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    Clinical Trial Results:
    STRONG-HF: Safety, Tolerability and Efficacy of Rapid Optimization, Helped by NT-proBNP TestinG, of Heart Failure Therapies

    Summary
    EudraCT number
    		 2018-000486-37
    Trial protocol
    		 AT   HR  
    Global end of trial date
    13 Oct 2022

    Results information
    Results version number
    		 v2(current)
    This version publication date
    29 Dec 2022
    First version publication date
    28 Jul 2022
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    This trial has been completed. Results need to be entered.
    Summary report(s)
    		 Results unavailable

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CHF201701
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03412201
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Heart Initiative
    Sponsor organisation address
    1426 NC Highway 54 Suite B, Durham, United States, 27713
    Public contact
    Beth Davison, Heart Initiative, +1 919-699-0888, bdavisonheartinitiative@gmail.org
    Scientific contact
    Beth Davison, Heart Initiative, +1 919-699-0888, bdavisonheartinitiative@gmail.org
    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
    13 Oct 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Oct 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Oct 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess the effects of optimization of medical therapy with beta-blocker; ACEi, ARB or ARNi; and MRAs on 180-day all-cause mortality or heart failure readmission in patients admitted with acute heart failure and clinical and biological signs of congestion.
    Protection of trial subjects
    The study was in compliance with the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. Before enrolment, the study was approved by appropriate competent authorities and all sites obtained approval from the ethics committees. All patients provided written informed consent. A Data and Safety Monitoring Board assessed safety on an ongoing basis during the trial. All the local regulatory requirements pertinent to the safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 May 2018
    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
    Austria: 10
    Country: Number of subjects enrolled
    Mozambique: 59
    Country: Number of subjects enrolled
    Nigeria: 165
    Country: Number of subjects enrolled
    South Africa: 4
    Country: Number of subjects enrolled
    Tunisia: 12
    Country: Number of subjects enrolled
    Hungary: 6
    Country: Number of subjects enrolled
    Bulgaria: 43
    Country: Number of subjects enrolled
    Slovakia: 33
    Country: Number of subjects enrolled
    Serbia: 2
    Country: Number of subjects enrolled
    Russian Federation: 703
    Country: Number of subjects enrolled
    Argentina: 40
    Country: Number of subjects enrolled
    Colombia: 1
    Worldwide total number of subjects
    1078
    EEA total number of subjects
    92
    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)
    547
    From 65 to 84 years
    521
    85 years and over
    10

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited between May 10, 2018 and Sept 23, 2022 from 87 hospitals in 14 countries.

    Pre-assignment
    Screening details
    		 A total of 1641 patients were screened, of whom 556 did not pass screening (533 did not meet eligibility criteria, 7 decided not to participate, and 16 did not provide a reason). 1085 patients were randomly assigned to treatment, 7 of whom were randomly assigned in error, such that 1078 patients were validly assigned to either high intensity care o

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 High Intensity Care
    Arm description
    		 Follow-up and management of heart failure medications provided by specialists at participating institutions. Doses of oral heart failure medications optimized within 2 weeks, provided clinical assessments and laboratory measures indicate that it is safe to increase doses.
    Arm type
    		 Experimental

    Investigational medicinal product name
    beta-blocker, renin-angiotensin system blocker, mineralocorticoid receptor blocker
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Doses of oral heart failure medications optimized within 2 weeks, provided clinical assessments and laboratory measures indicate that it is safe to increase doses.

    Arm title
    		 Usual Care
    Arm description
    		 Follow-up and management of heart failure medications provided by the patient's general physician and/or cardiologist according to local medical standards.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    heart failure medications
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Follow-up and management of heart failure medications provided by the patient's general physician and/or cardiologist according to local medical standards.

    Number of subjects in period 1
    		High Intensity Care Usual Care
    Started
    542
    536
    Completed
    467
    459
    Not completed
    75
    77
         Adverse event, serious fatal
    40
    48
         Study terminated
    25
    23
         Other reason
    10
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    High Intensity Care
    Reporting group description
    		 Follow-up and management of heart failure medications provided by specialists at participating institutions. Doses of oral heart failure medications optimized within 2 weeks, provided clinical assessments and laboratory measures indicate that it is safe to increase doses.

    Reporting group title
    Usual Care
    Reporting group description
    		 Follow-up and management of heart failure medications provided by the patient's general physician and/or cardiologist according to local medical standards.

    Reporting group values
    		 High Intensity Care Usual Care Total
    Number of subjects
    		 542 536 1078
    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)
    		 273 274 547
        From 65-84 years
    		 261 260 521
        85 years and over
    		 8 2 10
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.9 ± 13.5 63.0 ± 13.7 -
    Gender categorical
    Units: Subjects
        Female
    		 216 200 416
        Male
    		 326 336 662
    Race
    Units: Subjects
        Black
    		 115 115 230
        White or Caucasian
    		 418 414 832
        Native American
    		 1 0 1
        Other
    		 7 5 12
        Pacific Islander
    		 1 0 1
        Missing
    		 0 2 2
    Left ventricular ejection fraction category
    Units: Subjects
        ≤40%
    		 365 366 731
        >40%
    		 177 170 347
    Region of Enrollment
    Units: Subjects
        Africa
    		 122 118 240
        Europe
    		 47 47 94
        Russia
    		 351 352 703
        South America
    		 22 19 41

    End points

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    End points reporting groups
    Reporting group title
    High Intensity Care
    Reporting group description
    		 Follow-up and management of heart failure medications provided by specialists at participating institutions. Doses of oral heart failure medications optimized within 2 weeks, provided clinical assessments and laboratory measures indicate that it is safe to increase doses.

    Reporting group title
    Usual Care
    Reporting group description
    		 Follow-up and management of heart failure medications provided by the patient's general physician and/or cardiologist according to local medical standards.

    Primary: 180-day All-cause Mortality or Heart Failure Readmission

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    End point title
    		 180-day All-cause Mortality or Heart Failure Readmission
    End point description
    Cumulative risk of either readmission for heart failure or death at 180 days
    End point type
    Primary
    End point timeframe
    180 days
    End point values
    		 High Intensity Care Usual Care
    Number of subjects analysed
    506 [1]
    502 [2]
    Units: Weighted Adjusted KM Event Rate (%)
        number (not applicable)
    15.2
    23.3
    Notes
    [1] - All patients randomized at sites that followed patients to day 180.
    [2] - All patients randomized at sites that followed patients to day 180.
    Statistical analysis title
    		 Primary Outcome
    Statistical analysis description
    180-day All-cause Mortality or Heart Failure Readmission
    Comparison groups
    High Intensity Care v Usual Care
    Number of subjects included in analysis
    1008
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.0021 [4]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    8.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.9
         upper limit
    		 13.2
    Notes
    [3] - χ² test of the difference in 180-day event rates between groups, calculated from the difference in Kaplan-Meier estimates of the cumulative risks at 180 days adjusted for LVEF (≤40% vs >40%) and geographical region using Mantel-Haenszel weights, and from the variance calculated from their associated SEs. Weighted average of difference in two cohorts. Main result down-weights result in early cohort proportional to half its sample size.
    [4] - A chi-square test statistic with 1df computed as D^2/V, where D is the difference in event rates with associated variance V.

    Secondary: Change in Quality of Life

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    End point title
    		 Change in Quality of Life
    End point description
    Change from baseline to 90 days in quality of life as measured using the EQ-5D visual analogue scale (VAS) which ranges from 0 to 100 with a higher score representing a better outcome. "EQ-5D" is the official name of a quality of life instrument developed by EuroQol.
    End point type
    Secondary
    End point timeframe
    90 days
    End point values
    		 High Intensity Care Usual Care
    Number of subjects analysed
    461 [5]
    454 [6]
    Units: score on a scale
        least squares mean (standard error)
    10.72 ± 0.88
    7.22 ± 0.90
    Notes
    [5] - Randomized patients with available data excluding subjects from Mozambique.
    [6] - Randomized patients with available data excluding subjects from Mozambique.
    Statistical analysis title
    		 Change in Quality of Life
    Statistical analysis description
    Change from baseline to 90 days in quality of life as measured using the EQ-5D visual analogue scale (VAS) which ranges from 0 to 100 with a higher score representing a better outcome. "EQ-5D" is the official name of a quality of life instrument developed by EuroQol. Subjects from Mozambique are excluded due to the unavailability of a linguistically validated translation of the EQ-5D in that country.
    Comparison groups
    High Intensity Care v Usual Care
    Number of subjects included in analysis
    915
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [7]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    3.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.74
         upper limit
    		 5.24
    Notes
    [7] - Statistics are estimated from an ANCOVA model with fixed terms for treatment, LVEF (≤40% vs >40%), geographical region, and baseline value. Treatment effect is the adjusted mean difference between treatment groups.

    Secondary: 180-day All-cause Mortality

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    End point title
    		 180-day All-cause Mortality
    End point description
    Cumulative risk of death at 180 days
    End point type
    Secondary
    End point timeframe
    180 days
    End point values
    		 High Intensity Care Usual Care
    Number of subjects analysed
    506 [8]
    502 [9]
    Units: Weighted Adjusted KM Event Rate (%)
        number (not applicable)
    8.48
    10.04
    Notes
    [8] - All patients randomized at sites that followed patients to day 180.
    [9] - All patients randomized at sites that followed patients to day 180.
    Statistical analysis title
    		 180-day All-cause Mortality
    Statistical analysis description
    Cumulative risk of death at 180 days
    Comparison groups
    High Intensity Care v Usual Care
    Number of subjects included in analysis
    1008
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.42 [11]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.3
         upper limit
    		 5.4
    Notes
    [10] - χ² test of the difference in 180-day event rates between groups, calculated from the difference in Kaplan-Meier estimates of the cumulative risks at 180 days adjusted for LVEF (≤40% vs >40%) and geographical region using Mantel-Haenszel weights, and from the variance calculated from their associated SEs. Weighted average of difference in two cohorts. Main result down-weights result in early cohort proportional to half its sample size.
    [11] - A chi-square test statistic with 1df computed as D^2/V, where D is the difference in event rates with associated variance V.

    Secondary: 90-day All-cause Mortality or Heart Failure Readmission

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    End point title
    		 90-day All-cause Mortality or Heart Failure Readmission
    End point description
    Cumulative risk of either readmission for heart failure or death at 90 days
    End point type
    Secondary
    End point timeframe
    90 days
    End point values
    		 High Intensity Care Usual Care
    Number of subjects analysed
    542 [12]
    536 [13]
    Units: Adjusted KM Event Rate (%)
        number (not applicable)
    10.4
    13.8
    Notes
    [12] - All patients validly randomized.
    [13] - All patients validly randomized.
    Statistical analysis title
    		 90-day All-cause Mortality or HF Readmission
    Statistical analysis description
    Cumulative risk of either readmission for heart failure or death at 90 days
    Comparison groups
    High Intensity Care v Usual Care
    Number of subjects included in analysis
    1078
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 = 0.081 [15]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    3.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 7.3
    Notes
    [14] - The difference in 90-day event rates is computed from Kaplan-Meier estimates adjusted for region and randomization stratification factor LVEF <=40/>40 using Mantel-Haenszel weights.
    [15] - A chi-square test statistic with 1df computed as D^2/V, where D is the difference in event rates with associated variance V.

    Other pre-specified: 180-day Cardiovascular Death

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    End point title
    		 180-day Cardiovascular Death
    End point description
    Cumulative risk of death due to cardiovascular cause at 180 days
    End point type
    Other pre-specified
    End point timeframe
    180 days
    End point values
    		 High Intensity Care Usual Care
    Number of subjects analysed
    506 [16]
    502 [17]
    Units: Weighted Adjusted KM Event Rate (%)
        number (not applicable)
    6.9
    9.3
    Notes
    [16] - All patients randomized at sites that followed patients to day 180.
    [17] - All patients randomized at sites that followed patients to day 180.
    Statistical analysis title
    		 180-day Cardiovascular Death
    Statistical analysis description
    Cumulative risk of death due to cardiovascular cause at 180 days
    Comparison groups
    High Intensity Care v Usual Care
    Number of subjects included in analysis
    1008
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [18]
    P-value
    		 = 0.19 [19]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    2.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2
         upper limit
    		 6.1
    Notes
    [18] - χ² test of the difference in 180-day event rates between groups, calculated from the difference in Kaplan-Meier estimates of the cumulative risks at 180 days adjusted for LVEF (≤40% vs >40%) and geographical region using Mantel-Haenszel weights, and from the variance calculated from their associated SEs. Weighted average of difference in two cohorts. Main result down-weights result in early cohort proportional to half its sample size.
    [19] - A chi-square test statistic with 1df computed as D^2/V, where D is the difference in event rates with associated variance V.

    Other pre-specified: 90-day Cardiovascular Death

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    End point title
    		 90-day Cardiovascular Death
    End point description
    Cumulative risk of death due to cardiovascular cause at 90 days
    End point type
    Other pre-specified
    End point timeframe
    90 days
    End point values
    		 High Intensity Care Usual Care
    Number of subjects analysed
    542 [20]
    536 [21]
    Units: Adjusted KM Event Rate (%)
        number (not applicable)
    3.3
    5.4
    Notes
    [20] - All patients validly randomized.
    [21] - All patients validly randomized.
    Statistical analysis title
    		 90-day Cardiovascular Death
    Statistical analysis description
    Cumulative risk of death due to cardiovascular cause at 90 days
    Comparison groups
    High Intensity Care v Usual Care
    Number of subjects included in analysis
    1078
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [22]
    P-value
    		 = 0.086 [23]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 4.6
    Notes
    [22] - The difference in 90-day event rates is computed from Kaplan-Meier estimates adjusted for region and randomization stratification factor LVEF <=40/>40 using Mantel-Haenszel weights.
    [23] - A chi-square test statistic with 1df computed as D^2/V, where D is the difference in event rates with associated variance V.

    Other pre-specified: 90-day All-cause Mortality

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    End point title
    		 90-day All-cause Mortality
    End point description
    Cumulative risk of death at 90 days
    End point type
    Other pre-specified
    End point timeframe
    90 days
    End point values
    		 High Intensity Care Usual Care
    Number of subjects analysed
    542 [24]
    536 [25]
    Units: Adjusted KM Event Rate (%)
        number (not applicable)
    4.3
    5.7
    Notes
    [24] - All patients validly randomized.
    [25] - All patients validly randomized.
    Statistical analysis title
    		 90-day All-cause Mortality
    Statistical analysis description
    Cumulative risk of death at 90 days
    Comparison groups
    High Intensity Care v Usual Care
    Number of subjects included in analysis
    1078
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [26]
    P-value
    		 = 0.28 [27]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2
         upper limit
    		 4
    Notes
    [26] - The difference in 90-day event rates is computed from Kaplan-Meier estimates adjusted for region and randomization stratification factor LVEF <=40/>40 using Mantel-Haenszel weights.
    [27] - A chi-square test statistic with 1df computed as D^2/V, where D is the difference in event rates with associated variance V.

    Other pre-specified: 180-day Heart Failure Readmission

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    End point title
    		 180-day Heart Failure Readmission
    End point description
    Cumulative risk of readmission for heart failure at 180 days
    End point type
    Other pre-specified
    End point timeframe
    180 days
    End point values
    		 High Intensity Care Usual Care
    Number of subjects analysed
    506 [28]
    502 [29]
    Units: Weighted Adjusted KM Event Rate (%)
        number (not applicable)
    9.5
    17.1
    Notes
    [28] - All patients randomized at sites that followed patients to day 180.
    [29] - All patients randomized at sites that followed patients to day 180.
    Statistical analysis title
    		 180-day Heart Failure Readmission
    Statistical analysis description
    Cumulative risk of readmission for heart failure at 180 days
    Comparison groups
    High Intensity Care v Usual Care
    Number of subjects included in analysis
    1008
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [30]
    P-value
    		 = 0.0011 [31]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    7.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3
         upper limit
    		 12.1
    Notes
    [30] - χ² test of the difference in 180-day event rates between groups, calculated from the difference in Kaplan-Meier estimates of the cumulative risks at 180 days adjusted for LVEF (≤40% vs >40%) and geographical region using Mantel-Haenszel weights, and from the variance calculated from their associated SEs. Weighted average of difference in two cohorts. Main result down-weights result in early cohort proportional to half its sample size.
    [31] - A chi-square test statistic with 1df computed as D^2/V, where D is the difference in event rates with associated variance V.

    Other pre-specified: 90-day Heart Failure Readmission

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    End point title
    		 90-day Heart Failure Readmission
    End point description
    Cumulative risk of readmission for heart failure at 90 days
    End point type
    Other pre-specified
    End point timeframe
    90 days
    End point values
    		 High Intensity Care Usual Care
    Number of subjects analysed
    542 [32]
    536 [33]
    Units: Adjusted KM Event Rate (%)
        number (not applicable)
    6.9
    9.5
    Notes
    [32] - All patients validly randomized.
    [33] - All patients validly randomized.
    Statistical analysis title
    		 90-day Heart Failure Readmission
    Statistical analysis description
    Cumulative risk of readmission for heart failure at 90 days
    Comparison groups
    High Intensity Care v Usual Care
    Number of subjects included in analysis
    1078
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [34]
    P-value
    		 = 0.13 [35]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    2.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 5.8
    Notes
    [34] - The difference in 90-day event rates is computed from Kaplan-Meier estimates adjusted for region and randomization stratification factor LVEF <=40/>40 using Mantel-Haenszel weights.
    [35] - A chi-square test statistic with 1df computed as D^2/V, where D is the difference in event rates with associated variance V.

    Other pre-specified: Finkelstein-Schoenfeld Hierarchical Composite

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    End point title
    		 Finkelstein-Schoenfeld Hierarchical Composite
    End point description
    Hierarchical composite endpoint comprising death, heart failure readmissions, and EQ-VAS analyzed using Finkelstein-Schoenfeld methodology
    End point type
    Other pre-specified
    End point timeframe
    90 days
    End point values
    		 High Intensity Care Usual Care
    Number of subjects analysed
    542 [36]
    536 [37]
    Units: percentage of favorable comparisons
        number (not applicable)
    40.4
    29.4
    Notes
    [36] - All patients validly randomized.
    [37] - All patients validly randomized.
    Statistical analysis title
    		 Finkelstein-Schoenfeld Hierarchical Composite
    Statistical analysis description
    Hierarchical composite endpoint comprising death, heart failure readmissions, and EQ-VAS analyzed using Finkelstein-Schoenfeld methodology.
    Comparison groups
    High Intensity Care v Usual Care
    Number of subjects included in analysis
    1078
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [38]
    P-value
    		 = 0.0002 [39]
    Method
    		 van Elteren’s test
    Parameter type
    		 Mann-Whitney odds
    Point estimate
    1.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.13
         upper limit
    		 1.46
    Notes
    [38] - Treatment effect is the Mann-Whitney odds adjusted for LVEF (≤40% vs >40%) and geographical region, using Mantel-Haenzsel weights.
    [39] - P-value calculated from van Elteren's test stratified by LVEF (≤40% vs >40%) and geographical region, using modified ridit scores.

    Other pre-specified: Change in NT-proBNP

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    End point title
    		 Change in NT-proBNP
    End point description
    Change from baseline to 90 days in NT-proBNP on the log scale
    End point type
    Other pre-specified
    End point timeframe
    90 days
    End point values
    		 High Intensity Care Usual Care
    Number of subjects analysed
    476 [40]
    475 [41]
    Units: ratio
        least squares mean (standard error)
    0.436 ± 1.072
    0.564 ± 1.074
    Notes
    [40] - Randomized patients with available data.
    [41] - Randomized patients with available data.
    Statistical analysis title
    		 Change in NT-proBNP
    Statistical analysis description
    Change from baseline to 90 days in NT-proBNP on the log scale
    Comparison groups
    High Intensity Care v Usual Care
    Number of subjects included in analysis
    951
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [42]
    P-value
    		 = 0.0003 [43]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted Geometric Mean Ratio
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 0.89
    Notes
    [42] - Comparison of the ratio of post-baseline value over the baseline value adjusted for the specified covariates between the high-intensity care group and the usual care group.
    [43] - Statistics are estimated based on an Analysis of Covariance (ANCOVA) model with fixed terms for treatment, LVEF <=40/>40, region, and baseline log-transformed NT-proBNP value.

    Other pre-specified: Change in Weight

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    End point title
    		 Change in Weight
    End point description
    Change from baseline to 90 days in weight in kg
    End point type
    Other pre-specified
    End point timeframe
    90 days
    End point values
    		 High Intensity Care Usual Care
    Number of subjects analysed
    489 [44]
    479 [45]
    Units: kg
        least squares mean (standard error)
    -1.78 ± 0.282
    -0.42 ± 0.290
    Notes
    [44] - Randomized patients with available data.
    [45] - Randomized patients with available data.
    Statistical analysis title
    		 Change in Weight
    Statistical analysis description
    Change from baseline to 90 days in weight in kg
    Comparison groups
    High Intensity Care v Usual Care
    Number of subjects included in analysis
    968
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [46]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.91
         upper limit
    		 -0.8
    Notes
    [46] - Statistics are estimated from an ANCOVA model with fixed terms for treatment, LVEF (≤40% vs >40%), geographical region, and baseline value. Treatment effect is the adjusted mean difference between treatment groups.

    Other pre-specified: Changes in Signs and Symptoms of Congestion: NYHA Class

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    End point title
    		 Changes in Signs and Symptoms of Congestion: NYHA Class
    End point description
    Changes from baseline to 90 days in New York Heart Association (NYHA) class which ranges from I to IV with a higher class representing a worse outcome.
    End point type
    Other pre-specified
    End point timeframe
    90 days
    End point values
    		 High Intensity Care Usual Care
    Number of subjects analysed
    495 [47]
    488 [48]
    Units: participants
        NYHA at baseline: I
    34
    27
        NYHA at baseline: II
    288
    306
        NYHA at baseline: III
    170
    152
        NYHA at baseline: IV
    3
    3
        NYHA at day 90: I
    116
    76
        NYHA at day 90: II
    297
    288
        NYHA at day 90: III
    77
    107
        NYHA at day 90: IV
    5
    17
    Notes
    [47] - Randomized patients with available data.
    [48] - Randomized patients with available data.
    Statistical analysis title
    		 Changes in Signs and Symptoms of Congestion: NYHA
    Statistical analysis description
    Changes from baseline to 90 days in New York Heart Association (NYHA) class which ranges from I to IV with a higher class representing a worse outcome.
    Comparison groups
    High Intensity Care v Usual Care
    Number of subjects included in analysis
    983
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [49]
    P-value
    		 < 0.0001 [50]
    Method
    		 van Elteren’s test
    Parameter type
    		 Mann-Whitney odds
    Point estimate
    1.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.22
         upper limit
    		 1.53
    Notes
    [49] - Treatment effect presented as Mann-Whitney odds stratified by LVEF (≤40% vs >40%), geographical region, and baseline value. A Mann-Whitney odds value of >1·0 favours high-intensity care.
    [50] - P value from van Elteren's test stratified by LVEF (≤40% vs >40%), geographical region, and baseline value.

    Other pre-specified: Changes in Signs and Symptoms of Congestion: Orthopnea

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    End point title
    		 Changes in Signs and Symptoms of Congestion: Orthopnea
    End point description
    Changes from baseline to 90 days in orthopnea rated on a scale from 0 to 3 with a higher score representing a worse outcome.
    End point type
    Other pre-specified
    End point timeframe
    90 days
    End point values
    		 High Intensity Care Usual Care
    Number of subjects analysed
    493 [51]
    486 [52]
    Units: participants
        0: None at baseline
    308
    304
        1: 1 pillow (10 cm) at baseline
    168
    165
        2: 2 pillows (20 cm) at baseline
    16
    16
        3: >30 degrees at baseline
    1
    1
        0: None at day 90
    381
    339
        1: 1 pillow (10 cm) at day 90
    99
    124
        2: 2 pillows (20 cm) at day 90
    10
    19
        3: >30 degrees at day 90
    3
    4
    Notes
    [51] - Randomized patients with available data.
    [52] - Randomized patients with available data.
    Statistical analysis title
    		 Changes in Orthopnea
    Statistical analysis description
    Changes from baseline to 90 days in orthopnea rated on a scale from 0 to 3 with a higher score representing a worse outcome.
    Comparison groups
    High Intensity Care v Usual Care
    Number of subjects included in analysis
    979
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [53]
    P-value
    		 = 0.0048 [54]
    Method
    		 van Elteren’s test
    Parameter type
    		 Mann-Whitney odds
    Point estimate
    1.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.07
         upper limit
    		 1.29
    Notes
    [53] - Treatment effect presented as Mann-Whitney odds stratified by LVEF (≤40% vs >40%), geographical region, and baseline value. A Mann-Whitney odds value of >1·0 favours high-intensity care.
    [54] - P value from van Elteren's test stratified by LVEF (≤40% vs >40%), geographical region, and baseline value.

    Other pre-specified: Changes in Signs and Symptoms of Congestion: Peripheral Edema

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    End point title
    		 Changes in Signs and Symptoms of Congestion: Peripheral Edema
    End point description
    Changes from baseline to 90 days in peripheral edema rated on a scale from 0 to 3 with a higher score representing a worse.
    End point type
    Other pre-specified
    End point timeframe
    90 days
    End point values
    		 High Intensity Care Usual Care
    Number of subjects analysed
    491 [55]
    483 [56]
    Units: participants
        None at baseline
    286
    278
        1+ at baseline
    175
    173
        2+ at baseline
    29
    27
        3+ at baseline
    1
    5
        None at day 90
    384
    315
        1+ at day 90
    91
    130
        2+ at day 90
    15
    33
        3+ at day 90
    1
    5
    Notes
    [55] - Randomized patients with available data.
    [56] - Randomized patients with available data.
    Statistical analysis title
    		 Changes in Peripheral Edema
    Statistical analysis description
    Changes from baseline to 90 days in peripheral edema rated on a scale from 0 to 3 with a higher score representing a worse outcome.
    Comparison groups
    High Intensity Care v Usual Care
    Number of subjects included in analysis
    974
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [57]
    P-value
    		 = 0.0002 [58]
    Method
    		 van Elteren’s test
    Parameter type
    		 Mann-Whitney odds
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.17
         upper limit
    		 1.44
    Notes
    [57] - Treatment effect presented as Mann-Whitney odds stratified by LVEF (≤40% vs >40%), geographical region, and baseline value. A Mann-Whitney odds value of >1·0 favours high-intensity care.
    [58] - P value from van Elteren's test stratified by LVEF (≤40% vs >40%), geographical region, and baseline value.

    Other pre-specified: Changes in Signs and Symptoms of Congestion: Rales

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    End point title
    		 Changes in Signs and Symptoms of Congestion: Rales
    End point description
    Changes from baseline to 90 days in rales rated on a scale from 0 to 3 with a higher score representing a worse outcome.
    End point type
    Other pre-specified
    End point timeframe
    90 days
    End point values
    		 High Intensity Care Usual Care
    Number of subjects analysed
    490 [59]
    479 [60]
    Units: participants
        0: None at baseline
    417
    411
        1: <1/3 at baseline
    63
    63
        2: 1/3 to 2/3 at baseline
    10
    5
        3: >2/3 at baseline
    0
    0
        0: None at day 90
    454
    421
        1: <1/3 at day 90
    33
    57
        2: 1/3 to 2/3 at day 90
    3
    1
        3: >2/3 at day 90
    0
    0
    Notes
    [59] - Randomized patients with available data.
    [60] - Randomized patients with available data.
    Statistical analysis title
    		 Changes in Rales
    Statistical analysis description
    Changes from baseline to 90 days in rales rated on a scale from 0 to 3 with a higher score representing a worse outcome.
    Comparison groups
    High Intensity Care v Usual Care
    Number of subjects included in analysis
    969
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [61]
    P-value
    		 = 0.073 [62]
    Method
    		 van Elteren’s test
    Parameter type
    		 Mann-Whitney odds
    Point estimate
    1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 1.15
    Notes
    [61] - Treatment effect presented as Mann-Whitney odds stratified by LVEF (≤40% vs >40%), geographical region, and baseline value. A Mann-Whitney odds value of >1·0 favours high-intensity care.
    [62] - P value from van Elteren's test stratified by LVEF (≤40% vs >40%), geographical region, and baseline value.

    Other pre-specified: Changes in Signs and Symptoms of Congestion: JVP

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    End point title
    		 Changes in Signs and Symptoms of Congestion: JVP
    End point description
    Changes from baseline to 90 days in jugular venous pulse (JVP) rated on a scale from 1 to 3 with a higher score representing a worse outcome.
    End point type
    Other pre-specified
    End point timeframe
    90 days
    End point values
    		 High Intensity Care Usual Care
    Number of subjects analysed
    450 [63]
    428 [64]
    Units: participants
        1: <6 cm at baseline
    383
    359
        2: 6–10 cm at baseline
    64
    66
        3: >10 cm at baseline
    3
    3
        1: <6 cm at day 90
    418
    377
        2: 6–10 cm at day 90
    30
    40
        3: >10 cm at day 90
    2
    11
    Notes
    [63] - Randomized patients with available data.
    [64] - Randomized patients with available data.
    Statistical analysis title
    		 Changes in JVP
    Statistical analysis description
    Changes from baseline to 90 days in jugular venous pulse (JVP) rated on a scale from 1 to 3 with a higher score representing a worse outcome.
    Comparison groups
    High Intensity Care v Usual Care
    Number of subjects included in analysis
    878
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [65]
    P-value
    		 = 0.015 [66]
    Method
    		 van Elteren’s test
    Parameter type
    		 Mann-Whitney odds
    Point estimate
    1.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.05
         upper limit
    		 1.21
    Notes
    [65] - Treatment effect presented as Mann-Whitney odds stratified by LVEF (≤40% vs >40%), geographical region, and baseline value. A Mann-Whitney odds value of >1·0 favours high-intensity care.
    [66] - P value from van Elteren's test stratified by LVEF (≤40% vs >40%), geographical region, and baseline value.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 90
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    High Intensity Care
    Reporting group description
    		 Follow-up and management of heart failure medications provided by specialists at participating institutions. Doses of oral heart failure medications optimized within 2 weeks, provided clinical assessments and laboratory measures indicate that it is safe to increase doses.

    Reporting group title
    Usual Care
    Reporting group description
    		 Follow-up and management of heart failure medications provided by the patient's general physician and/or cardiologist according to local medical standards.

    Serious adverse events
    		 High Intensity Care Usual Care
    Total subjects affected by serious adverse events
         subjects affected / exposed
    88 / 542 (16.24%)
    92 / 536 (17.16%)
         number of deaths (all causes)
    23
    30
         number of deaths resulting from adverse events
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 542 (0.18%)
    1 / 536 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 542 (0.00%)
    1 / 536 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Surgical and medical procedures
    Chemotherapy
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    High frequency ablation
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Sudden cardiac death
         subjects affected / exposed
    0 / 542 (0.00%)
    1 / 536 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sudden death
         subjects affected / exposed
    5 / 542 (0.92%)
    10 / 536 (1.87%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 10
         deaths causally related to treatment / all
    0 / 5
    0 / 10
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 542 (0.18%)
    3 / 536 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Pulmonary oedema
         subjects affected / exposed
    1 / 542 (0.18%)
    1 / 536 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    0 / 542 (0.00%)
    1 / 536 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    2 / 542 (0.37%)
    0 / 536 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    3 / 542 (0.55%)
    0 / 536 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 542 (0.37%)
    2 / 536 (0.37%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 542 (0.00%)
    1 / 536 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 542 (0.18%)
    1 / 536 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    38 / 542 (7.01%)
    47 / 536 (8.77%)
         occurrences causally related to treatment / all
    0 / 42
    0 / 52
         deaths causally related to treatment / all
    0 / 7
    0 / 10
    Cardiac failure acute
         subjects affected / exposed
    0 / 542 (0.00%)
    2 / 536 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 542 (0.18%)
    6 / 536 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    1 / 542 (0.18%)
    1 / 536 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ventricular tachycardia
         subjects affected / exposed
    1 / 542 (0.18%)
    2 / 536 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    4 / 542 (0.74%)
    2 / 536 (0.37%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Hemianopia homonymous
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 542 (0.00%)
    2 / 536 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia strangulated
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    0 / 542 (0.00%)
    1 / 536 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 542 (0.00%)
    1 / 536 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    3 / 542 (0.55%)
    1 / 536 (0.19%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteochondrosis
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis infective
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Corona virus infection
         subjects affected / exposed
    10 / 542 (1.85%)
    6 / 536 (1.12%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 6
         deaths causally related to treatment / all
    0 / 4
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 542 (0.18%)
    1 / 536 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    0 / 542 (0.00%)
    1 / 536 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    0 / 542 (0.00%)
    1 / 536 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis externa
         subjects affected / exposed
    0 / 542 (0.00%)
    1 / 536 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 542 (0.74%)
    1 / 536 (0.19%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pneumonia viral
         subjects affected / exposed
    7 / 542 (1.29%)
    3 / 536 (0.56%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 3
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic metabolic decompensation
         subjects affected / exposed
    0 / 542 (0.00%)
    1 / 536 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 High Intensity Care Usual Care
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    157 / 542 (28.97%)
    77 / 536 (14.37%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign gastric neoplasm
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 542 (0.55%)
    2 / 536 (0.37%)
         occurrences all number
    3
    2
    Hypertensive crisis
         subjects affected / exposed
    4 / 542 (0.74%)
    2 / 536 (0.37%)
         occurrences all number
    4
    2
    Hypotension
         subjects affected / exposed
    26 / 542 (4.80%)
    2 / 536 (0.37%)
         occurrences all number
    33
    2
    Orthostatic hypotension
         subjects affected / exposed
    3 / 542 (0.55%)
    0 / 536 (0.00%)
         occurrences all number
    3
    0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 542 (0.00%)
    1 / 536 (0.19%)
         occurrences all number
    0
    1
    Surgical and medical procedures
    Chemotherapy
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 542 (0.37%)
    1 / 536 (0.19%)
         occurrences all number
    2
    1
    Chest pain
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    2 / 542 (0.37%)
    2 / 536 (0.37%)
         occurrences all number
    2
    2
    Pain
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Swelling
         subjects affected / exposed
    0 / 542 (0.00%)
    1 / 536 (0.19%)
         occurrences all number
    0
    1
    Immune system disorders
    Amyloidosis
         subjects affected / exposed
    0 / 542 (0.00%)
    1 / 536 (0.19%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Gynaecomastia
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Metrorrhagia
         subjects affected / exposed
    0 / 542 (0.00%)
    1 / 536 (0.19%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 542 (0.37%)
    1 / 536 (0.19%)
         occurrences all number
    2
    1
    Dyspnoea
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 542 (0.18%)
    1 / 536 (0.19%)
         occurrences all number
    1
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Angiocardiogram
         subjects affected / exposed
    0 / 542 (0.00%)
    1 / 536 (0.19%)
         occurrences all number
    0
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    3 / 542 (0.55%)
    0 / 536 (0.00%)
         occurrences all number
    3
    0
    Blood potassium increased
         subjects affected / exposed
    2 / 542 (0.37%)
    0 / 536 (0.00%)
         occurrences all number
    2
    0
    Blood pressure decreased
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Blood pressure increased
         subjects affected / exposed
    7 / 542 (1.29%)
    6 / 536 (1.12%)
         occurrences all number
    8
    7
    Blood uric acid increased
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Glomerular filtration rate decreased
         subjects affected / exposed
    2 / 542 (0.37%)
    0 / 536 (0.00%)
         occurrences all number
    2
    0
    N-terminal prohormone brain natriuretic peptide increased
         subjects affected / exposed
    3 / 542 (0.55%)
    0 / 536 (0.00%)
         occurrences all number
    4
    0
    Platelet count decreased
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Chest injury
         subjects affected / exposed
    0 / 542 (0.00%)
    1 / 536 (0.19%)
         occurrences all number
    0
    1
    Contusion
         subjects affected / exposed
    2 / 542 (0.37%)
    3 / 536 (0.56%)
         occurrences all number
    2
    3
    Humerus fracture
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Ligament sprain
         subjects affected / exposed
    0 / 542 (0.00%)
    1 / 536 (0.19%)
         occurrences all number
    0
    1
    Skin laceration
         subjects affected / exposed
    0 / 542 (0.00%)
    1 / 536 (0.19%)
         occurrences all number
    0
    1
    Toxicity to various agents
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Arrhythmia
         subjects affected / exposed
    0 / 542 (0.00%)
    1 / 536 (0.19%)
         occurrences all number
    0
    1
    Atrial fibrillation
         subjects affected / exposed
    2 / 542 (0.37%)
    1 / 536 (0.19%)
         occurrences all number
    2
    1
    Bradycardia
         subjects affected / exposed
    4 / 542 (0.74%)
    2 / 536 (0.37%)
         occurrences all number
    4
    2
    Cardiac failure
         subjects affected / exposed
    45 / 542 (8.30%)
    30 / 536 (5.60%)
         occurrences all number
    51
    31
    Cardiac failure acute
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Cardiac failure chronic
         subjects affected / exposed
    3 / 542 (0.55%)
    1 / 536 (0.19%)
         occurrences all number
    3
    1
    Coronary artery disease
         subjects affected / exposed
    0 / 542 (0.00%)
    1 / 536 (0.19%)
         occurrences all number
    0
    1
    Extrasystoles
         subjects affected / exposed
    0 / 542 (0.00%)
    1 / 536 (0.19%)
         occurrences all number
    0
    1
    Tachycardia
         subjects affected / exposed
    0 / 542 (0.00%)
    5 / 536 (0.93%)
         occurrences all number
    0
    5
    Nervous system disorders
    Burning sensation
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Dizziness
         subjects affected / exposed
    4 / 542 (0.74%)
    0 / 536 (0.00%)
         occurrences all number
    4
    0
    Dizziness exertional
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Dizziness postural
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Dysgeusia
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    2 / 542 (0.37%)
    1 / 536 (0.19%)
         occurrences all number
    2
    1
    Loss of consciousness
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Paraesthesia
         subjects affected / exposed
    2 / 542 (0.37%)
    0 / 536 (0.00%)
         occurrences all number
    2
    0
    Somnolence
         subjects affected / exposed
    1 / 542 (0.18%)
    1 / 536 (0.19%)
         occurrences all number
    1
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 542 (0.55%)
    0 / 536 (0.00%)
         occurrences all number
    3
    0
    Anaemia of chronic disease
         subjects affected / exposed
    1 / 542 (0.18%)
    1 / 536 (0.19%)
         occurrences all number
    1
    1
    Leukocytosis
         subjects affected / exposed
    1 / 542 (0.18%)
    1 / 536 (0.19%)
         occurrences all number
    1
    1
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 542 (0.00%)
    1 / 536 (0.19%)
         occurrences all number
    0
    1
    Constipation
         subjects affected / exposed
    2 / 542 (0.37%)
    2 / 536 (0.37%)
         occurrences all number
    2
    2
    Diarrhoea
         subjects affected / exposed
    3 / 542 (0.55%)
    1 / 536 (0.19%)
         occurrences all number
    3
    1
    Dry mouth
         subjects affected / exposed
    2 / 542 (0.37%)
    0 / 536 (0.00%)
         occurrences all number
    2
    0
    Dyspepsia
         subjects affected / exposed
    3 / 542 (0.55%)
    0 / 536 (0.00%)
         occurrences all number
    3
    0
    Eructation
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal motility disorder
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Haemorrhoids
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    2 / 542 (0.37%)
    0 / 536 (0.00%)
         occurrences all number
    2
    0
    Toothache
         subjects affected / exposed
    0 / 542 (0.00%)
    1 / 536 (0.19%)
         occurrences all number
    0
    1
    Hepatobiliary disorders
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 542 (0.18%)
    1 / 536 (0.19%)
         occurrences all number
    1
    1
    Skin ulcer
         subjects affected / exposed
    0 / 542 (0.00%)
    1 / 536 (0.19%)
         occurrences all number
    0
    1
    Stasis dermatitis
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 542 (0.37%)
    0 / 536 (0.00%)
         occurrences all number
    2
    0
    Renal failure
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Renal impairment
         subjects affected / exposed
    12 / 542 (2.21%)
    0 / 536 (0.00%)
         occurrences all number
    14
    0
    Urinary retention
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    2 / 542 (0.37%)
    1 / 536 (0.19%)
         occurrences all number
    2
    1
    Back pain
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Gouty arthritis
         subjects affected / exposed
    2 / 542 (0.37%)
    1 / 536 (0.19%)
         occurrences all number
    2
    1
    Hypercreatinaemia
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Muscular weakness
         subjects affected / exposed
    4 / 542 (0.74%)
    0 / 536 (0.00%)
         occurrences all number
    4
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 542 (0.00%)
    1 / 536 (0.19%)
         occurrences all number
    0
    1
    Corona virus infection
         subjects affected / exposed
    4 / 542 (0.74%)
    2 / 536 (0.37%)
         occurrences all number
    4
    2
    Influenza
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Malaria
         subjects affected / exposed
    0 / 542 (0.00%)
    1 / 536 (0.19%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    8 / 542 (1.48%)
    3 / 536 (0.56%)
         occurrences all number
    8
    3
    Peritonitis
         subjects affected / exposed
    0 / 542 (0.00%)
    1 / 536 (0.19%)
         occurrences all number
    0
    1
    Pharyngitis
         subjects affected / exposed
    0 / 542 (0.00%)
    1 / 536 (0.19%)
         occurrences all number
    0
    1
    Pulpitis dental
         subjects affected / exposed
    0 / 542 (0.00%)
    1 / 536 (0.19%)
         occurrences all number
    0
    1
    Respiratory tract infection viral
         subjects affected / exposed
    3 / 542 (0.55%)
    5 / 536 (0.93%)
         occurrences all number
    3
    5
    Sepsis
         subjects affected / exposed
    0 / 542 (0.00%)
    1 / 536 (0.19%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Viral infection
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Vulvovaginal mycotic infection
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Dehydration
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Diabetic metabolic decompensation
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Fluid retention
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Gout
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 542 (0.00%)
    1 / 536 (0.19%)
         occurrences all number
    0
    1
    Hyperkalaemia
         subjects affected / exposed
    17 / 542 (3.14%)
    0 / 536 (0.00%)
         occurrences all number
    18
    0
    Hyperuricaemia
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 542 (0.18%)
    1 / 536 (0.19%)
         occurrences all number
    1
    1
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 542 (0.18%)
    0 / 536 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jun 2019
    After the study started, the protocol was amended to add a patient contact at 180 days for safety.
    11 Jan 2021
    After the study started, the protocol was amended to increase study power by changing the timing of assessment for the primary endpoint from 90 to 180 days and increasing target enrolment from 900 to 1800.

    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.
    The study was terminated on Sept 23, 2022, following the recommendation of the DSMB due to a larger-than-expected difference in risk of the primary endpoint between the groups based on an analysis when 1069 total patients had been randomly assigned.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34529313
    http://www.ncbi.nlm.nih.gov/pubmed/31423712
    http://www.ncbi.nlm.nih.gov/pubmed/36356631
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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