VICTORIA: A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction (HFrEF) (MK-1242-001)

Sponsor
Merck Sharp & Dohme LLC (Industry)
Overall Status
Completed
CT.gov ID
NCT02861534
Collaborator
Bayer (Industry), Canadian VIGOUR Centre (Other), Duke Clinical Research Institute (Other)
5,050
2
35.4

Study Details

Study Description

Brief Summary

This is a randomized, placebo-controlled, parallel-group, multi-center, double-blind, event driven study of vericiguat (MK-1242) in participants with heart failure with reduced ejection fraction (HFrEF). The primary hypothesis is vericiguat (MK-1242) is superior to placebo in increasing the time to first occurrence of the composite of cardiovascular (CV) death or heart failure (HF) hospitalization in participants with HFrEF.

Condition or Disease Intervention/Treatment Phase
Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
5050 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
A Randomized Parallel-Group, Placebo-Controlled, Double-Blind, Event-Driven, Multi-Center Pivotal Phase III Clinical Outcome Trial of Efficacy and Safety of the Oral sGC Stimulator Vericiguat in Subjects With Heart Failure With Reduced Ejection Fraction (HFrEF) - VerICiguaT GlObal Study in Subjects With Heart Failure With Reduced EjectIon FrAction (VICTORIA)
Actual Study Start Date :
Sep 20, 2016
Actual Primary Completion Date :
Jun 18, 2019
Actual Study Completion Date :
Sep 2, 2019

Arms and Interventions

Arm Intervention/Treatment
Experimental: Vericiguat

Participants receive a starting dose of 2.5 mg of vericiguat taken orally once daily with food, on a background of HF standard of care. The vericiguat dose will be uptitrated to 5 mg and to 10 mg.

Drug: Vericiguat
2.5, 5.0, or 10.0 mg orally once daily
Other Names:
  • MK-1242
  • Placebo Comparator: Placebo

    Participants receive a starting matching placebo dose of 2.5 mg taken orally once daily with food, on a background of HF standard of care. The matching placebo dose will be uptitrated to 5 mg and to 10 mg.

    Drug: Placebo for vericiguat
    2.5, 5.0, or 10.0 mg orally once daily

    Outcome Measures

    Primary Outcome Measures

    1. Time to First Occurrence of Composite Endpoint of Cardiovascular (CV) Death or Heart Failure (HF) Hospitalization [Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)]

      Time to First Occurrence of Composite Endpoint of CV Death or HF Hospitalization was analyzed using a one-sided stratified log-rank test. Randomized participants without any HF hospitalization or CV death event at the time of analysis were censored at their last available information, the date of their non-CV death, or the primary analysis database cutoff date of 18-June-2019, whichever occurred first. A clinical events committee (CEC) reviewed and adjudicated the endpoint events. A time-to-event methodology was used to evaluate the results; the incidence rate of participants with an event (number of participants with an event per 100 participant-years at risk) is provided.

    Secondary Outcome Measures

    1. Time to the First Occurrence of CV Death [Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)]

      Time to First Occurrence of CV Death was analyzed using a one-sided stratified log-rank test. Randomized participants without a CV death at the time of analysis were censored at their last available information, the date of their non-CV death, or the primary analysis database cutoff date of 18-June-2019, whichever occurred first. A CEC reviewed and adjudicated the endpoint events. A time-to-event methodology was used to evaluate the results; the incidence rate of participants with an event (number of participants with an event per 100 participant-years at risk) is provided.

    2. Time to the First Occurrence of HF Hospitalization [Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)]

      Time to the First Occurrence of HF Hospitalization was analyzed using a one-sided stratified log-rank test. Randomized participants without any HF hospitalization at the time of analysis were censored at their last available information, the date of their death, or the primary analysis database cutoff date of 18-June-2019, whichever occurred first. A CEC reviewed and adjudicated the endpoint events. A time-to-event methodology was used to evaluate the results; the incidence rate of participants with an event (number of participants with an event per 100 participant-years at risk) is provided.

    3. Time to Total HF Hospitalizations (Including First and Recurrent Events) [Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)]

      Time to Total HF Hospitalizations (including first and recurring) was analyzed using an Andersen-Gill model. Randomized participants without any HF hospitalization at the time of analysis were censored at their last available information, the date of their death, or the primary analysis database cutoff date of 18-June-2019, whichever occurred first. A CEC reviewed and adjudicated the endpoint events. A time-to-event methodology was used to evaluate the results; the incidence rate of participants with an event (number of participants with an event per 100 participant-years of follow-up) is provided.

    4. Time to First Occurrence of Composite Endpoint of All-Cause Mortality or HF Hospitalization [Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)]

      Time to First Occurrence of Composite Endpoint of All-Cause Mortality or HF Hospitalization was analyzed using a one-sided stratified log-rank test. Randomized participants without any all-cause mortality event or HF hospitalization at the time of analysis were censored at their last available information or the primary analysis database cutoff date of 18-June-2019, whichever occurred first. A CEC reviewed and adjudicated the endpoint events. A time-to-event methodology was used to evaluate the results; the incidence rate of participants with an event (number of participants with an event per 100 participant-years at risk) is provided.

    5. Time to All-Cause Mortality [Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)]

      Time to All-Cause Mortality was analyzed using a one-sided stratified log-rank test. Randomized participants without any all-cause mortality event at the time of analysis were censored at their last available information or the primary analysis database cutoff date of 18-June-2019, whichever occurred first. A CEC reviewed and adjudicated the endpoint events. A time-to-event methodology was used to evaluate the results: the incidence rate of participants with an event (number of participants with an event per 100 participant-years at risk) is provided.

    6. Number of Participants Who Experienced One or More Adverse Events [Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)]

      An adverse event (AE) is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product.

    7. Number of Participants Who Discontinued Treatment Due to an Adverse Event [Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)]

      An adverse event (AE) is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product.

    8. Percentage of Participants Who Experienced Symptomatic Hypotension [Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)]

      Study participants were monitored for symptomatic hypotension, an event of clinical interest, and results were reported.

    9. Percentage of Participants Who Experienced Syncope [Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)]

      Study participants were monitored for syncope, an event of clinical interest, and results were reported.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • History of chronic HF (New York Heart Association [NYHA] Class II-IV) on standard therapy before qualifying HF decompensation

    • Previous HF hospitalization within 6 months prior to randomization or intravenous (IV) diuretic treatment for HF (without hospitalization) within 3 months.

    • Brain natriuretic peptide (BNP) levels: sinus rhythm-≥ 300 pg/mL; atrial fibrillation-≥ 500 pg/mL and N-terminal pro-Brain Natriuretic Peptide (NT-proBNP) levels: sinus rhythm- ≥ 1000 pg/mL; atrial fibrillation - ≥ 1600 pg/mL within 30 days prior to randomization

    • Left ventricular ejection fraction (LVEF) of <45% assessed within 12 months prior to randomization by any method

    • If female, is not of reproductive potential or agrees to avoid becoming pregnant while receiving study drug and for 14 days after the last dose of study drug by complying with one of the following: practice abstinence from heterosexual activity or use (or have her partner use) acceptable contraception during heterosexual activity.

    Exclusion Criteria:
    • Clinically unstable at the time of randomization as defined by either the administration of any IV treatment within 24 hours prior to randomization, and/or systolic blood pressure (SBP) <100 mmHg or symptomatic hypotension

    • Current or anticipated use of long-acting nitrates or nitric oxide (NO) donors including isosorbide dinitrate, isosorbide 5-mononitrate, pentaerythritol tetranitrate, nicorandil or transdermal nitroglycerin (NTG) patch, and molsidomine

    • Current or anticipated use of phosphodiesterase type 5 (PDE5) inhibitors such as vardenafil, tadalafil, and sildenafil

    • Current use or anticipated use of a soluble guanylate cyclase (sGC) stimulator such as riociguat

    • Known allergy or sensitivity to any sGC stimulator

    • Awaiting heart transplantation (United Network for Organ Sharing Class 1A / 1B or equivalent), receiving continuous IV infusion of an inotrope, or has/anticipates receiving an implanted ventricular assist device

    • Primary valvular heart disease requiring surgery or intervention, or is within 3 months after valvular surgery or intervention

    • Hypertrophic obstructive cardiomyopathy

    • Acute myocarditis, amyloidosis, sarcoidosis, Takotsubo cardiomyopathy

    • Post-heart transplant cardiomyopathy

    • Tachycardia-induced cardiomyopathy and/or uncontrolled tachyarrhythmia

    • Acute coronary syndrome (unstable angina, non-ST elevation myocardial infarction [NSTEMI], or ST elevation myocardial infarction [(STEMI]) or coronary revascularization (coronary artery bypass grafting [CABG] or percutaneous coronary intervention [PCI]) within 60 days, or indication for coronary revascularization at time of randomization

    • Symptomatic carotid stenosis, transient ischemic attack (TIA) or stroke within 60 days

    • Complex congenital heart disease

    • Active endocarditis or constrictive pericarditis

    • Estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m2 or chronic dialysis

    • Severe hepatic insufficiency such as with hepatic encephalopathy

    • Malignancy or other non-cardiac condition limiting life expectancy to <3 years

    • Require continuous home oxygen for severe pulmonary disease

    • Current alcohol and/or drug abuse

    • Participated in another interventional clinical study and treatment with another investigational product ≤30 days prior to randomization or plans to participate in any other trial/investigation during the duration of this study

    • Mental or legal incapacitation and is unable to provide informed consent

    • Immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is involved with this study

    • Interstitial Lung Disease

    • Is pregnant or breastfeeding or plans to become pregnant or to breastfeed during the course of the study

    Contacts and Locations

    Locations

    No locations specified.

    Sponsors and Collaborators

    • Merck Sharp & Dohme LLC
    • Bayer
    • Canadian VIGOUR Centre
    • Duke Clinical Research Institute

    Investigators

    • Study Director: Mahesh J. Patel, MD, Merck Sharp & Dohme LLC
    • Study Chair: Paul W. Armstrong, MD, Canadian VIGOUR Centre - University of Alberta
    • Principal Investigator: Christopher M. O'Connor, MD, Inova Heart and Vascular Institute
    • Principal Investigator: Burkert Pieske, MD, Charité University Medicine and German Heart Center

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Merck Sharp & Dohme LLC
    ClinicalTrials.gov Identifier:
    NCT02861534
    Other Study ID Numbers:
    • 1242-001
    • 2016-000671-25
    • MK-1242-001
    First Posted:
    Aug 10, 2016
    Last Update Posted:
    Nov 15, 2021
    Last Verified:
    Nov 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Vericiguat Placebo
    Arm/Group Description Participants received a starting dose of 2.5 mg of vericiguat taken orally once daily with food, on a background of heart failure (HF) standard of care. The vericiguat dose was uptitrated to 5 mg and to 10 mg. Participants received a starting matching placebo dose of 2.5 mg taken orally once daily with food, on a background of HF standard of care. The matching placebo dose was uptitrated to 5 mg and to 10 mg.
    Period Title: Overall Study
    STARTED 2526 2524
    Treated 2519 2515
    COMPLETED 1952 1937
    NOT COMPLETED 574 587

    Baseline Characteristics

    Arm/Group Title Vericiguat Placebo Total
    Arm/Group Description Participants received a starting dose of 2.5 mg of vericiguat taken orally once daily with food, on a background of heart failure (HF) standard of care. The vericiguat dose was uptitrated to 5 mg and to 10 mg. Participants received a starting matching placebo dose of 2.5 mg taken orally once daily with food, on a background of HF standard of care. The matching placebo dose was uptitrated to 5 mg and to 10 mg. Total of all reporting groups
    Overall Participants 2526 2524 5050
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    67.5
    (12.2)
    67.2
    (12.2)
    67.3
    (12.2)
    Sex: Female, Male (Count of Participants)
    Female
    605
    24%
    603
    23.9%
    1208
    23.9%
    Male
    1921
    76%
    1921
    76.1%
    3842
    76.1%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    24
    1%
    28
    1.1%
    52
    1%
    Asian
    571
    22.6%
    561
    22.2%
    1132
    22.4%
    Native Hawaiian or Other Pacific Islander
    3
    0.1%
    11
    0.4%
    14
    0.3%
    Black or African American
    123
    4.9%
    126
    5%
    249
    4.9%
    White
    1621
    64.2%
    1618
    64.1%
    3239
    64.1%
    More than one race
    183
    7.2%
    180
    7.1%
    363
    7.2%
    Unknown or Not Reported
    1
    0%
    0
    0%
    1
    0%

    Outcome Measures

    1. Secondary Outcome
    Title Time to the First Occurrence of CV Death
    Description Time to First Occurrence of CV Death was analyzed using a one-sided stratified log-rank test. Randomized participants without a CV death at the time of analysis were censored at their last available information, the date of their non-CV death, or the primary analysis database cutoff date of 18-June-2019, whichever occurred first. A CEC reviewed and adjudicated the endpoint events. A time-to-event methodology was used to evaluate the results; the incidence rate of participants with an event (number of participants with an event per 100 participant-years at risk) is provided.
    Time Frame Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants
    Arm/Group Title Vericiguat Placebo
    Arm/Group Description Participants received a starting dose of 2.5 mg of vericiguat taken orally once daily with food, on a background of HF standard of care. The vericiguat dose was uptitrated to 5 mg and to 10 mg. Participants received a starting matching placebo dose of 2.5 mg taken orally once daily with food, on a background of HF standard of care. The matching placebo dose was uptitrated to 5 mg and to 10 mg.
    Measure Participants 2526 2524
    Number [Parts w/ event per 100 part-yrs at risk]
    12.9
    13.9
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Vericiguat, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.269
    Comments
    Method Cox proportional hazard model
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.93
    Confidence Interval (2-Sided) 95%
    0.81 to 1.06
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Time to the First Occurrence of HF Hospitalization
    Description Time to the First Occurrence of HF Hospitalization was analyzed using a one-sided stratified log-rank test. Randomized participants without any HF hospitalization at the time of analysis were censored at their last available information, the date of their death, or the primary analysis database cutoff date of 18-June-2019, whichever occurred first. A CEC reviewed and adjudicated the endpoint events. A time-to-event methodology was used to evaluate the results; the incidence rate of participants with an event (number of participants with an event per 100 participant-years at risk) is provided.
    Time Frame Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants
    Arm/Group Title Vericiguat Placebo
    Arm/Group Description Participants received a starting dose of 2.5 mg of vericiguat taken orally once daily with food, on a background of HF standard of care. The vericiguat dose was uptitrated to 5 mg and to 10 mg. Participants received a starting matching placebo dose of 2.5 mg taken orally once daily with food, on a background of HF standard of care. The matching placebo dose was uptitrated to 5 mg and to 10 mg.
    Measure Participants 2526 2524
    Number [Parts w/ event per 100 part-yrs at risk]
    25.9
    29.1
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Vericiguat, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.048
    Comments
    Method Cox proportional hazard model
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.90
    Confidence Interval (2-Sided) 95%
    0.81 to 1.00
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Primary Outcome
    Title Time to First Occurrence of Composite Endpoint of Cardiovascular (CV) Death or Heart Failure (HF) Hospitalization
    Description Time to First Occurrence of Composite Endpoint of CV Death or HF Hospitalization was analyzed using a one-sided stratified log-rank test. Randomized participants without any HF hospitalization or CV death event at the time of analysis were censored at their last available information, the date of their non-CV death, or the primary analysis database cutoff date of 18-June-2019, whichever occurred first. A clinical events committee (CEC) reviewed and adjudicated the endpoint events. A time-to-event methodology was used to evaluate the results; the incidence rate of participants with an event (number of participants with an event per 100 participant-years at risk) is provided.
    Time Frame Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants
    Arm/Group Title Vericiguat Placebo
    Arm/Group Description Participants received a starting dose of 2.5 mg of vericiguat taken orally once daily with food, on a background of HF standard of care. The vericiguat dose was uptitrated to 5 mg and to 10 mg. Participants received a starting matching placebo dose of 2.5 mg taken orally once daily with food, on a background of HF standard of care. The matching placebo dose was uptitrated to 5 mg and to 10 mg.
    Measure Participants 2526 2524
    Number [Parts w/ event per 100 part-yrs at risk]
    33.6
    37.8
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Vericiguat, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.019
    Comments
    Method Cox proportional hazard model
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.90
    Confidence Interval (2-Sided) 95%
    0.82 to 0.98
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    4. Secondary Outcome
    Title Time to Total HF Hospitalizations (Including First and Recurrent Events)
    Description Time to Total HF Hospitalizations (including first and recurring) was analyzed using an Andersen-Gill model. Randomized participants without any HF hospitalization at the time of analysis were censored at their last available information, the date of their death, or the primary analysis database cutoff date of 18-June-2019, whichever occurred first. A CEC reviewed and adjudicated the endpoint events. A time-to-event methodology was used to evaluate the results; the incidence rate of participants with an event (number of participants with an event per 100 participant-years of follow-up) is provided.
    Time Frame Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants
    Arm/Group Title Vericiguat Placebo
    Arm/Group Description Participants received a starting dose of 2.5 mg of vericiguat taken orally once daily with food, on a background of HF standard of care. The vericiguat dose was uptitrated to 5 mg and to 10 mg. Participants received a starting matching placebo dose of 2.5 mg taken orally once daily with food, on a background of HF standard of care. The matching placebo dose was uptitrated to 5 mg and to 10 mg.
    Measure Participants 2526 2524
    Number [Parts w/ event per 100 part-yrs]
    38.3
    42.4
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Vericiguat, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.023
    Comments
    Method Andersen-Gill model
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.91
    Confidence Interval (2-Sided) 95%
    0.84 to 0.99
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    5. Secondary Outcome
    Title Time to First Occurrence of Composite Endpoint of All-Cause Mortality or HF Hospitalization
    Description Time to First Occurrence of Composite Endpoint of All-Cause Mortality or HF Hospitalization was analyzed using a one-sided stratified log-rank test. Randomized participants without any all-cause mortality event or HF hospitalization at the time of analysis were censored at their last available information or the primary analysis database cutoff date of 18-June-2019, whichever occurred first. A CEC reviewed and adjudicated the endpoint events. A time-to-event methodology was used to evaluate the results; the incidence rate of participants with an event (number of participants with an event per 100 participant-years at risk) is provided.
    Time Frame Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants
    Arm/Group Title Vericiguat Placebo
    Arm/Group Description Participants received a starting dose of 2.5 mg of vericiguat taken orally once daily with food, on a background of HF standard of care. The vericiguat dose was uptitrated to 5 mg and to 10 mg. Participants received a starting matching placebo dose of 2.5 mg taken orally once daily with food, on a background of HF standard of care. The matching placebo dose was uptitrated to 5 mg and to 10 mg.
    Measure Participants 2526 2524
    Number [Parts w/ event per 100 part-yrs at risk]
    35.9
    40.1
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Vericiguat, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.021
    Comments
    Method Cox proportional hazard model
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.90
    Confidence Interval (2-Sided) 95%
    0.83 to 0.98
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    6. Secondary Outcome
    Title Time to All-Cause Mortality
    Description Time to All-Cause Mortality was analyzed using a one-sided stratified log-rank test. Randomized participants without any all-cause mortality event at the time of analysis were censored at their last available information or the primary analysis database cutoff date of 18-June-2019, whichever occurred first. A CEC reviewed and adjudicated the endpoint events. A time-to-event methodology was used to evaluate the results: the incidence rate of participants with an event (number of participants with an event per 100 participant-years at risk) is provided.
    Time Frame Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants
    Arm/Group Title Vericiguat Placebo
    Arm/Group Description Participants received a starting dose of 2.5 mg of vericiguat taken orally once daily with food, on a background of HF standard of care. The vericiguat dose was uptitrated to 5 mg and to 10 mg. Participants received a starting matching placebo dose of 2.5 mg taken orally once daily with food, on a background of HF standard of care. The matching placebo dose was uptitrated to 5 mg and to 10 mg.
    Measure Participants 2526 2524
    Number [Parts w/ event per 100 part-yrs at risk]
    16.0
    16.9
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Vericiguat, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.377
    Comments
    Method Cox proportional hazard model
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.95
    Confidence Interval (2-Sided) 95%
    0.84 to 1.07
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    7. Secondary Outcome
    Title Number of Participants Who Experienced One or More Adverse Events
    Description An adverse event (AE) is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product.
    Time Frame Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least 1 dose of study treatment
    Arm/Group Title Vericiguat Placebo
    Arm/Group Description Participants received a starting dose of 2.5 mg of vericiguat taken orally once daily with food, on a background of HF standard of care. The vericiguat dose was uptitrated to 5 mg and to 10 mg. Participants received a starting matching placebo dose of 2.5 mg taken orally once daily with food, on a background of HF standard of care. The matching placebo dose was uptitrated to 5 mg and to 10 mg.
    Measure Participants 2519 2515
    Count of Participants [Participants]
    2027
    80.2%
    2036
    80.7%
    8. Secondary Outcome
    Title Number of Participants Who Discontinued Treatment Due to an Adverse Event
    Description An adverse event (AE) is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product.
    Time Frame Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least 1 dose of study treatment
    Arm/Group Title Vericiguat Placebo
    Arm/Group Description Participants received a starting dose of 2.5 mg of vericiguat taken orally once daily with food, on a background of HF standard of care. The vericiguat dose was uptitrated to 5 mg and to 10 mg. Participants received a starting matching placebo dose of 2.5 mg taken orally once daily with food, on a background of HF standard of care. The matching placebo dose was uptitrated to 5 mg and to 10 mg.
    Measure Participants 2519 2515
    Count of Participants [Participants]
    167
    6.6%
    158
    6.3%
    9. Secondary Outcome
    Title Percentage of Participants Who Experienced Symptomatic Hypotension
    Description Study participants were monitored for symptomatic hypotension, an event of clinical interest, and results were reported.
    Time Frame Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least 1 dose of study treatment
    Arm/Group Title Vericiguat Placebo
    Arm/Group Description Participants received a starting dose of 2.5 mg of vericiguat taken orally once daily with food, on a background of HF standard of care. The vericiguat dose was uptitrated to 5 mg and to 10 mg. Participants received a starting matching placebo dose of 2.5 mg taken orally once daily with food, on a background of HF standard of care. The matching placebo dose was uptitrated to 5 mg and to 10 mg.
    Measure Participants 2519 2515
    Number [Percentage of participants]
    9.1
    0.4%
    7.9
    0.3%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Vericiguat, Placebo
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.121
    Comments
    Method Miettinen & Nurminen method
    Comments
    Method of Estimation Estimation Parameter Difference in Percentage
    Estimated Value 1.2
    Confidence Interval (2-Sided) 95%
    -0.3 to 2.8
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    10. Secondary Outcome
    Title Percentage of Participants Who Experienced Syncope
    Description Study participants were monitored for syncope, an event of clinical interest, and results were reported.
    Time Frame Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least 1 dose of study treatment
    Arm/Group Title Vericiguat Placebo
    Arm/Group Description Participants received a starting dose of 2.5 mg of vericiguat taken orally once daily with food, on a background of HF standard of care. The vericiguat dose was uptitrated to 5 mg and to 10 mg. Participants received a starting matching placebo dose of 2.5 mg taken orally once daily with food, on a background of HF standard of care. The matching placebo dose was uptitrated to 5 mg and to 10 mg.
    Measure Participants 2519 2515
    Number [Percentage of participants]
    4.0
    0.2%
    3.5
    0.1%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Vericiguat, Placebo
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.303
    Comments
    Method Miettinen & Nurminen method
    Comments
    Method of Estimation Estimation Parameter Difference in Percentage
    Estimated Value 0.6
    Confidence Interval (2-Sided) 95%
    -0.5 to 1.6
    Parameter Dispersion Type:
    Value:
    Estimation Comments

    Adverse Events

    Time Frame Up to approximately 35 months (through Last Subject Last Visit date of 02-Sept-2019)
    Adverse Event Reporting Description Serious Adverse Events and Other Adverse Events: All randomized participants who received at least 1 dose of study treatment All-Cause Mortality: All randomized participants
    Arm/Group Title Vericiguat Placebo
    Arm/Group Description Participants received a starting dose of 2.5 mg of vericiguat taken orally once daily with food, on a background of HF standard of care. The vericiguat dose was uptitrated to 5 mg and to 10 mg. Participants received a starting matching placebo dose of 2.5 mg taken orally once daily with food, on a background of HF standard of care. The matching placebo dose was uptitrated to 5 mg and to 10 mg.
    All Cause Mortality
    Vericiguat Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 553/2526 (21.9%) 561/2524 (22.2%)
    Serious Adverse Events
    Vericiguat Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 852/2519 (33.8%) 897/2515 (35.7%)
    Blood and lymphatic system disorders
    Anaemia 41/2519 (1.6%) 50 24/2515 (1%) 25
    Anaemia of chronic disease 1/2519 (0%) 1 0/2515 (0%) 0
    Autoimmune haemolytic anaemia 1/2519 (0%) 1 0/2515 (0%) 0
    Bicytopenia 1/2519 (0%) 1 0/2515 (0%) 0
    Blood loss anaemia 0/2519 (0%) 0 1/2515 (0%) 1
    Bone marrow failure 0/2519 (0%) 0 1/2515 (0%) 1
    Coagulopathy 1/2519 (0%) 1 0/2515 (0%) 0
    Disseminated intravascular coagulation 1/2519 (0%) 1 0/2515 (0%) 0
    Hypocoagulable state 1/2519 (0%) 1 0/2515 (0%) 0
    Iron deficiency anaemia 3/2519 (0.1%) 3 2/2515 (0.1%) 2
    Normochromic normocytic anaemia 1/2519 (0%) 1 0/2515 (0%) 0
    Normocytic anaemia 1/2519 (0%) 1 1/2515 (0%) 1
    Pancytopenia 3/2519 (0.1%) 3 1/2515 (0%) 1
    Splenic infarction 1/2519 (0%) 1 0/2515 (0%) 0
    Thrombocytopenia 2/2519 (0.1%) 2 1/2515 (0%) 1
    Cardiac disorders
    Acute coronary syndrome 1/2519 (0%) 1 4/2515 (0.2%) 4
    Acute myocardial infarction 5/2519 (0.2%) 6 5/2515 (0.2%) 5
    Angina pectoris 9/2519 (0.4%) 10 8/2515 (0.3%) 9
    Angina unstable 2/2519 (0.1%) 2 7/2515 (0.3%) 13
    Aortic valve calcification 1/2519 (0%) 1 0/2515 (0%) 0
    Aortic valve incompetence 0/2519 (0%) 0 1/2515 (0%) 1
    Aortic valve stenosis 3/2519 (0.1%) 3 3/2515 (0.1%) 3
    Arrhythmia 1/2519 (0%) 1 0/2515 (0%) 0
    Arteriosclerosis coronary artery 2/2519 (0.1%) 2 0/2515 (0%) 0
    Atrial fibrillation 14/2519 (0.6%) 15 29/2515 (1.2%) 31
    Atrial flutter 6/2519 (0.2%) 7 7/2515 (0.3%) 7
    Atrial tachycardia 0/2519 (0%) 0 1/2515 (0%) 1
    Atrial thrombosis 0/2519 (0%) 0 2/2515 (0.1%) 2
    Atrioventricular block 2/2519 (0.1%) 2 0/2515 (0%) 0
    Atrioventricular block complete 0/2519 (0%) 0 2/2515 (0.1%) 2
    Atrioventricular block second degree 0/2519 (0%) 0 1/2515 (0%) 1
    Bradyarrhythmia 0/2519 (0%) 0 1/2515 (0%) 1
    Bradycardia 3/2519 (0.1%) 3 3/2515 (0.1%) 3
    Bundle branch block left 0/2519 (0%) 0 2/2515 (0.1%) 2
    Cardiac arrest 3/2519 (0.1%) 3 3/2515 (0.1%) 3
    Cardiac asthma 1/2519 (0%) 1 0/2515 (0%) 0
    Cardiac failure 82/2519 (3.3%) 88 116/2515 (4.6%) 128
    Cardiac failure acute 2/2519 (0.1%) 2 4/2515 (0.2%) 4
    Cardiac failure chronic 5/2519 (0.2%) 5 10/2515 (0.4%) 10
    Cardiac failure congestive 13/2519 (0.5%) 13 25/2515 (1%) 25
    Cardiac perforation 0/2519 (0%) 0 1/2515 (0%) 1
    Cardiac ventricular thrombosis 2/2519 (0.1%) 2 0/2515 (0%) 0
    Cardio-respiratory arrest 4/2519 (0.2%) 4 1/2515 (0%) 1
    Cardiogenic shock 8/2519 (0.3%) 8 4/2515 (0.2%) 4
    Cardiopulmonary failure 1/2519 (0%) 1 1/2515 (0%) 1
    Cardiorenal syndrome 3/2519 (0.1%) 3 2/2515 (0.1%) 2
    Cardiovascular disorder 1/2519 (0%) 1 0/2515 (0%) 0
    Cardiovascular insufficiency 1/2519 (0%) 1 0/2515 (0%) 0
    Congestive cardiomyopathy 3/2519 (0.1%) 3 3/2515 (0.1%) 3
    Coronary artery disease 7/2519 (0.3%) 8 3/2515 (0.1%) 3
    Coronary artery occlusion 0/2519 (0%) 0 1/2515 (0%) 1
    Coronary artery stenosis 3/2519 (0.1%) 4 2/2515 (0.1%) 2
    Extrasystoles 1/2519 (0%) 1 0/2515 (0%) 0
    Heart valve incompetence 1/2519 (0%) 1 0/2515 (0%) 0
    Intracardiac thrombus 0/2519 (0%) 0 2/2515 (0.1%) 2
    Ischaemic cardiomyopathy 1/2519 (0%) 1 2/2515 (0.1%) 2
    Left ventricular dysfunction 1/2519 (0%) 1 1/2515 (0%) 1
    Left ventricular failure 0/2519 (0%) 0 2/2515 (0.1%) 2
    Mitral valve incompetence 7/2519 (0.3%) 7 5/2515 (0.2%) 5
    Myocardial infarction 6/2519 (0.2%) 6 3/2515 (0.1%) 3
    Myocardial ischaemia 3/2519 (0.1%) 3 2/2515 (0.1%) 2
    Palpitations 2/2519 (0.1%) 2 1/2515 (0%) 1
    Pericardial effusion 0/2519 (0%) 0 1/2515 (0%) 1
    Pericarditis 1/2519 (0%) 1 0/2515 (0%) 0
    Sinus bradycardia 1/2519 (0%) 1 0/2515 (0%) 0
    Sinus node dysfunction 2/2519 (0.1%) 2 2/2515 (0.1%) 2
    Supraventricular tachycardia 1/2519 (0%) 1 0/2515 (0%) 0
    Tachyarrhythmia 0/2519 (0%) 0 1/2515 (0%) 1
    Tachycardia 0/2519 (0%) 0 1/2515 (0%) 1
    Ventricular arrhythmia 2/2519 (0.1%) 2 1/2515 (0%) 1
    Ventricular dysfunction 0/2519 (0%) 0 2/2515 (0.1%) 2
    Ventricular extrasystoles 2/2519 (0.1%) 2 2/2515 (0.1%) 2
    Ventricular fibrillation 9/2519 (0.4%) 10 7/2515 (0.3%) 9
    Ventricular tachycardia 14/2519 (0.6%) 18 27/2515 (1.1%) 29
    Congenital, familial and genetic disorders
    Corneal dystrophy 1/2519 (0%) 1 0/2515 (0%) 0
    Gastrointestinal arteriovenous malformation 1/2519 (0%) 1 0/2515 (0%) 0
    Hydrocele 1/2519 (0%) 1 0/2515 (0%) 0
    Phimosis 1/2519 (0%) 1 1/2515 (0%) 1
    Pyloric stenosis 1/2519 (0%) 1 0/2515 (0%) 0
    Ear and labyrinth disorders
    Vertigo 3/2519 (0.1%) 3 7/2515 (0.3%) 7
    Vertigo positional 1/2519 (0%) 1 3/2515 (0.1%) 4
    Endocrine disorders
    Basedow's disease 1/2519 (0%) 1 0/2515 (0%) 0
    Carcinoid syndrome 1/2519 (0%) 1 0/2515 (0%) 0
    Glucocorticoid deficiency 1/2519 (0%) 1 0/2515 (0%) 0
    Hyperthyroidism 4/2519 (0.2%) 4 1/2515 (0%) 1
    Hypoparathyroidism secondary 0/2519 (0%) 0 1/2515 (0%) 1
    Hypothyroidism 0/2519 (0%) 0 1/2515 (0%) 1
    Eye disorders
    Blindness 1/2519 (0%) 1 0/2515 (0%) 0
    Cataract 9/2519 (0.4%) 10 6/2515 (0.2%) 8
    Diabetic retinopathy 2/2519 (0.1%) 2 1/2515 (0%) 1
    Diplopia 1/2519 (0%) 1 0/2515 (0%) 0
    Eye haemorrhage 1/2519 (0%) 1 0/2515 (0%) 0
    Eyelid ptosis 0/2519 (0%) 0 1/2515 (0%) 1
    Glaucoma 1/2519 (0%) 1 0/2515 (0%) 0
    Macular cyst 0/2519 (0%) 0 1/2515 (0%) 1
    Retinal artery thrombosis 1/2519 (0%) 1 0/2515 (0%) 0
    Retinal haemorrhage 0/2519 (0%) 0 1/2515 (0%) 1
    Vitreous haemorrhage 2/2519 (0.1%) 2 1/2515 (0%) 1
    Gastrointestinal disorders
    Abdominal distension 0/2519 (0%) 0 1/2515 (0%) 1
    Abdominal pain 4/2519 (0.2%) 4 4/2515 (0.2%) 4
    Abdominal pain lower 0/2519 (0%) 0 1/2515 (0%) 1
    Abdominal pain upper 4/2519 (0.2%) 5 3/2515 (0.1%) 3
    Abdominal rigidity 1/2519 (0%) 1 0/2515 (0%) 0
    Alcoholic pancreatitis 1/2519 (0%) 1 0/2515 (0%) 0
    Anorectal ulcer 1/2519 (0%) 1 0/2515 (0%) 0
    Ascites 8/2519 (0.3%) 10 4/2515 (0.2%) 5
    Barrett's oesophagus 0/2519 (0%) 0 1/2515 (0%) 1
    Colitis 2/2519 (0.1%) 2 2/2515 (0.1%) 2
    Colitis ischaemic 1/2519 (0%) 1 1/2515 (0%) 1
    Constipation 3/2519 (0.1%) 3 2/2515 (0.1%) 2
    Dental caries 0/2519 (0%) 0 1/2515 (0%) 1
    Dental cyst 0/2519 (0%) 0 1/2515 (0%) 1
    Diarrhoea 10/2519 (0.4%) 10 7/2515 (0.3%) 7
    Diverticulum 1/2519 (0%) 1 0/2515 (0%) 0
    Diverticulum intestinal 1/2519 (0%) 1 1/2515 (0%) 1
    Duodenal ulcer 0/2519 (0%) 0 3/2515 (0.1%) 3
    Erosive oesophagitis 1/2519 (0%) 1 0/2515 (0%) 0
    Faecaloma 0/2519 (0%) 0 1/2515 (0%) 1
    Gastric haemorrhage 2/2519 (0.1%) 2 0/2515 (0%) 0
    Gastric perforation 1/2519 (0%) 1 0/2515 (0%) 0
    Gastric ulcer 1/2519 (0%) 1 2/2515 (0.1%) 2
    Gastric ulcer haemorrhage 1/2519 (0%) 1 2/2515 (0.1%) 2
    Gastritis 4/2519 (0.2%) 4 7/2515 (0.3%) 7
    Gastritis erosive 1/2519 (0%) 1 2/2515 (0.1%) 2
    Gastritis haemorrhagic 1/2519 (0%) 1 0/2515 (0%) 0
    Gastrointestinal angiodysplasia 1/2519 (0%) 1 2/2515 (0.1%) 2
    Gastrointestinal haemorrhage 12/2519 (0.5%) 14 7/2515 (0.3%) 7
    Gastrointestinal toxicity 1/2519 (0%) 1 0/2515 (0%) 0
    Gastrooesophageal reflux disease 0/2519 (0%) 0 4/2515 (0.2%) 4
    Gingival bleeding 1/2519 (0%) 1 0/2515 (0%) 0
    Haematemesis 1/2519 (0%) 1 0/2515 (0%) 0
    Haematochezia 0/2519 (0%) 0 1/2515 (0%) 1
    Haemorrhoidal haemorrhage 1/2519 (0%) 1 1/2515 (0%) 1
    Haemorrhoids 3/2519 (0.1%) 3 2/2515 (0.1%) 2
    Ileus 2/2519 (0.1%) 2 0/2515 (0%) 0
    Impaired gastric emptying 2/2519 (0.1%) 2 0/2515 (0%) 0
    Incarcerated inguinal hernia 0/2519 (0%) 0 3/2515 (0.1%) 3
    Incarcerated umbilical hernia 1/2519 (0%) 1 0/2515 (0%) 0
    Inguinal hernia 11/2519 (0.4%) 11 9/2515 (0.4%) 9
    Inguinal hernia strangulated 1/2519 (0%) 1 0/2515 (0%) 0
    Inguinal hernia, obstructive 1/2519 (0%) 1 0/2515 (0%) 0
    Intestinal infarction 0/2519 (0%) 0 1/2515 (0%) 1
    Intestinal ischaemia 1/2519 (0%) 1 2/2515 (0.1%) 2
    Intestinal obstruction 1/2519 (0%) 1 0/2515 (0%) 0
    Intra-abdominal haematoma 0/2519 (0%) 0 1/2515 (0%) 1
    Ischaemic enteritis 0/2519 (0%) 0 1/2515 (0%) 1
    Large intestinal haemorrhage 1/2519 (0%) 1 0/2515 (0%) 0
    Large intestinal obstruction 1/2519 (0%) 1 0/2515 (0%) 0
    Large intestinal stenosis 0/2519 (0%) 0 1/2515 (0%) 1
    Large intestinal ulcer 0/2519 (0%) 0 1/2515 (0%) 1
    Large intestinal ulcer haemorrhage 0/2519 (0%) 0 1/2515 (0%) 1
    Large intestinal ulcer perforation 1/2519 (0%) 1 0/2515 (0%) 0
    Large intestine polyp 1/2519 (0%) 2 4/2515 (0.2%) 4
    Lower gastrointestinal haemorrhage 1/2519 (0%) 1 1/2515 (0%) 1
    Melaena 1/2519 (0%) 1 2/2515 (0.1%) 2
    Nausea 2/2519 (0.1%) 2 0/2515 (0%) 0
    Obstructive pancreatitis 1/2519 (0%) 1 0/2515 (0%) 0
    Oesophageal achalasia 0/2519 (0%) 0 1/2515 (0%) 1
    Oesophageal stenosis 0/2519 (0%) 0 1/2515 (0%) 1
    Oesophageal varices haemorrhage 0/2519 (0%) 0 1/2515 (0%) 1
    Pancreatitis 1/2519 (0%) 1 0/2515 (0%) 0
    Pancreatitis acute 2/2519 (0.1%) 2 1/2515 (0%) 1
    Pancreatitis chronic 1/2519 (0%) 1 1/2515 (0%) 1
    Pancreatolithiasis 1/2519 (0%) 1 0/2515 (0%) 0
    Peptic ulcer 0/2519 (0%) 0 1/2515 (0%) 1
    Pneumatosis intestinalis 0/2519 (0%) 0 1/2515 (0%) 1
    Rectal haemorrhage 4/2519 (0.2%) 4 1/2515 (0%) 1
    Small intestinal obstruction 2/2519 (0.1%) 2 0/2515 (0%) 0
    Subileus 0/2519 (0%) 0 2/2515 (0.1%) 2
    Umbilical hernia 2/2519 (0.1%) 2 0/2515 (0%) 0
    Upper gastrointestinal haemorrhage 3/2519 (0.1%) 3 6/2515 (0.2%) 6
    Vomiting 4/2519 (0.2%) 4 2/2515 (0.1%) 2
    General disorders
    Asthenia 6/2519 (0.2%) 6 6/2515 (0.2%) 7
    Cardiac complication associated with device 1/2519 (0%) 1 0/2515 (0%) 0
    Chest discomfort 1/2519 (0%) 1 2/2515 (0.1%) 2
    Chest pain 10/2519 (0.4%) 10 8/2515 (0.3%) 14
    Device related thrombosis 0/2519 (0%) 0 1/2515 (0%) 1
    Discomfort 1/2519 (0%) 1 0/2515 (0%) 0
    General physical health deterioration 6/2519 (0.2%) 6 1/2515 (0%) 1
    Generalised oedema 1/2519 (0%) 1 0/2515 (0%) 0
    Hernia 1/2519 (0%) 1 0/2515 (0%) 0
    Impaired healing 0/2519 (0%) 0 1/2515 (0%) 1
    Implant site erythema 0/2519 (0%) 0 1/2515 (0%) 1
    Implant site haematoma 2/2519 (0.1%) 2 0/2515 (0%) 0
    Implant site haemorrhage 0/2519 (0%) 0 1/2515 (0%) 1
    Influenza like illness 0/2519 (0%) 0 1/2515 (0%) 1
    Medical device pain 1/2519 (0%) 1 0/2515 (0%) 0
    Medical device site haematoma 2/2519 (0.1%) 2 0/2515 (0%) 0
    Medical device site swelling 0/2519 (0%) 0 1/2515 (0%) 1
    Medical device site thrombosis 0/2519 (0%) 0 1/2515 (0%) 1
    Multiple organ dysfunction syndrome 2/2519 (0.1%) 2 4/2515 (0.2%) 4
    Non-cardiac chest pain 4/2519 (0.2%) 4 7/2515 (0.3%) 7
    Oedema 0/2519 (0%) 0 1/2515 (0%) 1
    Oedema peripheral 0/2519 (0%) 0 3/2515 (0.1%) 3
    Physical deconditioning 0/2519 (0%) 0 1/2515 (0%) 1
    Pyrexia 3/2519 (0.1%) 3 2/2515 (0.1%) 2
    Sensation of foreign body 1/2519 (0%) 1 0/2515 (0%) 0
    Strangulated hernia 0/2519 (0%) 0 1/2515 (0%) 1
    Sudden cardiac death 0/2519 (0%) 0 1/2515 (0%) 1
    UGT1A1 gene polymorphism 0/2519 (0%) 0 1/2515 (0%) 1
    Vascular stent occlusion 1/2519 (0%) 1 0/2515 (0%) 0
    Vascular stent stenosis 1/2519 (0%) 1 0/2515 (0%) 0
    Vascular stent thrombosis 0/2519 (0%) 0 1/2515 (0%) 1
    Hepatobiliary disorders
    Acute hepatic failure 1/2519 (0%) 1 3/2515 (0.1%) 3
    Bile duct stone 2/2519 (0.1%) 2 1/2515 (0%) 1
    Biloma 0/2519 (0%) 0 1/2515 (0%) 1
    Cholangitis 1/2519 (0%) 1 1/2515 (0%) 1
    Cholangitis acute 0/2519 (0%) 0 1/2515 (0%) 1
    Cholecystitis 4/2519 (0.2%) 4 4/2515 (0.2%) 4
    Cholecystitis acute 4/2519 (0.2%) 4 6/2515 (0.2%) 6
    Cholecystitis chronic 2/2519 (0.1%) 2 0/2515 (0%) 0
    Cholelithiasis 4/2519 (0.2%) 4 2/2515 (0.1%) 2
    Cholestasis 1/2519 (0%) 1 1/2515 (0%) 1
    Chronic hepatic failure 0/2519 (0%) 0 1/2515 (0%) 1
    Hepatic cirrhosis 2/2519 (0.1%) 2 1/2515 (0%) 1
    Hepatic congestion 4/2519 (0.2%) 4 0/2515 (0%) 0
    Hepatic failure 1/2519 (0%) 1 0/2515 (0%) 0
    Hepatitis acute 1/2519 (0%) 1 1/2515 (0%) 1
    Hepatitis toxic 0/2519 (0%) 0 1/2515 (0%) 1
    Hepatocellular injury 2/2519 (0.1%) 2 0/2515 (0%) 0
    Ischaemic hepatitis 4/2519 (0.2%) 4 2/2515 (0.1%) 2
    Jaundice cholestatic 1/2519 (0%) 1 0/2515 (0%) 0
    Liver disorder 2/2519 (0.1%) 2 0/2515 (0%) 0
    Liver injury 5/2519 (0.2%) 5 2/2515 (0.1%) 2
    Portosplenomesenteric venous thrombosis 0/2519 (0%) 0 1/2515 (0%) 1
    Immune system disorders
    Amyloidosis 1/2519 (0%) 1 0/2515 (0%) 0
    Infections and infestations
    Abscess limb 3/2519 (0.1%) 3 2/2515 (0.1%) 2
    Acinetobacter bacteraemia 1/2519 (0%) 1 0/2515 (0%) 0
    Amoebic dysentery 1/2519 (0%) 1 0/2515 (0%) 0
    Anal abscess 0/2519 (0%) 0 1/2515 (0%) 1
    Appendicitis 2/2519 (0.1%) 2 1/2515 (0%) 1
    Arteriovenous fistula site infection 0/2519 (0%) 0 1/2515 (0%) 1
    Atypical pneumonia 0/2519 (0%) 0 1/2515 (0%) 1
    Bacteraemia 0/2519 (0%) 0 1/2515 (0%) 1
    Bacterial sepsis 1/2519 (0%) 1 0/2515 (0%) 0
    Bronchitis 10/2519 (0.4%) 10 7/2515 (0.3%) 7
    Bronchitis viral 2/2519 (0.1%) 2 1/2515 (0%) 1
    Campylobacter gastroenteritis 1/2519 (0%) 1 0/2515 (0%) 0
    Cellulitis 25/2519 (1%) 27 19/2515 (0.8%) 20
    Cellulitis gangrenous 1/2519 (0%) 1 0/2515 (0%) 0
    Chest wall abscess 1/2519 (0%) 1 0/2515 (0%) 0
    Cholecystitis infective 0/2519 (0%) 0 2/2515 (0.1%) 2
    Chronic sinusitis 1/2519 (0%) 1 1/2515 (0%) 1
    Clostridium difficile colitis 2/2519 (0.1%) 2 0/2515 (0%) 0
    Complicated appendicitis 2/2519 (0.1%) 2 0/2515 (0%) 0
    Cystitis 1/2519 (0%) 1 0/2515 (0%) 0
    Cystitis bacterial 0/2519 (0%) 0 1/2515 (0%) 1
    Device related infection 4/2519 (0.2%) 4 2/2515 (0.1%) 2
    Diabetic foot infection 1/2519 (0%) 1 2/2515 (0.1%) 2
    Diarrhoea infectious 1/2519 (0%) 1 1/2515 (0%) 1
    Disseminated tuberculosis 0/2519 (0%) 0 1/2515 (0%) 1
    Diverticulitis 1/2519 (0%) 1 2/2515 (0.1%) 2
    Endocarditis 4/2519 (0.2%) 7 1/2515 (0%) 1
    Enteritis infectious 1/2519 (0%) 1 0/2515 (0%) 0
    Enterobacter bacteraemia 1/2519 (0%) 1 0/2515 (0%) 0
    Enterococcal bacteraemia 1/2519 (0%) 1 0/2515 (0%) 0
    Enterococcal infection 0/2519 (0%) 0 1/2515 (0%) 1
    Enterocolitis viral 0/2519 (0%) 0 1/2515 (0%) 1
    Epididymitis 2/2519 (0.1%) 2 0/2515 (0%) 0
    Erysipelas 2/2519 (0.1%) 2 6/2515 (0.2%) 6
    Escherichia urinary tract infection 1/2519 (0%) 1 0/2515 (0%) 0
    Extradural abscess 1/2519 (0%) 1 0/2515 (0%) 0
    Eye infection bacterial 0/2519 (0%) 0 1/2515 (0%) 1
    Febrile infection 0/2519 (0%) 0 1/2515 (0%) 1
    Fungaemia 1/2519 (0%) 1 0/2515 (0%) 0
    Gangrene 4/2519 (0.2%) 4 4/2515 (0.2%) 4
    Gas gangrene 0/2519 (0%) 0 1/2515 (0%) 1
    Gastroenteritis 16/2519 (0.6%) 16 10/2515 (0.4%) 10
    Gastroenteritis bacterial 0/2519 (0%) 0 1/2515 (0%) 1
    Gastroenteritis norovirus 0/2519 (0%) 0 1/2515 (0%) 1
    Gastroenteritis salmonella 1/2519 (0%) 1 1/2515 (0%) 1
    Gastroenteritis viral 0/2519 (0%) 0 1/2515 (0%) 1
    Groin abscess 0/2519 (0%) 0 2/2515 (0.1%) 2
    H1N1 influenza 1/2519 (0%) 1 0/2515 (0%) 0
    Haematoma infection 1/2519 (0%) 1 0/2515 (0%) 0
    Herpes zoster 0/2519 (0%) 0 1/2515 (0%) 1
    Implant site cellulitis 1/2519 (0%) 1 0/2515 (0%) 0
    Implant site infection 3/2519 (0.1%) 3 3/2515 (0.1%) 3
    Infected bite 0/2519 (0%) 0 1/2515 (0%) 1
    Infected skin ulcer 2/2519 (0.1%) 2 0/2515 (0%) 0
    Infection 0/2519 (0%) 0 3/2515 (0.1%) 3
    Infectious pleural effusion 1/2519 (0%) 1 1/2515 (0%) 1
    Infective exacerbation of chronic obstructive airways disease 1/2519 (0%) 1 3/2515 (0.1%) 3
    Influenza 11/2519 (0.4%) 11 8/2515 (0.3%) 8
    Intervertebral discitis 1/2519 (0%) 1 1/2515 (0%) 1
    Intestinal sepsis 0/2519 (0%) 0 1/2515 (0%) 1
    Klebsiella sepsis 0/2519 (0%) 0 1/2515 (0%) 1
    Liver abscess 0/2519 (0%) 0 1/2515 (0%) 1
    Localised infection 1/2519 (0%) 1 0/2515 (0%) 0
    Lower respiratory tract infection 7/2519 (0.3%) 8 4/2515 (0.2%) 4
    Lower respiratory tract infection viral 0/2519 (0%) 0 1/2515 (0%) 1
    Lung infection 10/2519 (0.4%) 12 3/2515 (0.1%) 3
    Measles 1/2519 (0%) 1 0/2515 (0%) 0
    Medical device site abscess 0/2519 (0%) 0 1/2515 (0%) 1
    Myocarditis infectious 1/2519 (0%) 1 0/2515 (0%) 0
    Necrotising fasciitis 2/2519 (0.1%) 2 0/2515 (0%) 0
    Nosocomial infection 1/2519 (0%) 1 0/2515 (0%) 0
    Ophthalmic herpes zoster 0/2519 (0%) 0 1/2515 (0%) 1
    Osteomyelitis 6/2519 (0.2%) 6 6/2515 (0.2%) 7
    Osteomyelitis acute 1/2519 (0%) 1 0/2515 (0%) 0
    Osteomyelitis chronic 1/2519 (0%) 1 0/2515 (0%) 0
    Otitis externa 1/2519 (0%) 1 0/2515 (0%) 0
    Parainfluenzae virus infection 1/2519 (0%) 1 1/2515 (0%) 1
    Parotid abscess 0/2519 (0%) 0 1/2515 (0%) 1
    Periodontitis 1/2519 (0%) 1 1/2515 (0%) 1
    Perirectal abscess 1/2519 (0%) 1 0/2515 (0%) 0
    Peritonitis 0/2519 (0%) 0 1/2515 (0%) 1
    Peritonitis bacterial 2/2519 (0.1%) 2 0/2515 (0%) 0
    Pertussis 0/2519 (0%) 0 1/2515 (0%) 1
    Pneumonia 104/2519 (4.1%) 113 116/2515 (4.6%) 127
    Pneumonia bacterial 3/2519 (0.1%) 3 4/2515 (0.2%) 4
    Pneumonia chlamydial 1/2519 (0%) 1 0/2515 (0%) 0
    Pneumonia mycoplasmal 0/2519 (0%) 0 1/2515 (0%) 1
    Pneumonia pneumococcal 0/2519 (0%) 0 1/2515 (0%) 1
    Pneumonia respiratory syncytial viral 0/2519 (0%) 0 1/2515 (0%) 1
    Pneumonia staphylococcal 0/2519 (0%) 0 1/2515 (0%) 1
    Pneumonia streptococcal 1/2519 (0%) 1 0/2515 (0%) 0
    Pneumonia viral 1/2519 (0%) 1 1/2515 (0%) 1
    Postoperative wound infection 2/2519 (0.1%) 2 1/2515 (0%) 1
    Pseudomembranous colitis 0/2519 (0%) 0 2/2515 (0.1%) 2
    Psoas abscess 1/2519 (0%) 1 0/2515 (0%) 0
    Pulmonary sepsis 2/2519 (0.1%) 2 3/2515 (0.1%) 3
    Pyelonephritis 1/2519 (0%) 1 0/2515 (0%) 0
    Pyelonephritis acute 0/2519 (0%) 0 1/2515 (0%) 1
    Pyelonephritis chronic 0/2519 (0%) 0 1/2515 (0%) 1
    Renal abscess 1/2519 (0%) 1 0/2515 (0%) 0
    Respiratory tract infection 5/2519 (0.2%) 5 4/2515 (0.2%) 4
    Respiratory tract infection viral 0/2519 (0%) 0 1/2515 (0%) 1
    Salmonella bacteraemia 0/2519 (0%) 0 1/2515 (0%) 1
    Sepsis 16/2519 (0.6%) 16 25/2515 (1%) 25
    Septic shock 11/2519 (0.4%) 11 14/2515 (0.6%) 14
    Serratia bacteraemia 1/2519 (0%) 1 0/2515 (0%) 0
    Sinusitis 0/2519 (0%) 0 1/2515 (0%) 1
    Skin bacterial infection 1/2519 (0%) 1 0/2515 (0%) 0
    Skin infection 2/2519 (0.1%) 4 0/2515 (0%) 0
    Staphylococcal bacteraemia 2/2519 (0.1%) 2 2/2515 (0.1%) 2
    Staphylococcal infection 1/2519 (0%) 1 0/2515 (0%) 0
    Staphylococcal sepsis 1/2519 (0%) 1 0/2515 (0%) 0
    Staphylococcal skin infection 1/2519 (0%) 1 0/2515 (0%) 0
    Streptococcal bacteraemia 1/2519 (0%) 1 0/2515 (0%) 0
    Subcutaneous abscess 1/2519 (0%) 1 0/2515 (0%) 0
    Systemic candida 1/2519 (0%) 1 0/2515 (0%) 0
    Thrombophlebitis septic 1/2519 (0%) 1 0/2515 (0%) 0
    Tooth abscess 0/2519 (0%) 0 1/2515 (0%) 1
    Tracheobronchitis 2/2519 (0.1%) 2 0/2515 (0%) 0
    Tuberculous pleurisy 1/2519 (0%) 1 0/2515 (0%) 0
    Typhoid fever 0/2519 (0%) 0 1/2515 (0%) 1
    Upper respiratory tract infection 11/2519 (0.4%) 11 10/2515 (0.4%) 10
    Ureter abscess 1/2519 (0%) 1 0/2515 (0%) 0
    Urinary tract infection 20/2519 (0.8%) 23 16/2515 (0.6%) 18
    Urosepsis 7/2519 (0.3%) 8 0/2515 (0%) 0
    Vestibular neuronitis 1/2519 (0%) 1 2/2515 (0.1%) 2
    Viral diarrhoea 0/2519 (0%) 0 1/2515 (0%) 1
    Viral infection 2/2519 (0.1%) 2 0/2515 (0%) 0
    Viral upper respiratory tract infection 3/2519 (0.1%) 3 0/2515 (0%) 0
    West Nile viral infection 0/2519 (0%) 0 1/2515 (0%) 1
    Wound infection 0/2519 (0%) 0 4/2515 (0.2%) 4
    Wound sepsis 0/2519 (0%) 0 2/2515 (0.1%) 2
    Injury, poisoning and procedural complications
    Accidental overdose 1/2519 (0%) 1 0/2515 (0%) 0
    Acetabulum fracture 0/2519 (0%) 0 1/2515 (0%) 1
    Alcohol poisoning 1/2519 (0%) 1 0/2515 (0%) 0
    Ankle fracture 2/2519 (0.1%) 2 0/2515 (0%) 0
    Arterial bypass occlusion 0/2519 (0%) 0 1/2515 (0%) 1
    Arteriovenous fistula site complication 1/2519 (0%) 1 0/2515 (0%) 0
    Asbestosis 1/2519 (0%) 1 0/2515 (0%) 0
    Bone fissure 1/2519 (0%) 1 0/2515 (0%) 0
    Burns second degree 1/2519 (0%) 1 1/2515 (0%) 1
    Burns third degree 0/2519 (0%) 0 2/2515 (0.1%) 2
    Cardiac valve replacement complication 0/2519 (0%) 0 1/2515 (0%) 1
    Cervical vertebral fracture 1/2519 (0%) 1 0/2515 (0%) 0
    Chest injury 0/2519 (0%) 0 1/2515 (0%) 1
    Concussion 3/2519 (0.1%) 3 0/2515 (0%) 0
    Contusion 1/2519 (0%) 1 0/2515 (0%) 0
    Coronary vascular graft stenosis 0/2519 (0%) 0 1/2515 (0%) 1
    Costal cartilage fracture 0/2519 (0%) 0 1/2515 (0%) 1
    Craniocerebral injury 1/2519 (0%) 1 2/2515 (0.1%) 2
    Facial bones fracture 0/2519 (0%) 0 1/2515 (0%) 1
    Fall 6/2519 (0.2%) 6 5/2515 (0.2%) 5
    Femoral neck fracture 2/2519 (0.1%) 3 8/2515 (0.3%) 8
    Femur fracture 3/2519 (0.1%) 3 12/2515 (0.5%) 12
    Fibula fracture 1/2519 (0%) 1 1/2515 (0%) 1
    Foot fracture 2/2519 (0.1%) 2 1/2515 (0%) 1
    Head injury 4/2519 (0.2%) 4 1/2515 (0%) 1
    Heat illness 0/2519 (0%) 0 1/2515 (0%) 1
    Hip fracture 6/2519 (0.2%) 6 3/2515 (0.1%) 3
    Humerus fracture 0/2519 (0%) 0 3/2515 (0.1%) 3
    Incision site haemorrhage 1/2519 (0%) 1 0/2515 (0%) 0
    Limb crushing injury 0/2519 (0%) 0 1/2515 (0%) 1
    Limb injury 1/2519 (0%) 1 5/2515 (0.2%) 5
    Lower limb fracture 1/2519 (0%) 1 2/2515 (0.1%) 2
    Lumbar vertebral fracture 0/2519 (0%) 0 1/2515 (0%) 1
    Multiple injuries 0/2519 (0%) 0 2/2515 (0.1%) 2
    Overdose 1/2519 (0%) 1 2/2515 (0.1%) 2
    Patella fracture 1/2519 (0%) 1 0/2515 (0%) 0
    Pelvic fracture 0/2519 (0%) 0 1/2515 (0%) 1
    Penis injury 1/2519 (0%) 1 0/2515 (0%) 0
    Post procedural haematuria 0/2519 (0%) 0 1/2515 (0%) 1
    Post procedural haemorrhage 0/2519 (0%) 0 1/2515 (0%) 1
    Post procedural hypothyroidism 0/2519 (0%) 0 1/2515 (0%) 2
    Postoperative hypotension 0/2519 (0%) 0 1/2515 (0%) 1
    Pubis fracture 2/2519 (0.1%) 2 1/2515 (0%) 1
    Radius fracture 1/2519 (0%) 1 0/2515 (0%) 0
    Rib fracture 1/2519 (0%) 1 1/2515 (0%) 1
    Road traffic accident 1/2519 (0%) 1 0/2515 (0%) 0
    Sedation complication 1/2519 (0%) 1 0/2515 (0%) 0
    Seroma 1/2519 (0%) 1 0/2515 (0%) 0
    Skin laceration 3/2519 (0.1%) 3 0/2515 (0%) 0
    Snake bite 0/2519 (0%) 0 1/2515 (0%) 1
    Spinal compression fracture 1/2519 (0%) 1 1/2515 (0%) 1
    Spinal fracture 0/2519 (0%) 0 2/2515 (0.1%) 2
    Subdural haematoma 6/2519 (0.2%) 6 1/2515 (0%) 1
    Subdural haemorrhage 0/2519 (0%) 0 1/2515 (0%) 1
    Suture related complication 1/2519 (0%) 1 0/2515 (0%) 0
    Tendon rupture 1/2519 (0%) 1 0/2515 (0%) 0
    Thermal burn 0/2519 (0%) 0 1/2515 (0%) 1
    Thoracic vertebral fracture 0/2519 (0%) 0 1/2515 (0%) 1
    Tibia fracture 1/2519 (0%) 1 2/2515 (0.1%) 2
    Toxicity to various agents 1/2519 (0%) 1 6/2515 (0.2%) 6
    Traumatic fracture 1/2519 (0%) 1 0/2515 (0%) 0
    Traumatic liver injury 0/2519 (0%) 0 1/2515 (0%) 1
    Traumatic ulcer 0/2519 (0%) 0 1/2515 (0%) 1
    Upper limb fracture 1/2519 (0%) 1 0/2515 (0%) 0
    Urinary retention postoperative 0/2519 (0%) 0 1/2515 (0%) 1
    Vascular graft occlusion 0/2519 (0%) 0 1/2515 (0%) 1
    Vascular pseudoaneurysm 1/2519 (0%) 1 3/2515 (0.1%) 3
    Vasoplegia syndrome 1/2519 (0%) 1 0/2515 (0%) 0
    Wrist fracture 1/2519 (0%) 1 0/2515 (0%) 0
    Investigations
    Alanine aminotransferase increased 0/2519 (0%) 0 1/2515 (0%) 1
    Angiocardiogram 1/2519 (0%) 1 1/2515 (0%) 1
    Anticoagulation drug level above therapeutic 2/2519 (0.1%) 2 1/2515 (0%) 1
    Aspartate aminotransferase increased 0/2519 (0%) 0 1/2515 (0%) 1
    Blood bilirubin increased 0/2519 (0%) 0 2/2515 (0.1%) 2
    Blood creatinine increased 1/2519 (0%) 1 1/2515 (0%) 1
    Blood potassium increased 1/2519 (0%) 1 0/2515 (0%) 0
    Blood sodium decreased 1/2519 (0%) 1 0/2515 (0%) 0
    Blood urea increased 0/2519 (0%) 0 1/2515 (0%) 1
    Bone density abnormal 1/2519 (0%) 1 0/2515 (0%) 0
    Cardiac index abnormal 1/2519 (0%) 1 0/2515 (0%) 0
    Cardiac stress test abnormal 0/2519 (0%) 0 1/2515 (0%) 1
    Catheterisation cardiac 1/2519 (0%) 1 1/2515 (0%) 1
    Cortisol decreased 0/2519 (0%) 0 1/2515 (0%) 1
    Ejection fraction decreased 0/2519 (0%) 0 3/2515 (0.1%) 3
    Gamma-glutamyltransferase increased 0/2519 (0%) 0 1/2515 (0%) 1
    Haemoglobin decreased 1/2519 (0%) 1 1/2515 (0%) 1
    Heart rate irregular 0/2519 (0%) 0 1/2515 (0%) 1
    Hepatic enzyme abnormal 1/2519 (0%) 1 0/2515 (0%) 0
    Hepatic enzyme increased 2/2519 (0.1%) 2 2/2515 (0.1%) 2
    Influenza A virus test positive 0/2519 (0%) 0 1/2515 (0%) 1
    International normalised ratio increased 1/2519 (0%) 1 2/2515 (0.1%) 2
    Liver function test abnormal 1/2519 (0%) 1 0/2515 (0%) 0
    Liver function test increased 1/2519 (0%) 1 1/2515 (0%) 1
    Occult blood positive 1/2519 (0%) 1 0/2515 (0%) 0
    Transaminases increased 0/2519 (0%) 0 1/2515 (0%) 1
    Troponin increased 1/2519 (0%) 1 0/2515 (0%) 0
    Weight decreased 1/2519 (0%) 1 1/2515 (0%) 1
    Weight increased 0/2519 (0%) 0 1/2515 (0%) 1
    Metabolism and nutrition disorders
    Cachexia 1/2519 (0%) 1 0/2515 (0%) 0
    Dehydration 7/2519 (0.3%) 7 12/2515 (0.5%) 13
    Diabetes mellitus 5/2519 (0.2%) 6 10/2515 (0.4%) 11
    Diabetes mellitus inadequate control 0/2519 (0%) 0 2/2515 (0.1%) 2
    Diabetes with hyperosmolarity 0/2519 (0%) 0 1/2515 (0%) 1
    Diabetic ketoacidosis 4/2519 (0.2%) 4 2/2515 (0.1%) 2
    Diabetic metabolic decompensation 0/2519 (0%) 0 1/2515 (0%) 1
    Fluid overload 2/2519 (0.1%) 2 1/2515 (0%) 1
    Gout 10/2519 (0.4%) 12 12/2515 (0.5%) 14
    Hyperammonaemia 1/2519 (0%) 1 0/2515 (0%) 0
    Hypercalcaemia 1/2519 (0%) 1 1/2515 (0%) 1
    Hyperglycaemia 6/2519 (0.2%) 6 4/2515 (0.2%) 4
    Hyperglycaemic hyperosmolar nonketotic syndrome 3/2519 (0.1%) 3 2/2515 (0.1%) 2
    Hyperkalaemia 13/2519 (0.5%) 13 14/2515 (0.6%) 14
    Hypernatraemia 1/2519 (0%) 1 0/2515 (0%) 0
    Hyperosmolar state 1/2519 (0%) 1 0/2515 (0%) 0
    Hypoalbuminaemia 0/2519 (0%) 0 2/2515 (0.1%) 2
    Hypocalcaemia 2/2519 (0.1%) 2 0/2515 (0%) 0
    Hypochloraemia 1/2519 (0%) 1 0/2515 (0%) 0
    Hypoglycaemia 12/2519 (0.5%) 13 9/2515 (0.4%) 9
    Hypokalaemia 7/2519 (0.3%) 8 7/2515 (0.3%) 7
    Hypomagnesaemia 1/2519 (0%) 1 0/2515 (0%) 0
    Hyponatraemia 5/2519 (0.2%) 5 5/2515 (0.2%) 5
    Hypophosphataemia 1/2519 (0%) 1 0/2515 (0%) 0
    Hypovolaemia 0/2519 (0%) 0 1/2515 (0%) 1
    Ketoacidosis 0/2519 (0%) 0 1/2515 (0%) 1
    Marasmus 1/2519 (0%) 1 0/2515 (0%) 0
    Metabolic acidosis 2/2519 (0.1%) 2 4/2515 (0.2%) 4
    Metabolic alkalosis 0/2519 (0%) 0 1/2515 (0%) 1
    Mineral metabolism disorder 1/2519 (0%) 1 0/2515 (0%) 0
    Type 2 diabetes mellitus 5/2519 (0.2%) 5 8/2515 (0.3%) 8
    Musculoskeletal and connective tissue disorders
    Arthralgia 4/2519 (0.2%) 4 1/2515 (0%) 1
    Arthritis 0/2519 (0%) 0 2/2515 (0.1%) 2
    Back pain 6/2519 (0.2%) 6 3/2515 (0.1%) 3
    Cervical spinal stenosis 1/2519 (0%) 1 0/2515 (0%) 0
    Chondritis 1/2519 (0%) 1 0/2515 (0%) 0
    Enthesopathy 1/2519 (0%) 1 0/2515 (0%) 0
    Gouty arthritis 7/2519 (0.3%) 9 6/2515 (0.2%) 7
    Gouty tophus 0/2519 (0%) 0 2/2515 (0.1%) 2
    Haematoma muscle 0/2519 (0%) 0 1/2515 (0%) 1
    Intervertebral disc disorder 0/2519 (0%) 0 1/2515 (0%) 1
    Intervertebral disc protrusion 0/2519 (0%) 0 1/2515 (0%) 1
    Lumbar spinal stenosis 1/2519 (0%) 2 5/2515 (0.2%) 5
    Muscular weakness 1/2519 (0%) 1 1/2515 (0%) 1
    Musculoskeletal chest pain 1/2519 (0%) 1 4/2515 (0.2%) 4
    Musculoskeletal pain 4/2519 (0.2%) 4 0/2515 (0%) 0
    Osteoarthritis 3/2519 (0.1%) 3 2/2515 (0.1%) 2
    Osteonecrosis 0/2519 (0%) 0 1/2515 (0%) 1
    Pain in extremity 1/2519 (0%) 1 3/2515 (0.1%) 4
    Pathological fracture 0/2519 (0%) 0 1/2515 (0%) 1
    Polyarthritis 1/2519 (0%) 1 1/2515 (0%) 1
    Rhabdomyolysis 0/2519 (0%) 0 1/2515 (0%) 1
    Rheumatoid arthritis 0/2519 (0%) 0 1/2515 (0%) 1
    Sjogren's syndrome 1/2519 (0%) 1 1/2515 (0%) 1
    Spinal pain 1/2519 (0%) 1 3/2515 (0.1%) 3
    Spinal stenosis 0/2519 (0%) 0 1/2515 (0%) 1
    Spondylitis 1/2519 (0%) 1 0/2515 (0%) 0
    Tendonitis 1/2519 (0%) 1 0/2515 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma gastric 3/2519 (0.1%) 3 1/2515 (0%) 1
    Adenocarcinoma of colon 2/2519 (0.1%) 2 1/2515 (0%) 1
    Adenocarcinoma pancreas 0/2519 (0%) 0 1/2515 (0%) 1
    Adrenal gland cancer metastatic 0/2519 (0%) 0 1/2515 (0%) 1
    Angiocentric lymphoma 1/2519 (0%) 1 0/2515 (0%) 0
    Basal cell carcinoma 1/2519 (0%) 1 2/2515 (0.1%) 2
    Benign gastric neoplasm 1/2519 (0%) 1 1/2515 (0%) 1
    Benign neoplasm of bladder 1/2519 (0%) 1 0/2515 (0%) 0
    Bladder cancer 2/2519 (0.1%) 2 0/2515 (0%) 0
    Bladder cancer recurrent 1/2519 (0%) 1 0/2515 (0%) 0
    Bladder neoplasm 1/2519 (0%) 1 1/2515 (0%) 1
    Bladder transitional cell carcinoma 0/2519 (0%) 0 2/2515 (0.1%) 2
    Bowen's disease 0/2519 (0%) 0 1/2515 (0%) 2
    Breast cancer 0/2519 (0%) 0 4/2515 (0.2%) 4
    Bronchial carcinoma 1/2519 (0%) 1 0/2515 (0%) 0
    Chronic lymphocytic leukaemia 0/2519 (0%) 0 1/2515 (0%) 1
    Colon adenoma 0/2519 (0%) 0 1/2515 (0%) 1
    Colon cancer 1/2519 (0%) 1 1/2515 (0%) 1
    Colon neoplasm 0/2519 (0%) 0 1/2515 (0%) 1
    Cutaneous T-cell lymphoma 1/2519 (0%) 2 0/2515 (0%) 0
    Diffuse large B-cell lymphoma 0/2519 (0%) 0 1/2515 (0%) 1
    Gastric cancer 3/2519 (0.1%) 3 1/2515 (0%) 1
    Glioblastoma multiforme 1/2519 (0%) 1 0/2515 (0%) 0
    Hepatic cancer 1/2519 (0%) 1 0/2515 (0%) 0
    Hepatic cancer metastatic 0/2519 (0%) 0 1/2515 (0%) 1
    Hepatic neoplasm 0/2519 (0%) 0 1/2515 (0%) 1
    Hepatobiliary cancer 1/2519 (0%) 1 0/2515 (0%) 0
    Hepatocellular carcinoma 0/2519 (0%) 0 2/2515 (0.1%) 2
    Inflammatory pseudotumour 0/2519 (0%) 0 1/2515 (0%) 1
    Lung adenocarcinoma 1/2519 (0%) 1 1/2515 (0%) 1
    Lung cancer metastatic 1/2519 (0%) 1 0/2515 (0%) 0
    Lung neoplasm malignant 0/2519 (0%) 0 4/2515 (0.2%) 4
    Lymphoma 1/2519 (0%) 1 0/2515 (0%) 0
    Lymphoproliferative disorder 0/2519 (0%) 0 1/2515 (0%) 1
    Malignant melanoma 1/2519 (0%) 1 1/2515 (0%) 1
    Meningioma 0/2519 (0%) 0 1/2515 (0%) 1
    Metastases to abdominal cavity 1/2519 (0%) 1 0/2515 (0%) 0
    Metastases to bone 1/2519 (0%) 1 0/2515 (0%) 0
    Metastases to central nervous system 1/2519 (0%) 1 1/2515 (0%) 1
    Metastases to lung 1/2519 (0%) 1 0/2515 (0%) 0
    Metastases to lymph nodes 0/2519 (0%) 0 1/2515 (0%) 1
    Metastatic neoplasm 0/2519 (0%) 0 1/2515 (0%) 1
    Myelodysplastic syndrome 1/2519 (0%) 1 0/2515 (0%) 0
    Oesophageal carcinoma 1/2519 (0%) 1 0/2515 (0%) 0
    Oropharyngeal cancer 1/2519 (0%) 1 0/2515 (0%) 0
    Oropharyngeal squamous cell carcinoma 1/2519 (0%) 1 0/2515 (0%) 0
    Ovarian cancer 0/2519 (0%) 0 1/2515 (0%) 1
    Pancreatic carcinoma 1/2519 (0%) 1 1/2515 (0%) 1
    Pancreatic carcinoma metastatic 1/2519 (0%) 1 0/2515 (0%) 0
    Plasma cell myeloma 1/2519 (0%) 1 2/2515 (0.1%) 2
    Plasmacytoma 0/2519 (0%) 0 1/2515 (0%) 1
    Polycythaemia vera 0/2519 (0%) 0 1/2515 (0%) 1
    Prostate cancer 2/2519 (0.1%) 2 5/2515 (0.2%) 5
    Prostate cancer metastatic 1/2519 (0%) 1 0/2515 (0%) 0
    Rectal cancer 0/2519 (0%) 0 2/2515 (0.1%) 2
    Rectosigmoid cancer 1/2519 (0%) 1 0/2515 (0%) 0
    Renal cancer 1/2519 (0%) 1 1/2515 (0%) 1
    Renal neoplasm 3/2519 (0.1%) 3 0/2515 (0%) 0
    Retroperitoneal cancer 1/2519 (0%) 1 0/2515 (0%) 0
    Skin cancer 1/2519 (0%) 1 0/2515 (0%) 0
    Squamous cell carcinoma 1/2519 (0%) 1 0/2515 (0%) 0
    Squamous cell carcinoma of head and neck 2/2519 (0.1%) 2 0/2515 (0%) 0
    Squamous cell carcinoma of lung 1/2519 (0%) 1 0/2515 (0%) 0
    Squamous cell carcinoma of the oral cavity 0/2519 (0%) 0 1/2515 (0%) 1
    Sweat gland tumour 1/2519 (0%) 1 0/2515 (0%) 0
    T-cell lymphoma 1/2519 (0%) 1 0/2515 (0%) 0
    Tongue neoplasm malignant stage unspecified 1/2519 (0%) 1 0/2515 (0%) 0
    Tumour ulceration 0/2519 (0%) 0 1/2515 (0%) 1
    Uterine cancer 0/2519 (0%) 0 1/2515 (0%) 1
    Uterine leiomyoma 1/2519 (0%) 1 0/2515 (0%) 0
    Waldenstrom's macroglobulinaemia 1/2519 (0%) 1 0/2515 (0%) 0
    Nervous system disorders
    Altered state of consciousness 1/2519 (0%) 1 0/2515 (0%) 0
    Autonomic neuropathy 1/2519 (0%) 1 0/2515 (0%) 0
    Axonal neuropathy 1/2519 (0%) 1 0/2515 (0%) 0
    Brain hypoxia 1/2519 (0%) 1 0/2515 (0%) 0
    Brain injury 2/2519 (0.1%) 2 1/2515 (0%) 1
    Brain oedema 0/2519 (0%) 0 1/2515 (0%) 1
    Carotid artery stenosis 0/2519 (0%) 0 3/2515 (0.1%) 3
    Cauda equina syndrome 1/2519 (0%) 1 0/2515 (0%) 0
    Cerebral artery embolism 0/2519 (0%) 0 1/2515 (0%) 1
    Cerebral artery stenosis 0/2519 (0%) 0 1/2515 (0%) 1
    Cerebral haemorrhage 1/2519 (0%) 1 1/2515 (0%) 1
    Cerebral infarction 1/2519 (0%) 1 2/2515 (0.1%) 2
    Cerebral ischaemia 1/2519 (0%) 1 1/2515 (0%) 1
    Cerebrovascular accident 3/2519 (0.1%) 3 6/2515 (0.2%) 6
    Cerebrovascular disorder 1/2519 (0%) 1 0/2515 (0%) 0
    Cognitive disorder 0/2519 (0%) 0 1/2515 (0%) 1
    Coma 1/2519 (0%) 1 0/2515 (0%) 0
    Dementia 2/2519 (0.1%) 2 0/2515 (0%) 0
    Dementia Alzheimer's type 0/2519 (0%) 0 2/2515 (0.1%) 2
    Diabetic neuropathy 0/2519 (0%) 0 2/2515 (0.1%) 2
    Dizziness 6/2519 (0.2%) 6 2/2515 (0.1%) 2
    Dizziness postural 0/2519 (0%) 0 1/2515 (0%) 1
    Dysarthria 0/2519 (0%) 0 2/2515 (0.1%) 2
    Encephalopathy 0/2519 (0%) 0 2/2515 (0.1%) 2
    Facial paralysis 0/2519 (0%) 0 1/2515 (0%) 1
    Generalised tonic-clonic seizure 0/2519 (0%) 0 1/2515 (0%) 1
    Headache 1/2519 (0%) 1 1/2515 (0%) 1
    Hemiparesis 1/2519 (0%) 1 0/2515 (0%) 0
    Hepatic encephalopathy 0/2519 (0%) 0 1/2515 (0%) 1
    Hydrocephalus 0/2519 (0%) 0 1/2515 (0%) 1
    Hypoxic-ischaemic encephalopathy 0/2519 (0%) 0 1/2515 (0%) 1
    Ischaemic stroke 2/2519 (0.1%) 2 2/2515 (0.1%) 2
    Lethargy 0/2519 (0%) 0 1/2515 (0%) 1
    Loss of consciousness 0/2519 (0%) 0 1/2515 (0%) 1
    Lumbar radiculopathy 2/2519 (0.1%) 2 0/2515 (0%) 0
    Metabolic encephalopathy 1/2519 (0%) 1 2/2515 (0.1%) 2
    Myelopathy 1/2519 (0%) 1 0/2515 (0%) 0
    Myoclonus 0/2519 (0%) 0 2/2515 (0.1%) 2
    Neuropathy peripheral 2/2519 (0.1%) 2 0/2515 (0%) 0
    Paraesthesia 0/2519 (0%) 0 1/2515 (0%) 1
    Post stroke epilepsy 1/2519 (0%) 1 0/2515 (0%) 0
    Presyncope 4/2519 (0.2%) 4 0/2515 (0%) 0
    Sciatica 0/2519 (0%) 0 1/2515 (0%) 1
    Seizure 2/2519 (0.1%) 2 2/2515 (0.1%) 2
    Spinal cord compression 0/2519 (0%) 0 1/2515 (0%) 1
    Status epilepticus 1/2519 (0%) 1 0/2515 (0%) 0
    Subarachnoid haemorrhage 1/2519 (0%) 1 1/2515 (0%) 1
    Syncope 43/2519 (1.7%) 45 33/2515 (1.3%) 35
    Tension headache 1/2519 (0%) 1 0/2515 (0%) 0
    Toxic encephalopathy 0/2519 (0%) 0 1/2515 (0%) 1
    Transient ischaemic attack 2/2519 (0.1%) 2 2/2515 (0.1%) 2
    Vascular dementia 0/2519 (0%) 0 1/2515 (0%) 1
    Vertebrobasilar insufficiency 1/2519 (0%) 1 0/2515 (0%) 0
    Product Issues
    Device battery issue 1/2519 (0%) 1 4/2515 (0.2%) 4
    Device dislocation 0/2519 (0%) 0 2/2515 (0.1%) 3
    Device failure 0/2519 (0%) 0 1/2515 (0%) 1
    Device ineffective 0/2519 (0%) 0 1/2515 (0%) 1
    Device malfunction 1/2519 (0%) 1 4/2515 (0.2%) 4
    Lead dislodgement 1/2519 (0%) 2 0/2515 (0%) 0
    Psychiatric disorders
    Alcohol abuse 0/2519 (0%) 0 1/2515 (0%) 1
    Anxiety 1/2519 (0%) 1 0/2515 (0%) 0
    Anxiety disorder 0/2519 (0%) 0 1/2515 (0%) 1
    Confusional state 1/2519 (0%) 1 2/2515 (0.1%) 2
    Delirium 0/2519 (0%) 0 3/2515 (0.1%) 4
    Depression 1/2519 (0%) 1 0/2515 (0%) 0
    Drug use disorder 1/2519 (0%) 1 0/2515 (0%) 0
    Mental status changes 0/2519 (0%) 0 2/2515 (0.1%) 2
    Panic attack 1/2519 (0%) 1 0/2515 (0%) 0
    Suicide attempt 1/2519 (0%) 1 0/2515 (0%) 0
    Renal and urinary disorders
    Acute kidney injury 66/2519 (2.6%) 69 51/2515 (2%) 53
    Azotaemia 0/2519 (0%) 0 1/2515 (0%) 1
    Bladder cyst 1/2519 (0%) 1 0/2515 (0%) 0
    Bladder mass 0/2519 (0%) 0 1/2515 (0%) 1
    Calculus bladder 2/2519 (0.1%) 2 0/2515 (0%) 0
    Chronic kidney disease 40/2519 (1.6%) 42 31/2515 (1.2%) 31
    Costovertebral angle tenderness 0/2519 (0%) 0 1/2515 (0%) 1
    End stage renal disease 2/2519 (0.1%) 2 1/2515 (0%) 1
    Haematuria 3/2519 (0.1%) 3 7/2515 (0.3%) 7
    Nephritis 0/2519 (0%) 0 1/2515 (0%) 1
    Nephrolithiasis 1/2519 (0%) 1 0/2515 (0%) 0
    Nephropathy 3/2519 (0.1%) 3 1/2515 (0%) 1
    Nephrotic syndrome 0/2519 (0%) 0 1/2515 (0%) 1
    Renal artery stenosis 1/2519 (0%) 1 1/2515 (0%) 1
    Renal colic 1/2519 (0%) 1 0/2515 (0%) 0
    Renal cyst 1/2519 (0%) 1 0/2515 (0%) 0
    Renal failure 24/2519 (1%) 25 30/2515 (1.2%) 31
    Renal impairment 6/2519 (0.2%) 6 7/2515 (0.3%) 7
    Renal infarct 0/2519 (0%) 0 1/2515 (0%) 1
    Renal mass 1/2519 (0%) 1 0/2515 (0%) 0
    Urate nephropathy 1/2519 (0%) 1 0/2515 (0%) 0
    Ureterolithiasis 2/2519 (0.1%) 2 0/2515 (0%) 0
    Urethral stenosis 0/2519 (0%) 0 1/2515 (0%) 1
    Urinary retention 2/2519 (0.1%) 2 2/2515 (0.1%) 2
    Reproductive system and breast disorders
    Benign prostatic hyperplasia 1/2519 (0%) 1 8/2515 (0.3%) 8
    Endometrial hyperplasia 1/2519 (0%) 1 0/2515 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema 4/2519 (0.2%) 5 1/2515 (0%) 1
    Acute respiratory failure 9/2519 (0.4%) 9 7/2515 (0.3%) 7
    Asthma 6/2519 (0.2%) 6 4/2515 (0.2%) 6
    Atelectasis 1/2519 (0%) 1 0/2515 (0%) 0
    Bronchial haemorrhage 0/2519 (0%) 0 1/2515 (0%) 1
    Bronchitis chronic 2/2519 (0.1%) 2 0/2515 (0%) 0
    Bronchospasm 0/2519 (0%) 0 1/2515 (0%) 1
    Chronic obstructive pulmonary disease 38/2519 (1.5%) 51 30/2515 (1.2%) 50
    Chylothorax 1/2519 (0%) 1 0/2515 (0%) 0
    Cough 0/2519 (0%) 0 2/2515 (0.1%) 2
    Dyspnoea 11/2519 (0.4%) 11 7/2515 (0.3%) 7
    Dyspnoea exertional 0/2519 (0%) 0 3/2515 (0.1%) 3
    Epistaxis 1/2519 (0%) 1 2/2515 (0.1%) 2
    Haemoptysis 0/2519 (0%) 0 2/2515 (0.1%) 3
    Haemothorax 0/2519 (0%) 0 2/2515 (0.1%) 2
    Hyperventilation 1/2519 (0%) 1 0/2515 (0%) 0
    Hypoxia 0/2519 (0%) 0 1/2515 (0%) 1
    Interstitial lung disease 0/2519 (0%) 0 1/2515 (0%) 1
    Obstructive airways disorder 0/2519 (0%) 0 1/2515 (0%) 1
    Pleural effusion 6/2519 (0.2%) 8 13/2515 (0.5%) 15
    Pleurisy 0/2519 (0%) 0 1/2515 (0%) 1
    Pleuritic pain 0/2519 (0%) 0 1/2515 (0%) 1
    Pneumonia aspiration 6/2519 (0.2%) 7 2/2515 (0.1%) 2
    Pneumothorax 2/2519 (0.1%) 2 4/2515 (0.2%) 4
    Pulmonary congestion 1/2519 (0%) 1 0/2515 (0%) 0
    Pulmonary embolism 4/2519 (0.2%) 4 6/2515 (0.2%) 6
    Pulmonary haematoma 0/2519 (0%) 0 1/2515 (0%) 1
    Pulmonary hypertension 1/2519 (0%) 1 0/2515 (0%) 0
    Pulmonary infarction 0/2519 (0%) 0 1/2515 (0%) 1
    Pulmonary mass 0/2519 (0%) 0 1/2515 (0%) 1
    Pulmonary oedema 4/2519 (0.2%) 4 3/2515 (0.1%) 4
    Respiratory disorder 1/2519 (0%) 1 0/2515 (0%) 0
    Respiratory failure 3/2519 (0.1%) 3 5/2515 (0.2%) 5
    Rhinitis hypertrophic 1/2519 (0%) 1 0/2515 (0%) 0
    Sleep apnoea syndrome 1/2519 (0%) 1 1/2515 (0%) 1
    Tonsillar haemorrhage 1/2519 (0%) 2 0/2515 (0%) 0
    Skin and subcutaneous tissue disorders
    Angioedema 1/2519 (0%) 1 1/2515 (0%) 1
    Dermatitis bullous 0/2519 (0%) 0 1/2515 (0%) 1
    Diabetic foot 1/2519 (0%) 1 4/2515 (0.2%) 4
    Drug eruption 1/2519 (0%) 1 0/2515 (0%) 0
    Ecchymosis 0/2519 (0%) 0 1/2515 (0%) 1
    Haemorrhage subcutaneous 1/2519 (0%) 1 0/2515 (0%) 0
    Henoch-Schonlein purpura 0/2519 (0%) 0 1/2515 (0%) 1
    Neurodermatitis 0/2519 (0%) 0 1/2515 (0%) 1
    Psoriasis 1/2519 (0%) 1 0/2515 (0%) 0
    Skin necrosis 1/2519 (0%) 1 1/2515 (0%) 1
    Skin ulcer 5/2519 (0.2%) 5 9/2515 (0.4%) 14
    Stasis dermatitis 0/2519 (0%) 0 1/2515 (0%) 1
    Stevens-Johnson syndrome 0/2519 (0%) 0 1/2515 (0%) 1
    Urticaria 1/2519 (0%) 1 0/2515 (0%) 0
    Surgical and medical procedures
    Aortic aneurysm repair 0/2519 (0%) 0 1/2515 (0%) 1
    Arrhythmia prophylaxis 0/2519 (0%) 0 1/2515 (0%) 1
    Cardiac pacemaker replacement 0/2519 (0%) 0 1/2515 (0%) 1
    Cardiac rehabilitation therapy 1/2519 (0%) 1 0/2515 (0%) 0
    Cardiac resynchronisation therapy 2/2519 (0.1%) 2 7/2515 (0.3%) 7
    Cardiovascular event prophylaxis 1/2519 (0%) 1 4/2515 (0.2%) 4
    Cardioversion 1/2519 (0%) 3 0/2515 (0%) 0
    Central venous catheter removal 0/2519 (0%) 0 1/2515 (0%) 1
    Gastrectomy 0/2519 (0%) 0 1/2515 (0%) 1
    Implantable defibrillator insertion 5/2519 (0.2%) 5 2/2515 (0.1%) 2
    Implantable defibrillator removal 1/2519 (0%) 1 0/2515 (0%) 0
    Implantable defibrillator replacement 1/2519 (0%) 1 0/2515 (0%) 0
    Inguinal hernia repair 1/2519 (0%) 1 0/2515 (0%) 0
    Intraocular lens implant 0/2519 (0%) 0 1/2515 (0%) 1
    Leg amputation 1/2519 (0%) 1 0/2515 (0%) 0
    Nephroprotective therapy 0/2519 (0%) 0 1/2515 (0%) 1
    Therapeutic procedure 1/2519 (0%) 1 0/2515 (0%) 0
    Toe operation 1/2519 (0%) 1 0/2515 (0%) 0
    Vascular disorders
    Aortic aneurysm 1/2519 (0%) 1 2/2515 (0.1%) 2
    Aortic dissection 1/2519 (0%) 1 0/2515 (0%) 0
    Aortic stenosis 1/2519 (0%) 1 1/2515 (0%) 1
    Arterial occlusive disease 0/2519 (0%) 0 1/2515 (0%) 1
    Bleeding varicose vein 1/2519 (0%) 1 2/2515 (0.1%) 2
    Circulatory collapse 0/2519 (0%) 0 1/2515 (0%) 1
    Deep vein thrombosis 1/2519 (0%) 1 1/2515 (0%) 1
    Diabetic vascular disorder 1/2519 (0%) 1 0/2515 (0%) 0
    Dry gangrene 0/2519 (0%) 0 1/2515 (0%) 1
    Extremity necrosis 1/2519 (0%) 1 0/2515 (0%) 0
    Haematoma 4/2519 (0.2%) 4 2/2515 (0.1%) 3
    Haemorrhagic vasculitis 0/2519 (0%) 0 1/2515 (0%) 1
    Hypertension 5/2519 (0.2%) 5 4/2515 (0.2%) 4
    Hypertensive crisis 1/2519 (0%) 1 5/2515 (0.2%) 5
    Hypotension 33/2519 (1.3%) 34 44/2515 (1.7%) 45
    Hypovolaemic shock 2/2519 (0.1%) 2 0/2515 (0%) 0
    Iliac artery occlusion 1/2519 (0%) 1 0/2515 (0%) 0
    Intermittent claudication 2/2519 (0.1%) 2 1/2515 (0%) 1
    Ischaemia 1/2519 (0%) 1 0/2515 (0%) 0
    Lymphorrhoea 1/2519 (0%) 1 0/2515 (0%) 0
    Orthostatic hypotension 6/2519 (0.2%) 6 1/2515 (0%) 1
    Peripheral arterial occlusive disease 6/2519 (0.2%) 6 11/2515 (0.4%) 12
    Peripheral artery occlusion 1/2519 (0%) 1 0/2515 (0%) 0
    Peripheral artery stenosis 1/2519 (0%) 1 0/2515 (0%) 0
    Peripheral artery thrombosis 0/2519 (0%) 0 1/2515 (0%) 1
    Peripheral embolism 1/2519 (0%) 1 2/2515 (0.1%) 2
    Peripheral ischaemia 2/2519 (0.1%) 2 3/2515 (0.1%) 3
    Peripheral vascular disorder 4/2519 (0.2%) 6 3/2515 (0.1%) 3
    Peripheral venous disease 1/2519 (0%) 1 0/2515 (0%) 0
    Shock 1/2519 (0%) 1 1/2515 (0%) 1
    Shock haemorrhagic 0/2519 (0%) 0 2/2515 (0.1%) 2
    Thrombophlebitis 1/2519 (0%) 1 2/2515 (0.1%) 2
    Varicose vein 1/2519 (0%) 1 0/2515 (0%) 0
    Varicose vein ruptured 1/2519 (0%) 1 0/2515 (0%) 0
    Vascular occlusion 1/2519 (0%) 1 0/2515 (0%) 0
    Other (Not Including Serious) Adverse Events
    Vericiguat Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 958/2519 (38%) 925/2515 (36.8%)
    Blood and lymphatic system disorders
    Anaemia 165/2519 (6.6%) 181 134/2515 (5.3%) 139
    Cardiac disorders
    Cardiac failure 160/2519 (6.4%) 219 157/2515 (6.2%) 221
    Gastrointestinal disorders
    Diarrhoea 127/2519 (5%) 141 120/2515 (4.8%) 136
    Infections and infestations
    Nasopharyngitis 126/2519 (5%) 153 131/2515 (5.2%) 163
    Metabolism and nutrition disorders
    Hyperkalaemia 112/2519 (4.4%) 124 138/2515 (5.5%) 167
    Nervous system disorders
    Dizziness 169/2519 (6.7%) 195 152/2515 (6%) 169
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea 127/2519 (5%) 161 132/2515 (5.2%) 158
    Vascular disorders
    Hypotension 369/2519 (14.6%) 487 331/2515 (13.2%) 437

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or presentations regarding this trial 45 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission; this confidentiality does not include efficacy and safety results. Sponsor review can be expedited to meet publication timelines.

    Results Point of Contact

    Name/Title Senior Vice President, Global Clinical Development
    Organization Merck Sharp & Dohme Corp.
    Phone 1-800-672-6372
    Email ClinicalTrialsDisclosure@merck.com
    Responsible Party:
    Merck Sharp & Dohme LLC
    ClinicalTrials.gov Identifier:
    NCT02861534
    Other Study ID Numbers:
    • 1242-001
    • 2016-000671-25
    • MK-1242-001
    First Posted:
    Aug 10, 2016
    Last Update Posted:
    Nov 15, 2021
    Last Verified:
    Nov 1, 2021