Acute Coronary Syndromes (ACS), Myocardial Infarction (MI)
Conditions
Keywords
Acute Coronary Syndrome (ACS), Percutaneous Coronary Intervention (PCI), non-ST-segment elevation myocardial infarction (NSTEMI), ST-segment elevation myocardial infarction (STEMI)
Brief summary
The primary objective of this study is to demonstrate that the efficacy of cangrelor is superior, or at least non-inferior, to that of clopidogrel in subjects requiring PCI.
Interventions
DRUGCangrelor (P2Y12 inhibitor)
IV bolus (30 mcg/kg) & infusion (4 mcg/kg/min) initiated prior to PCI, as soon as possible following randomization (after need for PCI is confirmed) but not more than 30 minutes prior to placement of arterial access. Infusion is to continue for at least 2 hours, or until the end of the PCI, whichever is longer with the option to extend up to 4 hours maximum (per investigator discretion).
DRUGclopidogrel (oral P2Y12 inhibitor)
600 mg active clopidogrel administered as soon as possible following randomization (after need for PCI confirmed), but not more than 30 minutes prior to the placement of the arterial access.
placebo bolus (30 mcg/kg) & placebo infusion (4 mcg/kg/min) administered from randomization for at least 2 hours, or until the end of the PCI, whichever is longer with the option to extend up to 4 hours maximum (per investigator discretion)
Placebo capsules given at the end of infusion to mimic 600mg clopidogrel dosing
DRUGPlacebo capsules - as soon as possible after randomization
Placebo capsules given as soon as possible after randomization to mimic 600mg clopidogrel dosing
Sponsors
The Medicines Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
To be included in this study, subjects must meet the following criteria: * Angiography demonstrating atherosclerosis amenable to treatment by percutaneous coronary intervention (PCI) with or without stent implantation and diagnosis of Acute Coronary Syndrome (ACS) by elevated cardiac markers or ischemic chest discomfort w/electrocardiogram changes + age \> 65 or diabetes or ST-elevation MI.
Exclusion criteria
Subjects will be excluded from the study if they present with any of the following: 1. Not a candidate for PCI 2. Increased bleeding risk: ischemic stroke within the last year or any previous hemorrhagic stroke, tumor, cerebral arteriovenous malformation, or intracranial aneurysm; recent (\<1 month) trauma or major surgery (including by-pass surgery); currently receiving warfarin, active bleeding 3. Impaired hemostasis: known International Normalized Ratio (INR) \>1.5 at screening; past or present bleeding disorder (including congenital bleeding disorders such as von Willebrand's disease or hemophilia, acquired bleeding disorders, and unexplained clinically significant bleeding disorders), thrombocytopenia (platelet count \<100,000/µL), or history of thrombocytopenia or neutropenia associated with clopidogrel 4. Severe hypertension not adequately controlled by antihypertensive therapy at the time of randomization 5. Receipt of fibrinolytic therapy in the 12 hours preceding randomization 6. Receipt of clopidogrel dose exceeding maintenance dose (ie, \>75 mg) at any time in the 5 days preceding randomization 7. Inability to swallow study capsules 8. Glycoprotein IIb/IIIa (GPI) Inhibitor usage within the previous 12 hours \[applicable to unstable angina (UA) and non-ST-elevation myocardial infarction (NSTEMI) patients\] Subjects excluded for any of the above reasons may be re-screened for participation at any time if the exclusion characteristic has changed.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of All-cause Mortality, Myocardial Infarction (MI), and Ischemia-driven Revascularization (IDR) | randomization through 48 hours after randomization | (composite incidence) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Individual Incidence of All-cause Mortality | randomization through 48 hours after randomization | — |
| Individual Incidence of IDR | randomization through 48 hours after randomization | — |
| Incidence of Stroke | randomization through 48 hours after randomization | Stroke is defined as a sudden, focal neurological defect resulting from a cerebrovascular cause that is not reversible within 24 hours and not due to a readily identifiable cause such as a tumor or trauma. All suspected strokes were reviewed and adjudicated by the Clinical Events Committee (CEC) who considered all clinically relevant information and imaging studies to classify all strokes as: * primary hemorrhagic - stroke with focal collections of intracranial blood * ischemic cerebral infarction - stroke without focal collections of intracranial blood * infarction with hemorrhagic conversion - cerebral infarction with blood thought to represent hemorrhagic conversion and not primary bleeding * uncertain - no imaging or autopsy data are available. |
| Incidence of Abrupt Closure, Threatened Abrupt Closure, Need for Urgent Coronary Artery Bypass Graft (CABG) Surgery, or Unsuccessful Procedure During the Index PCI | during index PCI | (a patient could have multiple procedural events) |
| Incidence of All-cause Mortality, MI or IDR | randomization through 30 days after randomization | (composite incidence) |
| Incidence of All-cause Mortality or MI | randomization through 30 days after randomization | (composite incidence) |
| Incidence of All-cause Mortality | randomization through 30 days after randomization | — |
| Incidence of All-cause Mortality and MI | randomization through 48 hours after randomization | (composite incidence) |
| Incidence of IDR | randomization through 30 days after randomization | — |
| Incidence of All Cause Mortality | randomization through 1 year after randomization | (excluding STEMI) |
| Incidence of GUSTO Severe / Life-threatening Bleeding | randomization through 48 hours after randomization | Major bleeding (non-CABG-related) - Safety population |
| Incidence of Thrombolysis in Myocardial Infarction (TIMI) Major Bleeding | randomization through 48 hours after randomization | Major bleeding (non-CABG-related) - Safety population |
| Incidence of ACUITY Major Bleeding | randomization through 48 hours after randomization | Major bleeding (non-CABG-related) - Safety population |
| Incidence of ACUITY Major Bleeding (Without Hematoma >/= 5 cm) | randomization through 48 hours after randomization | excludes ACUITY major bleeding for which the only qualifying event was hematoma \>/= 5 cm |
| Incidence of MI | randomization through 30 days after randomization | — |
Countries
United States
Participant flow
Recruitment details
Patients were selected for randomization based on the need for percutaneous coronary intervention (PCI). Randomization could only occur after the need for PCI was confirmed by angiography, with the exception of ST-segment elevation myocardial infarction (STEMI) patients, who could be enrolled upon confirmation of STEMI by electrocardiogram (ECG).
Participants by arm
| Arm | Count |
|---|---|
| Cangrelor Arm cangrelor arm: placebo capsules (to match) at PCI start + cangrelor bolus (30 mcg/kg) & infusion (4mcg/kg/min) followed by clopidogrel (600 mg) post infusion | 4,433 |
| Clopidogrel Arm clopidogrel arm: clopidogrel capsules (600 mg) at PCI start + placebo bolus & infusion (to match) followed by placebo capsules post infusion | 4,444 |
| Total | 8,877 |
Baseline characteristics
| Characteristic | Clopidogrel Arm | Total | Cangrelor Arm |
|---|---|---|---|
| Age, Continuous | 62.2 years STANDARD_DEVIATION 11.5 | 62.2 years STANDARD_DEVIATION 11.4 | 62.2 years STANDARD_DEVIATION 11.3 |
| Region of Enrollment Argentina | 26 participants | 51 participants | 25 participants |
| Region of Enrollment Australia | 237 participants | 470 participants | 233 participants |
| Region of Enrollment Austria | 215 participants | 430 participants | 215 participants |
| Region of Enrollment Brazil | 116 participants | 227 participants | 111 participants |
| Region of Enrollment Canada | 5 participants | 15 participants | 10 participants |
| Region of Enrollment Georgia | 230 participants | 458 participants | 228 participants |
| Region of Enrollment Germany | 156 participants | 318 participants | 162 participants |
| Region of Enrollment India | 260 participants | 520 participants | 260 participants |
| Region of Enrollment Italy | 167 participants | 336 participants | 169 participants |
| Region of Enrollment New Zealand | 116 participants | 226 participants | 110 participants |
| Region of Enrollment Poland | 232 participants | 463 participants | 231 participants |
| Region of Enrollment Spain | 7 participants | 18 participants | 11 participants |
| Region of Enrollment Ukraine | 39 participants | 78 participants | 39 participants |
| Region of Enrollment United States | 2638 participants | 5267 participants | 2629 participants |
| Sex: Female, Male Female | 1235 Participants | 2393 Participants | 1158 Participants |
| Sex: Female, Male Male | 3209 Participants | 6484 Participants | 3275 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1,149 / 4,374 | 1,159 / 4,365 |
| serious Total, serious adverse events | 125 / 4,374 | 127 / 4,365 |
Outcome results
Primary
Incidence of All-cause Mortality, Myocardial Infarction (MI), and Ischemia-driven Revascularization (IDR)
(composite incidence)
Time frame: randomization through 48 hours after randomization
Population: mITT (excluding STEMI)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cangrelor Arm | Incidence of All-cause Mortality, Myocardial Infarction (MI), and Ischemia-driven Revascularization (IDR) | 290 participants |
| Clopidogrel Arm | Incidence of All-cause Mortality, Myocardial Infarction (MI), and Ischemia-driven Revascularization (IDR) | 276 participants |
Secondary
Incidence of Abrupt Closure, Threatened Abrupt Closure, Need for Urgent Coronary Artery Bypass Graft (CABG) Surgery, or Unsuccessful Procedure During the Index PCI
(a patient could have multiple procedural events)
Time frame: during index PCI
Population: mITT (excluding STEMI) and based on available data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cangrelor Arm | Incidence of Abrupt Closure, Threatened Abrupt Closure, Need for Urgent Coronary Artery Bypass Graft (CABG) Surgery, or Unsuccessful Procedure During the Index PCI | 127 participants |
| Clopidogrel Arm | Incidence of Abrupt Closure, Threatened Abrupt Closure, Need for Urgent Coronary Artery Bypass Graft (CABG) Surgery, or Unsuccessful Procedure During the Index PCI | 141 participants |
Secondary
Incidence of ACUITY Major Bleeding
Major bleeding (non-CABG-related) - Safety population
Time frame: randomization through 48 hours after randomization
Population: Safety Population (inclusive of STEMI patients)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cangrelor Arm | Incidence of ACUITY Major Bleeding | 151 participants |
| Clopidogrel Arm | Incidence of ACUITY Major Bleeding | 120 participants |
Secondary
Incidence of ACUITY Major Bleeding (Without Hematoma >/= 5 cm)
excludes ACUITY major bleeding for which the only qualifying event was hematoma \>/= 5 cm
Time frame: randomization through 48 hours after randomization
Population: Safety Population (inclusive of STEMI patients)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cangrelor Arm | Incidence of ACUITY Major Bleeding (Without Hematoma >/= 5 cm) | 78 participants |
| Clopidogrel Arm | Incidence of ACUITY Major Bleeding (Without Hematoma >/= 5 cm) | 65 participants |
Secondary
Incidence of All-cause Mortality
Time frame: randomization through 30 days after randomization
Population: mITT (excluding STEMI), based on 30-day completers
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cangrelor Arm | Incidence of All-cause Mortality | 34 participants |
| Clopidogrel Arm | Incidence of All-cause Mortality | 29 participants |
Secondary
Incidence of All Cause Mortality
(excluding STEMI)
Time frame: randomization through 1 year after randomization
Population: mITT (excluding STEMI), based on 1 year completers
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cangrelor Arm | Incidence of All Cause Mortality | 116 participants |
| Clopidogrel Arm | Incidence of All Cause Mortality | 120 participants |
Secondary
Incidence of All-cause Mortality and MI
(composite incidence)
Time frame: randomization through 48 hours after randomization
Population: mITT (excluding STEMI)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cangrelor Arm | Incidence of All-cause Mortality and MI | 285 participants |
| Clopidogrel Arm | Incidence of All-cause Mortality and MI | 261 participants |
Secondary
Incidence of All-cause Mortality, MI or IDR
(composite incidence)
Time frame: randomization through 30 days after randomization
Population: mITT (excluding STEMI), based on 30-day completers
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cangrelor Arm | Incidence of All-cause Mortality, MI or IDR | 343 participants |
| Clopidogrel Arm | Incidence of All-cause Mortality, MI or IDR | 327 participants |
Secondary
Incidence of All-cause Mortality or MI
(composite incidence)
Time frame: randomization through 30 days after randomization
Population: mITT (excluding STEMI), based on 30-day completers
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cangrelor Arm | Incidence of All-cause Mortality or MI | 321 participants |
| Clopidogrel Arm | Incidence of All-cause Mortality or MI | 298 participants |
Secondary
Incidence of GUSTO Severe / Life-threatening Bleeding
Major bleeding (non-CABG-related) - Safety population
Time frame: randomization through 48 hours after randomization
Population: Safety Population (inclusive of STEMI patients)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cangrelor Arm | Incidence of GUSTO Severe / Life-threatening Bleeding | 10 participants |
| Clopidogrel Arm | Incidence of GUSTO Severe / Life-threatening Bleeding | 11 participants |
Secondary
Incidence of IDR
Time frame: randomization through 30 days after randomization
Population: mITT (excluding STEMI), based on 30-day completers
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cangrelor Arm | Incidence of IDR | 44 participants |
| Clopidogrel Arm | Incidence of IDR | 52 participants |
Secondary
Incidence of MI
Time frame: randomization through 30 days after randomization
Population: mITT (excluding STEMI), based on 30-day completers
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cangrelor Arm | Incidence of MI | 297 participants |
| Clopidogrel Arm | Incidence of MI | 276 participants |
Secondary
Incidence of Stroke
Stroke is defined as a sudden, focal neurological defect resulting from a cerebrovascular cause that is not reversible within 24 hours and not due to a readily identifiable cause such as a tumor or trauma. All suspected strokes were reviewed and adjudicated by the Clinical Events Committee (CEC) who considered all clinically relevant information and imaging studies to classify all strokes as: * primary hemorrhagic - stroke with focal collections of intracranial blood * ischemic cerebral infarction - stroke without focal collections of intracranial blood * infarction with hemorrhagic conversion - cerebral infarction with blood thought to represent hemorrhagic conversion and not primary bleeding * uncertain - no imaging or autopsy data are available.
Time frame: randomization through 48 hours after randomization
Population: mITT (excluding STEMI)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cangrelor Arm | Incidence of Stroke | primary hemorrhagic | 1 participants |
| Cangrelor Arm | Incidence of Stroke | cerebral infarction | 5 participants |
| Cangrelor Arm | Incidence of Stroke | uncertain type | 0 participants |
| Cangrelor Arm | Incidence of Stroke | infarction with hemorrhagic conversion | 0 participants |
| Clopidogrel Arm | Incidence of Stroke | cerebral infarction | 7 participants |
| Clopidogrel Arm | Incidence of Stroke | primary hemorrhagic | 0 participants |
| Clopidogrel Arm | Incidence of Stroke | infarction with hemorrhagic conversion | 0 participants |
| Clopidogrel Arm | Incidence of Stroke | uncertain type | 0 participants |
Secondary
Incidence of Stroke
Time frame: randomization through 30 days after randomization
Population: mITT (excluding STEMI), based on available data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cangrelor Arm | Incidence of Stroke | 5 participants |
| Clopidogrel Arm | Incidence of Stroke | 7 participants |
Secondary
Incidence of Thrombolysis in Myocardial Infarction (TIMI) Major Bleeding
Major bleeding (non-CABG-related) - Safety population
Time frame: randomization through 48 hours after randomization
Population: Safety Population (inclusive of STEMI patients)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cangrelor Arm | Incidence of Thrombolysis in Myocardial Infarction (TIMI) Major Bleeding | 19 participants |
| Clopidogrel Arm | Incidence of Thrombolysis in Myocardial Infarction (TIMI) Major Bleeding | 14 participants |
Secondary
Individual Incidence of All-cause Mortality
Time frame: randomization through 48 hours after randomization
Population: mITT (excluding STEMI)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cangrelor Arm | Individual Incidence of All-cause Mortality | 8 participants |
| Clopidogrel Arm | Individual Incidence of All-cause Mortality | 5 participants |
Secondary
Individual Incidence of IDR
Time frame: randomization through 48 hours after randomization
Population: mITT (excluding STEMI)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cangrelor Arm | Individual Incidence of IDR | 13 participants |
| Clopidogrel Arm | Individual Incidence of IDR | 23 participants |