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CURRENT/OASIS7: Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent EveNTs/Optimal Antiplatelet Strategy for InterventionS

Sponsor
Sanofi (Industry)
Overall Status
Completed
CT.gov ID
NCT00335452
Collaborator
Bristol-Myers Squibb (Industry)
25,086
Enrollment
38
Locations
4
Arms
39
Duration (Months)
660.2
Patients Per Site
16.9
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate whether a higher dosage of clopidogrel with aspirin (two doses) will decrease the risk of ischemic complications (cardiac death (CV death), myocardial infarction (MI), stroke) after a percutaneous coronary intervention (PCI).

Condition or Disease Intervention/Treatment Phase
Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
25086 participants
Allocation:
Randomized
Intervention Model:
Factorial Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
Randomized, Multinational, Double-blind Study, Comparing a High Loading Dose Regimen of Clopidogrel Versus Standard Dose in Patients With Unstable Angina or Myocardial Infarction Managed With an Early Invasive Strategy.
Study Start Date :
Jun 1, 2006
Actual Primary Completion Date :
Sep 1, 2009
Actual Study Completion Date :
Sep 1, 2009

Arms and Interventions

Arm Intervention/Treatment
Experimental: Clopidogrel high dose treatment regimen + ASA high dose

Drug: Clopidogrel
oral administration
Other Names:
  • SR25990
  • Plavix

    • Drug: acetylsalicyclic acid (ASA)
    oral administration
    Experimental: Clopidogrel high dose treatment regimen + ASA low dose

    Drug: Clopidogrel
    oral administration
    Other Names:
  • SR25990
  • Plavix

    • Drug: acetylsalicyclic acid (ASA)
    oral administration
    Active Comparator: Clopidogrel standard treatment regimen + ASA high dose

    Drug: Clopidogrel
    oral administration
    Other Names:
  • SR25990
  • Plavix

    • Drug: acetylsalicyclic acid (ASA)
    oral administration
    Active Comparator: Clopidogrel standard treatment regimen + ASA low dose

    Drug: Clopidogrel
    oral administration
    Other Names:
  • SR25990
  • Plavix

    • Drug: acetylsalicyclic acid (ASA)
    oral administration

    Outcome Measures

    Primary Outcome Measures

    1. First Occurrence of CV Death / MI / Stroke - Clopidogrel Treatment Regimen Comparison [30 days]

      The primary endpoint is the first occurrence of any of the following events: Cardiovascular death (any death with a clear cardiovascular or unknown cause), Myocardial Infarction (diagnosis of new Myocardial Infarction (MI) - nonfatal or fatal) Stroke (presence of a new focal neurologic deficit thought to be vascular in origin, with signs or symptoms lasting more than 24 hours - nonfatal or fatal) reported between the randomization and Day 30 (inclusive), and validated by the blinded Event Adjudication Committee (EAC).

    2. First Occurrence of CV Death / MI / Stroke - ASA Dose Comparison [30 days]

    3. First Occurrence of CV Death / MI / Stroke - Interaction Clopidogrel Treatment Regimen and ASA Dose Level [30 days]

    4. First Occurrence of CV Death / MI / Stroke - Clopidogrel Treatment Regimen Comparison in PCI Subgroup [30 days]

    Secondary Outcome Measures

    1. Occurrence of Major Bleeding - Clopidogrel Dose Regimen Comparison [30 days]

      Major bleeding is defined as any severe bleeding (associated with any of the following: death, leading to a drop in hemoglobin ≥ 5 g/dl, significant hypotension with the need for inotropic agents, symptomatic intracranial hemorrhage, requirement for surgery or for a transfusion ≥ 4 units of red blood cells or equivalent whole blood) and other major bleeding (significantly disabling bleeding, or intraocular bleeding leading to significant loss of vision or bleeding requiring transfusion of 2-3 units of red blood cells or equivalent whole blood) after validation by the independent EAC.

    2. Occurrence of Major Bleeding - ASA Dose Level Comparison [30 days]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Diagnosed with acute coronary disease with clinical symptoms and at least electrocardiogram changes or cardiac enzymes elevated
    Exclusion Criteria:

    • Use of anticoagulants within 10 days with an international normalized ratio (INR) > 1.5 or planned use during the hospitalisation period

    • Administration of clopidogrel > 75 mg prior to randomization

    • Contraindication to clopidogrel or aspirin

    • Active bleeding or significant risk of bleeding

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Sanofi-Aventis Administrative Office Bridgewater New Jersey United States 08807
    2 Sanofi-Aventis Administrative Office Buenos Aires Argentina
    3 sanofi-aventis Australia & New Zealand administrative office Macquarie Park Australia
    4 Sanofi-Aventis Administrative Office Vienna Austria
    5 Sanofi-Aventis Administrative Office Diegem Belgium
    6 Sanofi-Aventis Administrative Office Sao Paulo Brazil
    7 Sanofi-Aventis Administrative Office Sofia Bulgaria
    8 Sanofi-Aventis Administrative Office Laval Canada
    9 Sanofi-Aventis Administrative Office Santiago de Chile Chile
    10 Sanofi-Aventis Administrative Office Beijing China
    11 Sanofi-Aventis Administrative Office Zagreb Croatia
    12 Sanofi-Aventis Administrative Office Praha Czech Republic
    13 Sanofi-Aventis Administrative Office Tallinn Estonia
    14 Sanofi-Aventis Administrative Office Helsinki Finland
    15 Sanofi-Aventis Administrative Office Paris France
    16 Sanofi-Aventis Administrative Office Berlin Germany
    17 Sanofi-Aventis Administrative Office Athens Greece
    18 Sanofi-Aventis Administrative Office Mumbai India
    19 Sanofi-Aventis Administrative Office Dublin Ireland
    20 Sanofi-Aventis Administrative Office Natanya Israel
    21 Sanofi-Aventis Administrative Office Milano Italy
    22 Sanofi-Aventis Administrative Office Seoul Korea, Republic of
    23 Sanofi-Aventis Administrative Office Riga Latvia
    24 Sanofi-Aventis Administrative Office Vilnius Lithuania
    25 Sanofi-Aventis Administrative Office Kuala Lumpur Malaysia
    26 Sanofi-Aventis Administrative Office Mexico Mexico
    27 Sanofi-Aventis Administrative Office Gouda Netherlands
    28 Sanofi-Aventis Administrative Office Warszawa Poland
    29 Sanofi-Aventis Administrative Office Bucuresti Romania
    30 Sanofi-Aventis Administrative Office Moscow Russian Federation
    31 Sanofi-Aventis Administrative Office Singapore Singapore
    32 Sanofi-Aventis Administrative Office Brastislava Slovakia
    33 Sanofi-Aventis Administrative Office Midrand South Africa
    34 Sanofi-Aventis Admnistrative Office Madrid Spain
    35 Sanofi-Aventis Administrative Office Bromma Sweden
    36 Sanofi-Aventis Administrative Office Geneva Switzerland
    37 Sanofi-Aventis Administrative Office Istanbul Turkey
    38 Sanofi-Aventis Administrative Office Guildford Surrey United Kingdom

    Sponsors and Collaborators

    • Sanofi
    • Bristol-Myers Squibb

    Investigators

    • Principal Investigator: Shamir MEHTA, MD, Hamilton General Hospital, McMaster University, CANADA

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    , ,
    ClinicalTrials.gov Identifier:
    NCT00335452
    Other Study ID Numbers:
    • EFC5965
    • EUDRACT: 2006-000313-38
    First Posted:
    Jun 9, 2006
    Last Update Posted:
    Nov 18, 2010
    Last Verified:
    Nov 1, 2010
    Keywords provided by , ,
    platelet aggregation inhibitors
    acute coronary disease
    percutaneous coronary
    Additional relevant MeSH terms:
    Coronary Disease
    Coronary Artery Disease
    Clopidogrel

    Study Results

    Participant Flow

    Recruitment Details 25086 patients were enrolled and randomized between June 2006 and August 2009 in 597 sites in 39 countries. Because the observed overall blinded event rate was substantially lower than expected, the number of patients to be enrolled was increased from 18000 to 20000, then to 25000.
    Pre-assignment Detail Treatment assignment was performed through an automated voice randomization service (AreS). At the same time, the AReS provided allocation to a Clopidogrel treatment regimen according to a pre-defined randomization list and to a ASA dose according to a factorial design.
    Arm/Group Title Clopidogrel 300/75/75 mg + ASA Low Dose Clopidogrel 300/75/75 mg + ASA High Dose Clopidogrel 600/150/75 mg + ASA Low Dose Clopidogrel 600/150/75 mg + ASA High Dose
    Arm/Group Description Day 1: Clopidogrel 300 mg loading dose + ASA ≥ 300 mg Day 2 to Day 7: Clopidogrel 75 mg + ASA 75-100 mg Day 8 to Day 30: Clopidogrel 75 mg + ASA 75-100 mg Day 1: Clopidogrel 300 mg loading dose + ASA ≥ 300 mg Day 2 to Day 7: Clopidogrel 75 mg + ASA 300-325 mg Day 8 to Day 30: Clopidogrel 75 mg + ASA 300-325 mg Day 1: Clopidogrel 600 mg loading dose + ASA ≥ 300 mg Day 2 to Day 7: Clopidogrel 150 mg + ASA 75-100 mg Day 8 to Day 30: Clopidogrel 75 mg + ASA 75-100 mg Day 1: Clopidogrel 600 mg loading dose + ASA ≥ 300 mg Day 2 to Day 7: Clopidogrel 150 mg + ASA 300-325 mg Day 8 to Day 30: Clopidogrel 75 mg + ASA 300-325 mg
    Period Title: Overall Study
    STARTED 6312 6254 6267 6253
    TREATED WITH CLOPIDOGREL 6271 6218 6228 6217
    TREATED WITH ASA 6302 6251 6261 6247
    COMPLETED 6154 6107 6108 6122
    NOT COMPLETED 158 147 159 131

    Baseline Characteristics

    Arm/Group Title Clopidogrel 300/75/75 mg + ASA Low Dose Clopidogrel 300/75/75 mg + ASA High Dose Clopidogrel 600/150/75 mg + ASA Low Dose Clopidogrel 600/150/75 mg + ASA High Dose Total
    Arm/Group Description Total of all reporting groups
    Overall Participants 6312 6254 6267 6253 25086
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    61.3
    (11.7)
    61.5
    (11.7)
    61.2
    (11.8)
    61.4
    (11.9)
    61.3
    (11.8)
    Age, Customized (participants) [Number]
    < 65 years
    3792
    60.1%
    3740
    59.8%
    3787
    60.4%
    3735
    59.7%
    15054
    60%
    65 - 74 years
    1573
    24.9%
    1576
    25.2%
    1543
    24.6%
    1543
    24.7%
    6235
    24.9%
    ≥ 75 years
    947
    15%
    937
    15%
    937
    15%
    975
    15.6%
    3796
    15.1%
    Missing
    0
    0%
    1
    0%
    0
    0%
    0
    0%
    1
    0%
    Sex: Female, Male (Count of Participants)
    Female
    1702
    27%
    1756
    28.1%
    1671
    26.7%
    1742
    27.9%
    6871
    27.4%
    Male
    4610
    73%
    4498
    71.9%
    4596
    73.3%
    4511
    72.1%
    18215
    72.6%
    Region of Enrollment (participants) [Number]
    Argentina
    182
    2.9%
    159
    2.5%
    162
    2.6%
    174
    2.8%
    677
    2.7%
    Australia
    97
    1.5%
    100
    1.6%
    96
    1.5%
    95
    1.5%
    388
    1.5%
    Austria
    41
    0.6%
    35
    0.6%
    35
    0.6%
    40
    0.6%
    151
    0.6%
    Belgium
    55
    0.9%
    61
    1%
    59
    0.9%
    53
    0.8%
    228
    0.9%
    Brazil
    292
    4.6%
    275
    4.4%
    270
    4.3%
    288
    4.6%
    1125
    4.5%
    Bulgaria
    111
    1.8%
    122
    2%
    125
    2%
    112
    1.8%
    470
    1.9%
    Canada
    349
    5.5%
    379
    6.1%
    373
    6%
    347
    5.5%
    1448
    5.8%
    Chile
    95
    1.5%
    85
    1.4%
    82
    1.3%
    90
    1.4%
    352
    1.4%
    China
    510
    8.1%
    492
    7.9%
    500
    8%
    515
    8.2%
    2017
    8%
    Croatia
    114
    1.8%
    145
    2.3%
    144
    2.3%
    114
    1.8%
    517
    2.1%
    Czech Republic
    257
    4.1%
    275
    4.4%
    277
    4.4%
    258
    4.1%
    1067
    4.3%
    Estonia
    1
    0%
    0
    0%
    0
    0%
    1
    0%
    2
    0%
    Finland
    132
    2.1%
    127
    2%
    127
    2%
    132
    2.1%
    518
    2.1%
    France
    177
    2.8%
    163
    2.6%
    165
    2.6%
    175
    2.8%
    680
    2.7%
    Germany
    471
    7.5%
    450
    7.2%
    453
    7.2%
    470
    7.5%
    1844
    7.4%
    Greece
    20
    0.3%
    21
    0.3%
    23
    0.4%
    21
    0.3%
    85
    0.3%
    India
    658
    10.4%
    650
    10.4%
    645
    10.3%
    646
    10.3%
    2599
    10.4%
    Ireland
    24
    0.4%
    13
    0.2%
    15
    0.2%
    23
    0.4%
    75
    0.3%
    Israel
    286
    4.5%
    272
    4.3%
    275
    4.4%
    282
    4.5%
    1115
    4.4%
    Italy
    232
    3.7%
    260
    4.2%
    258
    4.1%
    231
    3.7%
    981
    3.9%
    Korea, Republic of
    161
    2.6%
    149
    2.4%
    152
    2.4%
    165
    2.6%
    627
    2.5%
    Latvia
    16
    0.3%
    16
    0.3%
    15
    0.2%
    15
    0.2%
    62
    0.2%
    Lithuania
    26
    0.4%
    31
    0.5%
    30
    0.5%
    28
    0.4%
    115
    0.5%
    Malaysia
    29
    0.5%
    39
    0.6%
    39
    0.6%
    28
    0.4%
    135
    0.5%
    Mexico
    16
    0.3%
    17
    0.3%
    19
    0.3%
    17
    0.3%
    69
    0.3%
    Netherlands
    46
    0.7%
    48
    0.8%
    48
    0.8%
    46
    0.7%
    188
    0.7%
    New Zealand
    36
    0.6%
    31
    0.5%
    29
    0.5%
    29
    0.5%
    125
    0.5%
    Poland
    365
    5.8%
    322
    5.1%
    325
    5.2%
    362
    5.8%
    1374
    5.5%
    Romania
    47
    0.7%
    30
    0.5%
    33
    0.5%
    48
    0.8%
    158
    0.6%
    Russian Federation
    132
    2.1%
    137
    2.2%
    138
    2.2%
    131
    2.1%
    538
    2.1%
    Singapore
    10
    0.2%
    13
    0.2%
    15
    0.2%
    10
    0.2%
    48
    0.2%
    Slovakia
    93
    1.5%
    84
    1.3%
    83
    1.3%
    92
    1.5%
    352
    1.4%
    South Africa
    24
    0.4%
    14
    0.2%
    14
    0.2%
    23
    0.4%
    75
    0.3%
    Spain
    264
    4.2%
    276
    4.4%
    283
    4.5%
    263
    4.2%
    1086
    4.3%
    Sweden
    10
    0.2%
    11
    0.2%
    9
    0.1%
    10
    0.2%
    40
    0.2%
    Switzerland
    51
    0.8%
    64
    1%
    64
    1%
    48
    0.8%
    227
    0.9%
    Turkey
    79
    1.3%
    96
    1.5%
    94
    1.5%
    78
    1.2%
    347
    1.4%
    United Kingdom
    28
    0.4%
    29
    0.5%
    34
    0.5%
    28
    0.4%
    119
    0.5%
    United States
    775
    12.3%
    763
    12.2%
    759
    12.1%
    765
    12.2%
    3062
    12.2%
    Qualifying condition (participants) [Number]
    Suspected Unstable Angina (UA)
    1809
    28.7%
    1771
    28.3%
    1757
    28%
    1877
    30%
    7214
    28.8%
    Suspected MI without ST elevation (NSTEMI)
    2662
    42.2%
    2662
    42.6%
    2668
    42.6%
    2539
    40.6%
    10531
    42%
    MI with ST elevation (STEMI)
    1839
    29.1%
    1817
    29.1%
    1839
    29.3%
    1832
    29.3%
    7327
    29.2%
    Missing
    2
    0%
    4
    0.1%
    3
    0%
    5
    0.1%
    14
    0.1%
    Intended PCI performed (participants) [Number]
    Yes
    4377
    69.3%
    4326
    69.2%
    4262
    68%
    4298
    68.7%
    17263
    68.8%
    No
    1935
    30.7%
    1928
    30.8%
    2005
    32%
    1955
    31.3%
    7823
    31.2%

    Outcome Measures

    1. Primary Outcome
    Title First Occurrence of CV Death / MI / Stroke - Clopidogrel Treatment Regimen Comparison
    Description The primary endpoint is the first occurrence of any of the following events: Cardiovascular death (any death with a clear cardiovascular or unknown cause), Myocardial Infarction (diagnosis of new Myocardial Infarction (MI) - nonfatal or fatal) Stroke (presence of a new focal neurologic deficit thought to be vascular in origin, with signs or symptoms lasting more than 24 hours - nonfatal or fatal) reported between the randomization and Day 30 (inclusive), and validated by the blinded Event Adjudication Committee (EAC).
    Time Frame 30 days

    Outcome Measure Data

    Analysis Population Description
    The analysis is on the intent-to-treat population (ITT) that consists of all patients randomized irrespective of whether they received study medication, underwent a PCI, or otherwise complied with the study protocol.
    Arm/Group Title Clopidogrel 300/75/75 mg + ASA Clopidogrel 600/150/75 mg + ASA
    Arm/Group Description Patients randomized to the Clopidogrel 300/75/75 mg dose regimen irrespective of the ASA dose Patients randomized to the Clopidogrel 600/150/75 mg dose regimen irrespective of the ASA dose
    Measure Participants 12566 12520
    CV death/MI/Stroke
    557
    8.8%
    522
    8.3%
    - CV death
    222
    3.5%
    226
    3.6%
    - MI (fatal or not)
    274
    4.3%
    237
    3.8%
    - Stroke (fatal or not)
    61
    1%
    59
    0.9%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Clopidogrel 300/75/75 mg + ASA, Clopidogrel 600/150/75 mg + ASA
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.3037
    Comments The a priori threshold for statistical significance is ≤0.05.
    Method Log Rank
    Comments Two-sided stratified by ASA dose level (low or high) and qualifying condition (UA/NSTEMI or STEMI) log-rank test.
    Method of Estimation Estimation Parameter Relative Risk Reduction (%)
    Estimated Value 6.1
    Confidence Interval (2-Sided) 95%
    -5.8 to 16.6
    Parameter Dispersion Type:
    Value:
    Estimation Comments The relative risk reduction (high dose treatment regimen (600/150/75 mg) versus standard treatment regimen (300/75/75 mg)) is estimated using stratified Cox proportional hazards model controlling for ASA dose level and qualifying condition.
    2. Secondary Outcome
    Title Occurrence of Major Bleeding - Clopidogrel Dose Regimen Comparison
    Description Major bleeding is defined as any severe bleeding (associated with any of the following: death, leading to a drop in hemoglobin ≥ 5 g/dl, significant hypotension with the need for inotropic agents, symptomatic intracranial hemorrhage, requirement for surgery or for a transfusion ≥ 4 units of red blood cells or equivalent whole blood) and other major bleeding (significantly disabling bleeding, or intraocular bleeding leading to significant loss of vision or bleeding requiring transfusion of 2-3 units of red blood cells or equivalent whole blood) after validation by the independent EAC.
    Time Frame 30 days

    Outcome Measure Data

    Analysis Population Description
    The analysis is on the intent-to-treat population (ITT) that consists of all patients randomized irrespective of whether they received study medication, underwent a PCI, or otherwise complied with the study protocol.
    Arm/Group Title Clopidogrel 300/75/75 mg + ASA Clopidogrel 600/150/75 mg + ASA
    Arm/Group Description Patients randomized to the Clopidogrel 300/75/75 mg dose regimen irrespective of the ASA dose Patients randomized to the Clopidogrel 600/150/75 mg dose regimen irrespective of the ASA dose.
    Measure Participants 12566 12520
    Major bleeding
    255
    4%
    313
    5%
    - Severe bleeding
    195
    3.1%
    236
    3.8%
    - Major but not severe bleeding
    65
    1%
    83
    1.3%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Clopidogrel 300/75/75 mg + ASA, Clopidogrel 600/150/75 mg + ASA
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.012
    Comments The a priori threshold for statistical significance is ≤0.05.
    Method Regression, Logistic
    Comments logistic regression model including terms for ASA dose level (low or high) and qualifying condition (UA/NSTEMI or STEMI).
    3. Primary Outcome
    Title First Occurrence of CV Death / MI / Stroke - ASA Dose Comparison
    Description
    Time Frame 30 days

    Outcome Measure Data

    Analysis Population Description
    The analysis is on the the ASA treated population that consists of all patients randomized and having receiving at least one dose of ASA. All patients were included in the treatment group to which they were allocated by the AReS.
    Arm/Group Title Clopidogrel + ASA Low Dose Clopidogrel + ASA High Dose
    Arm/Group Description Patients treated with ASA low dose irrespective of the Clopidogrel treatment regimen Patients treated with ASA high dose irrespective of the Clopidogrel treatment regimen
    Measure Participants 12563 12498
    CV death/MI/Stroke
    546
    8.7%
    527
    8.4%
    - CV death
    231
    3.7%
    211
    3.4%
    - MI (fatal or not)
    260
    4.1%
    251
    4%
    - Stroke (fatal or not)
    55
    0.9%
    65
    1%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Clopidogrel 300/75/75 mg + ASA, Clopidogrel 600/150/75 mg + ASA
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.6047
    Comments The a priori threshold for statistical significance is ≤0.05.
    Method Log Rank
    Comments Two-sided stratified by clopidogrel treatment regimen (300/75/75 mg or 600/150/75 mg) log-rank test.
    Method of Estimation Estimation Parameter Relative Risk Reduction (%)
    Estimated Value 3.1
    Confidence Interval (2-Sided) 95%
    -9.2 to 14.0
    Parameter Dispersion Type:
    Value:
    Estimation Comments The relative risk reduction (ASA high dose versus ASA low dose) is estimated using stratified Cox proportional hazards model controlling for Clopidogrel treatment regimen.
    4. Primary Outcome
    Title First Occurrence of CV Death / MI / Stroke - Interaction Clopidogrel Treatment Regimen and ASA Dose Level
    Description
    Time Frame 30 days

    Outcome Measure Data

    Analysis Population Description
    The analysis is on the intent-to-treat population (ITT) that consists of all patients randomized irrespective of whether they received study medication, underwent a PCI, or otherwise complied with the study protocol.
    Arm/Group Title Clopidogrel 300/75/75 mg + ASA Low Dose Clopidogrel 300/75/75 mg + ASA High Dose Clopidogrel 600/150/75 mg + ASA Low Dose Clopidogrel 600/150/75 mg + ASA High Dose
    Arm/Group Description
    Measure Participants 6312 6254 6267 6253
    Number [participants]
    267
    4.2%
    290
    4.6%
    282
    4.5%
    240
    3.8%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Clopidogrel 300/75/75 mg + ASA, Clopidogrel 600/150/75 mg + ASA Low Dose
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.4579
    Comments The a priori threshold for statistical significance is ≤0.05.
    Method Log Rank
    Comments Two-sided stratified by qualifying condition (UA/NSTEMI or STEMI) log-rank test.
    Method of Estimation Estimation Parameter Relative Risk Reduction (%)
    Estimated Value -6.5
    Confidence Interval (2-Sided) 95%
    -26.0 to 9.9
    Parameter Dispersion Type:
    Value:
    Estimation Comments The relative risk reduction (high dose treatment regimen (600/150/75 mg) versus standard treatment regimen (300/75/75 mg)) is estimated using a stratified Cox proportional hazards model controlling for qualifying condition.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Clopidogrel 600/150/75 mg + ASA, Clopidogrel 600/150/75 mg + ASA High Dose
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0262
    Comments The a priori threshold for statistical significance is ≤0.05.
    Method Log Rank
    Comments Two-sided stratified by qualifying condition (UA/NSTEMI or STEMI) log-rank test.
    Method of Estimation Estimation Parameter Relative Risk Reduction (%)
    Estimated Value 17.6
    Confidence Interval (2-Sided) 95%
    2.2 to 30.5
    Parameter Dispersion Type:
    Value:
    Estimation Comments The relative risk reduction (high dose treatment regimen (600/150/75 mg) versus standard treatment regimen (300/75/75 mg)) is estimated using a stratified Cox proportional hazards model controlling for qualifying condition.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Clopidogrel 300/75/75 mg + ASA, Clopidogrel 600/150/75 mg + ASA, Clopidogrel 600/150/75 mg + ASA Low Dose, Clopidogrel 600/150/75 mg + ASA High Dose
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0355
    Comments The a priori threshold for statistical significance is ≤0.05.
    Method Chi-squared
    Comments Interaction chi-squared test of the Cox proportional hazards model.
    5. Primary Outcome
    Title First Occurrence of CV Death / MI / Stroke - Clopidogrel Treatment Regimen Comparison in PCI Subgroup
    Description
    Time Frame 30 days

    Outcome Measure Data

    Analysis Population Description
    The intent-to-treat (ITT) analysis is done on the randomized patients who underwent PCI during the study.
    Arm/Group Title Clopidogrel 300/75/75 mg + ASA Clopidogrel 600/150/75 mg + ASA
    Arm/Group Description Patients randomized to the Clopidogrel 300/75/75 mg dose regimen irrespective of the ASA dose Patients randomized to the Clopidogrel 600/150/75 mg dose regimen irrespective of the ASA dose
    Measure Participants 8703 8560
    CV death/MI/Stroke
    392
    6.2%
    330
    5.3%
    - CV death
    132
    2.1%
    130
    2.1%
    - MI (fatal or not)
    225
    3.6%
    172
    2.8%
    - Stroke (fatal or not)
    35
    0.6%
    28
    0.4%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Clopidogrel 300/75/75 mg + ASA, Clopidogrel 600/150/75 mg + ASA
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0332
    Comments The a priori threshold for statistical significance is ≤0.05.
    Method Log Rank
    Comments Two-sided stratified by ASA dose level (low or high) and qualifying condition (UA/NSTEMI or STEMI) Log-rank test. No adjustment was made.
    Method of Estimation Estimation Parameter Relative Risk Reduction (%)
    Estimated Value 14.7
    Confidence Interval (2-Sided) 95%
    1.2 to 26.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments The relative risk reduction (high dose treatment regimen (600/150/75 mg) versus standard treatment regimen (300/75/75 mg)) is estimated using a stratified Cox proportional hazards model controlling for ASA dose level and qualifying condition.
    6. Secondary Outcome
    Title Occurrence of Major Bleeding - ASA Dose Level Comparison
    Description
    Time Frame 30 days

    Outcome Measure Data

    Analysis Population Description
    The analysis is on the treated patient population that consists of all patients randomized and having receiving at least one dose of ASA. All patients were included in the treatment group to which they were allocated by the AReS.
    Arm/Group Title Clopidogrel + ASA Low Dose Clopidogrel + ASA High Dose
    Arm/Group Description Patients treated with ASA low dose irrespective of the Clopidogrel treatment regimen Patients treated with ASA high dose irrespective of the Clopidogrel treatment regimen
    Measure Participants 12563 12498
    Major bleeding
    285
    4.5%
    282
    4.5%
    - Severe bleeding
    215
    3.4%
    216
    3.5%
    - Major but not severe bleeding
    74
    1.2%
    73
    1.2%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Clopidogrel 300/75/75 mg + ASA, Clopidogrel 600/150/75 mg + ASA
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.945
    Comments The a priori threshold for statistical significance is ≤0.05.
    Method Regression, Logistic
    Comments Logistic regression model including a term for Clopidogrel treatment regimen (300/75/75 mg or 600/150/75 mg).
    7. Post-Hoc Outcome
    Title Occurrence of Stent Thrombosis - Clopidogrel Treatment Regimen Comparison
    Description This includes definite stent thrombosis (confirmed by angiography or evidence of recent thrombus determined at autopsy or by examination of tissue retrieved following thrombectomy) and probable stent thrombosis (unexplained death having occurred after intracoronary stenting or, MI related to acute ischemia in the territory of the implanted stent without angiographic confirmation and in the absence of any obvious cause) after validation by the EAC.
    Time Frame 30 days

    Outcome Measure Data

    Analysis Population Description
    The analysis is on the intent-to-treat population (ITT) that consists of all patients randomized irrespective of whether they received study medication, underwent a PCI, or otherwise complied with the study protocol.
    Arm/Group Title Clopidogrel 300/75/75 mg + ASA Clopidogrel 600/150/75 mg + ASA
    Arm/Group Description Patients randomized to the Clopidogrel 300/75/75 mg dose regimen irrespective of the ASA dose Patients randomized to the Clopidogrel 600/150/75 mg dose regimen irrespective of the ASA dose
    Measure Participants 12566 12520
    Stent trombosis
    200
    3.2%
    135
    2.2%
    - Definite
    111
    1.8%
    58
    0.9%
    - Probable
    89
    1.4%
    77
    1.2%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Clopidogrel 300/75/75 mg + ASA, Clopidogrel 600/150/75 mg + ASA
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0004
    Comments The a priori threshold for statistical significance is ≤0.05.
    Method Log Rank
    Comments Two-sided stratified by ASA dose level (low or high) and qualifying condition (UA/NSTEMI or STEMI) log-rank test.
    Method of Estimation Estimation Parameter Relative Risk Reduction (%)
    Estimated Value 32.6
    Confidence Interval (2-Sided) 95%
    16.2 to 45.8
    Parameter Dispersion Type:
    Value:
    Estimation Comments The relative risk reduction (high dose treatment regimen (600/150/75 mg) versus standard treatment regimen (300/75/75 mg)) is estimated using a stratified Cox proportional hazards model controlling for ASA dose level and qualifying condition.

    Adverse Events

    Time Frame 30 days
    Adverse Event Reporting Description The analysis is on the intent-to-treat population (ITT). All patients were included in the treatment arm to which they were allocated by the AReS. Any adverse event that developed or worsened on or after randomization up to the day of the final follow-up visit was included.
    Arm/Group Title Clopidogrel 300/75/75 mg + ASA Low Dose Clopidogrel 300/75/75 mg + ASA High Dose Clopidogrel 600/150/75 mg + ASA Low Dose Clopidogrel 600/150/75 mg + ASA High Dose
    Arm/Group Description Day 1: Clopidogrel 300 mg loading dose + ASA ≥ 300 mg Day 2 to Day 7: Clopidogrel 75 mg + ASA 75-100 mg Day 8 to Day 30: Clopidogrel 75 mg + ASA 75-100 mg Day 1: Clopidogrel 300 mg loading dose + ASA ≥ 300 mg Day 2 to Day 7: Clopidogrel 75 mg + ASA 300-325 mg Day 8 to Day 30: Clopidogrel 75 mg + ASA 300-325 mg Day 1: Clopidogrel 600 mg loading dose + ASA ≥ 300 mg Day 2 to Day 7: Clopidogrel 150 mg + ASA 75-100 mg Day 8 to Day 30: Clopidogrel 75 mg + ASA 75-100 mg Day 1: Clopidogrel 600 mg loading dose + ASA ≥ 300 mg Day 2 to Day 7: Clopidogrel 150 mg + ASA 300-325 mg Day 8 to Day 30: Clopidogrel 75 mg + ASA 300-325 mg
    All Cause Mortality
    Clopidogrel 300/75/75 mg + ASA Low Dose Clopidogrel 300/75/75 mg + ASA High Dose Clopidogrel 600/150/75 mg + ASA Low Dose Clopidogrel 600/150/75 mg + ASA High Dose
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Clopidogrel 300/75/75 mg + ASA Low Dose Clopidogrel 300/75/75 mg + ASA High Dose Clopidogrel 600/150/75 mg + ASA Low Dose Clopidogrel 600/150/75 mg + ASA High Dose
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 322/6312 (5.1%) 329/6254 (5.3%) 372/6267 (5.9%) 332/6253 (5.3%)
    Blood and lymphatic system disorders
    Haemorrhagic anaemia 7/6312 (0.1%) 5/6254 (0.1%) 4/6267 (0.1%) 6/6253 (0.1%)
    Anaemia 5/6312 (0.1%) 1/6254 (0%) 3/6267 (0%) 5/6253 (0.1%)
    Thrombocytopenia 2/6312 (0%) 3/6254 (0%) 4/6267 (0.1%) 2/6253 (0%)
    Nephrogenic anaemia 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 2/6253 (0%)
    Heparin-induced thrombocytopenia 0/6312 (0%) 2/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Anaemia of chronic disease 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Eosinophilia 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Normochromic normocytic anaemia 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Disseminated intravascular coagulation 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Iron deficiency anaemia 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    White blood cell disorder 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Lymphadenopathy 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Microcytic anaemia 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Splenic infarction 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Cardiac disorders
    Pericardial haemorrhage 15/6312 (0.2%) 12/6254 (0.2%) 18/6267 (0.3%) 11/6253 (0.2%)
    Intracardiac thrombus 1/6312 (0%) 2/6254 (0%) 1/6267 (0%) 5/6253 (0.1%)
    Pericarditis 3/6312 (0%) 1/6254 (0%) 2/6267 (0%) 1/6253 (0%)
    Acute left ventricular failure 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Atrial thrombosis 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Cardiac perforation 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Cardiogenic shock 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Interventricular septum rupture 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Myopericarditis 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Mitral valve incompetence 0/6312 (0%) 1/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Cardiac tamponade 2/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Bradyarrhythmia 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Cardiac arrest 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Cardiac failure congestive 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Haemorrhage coronary artery 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Myocarditis 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Right ventricular dysfunction 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Cardiac failure 0/6312 (0%) 2/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Cardiopulmonary failure 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Coronary artery thrombosis 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Myocardial infarction 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Pericardial effusion 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Cardio-respiratory arrest 2/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Dressler's syndrome 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Left ventricular failure 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Palpitations 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Congenital, familial and genetic disorders
    Ventricular septal defect 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Gastrointestinal angiodysplasia haemorrhagic 0/6312 (0%) 1/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Atrial septal defect 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Phimosis 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Ear and labyrinth disorders
    Vertigo 1/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Deafness 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Hypoacusis 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Endocrine disorders
    Pituitary cyst 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Eye disorders
    Diplopia 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Retinal detachment 1/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Glaucoma 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Gastrointestinal disorders
    Gastrointestinal haemorrhage 13/6312 (0.2%) 12/6254 (0.2%) 15/6267 (0.2%) 15/6253 (0.2%)
    Retroperitoneal haemorrhage 2/6312 (0%) 4/6254 (0.1%) 9/6267 (0.1%) 8/6253 (0.1%)
    Upper gastrointestinal haemorrhage 3/6312 (0%) 6/6254 (0.1%) 3/6267 (0%) 6/6253 (0.1%)
    Gastritis 2/6312 (0%) 3/6254 (0%) 2/6267 (0%) 3/6253 (0%)
    Gastrointestinal ulcer haemorrhage 0/6312 (0%) 1/6254 (0%) 2/6267 (0%) 3/6253 (0%)
    Abdominal pain upper 0/6312 (0%) 1/6254 (0%) 1/6267 (0%) 3/6253 (0%)
    Gastric haemorrhage 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 3/6253 (0%)
    Retroperitoneal haematoma 1/6312 (0%) 1/6254 (0%) 2/6267 (0%) 2/6253 (0%)
    Duodenal ulcer haemorrhage 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 2/6253 (0%)
    Peptic ulcer 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 2/6253 (0%)
    Constipation 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 2/6253 (0%)
    Pancreatitis acute 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 2/6253 (0%)
    Colitis ischaemic 0/6312 (0%) 1/6254 (0%) 1/6267 (0%) 1/6253 (0%)
    Duodenal ulcer 0/6312 (0%) 1/6254 (0%) 1/6267 (0%) 1/6253 (0%)
    Diarrhoea 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 1/6253 (0%)
    Gastritis haemorrhagic 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Oesophagitis haemorrhagic 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Abdominal discomfort 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Gastritis erosive 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Haematemesis 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Intestinal ischaemia 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Tongue haemorrhage 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Pancreatitis 0/6312 (0%) 4/6254 (0.1%) 2/6267 (0%) 0/6253 (0%)
    Gastrooesophageal reflux disease 0/6312 (0%) 3/6254 (0%) 2/6267 (0%) 0/6253 (0%)
    Haemorrhoidal haemorrhage 0/6312 (0%) 2/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Gastric ulcer haemorrhage 2/6312 (0%) 1/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Abdominal pain 1/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Colonic pseudo-obstruction 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Gastric ulcer 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Gastrointestinal pain 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Ileus 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Lumbar hernia 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Nausea 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Rectal haemorrhage 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Small intestinal obstruction 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Vomiting 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Dysphagia 1/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Diverticulum intestinal haemorrhagic 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Enterocolitis haemorrhagic 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Gastrointestinal ischaemia 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Haemorrhagic erosive gastritis 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Intestinal obstruction 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Peptic ulcer haemorrhage 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Periodontitis 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Peritonitis 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Acute abdomen 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Diverticular perforation 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Gastric polyps 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Hiatus hernia 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Large intestinal haemorrhage 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Melaena 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Mesenteric vein thrombosis 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Reflux oesophagitis 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    General disorders
    Puncture site haemorrhage 17/6312 (0.3%) 21/6254 (0.3%) 22/6267 (0.4%) 31/6253 (0.5%)
    Pyrexia 1/6312 (0%) 5/6254 (0.1%) 0/6267 (0%) 4/6253 (0.1%)
    Vessel puncture site haematoma 2/6312 (0%) 2/6254 (0%) 1/6267 (0%) 2/6253 (0%)
    Chest pain 2/6312 (0%) 3/6254 (0%) 5/6267 (0.1%) 1/6253 (0%)
    Multi-organ failure 1/6312 (0%) 2/6254 (0%) 3/6267 (0%) 1/6253 (0%)
    Non-cardiac chest pain 4/6312 (0.1%) 2/6254 (0%) 2/6267 (0%) 1/6253 (0%)
    Catheter site haematoma 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Implant site haemorrhage 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Inflammation 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Necrosis 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Systemic inflammatory response syndrome 0/6312 (0%) 1/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Oedema peripheral 1/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Application site erosion 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Catheter site haemorrhage 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Gait disturbance 1/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Mechanical complication of implant 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Implant site haematoma 2/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Fatigue 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Hepatobiliary disorders
    Cholecystitis acute 3/6312 (0%) 4/6254 (0.1%) 1/6267 (0%) 2/6253 (0%)
    Cholelithiasis 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Bile duct obstruction 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Hepatitis 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Cholecystitis 1/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Cholangitis 2/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Hepatic failure 2/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Acute hepatic failure 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Biliary colic 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Hyperbilirubinaemia 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Immune system disorders
    Hypersensitivity 3/6312 (0%) 0/6254 (0%) 1/6267 (0%) 3/6253 (0%)
    Anaphylactic shock 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Anaphylactic reaction 1/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Drug hypersensitivity 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Infections and infestations
    Pneumonia 21/6312 (0.3%) 11/6254 (0.2%) 22/6267 (0.4%) 16/6253 (0.3%)
    Septic shock 4/6312 (0.1%) 2/6254 (0%) 5/6267 (0.1%) 4/6253 (0.1%)
    Urinary tract infection 3/6312 (0%) 0/6254 (0%) 3/6267 (0%) 3/6253 (0%)
    Postoperative wound infection 3/6312 (0%) 3/6254 (0%) 2/6267 (0%) 3/6253 (0%)
    Bronchopneumonia 0/6312 (0%) 0/6254 (0%) 2/6267 (0%) 2/6253 (0%)
    Bronchitis 2/6312 (0%) 2/6254 (0%) 1/6267 (0%) 2/6253 (0%)
    Gastroenteritis 4/6312 (0.1%) 1/6254 (0%) 1/6267 (0%) 2/6253 (0%)
    Lobar pneumonia 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 2/6253 (0%)
    Diverticulitis 1/6312 (0%) 2/6254 (0%) 0/6267 (0%) 2/6253 (0%)
    Cellulitis 1/6312 (0%) 0/6254 (0%) 2/6267 (0%) 1/6253 (0%)
    Lower respiratory tract infection 3/6312 (0%) 1/6254 (0%) 1/6267 (0%) 1/6253 (0%)
    Lung infection 2/6312 (0%) 1/6254 (0%) 1/6267 (0%) 1/6253 (0%)
    Pseudomembranous colitis 0/6312 (0%) 1/6254 (0%) 1/6267 (0%) 1/6253 (0%)
    Post procedural infection 1/6312 (0%) 0/6254 (0%) 1/6267 (0%) 1/6253 (0%)
    Post procedural sepsis 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Viral infection 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Bronchiolitis 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Catheter related infection 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Graft infection 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Infected skin ulcer 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Necrotising fasciitis 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Sepsis 4/6312 (0.1%) 3/6254 (0%) 5/6267 (0.1%) 0/6253 (0%)
    Wound infection 1/6312 (0%) 4/6254 (0.1%) 3/6267 (0%) 0/6253 (0%)
    Appendicitis 0/6312 (0%) 2/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Bacteraemia 1/6312 (0%) 1/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Endocarditis 1/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Application site infection 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Gallbladder empyema 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Gastrointestinal infection 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Haematoma infection 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Influenza 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Pulmonary sepsis 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Sinusitis 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Mediastinitis 0/6312 (0%) 3/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Dengue fever 0/6312 (0%) 2/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Osteomyelitis 1/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Pyelonephritis 1/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Upper respiratory tract infection 1/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Catheter sepsis 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Erysipelas 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Gangrene 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Meningitis coxsackie viral 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Pneumonia primary atypical 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Post procedural pneumonia 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Pyelonephritis acute 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Respiratory tract infection 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Endocarditis bacterial 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Escherichia sepsis 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Incision site infection 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Liver abscess 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Lower respiratory tract infection viral 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Myocarditis infectious 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Peridiverticulitis 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Peritoneal infection 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Puncture site infection 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Staphylococcal mediastinitis 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Urosepsis 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Injury, poisoning and procedural complications
    Operative haemorrhage 39/6312 (0.6%) 50/6254 (0.8%) 57/6267 (0.9%) 48/6253 (0.8%)
    Vascular pseudoaneurysm 7/6312 (0.1%) 8/6254 (0.1%) 7/6267 (0.1%) 9/6253 (0.1%)
    Post procedural haemorrhage 12/6312 (0.2%) 16/6254 (0.3%) 18/6267 (0.3%) 6/6253 (0.1%)
    Wound dehiscence 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 2/6253 (0%)
    Fall 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Compression fracture 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Confusion postoperative 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Deep vein thrombosis postoperative 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Fat embolism 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Lower limb fracture 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Overdose 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Subcutaneous haematoma 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Incision site haemorrhage 1/6312 (0%) 0/6254 (0%) 2/6267 (0%) 0/6253 (0%)
    Collapse of lung 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Femur fracture 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Haematuria traumatic 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Haemolytic transfusion reaction 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Hepatic haematoma 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Post procedural haematoma 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Postoperative fever 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Rib fracture 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Tibia fracture 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Vascular pseudoaneurysm ruptured 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Agitation postoperative 0/6312 (0%) 2/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Postpericardiotomy syndrome 0/6312 (0%) 2/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Subdural haematoma 1/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Traumatic haemorrhage 1/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Anaesthetic complication pulmonary 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Cardiac procedure complication 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Complication of device removal 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Facial bones fracture 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Incisional hernia, obstructive 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Joint dislocation 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Wound 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Anaemia postoperative 2/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Chest injury 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Hip fracture 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Mechanical ventilation complication 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Procedural hypotension 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Subdural haemorrhage 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Investigations
    Haemoglobin decreased 1/6312 (0%) 0/6254 (0%) 5/6267 (0.1%) 2/6253 (0%)
    Blood creatinine increased 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 1/6253 (0%)
    Platelet count decreased 1/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Hepatic enzyme increased 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Metabolism and nutrition disorders
    Dehydration 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 3/6253 (0%)
    Gout 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 1/6253 (0%)
    Hypoglycaemia 4/6312 (0.1%) 2/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Hyperkalaemia 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Diabetes mellitus 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Hydraemia 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Hyponatraemia 1/6312 (0%) 0/6254 (0%) 2/6267 (0%) 0/6253 (0%)
    Hyperglycaemia 0/6312 (0%) 0/6254 (0%) 2/6267 (0%) 0/6253 (0%)
    Diabetes mellitus inadequate control 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Fluid retention 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Hypocalcaemia 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Fluid overload 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Musculoskeletal and connective tissue disorders
    Compartment syndrome 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 1/6253 (0%)
    Musculoskeletal chest pain 2/6312 (0%) 1/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Myalgia 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Osteoarthritis 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Gouty tophus 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Musculoskeletal pain 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Gouty arthritis 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Intervertebral disc protrusion 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Muscle haemorrhage 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Muscular weakness 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Osteochondrosis 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute leukaemia 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 1/6253 (0%)
    Lung neoplasm malignant 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 1/6253 (0%)
    Benign hepatic neoplasm 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Pituitary tumour benign 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Bronchial carcinoma 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Colon cancer 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Lung adenocarcinoma metastatic 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Metastases to lung 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Pancreatic carcinoma 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Rectosigmoid cancer 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Laryngeal cancer 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Lung adenocarcinoma 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Tumour associated fever 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Breast cancer 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Gastric cancer 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Metastatic carcinoma of the bladder 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Metastatic gastric cancer 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Nervous system disorders
    Haemorrhage intracranial 1/6312 (0%) 1/6254 (0%) 1/6267 (0%) 2/6253 (0%)
    Haemorrhagic stroke 1/6312 (0%) 3/6254 (0%) 2/6267 (0%) 1/6253 (0%)
    Transient ischaemic attack 0/6312 (0%) 0/6254 (0%) 2/6267 (0%) 1/6253 (0%)
    Grand mal convulsion 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Critical illness polyneuropathy 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Optic neuritis 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Spinal cord ischaemia 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Syncope 2/6312 (0%) 0/6254 (0%) 2/6267 (0%) 0/6253 (0%)
    Presyncope 1/6312 (0%) 1/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Convulsion 1/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Dizziness 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Drop attacks 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Encephalomalacia 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Loss of consciousness 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Paraesthesia 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Brain stem syndrome 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Carotid artery stenosis 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Dysarthria 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Headache 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Hypertensive encephalopathy 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Migraine without aura 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Multiple sclerosis 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Anoxic encephalopathy 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Neurological symptom 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Spinal cord infarction 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Psychiatric disorders
    Depression 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Major depression 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Psychotic disorder 1/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Confusional state 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Delirium 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Anxiety 1/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Completed suicide 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Generalised anxiety disorder 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Mental status changes 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Post-traumatic stress disorder 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Alcohol withdrawal syndrome 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Bipolar i disorder 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Mental disorder due to a general medical condition 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Suicide attempt 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Renal and urinary disorders
    Renal failure acute 11/6312 (0.2%) 9/6254 (0.1%) 18/6267 (0.3%) 10/6253 (0.2%)
    Renal failure 7/6312 (0.1%) 7/6254 (0.1%) 8/6267 (0.1%) 8/6253 (0.1%)
    Haematuria 5/6312 (0.1%) 4/6254 (0.1%) 4/6267 (0.1%) 5/6253 (0.1%)
    Renal failure chronic 2/6312 (0%) 2/6254 (0%) 0/6267 (0%) 3/6253 (0%)
    Calculus ureteric 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 2/6253 (0%)
    Cystitis haemorrhagic 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 1/6253 (0%)
    Renal colic 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Nephropathy toxic 2/6312 (0%) 2/6254 (0%) 2/6267 (0%) 0/6253 (0%)
    Nephrolithiasis 1/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Renal impairment 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Hydronephrosis 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Renal cyst 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Nephropathy 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Urethral stenosis 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Reproductive system and breast disorders
    Menorrhagia 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Ovarian haemorrhage 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Prostatitis 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism 5/6312 (0.1%) 7/6254 (0.1%) 5/6267 (0.1%) 10/6253 (0.2%)
    Atelectasis 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 3/6253 (0%)
    Chronic obstructive pulmonary disease 2/6312 (0%) 4/6254 (0.1%) 5/6267 (0.1%) 2/6253 (0%)
    Respiratory failure 3/6312 (0%) 4/6254 (0.1%) 4/6267 (0.1%) 2/6253 (0%)
    Pneumothorax 5/6312 (0.1%) 1/6254 (0%) 2/6267 (0%) 2/6253 (0%)
    Epistaxis 0/6312 (0%) 1/6254 (0%) 1/6267 (0%) 2/6253 (0%)
    Haemothorax 0/6312 (0%) 1/6254 (0%) 1/6267 (0%) 2/6253 (0%)
    Respiratory arrest 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 2/6253 (0%)
    Pleural effusion 3/6312 (0%) 0/6254 (0%) 3/6267 (0%) 1/6253 (0%)
    Acute respiratory distress syndrome 2/6312 (0%) 0/6254 (0%) 1/6267 (0%) 1/6253 (0%)
    Pneumonitis 1/6312 (0%) 0/6254 (0%) 1/6267 (0%) 1/6253 (0%)
    Pneumonia aspiration 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 1/6253 (0%)
    Pulmonary congestion 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 1/6253 (0%)
    Pulmonary oedema 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 1/6253 (0%)
    Haemoptysis 1/6312 (0%) 2/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Respiratory distress 1/6312 (0%) 1/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Thoracic haemorrhage 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Apnoea 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Lung disorder 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Respiratory depression 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Sleep apnoea syndrome 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Acute respiratory failure 1/6312 (0%) 2/6254 (0%) 2/6267 (0%) 0/6253 (0%)
    Pleural haemorrhage 1/6312 (0%) 1/6254 (0%) 2/6267 (0%) 0/6253 (0%)
    Cough 0/6312 (0%) 1/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Hypoxia 0/6312 (0%) 1/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Pulmonary alveolar haemorrhage 1/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Acute pulmonary oedema 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Pleurisy 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Emphysema 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Idiopathic pulmonary fibrosis 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Laryngospasm 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Upper respiratory tract congestion 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Dyspnoea 2/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Skin and subcutaneous tissue disorders
    Rash 2/6312 (0%) 0/6254 (0%) 0/6267 (0%) 3/6253 (0%)
    Dermatitis allergic 1/6312 (0%) 1/6254 (0%) 1/6267 (0%) 1/6253 (0%)
    Haemorrhage subcutaneous 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Palmar-plantar erythrodysaesthesia syndrome 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Rash maculo-papular 0/6312 (0%) 0/6254 (0%) 2/6267 (0%) 0/6253 (0%)
    Angioedema 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Drug eruption 1/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Urticaria 1/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Erythema 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Henoch-schonlein purpura 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Skin haemorrhage 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Vascular disorders
    Deep vein thrombosis 3/6312 (0%) 1/6254 (0%) 6/6267 (0.1%) 7/6253 (0.1%)
    Haemorrhage 3/6312 (0%) 5/6254 (0.1%) 5/6267 (0.1%) 2/6253 (0%)
    Hypotension 3/6312 (0%) 0/6254 (0%) 2/6267 (0%) 1/6253 (0%)
    Hypertension 1/6312 (0%) 0/6254 (0%) 2/6267 (0%) 1/6253 (0%)
    Peripheral ischaemia 0/6312 (0%) 1/6254 (0%) 1/6267 (0%) 1/6253 (0%)
    Hypertensive crisis 1/6312 (0%) 0/6254 (0%) 1/6267 (0%) 1/6253 (0%)
    Arterial thrombosis limb 0/6312 (0%) 2/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Haematoma 1/6312 (0%) 1/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Aortic aneurysm rupture 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Shock 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Thrombosis 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Vena cava thrombosis 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Venous thrombosis limb 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 1/6253 (0%)
    Peripheral embolism 0/6312 (0%) 0/6254 (0%) 2/6267 (0%) 0/6253 (0%)
    Peripheral vascular disorder 0/6312 (0%) 0/6254 (0%) 2/6267 (0%) 0/6253 (0%)
    Arteriovenous fistula 0/6312 (0%) 3/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Aortic dissection 2/6312 (0%) 1/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Femoral artery occlusion 1/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Peripheral arterial occlusive disease 1/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Arterial occlusive disease 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Iliac artery occlusion 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Orthostatic hypotension 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Phlebitis 0/6312 (0%) 0/6254 (0%) 1/6267 (0%) 0/6253 (0%)
    Artery dissection 1/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Arterial haemorrhage 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Arterial rupture 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Shock haemorrhagic 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Venous thrombosis 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Wound haemorrhage 0/6312 (0%) 1/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Femoral artery dissection 2/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Venous haemorrhage 1/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)
    Other (Not Including Serious) Adverse Events
    Clopidogrel 300/75/75 mg + ASA Low Dose Clopidogrel 300/75/75 mg + ASA High Dose Clopidogrel 600/150/75 mg + ASA Low Dose Clopidogrel 600/150/75 mg + ASA High Dose
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/6312 (0%) 0/6254 (0%) 0/6267 (0%) 0/6253 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    Publication of the study is made jointly in the name of all wholehearted collaborators. Other papers are authored based on the contributions of the individuals to the overall study. Sub-studies with scientific merit which have received prior approvals of the Steering Committee may be published separately in the names of contributing Investigators. A copy of all manuscripts are provided to the Sponsors for their review and the final decision to publish is made by the Steering Committee.

    Results Point of Contact

    Name/Title Trial Information Transparency Team
    Organization sanofi-aventis
    Phone
    Email GV-Contact-us@sanofi-aventis.com
    Responsible Party:
    , ,
    ClinicalTrials.gov Identifier:
    NCT00335452
    Other Study ID Numbers:
    • EFC5965
    • EUDRACT: 2006-000313-38
    First Posted:
    Jun 9, 2006
    Last Update Posted:
    Nov 18, 2010
    Last Verified:
    Nov 1, 2010