295 (0.68%)
    5 / 592 (0.84%)
    3 / 297 (1.01%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 7
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    14 / 295 (4.75%)
    25 / 592 (4.22%)
    11 / 297 (3.70%)
         occurrences causally related to treatment / all
    1 / 15
    1 / 28
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 295 (0.34%)
    3 / 592 (0.51%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular dissociation
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    2 / 295 (0.68%)
    3 / 592 (0.51%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradyarrhythmia
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         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 failure chronic
         subjects affected / exposed
    4 / 295 (1.36%)
    7 / 592 (1.18%)
    3 / 297 (1.01%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 9
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    5 / 295 (1.69%)
    10 / 592 (1.69%)
    5 / 297 (1.68%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 14
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    15 / 295 (5.08%)
    30 / 592 (5.07%)
    15 / 297 (5.05%)
         occurrences causally related to treatment / all
    1 / 18
    2 / 38
    1 / 20
         deaths causally related to treatment / all
    0 / 3
    0 / 6
    0 / 3
    Cardiac arrest
         subjects affected / exposed
    0 / 295 (0.00%)
    6 / 592 (1.01%)
    6 / 297 (2.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
    Cardiac amyloidosis
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Bradycardia
         subjects affected / exposed
    0 / 295 (0.00%)
    3 / 592 (0.51%)
    3 / 297 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    8 / 295 (2.71%)
    16 / 592 (2.70%)
    8 / 297 (2.69%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 20
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    Cardiac valve disease
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 295 (0.34%)
    3 / 592 (0.51%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
    Cardiogenic shock
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Cardiovascular insufficiency
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Chronic left ventricular failure
         subjects affected / exposed
    0 / 295 (0.00%)
    2 / 592 (0.34%)
    2 / 297 (0.67%)
         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
    7 / 295 (2.37%)
    10 / 592 (1.69%)
    3 / 297 (1.01%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 10
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         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 infarction
         subjects affected / exposed
    3 / 295 (1.02%)
    10 / 592 (1.69%)
    7 / 297 (2.36%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 10
    0 / 7
         deaths causally related to treatment / all
    0 / 2
    0 / 7
    0 / 5
    Myocardial ischaemia
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 295 (0.34%)
    2 / 592 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Ventricular extrasystoles
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Brain stem infarction
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         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 oedema
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Bell's palsy
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    1 / 295 (0.34%)
    2 / 592 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic neuropathy
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dementia Alzheimer's type
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    4 / 295 (1.36%)
    7 / 592 (1.18%)
    3 / 297 (1.01%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 8
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Cerebellar stroke
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Cerebral haematoma
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebellar haemorrhage
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    2 / 295 (0.68%)
    2 / 592 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 295 (0.00%)
    2 / 592 (0.34%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 295 (0.34%)
    3 / 592 (0.51%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 295 (0.00%)
    2 / 592 (0.34%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 295 (0.34%)
    2 / 592 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Headache
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 295 (0.34%)
    2 / 592 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 295 (0.34%)
    4 / 592 (0.68%)
    3 / 297 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    Lacunar stroke
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    3 / 295 (1.02%)
    4 / 592 (0.68%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myelopathy
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intracranial aneurysm
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    6 / 295 (2.03%)
    11 / 592 (1.86%)
    5 / 297 (1.68%)
         occurrences causally related to treatment / all
    2 / 9
    4 / 15
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 295 (0.34%)
    2 / 592 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 295 (0.34%)
    3 / 592 (0.51%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 295 (1.02%)
    9 / 592 (1.52%)
    6 / 297 (2.02%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 11
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombasthenia
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Splenic infarction
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombotic thrombocytopenic purpura
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    0 / 295 (0.00%)
    2 / 592 (0.34%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chondrodermatitis nodularis chronica helicis
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Diabetic retinopathy
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    2 / 295 (0.68%)
    4 / 592 (0.68%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal degeneration
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Macular degeneration
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Glaucoma
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epiretinal membrane
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         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
         subjects affected / exposed
    3 / 295 (1.02%)
    3 / 592 (0.51%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 295 (0.34%)
    2 / 592 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 295 (0.34%)
    2 / 592 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    2 / 295 (0.68%)
    2 / 592 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Faeces discoloured
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulum intestinal haemorrhagic
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         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
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal ulcer haemorrhage
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    3 / 295 (1.02%)
    6 / 592 (1.01%)
    3 / 297 (1.01%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 14
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Gastritis
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    2 / 295 (0.68%)
    2 / 592 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal mass
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 295 (0.68%)
    2 / 592 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mesenteric arterial occlusion
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Intestinal haemorrhage
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retroperitoneal haematoma
         subjects affected / exposed
    1 / 295 (0.34%)
    2 / 592 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngo-oesophageal diverticulum
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    2 / 295 (0.68%)
    2 / 592 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 295 (0.00%)
    2 / 592 (0.34%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mouth haemorrhage
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 295 (0.34%)
    2 / 592 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    2 / 295 (0.68%)
    3 / 592 (0.51%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 295 (0.34%)
    2 / 592 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    1 / 295 (0.34%)
    2 / 592 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac cirrhosis
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    4 / 295 (1.36%)
    4 / 592 (0.68%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Cholestasis
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 295 (0.34%)
    2 / 592 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic mass
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eczema
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         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
    6 / 295 (2.03%)
    12 / 592 (2.03%)
    6 / 297 (2.02%)
         occurrences causally related to treatment / all
    1 / 6
    2 / 12
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Bladder mass
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    2 / 295 (0.68%)
    4 / 592 (0.68%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis interstitial
         subjects affected / exposed
    2 / 295 (0.68%)
    2 / 592 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic nephropathy
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysuria
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    2 / 295 (0.68%)
    2 / 592 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prerenal failure
         subjects affected / exposed
    1 / 295 (0.34%)
    2 / 592 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder tamponade
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract disorder
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         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 tubular necrosis
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 295 (0.00%)
    3 / 592 (0.51%)
    3 / 297 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 295 (0.68%)
    2 / 592 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    2 / 295 (0.68%)
    2 / 592 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 295 (0.00%)
    3 / 592 (0.51%)
    3 / 297 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    2 / 295 (0.68%)
    3 / 592 (0.51%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical spinal stenosis
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoroacetabular impingement
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gouty arthritis
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Loose body in joint
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    1 / 295 (0.34%)
    2 / 592 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    6 / 295 (2.03%)
    10 / 592 (1.69%)
    4 / 297 (1.35%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 11
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Plantar fasciitis
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 295 (0.00%)
    2 / 592 (0.34%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rheumatic disorder
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal disorder
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal stenosis
         subjects affected / exposed
    2 / 295 (0.68%)
    3 / 592 (0.51%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Synovitis
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vertebral foraminal stenosis
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    3 / 295 (1.02%)
    4 / 592 (0.68%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis bacterial
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    2 / 295 (0.68%)
    5 / 592 (0.84%)
    3 / 297 (1.01%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    COVID-19 pneumonia
         subjects affected / exposed
    4 / 295 (1.36%)
    8 / 592 (1.35%)
    4 / 297 (1.35%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 8
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    Candida infection
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocarditis bacterial
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 295 (0.00%)
    2 / 592 (0.34%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    2 / 295 (0.68%)
    3 / 592 (0.51%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 295 (0.34%)
    2 / 592 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    1 / 295 (0.34%)
    2 / 592 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 295 (0.34%)
    2 / 592 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carbuncle
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    2 / 295 (0.68%)
    2 / 592 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterococcal bacteraemia
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    2 / 295 (0.68%)
    3 / 592 (0.51%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine infection
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    10 / 295 (3.39%)
    19 / 592 (3.21%)
    9 / 297 (3.03%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 23
    0 / 9
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphangitis
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nosocomial infection
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    5 / 295 (1.69%)
    10 / 592 (1.69%)
    5 / 297 (1.68%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 10
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    Pneumonia aspiration
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Septic shock
         subjects affected / exposed
    2 / 295 (0.68%)
    4 / 592 (0.68%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    Post procedural infection
         subjects affected / exposed
    1 / 295 (0.34%)
    2 / 592 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psoas abscess
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         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
    6 / 295 (2.03%)
    7 / 592 (1.18%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 9
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    2 / 295 (0.68%)
    2 / 592 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 295 (0.34%)
    2 / 592 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         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
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    4 / 295 (1.36%)
    5 / 592 (0.84%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    2 / 295 (0.68%)
    3 / 592 (0.51%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    2 / 295 (0.68%)
    5 / 592 (0.84%)
    3 / 297 (1.01%)
         occurrences causally related to treatment / all
    2 / 2
    5 / 5
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 295 (0.34%)
    2 / 592 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    2 / 295 (0.68%)
    2 / 592 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 295 (0.34%)
    1 / 592 (0.17%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 295 (0.00%)
    1 / 592 (0.17%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 LCZ696 Total Valsartan
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    238 / 295 (80.68%)
    483 / 592 (81.59%)
    245 / 297 (82.49%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    21 / 295 (7.12%)
    52 / 592 (8.78%)
    31 / 297 (10.44%)
         occurrences all number
    22
    58
    36
    Hypotension
         subjects affected / exposed
    68 / 295 (23.05%)
    125 / 592 (21.11%)
    57 / 297 (19.19%)
         occurrences all number
    99
    167
    68
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    9 / 295 (3.05%)
    22 / 592 (3.72%)
    13 / 297 (4.38%)
         occurrences all number
    10
    23
    13
    Fatigue
         subjects affected / exposed
    16 / 295 (5.42%)
    39 / 592 (6.59%)
    23 / 297 (7.74%)
         occurrences all number
    18
    44
    26
    Asthenia
         subjects affected / exposed
    7 / 295 (2.37%)
    20 / 592 (3.38%)
    13 / 297 (4.38%)
         occurrences all number
    10
    25
    15
    Oedema peripheral
         subjects affected / exposed
    24 / 295 (8.14%)
    49 / 592 (8.28%)
    25 / 297 (8.42%)
         occurrences all number
    32
    59
    27
    Pyrexia
         subjects affected / exposed
    4 / 295 (1.36%)
    10 / 592 (1.69%)
    6 / 297 (2.02%)
         occurrences all number
    4
    10
    6
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    6 / 295 (2.03%)
    9 / 592 (1.52%)
    3 / 297 (1.01%)
         occurrences all number
    6
    9
    3
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    10 / 295 (3.39%)
    20 / 592 (3.38%)
    10 / 297 (3.37%)
         occurrences all number
    18
    30
    12
    Epistaxis
         subjects affected / exposed
    6 / 295 (2.03%)
    12 / 592 (2.03%)
    6 / 297 (2.02%)
         occurrences all number
    8
    21
    13
    Dyspnoea
         subjects affected / exposed
    21 / 295 (7.12%)
    55 / 592 (9.29%)
    34 / 297 (11.45%)
         occurrences all number
    28
    71
    43
    Cough
         subjects affected / exposed
    17 / 295 (5.76%)
    29 / 592 (4.90%)
    12 / 297 (4.04%)
         occurrences all number
    20
    33
    13
    Psychiatric disorders
    Depression
         subjects affected / exposed
    13 / 295 (4.41%)
    25 / 592 (4.22%)
    12 / 297 (4.04%)
         occurrences all number
    14
    29
    15
    Insomnia
         subjects affected / exposed
    4 / 295 (1.36%)
    12 / 592 (2.03%)
    8 / 297 (2.69%)
         occurrences all number
    4
    12
    8
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    9 / 295 (3.05%)
    16 / 592 (2.70%)
    7 / 297 (2.36%)
         occurrences all number
    10
    18
    8
    Blood pressure increased
         subjects affected / exposed
    4 / 295 (1.36%)
    16 / 592 (2.70%)
    12 / 297 (4.04%)
         occurrences all number
    6
    20
    14
    Glomerular filtration rate decreased
         subjects affected / exposed
    15 / 295 (5.08%)
    31 / 592 (5.24%)
    16 / 297 (5.39%)
         occurrences all number
    16
    32
    16
    SARS-CoV-2 test positive
         subjects affected / exposed
    2 / 295 (0.68%)
    9 / 592 (1.52%)
    7 / 297 (2.36%)
         occurrences all number
    2
    9
    7
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    6 / 295 (2.03%)
    15 / 592 (2.53%)
    9 / 297 (3.03%)
         occurrences all number
    7
    20
    13
    Fall
         subjects affected / exposed
    19 / 295 (6.44%)
    34 / 592 (5.74%)
    15 / 297 (5.05%)
         occurrences all number
    23
    49
    26
    Ligament sprain
         subjects affected / exposed
    7 / 295 (2.37%)
    10 / 592 (1.69%)
    3 / 297 (1.01%)
         occurrences all number
    7
    10
    3
    Skin laceration
         subjects affected / exposed
    6 / 295 (2.03%)
    13 / 592 (2.20%)
    7 / 297 (2.36%)
         occurrences all number
    10
    17
    7
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    17 / 295 (5.76%)
    39 / 592 (6.59%)
    22 / 297 (7.41%)
         occurrences all number
    19
    44
    25
    Angina pectoris
         subjects affected / exposed
    16 / 295 (5.42%)
    28 / 592 (4.73%)
    12 / 297 (4.04%)
         occurrences all number
    17
    31
    14
    Cardiac failure
         subjects affected / exposed
    14 / 295 (4.75%)
    39 / 592 (6.59%)
    25 / 297 (8.42%)
         occurrences all number
    16
    43
    27
    Cardiac failure chronic
         subjects affected / exposed
    3 / 295 (1.02%)
    13 / 592 (2.20%)
    10 / 297 (3.37%)
         occurrences all number
    3
    15
    12
    Palpitations
         subjects affected / exposed
    18 / 295 (6.10%)
    24 / 592 (4.05%)
    6 / 297 (2.02%)
         occurrences all number
    20
    26
    6
    Bradycardia
         subjects affected / exposed
    7 / 295 (2.37%)
    12 / 592 (2.03%)
    5 / 297 (1.68%)
         occurrences all number
    7
    12
    5
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    1 / 295 (0.34%)
    8 / 592 (1.35%)
    7 / 297 (2.36%)
         occurrences all number
    1
    9
    8
    Dizziness
         subjects affected / exposed
    28 / 295 (9.49%)
    59 / 592 (9.97%)
    31 / 297 (10.44%)
         occurrences all number
    33
    68
    35
    Headache
         subjects affected / exposed
    11 / 295 (3.73%)
    18 / 592 (3.04%)
    7 / 297 (2.36%)
         occurrences all number
    11
    18
    7
    Syncope
         subjects affected / exposed
    7 / 295 (2.37%)
    11 / 592 (1.86%)
    4 / 297 (1.35%)
         occurrences all number
    7
    12
    5
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    6 / 295 (2.03%)
    7 / 592 (1.18%)
    1 / 297 (0.34%)
         occurrences all number
    6
    7
    1
    Anaemia
         subjects affected / exposed
    24 / 295 (8.14%)
    45 / 592 (7.60%)
    21 / 297 (7.07%)
         occurrences all number
    25
    49
    24
    Eye disorders
    Cataract
         subjects affected / exposed
    6 / 295 (2.03%)
    14 / 592 (2.36%)
    8 / 297 (2.69%)
         occurrences all number
    6
    15
    9
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    6 / 295 (2.03%)
    18 / 592 (3.04%)
    12 / 297 (4.04%)
         occurrences all number
    6
    18
    12
    Large intestine polyp
         subjects affected / exposed
    4 / 295 (1.36%)
    10 / 592 (1.69%)
    6 / 297 (2.02%)
         occurrences all number
    4
    10
    6
    Gastrooesophageal reflux disease
         subjects affected / exposed
    6 / 295 (2.03%)
    12 / 592 (2.03%)
    6 / 297 (2.02%)
         occurrences all number
    6
    12
    6
    Dyspepsia
         subjects affected / exposed
    3 / 295 (1.02%)
    9 / 592 (1.52%)
    6 / 297 (2.02%)
         occurrences all number
    3
    9
    6
    Diarrhoea
         subjects affected / exposed
    13 / 295 (4.41%)
    32 / 592 (5.41%)
    19 / 297 (6.40%)
         occurrences all number
    13
    34
    21
    Nausea
         subjects affected / exposed
    10 / 295 (3.39%)
    18 / 592 (3.04%)
    8 / 297 (2.69%)
         occurrences all number
    12
    22
    10
    Vomiting
         subjects affected / exposed
    4 / 295 (1.36%)
    11 / 592 (1.86%)
    7 / 297 (2.36%)
         occurrences all number
    5
    13
    8
    Skin and subcutaneous tissue disorders
    Skin lesion
         subjects affected / exposed
    1 / 295 (0.34%)
    7 / 592 (1.18%)
    6 / 297 (2.02%)
         occurrences all number
    1
    7
    6
    Rash
         subjects affected / exposed
    3 / 295 (1.02%)
    12 / 592 (2.03%)
    9 / 297 (3.03%)
         occurrences all number
    3
    13
    10
    Pruritus
         subjects affected / exposed
    8 / 295 (2.71%)
    14 / 592 (2.36%)
    6 / 297 (2.02%)
         occurrences all number
    10
    17
    7
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    26 / 295 (8.81%)
    57 / 592 (9.63%)
    31 / 297 (10.44%)
         occurrences all number
    34
    72
    38
    Renal failure
         subjects affected / exposed
    5 / 295 (1.69%)
    12 / 592 (2.03%)
    7 / 297 (2.36%)
         occurrences all number
    5
    13
    8
    Haematuria
         subjects affected / exposed
    10 / 295 (3.39%)
    18 / 592 (3.04%)
    8 / 297 (2.69%)
         occurrences all number
    12
    20
    8
    Chronic kidney disease
         subjects affected / exposed
    5 / 295 (1.69%)
    13 / 592 (2.20%)
    8 / 297 (2.69%)
         occurrences all number
    5
    13
    8
    Acute kidney injury
         subjects affected / exposed
    14 / 295 (4.75%)
    27 / 592 (4.56%)
    13 / 297 (4.38%)
         occurrences all number
    15
    29
    14
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    12 / 295 (4.07%)
    23 / 592 (3.89%)
    11 / 297 (3.70%)
         occurrences all number
    13
    27
    14
    Osteoarthritis
         subjects affected / exposed
    10 / 295 (3.39%)
    19 / 592 (3.21%)
    9 / 297 (3.03%)
         occurrences all number
    12
    22
    10
    Myalgia
         subjects affected / exposed
    7 / 295 (2.37%)
    14 / 592 (2.36%)
    7 / 297 (2.36%)
         occurrences all number
    7
    16
    9
    Muscle spasms
         subjects affected / exposed
    6 / 295 (2.03%)
    15 / 592 (2.53%)
    9 / 297 (3.03%)
         occurrences all number
    6
    18
    12
    Joint swelling
         subjects affected / exposed
    5 / 295 (1.69%)
    11 / 592 (1.86%)
    6 / 297 (2.02%)
         occurrences all number
    5
    11
    6
    Back pain
         subjects affected / exposed
    22 / 295 (7.46%)
    50 / 592 (8.45%)
    28 / 297 (9.43%)
         occurrences all number
    23
    54
    31
    Arthralgia
         subjects affected / exposed
    25 / 295 (8.47%)
    57 / 592 (9.63%)
    32 / 297 (10.77%)
         occurrences all number
    30
    67
    37
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    18 / 295 (6.10%)
    31 / 592 (5.24%)
    13 / 297 (4.38%)
         occurrences all number
    28
    42
    14
    COVID-19
         subjects affected / exposed
    12 / 295 (4.07%)
    17 / 592 (2.87%)
    5 / 297 (1.68%)
         occurrences all number
    12
    17
    5
    Pneumonia
         subjects affected / exposed
    8 / 295 (2.71%)
    19 / 592 (3.21%)
    11 / 297 (3.70%)
         occurrences all number
    9
    21
    12
    Nasopharyngitis
         subjects affected / exposed
    26 / 295 (8.81%)
    51 / 592 (8.61%)
    25 / 297 (8.42%)
         occurrences all number
    40
    70
    30
    Lower respiratory tract infection
         subjects affected / exposed
    6 / 295 (2.03%)
    12 / 592 (2.03%)
    6 / 297 (2.02%)
         occurrences all number
    16
    28
    12
    Herpes zoster
         subjects affected / exposed
    6 / 295 (2.03%)
    8 / 592 (1.35%)
    2 / 297 (0.67%)
         occurrences all number
    7
    9
    2
    Cystitis
         subjects affected / exposed
    6 / 295 (2.03%)
    10 / 592 (1.69%)
    4 / 297 (1.35%)
         occurrences all number
    9
    14
    5
    Cellulitis
         subjects affected / exposed
    8 / 295 (2.71%)
    17 / 592 (2.87%)
    9 / 297 (3.03%)
         occurrences all number
    9
    19
    10
    Sinusitis
         subjects affected / exposed
    9 / 295 (3.05%)
    18 / 592 (3.04%)
    9 / 297 (3.03%)
         occurrences all number
    10
    20
    10
    Upper respiratory tract infection
         subjects affected / exposed
    13 / 295 (4.41%)
    19 / 592 (3.21%)
    6 / 297 (2.02%)
         occurrences all number
    13
    20
    7
    Urinary tract infection
         subjects affected / exposed
    26 / 295 (8.81%)
    47 / 592 (7.94%)
    21 / 297 (7.07%)
         occurrences all number
    30
    56
    26
    Metabolism and nutrition disorders
    Type 2 diabetes mellitus
         subjects affected / exposed
    7 / 295 (2.37%)
    11 / 592 (1.86%)
    4 / 297 (1.35%)
         occurrences all number
    7
    11
    4
    Iron deficiency
         subjects affected / exposed
    4 / 295 (1.36%)
    10 / 592 (1.69%)
    6 / 297 (2.02%)
         occurrences all number
    4
    10
    6
    Hyponatraemia
         subjects affected / exposed
    6 / 295 (2.03%)
    15 / 592 (2.53%)
    9 / 297 (3.03%)
         occurrences all number
    9
    18
    9
    Hypokalaemia
         subjects affected / exposed
    14 / 295 (4.75%)
    19 / 592 (3.21%)
    5 / 297 (1.68%)
         occurrences all number
    16
    21
    5
    Vitamin D deficiency
         subjects affected / exposed
    7 / 295 (2.37%)
    13 / 592 (2.20%)
    6 / 297 (2.02%)
         occurrences all number
    7
    13
    6
    Gout
         subjects affected / exposed
    9 / 295 (3.05%)
    21 / 592 (3.55%)
    12 / 297 (4.04%)
         occurrences all number
    12
    27
    15
    Diabetes mellitus
         subjects affected / exposed
    7 / 295 (2.37%)
    15 / 592 (2.53%)
    8 / 297 (2.69%)
         occurrences all number
    7
    16
    9
    Vitamin B12 deficiency
         subjects affected / exposed
    6 / 295 (2.03%)
    9 / 592 (1.52%)
    3 / 297 (1.01%)
         occurrences all number
    6
    9
    3
    Hyperkalaemia
         subjects affected / exposed
    31 / 295 (10.51%)
    72 / 592 (12.16%)
    41 / 297 (13.80%)
         occurrences all number
    49
    115
    66

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Jun 2017
    The key purpose of this amendment was to revise some of the study inclusion and exclusion criteria to remove unnecessary restrictions and to ensure the study population reflected the HFpEF population in the community. Although CLCZ696B2320 study was designed as an independent study to evaluate cognitive function and cerebral amyloid accretion in HFpEF patients, most of the inclusion and exclusion criteria were derived from the PARAGON-HF trial (an event-driven trial) as they were thought not to impact the objectives of the CLCZ696B2320 study. The initial screen failure rate was considerably higher than originally anticipated and many of the failures were because patients did not meet the MRI cerebrovascular criteria, which were intended to exclude patients with significant cerebrovascular pathology in whom the rate of change in cognitive function over time may differ from that in patients without significant background vascular disease. Based on CLCZ696B2320 study screening experience as well as available literature, the prevalence of cerebrovascular disease appeared to be significantly higher than originally anticipated and the existing exclusion criteria appeared to limit the population to the extent that the study cohort might not truly reflect the heart failure patient population seen in the community. Therefore, the following changes to the inclusion/exclusion criteria were made: Removed the requirement to meet MRI criteria for cerebrovascular and white matter lesions. Clinically significant cerebral pathology that may impact cognition remained as an exclusion criterion. Removed the existing exclusion criterion to allow participation of patients with a history of cardiomyopathies with an ejection fraction of >40% because exclusion of these patients was not relevant to the study objectives and these patients may benefit from treatment with LCZ696.
    18 Aug 2017
    The purpose of this amendment was to correct a typographical error.

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

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