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    Clinical Trial Results:
    A randomized, comparative effectiveness study of complete versus culprit-only revascularization strategies to treat multi-vessel disease after primary percutaneous coronary intervention for ST-segment elevation myocardial infarction

    Summary
    EudraCT number
    		 2013-002210-12
    Trial protocol
    		 ES  
    Global end of trial date
    07 Jun 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Jun 2022
    First version publication date
    25 Jun 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    COMPLETE-2013-05-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01740479
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Population Health Research Institute
    Sponsor organisation address
    237 Barton Street East, Hamilton, Canada,
    Public contact
    COMPLETE Project Office, Population Health Research Institute, 1 9055274322 x40444, complete@phri.ca
    Scientific contact
    COMPLETE Project Office, Population Health Research Institute, 1 9055274322 x40444, complete@phri.ca
    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
    07 Jun 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Jun 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Jun 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine whether, on a background of optimal medical therapy with low dose ASA and ticagrelor, a strategy of multi-vessel revascularization involving staged PCI using drug eluting stents of all suitable non-infarct related artery lesions is superior to a strategy of culprit lesion only revascularization in reducing the composite outcome of CV death or new MI in patients with multi-vessel disease who have undergone successful culprit lesion primary PCI for STEMI.
    Protection of trial subjects
    Consent process: The study was verbally described in detail to the subject. The subjects were given time to review the informed consent form, ask questions, discuss with family, and consider participation before they enrolled into the study. Measures were put in place to protect the personal health information of subjects: Access to medical records and study data were limited to authorized personnel only, access to electronic data was password protected and auditable, electronic data is stored on a network with firewalls and other security and back-up measures in place.
    Background therapy
    		 Guideline-based medical therapy was recommended in both treatment groups. Dual antiplatelet therapy with aspirin and ticagrelor for at least 1 year was recommended.22 Beyond 1 year, aspirin was recommended for all patients, and ticagrelor (60 mg twice daily) was recommended for patients who were not at high risk for bleeding. High-dose statin therapy, angiotensin-converting–enzyme inhibitors or angiotensin-receptor blockers, mineralocorticoid-receptor antagonists, and beta-blockers were recommended.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Feb 2013
    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
    Spain: 265
    Country: Number of subjects enrolled
    Australia: 60
    Country: Number of subjects enrolled
    Austria: 36
    Country: Number of subjects enrolled
    Belgium: 12
    Country: Number of subjects enrolled
    Brazil: 102
    Country: Number of subjects enrolled
    Canada: 1580
    Country: Number of subjects enrolled
    China: 89
    Country: Number of subjects enrolled
    Colombia: 3
    Country: Number of subjects enrolled
    Czechia: 39
    Country: Number of subjects enrolled
    Finland: 36
    Country: Number of subjects enrolled
    France: 119
    Country: Number of subjects enrolled
    Germany: 20
    Country: Number of subjects enrolled
    Greece: 75
    Country: Number of subjects enrolled
    Hungary: 42
    Country: Number of subjects enrolled
    Israel: 22
    Country: Number of subjects enrolled
    Italy: 272
    Country: Number of subjects enrolled
    Kuwait: 9
    Country: Number of subjects enrolled
    Lithuania: 21
    Country: Number of subjects enrolled
    Mexico: 18
    Country: Number of subjects enrolled
    North Macedonia: 108
    Country: Number of subjects enrolled
    Poland: 10
    Country: Number of subjects enrolled
    Portugal: 7
    Country: Number of subjects enrolled
    Romania: 5
    Country: Number of subjects enrolled
    Saudi Arabia: 24
    Country: Number of subjects enrolled
    Serbia: 83
    Country: Number of subjects enrolled
    South Africa: 28
    Country: Number of subjects enrolled
    Sweden: 40
    Country: Number of subjects enrolled
    Switzerland: 4
    Country: Number of subjects enrolled
    Tunisia: 19
    Country: Number of subjects enrolled
    United Kingdom: 713
    Country: Number of subjects enrolled
    United States: 180
    Worldwide total number of subjects
    4041
    EEA total number of subjects
    999
    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)
    2428
    From 65 to 84 years
    1546
    85 years and over
    67

    Subject disposition

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    Recruitment
    Recruitment details
    		 From February 1, 2013, through March 6, 2017, a total of 4041 patients from 140 centers in 31 countries were recruited and randomized.

    Pre-assignment
    Screening details
    		 Patients who presented to the hospital with STEMI were considered for inclusion in the trial if they could undergo randomization within 72 hours after successful culprit-lesion PCI.

    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
    		 Complete Revascularization
    Arm description
    		 A strategy of complete revascularization (consisting of PCI of all suitable nonculprit lesions) in patients with STEMI and multivessel coronary artery disease who had undergone successful culprit-lesion PCI.
    Arm type
    		 standard treatment

    Investigational medicinal product name
    N/A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Not assigned
    Routes of administration
    Not mentioned
    Dosage and administration details
    Guideline-based medical therapy was recommended in both treatment groups. Dual antiplatelet therapy with aspirin and ticagrelor for at least 1 year was recommended. Beyond 1 year, aspirin was recommended for all patients, and ticagrelor (60 mg twice daily) was recommended for patients who were not at high risk for bleeding. High-dose statin therapy, angiotensin-converting–enzyme inhibitors or angiotensin-receptor blockers, mineralocorticoid-receptor antagonists, and beta-blockers were recommended.

    Arm title
    		 Culprit Lesion Only Revascularization
    Arm description
    		 A strategy of no further revascularization in patients with STEMI and multivessel coronary artery disease who had undergone successful culprit-lesion PCI.
    Arm type
    		 standard treatment

    Investigational medicinal product name
    N/A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Not assigned
    Routes of administration
    Not mentioned
    Dosage and administration details
    Guideline-based medical therapy was recommended in both treatment groups. Dual antiplatelet therapy with aspirin and ticagrelor for at least 1 year was recommended. Beyond 1 year, aspirin was recommended for all patients, and ticagrelor (60 mg twice daily) was recommended for patients who were not at high risk for bleeding. High-dose statin therapy, angiotensin-converting–enzyme inhibitors or angiotensin-receptor blockers, mineralocorticoid-receptor antagonists, and beta-blockers were recommended.

    Number of subjects in period 1
    		Complete Revascularization Culprit Lesion Only Revascularization
    Started
    2016
    2025
    Completed
    1881
    1634
    Not completed
    135
    391
         Did not receive allocated intervention
    135
    391

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Complete Revascularization
    Reporting group description
    		 A strategy of complete revascularization (consisting of PCI of all suitable nonculprit lesions) in patients with STEMI and multivessel coronary artery disease who had undergone successful culprit-lesion PCI.

    Reporting group title
    Culprit Lesion Only Revascularization
    Reporting group description
    		 A strategy of no further revascularization in patients with STEMI and multivessel coronary artery disease who had undergone successful culprit-lesion PCI.

    Reporting group values
    		 Complete Revascularization Culprit Lesion Only Revascularization Total
    Number of subjects
    		 2016 2025 4041
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 1233 1195 2428
        Adults (65 years and over)
    		 783 830 1613
    Gender categorical
    Units: Subjects
        Female
    		 393 423 816
        Male
    		 1623 1602 3225
    Time from symptom onset to index PCI
    Units: Subjects
        <6 hr
    		 1383 1341 2724
        6 to 12 hr
    		 322 354 676
        >12 hr
    		 289 305 594
        Not recorded
    		 22 25 47
    Glycated hemoglobin
    Units: percent
        arithmetic mean (standard deviation)
    		 6.3 ( 1.6 ) 6.3 ( 1.6 ) -
    Low-density lipoprotein cholesterol
    Units: millimole(s)/litre
        arithmetic mean (standard deviation)
    		 3.1 ( 1.2 ) 3.1 ( 1.2 ) -
    Peak creatinine
    Units: micromole(s)/litre
        arithmetic mean (standard deviation)
    		 84.7 ( 30.8 ) 85.2 ( 26.8 ) -

    End points

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    End points reporting groups
    Reporting group title
    Complete Revascularization
    Reporting group description
    		 A strategy of complete revascularization (consisting of PCI of all suitable nonculprit lesions) in patients with STEMI and multivessel coronary artery disease who had undergone successful culprit-lesion PCI.

    Reporting group title
    Culprit Lesion Only Revascularization
    Reporting group description
    		 A strategy of no further revascularization in patients with STEMI and multivessel coronary artery disease who had undergone successful culprit-lesion PCI.

    Primary: Co-Primary Outcomes

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    End point title
    		 Co-Primary Outcomes
    End point description
    End point type
    Primary
    End point timeframe
    Outcome events were assessed up to the date of each patient’s final follow-up visit, which ranged from September 1, 2018, to June 7, 2019, when the database was locked. The mean follow-up time was 36.2 months, and the median follow-up time was 35.8 months
    End point values
    		 Complete Revascularization Culprit Lesion Only Revascularization
    Number of subjects analysed
    2016
    2025
    Units: subjects
        Cardiovascular death or myocardial infarction(MI)
    158
    213
        Cardiovascular death, MI,or ischemia-driven revasc
    179
    339
    Statistical analysis title
    		 Analysis of co-primary outcome 1
    Statistical analysis description
    Cardiovascular death or myocardial infarction
    Comparison groups
    Complete Revascularization v Culprit Lesion Only Revascularization
    Number of subjects included in analysis
    4041
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 0.91
    Statistical analysis title
    		 Analysis of co-primary outcome 2
    Statistical analysis description
    Cardiovascular death or myocardial infarction, or ischemia-driven revascularization
    Comparison groups
    Culprit Lesion Only Revascularization v Complete Revascularization
    Number of subjects included in analysis
    4041
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 0.61

    Secondary: Key Secondary Outcomes

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    End point title
    		 Key Secondary Outcomes
    End point description
    Cardiovascular death, myocardial infarction, ischemia-driven revascularization, unstable angina, or NYHA class IV heart failure
    End point type
    Secondary
    End point timeframe
    Outcome events were assessed up to the date of each patient’s final follow-up visit, which ranged from September 1, 2018, to June 7, 2019, when the database was locked. The mean follow-up time was 36.2 months, and the median follow-up time was 35.8 months
    End point values
    		 Complete Revascularization Culprit Lesion Only Revascularization
    Number of subjects analysed
    2016
    2025
    Units: subjects
        Key secondary outcome
    272
    426
    Statistical analysis title
    		 Analysis of key secondary outcome
    Statistical analysis description
    Composite of cardiovascular death, myocardial infarction, ischemia-driven revascularization, unstable angina, or NYHA class IV heart failure
    Comparison groups
    Complete Revascularization v Culprit Lesion Only Revascularization
    Number of subjects included in analysis
    4041
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 0.72

    Secondary: Other Secondary Outcomes

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    End point title
    		 Other Secondary Outcomes
    End point description
    End point type
    Secondary
    End point timeframe
    Outcome events were assessed up to the date of each patient’s final follow-up visit, which ranged from September 1, 2018, to June 7, 2019, when the database was locked. The mean follow-up time was 36.2 months, and the median follow-up time was 35.8 months
    End point values
    		 Complete Revascularization Culprit Lesion Only Revascularization
    Number of subjects analysed
    2016
    2025
    Units: subjects
        Myocardial infarction
    109
    160
        Ischemia-driven revascularization
    29
    160
        Unstable angina
    70
    130
        Death from cardiovascular causes
    59
    64
        Death from any cause
    96
    106
    Statistical analysis title
    		 Analysis of secondary outcomes - MI
    Comparison groups
    Complete Revascularization v Culprit Lesion Only Revascularization
    Number of subjects included in analysis
    4041
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 0.86
    Statistical analysis title
    		 Analysis of secondary outcomes - IDR
    Comparison groups
    Complete Revascularization v Culprit Lesion Only Revascularization
    Number of subjects included in analysis
    4041
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.12
         upper limit
    		 0.26
    Statistical analysis title
    		 Analysis of secondary outcomes - Unstable Angina
    Comparison groups
    Complete Revascularization v Culprit Lesion Only Revascularization
    Number of subjects included in analysis
    4041
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 0.71
    Statistical analysis title
    		 Analysis of secondary outcomes - Death CV causes
    Comparison groups
    Complete Revascularization v Culprit Lesion Only Revascularization
    Number of subjects included in analysis
    4041
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 1.32
    Statistical analysis title
    		 Analysis of secondary outcomes - Death Any Cause
    Comparison groups
    Complete Revascularization v Culprit Lesion Only Revascularization
    Number of subjects included in analysis
    4041
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.2

    Other pre-specified: Other Outcomes

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    End point title
    		 Other Outcomes
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Outcome events were assessed up to the date of each patient’s final follow-up visit, which ranged from September 1, 2018, to June 7, 2019, when the database was locked. The mean follow-up time was 36.2 months, and the median follow-up time was 35.8 months
    End point values
    		 Complete Revascularization Culprit Lesion Only Revascularization
    Number of subjects analysed
    2016
    2025
    Units: subjects
        Stroke
    38
    29
        NYHA class IV heart failure
    58
    56
        Stent thrombosis
    26
    19
    Statistical analysis title
    		 Analysis of other outcomes - Stroke
    Comparison groups
    Complete Revascularization v Culprit Lesion Only Revascularization
    Number of subjects included in analysis
    4041
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 2.13
    Statistical analysis title
    		 Analysis of other - NYHA class IV heart failure
    Comparison groups
    Complete Revascularization v Culprit Lesion Only Revascularization
    Number of subjects included in analysis
    4041
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 1.5
    Statistical analysis title
    		 Analysis of other outcomes - Stent thrombosis
    Comparison groups
    Complete Revascularization v Culprit Lesion Only Revascularization
    Number of subjects included in analysis
    4041
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 2.49

    Other pre-specified: Safety Outcomes

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    End point title
    		 Safety Outcomes
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Outcome events were assessed up to the date of each patient’s final follow-up visit, which ranged from September 1, 2018, to June 7, 2019, when the database was locked. The mean follow-up time was 36.2 months, and the median follow-up time was 35.8 months
    End point values
    		 Complete Revascularization Culprit Lesion Only Revascularization
    Number of subjects analysed
    2016
    2025
    Units: subjects
        Major bleeding
    58
    44
        Contrast-associated acute kidney injury
    30
    19
    Statistical analysis title
    		 Analysis of safety outcomes - Major bleeding
    Comparison groups
    Complete Revascularization v Culprit Lesion Only Revascularization
    Number of subjects included in analysis
    4041
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 1.97
    Statistical analysis title
    		 Analysis of safety-contrast-assoc acute kidney inj
    Comparison groups
    Complete Revascularization v Culprit Lesion Only Revascularization
    Number of subjects included in analysis
    4041
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 2.84

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Not applicable to this trial
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Not Applicable
    Dictionary version
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    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: NOT APPLICABLE TO THIS TRIAL

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Feb 2017
    To ensure that COMPLETE is adequately powered to detect a meaningful clinical difference, the primary outcome of the trial was expanded to a co-primary outcome of 1) cardiovascular death or new myocardial infarction, and 2) cardiovascular death, new myocardial infarction or ischemia-driven revascularization. The sample size was re-calculated resulting in a modest increase in sample size from 3900 to 4000 participants. This amendment also incorporates results from recently published trials into the study background and rationale, harmonizes study objectives and hypotheses with revised study outcomes, and provides additional guidance for the conduct and timing of follow-up visits. For those participants whose qualifying early PCI for STEMI was a pharmacoinvasive strategy, the window for enrolment was extended from 3-12 hours to 3-24 hours after initial PCI. A definition for the outcome event of Unstable Angina and untoward medical event were added and minor changes to the definitions for ischemia-driven revascularization, stent thrombosis and heart failure were updated in accordance with the definitions used by the Event Adjudication Committee.

    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.
    We did not evaluate non-culprit-lesion PCI that was performed during the same procedure as that for the index culprit-lesion PCI for STEMI. Although cardiogenic shock was not an exclusion criterion, no patients with cardiogenic shock were enrolled.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31475795
    http://www.ncbi.nlm.nih.gov/pubmed/31779786
    http://www.ncbi.nlm.nih.gov/pubmed/32912441
    http://www.ncbi.nlm.nih.gov/pubmed/34320839
    http://www.ncbi.nlm.nih.gov/pubmed/32646305
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