Coronary Artery Disease
Conditions
Keywords
thienopyridine, antiplatelet, prasugrel, clopidogrel
Brief summary
This study is being conducted to determine if smoking will influence the platelet aggregation inhibition ability of clopidogrel and prasugrel. It will also determine if smoking has any effect on the plasma concentrations of the active metabolite of prasugrel and the active and inactive metabolites of clopidogrel. The primary hypothesis is that smoking status will influence the antiplatelet effects and active metabolite concentrations of clopidogrel but will have no impact on prasugrel's antiplatelet effects or active metabolite concentrations.
Detailed description
Subjects will be stratified according to smoking status prior to being randomized to 1 of the 2 treatment sequences: prasugrel 10 mg daily for 10 days followed by clopidogrel 75 mg daily for 10 days or clopidogrel 75 mg daily for 10 days followed by prasugrel 10 mg daily for 10 days. There will be a 14-day Washout Period between Active Treatment Period 1 (when subjects receive the first drug of the sequence) and the second Active Treatment Period 2 (Period 3) (when subjects receive the second drug of the sequence). All subjects will remain on the same dose of aspirin from baseline throughout the study.
Interventions
DRUGPrasugrel
One 10 mg film-coated, oral tablet daily x 10 days. In addition, aspirin 81 mg to 325 mg daily will be taken.
DRUGClopidogrel
One 75 mg film-coated, oral tablet daily x 10 days. In addition, aspirin 81 mg to 325 mg daily will be taken.
Sponsors
Daiichi Sankyo
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 74 Years
Healthy volunteers
No
Inclusion criteria
* Male or female subjects \> or = 18 years and \<75 years of age; * Weight \> or = 60 kg; * On aspirin therapy (81 mg to 325 mg daily) at the time of screening and able to maintain a consistent aspirin dosing regimen from the baseline visit through the final study visit; * Subjects who do not have contraindications for a thienopyridine (ie, prasugrel, clopidogrel, or ticlopidine) and have a history of stable atherosclerosis represented by CAD, defined as any of the following: * Chronic stable angina; * Documented prior ACS event \> or = 30 days before screening and not currently prescribed or currently on thienopyridine therapy; * Previous coronary revascularization including percutaneous transluminal coronary angioplasty, stent, or coronary artery bypass graft; * Coronary Artery Disease (\> or = 40% obstruction) in at least one coronary vessel after angiography; * Documented history of positive stress test; or * High coronary artery calcium score (\> or = 90th percentile for age and gender) determined by cardiac computed tomography scan; * Current smokers who smoke \> or = ½ pack per day of cigarettes with a NicAlert™ level of 6; * Non-smokers with a NicAlert level of 0, 1, or 2; * Female subjects who meet one of the following: * Women of childbearing potential with a negative serum pregnancy test at screening, who are not breastfeeding, do not plan to become pregnant during the study, and agree to use an approved method of birth control during the study. Approved methods of birth control are intrauterine device, diaphragm plus spermicide, or female condom plus spermicide. Abstinence, partner's use of condoms, partner's vasectomy, and hormonal contraceptives are NOT acceptable methods of contraception; * Women who have been postmenopausal for at least 1 year or have had a hysterectomy, bilateral salpingo-oophorectomy, or tubal ligation at least 6 months prior to signing the Informed Consent Form (ICF); and * Subjects with a competent mental condition to provide written informed consent before entering the study.
Exclusion criteria
* Subjects who received a bare metal stent and/or a drug-eluting stent within the last 12 months; * Subjects who have had an angiogram \< or = 7 days before randomization; * Any other formal indication for the use of a thienopyridine; * Subjects with a history of refractory ventricular arrhythmias; * Subjects with a history of an implantable defibrillator device; * Subjects with a history or evidence of congestive heart failure (New York Heart Association Class III or above) within 6 months prior to screening; * Subjects with significant hypertension (systolic blood pressure \>180 mmHg or diastolic blood pressure \>110 mmHg) at either the time of screening or baseline assessment; * Bleeding risk
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Inhibition of Platelet Aggregation (IPA) in Prasugrel-treated and Clopidogrel-treated Smokers and Non-smokers Following 9 Days of Maintenance Therapy. | Baseline to day 10 for Active Treatment Periods 1 and 2 | IPA will be measured by the Accumetrics P2Y12 Assay Device. Response will be assessed in P2Y12 Reaction Units and as Platelet Reactivity Index (vasodilator-stimulated phosphoprotein assay). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Assessment of Vasodilator Stimulated Phosphoprotein (VASP) by Treatment and Smoking Status | Day 10 for Active Treatment Periods 1 and 2 | Day 10 occurs in each treatment period at which time data collections are made. Numerous studies have established an association between high on-treatment platelet reactivity with clopidogrel and an increased risk for post-PCI ischemic events. In this study, the percentages of responders and poor responders following treatment with prasugrel and clopidogrel were compared. Poor responders were defined based on an Accumetrics VerifyNow PRU \>235 and a VASP PRI \>50%, as assessed 24 hours after the 9th maintenance dose. |
| Responder Rate by Treatment and Smoking Status Based on P2Y12 Reaction Units (PRU) <= 235 | Day 10 for Active Treatment Periods 1 and 2 | — |
| Assessment of P2Y12 Reaction Units (PRU) by Treatment and Smoking Status | Day 10 for Active Treatment Periods 1 and 2 | Day 10 occurs in each treatment period at which time data collections are made. 12.1.4. Responders and Poor Responders Numerous studies have established an association between high on-treatment platelet reactivity with clopidogrel and an increased risk for post-PCI ischemic events. In this study, the percentages of responders and poor responders following treatment with prasugrel and clopidogrel were compared. Poor responders were defined based on an Accumetrics VerifyNow PRU \>235 and a VASP PRI \>50%, as assessed 24 hours after the 9th maintenance dose. |
| Characterization of the Pharmacokinetics (PK) Area Under Curve (AUC)(0-Last) of the Active Metabolite of Prasugrel and the Active Metabolite of Clopidogrel in Smokers and Non-smokers | After dose on Day 10 of Active Treatment Periods 1 and 2 | Blood samples for determination of plasma concentrations of the prasugrel active metabolite, clopidogrel active metabolite, and clopidogrel inactive metabolite will be collected following the administration of the 10th (last) maintenance dose of each of the 2 Active Treatment Periods at 0.5, 1, 2, 4, and 6 hours post-dose. |
| Characterization of the Pharmacokinetics (PK) Cmax of the Active Metabolite of Prasugrel and the Active Metabolite of Clopidogrel in Smokers and Non-smokers | After dose on Day 10 of Active Treatment Periods 1 and 2 | — |
| Responder Rate by Treatment and Smoking Status Based on Platelet Reactivity Index (PRI) <= 50% | Day 10 for Active Treatment Periods 1 and 2 | Numerous studies have established an association between high on-treatment platelet reactivity with clopidogrel and an increased risk for post-PCI ischemic events. In this study, the percentages of responders and poor responders following treatment with prasugrel and clopidogrel were compared. Poor responders were defined based on an Accumetrics VerifyNow PRU \>235 and a VASP PRI \>50%, as assessed 24 hours after the 9th maintenance dose. |
Countries
United States
Participant flow
Recruitment details
Phase 4, double-blind, double-dummy, randomized, crossover study of male and female subjects with stable CAD, who are currently receiving aspirin and do not have contraindications for a thienopyridine.
Pre-assignment details
Subjects will be stratified according to smoking status prior to being randomized to 1 of the 2 treatment sequences: prasugrel followed by clopidogrel or clopidogrel followed by prasugrel. There will be a 14-day Washout Period between Active Treatment Periods 1 and 2. All subjects will remain on the same dose of aspirin throughout the study.
Participants by arm
| Arm | Count |
|---|---|
| Clopidogrel Then Prasugrel Smokers Clopidogrel 75 mg film-coated tablet daily dose x 10 days To maintain blinding, placebo film-coated tablets matching prasugrel in appearance will be given daily × 10 days to subjects in the clopidogrel treatment group. In addition, aspirin 81 mg to 325 mg daily will be taken.
Prasugrel : One 10 mg film-coated, oral tablet daily x 10 days. In addition, aspirin 81 mg to 325 mg daily will be taken. | 27 |
| Clopidogrel Then Prasugrel Non-Smokers Clopidogrel 75 mg film-coated tablet daily dose x 10 days To maintain blinding, placebo film-coated tablets matching prasugrel in appearance will be given daily × 10 days to subjects in the clopidogrel treatment group. In addition, aspirin 81 mg to 325 mg daily will be taken.
Prasugrel : One 10 mg film-coated, oral tablet daily x 10 days. In addition, aspirin 81 mg to 325 mg daily will be taken. | 28 |
| Prasugrel Then Clopidogrel Smokers Prasugrel 10 mg film-coated tablet daily dose × 10 days. To maintain blinding, placebo film-coated tablets matching clopidogrel in appearance will be given daily × 10 days to subjects in the prasugrel treatment group. In addition, aspirin 81 mg to 325 mg daily will be taken.
Clopidogrel : One 75 mg film-coated, oral tablet daily x 10 days. In addition, aspirin 81 mg to 325 mg daily will be taken. | 27 |
| Prasugrel Then Clopidogrel Non-Smokers Prasugrel 10 mg film-coated tablet daily dose × 10 days. To maintain blinding, placebo film-coated tablets matching clopidogrel in appearance will be given daily × 10 days to subjects in the prasugrel treatment group. In addition, aspirin 81 mg to 325 mg daily will be taken.
Clopidogrel : One 75 mg film-coated, oral tablet daily x 10 days. In addition, aspirin 81 mg to 325 mg daily will be taken. | 28 |
| Total | 110 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Period 1 | Adverse Event | 0 | 0 | 1 | 0 |
| Period 1 | Protocol Violation | 0 | 0 | 1 | 1 |
| Period 2 | Adverse Event | 1 | 0 | 2 | 0 |
| Period 2 | Protocol Violation | 0 | 2 | 3 | 1 |
| Period 2 | Withdrawal by Subject | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Clopidogrel Then Prasugrel Smokers | Clopidogrel Then Prasugrel Non-Smokers | Prasugrel Then Clopidogrel Smokers | Prasugrel Then Clopidogrel Non-Smokers | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 9 Participants | 8 Participants | 3 Participants | 11 Participants | 31 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants | 20 Participants | 24 Participants | 17 Participants | 79 Participants |
| Age, Continuous | 59.3 years STANDARD_DEVIATION 8.19 | 59.6 years STANDARD_DEVIATION 8.6 | 56.7 years STANDARD_DEVIATION 8.03 | 61.9 years STANDARD_DEVIATION 7.86 | 59.4 years STANDARD_DEVIATION 8.27 |
| Alcohol Usage Currently consumes | 17 participants | 16 participants | 13 participants | 15 participants | 61 participants |
| Alcohol Usage Formerly consumed | 4 participants | 3 participants | 6 participants | 5 participants | 18 participants |
| Alcohol Usage Never consumed | 6 participants | 9 participants | 8 participants | 8 participants | 31 participants |
| Body Mass Index | 29.20 kg/m^2 STANDARD_DEVIATION 3.945 | 31.12 kg/m^2 STANDARD_DEVIATION 5.821 | 30.70 kg/m^2 STANDARD_DEVIATION 5.131 | 32.94 kg/m^2 STANDARD_DEVIATION 6.592 | 31.01 kg/m^2 STANDARD_DEVIATION 5.562 |
| Body Mass Index Group <30 kg/m^2 | 19 participants | 10 participants | 13 participants | 10 participants | 52 participants |
| Body Mass Index Group >=30 kg/m^2 | 8 participants | 18 participants | 14 participants | 18 participants | 58 participants |
| Cardiovascular history Diabetes mellitus | 5 participants | 9 participants | 8 participants | 9 participants | 31 participants |
| Cardiovascular history Hyperlipidemia | 26 participants | 24 participants | 26 participants | 27 participants | 103 participants |
| Cardiovascular history Hypertension | 19 participants | 16 participants | 21 participants | 20 participants | 76 participants |
| Cardiovascular history Peripheral artery disease | 3 participants | 0 participants | 5 participants | 2 participants | 10 participants |
| CYP2C19 Phenotype Metabolic Extent Extensive metabolizers | 21 participants | 24 participants | 21 participants | 22 participants | 88 participants |
| CYP2C19 Phenotype Metabolic Extent Missing | 1 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| CYP2C19 Phenotype Metabolic Extent Reduced metabolizers | 5 participants | 4 participants | 6 participants | 6 participants | 21 participants |
| CYP2C19 Phenotype Metabolic Rate Extensive | 18 participants | 23 participants | 20 participants | 22 participants | 83 participants |
| CYP2C19 Phenotype Metabolic Rate Intermediate | 5 participants | 4 participants | 6 participants | 4 participants | 19 participants |
| CYP2C19 Phenotype Metabolic Rate not reported | 1 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| CYP2C19 Phenotype Metabolic Rate Poor | 0 participants | 0 participants | 0 participants | 2 participants | 2 participants |
| CYP2C19 Phenotype Metabolic Rate Ultrarapid | 3 participants | 1 participants | 1 participants | 0 participants | 5 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 4 Participants | 3 Participants | 3 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants | 24 Participants | 24 Participants | 25 Participants | 94 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height | 172.3 cm STANDARD_DEVIATION 8.15 | 172.5 cm STANDARD_DEVIATION 10.95 | 172.5 cm STANDARD_DEVIATION 10.72 | 173.7 cm STANDARD_DEVIATION 8.17 | 172.8 cm STANDARD_DEVIATION 9.48 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 6 Participants | 4 Participants | 6 Participants | 23 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 19 Participants | 22 Participants | 22 Participants | 22 Participants | 85 Participants |
| Region of Enrollment United States | 27 participants | 28 participants | 27 participants | 28 participants | 110 participants |
| Sex: Female, Male Female | 8 Participants | 7 Participants | 9 Participants | 7 Participants | 31 Participants |
| Sex: Female, Male Male | 19 Participants | 21 Participants | 18 Participants | 21 Participants | 79 Participants |
| Smoking History Currently Smoke | 27 participants | 0 participants | 27 participants | 0 participants | 54 participants |
| Smoking History Formerly Smoked | 0 participants | 14 participants | 0 participants | 17 participants | 31 participants |
| Smoking History Never Smoked | 0 participants | 14 participants | 0 participants | 11 participants | 25 participants |
| Weight | 87.04 kg STANDARD_DEVIATION 15.243 | 92.45 kg STANDARD_DEVIATION 18.433 | 91.74 kg STANDARD_DEVIATION 20.109 | 99.91 kg STANDARD_DEVIATION 23.096 | 92.85 kg STANDARD_DEVIATION 19.74 |
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 | 5 / 54 | 6 / 55 | 10 / 50 | 6 / 54 |
| serious Total, serious adverse events | 4 / 54 | 0 / 55 | 0 / 50 | 0 / 54 |
Outcome results
Primary
Inhibition of Platelet Aggregation (IPA) in Prasugrel-treated and Clopidogrel-treated Smokers and Non-smokers Following 9 Days of Maintenance Therapy.
IPA will be measured by the Accumetrics P2Y12 Assay Device. Response will be assessed in P2Y12 Reaction Units and as Platelet Reactivity Index (vasodilator-stimulated phosphoprotein assay).
Time frame: Baseline to day 10 for Active Treatment Periods 1 and 2
Population: 1 prasugrel smoker was unevaluable for this measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Prasugrel Smokers | Inhibition of Platelet Aggregation (IPA) in Prasugrel-treated and Clopidogrel-treated Smokers and Non-smokers Following 9 Days of Maintenance Therapy. | 70.3 percentage of device derived inhibition | Standard Error 2.91 |
| Prasugrel Non-Smokers | Inhibition of Platelet Aggregation (IPA) in Prasugrel-treated and Clopidogrel-treated Smokers and Non-smokers Following 9 Days of Maintenance Therapy. | 65.6 percentage of device derived inhibition | Standard Error 2.86 |
| Clopidogrel Smokers | Inhibition of Platelet Aggregation (IPA) in Prasugrel-treated and Clopidogrel-treated Smokers and Non-smokers Following 9 Days of Maintenance Therapy. | 38.6 percentage of device derived inhibition | Standard Error 3.01 |
| Clopidogrel Non-Smokers | Inhibition of Platelet Aggregation (IPA) in Prasugrel-treated and Clopidogrel-treated Smokers and Non-smokers Following 9 Days of Maintenance Therapy. | 30.9 percentage of device derived inhibition | Standard Error 2.81 |
Comparison: For the sample size calculations for the co-primary endpoints, no Type 1 error rate was adjusted and both co-primary endpoints will be tested at the 0.05 level.p-value: 0.062495% CI: [-0.4, 15.8]Mixed Models Analysis
p-value: <0.000195% CI: [25.1, 38.4]Mixed Models Analysis
p-value: 0.24495% CI: [-3.3, 12.8]Mixed Models Analysis
p-value: <0.000195% CI: [28.4, 41]Mixed Models Analysis
p-value: <0.000195% CI: [18.8, 35.2]Mixed Models Analysis
Secondary
Assessment of P2Y12 Reaction Units (PRU) by Treatment and Smoking Status
Day 10 occurs in each treatment period at which time data collections are made. 12.1.4. Responders and Poor Responders Numerous studies have established an association between high on-treatment platelet reactivity with clopidogrel and an increased risk for post-PCI ischemic events. In this study, the percentages of responders and poor responders following treatment with prasugrel and clopidogrel were compared. Poor responders were defined based on an Accumetrics VerifyNow PRU \>235 and a VASP PRI \>50%, as assessed 24 hours after the 9th maintenance dose.
Time frame: Day 10 for Active Treatment Periods 1 and 2
Population: 1 prasugrel smoker was unevaluable for this measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Prasugrel Smokers | Assessment of P2Y12 Reaction Units (PRU) by Treatment and Smoking Status | 85.1 P2Y12 reaction unit | Standard Error 8.99 |
| Prasugrel Non-Smokers | Assessment of P2Y12 Reaction Units (PRU) by Treatment and Smoking Status | 106.3 P2Y12 reaction unit | Standard Error 8.73 |
| Clopidogrel Smokers | Assessment of P2Y12 Reaction Units (PRU) by Treatment and Smoking Status | 178.9 P2Y12 reaction unit | Standard Error 9.26 |
| Clopidogrel Non-Smokers | Assessment of P2Y12 Reaction Units (PRU) by Treatment and Smoking Status | 215.1 P2Y12 reaction unit | Standard Error 8.59 |
p-value: 0.004895% CI: [-61.1, -11.2]Mixed Models Analysis
p-value: <0.000195% CI: [-116.7, -71]Mixed Models Analysis
p-value: 0.092495% CI: [-45.9, 3.5]Mixed Models Analysis
p-value: <0.000195% CI: [-130.3, -87.3]Mixed Models Analysis
p-value: <0.000195% CI: [-97.8, -47.5]Mixed Models Analysis
Secondary
Assessment of Vasodilator Stimulated Phosphoprotein (VASP) by Treatment and Smoking Status
Day 10 occurs in each treatment period at which time data collections are made. Numerous studies have established an association between high on-treatment platelet reactivity with clopidogrel and an increased risk for post-PCI ischemic events. In this study, the percentages of responders and poor responders following treatment with prasugrel and clopidogrel were compared. Poor responders were defined based on an Accumetrics VerifyNow PRU \>235 and a VASP PRI \>50%, as assessed 24 hours after the 9th maintenance dose.
Time frame: Day 10 for Active Treatment Periods 1 and 2
Population: 1 prasugrel smoker was unevaluable for this measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Prasugrel Smokers | Assessment of Vasodilator Stimulated Phosphoprotein (VASP) by Treatment and Smoking Status | 25.4 % vasodilator stimulated phosphoprotein | Standard Error 2.64 |
| Prasugrel Non-Smokers | Assessment of Vasodilator Stimulated Phosphoprotein (VASP) by Treatment and Smoking Status | 31.2 % vasodilator stimulated phosphoprotein | Standard Error 2.59 |
| Clopidogrel Smokers | Assessment of Vasodilator Stimulated Phosphoprotein (VASP) by Treatment and Smoking Status | 48.1 % vasodilator stimulated phosphoprotein | Standard Error 2.73 |
| Clopidogrel Non-Smokers | Assessment of Vasodilator Stimulated Phosphoprotein (VASP) by Treatment and Smoking Status | 55.7 % vasodilator stimulated phosphoprotein | Standard Error 2.54 |
p-value: 0.042395% CI: [-15, -0.3]Mixed Models Analysis
p-value: <0.000195% CI: [-29, -16.4]Mixed Models Analysis
p-value: 0.118495% CI: [-13.1, 1.5]Mixed Models Analysis
p-value: <0.000195% CI: [-30.5, -18.5]Mixed Models Analysis
p-value: <0.000195% CI: [-24.3, -9.5]Mixed Models Analysis
Secondary
Characterization of the Pharmacokinetics (PK) Area Under Curve (AUC)(0-Last) of the Active Metabolite of Prasugrel and the Active Metabolite of Clopidogrel in Smokers and Non-smokers
Blood samples for determination of plasma concentrations of the prasugrel active metabolite, clopidogrel active metabolite, and clopidogrel inactive metabolite will be collected following the administration of the 10th (last) maintenance dose of each of the 2 Active Treatment Periods at 0.5, 1, 2, 4, and 6 hours post-dose.
Time frame: After dose on Day 10 of Active Treatment Periods 1 and 2
Population: 1 Clopidogrel smoker participant was not evaluable for this measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Prasugrel Smokers | Characterization of the Pharmacokinetics (PK) Area Under Curve (AUC)(0-Last) of the Active Metabolite of Prasugrel and the Active Metabolite of Clopidogrel in Smokers and Non-smokers | 53.7 hr*ng/mL | Geometric Coefficient of Variation 41.2 |
| Prasugrel Non-Smokers | Characterization of the Pharmacokinetics (PK) Area Under Curve (AUC)(0-Last) of the Active Metabolite of Prasugrel and the Active Metabolite of Clopidogrel in Smokers and Non-smokers | 48.1 hr*ng/mL | Geometric Coefficient of Variation 52 |
| Clopidogrel Smokers | Characterization of the Pharmacokinetics (PK) Area Under Curve (AUC)(0-Last) of the Active Metabolite of Prasugrel and the Active Metabolite of Clopidogrel in Smokers and Non-smokers | 19.9 hr*ng/mL | Geometric Coefficient of Variation 55.8 |
| Clopidogrel Non-Smokers | Characterization of the Pharmacokinetics (PK) Area Under Curve (AUC)(0-Last) of the Active Metabolite of Prasugrel and the Active Metabolite of Clopidogrel in Smokers and Non-smokers | 16.2 hr*ng/mL | Geometric Coefficient of Variation 87.4 |
Comparison: Prasugrel active metabolite R-13872790% CI: [93.7, 130.8]Mixed Models Analysis
Comparison: active metabolite R-13096490% CI: [99.8, 140.4]Mixed Models Analysis
Secondary
Characterization of the Pharmacokinetics (PK) Cmax of the Active Metabolite of Prasugrel and the Active Metabolite of Clopidogrel in Smokers and Non-smokers
Time frame: After dose on Day 10 of Active Treatment Periods 1 and 2
Population: 1 clopidogrel smoker was not evaluable for this measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Prasugrel Smokers | Characterization of the Pharmacokinetics (PK) Cmax of the Active Metabolite of Prasugrel and the Active Metabolite of Clopidogrel in Smokers and Non-smokers | 42.9 ng/mL | Geometric Coefficient of Variation 66.1 |
| Prasugrel Non-Smokers | Characterization of the Pharmacokinetics (PK) Cmax of the Active Metabolite of Prasugrel and the Active Metabolite of Clopidogrel in Smokers and Non-smokers | 35.9 ng/mL | Geometric Coefficient of Variation 80.7 |
| Clopidogrel Smokers | Characterization of the Pharmacokinetics (PK) Cmax of the Active Metabolite of Prasugrel and the Active Metabolite of Clopidogrel in Smokers and Non-smokers | 14.1 ng/mL | Geometric Coefficient of Variation 84.3 |
| Clopidogrel Non-Smokers | Characterization of the Pharmacokinetics (PK) Cmax of the Active Metabolite of Prasugrel and the Active Metabolite of Clopidogrel in Smokers and Non-smokers | 10.8 ng/mL | Geometric Coefficient of Variation 116.3 |
Comparison: Prasugrel active metabolite R-13872790% CI: [94.4, 147.3]Mixed Models Analysis
Comparison: Clopidogrel active metabolite R-13096490% CI: [98.6, 155.4]Mixed Models Analysis
Secondary
Responder Rate by Treatment and Smoking Status Based on P2Y12 Reaction Units (PRU) <= 235
Time frame: Day 10 for Active Treatment Periods 1 and 2
Population: 1 prasugrel smoker participant was not evaluable for this measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Prasugrel Smokers | Responder Rate by Treatment and Smoking Status Based on P2Y12 Reaction Units (PRU) <= 235 | 98.0 % participants with PRU <=235 |
| Prasugrel Non-Smokers | Responder Rate by Treatment and Smoking Status Based on P2Y12 Reaction Units (PRU) <= 235 | 96.2 % participants with PRU <=235 |
| Clopidogrel Smokers | Responder Rate by Treatment and Smoking Status Based on P2Y12 Reaction Units (PRU) <= 235 | 76.6 % participants with PRU <=235 |
| Clopidogrel Non-Smokers | Responder Rate by Treatment and Smoking Status Based on P2Y12 Reaction Units (PRU) <= 235 | 61.1 % participants with PRU <=235 |
p-value: 0.133195% CI: [0.8, 5.32]Regression, Logistic
p-value: 0.581395% CI: [0.17, 23.65]Regression, Logistic
p-value: 0.012795% CI: [1.85, 148.23]Regression, Logistic
p-value: 0.001395% CI: [3.13, 93.65]Regression, Logistic
Secondary
Responder Rate by Treatment and Smoking Status Based on Platelet Reactivity Index (PRI) <= 50%
Numerous studies have established an association between high on-treatment platelet reactivity with clopidogrel and an increased risk for post-PCI ischemic events. In this study, the percentages of responders and poor responders following treatment with prasugrel and clopidogrel were compared. Poor responders were defined based on an Accumetrics VerifyNow PRU \>235 and a VASP PRI \>50%, as assessed 24 hours after the 9th maintenance dose.
Time frame: Day 10 for Active Treatment Periods 1 and 2
Population: 1 prasugrel smoker participant was not evaluable for this measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Prasugrel Smokers | Responder Rate by Treatment and Smoking Status Based on Platelet Reactivity Index (PRI) <= 50% | 96.0 % participants with PRI <=50% |
| Prasugrel Non-Smokers | Responder Rate by Treatment and Smoking Status Based on Platelet Reactivity Index (PRI) <= 50% | 82.7 % participants with PRI <=50% |
| Clopidogrel Smokers | Responder Rate by Treatment and Smoking Status Based on Platelet Reactivity Index (PRI) <= 50% | 51.1 % participants with PRI <=50% |
| Clopidogrel Non-Smokers | Responder Rate by Treatment and Smoking Status Based on Platelet Reactivity Index (PRI) <= 50% | 44.4 % participants with PRI <=50% |
p-value: 0.568495% CI: [0.49, 3.67]Regression, Logistic
p-value: 0.044795% CI: [1.05, 42.92]Regression, Logistic
p-value: 0.000395% CI: [6.8, 505.58]Regression, Logistic
p-value: 0.000695% CI: [2.95, 46.52]Regression, Logistic