Acute Coronary Disease, Angina Unstable
Conditions
Keywords
platelet aggregation inhibitors, acute coronary disease, percutaneous coronary
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).
Interventions
DRUGClopidogrel
oral administration
oral administration
Sponsors
Bristol-Myers Squibb
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| First Occurrence of CV Death / MI / Stroke - ASA Dose Comparison | 30 days | — |
| First Occurrence of CV Death / MI / Stroke - Interaction Clopidogrel Treatment Regimen and ASA Dose Level | 30 days | — |
| First Occurrence of CV Death / MI / Stroke - Clopidogrel Treatment Regimen Comparison in PCI Subgroup | 30 days | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| Occurrence of Major Bleeding - ASA Dose Level Comparison | 30 days | — |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, China, Croatia, Czechia, Estonia, Finland, France, Germany, Greece, India, Ireland, Israel, Italy, Latvia, Lithuania, Malaysia, Mexico, Netherlands, Poland, Romania, Russia, Singapore, Slovakia, South Africa, South Korea, Spain, Sweden, Switzerland, Turkey (Türkiye), United Kingdom, United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| Clopidogrel 300/75/75 mg + ASA Low Dose | 6,312 |
| Clopidogrel 300/75/75 mg + ASA High Dose | 6,254 |
| Clopidogrel 600/150/75 mg + ASA Low Dose | 6,267 |
| Clopidogrel 600/150/75 mg + ASA High Dose | 6,253 |
| Total | 25,086 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 156 | 144 | 158 | 129 |
| Overall Study | Lost to Follow-up | 2 | 3 | 1 | 2 |
Baseline characteristics
| Characteristic | Total | Clopidogrel 600/150/75 mg + ASA Low Dose | Clopidogrel 300/75/75 mg + ASA High Dose | Clopidogrel 300/75/75 mg + ASA Low Dose | Clopidogrel 600/150/75 mg + ASA High Dose |
|---|---|---|---|---|---|
| Age Continuous | 61.3 years STANDARD_DEVIATION 11.8 | 61.2 years STANDARD_DEVIATION 11.8 | 61.5 years STANDARD_DEVIATION 11.7 | 61.3 years STANDARD_DEVIATION 11.7 | 61.4 years STANDARD_DEVIATION 11.9 |
| Age, Customized 65 - 74 years | 6235 participants | 1543 participants | 1576 participants | 1573 participants | 1543 participants |
| Age, Customized < 65 years | 15054 participants | 3787 participants | 3740 participants | 3792 participants | 3735 participants |
| Age, Customized ≥ 75 years | 3796 participants | 937 participants | 937 participants | 947 participants | 975 participants |
| Age, Customized Missing | 1 participants | 0 participants | 1 participants | 0 participants | 0 participants |
| Intended PCI performed No | 7823 participants | 2005 participants | 1928 participants | 1935 participants | 1955 participants |
| Intended PCI performed Yes | 17263 participants | 4262 participants | 4326 participants | 4377 participants | 4298 participants |
| Qualifying condition Missing | 14 participants | 3 participants | 4 participants | 2 participants | 5 participants |
| Qualifying condition MI with ST elevation (STEMI) | 7327 participants | 1839 participants | 1817 participants | 1839 participants | 1832 participants |
| Qualifying condition Suspected MI without ST elevation (NSTEMI) | 10531 participants | 2668 participants | 2662 participants | 2662 participants | 2539 participants |
| Qualifying condition Suspected Unstable Angina (UA) | 7214 participants | 1757 participants | 1771 participants | 1809 participants | 1877 participants |
| Region of Enrollment Argentina | 677 participants | 162 participants | 159 participants | 182 participants | 174 participants |
| Region of Enrollment Australia | 388 participants | 96 participants | 100 participants | 97 participants | 95 participants |
| Region of Enrollment Austria | 151 participants | 35 participants | 35 participants | 41 participants | 40 participants |
| Region of Enrollment Belgium | 228 participants | 59 participants | 61 participants | 55 participants | 53 participants |
| Region of Enrollment Brazil | 1125 participants | 270 participants | 275 participants | 292 participants | 288 participants |
| Region of Enrollment Bulgaria | 470 participants | 125 participants | 122 participants | 111 participants | 112 participants |
| Region of Enrollment Canada | 1448 participants | 373 participants | 379 participants | 349 participants | 347 participants |
| Region of Enrollment Chile | 352 participants | 82 participants | 85 participants | 95 participants | 90 participants |
| Region of Enrollment China | 2017 participants | 500 participants | 492 participants | 510 participants | 515 participants |
| Region of Enrollment Croatia | 517 participants | 144 participants | 145 participants | 114 participants | 114 participants |
| Region of Enrollment Czech Republic | 1067 participants | 277 participants | 275 participants | 257 participants | 258 participants |
| Region of Enrollment Estonia | 2 participants | 0 participants | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Finland | 518 participants | 127 participants | 127 participants | 132 participants | 132 participants |
| Region of Enrollment France | 680 participants | 165 participants | 163 participants | 177 participants | 175 participants |
| Region of Enrollment Germany | 1844 participants | 453 participants | 450 participants | 471 participants | 470 participants |
| Region of Enrollment Greece | 85 participants | 23 participants | 21 participants | 20 participants | 21 participants |
| Region of Enrollment India | 2599 participants | 645 participants | 650 participants | 658 participants | 646 participants |
| Region of Enrollment Ireland | 75 participants | 15 participants | 13 participants | 24 participants | 23 participants |
| Region of Enrollment Israel | 1115 participants | 275 participants | 272 participants | 286 participants | 282 participants |
| Region of Enrollment Italy | 981 participants | 258 participants | 260 participants | 232 participants | 231 participants |
| Region of Enrollment Korea, Republic of | 627 participants | 152 participants | 149 participants | 161 participants | 165 participants |
| Region of Enrollment Latvia | 62 participants | 15 participants | 16 participants | 16 participants | 15 participants |
| Region of Enrollment Lithuania | 115 participants | 30 participants | 31 participants | 26 participants | 28 participants |
| Region of Enrollment Malaysia | 135 participants | 39 participants | 39 participants | 29 participants | 28 participants |
| Region of Enrollment Mexico | 69 participants | 19 participants | 17 participants | 16 participants | 17 participants |
| Region of Enrollment Netherlands | 188 participants | 48 participants | 48 participants | 46 participants | 46 participants |
| Region of Enrollment New Zealand | 125 participants | 29 participants | 31 participants | 36 participants | 29 participants |
| Region of Enrollment Poland | 1374 participants | 325 participants | 322 participants | 365 participants | 362 participants |
| Region of Enrollment Romania | 158 participants | 33 participants | 30 participants | 47 participants | 48 participants |
| Region of Enrollment Russian Federation | 538 participants | 138 participants | 137 participants | 132 participants | 131 participants |
| Region of Enrollment Singapore | 48 participants | 15 participants | 13 participants | 10 participants | 10 participants |
| Region of Enrollment Slovakia | 352 participants | 83 participants | 84 participants | 93 participants | 92 participants |
| Region of Enrollment South Africa | 75 participants | 14 participants | 14 participants | 24 participants | 23 participants |
| Region of Enrollment Spain | 1086 participants | 283 participants | 276 participants | 264 participants | 263 participants |
| Region of Enrollment Sweden | 40 participants | 9 participants | 11 participants | 10 participants | 10 participants |
| Region of Enrollment Switzerland | 227 participants | 64 participants | 64 participants | 51 participants | 48 participants |
| Region of Enrollment Turkey | 347 participants | 94 participants | 96 participants | 79 participants | 78 participants |
| Region of Enrollment United Kingdom | 119 participants | 34 participants | 29 participants | 28 participants | 28 participants |
| Region of Enrollment United States | 3062 participants | 759 participants | 763 participants | 775 participants | 765 participants |
| Sex: Female, Male Female | 6871 Participants | 1671 Participants | 1756 Participants | 1702 Participants | 1742 Participants |
| Sex: Female, Male Male | 18215 Participants | 4596 Participants | 4498 Participants | 4610 Participants | 4511 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 6,312 | 0 / 6,254 | 0 / 6,267 | 0 / 6,253 |
| serious Total, serious adverse events | 322 / 6,312 | 329 / 6,254 | 372 / 6,267 | 332 / 6,253 |
Outcome results
Primary
First Occurrence of CV Death / MI / Stroke - ASA Dose Comparison
Time frame: 30 days
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Clopidogrel 300/75/75 mg + ASA | First Occurrence of CV Death / MI / Stroke - ASA Dose Comparison | CV death/MI/Stroke | 546 participants |
| Clopidogrel 300/75/75 mg + ASA | First Occurrence of CV Death / MI / Stroke - ASA Dose Comparison | - MI (fatal or not) | 260 participants |
| Clopidogrel 300/75/75 mg + ASA | First Occurrence of CV Death / MI / Stroke - ASA Dose Comparison | - CV death | 231 participants |
| Clopidogrel 300/75/75 mg + ASA | First Occurrence of CV Death / MI / Stroke - ASA Dose Comparison | - Stroke (fatal or not) | 55 participants |
| Clopidogrel 600/150/75 mg + ASA | First Occurrence of CV Death / MI / Stroke - ASA Dose Comparison | - CV death | 211 participants |
| Clopidogrel 600/150/75 mg + ASA | First Occurrence of CV Death / MI / Stroke - ASA Dose Comparison | CV death/MI/Stroke | 527 participants |
| Clopidogrel 600/150/75 mg + ASA | First Occurrence of CV Death / MI / Stroke - ASA Dose Comparison | - Stroke (fatal or not) | 65 participants |
| Clopidogrel 600/150/75 mg + ASA | First Occurrence of CV Death / MI / Stroke - ASA Dose Comparison | - MI (fatal or not) | 251 participants |
p-value: 0.604795% CI: [-9.2, 14]Log Rank
Primary
First Occurrence of CV Death / MI / Stroke - Clopidogrel Treatment Regimen Comparison
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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Clopidogrel 300/75/75 mg + ASA | First Occurrence of CV Death / MI / Stroke - Clopidogrel Treatment Regimen Comparison | CV death/MI/Stroke | 557 participants |
| Clopidogrel 300/75/75 mg + ASA | First Occurrence of CV Death / MI / Stroke - Clopidogrel Treatment Regimen Comparison | - CV death | 222 participants |
| Clopidogrel 300/75/75 mg + ASA | First Occurrence of CV Death / MI / Stroke - Clopidogrel Treatment Regimen Comparison | - MI (fatal or not) | 274 participants |
| Clopidogrel 300/75/75 mg + ASA | First Occurrence of CV Death / MI / Stroke - Clopidogrel Treatment Regimen Comparison | - Stroke (fatal or not) | 61 participants |
| Clopidogrel 600/150/75 mg + ASA | First Occurrence of CV Death / MI / Stroke - Clopidogrel Treatment Regimen Comparison | - Stroke (fatal or not) | 59 participants |
| Clopidogrel 600/150/75 mg + ASA | First Occurrence of CV Death / MI / Stroke - Clopidogrel Treatment Regimen Comparison | CV death/MI/Stroke | 522 participants |
| Clopidogrel 600/150/75 mg + ASA | First Occurrence of CV Death / MI / Stroke - Clopidogrel Treatment Regimen Comparison | - MI (fatal or not) | 237 participants |
| Clopidogrel 600/150/75 mg + ASA | First Occurrence of CV Death / MI / Stroke - Clopidogrel Treatment Regimen Comparison | - CV death | 226 participants |
p-value: 0.303795% CI: [-5.8, 16.6]Log Rank
Primary
First Occurrence of CV Death / MI / Stroke - Clopidogrel Treatment Regimen Comparison in PCI Subgroup
Time frame: 30 days
Population: The intent-to-treat (ITT) analysis is done on the randomized patients who underwent PCI during the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Clopidogrel 300/75/75 mg + ASA | First Occurrence of CV Death / MI / Stroke - Clopidogrel Treatment Regimen Comparison in PCI Subgroup | CV death/MI/Stroke | 392 participants |
| Clopidogrel 300/75/75 mg + ASA | First Occurrence of CV Death / MI / Stroke - Clopidogrel Treatment Regimen Comparison in PCI Subgroup | - CV death | 132 participants |
| Clopidogrel 300/75/75 mg + ASA | First Occurrence of CV Death / MI / Stroke - Clopidogrel Treatment Regimen Comparison in PCI Subgroup | - MI (fatal or not) | 225 participants |
| Clopidogrel 300/75/75 mg + ASA | First Occurrence of CV Death / MI / Stroke - Clopidogrel Treatment Regimen Comparison in PCI Subgroup | - Stroke (fatal or not) | 35 participants |
| Clopidogrel 600/150/75 mg + ASA | First Occurrence of CV Death / MI / Stroke - Clopidogrel Treatment Regimen Comparison in PCI Subgroup | - Stroke (fatal or not) | 28 participants |
| Clopidogrel 600/150/75 mg + ASA | First Occurrence of CV Death / MI / Stroke - Clopidogrel Treatment Regimen Comparison in PCI Subgroup | CV death/MI/Stroke | 330 participants |
| Clopidogrel 600/150/75 mg + ASA | First Occurrence of CV Death / MI / Stroke - Clopidogrel Treatment Regimen Comparison in PCI Subgroup | - MI (fatal or not) | 172 participants |
| Clopidogrel 600/150/75 mg + ASA | First Occurrence of CV Death / MI / Stroke - Clopidogrel Treatment Regimen Comparison in PCI Subgroup | - CV death | 130 participants |
p-value: 0.033295% CI: [1.2, 26.3]Log Rank
Primary
First Occurrence of CV Death / MI / Stroke - Interaction Clopidogrel Treatment Regimen and ASA Dose Level
Time frame: 30 days
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Clopidogrel 300/75/75 mg + ASA | First Occurrence of CV Death / MI / Stroke - Interaction Clopidogrel Treatment Regimen and ASA Dose Level | 267 participants |
| Clopidogrel 600/150/75 mg + ASA | First Occurrence of CV Death / MI / Stroke - Interaction Clopidogrel Treatment Regimen and ASA Dose Level | 290 participants |
| Clopidogrel 600/150/75 mg + ASA Low Dose | First Occurrence of CV Death / MI / Stroke - Interaction Clopidogrel Treatment Regimen and ASA Dose Level | 282 participants |
| Clopidogrel 600/150/75 mg + ASA High Dose | First Occurrence of CV Death / MI / Stroke - Interaction Clopidogrel Treatment Regimen and ASA Dose Level | 240 participants |
p-value: 0.457995% CI: [-26, 9.9]Log Rank
p-value: 0.026295% CI: [2.2, 30.5]Log Rank
p-value: 0.0355Chi-squared
Secondary
Occurrence of Major Bleeding - ASA Dose Level Comparison
Time frame: 30 days
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Clopidogrel 300/75/75 mg + ASA | Occurrence of Major Bleeding - ASA Dose Level Comparison | Major bleeding | 285 participants |
| Clopidogrel 300/75/75 mg + ASA | Occurrence of Major Bleeding - ASA Dose Level Comparison | - Severe bleeding | 215 participants |
| Clopidogrel 300/75/75 mg + ASA | Occurrence of Major Bleeding - ASA Dose Level Comparison | - Major but not severe bleeding | 74 participants |
| Clopidogrel 600/150/75 mg + ASA | Occurrence of Major Bleeding - ASA Dose Level Comparison | Major bleeding | 282 participants |
| Clopidogrel 600/150/75 mg + ASA | Occurrence of Major Bleeding - ASA Dose Level Comparison | - Severe bleeding | 216 participants |
| Clopidogrel 600/150/75 mg + ASA | Occurrence of Major Bleeding - ASA Dose Level Comparison | - Major but not severe bleeding | 73 participants |
p-value: 0.945Regression, Logistic
Secondary
Occurrence of Major Bleeding - Clopidogrel Dose Regimen Comparison
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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Clopidogrel 300/75/75 mg + ASA | Occurrence of Major Bleeding - Clopidogrel Dose Regimen Comparison | Major bleeding | 255 participants |
| Clopidogrel 300/75/75 mg + ASA | Occurrence of Major Bleeding - Clopidogrel Dose Regimen Comparison | - Severe bleeding | 195 participants |
| Clopidogrel 300/75/75 mg + ASA | Occurrence of Major Bleeding - Clopidogrel Dose Regimen Comparison | - Major but not severe bleeding | 65 participants |
| Clopidogrel 600/150/75 mg + ASA | Occurrence of Major Bleeding - Clopidogrel Dose Regimen Comparison | Major bleeding | 313 participants |
| Clopidogrel 600/150/75 mg + ASA | Occurrence of Major Bleeding - Clopidogrel Dose Regimen Comparison | - Severe bleeding | 236 participants |
| Clopidogrel 600/150/75 mg + ASA | Occurrence of Major Bleeding - Clopidogrel Dose Regimen Comparison | - Major but not severe bleeding | 83 participants |
p-value: 0.012Regression, Logistic
Post Hoc
Occurrence of Stent Thrombosis - Clopidogrel Treatment Regimen Comparison
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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Clopidogrel 300/75/75 mg + ASA | Occurrence of Stent Thrombosis - Clopidogrel Treatment Regimen Comparison | Stent trombosis | 200 participants |
| Clopidogrel 300/75/75 mg + ASA | Occurrence of Stent Thrombosis - Clopidogrel Treatment Regimen Comparison | - Definite | 111 participants |
| Clopidogrel 300/75/75 mg + ASA | Occurrence of Stent Thrombosis - Clopidogrel Treatment Regimen Comparison | - Probable | 89 participants |
| Clopidogrel 600/150/75 mg + ASA | Occurrence of Stent Thrombosis - Clopidogrel Treatment Regimen Comparison | Stent trombosis | 135 participants |
| Clopidogrel 600/150/75 mg + ASA | Occurrence of Stent Thrombosis - Clopidogrel Treatment Regimen Comparison | - Definite | 58 participants |
| Clopidogrel 600/150/75 mg + ASA | Occurrence of Stent Thrombosis - Clopidogrel Treatment Regimen Comparison | - Probable | 77 participants |
p-value: 0.000495% CI: [16.2, 45.8]Log Rank