Acute Coronary Syndrome (ACS)
Conditions
Brief summary
The purpose of this study is to demonstrate that patients receiving cangrelor infusion before coronary artery bypass grafting have an acceptable safety profile and can undergo surgery without excessive bleeding peri-operatively.
Interventions
DRUGcangrelor
OTHERPlacebo
Placebo IV infusion administered in the same fashion as the active study drug in order to maintain the blind in the study.
Sponsors
The Medicines Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
* Written informed consent * 18 Years of Age * Non emergent coronary bypass graft surgery * Received a thienopyridine within 48 hours prior to enrollment
Exclusion criteria
* Confirmed or suspected pregnancy * Cerebrovascular accident within one yar * Intracranial neoplasm * History of bleeding diathesis * Thrombocytopenia
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Stage I: Percentage of Patient Samples That Maintained Platelet Inhibition Levels of Greater Than or Equal to 60% as Reported by the VerifyNow P2Y12 Point of Care Assay. | During study drug infusion up to 1-6 hours prior to surgery | Endpoint was selected as an approximation of the antiplatelet effect expected to be maintained if oral P2Y12 inhibitors had not been discontinued (60% inhibition of platelets). |
| Stage II: The Percentage of Patients That Maintained Platelet Reaction Units (PRU) < 240, as Determined by the VerifyNow P2Y12 Point of Care Assay, Measured During Study Drug Infusion Pre-surgery. | During study drug infusion up to 1-6 hours prior to surgery | This endpoint was selected as it is considered by consensus of the Working Group on Platelet Reactivity to be the threshold for the level of platelet inhibition required to maintain a low risk of coronary thrombosis and cardiac ischemic events. Patients had multiple samples and all on-infusion samples had to be \<240 PRU to meet the endpoint. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Stage II: Analysis of Platelet Reactivity (ITT Population) / Patients With Platelet Reactivity < 240 PRU | baseline until just prior to surgery (post infusion) | This endpoint analyzed the percent of patients with platelet reactivity \< 240 PRU at the following timepoints: * Baseline - Prior to study drug infusion (washout period from oral P2Y12 inhibition) * Last sample during infusion * Following discontinuation of study drug infusion |
| Incidence of Excessive Coronary Artery Bypass Graft (CABG)-Related Bleeding | Randomization through Hospital discharge | Defined as the occurrence of surgical re-exploration, 24-hour chest tube output of \>1.5 liters (L), and/or packed red blood cell transfusions \> 4 units |
| Non-CABG (Preoperative) Bleeding - Protocol-defined GUSTO Severe/Life-threatening, Moderate and Mild | Randomization until start of CABG surgery | — |
| Patients With Blood Product Transfusions up to 7 Days After Surgery or Discharge, Whichever Was Sooner | Through 7 days or hospital discharge, whichever was sooner | — |
Countries
United States
Participant flow
Recruitment details
This study enrolled patients with acute coronary syndrome (ACS) or who had previously received stents, who were required to discontinue maintenance oral P2Y12 therapy before cardiac surgery. Patients who had discontinued oral therapy within the previous 72 hours were eligible. Patients were hospitalized during the enrollment period.
Pre-assignment details
Stage I was an open-label, dose-finding stage to identify the dose of cangrelor that achieved a level of antiplatelet effect after discontinuation of oral P2Y12 therapy equivalent to the previous oral P2Y12 maintenance therapy. These patients were not enrolled in Stage II. Stage II was randomized, double-blind, placebo-controlled.
Participants by arm
| Arm | Count |
|---|---|
| Stage I, Cohort I - 0.5 mcg/kg/Min Cangrelor Patients who received cangrelor as a continuous IV infusion of 0.5 mcg/kg/min for a minimum of 48 hours and a maximum of 7 days. | 5 |
| Stage I, Cohort II - 0.75 mcg/kg/Min Cangrelor Patients who received cangrelor as a continuous IV infusion of 0.75 mcg/kg/min for a minimum of 48 hours and a maximum of 7 days. | 6 |
| Stage II Cangrelor Arm (0.75 mcg/kg/Min) Patients who received cangrelor as a continuous IV infusion of 0.75 mcg/kg/min for a minimum of 48 hours and a maximum of 7 days. | 106 |
| Stage II Placebo Arm Patients who received matching placebo as a continuous IV infusion of 0.75 mcg/kg/min for a minimum of 48 hours and a maximum of 7 days. | 101 |
| Total | 218 |
Baseline characteristics
| Characteristic | Stage I, Cohort I - 0.5 mcg/kg/Min Cangrelor | Stage I, Cohort II - 0.75 mcg/kg/Min Cangrelor | Stage II Cangrelor Arm (0.75 mcg/kg/Min) | Stage II Placebo Arm | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 3 Participants | 54 Participants | 42 Participants | 101 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 3 Participants | 52 Participants | 59 Participants | 117 Participants |
| Region of Enrollment Austria | 0 participants | 0 participants | 1 participants | 6 participants | 7 participants |
| Region of Enrollment Czech Republic | 0 participants | 0 participants | 26 participants | 29 participants | 55 participants |
| Region of Enrollment Netherlands | 0 participants | 0 participants | 5 participants | 6 participants | 11 participants |
| Region of Enrollment United Kingdom | 0 participants | 0 participants | 8 participants | 4 participants | 12 participants |
| Region of Enrollment United States | 5 participants | 6 participants | 66 participants | 59 participants | 136 participants |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 26 Participants | 27 Participants | 55 Participants |
| Sex: Female, Male Male | 5 Participants | 4 Participants | 80 Participants | 74 Participants | 163 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 | 3 / 5 | 5 / 6 | 27 / 106 | 23 / 101 |
| serious Total, serious adverse events | 0 / 5 | 0 / 6 | 11 / 106 | 9 / 101 |
Outcome results
Primary
Stage II: The Percentage of Patients That Maintained Platelet Reaction Units (PRU) < 240, as Determined by the VerifyNow P2Y12 Point of Care Assay, Measured During Study Drug Infusion Pre-surgery.
This endpoint was selected as it is considered by consensus of the Working Group on Platelet Reactivity to be the threshold for the level of platelet inhibition required to maintain a low risk of coronary thrombosis and cardiac ischemic events. Patients had multiple samples and all on-infusion samples had to be \<240 PRU to meet the endpoint.
Time frame: During study drug infusion up to 1-6 hours prior to surgery
Population: Based on available data from ITT population; ITT population (Cangrelor N = 93) / (Placebo N = 90).~Valid PRU results were not available during the infusion period for 15 patients (9 cangrelor and 6 placebo).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage I, Cohort I - Cangrelor 0.5 mcg/kg/Min | Stage II: The Percentage of Patients That Maintained Platelet Reaction Units (PRU) < 240, as Determined by the VerifyNow P2Y12 Point of Care Assay, Measured During Study Drug Infusion Pre-surgery. | 98.8 Percent of patients |
| Stage I, Cohort II - Cangrelor 0.75 mcg/kg/Min | Stage II: The Percentage of Patients That Maintained Platelet Reaction Units (PRU) < 240, as Determined by the VerifyNow P2Y12 Point of Care Assay, Measured During Study Drug Infusion Pre-surgery. | 19.0 Percent of patients |
Primary
Stage I: Percentage of Patient Samples That Maintained Platelet Inhibition Levels of Greater Than or Equal to 60% as Reported by the VerifyNow P2Y12 Point of Care Assay.
Endpoint was selected as an approximation of the antiplatelet effect expected to be maintained if oral P2Y12 inhibitors had not been discontinued (60% inhibition of platelets).
Time frame: During study drug infusion up to 1-6 hours prior to surgery
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage I, Cohort I - Cangrelor 0.5 mcg/kg/Min | Stage I: Percentage of Patient Samples That Maintained Platelet Inhibition Levels of Greater Than or Equal to 60% as Reported by the VerifyNow P2Y12 Point of Care Assay. | 76.5 percentage of samples |
| Stage I, Cohort II - Cangrelor 0.75 mcg/kg/Min | Stage I: Percentage of Patient Samples That Maintained Platelet Inhibition Levels of Greater Than or Equal to 60% as Reported by the VerifyNow P2Y12 Point of Care Assay. | 94.4 percentage of samples |
Secondary
Incidence of Excessive Coronary Artery Bypass Graft (CABG)-Related Bleeding
Defined as the occurrence of surgical re-exploration, 24-hour chest tube output of \>1.5 liters (L), and/or packed red blood cell transfusions \> 4 units
Time frame: Randomization through Hospital discharge
Population: This analysis included only those patients who proceeded to have a CABG surgery as required per the protocol. The patients who did not have a CABG surgery were excluded from the denominator.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage I, Cohort I - Cangrelor 0.5 mcg/kg/Min | Incidence of Excessive Coronary Artery Bypass Graft (CABG)-Related Bleeding | 12 Patients |
| Stage I, Cohort II - Cangrelor 0.75 mcg/kg/Min | Incidence of Excessive Coronary Artery Bypass Graft (CABG)-Related Bleeding | 10 Patients |
| Stage I, Cohort I - Cangrelor 0.5 mcg/kg/Min | Incidence of Excessive Coronary Artery Bypass Graft (CABG)-Related Bleeding | 0 Patients |
| Stage I, Cohort II - Cangrelor 0.75 mcg/kg/Min | Incidence of Excessive Coronary Artery Bypass Graft (CABG)-Related Bleeding | 1 Patients |
Secondary
Non-CABG (Preoperative) Bleeding - Protocol-defined GUSTO Severe/Life-threatening, Moderate and Mild
Time frame: Randomization until start of CABG surgery
Population: This analysis included only those patients who proceeded to have a CABG surgery as required per the protocol. The patients who did not have a CABG surgery were excluded from the denominator.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Stage I, Cohort I - Cangrelor 0.5 mcg/kg/Min | Non-CABG (Preoperative) Bleeding - Protocol-defined GUSTO Severe/Life-threatening, Moderate and Mild | GUSTO severe/life threatening | 2 participants |
| Stage I, Cohort I - Cangrelor 0.5 mcg/kg/Min | Non-CABG (Preoperative) Bleeding - Protocol-defined GUSTO Severe/Life-threatening, Moderate and Mild | GUSTO mild | 8 participants |
| Stage I, Cohort I - Cangrelor 0.5 mcg/kg/Min | Non-CABG (Preoperative) Bleeding - Protocol-defined GUSTO Severe/Life-threatening, Moderate and Mild | GUSTO moderate | 10 participants |
| Stage I, Cohort II - Cangrelor 0.75 mcg/kg/Min | Non-CABG (Preoperative) Bleeding - Protocol-defined GUSTO Severe/Life-threatening, Moderate and Mild | GUSTO severe/life threatening | 1 participants |
| Stage I, Cohort II - Cangrelor 0.75 mcg/kg/Min | Non-CABG (Preoperative) Bleeding - Protocol-defined GUSTO Severe/Life-threatening, Moderate and Mild | GUSTO mild | 5 participants |
| Stage I, Cohort II - Cangrelor 0.75 mcg/kg/Min | Non-CABG (Preoperative) Bleeding - Protocol-defined GUSTO Severe/Life-threatening, Moderate and Mild | GUSTO moderate | 4 participants |
| Stage I, Cohort I - Cangrelor 0.5 mcg/kg/Min | Non-CABG (Preoperative) Bleeding - Protocol-defined GUSTO Severe/Life-threatening, Moderate and Mild | GUSTO moderate | 0 participants |
| Stage I, Cohort I - Cangrelor 0.5 mcg/kg/Min | Non-CABG (Preoperative) Bleeding - Protocol-defined GUSTO Severe/Life-threatening, Moderate and Mild | GUSTO severe/life threatening | 0 participants |
| Stage I, Cohort I - Cangrelor 0.5 mcg/kg/Min | Non-CABG (Preoperative) Bleeding - Protocol-defined GUSTO Severe/Life-threatening, Moderate and Mild | GUSTO mild | 1 participants |
| Stage I, Cohort II - Cangrelor 0.75 mcg/kg/Min | Non-CABG (Preoperative) Bleeding - Protocol-defined GUSTO Severe/Life-threatening, Moderate and Mild | GUSTO severe/life threatening | 0 participants |
| Stage I, Cohort II - Cangrelor 0.75 mcg/kg/Min | Non-CABG (Preoperative) Bleeding - Protocol-defined GUSTO Severe/Life-threatening, Moderate and Mild | GUSTO mild | 1 participants |
| Stage I, Cohort II - Cangrelor 0.75 mcg/kg/Min | Non-CABG (Preoperative) Bleeding - Protocol-defined GUSTO Severe/Life-threatening, Moderate and Mild | GUSTO moderate | 2 participants |
Secondary
Patients With Blood Product Transfusions up to 7 Days After Surgery or Discharge, Whichever Was Sooner
Time frame: Through 7 days or hospital discharge, whichever was sooner
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage I, Cohort I - Cangrelor 0.5 mcg/kg/Min | Patients With Blood Product Transfusions up to 7 Days After Surgery or Discharge, Whichever Was Sooner | 34 patients |
| Stage I, Cohort II - Cangrelor 0.75 mcg/kg/Min | Patients With Blood Product Transfusions up to 7 Days After Surgery or Discharge, Whichever Was Sooner | 35 patients |
| Stage I, Cohort I - Cangrelor 0.5 mcg/kg/Min | Patients With Blood Product Transfusions up to 7 Days After Surgery or Discharge, Whichever Was Sooner | 1 patients |
| Stage I, Cohort II - Cangrelor 0.75 mcg/kg/Min | Patients With Blood Product Transfusions up to 7 Days After Surgery or Discharge, Whichever Was Sooner | 4 patients |
Secondary
Stage II: Analysis of Platelet Reactivity (ITT Population) / Patients With Platelet Reactivity < 240 PRU
This endpoint analyzed the percent of patients with platelet reactivity \< 240 PRU at the following timepoints: * Baseline - Prior to study drug infusion (washout period from oral P2Y12 inhibition) * Last sample during infusion * Following discontinuation of study drug infusion
Time frame: baseline until just prior to surgery (post infusion)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Stage I, Cohort I - Cangrelor 0.5 mcg/kg/Min | Stage II: Analysis of Platelet Reactivity (ITT Population) / Patients With Platelet Reactivity < 240 PRU | Prior to study drug infusion (washout period) | 62.4 percent of patients |
| Stage I, Cohort I - Cangrelor 0.5 mcg/kg/Min | Stage II: Analysis of Platelet Reactivity (ITT Population) / Patients With Platelet Reactivity < 240 PRU | Last sample during infusion | 98.8 percent of patients |
| Stage I, Cohort I - Cangrelor 0.5 mcg/kg/Min | Stage II: Analysis of Platelet Reactivity (ITT Population) / Patients With Platelet Reactivity < 240 PRU | Following discontinuation of study drug infusion | 26.9 percent of patients |
| Stage I, Cohort II - Cangrelor 0.75 mcg/kg/Min | Stage II: Analysis of Platelet Reactivity (ITT Population) / Patients With Platelet Reactivity < 240 PRU | Prior to study drug infusion (washout period) | 52.3 percent of patients |
| Stage I, Cohort II - Cangrelor 0.75 mcg/kg/Min | Stage II: Analysis of Platelet Reactivity (ITT Population) / Patients With Platelet Reactivity < 240 PRU | Last sample during infusion | 31.0 percent of patients |
| Stage I, Cohort II - Cangrelor 0.75 mcg/kg/Min | Stage II: Analysis of Platelet Reactivity (ITT Population) / Patients With Platelet Reactivity < 240 PRU | Following discontinuation of study drug infusion | 20.0 percent of patients |