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    Clinical Trial Results:
    A multicenter study to evaluate safety and tolerability in patients with chronic heart failure and reduced ejection fraction from PARADIGM-HF receiving open label LCZ696

    Summary
    EudraCT number
    		 2014-001971-30
    Trial protocol
    		 LV   LT   FI   NL   CZ   SE   SK   HU   PT   DK   EE   ES   IT   DE   BE   BG   FR   PL  
    Global end of trial date
    27 Dec 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Jan 2019
    First version publication date
    04 Jan 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLCZ696B2317
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02226120
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, +41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, +41 613241111, Novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 Dec 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to continue to evaluate the safety and tolerability of LCZ696 in heart failure patients from PARADIGM-HF receiving open-label investigational drug.
    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
    29 Oct 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 71
    Country: Number of subjects enrolled
    Poland: 24
    Country: Number of subjects enrolled
    Portugal: 18
    Country: Number of subjects enrolled
    Romania: 32
    Country: Number of subjects enrolled
    Slovakia: 90
    Country: Number of subjects enrolled
    Spain: 97
    Country: Number of subjects enrolled
    Sweden: 11
    Country: Number of subjects enrolled
    United Kingdom: 87
    Country: Number of subjects enrolled
    Belgium: 30
    Country: Number of subjects enrolled
    Bulgaria: 86
    Country: Number of subjects enrolled
    Czech Republic: 70
    Country: Number of subjects enrolled
    Denmark: 46
    Country: Number of subjects enrolled
    Estonia: 10
    Country: Number of subjects enrolled
    Finland: 7
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 86
    Country: Number of subjects enrolled
    Hungary: 81
    Country: Number of subjects enrolled
    Italy: 47
    Country: Number of subjects enrolled
    Latvia: 3
    Country: Number of subjects enrolled
    Lithuania: 10
    Country: Number of subjects enrolled
    Argentina: 93
    Country: Number of subjects enrolled
    Brazil: 100
    Country: Number of subjects enrolled
    Canada: 43
    Country: Number of subjects enrolled
    Chile: 7
    Country: Number of subjects enrolled
    Guatemala: 44
    Country: Number of subjects enrolled
    Hong Kong: 8
    Country: Number of subjects enrolled
    India: 136
    Country: Number of subjects enrolled
    Israel: 50
    Country: Number of subjects enrolled
    Korea, Republic of: 36
    Country: Number of subjects enrolled
    Malaysia: 9
    Country: Number of subjects enrolled
    Mexico: 23
    Country: Number of subjects enrolled
    Panama: 3
    Country: Number of subjects enrolled
    Peru: 38
    Country: Number of subjects enrolled
    Philippines: 60
    Country: Number of subjects enrolled
    Russian Federation: 238
    Country: Number of subjects enrolled
    Singapore: 11
    Country: Number of subjects enrolled
    South Africa: 54
    Country: Number of subjects enrolled
    Taiwan: 27
    Country: Number of subjects enrolled
    Thailand: 11
    Country: Number of subjects enrolled
    Turkey: 19
    Country: Number of subjects enrolled
    United States: 62
    Worldwide total number of subjects
    1980
    EEA total number of subjects
    908
    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)
    729
    From 65 to 84 years
    1196
    85 years and over
    55

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 417 sites in 41 countries worldwide. 2060 patients were enrolled in the open-label extension (OLE), out of which 1979 completed the screening phase. The number of patients included in the safety set was 1980 instead of 1979 due to the study drug administration records in the database.

    Pre-assignment
    Screening details
    		 The enrollment number in the protocol section (2007) reflects the number of participants as per the Novartis Clinical Trial Management System (CTMS). The total number in the participant flow and baseline characteristics sections reflects the number of participants enrolled/treated (1980).

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

    Arms
    Arm title
    		 LCZ696
    Arm description
    		 Angiotensin receptor antagonist neprilysin inhibitor (ARNI) with target dose of 200 mg bid
    Arm type
    		 Safety

    Investigational medicinal product name
    LCZ696
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    All patients previously treated with LCZ696 or enalapril in PARADIGM-HF were treated with LCZ696 at maximally tolerated doses with a target dose of 200 mg bid.

    Number of subjects in period 1
    		LCZ696
    Started
    1980
    Completed
    1660
    Not completed
    320
         Adverse event, serious fatal
    172
         Physician decision
    21
         Adverse event, non-fatal
    60
         Technical problems
    4
         Study terminated by sponsor
    1
         Non-compliance with study drug
    10
         Missing treatment disposition pages
    2
         Lost to follow-up
    13
         Withdrawal by parent/guardian
    36
         Protocol deviation
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    		 -

    Reporting group values
    		 Overall Study Total
    Number of subjects
    		 1980 1980
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 729 729
        From 65-84 years
    		 1196 1196
        85 years and over
    		 55 55
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 67.2 ( 10.56 ) -
    Gender categorical
    Units: Subjects
        Female
    		 453 453
        Male
    		 1527 1527
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 39 39
        Asian
    		 305 305
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Black or African American
    		 80 80
        White
    		 1450 1450
        More than one race
    		 0 0
        Unknown or Not Reported
    		 106 106

    End points

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    End points reporting groups
    Reporting group title
    LCZ696
    Reporting group description
    		 Angiotensin receptor antagonist neprilysin inhibitor (ARNI) with target dose of 200 mg bid

    Primary: Percentage of Participants with treatment emergent Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths as a measure of safety and tolerability of LCZ696

    		 Close Top of page
    End point title
    		 Percentage of Participants with treatment emergent Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths as a measure of safety and tolerability of LCZ696 [1]
    End point description
    The primary assessments for safety were the reporting of angioedema, AEs suspected to be related to LCZ696, AEs leading to study drug discontinuation and serious adverse events (SAE) including death. The assessment of safety were based primarily on the frequency of adverse events of special interest, sitting systolic and diastolic blood pressure, heart rate, and serious adverse events suspected by the investigators to be related to LCZ696 for the Safety set. Only descriptive analysis done.
    End point type
    Primary
    End point timeframe
    From first dose of study treatment to 30 days after last dose of study treatment
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis done
    End point values
    		 LCZ696
    Number of subjects analysed
    1980
    Units: Participants
    number (not applicable)
        AEs by Primary System Organ Class (SOC)
    65.1
        SAEs by Primary System Organ Class (SOC)
    28.03
        Deaths by Primary System Organ Class (SOC)
    9.39
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for AE
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    LCZ696
    Reporting group description
    		 LCZ696

    Serious adverse events
    		 LCZ696
    Total subjects affected by serious adverse events
         subjects affected / exposed
    555 / 1980 (28.03%)
         number of deaths (all causes)
    186
         number of deaths resulting from adverse events
    5
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    B-cell lymphoma
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bladder cancer recurrent
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bladder neoplasm
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bone cancer
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bone cancer metastatic
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Breast cancer
         subjects affected / exposed
    3 / 1980 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Cholangiocarcinoma
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Colon adenoma
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Laryngeal cancer
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Lung neoplasm
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    4 / 1980 (0.20%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    Oesophageal squamous cell carcinoma
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Plasma cell myeloma
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Rectal cancer
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal cancer
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    1 / 1
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Aortic embolus
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Circulatory collapse
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Diabetic vascular disorder
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Hypotension
         subjects affected / exposed
    18 / 1980 (0.91%)
         occurrences causally related to treatment / all
    14 / 18
         deaths causally related to treatment / all
    0 / 0
    Leriche syndrome
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Shock
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 1980 (0.15%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Cardiac death
         subjects affected / exposed
    4 / 1980 (0.20%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 4
    Chest discomfort
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Death
         subjects affected / exposed
    3 / 1980 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 3
    General physical health deterioration
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Malaise
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    7 / 1980 (0.35%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 5
    Non-cardiac chest pain
         subjects affected / exposed
    4 / 1980 (0.20%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    3 / 1980 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    15 / 1980 (0.76%)
         occurrences causally related to treatment / all
    0 / 15
         deaths causally related to treatment / all
    0 / 15
    Sudden death
         subjects affected / exposed
    13 / 1980 (0.66%)
         occurrences causally related to treatment / all
    1 / 13
         deaths causally related to treatment / all
    1 / 13
    Social circumstances
    Treatment noncompliance
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Acquired hydrocele
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acquired phimosis
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Genital ulceration
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    5 / 1980 (0.25%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    3 / 1980 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Asphyxia
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Bronchial oedema
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis chronic
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    10 / 1980 (0.51%)
         occurrences causally related to treatment / all
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    10 / 1980 (0.51%)
         occurrences causally related to treatment / all
    0 / 13
         deaths causally related to treatment / all
    0 / 1
    Dyspnoea exertional
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hiccups
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hydrothorax
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    3 / 1980 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    8 / 1980 (0.40%)
         occurrences causally related to treatment / all
    0 / 9
         deaths causally related to treatment / all
    0 / 6
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    8 / 1980 (0.40%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 1
    Respiratory acidosis
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Depression
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Disorientation
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mental disorder
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Product issues
    Device battery issue
         subjects affected / exposed
    3 / 1980 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Device malfunction
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lead dislodgement
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Arteriogram coronary
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood potassium decreased
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood potassium increased
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Ejection fraction abnormal
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Functional residual capacity decreased
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Liver function test increased
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Weight decreased
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Chest injury
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Craniocerebral injury
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Electric shock
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fall
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Femur fracture
         subjects affected / exposed
    5 / 1980 (0.25%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Fibula fracture
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fractured skull depressed
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hip fracture
         subjects affected / exposed
    3 / 1980 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Incisional hernia, obstructive
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Laceration
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Limb injury
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Multiple injuries
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pelvic fracture
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Procedural haemorrhage
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Respiratory fume inhalation disorder
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rib fracture
         subjects affected / exposed
    3 / 1980 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Road traffic accident
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Subarachnoid haemorrhage
         subjects affected / exposed
    3 / 1980 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Subdural haematoma
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Vascular graft occlusion
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Congenital, familial and genetic disorders
    Phimosis
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    3 / 1980 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Acute left ventricular failure
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    9 / 1980 (0.45%)
         occurrences causally related to treatment / all
    0 / 10
         deaths causally related to treatment / all
    0 / 3
    Adams-Stokes syndrome
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Angina pectoris
         subjects affected / exposed
    14 / 1980 (0.71%)
         occurrences causally related to treatment / all
    1 / 14
         deaths causally related to treatment / all
    0 / 0
    Angina unstable
         subjects affected / exposed
    10 / 1980 (0.51%)
         occurrences causally related to treatment / all
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    Arrhythmia
         subjects affected / exposed
    4 / 1980 (0.20%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    Atrial fibrillation
         subjects affected / exposed
    14 / 1980 (0.71%)
         occurrences causally related to treatment / all
    1 / 17
         deaths causally related to treatment / all
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    5 / 1980 (0.25%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Bradycardia
         subjects affected / exposed
    3 / 1980 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    13 / 1980 (0.66%)
         occurrences causally related to treatment / all
    1 / 13
         deaths causally related to treatment / all
    1 / 9
    Cardiac failure
         subjects affected / exposed
    144 / 1980 (7.27%)
         occurrences causally related to treatment / all
    2 / 184
         deaths causally related to treatment / all
    0 / 35
    Cardiac failure acute
         subjects affected / exposed
    21 / 1980 (1.06%)
         occurrences causally related to treatment / all
    1 / 26
         deaths causally related to treatment / all
    1 / 9
    Cardiac failure chronic
         subjects affected / exposed
    32 / 1980 (1.62%)
         occurrences causally related to treatment / all
    0 / 41
         deaths causally related to treatment / all
    0 / 5
    Cardiac failure congestive
         subjects affected / exposed
    20 / 1980 (1.01%)
         occurrences causally related to treatment / all
    2 / 26
         deaths causally related to treatment / all
    1 / 3
    Cardio-respiratory arrest
         subjects affected / exposed
    7 / 1980 (0.35%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 7
    Cardiogenic shock
         subjects affected / exposed
    8 / 1980 (0.40%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 5
    Cardiorenal syndrome
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiovascular disorder
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Congestive cardiomyopathy
         subjects affected / exposed
    4 / 1980 (0.20%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    Cor pulmonale
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Left ventricular dysfunction
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    4 / 1980 (0.20%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    Myocardial infarction
         subjects affected / exposed
    16 / 1980 (0.81%)
         occurrences causally related to treatment / all
    0 / 17
         deaths causally related to treatment / all
    0 / 9
    Myocardial ischaemia
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Nodal rhythm
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Systolic dysfunction
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    5 / 1980 (0.25%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    Ventricular fibrillation
         subjects affected / exposed
    5 / 1980 (0.25%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    31 / 1980 (1.57%)
         occurrences causally related to treatment / all
    0 / 37
         deaths causally related to treatment / all
    0 / 2
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Brain injury
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Brain oedema
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cerebellar infarction
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cerebral haemorrhage
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Cerebral infarction
         subjects affected / exposed
    6 / 1980 (0.30%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 1
    Cerebral ischaemia
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cerebrovascular accident
         subjects affected / exposed
    13 / 1980 (0.66%)
         occurrences causally related to treatment / all
    0 / 13
         deaths causally related to treatment / all
    0 / 4
    Cervicogenic vertigo
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Coma
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dementia
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dizziness
         subjects affected / exposed
    4 / 1980 (0.20%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Dysarthria
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Facial paralysis
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Hemianaesthesia
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Ischaemic cerebral infarction
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Ischaemic stroke
         subjects affected / exposed
    7 / 1980 (0.35%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 1
    Loss of consciousness
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Post stroke seizure
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Presyncope
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Radiculopathy
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Syncope
         subjects affected / exposed
    7 / 1980 (0.35%)
         occurrences causally related to treatment / all
    3 / 7
         deaths causally related to treatment / all
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    4 / 1980 (0.20%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Normocytic anaemia
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Open angle glaucoma
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Refraction disorder
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    9 / 1980 (0.45%)
         occurrences causally related to treatment / all
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    3 / 1980 (0.15%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Ascites
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 1980 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Diverticulum intestinal
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Duodenitis
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastritis
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal angiodysplasia
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Incarcerated inguinal hernia
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Intestinal pseudo-obstruction
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Large intestine polyp
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mesenteric vein thrombosis
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Mouth ulceration
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatic mass
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholangitis
         subjects affected / exposed
    3 / 1980 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Cholecystitis
         subjects affected / exposed
    3 / 1980 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Hepatic cirrhosis
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hepatic congestion
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diabetic foot
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    18 / 1980 (0.91%)
         occurrences causally related to treatment / all
    6 / 19
         deaths causally related to treatment / all
    0 / 1
    Chronic kidney disease
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Leukocyturia
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal failure
         subjects affected / exposed
    12 / 1980 (0.61%)
         occurrences causally related to treatment / all
    1 / 13
         deaths causally related to treatment / all
    0 / 1
    Renal impairment
         subjects affected / exposed
    8 / 1980 (0.40%)
         occurrences causally related to treatment / all
    1 / 8
         deaths causally related to treatment / all
    0 / 1
    Urethral stenosis
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary retention
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Joint effusion
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    3 / 1980 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Rheumatic disorder
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Abdominal sepsis
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Appendicitis
         subjects affected / exposed
    3 / 1980 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bursitis infective
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diabetic foot infection
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diverticulitis
         subjects affected / exposed
    3 / 1980 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Ecthyma
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Erysipelas
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gangrene
         subjects affected / exposed
    3 / 1980 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Gastroenteritis
         subjects affected / exposed
    5 / 1980 (0.25%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Hepatitis E
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatitis viral
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Implant site infection
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Infectious pleural effusion
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Localised infection
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    4 / 1980 (0.20%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Lung infection
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Orchitis
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Otitis media chronic
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ovarian abscess
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peritonitis
         subjects affected / exposed
    4 / 1980 (0.20%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Pneumococcal sepsis
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    47 / 1980 (2.37%)
         occurrences causally related to treatment / all
    0 / 48
         deaths causally related to treatment / all
    0 / 12
    Postoperative wound infection
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    3 / 1980 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    12 / 1980 (0.61%)
         occurrences causally related to treatment / all
    0 / 12
         deaths causally related to treatment / all
    0 / 6
    Sepsis syndrome
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Septic shock
         subjects affected / exposed
    10 / 1980 (0.51%)
         occurrences causally related to treatment / all
    0 / 10
         deaths causally related to treatment / all
    0 / 6
    Stoma site infection
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tooth infection
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    10 / 1980 (0.51%)
         occurrences causally related to treatment / all
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    Urosepsis
         subjects affected / exposed
    3 / 1980 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Viral diarrhoea
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Viral infection
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Wound sepsis
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    4 / 1980 (0.20%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    4 / 1980 (0.20%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Diabetic complication
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fluid overload
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 1980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 1980 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 LCZ696
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    352 / 1980 (17.78%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    252 / 1980 (12.73%)
         occurrences all number
    279
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    118 / 1980 (5.96%)
         occurrences all number
    140

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Mar 2015
    Amendment 1, issued 4 months after study start, introduced the following changes: • clarify the patient population from the CLCZ696B2314 (PARADIGM-HF) was eligible for enrolment in this study, as well as facilitate tracking of those patients.
    28 Apr 2015
    Amendment 2, issued 6 months after the study start, introduced a few administrative changes.

    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.
    Two patients had missing treatment epoch disposition pages but were included in Safety Analysis Set (SAF)
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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