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    Clinical Trial Results:
    Effect of Bivalirudin on Aortic Valve Intervention Outcomes 2/3 (BRAVO 2/3)

    Summary
    EudraCT number
    		 2012-000632-26
    Trial protocol
    		 GB   DE   NL   IT  
    Global end of trial date
    24 Jun 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Jul 2016
    First version publication date
    23 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TMC-BIV-11-02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01651780
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Clinicaltrials.gov: NCT01651780
    Sponsors
    Sponsor organisation name
    The Medicines Company
    Sponsor organisation address
    8 Sylvan Way, Parsippany, NJ, United States, 07054
    Public contact
    Global Health Science Center, The Medicines Company, 00800 84363326, medical.information@themedco.com
    Scientific contact
    Global Health Science Center, The Medicines Company, 00800 84363326, medical.information@themedco.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
    24 Jun 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Jun 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this study is to assess the safety and efficacy of using bivalirudin instead of unfractionated heparin (UFH) in transcatheter aortic valve replacements (TAVR). The primary hypothesis of BRAVO 3 was that bivalirudin would reduce major bleeding compared with heparin in TAVR procedures. Results for all particpants enrolled into the randomized trial (BRAVO 3) are presented.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Oct 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 75
    Country: Number of subjects enrolled
    Switzerland: 47
    Country: Number of subjects enrolled
    Netherlands: 20
    Country: Number of subjects enrolled
    United Kingdom: 18
    Country: Number of subjects enrolled
    France: 214
    Country: Number of subjects enrolled
    Germany: 353
    Country: Number of subjects enrolled
    Italy: 76
    Worldwide total number of subjects
    803
    EEA total number of subjects
    681
    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)
    21
    From 65 to 84 years
    454
    85 years and over
    328

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Screening was to take place within 30 days of the start of the study. Screening assessments included review of inclusion/exclusion criteria, signature of informed consent, 12-lead electrocardiogram (ECG), clinical laboratory assessments, measurement of left ventricular ejection fraction (LVEF), and the start of AE or serious AE (SAE) report.

    Period 1
    Period 1 title
    BRAVO 3 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bivalirudin
    Arm description
    		 Bivalirudin administered as a bolus and intravenous (IV) infusion. It was recommended that the bolus (0.75 milligrams per kilogram [mg/kg]) be directly administered through the valve delivery sheath immediately following its successful delivery via percutaneous femoral access. Systemic IV administration of the bolus dose was also acceptable. The bivalirudin IV infusion was initiated immediately after the bolus administration. All wires, catheters, and sheaths were to be flushed with heparinized saline.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bivalirudin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Anticoagulant and preservative solution for blood
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    The bivalirudin IV infusion was initiated immediately after the bolus administration at the following doses: Subjects with normal renal function ( glomerular filtration rate [GFR] ≥60 mL/min): 1.75 milligram per kilogram per hour (mg/kg/hr) continuous IV infusion until successful valve treatment was achieved Subjects with moderate renal impairment (GFR of 30-59 mL/min): 1.4 mg/kg/hr continuous IV infusion until successful valve treatment was achieved Subjects with severe renal impairment (GFR<30 mL/min): 1.0 mg/kg/hr continuous IV infusion until successful valve treatment was achieved The GFR was calculated centrally and provided to the investigators during randomization. The IV infusion was to continue until successful valve treatment was achieved. Routine assessment of the activated clotting time (ACT) was not required.

    Arm title
    		 Unfractionated heparin (UFH)
    Arm description
    		 The dose of UFH adhered to the standard institutional practice. An ACT target ≥250 seconds was recommended. All wires, catheters, and sheaths were to be flushed with heparinized saline.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Unfractionated Heparin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Anticoagulant and preservative solution for blood
    Routes of administration
    Intravenous use
    Dosage and administration details
    The dose of UFH should adhere to the standard institutional practice. An ACT target ≥ 250 seconds was recommended.

    Number of subjects in period 1
    		Bivalirudin Unfractionated heparin (UFH)
    Started
    405
    398
    Signed consent form (Intent to treat)
    404
    398
    Received at least 1 dose of study drug
    393 [1]
    394
    BRAVO 2 feasibility cohort
    65 [2]
    0 [3]
    Completed
    394
    388
    Not completed
    11
    10
         Consent withdrawn by subject
    1
    -
         Inclusion/Exclusion criteria not met
    3
    -
         Physician decision: Day 30 visit < 23 days
    1
    5
         Did not sign consent form
    1
    -
         Reason not specified: No 30 day visit
    2
    2
         Lost to follow-up
    1
    2
         Physician decision: No 30 day visit
    2
    1
    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: All but one patient in the bivalirudin group (did not sign consent form) comprised the intent-to-treat (ITT) population. In the ITT population, 11 patients in the bivalirudin and four patients in the UFH group did not receive randomized study drug.
    [2] - 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: The first two participants at each site who met inclusion criteria were treated with bivalirudin and comprised the feasibility cohort (BRAVO 2). This cohort was analyzed separately from the randomized trial cohort.
    [3] - 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: The first two participants at each site who met inclusion criteria were treated with bivalirudin and comprised the feasibility cohort (BRAVO 2). This cohort was analyzed separately from the randomized trial cohort and did not include participants treated with UFH.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bivalirudin
    Reporting group description
    		 Bivalirudin administered as a bolus and intravenous (IV) infusion. It was recommended that the bolus (0.75 milligrams per kilogram [mg/kg]) be directly administered through the valve delivery sheath immediately following its successful delivery via percutaneous femoral access. Systemic IV administration of the bolus dose was also acceptable. The bivalirudin IV infusion was initiated immediately after the bolus administration. All wires, catheters, and sheaths were to be flushed with heparinized saline.

    Reporting group title
    Unfractionated heparin (UFH)
    Reporting group description
    		 The dose of UFH adhered to the standard institutional practice. An ACT target ≥250 seconds was recommended. All wires, catheters, and sheaths were to be flushed with heparinized saline.

    Reporting group values
    		 Bivalirudin Unfractionated heparin (UFH) Total
    Number of subjects
    		 405 398 803
    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)
    		 11 10 21
        From 65-84 years
    		 230 224 454
        85 years and over
    		 164 164 328
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 82.3 ± 6.5 82.3 ± 6.5 -
    Gender categorical
    Units: Subjects
        Female
    		 195 196 391
        Male
    		 209 202 411
        Not recorded
    		 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Bivalirudin
    Reporting group description
    		 Bivalirudin administered as a bolus and intravenous (IV) infusion. It was recommended that the bolus (0.75 milligrams per kilogram [mg/kg]) be directly administered through the valve delivery sheath immediately following its successful delivery via percutaneous femoral access. Systemic IV administration of the bolus dose was also acceptable. The bivalirudin IV infusion was initiated immediately after the bolus administration. All wires, catheters, and sheaths were to be flushed with heparinized saline.

    Reporting group title
    Unfractionated heparin (UFH)
    Reporting group description
    		 The dose of UFH adhered to the standard institutional practice. An ACT target ≥250 seconds was recommended. All wires, catheters, and sheaths were to be flushed with heparinized saline.

    Subject analysis set title
    Bivalirudin: First half of study site's enrolled participants
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This includes the first half of the site’s enrolled participants, and only sites with more than 20 participants are included in this analysis.

    Subject analysis set title
    Bivalirudin: Second half of study site's enrolled participants
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This includes the second half of the site’s enrolled participants, and only sites with more than 20 participants are included in this analysis.

    Subject analysis set title
    UFH: First half of study site's enrolled participants
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This includes the first half of the site’s enrolled participants, and only sites with more than 20 participants are included in this analysis.

    Subject analysis set title
    UFH: Second half of study site's enrolled participants
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This includes the second half of the site’s enrolled participants, and only sites with more than 20 participants are included in this analysis.

    Primary: Major Bleeding (BARC ≥3b) at 48 hours or before hospital discharge

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    End point title
    		 Major Bleeding (BARC ≥3b) at 48 hours or before hospital discharge
    End point description
    Major bleeding (Bleeding Academic Research Consortium [BARC] type ≥3b) was defined as follows: • Bleeds that were evident clinically, or by laboratory or imaging results, which resulted in surgical intervention or administration of IV vasoactive drugs; overt bleeds with a hemoglobin drop of at least 5 grams per deciliter (g/dL); and bleeding that caused cardiac tamponade. • BARC 3c includes intracranial or intraocular bleeds that compromised vision. • BARC type 4 (Coronary Artery Bypass Grafting [CABG]-related bleeding) includes perioperative intracranial bleeding within 48 hours, bleeds that result in reoperation following closure of sternotomy for the purpose of controlling bleeding, bleeds that result in treatment with transfusion of ≥5 units of whole blood or packed red blood cells within a 48 hour period; and chest tube output ≥ 2 L within a 24-hour period. • BARC type 5, fatal bleeding, describes bleeds that directly result in death with no other cause.
    End point type
    Primary
    End point timeframe
    at 48 hours or hospital discharge, whichever occurs earlier
    End point values
    		 Bivalirudin Unfractionated heparin (UFH)
    Number of subjects analysed
    404
    398
    Units: Percentage of participants
        number (not applicable)
    6.9
    9
    Statistical analysis title
    		 Statistical analyses
    Comparison groups
    Unfractionated heparin (UFH) v Bivalirudin
    Number of subjects included in analysis
    802
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2692
    Method
    		 Chi-squared
    Parameter type
    		 Relative risk
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 1.23

    Primary: Net adverse clinical events (NACE) at up to 30 days

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    End point title
    		 Net adverse clinical events (NACE) at up to 30 days
    End point description
    The net adverse cardiac events (NACE) at 30 days is the composite of major adverse cardiovascular events (MACE) + major bleeding (BARC type ≥3b). The composite of MACE is defined as all-cause mortality, myocardial infarction (MI), and stroke. A participant was defined to have a composite event if the participant experienced at least 1 of the components. If the participant did not have any of the components, then he or she did not have the composite endpoint. If a participant had more than 1 of the components, he or she was only counted once in the determination of the total number of participants experiencing the composite endpoint.
    End point type
    Primary
    End point timeframe
    up to 30 days after procedure
    End point values
    		 Bivalirudin Unfractionated heparin (UFH)
    Number of subjects analysed
    404
    398
    Units: Percentage of participants
        number (not applicable)
    14.4
    16.1
    Statistical analysis title
    		 Statistical analysis
    Comparison groups
    Bivalirudin v Unfractionated heparin (UFH)
    Number of subjects included in analysis
    802
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.4967
    Method
    		 Chi-squared
    Parameter type
    		 Relative risk
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 1.24

    Secondary: NACE at 48 hours or before hospital discharge

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    End point title
    		 NACE at 48 hours or before hospital discharge
    End point description
    NACE at 48 hours or before hospital discharge is the composite of major adverse cardiovascular events (MACE) + major bleeding (BARC type ≥3b). The composite of MACE is defined as all-cause mortality, MI, and stroke. A participant was defined to have a composite event if the participant experienced at least 1 of the components. If the participant did not have any of the components, then he or she did not have the composite endpoint. If a participant had more than 1 of the components, he or she was only counted once in the determination of the total number of participants experiencing the composite endpoint.
    End point type
    Secondary
    End point timeframe
    at 48 hours or before hospital discharge
    End point values
    		 Bivalirudin Unfractionated heparin (UFH)
    Number of subjects analysed
    404
    398
    Units: Percentage of participants
        number (not applicable)
    8.9
    12.6
    No statistical analyses for this end point

    Secondary: Major adverse cardiac events (MACE) including death, non-fatal MI, and stroke

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    End point title
    		 Major adverse cardiac events (MACE) including death, non-fatal MI, and stroke
    End point description
    The percentage of participants reporting a MACE overall and the individual components of MACE (including death, non-fatal MI, and stroke) are presented.
    End point type
    Secondary
    End point timeframe
    at 48 hours or before hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days) follow-up
    End point values
    		 Bivalirudin Unfractionated heparin (UFH)
    Number of subjects analysed
    404
    398
    Units: Percentage of participants
    number (not applicable)
        MACE at 48 hours or before hospital discharge
    3.5
    4.8
        Death at 48 hours or before hospital discharge
    1.5
    1.8
        MI at 48 hours or before hospital discharge
    0
    1.3
        Stroke at 48 hours or before hospital discharge
    2
    2
        MACE at up to 30 days
    7.7
    8
        Death at up to 30 days
    4.7
    4.8
        MI at up to 30 days
    0.5
    1.8
        Stroke at up to 30 days
    3.5
    2.8
    No statistical analyses for this end point

    Secondary: Major bleeding according to additional scales (VARC, TIMI, GUSTO, ACUITY/HORIZONS);

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    End point title
    		 Major bleeding according to additional scales (VARC, TIMI, GUSTO, ACUITY/HORIZONS);
    End point description
    Percentage of participants wtih major bleeding according to the following scales: Valve Academic Research Consortium (VARC)= life threatening, disabling bleeding or major bleeding Thrombolysis in Myocardial Infarction (TIMI)=major bleeding Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)=severe or life-threatening bleeding Acute Catheterization and Urgent Intervention Triage StrategY (ACUITY)/ Harmonizing Outcomes with RevasculariZatiON and Stents (HORIZONS)=major bleeding
    End point type
    Secondary
    End point timeframe
    at 48 hours or hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days) follow-up
    End point values
    		 Bivalirudin Unfractionated heparin (UFH)
    Number of subjects analysed
    404
    398
    Units: Percentage of participants
    number (not applicable)
        VARC at 48 hours or before hospital discharge
    21.8
    19.6
        TIMI at 48 hours or before hospital discharge
    4
    6.5
        GUSTO 48 hours or hospital discharge
    3.7
    3.3
        ACUITY/HORIZONS at 48 hours or hospital discharge
    26
    24.4
        VARC at 30 days
    26.5
    24.6
        TIMI at 30 days
    5.7
    7.3
        GUSTO at 30 days
    4.2
    4.3
        ACUITY/HORIZONS at 30 days
    33.4
    29.6
    No statistical analyses for this end point

    Secondary: Transient ischemic attack

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    End point title
    		 Transient ischemic attack
    End point description
    The percentage of participants reporting transient ischemic attack is presented.
    End point type
    Secondary
    End point timeframe
    at 48 hours or before hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days) follow-up
    End point values
    		 Bivalirudin Unfractionated heparin (UFH)
    Number of subjects analysed
    404
    398
    Units: Percentage of participants
    number (not applicable)
        at 48 hours or before hospital discharge
    0
    0
        at up to 30 days (±7 days) follow-up
    0
    0
    No statistical analyses for this end point

    Secondary: Acute kidney injury

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    End point title
    		 Acute kidney injury
    End point description
    The percentage of participants reporting acute kidney injury is presented.
    End point type
    Secondary
    End point timeframe
    at 48 hours or hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days) follow-up
    End point values
    		 Bivalirudin Unfractionated heparin (UFH)
    Number of subjects analysed
    404
    398
    Units: Percentage of participants
    number (not applicable)
        at 48 hours or before hospital discharge
    10.9
    6.5
        at up to 30 days (±7 days) follow-up
    18.8
    13.8
    No statistical analyses for this end point

    Secondary: Major vascular complications

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    End point title
    		 Major vascular complications
    End point description
    The percentage of patients reporting a major vascular complications as defined by VARC is presented.
    End point type
    Secondary
    End point timeframe
    at 48 hours or before hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days) follow-up
    End point values
    		 Bivalirudin Unfractionated heparin (UFH)
    Number of subjects analysed
    404
    398
    Units: Percentage of participants
    number (not applicable)
        at 48 hours or before hospital discharge
    8.7
    9
        at up to 30 days (±7 days) follow-up
    9.2
    9.5
    No statistical analyses for this end point

    Secondary: Acquired thrombocytopenia

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    End point title
    		 Acquired thrombocytopenia
    End point description
    The percentage of participants reporting acquired thrombocytopenia is presented.
    End point type
    Secondary
    End point timeframe
    at 48 hours or before hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days) follow-up
    End point values
    		 Bivalirudin Unfractionated heparin (UFH)
    Number of subjects analysed
    404
    398
    Units: Percentage of participants
    number (not applicable)
        at 48 hours or before hospital discharge
    16.6
    17.3
        at up to 30 days (±7 days)
    24
    23.1
    No statistical analyses for this end point

    Secondary: New onset atrial fibrillation/flutter

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    End point title
    		 New onset atrial fibrillation/flutter
    End point description
    The percentage of participants reporting new onset atrial fibrillation/flutter is presented.
    End point type
    Secondary
    End point timeframe
    at 48 hours or before hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days) follow-up
    End point values
    		 Bivalirudin Unfractionated heparin (UFH)
    Number of subjects analysed
    404
    398
    Units: Percentage of participants
    number (not applicable)
        at 48 hours or before hospital discharge
    3.2
    2.5
        at up to 30 days (±7 days) follow-up
    5.4
    4
    No statistical analyses for this end point

    Secondary: Economic analysis of using bivalirudin in Transcatheter-aortic valve replacement (TAVR)

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    End point title
    		 Economic analysis of using bivalirudin in Transcatheter-aortic valve replacement (TAVR)
    End point description
    The effect of timing on bleeding event rates (the percentage of particpants with an incidence of major bleeding) is presented.
    End point type
    Secondary
    End point timeframe
    at hospital discharge (but also includes any subsequent hospitalizations)
    End point values
    		 Bivalirudin: First half of study site's enrolled participants Bivalirudin: Second half of study site's enrolled participants UFH: First half of study site's enrolled participants UFH: Second half of study site's enrolled participants
    Number of subjects analysed
    173
    171
    173
    165
    Units: Percentage of participants
        number (not applicable)
    6.4
    6.4
    11.6
    8.5
    No statistical analyses for this end point

    Secondary: Bleeding BARC 3a, BARC types 1 or 2, and TIMI minor

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    End point title
    		 Bleeding BARC 3a, BARC types 1 or 2, and TIMI minor
    End point description
    The percentage of particpants with moderate bleeding as defined by BARC 3a and minor bleeding as defined as BARC type 1 & 2 and TIMI minor is presented.
    End point type
    Secondary
    End point timeframe
    at 48 hours or hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days) follow-up
    End point values
    		 Bivalirudin Unfractionated heparin (UFH)
    Number of subjects analysed
    404
    398
    Units: Percentage of participants
    number (not applicable)
        BARC 3a at 48 hours or hospital discharge
    15.6
    13.3
        BARC types 1 and 2 at 48 hours or discharge
    20.8
    21.1
        TIMI minor at 48 hours or hospital discharge
    16.6
    14.3
        BARC 3a at 30 days
    18.8
    17.3
        BARC types 1 and 2 at 30 days
    27.7
    25.6
        TIMI minor at 30 days
    21.3
    19.3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 30 days (± 7 days) follow up.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Bivalirudin
    Reporting group description
    		 Safety population=all randomized participants who signed informed consent and received at least 1 dose of study drug

    Reporting group title
    Unfractionated Heparin (UFH)
    Reporting group description
    		 Safety population=all randomized participants who signed informed consent and received at least 1 dose of study drug

    Serious adverse events
    		 Bivalirudin Unfractionated Heparin (UFH)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    112 / 393 (28.50%)
    116 / 394 (29.44%)
         number of deaths (all causes)
    19
    21
         number of deaths resulting from adverse events
    4
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer
         subjects affected / exposed
    0 / 393 (0.00%)
    2 / 394 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 393 (0.51%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 393 (0.00%)
    2 / 394 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic dissection
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral artery dissection
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemodynamic instability
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Intestinal anastomosis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Device leakage
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis in device
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hyperthermia
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 393 (0.51%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Panic attack
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Cardiac valve replacement complication
         subjects affected / exposed
    3 / 393 (0.76%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac valve rupture
         subjects affected / exposed
    0 / 393 (0.00%)
    2 / 394 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 393 (0.00%)
    2 / 394 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax traumatic
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular procedure complication
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac disorders
    Atrioventricular block complete
         subjects affected / exposed
    46 / 393 (11.70%)
    34 / 394 (8.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bundle branch block left
         subjects affected / exposed
    7 / 393 (1.78%)
    10 / 394 (2.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    6 / 393 (1.53%)
    10 / 394 (2.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 3
    Bradycardia
         subjects affected / exposed
    2 / 393 (0.51%)
    7 / 394 (1.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 393 (0.51%)
    7 / 394 (1.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Atrioventricular block second degree
         subjects affected / exposed
    2 / 393 (0.51%)
    6 / 394 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block first degree
         subjects affected / exposed
    3 / 393 (0.76%)
    4 / 394 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    2 / 393 (0.51%)
    4 / 394 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    4 / 393 (1.02%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 393 (0.25%)
    3 / 394 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Aortic valve incompetence
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiogenic shock
         subjects affected / exposed
    0 / 393 (0.00%)
    2 / 394 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coronary artery occlusion
         subjects affected / exposed
    0 / 393 (0.00%)
    2 / 394 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ventricular fibrillation
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachyarrhythmia
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bifascicular block
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradyarrhythmia
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac perforation
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic cardiomyopathy
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Low cardiac output syndrome
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pericardial effusion
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sick sinus syndrome
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bundle branch block
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    3 / 393 (0.76%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    1 / 3
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cognitive disorder
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myasthenia gravis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Retroperitoneal haemorrhage
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Abdominal hernia
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Abdominal pain
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal infarction
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Umbilical hernia, obstructive
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    0 / 393 (0.00%)
    2 / 394 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    2 / 393 (0.51%)
    2 / 394 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 393 (0.00%)
    2 / 394 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchitis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella infection
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonas infection
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic encephalopathy
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Bivalirudin Unfractionated Heparin (UFH)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    73 / 393 (18.58%)
    70 / 394 (17.77%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    19 / 393 (4.83%)
    16 / 394 (4.06%)
         occurrences all number
    19
    16
    Cardiac disorders
    Bundle branch block left
         subjects affected / exposed
    15 / 393 (3.82%)
    16 / 394 (4.06%)
         occurrences all number
    15
    16
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    12 / 393 (3.05%)
    19 / 394 (4.82%)
         occurrences all number
    14
    19
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    14 / 393 (3.56%)
    10 / 394 (2.54%)
         occurrences all number
    14
    10
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    13 / 393 (3.31%)
    9 / 394 (2.28%)
         occurrences all number
    13
    10

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Aug 2012
    Amendment number 1 on 29 August 2012 included the following clinical changes to the protocol: • Clarification of secondary endpoints. Valve performance indicators and TAVR-specific complications and rate of persistent, profound hypotension were deleted. • Correction on listed document for information on potential risks of bivalirudin. • Inclusion of patients with severe renal impairment was specified on request of regulatory authorities; only dialysis-dependent patients were excluded. • Clarification of 30 days patient management following PCI irrespective of drug-eluting stents (DES) or bare-metal stents (BMS). • The following examinations had only to be done once if screening and randomisation were close together (≤48 hrs): medical history, medical examination, neurological assessment (Rankin score), blood hematology, blood chemistry. • Dose justification for bivalirudin was added at the request of regulatory authorities • Neurological examination for the study population was specified. Detailed neurological assessment (only for the magnetic resonance imaging [MRI]-substudy) has been clarified. • LVEF to be done only at screening. • International normalized ratio (INR) to be done only at randomization. • Pregnancy test added at the request of regulatory authorities. • Any ECG source can be used for the ECG examination: 12-lead ECG examination changed to ECG. • Changes to enrollment and pre-procedure management • Arterial site and sheath size were deleted. • Management of bleeding while on treatment with bivalirudin added on request of regulatory authority. • Examinations for follow-up visit were updated. • Scheduled corrected to include AE-recording up to hospital discharge. • Observational period up to day 30 specified. • Pre-TAVR-MRI not needed for MRI-substudy. • In addition, several administrative changes were made and typos were fixed.
    12 Feb 2014
    Amendment number 2 on 12 February 2014 included the following clinical changes to the protocol: • Change to the primary endpoint. The definition of the primary study endpoint of major bleeding changed to BARC type ≥ 3b (from BARC type ≥ 3). • Change to the secondary endpoints related to and consistent with the change to the primary endpoint. • Text describing BARC bleeding by type revised for consistency with the current primary and secondary endpoint designations and for completeness. • Clarification to procedures for 30-day follow-up to specify that in the event of phone follow-up for study patients, data collection was with the health care professional. • Clarification to procedures for study drug administration to specify flushing with heparinized saline, in line with best practices and supportive documentation. • Clarification to procedure for bivalirudin vial reconstitution to most accurately convey time that may be needed for dissolution. • Change to BRAVO MRI Substudy neurological assessments to designate National Institutes of Health Stroke Scale (NIHSS) and Mini-Mental State Examination (MMSE) as optional. • Clarification to BRAVO Economic Substudy text with more precise wording and additional description. • In addition, several administrative changes were made and typos were fixed.
    30 Aug 2014
    Amendment number 3 on 30 August 2014 complied with a recommendation from the Data and Safety Monitoring Board (DSMB) to increase the sample size of the trial based on DSMB review of the second interim analysis of the trial according to prespecified statistical methods. The BRAVO 2/3 study sample size was designed to achieve 80% power and was based on estimated bleeding rate. The trial was also designed to include a second interim analysis after the enrolment of 340 randomised patients (approximately 2/3 of the projected study enrolment). The second interim analysis was an unblinded determination of major bleeding rates in each BRAVO 2/3 treatment group, observed relative risk reduction, and conditional power based on assumed sample sizes. The DSMB reviewed summary reports of the second interim analysis and the adaptive sample size calculations prepared by independent statisticians and convened on 22 May 2014 to determine their recommendation. On 23 May 2014, the DSMB issued a recommendation to continue the trial unmodified until the final number of randomized patients reached the upper limit of 800 patients defined in the interim statistical analysis plan. Accordingly, the following changes were made to the protocol: • Change to the total number of patients to be included in the trial, from 620 to 870. • Change to the number of randomized patients to be included in the trial, from 550 to 800. • A description of DSMB review of the second interim analysis results and addition of the consequent DSMB recommendation.

    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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