Acute Coronary Syndrome
Conditions
Keywords
Plavix, Effient
Brief summary
This study will evaluate the use of a prasugrel 60 mg loading dose (LD) administered during percutaneous coronary intervention (PCI) with and without a prior LD of clopidogrel on platelet inhibition in patients presenting with acute coronary syndrome (ACS). Platelet inhibition following a prasugrel LD in clopidogrel pretreated patients' will be determined in a time-dependent manner for two different prasugrel loading doses (30 mg and 60 mg). Understanding the effects of this combination on platelet inhibition will provide guidance to physicians on the use of prasugrel in patients who have already been pretreated with clopidogrel.
Interventions
DRUGPrasugrel
Loading dose administered once orally and maintenance dose administered orally 24 hours after loading dose, then every 24 hours for 72 hours.
DRUGClopidogrel
Loading dose administered once orally.
DRUGPlacebo
Loading dose administered once orally
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 74 Years
Healthy volunteers
No
Inclusion criteria
* Participants hospitalized with acute coronary syndrome (ACS) \[unstable angina (UA), non-ST elevation myocardial infarction (NSTEMI), or ST elevation myocardial infarction (STEMI)\] as determined by the investigator, and who are anticipated to undergo percutaneous coronary intervention (PCI) as a treatment for the ACS event within 24 hours of the clopidogrel/placebo loading dose * Participants provide signed informed consent form (ICF) * Participants weigh at least 60 kilograms (kg) at the time of screening * Women of child-bearing potential (that is, women who are not surgically or chemically sterilized and who are between menarche and 1-year postmenopause), test negative for pregnancy at the time of enrollment based on a urine or serum pregnancy test
Exclusion criteria
* Have cardiogenic shock at the time of randomization (systolic blood pressure greater than 90 millimeters of mercury (mm Hg) associated with clinical evidence of end-organ hypoperfusion, or participants requiring vasopressors to maintain systolic blood pressure over 90 mm Hg and associated with clinical evidence of end-organ hypoperfusion * Have refractory ventricular arrhythmias * Have New York Heart Association (NYHA) Class IV congestive heart failure * Have systolic blood pressure greater than 180 mm Hg, or diastolic blood pressure greater than 100 mm Hg on more than 1 assessment at any time from participant presentation of ACS treatment to enrollment * Have received fibrin-specific fibrinolytic therapy less than 24 hours prior to randomization * Have received nonfibrin-specific fibrinolytic therapy less than 48 hours prior to randomization * Have active internal bleeding or history of bleeding diathesis * Have clinical findings, in the judgment of the investigator, associated with an increased risk of bleeding * Prior history of ischemic or hemorrhagic stroke * Intracranial neoplasm, arteriovenous malformation, or aneurysm * Prior history of transient ischemic attack (TIA) * Have an International Normalized Ratio (INR) known to be greater than 1.5 at the time of evaluation * Have a platelet count of less than 100,000 per cubic millimeter (mm\^3) at the time of evaluation * Have anemia \[hemoglobin (Hgb) less than 10 grams per deciliter (g/dL)\] at the time of evaluation * Have received 1 or more doses of a thienopyridine (ticlopidine, clopidogrel, or prasugrel) or other adenosine diphosphate (ADP) receptor inhibitor within 10 days prior to screening * Have been administered glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitor within the past 7 days or planned use of a GPIIb/IIIa inhibitor during PCI * Are receiving or will receive oral anticoagulation or other antiplatelet therapy, other than aspirin (ASA), which cannot be safely discontinued for the duration of the study. * Are receiving daily treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase-2 (COX2) inhibitors that cannot be discontinued during the study * Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational drug or device or off-label use of a drug or device, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study * Have previously completed or withdrawn from this study or any other study investigating prasugrel * Are women who are known to be pregnant, who have given birth within the past 90 days, or who are breastfeeding * Have a concomitant medical illness (for example, terminal malignancy) that in the opinion of the investigator, is associated with reduced survival over the expected treatment period * Have known severe hepatic dysfunction (that is, with cirrhosis or portal hypertension) * Have a history of intolerance or allergy to aspirin or approved thienopyridines (ticlopidine, clopidogrel or prasugrel) * May be unable to cooperate with protocol requirements and follow-up procedures
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adenosine Diphosphate (ADP)-Induced P2Y12 Receptor-Mediated Platelet Aggregation 6 Hours After Prasugrel Loading Dose (LD) | 6 hours after prasugrel loading dose | ADP-induced P2Y12 receptor mediated platelet aggregation serves as a biomarker of platelet function. It is measured in P2Y12 Reaction Units (PRU) with lower PRU reflecting stronger inhibition of P2Y12 and reduced platelet aggregation. Least Squares (LS) Mean values were controlled for treatment, visit, treatment and visit interaction, and country. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline to 72 Hours in Laboratory Measurements - Hematocrit | Baseline, 72 hours | — |
| Mean Change From Baseline to 72 Hours in Laboratory Measurements - Hemoglobin | Baseline, 72 hours | — |
| Percentage of Inhibition of Platelet Aggregation | Baseline and 2 and 6 and 24 and 72 hours after loading dose | Adenosine Diphosphate (ADP)-induced P2Y12 receptor mediated platelet aggregation serves as a biomarker of platelet function. It is measured in P2Y12 Reaction Units (PRU) with lower PRU reflecting stronger inhibition of P2Y12 and reduced platelet aggregation. The internal BASE standard is an independent measurement and serves as an estimate of the participant's baseline platelet aggregation independent of P2Y12 receptor inhibition. Percent Inhibition of Platelet Aggregation=(1-\[PRU/BASE) x 100%, high numbers represent increased platelet inhibition. Least Squares (LS) Mean values were controlled for treatment, visit, treatment and visit interaction, and country. |
| Adenosine Diphosphate (ADP)-Induced P2Y12 Receptor-Mediated Platelet Aggregation at Baseline, 2, 24 and 72 Hours After Prasugrel Loading Dose (LD) | Baseline and 2 hours and 24 hours and 72 hours after prasugrel loading dose | ADP-induced P2Y12 receptor mediated platelet aggregation serves as a biomarker of platelet function. It is measured in P2Y12 Reaction Units (PRU) with lower PRU reflecting stronger inhibition of P2Y12 and reduced platelet aggregation. Least Squares (LS) Mean values were controlled for treatment, visit, treatment and visit interaction, and country. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Baseline through 72 hours after prasugrel loading dose | TEAE is a worsening or new occurrence of adverse event (AE) during treatment compared to baseline. A summary of serious adverse events (SAE) and other nonserious AE are located in the Reported Adverse Events section. |
| P2Y12 Reaction Units (PRU) of Clopidogrel Treated Participants at Baseline by Cytochrome P450 2C19 (CYP2C19)-Predicted Functional Groups - CYP2C19 Extensive Metabolizers (EM) and Reduced Metabolizers (RM) | Baseline | CYP2C19 is a drug metabolizing enzyme. CYP2C19 Extensive metabolizers (EM) are individuals with two fully active / normal function CYP2C19 alleles (\*1/\*1, \*1/\*17). CYP2C19 Reduced metabolizers (RM) are individuals with at least one reduced-function CYP2C19 allele (\*2/\*2, \*1/\*2). Least Squares (LS) Mean values were controlled for CYP2C19 genetic group. |
| P2Y12 Reaction Units (PRU) at 6 Hours Post-Prasugrel Loading Dose (LD) by Cytochrome P450 2C19 (CYP2C19)-Predicted Functional Groups - Extensive Metabolizers (EM) and Reduced Metabolizers (RM) | 6 hours after prasugrel loading dose | CYP2C19 is a drug metabolizing enzyme. CYP2C19 Extensive metabolizers (EM) are individuals with two fully active / normal function CYP2C19 alleles (\*1/\*1, \*1/\*17). CYP2C19 Reduced metabolizers (RM) are individuals with at least one reduced-function CYP2C19 allele (\*2/\*2, \*1/\*2). Least Squares (LS) Mean values were controlled for CYP2C19 genetic group. |
| Percentage of Poor Responders | Baseline and 2 and 6 and 24 and 72 hours after loading dose | Poor responders are those who had P2Y12 Reaction Units (PRU)≥ 240. |
Countries
India
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo and 60-mg Prasugrel Placebo loading dose (LD) administered once orally before percutaneous coronary intervention (PCI) and 60-milligram (mg) prasugrel LD administered once orally during PCI, followed by 10-mg prasugrel maintenance dose administered orally 24 hours after LD, then every 24 hours for 72 hours. | 52 |
| 600-mg Clopidogrel and 60-mg Prasugrel 600-mg clopidogrel LD administered once orally before PCI and 60-mg prasugrel LD administered once orally during PCI, followed by 10-mg prasugrel maintenance dose administered orally 24 hours after LD, then every 24 hours for 72 hours. | 47 |
| 600-mg Clopidogrel and 30-mg Prasugrel 600-mg clopidogrel LD administered once orally before PCI and 30-mg prasugrel LD administered once orally during PCI, followed by 10-mg prasugrel maintenance dose administered orally 24 hours after LD, then every 24 hours for 72 hours. | 50 |
| Total | 149 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
| Overall Study | Physician Decision | 18 | 15 | 17 |
| Overall Study | Withdrawal by Subject | 6 | 6 | 9 |
Baseline characteristics
| Characteristic | Placebo and 60-mg Prasugrel | Total | 600-mg Clopidogrel and 30-mg Prasugrel | 600-mg Clopidogrel and 60-mg Prasugrel |
|---|---|---|---|---|
| Age Continuous | 58.1 years STANDARD_DEVIATION 9.47 | 58.1 years STANDARD_DEVIATION 8.86 | 58.7 years STANDARD_DEVIATION 8.07 | 57.5 years STANDARD_DEVIATION 9.12 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 13 Participants | 40 Participants | 13 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 30 Participants | 88 Participants | 30 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 9 Participants | 21 Participants | 7 Participants | 5 Participants |
| Qualifying Acute Coronary Syndrome (ACS) Event Non-ST-elevation Myocardial Infarction | 20 participants | 59 participants | 21 participants | 18 participants |
| Qualifying Acute Coronary Syndrome (ACS) Event ST-elevation Myocardial Infarction | 11 participants | 31 participants | 7 participants | 13 participants |
| Qualifying Acute Coronary Syndrome (ACS) Event Unstable Angina | 21 participants | 59 participants | 22 participants | 16 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 13 Participants | 34 Participants | 9 Participants | 12 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 6 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 3 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 37 Participants | 106 Participants | 38 Participants | 31 Participants |
| Region of Enrollment Argentina | 2 participants | 10 participants | 4 participants | 4 participants |
| Region of Enrollment Australia | 1 participants | 6 participants | 2 participants | 3 participants |
| Region of Enrollment Brazil | 6 participants | 17 participants | 6 participants | 5 participants |
| Region of Enrollment Canada | 11 participants | 29 participants | 10 participants | 8 participants |
| Region of Enrollment India | 10 participants | 30 participants | 9 participants | 11 participants |
| Region of Enrollment Mexico | 8 participants | 19 participants | 5 participants | 6 participants |
| Region of Enrollment Turkey | 7 participants | 16 participants | 7 participants | 2 participants |
| Region of Enrollment United States | 7 participants | 22 participants | 7 participants | 8 participants |
| Sex: Female, Male Female | 13 Participants | 30 Participants | 9 Participants | 8 Participants |
| Sex: Female, Male Male | 39 Participants | 119 Participants | 41 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 37 / 109 | 31 / 79 | 31 / 88 |
| serious Total, serious adverse events | 2 / 109 | 8 / 79 | 1 / 88 |
Outcome results
Primary
Adenosine Diphosphate (ADP)-Induced P2Y12 Receptor-Mediated Platelet Aggregation 6 Hours After Prasugrel Loading Dose (LD)
ADP-induced P2Y12 receptor mediated platelet aggregation serves as a biomarker of platelet function. It is measured in P2Y12 Reaction Units (PRU) with lower PRU reflecting stronger inhibition of P2Y12 and reduced platelet aggregation. Least Squares (LS) Mean values were controlled for treatment, visit, treatment and visit interaction, and country.
Time frame: 6 hours after prasugrel loading dose
Population: All randomized participants who received the prasugrel LD and had at least one evaluable PRU measurement after LD.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo and 60-mg Prasugrel | Adenosine Diphosphate (ADP)-Induced P2Y12 Receptor-Mediated Platelet Aggregation 6 Hours After Prasugrel Loading Dose (LD) | 57.86 PRU | Standard Error 11.86 |
| 600-mg Clopidogrel and 60-mg Prasugrel | Adenosine Diphosphate (ADP)-Induced P2Y12 Receptor-Mediated Platelet Aggregation 6 Hours After Prasugrel Loading Dose (LD) | 35.61 PRU | Standard Error 12.36 |
| 600-mg Clopidogrel and 30-mg Prasugrel | Adenosine Diphosphate (ADP)-Induced P2Y12 Receptor-Mediated Platelet Aggregation 6 Hours After Prasugrel Loading Dose (LD) | 53.92 PRU | Standard Error 11.74 |
p-value: 0.18895% CI: [-10.98, 55.47]Mixed Model Repeated Measures Analysis
p-value: 0.80995% CI: [-28.2, 36.07]Mixed Model Repeated Measures Analysis
Secondary
Adenosine Diphosphate (ADP)-Induced P2Y12 Receptor-Mediated Platelet Aggregation at Baseline, 2, 24 and 72 Hours After Prasugrel Loading Dose (LD)
ADP-induced P2Y12 receptor mediated platelet aggregation serves as a biomarker of platelet function. It is measured in P2Y12 Reaction Units (PRU) with lower PRU reflecting stronger inhibition of P2Y12 and reduced platelet aggregation. Least Squares (LS) Mean values were controlled for treatment, visit, treatment and visit interaction, and country.
Time frame: Baseline and 2 hours and 24 hours and 72 hours after prasugrel loading dose
Population: All randomized participants who received prasugrel LD and had at least one evaluable PRU measurement after prasugrel LD.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo and 60-mg Prasugrel | Adenosine Diphosphate (ADP)-Induced P2Y12 Receptor-Mediated Platelet Aggregation at Baseline, 2, 24 and 72 Hours After Prasugrel Loading Dose (LD) | Baseline | 265.51 PRU | Standard Error 13.01 |
| Placebo and 60-mg Prasugrel | Adenosine Diphosphate (ADP)-Induced P2Y12 Receptor-Mediated Platelet Aggregation at Baseline, 2, 24 and 72 Hours After Prasugrel Loading Dose (LD) | 2 Hours after Prasugrel LD | 122.55 PRU | Standard Error 17.28 |
| Placebo and 60-mg Prasugrel | Adenosine Diphosphate (ADP)-Induced P2Y12 Receptor-Mediated Platelet Aggregation at Baseline, 2, 24 and 72 Hours After Prasugrel Loading Dose (LD) | 24 Hours after Prasugrel LD | 62.73 PRU | Standard Error 10.43 |
| Placebo and 60-mg Prasugrel | Adenosine Diphosphate (ADP)-Induced P2Y12 Receptor-Mediated Platelet Aggregation at Baseline, 2, 24 and 72 Hours After Prasugrel Loading Dose (LD) | 72 Hours after Prasugrel LD | 56.95 PRU | Standard Error 8.4 |
| 600-mg Clopidogrel and 60-mg Prasugrel | Adenosine Diphosphate (ADP)-Induced P2Y12 Receptor-Mediated Platelet Aggregation at Baseline, 2, 24 and 72 Hours After Prasugrel Loading Dose (LD) | 72 Hours after Prasugrel LD | 48.08 PRU | Standard Error 9.09 |
| 600-mg Clopidogrel and 60-mg Prasugrel | Adenosine Diphosphate (ADP)-Induced P2Y12 Receptor-Mediated Platelet Aggregation at Baseline, 2, 24 and 72 Hours After Prasugrel Loading Dose (LD) | Baseline | 248.58 PRU | Standard Error 13.99 |
| 600-mg Clopidogrel and 60-mg Prasugrel | Adenosine Diphosphate (ADP)-Induced P2Y12 Receptor-Mediated Platelet Aggregation at Baseline, 2, 24 and 72 Hours After Prasugrel Loading Dose (LD) | 24 Hours after Prasugrel LD | 34.05 PRU | Standard Error 10.88 |
| 600-mg Clopidogrel and 60-mg Prasugrel | Adenosine Diphosphate (ADP)-Induced P2Y12 Receptor-Mediated Platelet Aggregation at Baseline, 2, 24 and 72 Hours After Prasugrel Loading Dose (LD) | 2 Hours after Prasugrel LD | 113.10 PRU | Standard Error 18.07 |
| 600-mg Clopidogrel and 30-mg Prasugrel | Adenosine Diphosphate (ADP)-Induced P2Y12 Receptor-Mediated Platelet Aggregation at Baseline, 2, 24 and 72 Hours After Prasugrel Loading Dose (LD) | 72 Hours after Prasugrel LD | 60.29 PRU | Standard Error 9.05 |
| 600-mg Clopidogrel and 30-mg Prasugrel | Adenosine Diphosphate (ADP)-Induced P2Y12 Receptor-Mediated Platelet Aggregation at Baseline, 2, 24 and 72 Hours After Prasugrel Loading Dose (LD) | 2 Hours after Prasugrel LD | 117.10 PRU | Standard Error 17.47 |
| 600-mg Clopidogrel and 30-mg Prasugrel | Adenosine Diphosphate (ADP)-Induced P2Y12 Receptor-Mediated Platelet Aggregation at Baseline, 2, 24 and 72 Hours After Prasugrel Loading Dose (LD) | 24 Hours after Prasugrel LD | 51.43 PRU | Standard Error 10.72 |
| 600-mg Clopidogrel and 30-mg Prasugrel | Adenosine Diphosphate (ADP)-Induced P2Y12 Receptor-Mediated Platelet Aggregation at Baseline, 2, 24 and 72 Hours After Prasugrel Loading Dose (LD) | Baseline | 229.62 PRU | Standard Error 13.38 |
p-value: 0.3795% CI: [-20.26, 54.12]Mixed Model Repeated Measures Analysis
p-value: 0.05295% CI: [-0.29, 72.06]Mixed Model Repeated Measures Analysis
p-value: 0.70395% CI: [-39.55, 58.45]Mixed Model Repeated Measures Analysis
p-value: 0.82395% CI: [-42.53, 53.44]Mixed Model Repeated Measures Analysis
p-value: 0.05495% CI: [-0.47, 57.84]Mixed Model Repeated Measures Analysis
p-value: 0.43695% CI: [-17.29, 39.9]Mixed Model Repeated Measures Analysis
p-value: 0.46395% CI: [-14.96, 32.71]Mixed Model Repeated Measures Analysis
p-value: 0.77795% CI: [-26.62, 19.94]Mixed Model Repeated Measures Analysis
Secondary
Mean Change From Baseline to 72 Hours in Laboratory Measurements - Hematocrit
Time frame: Baseline, 72 hours
Population: All randomized participants who received prasugrel loading dose (LD) and had a Hematocrit measurement 72 hours after LD.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo and 60-mg Prasugrel | Mean Change From Baseline to 72 Hours in Laboratory Measurements - Hematocrit | 0.0 proportion of 1.0 | Standard Deviation 0.04 |
| 600-mg Clopidogrel and 60-mg Prasugrel | Mean Change From Baseline to 72 Hours in Laboratory Measurements - Hematocrit | 0.0 proportion of 1.0 | Standard Deviation 0.03 |
| 600-mg Clopidogrel and 30-mg Prasugrel | Mean Change From Baseline to 72 Hours in Laboratory Measurements - Hematocrit | 0.0 proportion of 1.0 | Standard Deviation 0.03 |
Secondary
Mean Change From Baseline to 72 Hours in Laboratory Measurements - Hemoglobin
Time frame: Baseline, 72 hours
Population: All randomized participants who received prasugrel loading dose (LD) and had a Hemoglobin measurement 72 hours after LD.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo and 60-mg Prasugrel | Mean Change From Baseline to 72 Hours in Laboratory Measurements - Hemoglobin | -0.9 gram per deciliter (g/dL) | Standard Deviation 1.41 |
| 600-mg Clopidogrel and 60-mg Prasugrel | Mean Change From Baseline to 72 Hours in Laboratory Measurements - Hemoglobin | -0.6 gram per deciliter (g/dL) | Standard Deviation 1.03 |
| 600-mg Clopidogrel and 30-mg Prasugrel | Mean Change From Baseline to 72 Hours in Laboratory Measurements - Hemoglobin | -0.6 gram per deciliter (g/dL) | Standard Deviation 1.04 |
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs)
TEAE is a worsening or new occurrence of adverse event (AE) during treatment compared to baseline. A summary of serious adverse events (SAE) and other nonserious AE are located in the Reported Adverse Events section.
Time frame: Baseline through 72 hours after prasugrel loading dose
Population: Participants who received any treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo and 60-mg Prasugrel | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Serious Adverse Events | 2 participants |
| Placebo and 60-mg Prasugrel | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Nonserious Adverse Events | 37 participants |
| 600-mg Clopidogrel and 60-mg Prasugrel | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Serious Adverse Events | 8 participants |
| 600-mg Clopidogrel and 60-mg Prasugrel | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Nonserious Adverse Events | 31 participants |
| 600-mg Clopidogrel and 30-mg Prasugrel | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Serious Adverse Events | 1 participants |
| 600-mg Clopidogrel and 30-mg Prasugrel | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Nonserious Adverse Events | 31 participants |
Secondary
P2Y12 Reaction Units (PRU) at 6 Hours Post-Prasugrel Loading Dose (LD) by Cytochrome P450 2C19 (CYP2C19)-Predicted Functional Groups - Extensive Metabolizers (EM) and Reduced Metabolizers (RM)
CYP2C19 is a drug metabolizing enzyme. CYP2C19 Extensive metabolizers (EM) are individuals with two fully active / normal function CYP2C19 alleles (\*1/\*1, \*1/\*17). CYP2C19 Reduced metabolizers (RM) are individuals with at least one reduced-function CYP2C19 allele (\*2/\*2, \*1/\*2). Least Squares (LS) Mean values were controlled for CYP2C19 genetic group.
Time frame: 6 hours after prasugrel loading dose
Population: All randomized participants who received prasugrel LD and had PRU measurements 6 hours after prasugrel LD and provided a DNA sample.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo and 60-mg Prasugrel | P2Y12 Reaction Units (PRU) at 6 Hours Post-Prasugrel Loading Dose (LD) by Cytochrome P450 2C19 (CYP2C19)-Predicted Functional Groups - Extensive Metabolizers (EM) and Reduced Metabolizers (RM) | 39.036 PRU | Standard Error 11.397 |
| 600-mg Clopidogrel and 60-mg Prasugrel | P2Y12 Reaction Units (PRU) at 6 Hours Post-Prasugrel Loading Dose (LD) by Cytochrome P450 2C19 (CYP2C19)-Predicted Functional Groups - Extensive Metabolizers (EM) and Reduced Metabolizers (RM) | 47.750 PRU | Standard Error 30.153 |
| 600-mg Clopidogrel and 30-mg Prasugrel | P2Y12 Reaction Units (PRU) at 6 Hours Post-Prasugrel Loading Dose (LD) by Cytochrome P450 2C19 (CYP2C19)-Predicted Functional Groups - Extensive Metabolizers (EM) and Reduced Metabolizers (RM) | 20.190 PRU | Standard Error 13.16 |
| 600 mg Clopidogrel and 60 mg Prasugrel - CYP2C19 RM | P2Y12 Reaction Units (PRU) at 6 Hours Post-Prasugrel Loading Dose (LD) by Cytochrome P450 2C19 (CYP2C19)-Predicted Functional Groups - Extensive Metabolizers (EM) and Reduced Metabolizers (RM) | 23.625 PRU | Standard Error 21.321 |
| 600 mg Clopidogrel and 30 mg Prasugrel - CYP2C19 EM | P2Y12 Reaction Units (PRU) at 6 Hours Post-Prasugrel Loading Dose (LD) by Cytochrome P450 2C19 (CYP2C19)-Predicted Functional Groups - Extensive Metabolizers (EM) and Reduced Metabolizers (RM) | 36.478 PRU | Standard Error 12.575 |
| 600 mg Clopidogrel and 30 mg Prasugrel - CYP2C19 RM | P2Y12 Reaction Units (PRU) at 6 Hours Post-Prasugrel Loading Dose (LD) by Cytochrome P450 2C19 (CYP2C19)-Predicted Functional Groups - Extensive Metabolizers (EM) and Reduced Metabolizers (RM) | 24.778 PRU | Standard Error 20.102 |
Comparison: A linear ANOVA model with PRU values of 6 hours post Prasugrel LD as response and treatment, CYP2C19 metabolizer status, interaction of treatment-by-CYP2C19 metabolizer status as fixed effects.p-value: 0.787595% CI: [-72.78, 55.36]ANOVA
Comparison: A linear ANOVA model with PRU values of 6 hours Post-Prasugrel LD as response and treatment, CYP2C19 metabolizer status, interaction of treatment-by-CYP2C19 metabolizer status as fixed effects.p-value: 0.891395% CI: [-53.23, 46.37]ANOVA
Comparison: A linear ANOVA model with PRU values of 6 hours Post-Prasugrel LD as response and treatment, CYP2C19 metabolizer status, interaction of treatment-by-CYP2C19 metabolizer status as fixed effects.p-value: 0.622995% CI: [-35.43, 58.83]ANOVA
Secondary
P2Y12 Reaction Units (PRU) of Clopidogrel Treated Participants at Baseline by Cytochrome P450 2C19 (CYP2C19)-Predicted Functional Groups - CYP2C19 Extensive Metabolizers (EM) and Reduced Metabolizers (RM)
CYP2C19 is a drug metabolizing enzyme. CYP2C19 Extensive metabolizers (EM) are individuals with two fully active / normal function CYP2C19 alleles (\*1/\*1, \*1/\*17). CYP2C19 Reduced metabolizers (RM) are individuals with at least one reduced-function CYP2C19 allele (\*2/\*2, \*1/\*2). Least Squares (LS) Mean values were controlled for CYP2C19 genetic group.
Time frame: Baseline
Population: All randomized participants who were treated with Clopidogrel and had PRU measurement at Baseline and provided a DNA sample.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo and 60-mg Prasugrel | P2Y12 Reaction Units (PRU) of Clopidogrel Treated Participants at Baseline by Cytochrome P450 2C19 (CYP2C19)-Predicted Functional Groups - CYP2C19 Extensive Metabolizers (EM) and Reduced Metabolizers (RM) | 243.549 PRU | Standard Error 11.244 |
| 600-mg Clopidogrel and 60-mg Prasugrel | P2Y12 Reaction Units (PRU) of Clopidogrel Treated Participants at Baseline by Cytochrome P450 2C19 (CYP2C19)-Predicted Functional Groups - CYP2C19 Extensive Metabolizers (EM) and Reduced Metabolizers (RM) | 240.100 PRU | Standard Error 17.955 |
Comparison: A linear ANOVA model with PRU values at baseline for clopidogrel treated participants as response and CYP2C19 metabolizer status as covariate of main interest.p-value: 0.871195% CI: [-38.81, 45.71]ANOVA
Secondary
Percentage of Inhibition of Platelet Aggregation
Adenosine Diphosphate (ADP)-induced P2Y12 receptor mediated platelet aggregation serves as a biomarker of platelet function. It is measured in P2Y12 Reaction Units (PRU) with lower PRU reflecting stronger inhibition of P2Y12 and reduced platelet aggregation. The internal BASE standard is an independent measurement and serves as an estimate of the participant's baseline platelet aggregation independent of P2Y12 receptor inhibition. Percent Inhibition of Platelet Aggregation=(1-\[PRU/BASE) x 100%, high numbers represent increased platelet inhibition. Least Squares (LS) Mean values were controlled for treatment, visit, treatment and visit interaction, and country.
Time frame: Baseline and 2 and 6 and 24 and 72 hours after loading dose
Population: All randomized participants who received prasugrel loading dose (LD) and had at least one evaluable PRU measurement after prasugrel LD.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo and 60-mg Prasugrel | Percentage of Inhibition of Platelet Aggregation | 24 Hours after Prasugrel LD | 77.57 percentage of inhibition | Standard Error 3.56 |
| Placebo and 60-mg Prasugrel | Percentage of Inhibition of Platelet Aggregation | 6 Hours after Prasugrel LD | 79.87 percentage of inhibition | Standard Error 3.95 |
| Placebo and 60-mg Prasugrel | Percentage of Inhibition of Platelet Aggregation | Baseline | 9.71 percentage of inhibition | Standard Error 3.44 |
| Placebo and 60-mg Prasugrel | Percentage of Inhibition of Platelet Aggregation | 2 Hours after Prasugrel LD | 56.04 percentage of inhibition | Standard Error 5.88 |
| Placebo and 60-mg Prasugrel | Percentage of Inhibition of Platelet Aggregation | 72 Hours after Prasugrel LD | 78.48 percentage of inhibition | Standard Error 2.95 |
| 600-mg Clopidogrel and 60-mg Prasugrel | Percentage of Inhibition of Platelet Aggregation | 6 Hours after Prasugrel LD | 86.77 percentage of inhibition | Standard Error 4.13 |
| 600-mg Clopidogrel and 60-mg Prasugrel | Percentage of Inhibition of Platelet Aggregation | Baseline | 13.02 percentage of inhibition | Standard Error 3.7 |
| 600-mg Clopidogrel and 60-mg Prasugrel | Percentage of Inhibition of Platelet Aggregation | 2 Hours after Prasugrel LD | 58.75 percentage of inhibition | Standard Error 6.16 |
| 600-mg Clopidogrel and 60-mg Prasugrel | Percentage of Inhibition of Platelet Aggregation | 24 Hours after Prasugrel LD | 87.64 percentage of inhibition | Standard Error 3.74 |
| 600-mg Clopidogrel and 60-mg Prasugrel | Percentage of Inhibition of Platelet Aggregation | 72 Hours after Prasugrel LD | 83.51 percentage of inhibition | Standard Error 3.28 |
| 600-mg Clopidogrel and 30-mg Prasugrel | Percentage of Inhibition of Platelet Aggregation | 72 Hours after Prasugrel LD | 78.17 percentage of inhibition | Standard Error 3.27 |
| 600-mg Clopidogrel and 30-mg Prasugrel | Percentage of Inhibition of Platelet Aggregation | 24 Hours after Prasugrel LD | 78.56 percentage of inhibition | Standard Error 3.68 |
| 600-mg Clopidogrel and 30-mg Prasugrel | Percentage of Inhibition of Platelet Aggregation | Baseline | 14.94 percentage of inhibition | Standard Error 3.54 |
| 600-mg Clopidogrel and 30-mg Prasugrel | Percentage of Inhibition of Platelet Aggregation | 6 Hours after Prasugrel LD | 78.55 percentage of inhibition | Standard Error 3.93 |
| 600-mg Clopidogrel and 30-mg Prasugrel | Percentage of Inhibition of Platelet Aggregation | 2 Hours after Prasugrel LD | 54.89 percentage of inhibition | Standard Error 5.95 |
p-value: 0.50595% CI: [-13.1, 6.48]Mixed Model Repeated Measures Analysis
p-value: 0.27895% CI: [-14.74, 4.27]Mixed Model Repeated Measures Analysis
p-value: 0.74995% CI: [-19.44, 14.02]Mixed Model Repeated Measures Analysis
p-value: 0.8995% CI: [-15.24, 17.53]Mixed Model Repeated Measures Analysis
p-value: 0.22395% CI: [-18.02, 4.24]Mixed Model Repeated Measures Analysis
p-value: 0.80895% CI: [-9.44, 12.1]Mixed Model Repeated Measures Analysis
p-value: 0.04995% CI: [-20.11, -0.04]Mixed Model Repeated Measures Analysis
p-value: 0.84295% CI: [-10.85, 8.86]Mixed Model Repeated Measures Analysis
p-value: 0.24795% CI: [-13.58, 3.52]Mixed Model Repeated Measures Analysis
p-value: 0.94295% CI: [-8.09, 8.71]Mixed Model Repeated Measures Analysis
Secondary
Percentage of Poor Responders
Poor responders are those who had P2Y12 Reaction Units (PRU)≥ 240.
Time frame: Baseline and 2 and 6 and 24 and 72 hours after loading dose
Population: All randomized participants who received prasugrel loading dose (LD) and had at least one evaluable PRU measurement after prasugrel LD.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo and 60-mg Prasugrel | Percentage of Poor Responders | 24 Hours after Prasugrel LD | 9.5 percentage of participants |
| Placebo and 60-mg Prasugrel | Percentage of Poor Responders | 6 Hours after Prasugrel LD | 11.6 percentage of participants |
| Placebo and 60-mg Prasugrel | Percentage of Poor Responders | Baseline | 68.1 percentage of participants |
| Placebo and 60-mg Prasugrel | Percentage of Poor Responders | 2 Hours after Prasugrel LD | 23.3 percentage of participants |
| Placebo and 60-mg Prasugrel | Percentage of Poor Responders | 72 Hours after Prasugrel LD | 0 percentage of participants |
| 600-mg Clopidogrel and 60-mg Prasugrel | Percentage of Poor Responders | 6 Hours after Prasugrel LD | 5.3 percentage of participants |
| 600-mg Clopidogrel and 60-mg Prasugrel | Percentage of Poor Responders | Baseline | 66.7 percentage of participants |
| 600-mg Clopidogrel and 60-mg Prasugrel | Percentage of Poor Responders | 2 Hours after Prasugrel LD | 12.8 percentage of participants |
| 600-mg Clopidogrel and 60-mg Prasugrel | Percentage of Poor Responders | 24 Hours after Prasugrel LD | 2.9 percentage of participants |
| 600-mg Clopidogrel and 60-mg Prasugrel | Percentage of Poor Responders | 72 Hours after Prasugrel LD | 0 percentage of participants |
| 600-mg Clopidogrel and 30-mg Prasugrel | Percentage of Poor Responders | 72 Hours after Prasugrel LD | 0 percentage of participants |
| 600-mg Clopidogrel and 30-mg Prasugrel | Percentage of Poor Responders | 24 Hours after Prasugrel LD | 8.8 percentage of participants |
| 600-mg Clopidogrel and 30-mg Prasugrel | Percentage of Poor Responders | Baseline | 51.2 percentage of participants |
| 600-mg Clopidogrel and 30-mg Prasugrel | Percentage of Poor Responders | 6 Hours after Prasugrel LD | 4.4 percentage of participants |
| 600-mg Clopidogrel and 30-mg Prasugrel | Percentage of Poor Responders | 2 Hours after Prasugrel LD | 21.4 percentage of participants |