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    Clinical Trial Results:
    Randomized Evaluation of Decreased Usage of betablocCkErs after myocardial infarction in the SWEDEHEART registry REDUCe SWEDEHEART

    Summary
    EudraCT number
    		 2017-002336-17
    Trial protocol
    		 SE   EE  
    Global end of trial date
    16 Nov 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Jun 2024
    First version publication date
    14 Jun 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    REDUCe_2017-05-22
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03278509
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Karolinska Institutet
    Sponsor organisation address
    Entrévägen 2, target J, floor 5, Stockholm, Sweden,
    Public contact
    Tomas Jernberg, Karolinska Institutet, +46 0701671474, tomas.jernberg@sll.se
    Scientific contact
    Tomas Jernberg, Karolinska Institutet, +46 0701671474, tomas.jernberg@sll.se
    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
    08 Mar 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Nov 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Nov 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine whether long-term treatment with oral beta-blockade in patients with MI and preserved LV systolic ejection fraction reduces the composite of death of any cause or new MI
    Protection of trial subjects
    The steering committee appointed a data safety monitoring board (DSMB). The DSMB ensured the safety of the intervention as well as the general execution of the trial on behalf of the trial participants. The responsibilities of the DSMB were defined in a separate charter agreed upon by the steering committee and the DSMB members. Two interim analyses of patient safety were performed by the DSMB after 2 and 4 years of recruitment. No other assessment or reporting of adverse events was to be performed in this study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Sep 2017
    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
    Sweden: 4788
    Country: Number of subjects enrolled
    Estonia: 32
    Country: Number of subjects enrolled
    New Zealand: 200
    Worldwide total number of subjects
    5020
    EEA total number of subjects
    4820
    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)
    2431
    From 65 to 84 years
    2487
    85 years and over
    102

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 5023 patients with myocardial infarction, who had undergone coronary angiography and echocardiography with a preserved left ventricular ejection fraction (≥50%), were enrolled in the trial. Prior to randomization, 3 patients were excluded due to lack of documented informed consent.

    Pre-assignment
    Screening details
    		 Patients that were residents of the three trial countries, and who were treated for myocardial infarction with preserved left ventricular ejection fraction and obstructive coronary artery disease, were eligible to enroll in the trial. Major exclusion criteria were an indication for or contraindication to beta-blocker treatment.

    Pre-assignment period milestones
    Number of subjects started
    		 5020
    Number of subjects completed
    		 5020

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Beta-blockers
    Arm description
    		 Patients assigned treatment with either metoprolol or bisoprolol.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Metoprolol succinate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral, 100 mg daily

    Investigational medicinal product name
    Bisoprolol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral, 5 mg daily

    Arm title
    		 No beta-blockers
    Arm description
    		 Patients not assigned beta-blockers
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Beta-blockers No beta-blockers
    Started
    2508
    2512
    Completed
    2508
    2512

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Beta-blockers
    Reporting group description
    		 Patients assigned treatment with either metoprolol or bisoprolol.

    Reporting group title
    No beta-blockers
    Reporting group description
    		 Patients not assigned beta-blockers

    Reporting group values
    		 Beta-blockers No beta-blockers Total
    Number of subjects
    		 2508 2512 5020
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 1203 1228 2431
        From 65-84 years
    		 1257 1230 2487
        85 years and over
    		 48 54 102
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 65.0 (57.0 to 73.0) 65.0 (57.0 to 73.0) -
    Gender categorical
    Units: Subjects
        Female
    		 563 568 1131
        Male
    		 1945 1944 3889
    In hospital course, Coronary angiography
    Units: Subjects
        No stenosis
    		 26 25 51
        One-vessel disease
    		 1378 1378 2756
        Two-vessel disease
    		 676 668 1344
        Left main or three-vessel disease
    		 404 420 824
        Missing
    		 24 21 45
    In-hospital course, PCI or CABG
    Units: Subjects
        PCI
    		 2387 2376 4763
        CABG
    		 92 103 195
        Missing
    		 29 33 62
    Medication at discharge, Aspirin
    Units: Subjects
        Aspirin
    		 2450 2440 4890
        No aspirin
    		 57 72 129
        Missing
    		 1 0 1
    Medication at discharge, P2Y12 receptor blocker
    Units: Subjects
        P2Y12 receptor blocker
    		 2411 2398 4809
        Other
    		 8 21 29
        No antiplatelet therapy
    		 88 93 181
        Missing
    		 1 0 1
    Medication at discharge, Beta-blocker
    Units: Subjects
        Beta-blocker
    		 2399 247 2646
        No beta-blocker
    		 106 2265 2371
        Missing
    		 1 0 1
        Unknown
    		 2 0 2
    Medication at discharge, ACE inhibitor or ARB
    Units: Subjects
        ACE inhibitor or ARB
    		 1985 2040 4025
        No ACE inhibitor or ARB
    		 522 472 994
        Missing
    		 1 0 1
    Medication at discharge, Statins
    Units: Subjects
        Statins
    		 2481 2461 4942
        No statins
    		 26 49 75
        Missing
    		 1 0 1
        Unknown
    		 0 2 2
    Medication at discharge, Diuretic agent
    Units: Subjects
        Diuretic agents
    		 211 191 402
        No diuretic agent
    		 2296 2321 4617
        Missing
    		 1 0 1
    Medication at discharge, Calcium-channel blocker
    Units: Subjects
        Ca-channel blocker
    		 416 496 912
        No Ca-channel blocker
    		 2091 2015 4106
        Missing
    		 1 0 1
        Unknown
    		 0 1 1
    Risk factors, Current smoking
    Units: Subjects
        Smoker
    		 478 530 1008
        Previous smoker
    		 915 860 1775
        Never
    		 1073 1093 2166
        Unknown
    		 42 29 71
    Risk factors, Hypertension
    Units: Subjects
        Hypertension
    		 1155 1163 2318
        No hypertension
    		 1352 1346 2698
        Unknown
    		 1 3 4
    Risk factors, Diabetes mellitus
    Units: Subjects
        DM Type II
    		 185 177 362
        DM Type I
    		 10 21 31
        Unclear what type
    		 151 156 307
        No DM
    		 2159 2154 4313
        Unknown
    		 2 3 5
        Missing
    		 1 1 2
    Previous Cardiovascular disease, Myocardial infarction
    Units: Subjects
        Previous myocardial infarction
    		 165 192 357
        No myocardial infarction
    		 2338 2315 4653
        Unknown
    		 5 5 10
    Previous Cardiovascular disease, PCI
    Units: Subjects
        Previous PCI
    		 147 175 322
        No PCI
    		 2357 2330 4687
        Unknown
    		 4 7 11
    Previous Cardiovascular disease, Cardiac surgery
    Units: Subjects
        CABG
    		 33 36 69
        Other heart surgery
    		 7 7 14
        No previous cardiac surgery
    		 2464 2464 4928
        Unknown
    		 4 5 9
    Previous Cardiovascular disease, Stroke
    Units: Subjects
        Previous stroke
    		 52 67 119
        No stroke
    		 2454 2440 4894
        Unknown
    		 2 5 7
    Previous Cardiovascular disease, Chronic heart failure
    Units: Subjects
        Heart failure with normal LVEF (>=50%)
    		 0 3 3
        Heart failure with slightly reduced LVEF (40-49%)
    		 10 18 28
        Heart failure with moderately reduced LVEF (30-39%
    		 0 0 0
        Heart failure with severely reduced LVEF (<30%)
    		 1 0 1
        Heart failure with unknown LVEF
    		 2 1 3
        No heart failure
    		 2473 2459 4932
        Unknown
    		 22 31 53
    Reason for admission
    Units: Subjects
        Chest pain
    		 2421 2417 4838
        Dyspnea
    		 23 27 50
        Cardiac arrest
    		 1 6 7
        Other
    		 62 62 124
        Unknown
    		 1 0 1
    Characteristics at presentation, CPR
    Units: Subjects
        CPR before hospitalization
    		 10 11 21
        No CPR
    		 2473 2474 4947
        Unknown
    		 25 27 52
    Characteristics at presentation, Pulmonary rales
    Units: Subjects
        Basal rales
    		 28 41 69
        Rales above the basal half of the lungs
    		 0 1 1
        Pulmonary edema
    		 1 1 2
        No pulmonary rales
    		 2416 2419 4835
        Unknown
    		 63 50 113
    Characteristics at presentation, Atrial fibrillation
    Units: Subjects
        AF/AFF
    		 21 23 44
        Sinus rythm
    		 2451 2467 4918
        Other
    		 30 14 44
        Unknown
    		 6 8 14
    Characteristics at presentation, Infarct type
    Units: Subjects
        STEMI
    		 877 892 1769
        NSTEMI
    		 1623 1597 3220
        No myocardial infarction
    		 7 23 30
        Unknown
    		 1 0 1
    Characteristics at presentation, Current oral beta-blocker treatment
    Units: Subjects
        Oral beta-blocker treatment
    		 269 302 571
        No oral beta-blockers
    		 2199 2170 4369
        Unknown
    		 40 40 80
    Heart rate
    Units: beats/min
        median (inter-quartile range (Q1-Q3))
    		 74 (65 to 85) 73 (64 to 84) -
    Systolic blood pressure
    Units: mmHg
        median (inter-quartile range (Q1-Q3))
    		 150 (135 to 170) 151 (136 to 170) -

    End points

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    End points reporting groups
    Reporting group title
    Beta-blockers
    Reporting group description
    		 Patients assigned treatment with either metoprolol or bisoprolol.

    Reporting group title
    No beta-blockers
    Reporting group description
    		 Patients not assigned beta-blockers

    Subject analysis set title
    Beta-blockers
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects followed for a median of 3.5 (2.2-4.7) years

    Subject analysis set title
    No beta-blockers
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects followed for a median of 3.5 (2.2-4.7) years

    Subject analysis set title
    Beta-blockers, SEPHIA 6-10w
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All subjects included in the SEPHIA registry, attending the follow-up visit at 6-10 weeks after myocardial infarction

    Subject analysis set title
    No beta-blockers, SEPHIA 6-10w
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All subjects included in the SEPHIA registry, attending the follow-up visit at 6-10 weeks after myocardial infarction

    Subject analysis set title
    Beta-blockers, SEPHIA 11-13m
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All subjects included in the SEPHIA registry, attending the follow-up visit at 11-13 months after myocardial infarction

    Subject analysis set title
    No beta-blockers, SEPHIA 11-13m
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All subjects included in the SEPHIA registry, attending the follow-up visit at 11-13 months after myocardial infarction

    Primary: Death from any cause or new myocardial infarction

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    End point title
    		 Death from any cause or new myocardial infarction
    End point description
    End point type
    Primary
    End point timeframe
    Subjects followed for a median of 3.5 (2.2-4.7) years
    End point values
    		 Beta-blockers No beta-blockers
    Number of subjects analysed
    2508
    2512
    Units: Number
    199
    208
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    Beta-blockers v No beta-blockers
    Number of subjects included in analysis
    5020
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.645
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.955
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.787
         upper limit
    		 1.16

    Secondary: All-cause mortality

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    End point title
    		 All-cause mortality
    End point description
    End point type
    Secondary
    End point timeframe
    Subjects followed for a median of 3.5 (2.2-4.7) years
    End point values
    		 Beta-blockers No beta-blockers
    Number of subjects analysed
    2508
    2512
    Units: Number of subjects
        All-cause mortality
    97
    103
    Statistical analysis title
    		 Secondary analyses
    Comparison groups
    Beta-blockers v No beta-blockers
    Number of subjects included in analysis
    5020
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.663
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.713
         upper limit
    		 1.241

    Secondary: Cardiovascular mortality

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    End point title
    		 Cardiovascular mortality
    End point description
    End point type
    Secondary
    End point timeframe
    Subjects followed for a median of 3.5 (2.2-4.7) years
    End point values
    		 Beta-blockers No beta-blockers
    Number of subjects analysed
    2508
    2512
    Units: Number of subjects
        Cardiovascular death
    38
    33
    Statistical analysis title
    		 Secondary analyses
    Comparison groups
    Beta-blockers v No beta-blockers
    Number of subjects included in analysis
    5020
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.553
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.152
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.722
         upper limit
    		 1.836

    Secondary: New myocardial infarction

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    End point title
    		 New myocardial infarction
    End point description
    End point type
    Secondary
    End point timeframe
    Subjects followed for a median of 3.5 (2.2-4.7) years
    End point values
    		 Beta-blockers No beta-blockers
    Number of subjects analysed
    2508
    2512
    Units: Number of subjects
        Myocardial infarction
    112
    117
    Statistical analysis title
    		 Secondary analyses
    Comparison groups
    Beta-blockers v No beta-blockers
    Number of subjects included in analysis
    5020
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.739
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.957
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.738
         upper limit
    		 1.24

    Secondary: Readmission because of atrial fibrillation

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    End point title
    		 Readmission because of atrial fibrillation
    End point description
    End point type
    Secondary
    End point timeframe
    Subjects followed for a median of 3.5 (2.2-4.7) years
    End point values
    		 Beta-blockers No beta-blockers
    Number of subjects analysed
    2508
    2512
    Units: Number of subjects
        Atrial fibrillation
    27
    34
    Statistical analysis title
    		 Secondary analyses
    Comparison groups
    Beta-blockers v No beta-blockers
    Number of subjects included in analysis
    5020
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3666
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.792
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.478
         upper limit
    		 1.313

    Secondary: Readmission because of heart failure

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    End point title
    		 Readmission because of heart failure
    End point description
    End point type
    Secondary
    End point timeframe
    Subjects followed for a median of 3.5 (2.2-4.7) years
    End point values
    		 Beta-blockers No beta-blockers
    Number of subjects analysed
    2508
    2512
    Units: Number of subjects
        Heart failure
    20
    22
    Statistical analysis title
    		 Secondary analyses
    Comparison groups
    Beta-blockers v No beta-blockers
    Number of subjects included in analysis
    5020
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.757
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.909
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.496
         upper limit
    		 1.665

    Secondary: Readmission because of bradycardia, AV-block 2-3, need for pacemaker, hypotension or syncope

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    End point title
    		 Readmission because of bradycardia, AV-block 2-3, need for pacemaker, hypotension or syncope
    End point description
    End point type
    Secondary
    End point timeframe
    Subjects followed for a median of 3.5 (2.2-4.7) years
    End point values
    		 Beta-blockers No beta-blockers
    Number of subjects analysed
    2508
    2512
    Units: Number of subjects
        Bradycardia, AV-block, PPM, hypotension, syncope
    86
    80
    Statistical analysis title
    		 Secondary analyses
    Comparison groups
    Beta-blockers v No beta-blockers
    Number of subjects included in analysis
    5020
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.641
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.075
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.793
         upper limit
    		 1.458

    Secondary: Readmission to hospital because of asthma or COPD

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    End point title
    		 Readmission to hospital because of asthma or COPD
    End point description
    End point type
    Secondary
    End point timeframe
    Subjects followed for a median of 3.5 (2.2-4.7) years
    End point values
    		 Beta-blockers No beta-blockers
    Number of subjects analysed
    2508
    2512
    Units: Number of subjects
        Asthma or chronic obstructive pulmonary disease
    15
    16
    Statistical analysis title
    		 Secondary analyses
    Comparison groups
    Beta-blockers v No beta-blockers
    Number of subjects included in analysis
    5020
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.855
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.937
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.463
         upper limit
    		 1.894

    Secondary: Readmission because of stroke

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    End point title
    		 Readmission because of stroke
    End point description
    End point type
    Secondary
    End point timeframe
    Subjects followed for a median of 3.5 (2.2-4.7) years
    End point values
    		 Beta-blockers No beta-blockers
    Number of subjects analysed
    2508
    2512
    Units: Number of subjects
        Stroke
    36
    46
    Statistical analysis title
    		 Secondary analyses
    Comparison groups
    Beta-blockers v No beta-blockers
    Number of subjects included in analysis
    5020
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2698
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.782
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.506
         upper limit
    		 1.21

    Secondary: CCS Angina class at 6-10 weeks

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    End point title
    		 CCS Angina class at 6-10 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Assessed at the 6-10 week visit.
    End point values
    		 Beta-blockers, SEPHIA 6-10w No beta-blockers, SEPHIA 6-10w
    Number of subjects analysed
    1909
    1927
    Units: Number of subjects
        No angina
    1667
    1669
        CCS I
    82
    90
        CCS II
    29
    27
        CCS III
    7
    5
        CCS IV
    3
    0
        Non-ischaemic
    121
    136
    Statistical analysis title
    		 CCS Angina Class Proportional Odds
    Comparison groups
    No beta-blockers, SEPHIA 6-10w v Beta-blockers, SEPHIA 6-10w
    Number of subjects included in analysis
    3836
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.964
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 1.3

    Secondary: CCS Angina Class at 11-13 months

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    End point title
    		 CCS Angina Class at 11-13 months
    End point description
    End point type
    Secondary
    End point timeframe
    Assessed at the 11-13 month visit.
    End point values
    		 Beta-blockers, SEPHIA 11-13m No beta-blockers, SEPHIA 11-13m
    Number of subjects analysed
    1832
    1886
    Units: Number of subjects
        No angina
    1601
    1652
        CCS I
    82
    79
        CCS II
    28
    27
        CCS III
    7
    8
        CCS IV
    5
    4
        Non-ischaemic
    109
    116
    Statistical analysis title
    		 CCS Angina Class Proportional Odds
    Comparison groups
    Beta-blockers, SEPHIA 11-13m v No beta-blockers, SEPHIA 11-13m
    Number of subjects included in analysis
    3718
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.618
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 1.39

    Secondary: NYHA Dyspnea Class at 6-10 weeks

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    End point title
    		 NYHA Dyspnea Class at 6-10 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Assessed at the 6-10 week visit.
    End point values
    		 Beta-blockers, SEPHIA 6-10w No beta-blockers, SEPHIA 6-10w
    Number of subjects analysed
    1909
    1927
    Units: Number of subjects
        No dyspnea
    1524
    1569
        NYHA I
    71
    61
        NYHA II
    101
    86
        NYHA III
    15
    17
        NYHA IV
    5
    2
        Other reason
    193
    192
    Statistical analysis title
    		 NYHA Dyspnea Class Proportional Odds
    Comparison groups
    Beta-blockers, SEPHIA 6-10w v No beta-blockers, SEPHIA 6-10w
    Number of subjects included in analysis
    3836
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.126
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.95
         upper limit
    		 1.47

    Secondary: NYHA Dyspnea Class at 11-13 months

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    End point title
    		 NYHA Dyspnea Class at 11-13 months
    End point description
    End point type
    Secondary
    End point timeframe
    Assessed at the 11-13 month visit
    End point values
    		 Beta-blockers, SEPHIA 11-13m No beta-blockers, SEPHIA 11-13m
    Number of subjects analysed
    1832
    1886
    Units: Number of subjects
        No dyspnea
    1489
    1576
        NYHA I
    84
    54
        NYHA II
    66
    67
        NYHA III
    12
    14
        NYHA IV
    2
    5
        Other reason
    179
    170
    Statistical analysis title
    		 NYHA Dyspnea Class Proportional Odds
    Comparison groups
    Beta-blockers, SEPHIA 11-13m v No beta-blockers, SEPHIA 11-13m
    Number of subjects included in analysis
    3718
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1107
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.96
         upper limit
    		 1.53

    Secondary: EQ-5D VAS at 6-10 weeks and 11-13 months

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    End point title
    		 EQ-5D VAS at 6-10 weeks and 11-13 months
    End point description
    End point type
    Secondary
    End point timeframe
    Assessed at the 6-10 week visit and the 11-13 month visit.
    End point values
    		 Beta-blockers, SEPHIA 6-10w No beta-blockers, SEPHIA 6-10w Beta-blockers, SEPHIA 11-13m No beta-blockers, SEPHIA 11-13m
    Number of subjects analysed
    1909
    1927
    1834
    1886
    Units: Score
    median (inter-quartile range (Q1-Q3))
        EQ-5D VAS
    76 (65 to 85)
    75 (65 to 85)
    80 (70 to 90)
    80 (70 to 90)
    Statistical analysis title
    		 EQ5D-VAS comparison at 6-10 weeks
    Comparison groups
    Beta-blockers, SEPHIA 6-10w v No beta-blockers, SEPHIA 6-10w
    Number of subjects included in analysis
    3836
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.25
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.95
         upper limit
    		 0.51
    Statistical analysis title
    		 EQ5D-VAS comparison at 11-13 months
    Comparison groups
    Beta-blockers, SEPHIA 11-13m v No beta-blockers, SEPHIA 11-13m
    Number of subjects included in analysis
    3720
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.94
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.11
         upper limit
    		 1.2

    Secondary: EQ-5D mobility score at 6-10 weeks and 11-13 months

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    End point title
    		 EQ-5D mobility score at 6-10 weeks and 11-13 months
    End point description
    End point type
    Secondary
    End point timeframe
    Assessed at the 6-10 week and 11-13 month visits
    End point values
    		 Beta-blockers, SEPHIA 6-10w No beta-blockers, SEPHIA 6-10w Beta-blockers, SEPHIA 11-13m No beta-blockers, SEPHIA 11-13m
    Number of subjects analysed
    1800
    1819
    1745
    1805
    Units: Number of subjects
        I have no problems in walking about
    1569
    1592
    1487
    1556
        I have some problems in walking about
    227
    223
    256
    244
        I am confined to bed
    4
    4
    2
    5
    Statistical analysis title
    		 EQ5D mobility score comparison at 6-10 weeks
    Comparison groups
    Beta-blockers, SEPHIA 6-10w v No beta-blockers, SEPHIA 6-10w
    Number of subjects included in analysis
    3619
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.749
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 1.26
    Statistical analysis title
    		 EQ5D mobility score comparison at 10-13 months
    Comparison groups
    Beta-blockers, SEPHIA 11-13m v No beta-blockers, SEPHIA 11-13m
    Number of subjects included in analysis
    3550
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.412
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 1.31

    Secondary: EQ-5D self-care score at 6-10 weeks and 11-13 months

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    End point title
    		 EQ-5D self-care score at 6-10 weeks and 11-13 months
    End point description
    End point type
    Secondary
    End point timeframe
    Assessed at the 6-10 week and 11-13 month visits
    End point values
    		 Beta-blockers, SEPHIA 6-10w No beta-blockers, SEPHIA 6-10w Beta-blockers, SEPHIA 11-13m No beta-blockers, SEPHIA 11-13m
    Number of subjects analysed
    1797
    1818
    1745
    1805
    Units: Number of subjects
        I have no problems with self-care
    1762
    1788
    1718
    1778
        I have some problems washing or dressing myself
    33
    28
    27
    22
        I am unable to wash or dress myself
    2
    2
    0
    5
    Statistical analysis title
    		 EQ5D self-care score comparison at 6-10 weeks
    Comparison groups
    Beta-blockers, SEPHIA 6-10w v No beta-blockers, SEPHIA 6-10w
    Number of subjects included in analysis
    3615
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.501
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 1.95
    Statistical analysis title
    		 EQ5D self-care score comparison at 10-13 months
    Comparison groups
    Beta-blockers, SEPHIA 11-13m v No beta-blockers, SEPHIA 11-13m
    Number of subjects included in analysis
    3550
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.909
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1.77

    Secondary: EQ-5D usual activities score at 6-10 weeks and 11-13 months

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    End point title
    		 EQ-5D usual activities score at 6-10 weeks and 11-13 months
    End point description
    End point type
    Secondary
    End point timeframe
    Assessed at the 6-10 week and 11-13 month visits
    End point values
    		 Beta-blockers, SEPHIA 6-10w No beta-blockers, SEPHIA 6-10w Beta-blockers, SEPHIA 11-13m No beta-blockers, SEPHIA 11-13m
    Number of subjects analysed
    1795
    1816
    1745
    1804
    Units: Number of subjects
        I have no problems performing usual activities
    1622
    1607
    1590
    1646
        I have some problems performing usual activities
    159
    191
    141
    135
        I am unable to perform usual activities
    14
    18
    14
    23
    Statistical analysis title
    		 EQ5D usual activity score comparison at 6-10 weeks
    Comparison groups
    Beta-blockers, SEPHIA 6-10w v No beta-blockers, SEPHIA 6-10w
    Number of subjects included in analysis
    3611
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0667
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1.01
    Statistical analysis title
    		 EQ5D usual activity score comparison at 10-13m
    Comparison groups
    Beta-blockers, SEPHIA 11-13m v No beta-blockers, SEPHIA 11-13m
    Number of subjects included in analysis
    3549
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.932
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.27

    Secondary: EQ-5D pain/discomfort score at 6-10 weeks and 11-13 months

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    End point title
    		 EQ-5D pain/discomfort score at 6-10 weeks and 11-13 months
    End point description
    End point type
    Secondary
    End point timeframe
    Assessed at the 6-10 week and 11-13 month visits
    End point values
    		 Beta-blockers, SEPHIA 6-10w No beta-blockers, SEPHIA 6-10w Beta-blockers, SEPHIA 11-13m No beta-blockers, SEPHIA 11-13m
    Number of subjects analysed
    1789
    1812
    1745
    1801
    Units: Number of subjects
        I have no pain or discomfort
    1140
    1145
    1050
    1067
        I have moderate pain or discomfort
    594
    608
    618
    664
        I have extreme pain or discomfort
    55
    59
    77
    70
    Statistical analysis title
    		 EQ5D pain/discomfort score comparison at 6-10w
    Comparison groups
    Beta-blockers, SEPHIA 6-10w v No beta-blockers, SEPHIA 6-10w
    Number of subjects included in analysis
    3601
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.719
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 1.12
    Statistical analysis title
    		 EQ5D pain/discomfort score comparison at 10-13m
    Comparison groups
    Beta-blockers, SEPHIA 11-13m v No beta-blockers, SEPHIA 11-13m
    Number of subjects included in analysis
    3546
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.685
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 1.11

    Secondary: EQ-5D anxiety/depression score at 6-10 weeks and 11-13 months

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    End point title
    		 EQ-5D anxiety/depression score at 6-10 weeks and 11-13 months
    End point description
    End point type
    Secondary
    End point timeframe
    Assessed at the 6-10 week and 11-13 month visits
    End point values
    		 Beta-blockers, SEPHIA 6-10w No beta-blockers, SEPHIA 6-10w Beta-blockers, SEPHIA 11-13m No beta-blockers, SEPHIA 11-13m
    Number of subjects analysed
    1787
    1804
    1736
    1790
    Units: Number of subjects
        I am not anxious or depressed
    1204
    1220
    1301
    1320
        I am moderately anxious or depressed
    536
    530
    402
    422
        I am extremely anxious or depressed
    47
    54
    33
    48
    Statistical analysis title
    		 EQ5D anxiety/depression score comparison at 6-10w
    Comparison groups
    Beta-blockers, SEPHIA 6-10w v No beta-blockers, SEPHIA 6-10w
    Number of subjects included in analysis
    3591
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.936
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 1.16
    Statistical analysis title
    		 EQ5D anxiety/depression score comparison at 10-13m
    Comparison groups
    Beta-blockers, SEPHIA 11-13m v No beta-blockers, SEPHIA 11-13m
    Number of subjects included in analysis
    3526
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.353
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.08

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Only serious adverse events that were not considered trial endpoints were collected during the trial.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 N/A
    Dictionary version
    N/A
    Reporting groups
    Reporting group title
    Beta-blockers
    Reporting group description
    		 -

    Reporting group title
    No beta-blockers
    Reporting group description
    		 -

    Serious adverse events
    		 Beta-blockers No beta-blockers
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 2508 (0.00%)
    0 / 2512 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Beta-blockers No beta-blockers
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 2508 (0.00%)
    0 / 2512 (0.00%)
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: No non-serious events were collected during the trial and no serious adverse events were recorded.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Sep 2021
    During the trial, the total blinded event counts indicated an actual event rate of 3% per year instead of 7.2%. The sponsor, together with the steering committee and patient representatives, concluded that a 25% lower risk (corresponding to a 0.9-percentage-point lower absolute risk) would still be a clinically relevant effect to detect. To detect a hazard ratio of 0.75, with 80% power at a two-sided significance level of 5%, a total number of 379 primary end-point events would be required, which was expected to occur with the enrollment of approximately 5000 patients instead of the initially planned 7000 patients. In September 2021, the protocol was revised accordingly.

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

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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/38587241
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