Atherosclerosis, Myocardial Ischemia, Myocardial Infarction
Conditions
Brief summary
The study is designed to assess safety and effects of vorapaxar, when added to standard of care (aspirin and clopidigrel), in Japanese subjects with acute coronary syndrome. The study may also provide information about the effect of vorapaxar on preventing heart attack and stroke in this subject population.
Detailed description
The study drug (loading dose) is administered at least 1 hour before catheterization for diagnostic imaging or percutaneous coronary interventions (PCI). The incidence of bleeding is thought to be an important index to assess the safety of this drug, therefore thrombolysis in myocardial infarction (TIMI) is evaluated.
Interventions
DRUGVorapaxar
Oral tablets; single 20-mg or 40-mg loading dose on first day followed by daily 1-mg or 2.5-mg maintenance dose for 59 days
DRUGPlacebo
Oral tablets; matching placebo for SCH 530348 loading and maintenance doses for 59 days
DRUGAspirin
Loading dose of 75-325 mg on Day 1, then 75-100 mg once daily for 60 days.
DRUGClopidogrel
100 mg two or three times daily for 60 days.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Men and women aged 18 years or more with history of cardiac ischemia related chest discomfort of \> 10 minutes duration \< 24 hours prior to randomization, and having at least 1 of the following A or B. Participants who are planned to undergo PCI will be the target participants. * A: Positive biomarkers \[Elevated troponin I or creatinine kinase MB isozyme greater than the site's upper limit of normal (ULN)\] at or before registration * B: Electrocardiogram (ECG) changes: ST segment depression \>= 0.1 mV (\>=1 mm), or transient (\<30 minutes) ST segment elevation \>= 0.1 mV (\>=1 mm) in at least 2 contiguous leads * Willing to give appropriate informed consent and complete all study-related procedures, and able to adhere to dosing and all visit schedules. * Women of child-bearing potential (all postmenarchal women who are \<1 years menopausal or who have not had surgical sterilization or a hysterectomy are considered to be women of child-bearing potential) must agree to use a medically accepted method of contraception while receiving protocol-specified medication, and for 60 days after stopping the medication.
Exclusion criteria
* Pregnant and nursing mothers (premenopausal women should have a negative pregnancy test result confirmed before enrollment) * Any serious illness or any condition that the investigator feels would pose a significant hazard to the participant if investigational therapy were initiated * known hypersensitivity to any component of the current investigational product; * Participation in a study of experimental therapy or use of any investigational drug within 30 days before enrollment * Member of the staff personnel directly involved with this study; * Family member of the investigational study staff; * History of a bleeding diathesis, or evidence of active abnormal bleeding within 30 days before enrollment * History of a hemorrhagic stroke at any time * Severe hypertension (systolic blood pressure \>200 mm Hg or diastolic blood pressure \>110 mm Hg) while receiving therapy; * Major surgery within 2 weeks prior to enrollment * Known platelet count \<100,000/mm\^3 * Uncontrolled cardiac arrhythmia; * Known impairment of renal function (serum creatinine \>2.0 mg/dL \[\>176.8 umol/L\]), dysproteinemia, nephrotic syndrome, or other renal disease; * Active or chronic hepatobiliary or hepatic disease, or aspartate aminotransferase (AST) or alanine aminotransferase (ALT) activity more than two times greater than the upper limit of the laboratory reference range * Anticipated staged PCI * Concurrent or anticipated treatment with warfarin, factor Xa inhibitor, direct thrombin inhibitor, or antiplatelet agents except aspirin and ticlopidine after enrollment * Anticipated intracoronary brachytherapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing Adverse Events (AEs) Who Underwent Percutaneous Coronary Interventions (PCI) | Up to Day 60 | An AE is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration, whether or not considered related to the study drug. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Major, Minor, and Non-Thrombolysis in Myocardial Infarction Cooperative Group (TIMI) Bleeding Events Among Participants Who Underwent PCI | Up to Day 60 | Major TIMI bleeding was defined as any intracranial bleeding (excluding microhemorrhages \<10 mm evident only on gradient-echo magnetic resonance imaging \[MRI\]), clinically overt signs of hemorrhage associated with a drop in hemoglobin of ≥5 g/dL, or fatal bleeding (bleeding that directly results in death within 7 days). Minor TIMI bleeding was defined as any clinically overt bleeding resulting in hemoglobin drop of 3 to \<5 g/dL. Non-TIMI bleeding included all bleeding events not covered under Major TIMI bleeding or Minor TIMI bleeding. Analysis of data was by maintenance dose group. |
| Number of Participants Who Underwent PCI With Inhibition of Platelet Aggregation By Study Visit | Baseline, Day 30, Day 60, Day 74, Day 90, Day 121 | Blood samples were collected from participants at Baseline and Days 30, 60, 74, 90, and 121 to determine the extent of inhibition of platelet aggregation induced by thrombin-receptor agonist peptide (TRAP). Analysis of data was by maintenance dose group. |
| Median High-Sensitivity C-Reactive Protein (Hs-CRP) Levels Among Participants Who Underwent PCI By Study Visit | Baseline, Day 30, Day 60 | Participant blood samples were collected at Baseline and on Days 30 and 60 to evaluate the median level of hs-CRP. hs-CRP is a protein marker in the blood associated with inflammation with higher values indicating a greater degree of inflammation. Analysis of data was by maintenance dose group. |
| Mean CD40 Ligand Levels Among Participants Who Underwent PCI | Baseline, Day 30, Day 60 | Participant blood samples were collected at Baseline and Days 30 and 60 to evaluate the mean level of CD40 ligand present. CD40 ligand is a protein primarily found on activated T-cells, with higher levels indicating better immunological health. Analysis of data was by maintenance dose group. |
| Mean Membrane-Bound P-Selectin Levels Among Participants Who Underwent PCI | Baseline, Day 30, Day 60 | Participant blood samples were collected at Baseline and Days 30 and 60 to evaluate the mean level of membrane-bound P-selectin. Membrane-bound P-selectin was measured using flow cytometry and a monoclonal antibody to P-selectin. Intensity levels are reported in arbitrary units 0 (dark) to 1023 (bright). Higher values correspond to greater membrane-bound P-Selectin levels. Analysis of data was by maintenance dose group. |
| Number of Participants Who Underwent PCI With Clinically Important Bleeding Events During Treatment and After Hospital Discharge | Up to Day 121 | Clinically important bleeding events were defined as intracranial hemorrhage, bleeding requiring hospitalization, or TIMI major bleeding. Analysis of data was by loading/maintenance dose group. |
| Number of Participants With Major, Minor, and Non-TIMI Bleeding Events Among Participants Who Did Not Undergo PCI | Up to Day 60 | Major TIMI bleeding was defined as any intracranial bleeding (excluding microhemorrhages \<10 mm evident only on gradient-echo MRI), clinically overt signs of hemorrhage associated with a drop in hemoglobin of ≥5 g/dL, or fatal bleeding (bleeding that directly results in death within 7 days). Minor TIMI bleeding was defined as any clinically overt bleeding resulting in hemoglobin drop of 3 to \<5 g/dL. Non-TIMI bleeding included all bleeding events not covered under Major TIMI bleeding or Minor TIMI bleeding. Analysis of data was by loading dose group. |
| Number of Participants Experiencing Non-Major Adverse Cardiac Events (MACE) Who Underwent PCI | Up to Day 121 | An AE is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration, whether or not considered related to the study drug. MACE events were defined as nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization due to recurrent ischemia, or urgent coronary revascularization performed ≥ 30 days after administration of the loading dose (Day 1). All MACE events were excluded from this analysis. Analysis of data was by loading/maintenance dose group. |
| Number of Participants Who Did Not Undergo PCI But Had Coronary Artery Bypass Graft (CABG) Who Experienced Bleeding Events | Up to 10 Hours Post-CABG | Bleeding events were evaluated up to 10 hours post-CABG among participants who did not undergo PCI. |
| Number of Participants Who Did Not Undergo PCI But Had Bleeding Events That Required Transfusion | Up to Day 60 | Bleeding events were evaluated among participants that did not undergo PCI to determine the number of participants that required blood transfusion. Analysis of data was by loading dose group. |
| Number of Participants Who Did Not Undergo PCI But Had Bleeding Events That Required Subsequent Hospitalization | Up to Day 30 | Bleeding events were evaluated among participants that did not undergo PCI to determine the number of participants who required a subsequent hospitalization. Analysis of data was by loading dose group. |
| Median Hs-CRP Levels Among Participants Who Did Not Undergo PCI | Baseline Up To Day 60 | Participant blood samples were collected at baseline and at the time of hospital discharge to determine the median serum level of hs-CRP. Analysis of data was by loading dose group. |
| Mean CD40 Ligand Levels Among Participants Who Did Not Undergo PCI | Baseline Up To Day 60 | Participant blood samples were collected at baseline and at the time of hospital discharge to determine the mean serum level of CD40 ligand. Analysis of data was by loading dose group. |
| Number of Participants Who Did Not Undergo PCI That Had Clinically Important Bleeding Events | Baseline Up To Day 60 | Clinically important bleeding events were defined as intracranial hemorrhage, bleeding requiring blood transfusion, bleeding requiring hospitalization, and TIMI major bleeding. Analysis of data was by loading dose group. |
| Number of Participants Experiencing Non-MACE AEs Among Participants Who Did Not Undergo PCI | Up to Day 121 | An AE is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration, whether or not considered related to the study drug. MACE events were defined as nonfatal MI, nonfatal stroke, hospitalization due to recurrent ischemia, or urgent coronary revascularization performed ≥ 30 days after administration of the loading dose (Day 1). All MACE events were excluded from this analysis. Analysis of data was by loading dose group. |
Participant flow
Pre-assignment details
Of 120 participants enrolled and randomized to treatment, 117 participants were treated with study drug. 92 participants underwent percutaneous coronary intervention (PCI) and 25 did not.
Participants by arm
| Arm | Count |
|---|---|
| Vorapaxar 20 mg (PCI) Vorapaxar 20 mg as loading dose is administered to PCI participants as the initial dose. From Day 2, 1 mg or 2.5 mg once daily is administered as the maintenance dose for 59 days (total duration of 60 days). | 40 |
| Vorapaxar 40 mg (PCI) Vorapaxar 40 mg as loading dose is administered to PCI participants as the initial dose. From Day 2, 1 mg or 2.5 mg once daily is administered as the maintenance dose for 59 days (total duration of 60 days). | 31 |
| Placebo/Placebo (PCI) Placebo as loading dose is administered as the initial dose to PCI participants. From Day 2, placebo once daily is administered as the maintenance dose for 59 days (total duration of 60 days). | 21 |
| Vorapaxar 20 mg (Non-PCI) Vorapaxar 20 mg as a loading dose is administered to non-PCI participants as the initial dose. From Day 2, 1 mg or 2.5 mg once daily is administered as the maintenance dose for 59 days (total duration 60 days). | 6 |
| Vorapaxar 40 mg (Non-PCI) Vorapaxar 40 mg as loading dose is administered to non-PCI participants as the initial dose. From Day 2, 1 mg or 2.5 mg once daily is administered as the maintenance dose for 59 days (total duration of 60 days). | 17 |
| Placebo/Placebo (Non-PCI) Placebo as loading dose is administered as the initial dose to non-PCI participants. From Day 2, placebo once daily is administered as the maintenance dose for 59 days (total duration of 60 days). | 2 |
| Total | 117 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 6 | 4 | 8 | 0 | 0 | 0 |
| Overall Study | Did not meet protocol eligibility | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Protocol-defined clinical event | 3 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 2 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Vorapaxar 20 mg (PCI) | Vorapaxar 40 mg (PCI) | Placebo/Placebo (PCI) | Vorapaxar 20 mg (Non-PCI) | Vorapaxar 40 mg (Non-PCI) | Placebo/Placebo (Non-PCI) | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 64.3 Years STANDARD_DEVIATION 9.2 | 64.5 Years STANDARD_DEVIATION 9 | 65.0 Years STANDARD_DEVIATION 10.8 | 59.0 Years STANDARD_DEVIATION 14.3 | 64.1 Years STANDARD_DEVIATION 13.6 | 66.5 Years STANDARD_DEVIATION 3.5 | 64.2 Years STANDARD_DEVIATION 10.3 |
| Sex: Female, Male Female | 5 Participants | 9 Participants | 5 Participants | 0 Participants | 9 Participants | 1 Participants | 29 Participants |
| Sex: Female, Male Male | 35 Participants | 22 Participants | 16 Participants | 6 Participants | 8 Participants | 1 Participants | 88 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 25 / 25 | 23 / 24 | 22 / 22 | 23 / 26 | 22 / 23 |
| serious Total, serious adverse events | 5 / 25 | 4 / 24 | 2 / 22 | 2 / 26 | 5 / 23 |
Outcome results
Primary
Number of Participants Experiencing Adverse Events (AEs) Who Underwent Percutaneous Coronary Interventions (PCI)
An AE is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration, whether or not considered related to the study drug.
Time frame: Up to Day 60
Population: The population included all enrolled participants who received at least 1 dose of study drug and underwent PCI.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vorapaxar 20 mg Loading Dose PCI | Number of Participants Experiencing Adverse Events (AEs) Who Underwent Percutaneous Coronary Interventions (PCI) | 40 Participants |
| Vorapaxar 40 mg Loading Dose PCI | Number of Participants Experiencing Adverse Events (AEs) Who Underwent Percutaneous Coronary Interventions (PCI) | 30 Participants |
| Placebo/Placebo PCI | Number of Participants Experiencing Adverse Events (AEs) Who Underwent Percutaneous Coronary Interventions (PCI) | 21 Participants |
Secondary
Mean CD40 Ligand Levels Among Participants Who Did Not Undergo PCI
Participant blood samples were collected at baseline and at the time of hospital discharge to determine the mean serum level of CD40 ligand. Analysis of data was by loading dose group.
Time frame: Baseline Up To Day 60
Population: The population consisted of all enrolled participants who received at least 1 dose of study drug, did not undergo PCI, and had CD40 ligand data available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vorapaxar 20 mg Loading Dose PCI | Mean CD40 Ligand Levels Among Participants Who Did Not Undergo PCI | Baseline | 8.4 ng/mL | Standard Error 1.1 |
| Vorapaxar 20 mg Loading Dose PCI | Mean CD40 Ligand Levels Among Participants Who Did Not Undergo PCI | Time of Hospital Discharge | 10.1 ng/mL | Standard Error 2.86 |
| Vorapaxar 40 mg Loading Dose PCI | Mean CD40 Ligand Levels Among Participants Who Did Not Undergo PCI | Baseline | 4.6 ng/mL | Standard Error 0.79 |
| Vorapaxar 40 mg Loading Dose PCI | Mean CD40 Ligand Levels Among Participants Who Did Not Undergo PCI | Time of Hospital Discharge | 7.1 ng/mL | Standard Error 0.83 |
| Placebo/Placebo PCI | Mean CD40 Ligand Levels Among Participants Who Did Not Undergo PCI | Time of Hospital Discharge | 12.9 ng/mL | Standard Error 4.64 |
| Placebo/Placebo PCI | Mean CD40 Ligand Levels Among Participants Who Did Not Undergo PCI | Baseline | 11.1 ng/mL | Standard Error 4.06 |
Secondary
Mean CD40 Ligand Levels Among Participants Who Underwent PCI
Participant blood samples were collected at Baseline and Days 30 and 60 to evaluate the mean level of CD40 ligand present. CD40 ligand is a protein primarily found on activated T-cells, with higher levels indicating better immunological health. Analysis of data was by maintenance dose group.
Time frame: Baseline, Day 30, Day 60
Population: The population included all enrolled participants who received at least 1 dose of study drug and underwent PCI with CD40 ligand data available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vorapaxar 20 mg Loading Dose PCI | Mean CD40 Ligand Levels Among Participants Who Underwent PCI | Day 60 (n=30, 25, 13) | 5.6 ng/mL | Standard Error 0.55 |
| Vorapaxar 20 mg Loading Dose PCI | Mean CD40 Ligand Levels Among Participants Who Underwent PCI | Day 30 (n=35, 34, 31) | 5.9 ng/mL | Standard Error 0.52 |
| Vorapaxar 20 mg Loading Dose PCI | Mean CD40 Ligand Levels Among Participants Who Underwent PCI | Baseline (n=37, 34, 21) | 5.6 ng/mL | Standard Error 0.56 |
| Vorapaxar 40 mg Loading Dose PCI | Mean CD40 Ligand Levels Among Participants Who Underwent PCI | Day 60 (n=30, 25, 13) | 5.4 ng/mL | Standard Error 0.58 |
| Vorapaxar 40 mg Loading Dose PCI | Mean CD40 Ligand Levels Among Participants Who Underwent PCI | Baseline (n=37, 34, 21) | 6.9 ng/mL | Standard Error 0.6 |
| Vorapaxar 40 mg Loading Dose PCI | Mean CD40 Ligand Levels Among Participants Who Underwent PCI | Day 30 (n=35, 34, 31) | 5.9 ng/mL | Standard Error 0.63 |
| Placebo/Placebo PCI | Mean CD40 Ligand Levels Among Participants Who Underwent PCI | Day 30 (n=35, 34, 31) | 6.2 ng/mL | Standard Error 0.73 |
| Placebo/Placebo PCI | Mean CD40 Ligand Levels Among Participants Who Underwent PCI | Baseline (n=37, 34, 21) | 4.8 ng/mL | Standard Error 0.79 |
| Placebo/Placebo PCI | Mean CD40 Ligand Levels Among Participants Who Underwent PCI | Day 60 (n=30, 25, 13) | 5.7 ng/mL | Standard Error 1.21 |
Secondary
Mean Membrane-Bound P-Selectin Levels Among Participants Who Underwent PCI
Participant blood samples were collected at Baseline and Days 30 and 60 to evaluate the mean level of membrane-bound P-selectin. Membrane-bound P-selectin was measured using flow cytometry and a monoclonal antibody to P-selectin. Intensity levels are reported in arbitrary units 0 (dark) to 1023 (bright). Higher values correspond to greater membrane-bound P-Selectin levels. Analysis of data was by maintenance dose group.
Time frame: Baseline, Day 30, Day 60
Population: The population included all enrolled participants that received at least 1 dose of study drug and underwent PCI with membrane-bound P-selectin data available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vorapaxar 20 mg Loading Dose PCI | Mean Membrane-Bound P-Selectin Levels Among Participants Who Underwent PCI | Day 60 (n=2, 3, 1) | 25.0 Arbitrary Units | Standard Error 2.8 |
| Vorapaxar 20 mg Loading Dose PCI | Mean Membrane-Bound P-Selectin Levels Among Participants Who Underwent PCI | Day 30 (n=3, 4, 3) | 20.6 Arbitrary Units | Standard Error 1.76 |
| Vorapaxar 20 mg Loading Dose PCI | Mean Membrane-Bound P-Selectin Levels Among Participants Who Underwent PCI | Baseline (n=4, 4, 3) | 24.8 Arbitrary Units | Standard Error 2.86 |
| Vorapaxar 40 mg Loading Dose PCI | Mean Membrane-Bound P-Selectin Levels Among Participants Who Underwent PCI | Day 30 (n=3, 4, 3) | 16.4 Arbitrary Units | Standard Error 0.85 |
| Vorapaxar 40 mg Loading Dose PCI | Mean Membrane-Bound P-Selectin Levels Among Participants Who Underwent PCI | Baseline (n=4, 4, 3) | 16.5 Arbitrary Units | Standard Error 0.83 |
| Vorapaxar 40 mg Loading Dose PCI | Mean Membrane-Bound P-Selectin Levels Among Participants Who Underwent PCI | Day 60 (n=2, 3, 1) | 14.9 Arbitrary Units | Standard Error 0.62 |
| Placebo/Placebo PCI | Mean Membrane-Bound P-Selectin Levels Among Participants Who Underwent PCI | Baseline (n=4, 4, 3) | 15.9 Arbitrary Units | Standard Error 1.25 |
| Placebo/Placebo PCI | Mean Membrane-Bound P-Selectin Levels Among Participants Who Underwent PCI | Day 60 (n=2, 3, 1) | 19.4 Arbitrary Units | — |
| Placebo/Placebo PCI | Mean Membrane-Bound P-Selectin Levels Among Participants Who Underwent PCI | Day 30 (n=3, 4, 3) | 18.8 Arbitrary Units | Standard Error 0.91 |
Secondary
Median High-Sensitivity C-Reactive Protein (Hs-CRP) Levels Among Participants Who Underwent PCI By Study Visit
Participant blood samples were collected at Baseline and on Days 30 and 60 to evaluate the median level of hs-CRP. hs-CRP is a protein marker in the blood associated with inflammation with higher values indicating a greater degree of inflammation. Analysis of data was by maintenance dose group.
Time frame: Baseline, Day 30, Day 60
Population: The population included all enrolled participants who received at least 1 dose of study drug and underwent PCI with hs-CRP data available.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Vorapaxar 20 mg Loading Dose PCI | Median High-Sensitivity C-Reactive Protein (Hs-CRP) Levels Among Participants Who Underwent PCI By Study Visit | Day 60 (n=30, 25, 13) | 1.20 mg/L |
| Vorapaxar 20 mg Loading Dose PCI | Median High-Sensitivity C-Reactive Protein (Hs-CRP) Levels Among Participants Who Underwent PCI By Study Visit | Baseline (n=37, 34, 21) | 1.30 mg/L |
| Vorapaxar 20 mg Loading Dose PCI | Median High-Sensitivity C-Reactive Protein (Hs-CRP) Levels Among Participants Who Underwent PCI By Study Visit | Day 30 (n=35, 34, 21) | 1.28 mg/L |
| Vorapaxar 40 mg Loading Dose PCI | Median High-Sensitivity C-Reactive Protein (Hs-CRP) Levels Among Participants Who Underwent PCI By Study Visit | Day 30 (n=35, 34, 21) | 1.01 mg/L |
| Vorapaxar 40 mg Loading Dose PCI | Median High-Sensitivity C-Reactive Protein (Hs-CRP) Levels Among Participants Who Underwent PCI By Study Visit | Day 60 (n=30, 25, 13) | 0.79 mg/L |
| Vorapaxar 40 mg Loading Dose PCI | Median High-Sensitivity C-Reactive Protein (Hs-CRP) Levels Among Participants Who Underwent PCI By Study Visit | Baseline (n=37, 34, 21) | 2.00 mg/L |
| Placebo/Placebo PCI | Median High-Sensitivity C-Reactive Protein (Hs-CRP) Levels Among Participants Who Underwent PCI By Study Visit | Baseline (n=37, 34, 21) | 1.78 mg/L |
| Placebo/Placebo PCI | Median High-Sensitivity C-Reactive Protein (Hs-CRP) Levels Among Participants Who Underwent PCI By Study Visit | Day 60 (n=30, 25, 13) | 1.27 mg/L |
| Placebo/Placebo PCI | Median High-Sensitivity C-Reactive Protein (Hs-CRP) Levels Among Participants Who Underwent PCI By Study Visit | Day 30 (n=35, 34, 21) | 2.99 mg/L |
Secondary
Median Hs-CRP Levels Among Participants Who Did Not Undergo PCI
Participant blood samples were collected at baseline and at the time of hospital discharge to determine the median serum level of hs-CRP. Analysis of data was by loading dose group.
Time frame: Baseline Up To Day 60
Population: The population consisted of all enrolled participants who received at least 1 dose of study drug, did not undergo PCI, and had hs-CRP data available.
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Vorapaxar 20 mg Loading Dose PCI | Median Hs-CRP Levels Among Participants Who Did Not Undergo PCI | Baseline | 2.57 mg/L | Standard Deviation 5.7 |
| Vorapaxar 20 mg Loading Dose PCI | Median Hs-CRP Levels Among Participants Who Did Not Undergo PCI | Time of Hospital Discharge | 3.56 mg/L | Standard Deviation 10.12 |
| Vorapaxar 40 mg Loading Dose PCI | Median Hs-CRP Levels Among Participants Who Did Not Undergo PCI | Baseline | 1.05 mg/L | Standard Deviation 2.23 |
| Vorapaxar 40 mg Loading Dose PCI | Median Hs-CRP Levels Among Participants Who Did Not Undergo PCI | Time of Hospital Discharge | 2.65 mg/L | Standard Deviation 5 |
| Placebo/Placebo PCI | Median Hs-CRP Levels Among Participants Who Did Not Undergo PCI | Baseline | 6.94 mg/L | Standard Deviation 12.01 |
| Placebo/Placebo PCI | Median Hs-CRP Levels Among Participants Who Did Not Undergo PCI | Time of Hospital Discharge | 3.96 mg/L | Standard Deviation 0.91 |
Secondary
Number of Participants Experiencing Non-MACE AEs Among Participants Who Did Not Undergo PCI
An AE is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration, whether or not considered related to the study drug. MACE events were defined as nonfatal MI, nonfatal stroke, hospitalization due to recurrent ischemia, or urgent coronary revascularization performed ≥ 30 days after administration of the loading dose (Day 1). All MACE events were excluded from this analysis. Analysis of data was by loading dose group.
Time frame: Up to Day 121
Population: The population consisted of all enrolled participants who received at least 1 dose of study drug, did not undergo PCI, and had non-MACE AE data available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vorapaxar 20 mg Loading Dose PCI | Number of Participants Experiencing Non-MACE AEs Among Participants Who Did Not Undergo PCI | 6 Participants |
| Vorapaxar 40 mg Loading Dose PCI | Number of Participants Experiencing Non-MACE AEs Among Participants Who Did Not Undergo PCI | 15 Participants |
| Placebo/Placebo PCI | Number of Participants Experiencing Non-MACE AEs Among Participants Who Did Not Undergo PCI | 1 Participants |
Secondary
Number of Participants Experiencing Non-Major Adverse Cardiac Events (MACE) Who Underwent PCI
An AE is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration, whether or not considered related to the study drug. MACE events were defined as nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization due to recurrent ischemia, or urgent coronary revascularization performed ≥ 30 days after administration of the loading dose (Day 1). All MACE events were excluded from this analysis. Analysis of data was by loading/maintenance dose group.
Time frame: Up to Day 121
Population: The population included all enrolled participants who received at least 1 dose of study drug and underwent PCI with Non-Major MACE data available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vorapaxar 20 mg Loading Dose PCI | Number of Participants Experiencing Non-Major Adverse Cardiac Events (MACE) Who Underwent PCI | 21 Participants |
| Vorapaxar 40 mg Loading Dose PCI | Number of Participants Experiencing Non-Major Adverse Cardiac Events (MACE) Who Underwent PCI | 19 Participants |
| Placebo/Placebo PCI | Number of Participants Experiencing Non-Major Adverse Cardiac Events (MACE) Who Underwent PCI | 16 Participants |
| Vorapaxar 40 mg/2.5 mg PCI | Number of Participants Experiencing Non-Major Adverse Cardiac Events (MACE) Who Underwent PCI | 14 Participants |
| Placebo/Placebo PCI | Number of Participants Experiencing Non-Major Adverse Cardiac Events (MACE) Who Underwent PCI | 21 Participants |
Secondary
Number of Participants Who Did Not Undergo PCI But Had Bleeding Events That Required Subsequent Hospitalization
Bleeding events were evaluated among participants that did not undergo PCI to determine the number of participants who required a subsequent hospitalization. Analysis of data was by loading dose group.
Time frame: Up to Day 30
Population: The population consisted of all enrolled participants who received at least 1 dose of study drug, did not undergo PCI, and had hospitalization data available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vorapaxar 20 mg Loading Dose PCI | Number of Participants Who Did Not Undergo PCI But Had Bleeding Events That Required Subsequent Hospitalization | 0 Participants |
| Vorapaxar 40 mg Loading Dose PCI | Number of Participants Who Did Not Undergo PCI But Had Bleeding Events That Required Subsequent Hospitalization | 1 Participants |
| Placebo/Placebo PCI | Number of Participants Who Did Not Undergo PCI But Had Bleeding Events That Required Subsequent Hospitalization | 0 Participants |
Secondary
Number of Participants Who Did Not Undergo PCI But Had Bleeding Events That Required Transfusion
Bleeding events were evaluated among participants that did not undergo PCI to determine the number of participants that required blood transfusion. Analysis of data was by loading dose group.
Time frame: Up to Day 60
Population: The population consisted of all enrolled participants who received at least 1 dose of study drug, did not undergo PCI, and had transfusion data available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vorapaxar 20 mg Loading Dose PCI | Number of Participants Who Did Not Undergo PCI But Had Bleeding Events That Required Transfusion | 1 Participants |
| Vorapaxar 40 mg Loading Dose PCI | Number of Participants Who Did Not Undergo PCI But Had Bleeding Events That Required Transfusion | 2 Participants |
| Placebo/Placebo PCI | Number of Participants Who Did Not Undergo PCI But Had Bleeding Events That Required Transfusion | 0 Participants |
Secondary
Number of Participants Who Did Not Undergo PCI But Had Coronary Artery Bypass Graft (CABG) Who Experienced Bleeding Events
Bleeding events were evaluated up to 10 hours post-CABG among participants who did not undergo PCI.
Time frame: Up to 10 Hours Post-CABG
Population: Evaluation of the bleeding events associated with CABG occurring after Vorapaxar treatment was not analyzed since only three participants in the non-PCI cohort underwent CABG in this study.
Secondary
Number of Participants Who Did Not Undergo PCI That Had Clinically Important Bleeding Events
Clinically important bleeding events were defined as intracranial hemorrhage, bleeding requiring blood transfusion, bleeding requiring hospitalization, and TIMI major bleeding. Analysis of data was by loading dose group.
Time frame: Baseline Up To Day 60
Population: The population consisted of all enrolled participants who received at least 1 dose of study drug, did not undergo PCI, and had bleeding event data available.
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Vorapaxar 20 mg Loading Dose PCI | Number of Participants Who Did Not Undergo PCI That Had Clinically Important Bleeding Events | Intracranial hemorrhage | 0 Participants | 1.1 |
| Vorapaxar 20 mg Loading Dose PCI | Number of Participants Who Did Not Undergo PCI That Had Clinically Important Bleeding Events | Bleeding requiring transfusion | 1 Participants | 2.86 |
| Vorapaxar 20 mg Loading Dose PCI | Number of Participants Who Did Not Undergo PCI That Had Clinically Important Bleeding Events | Bleeding requiring hospitalization | 0 Participants | — |
| Vorapaxar 20 mg Loading Dose PCI | Number of Participants Who Did Not Undergo PCI That Had Clinically Important Bleeding Events | Major TIMI bleeding | 1 Participants | — |
| Vorapaxar 40 mg Loading Dose PCI | Number of Participants Who Did Not Undergo PCI That Had Clinically Important Bleeding Events | Major TIMI bleeding | 2 Participants | — |
| Vorapaxar 40 mg Loading Dose PCI | Number of Participants Who Did Not Undergo PCI That Had Clinically Important Bleeding Events | Intracranial hemorrhage | 1 Participants | 0.79 |
| Vorapaxar 40 mg Loading Dose PCI | Number of Participants Who Did Not Undergo PCI That Had Clinically Important Bleeding Events | Bleeding requiring hospitalization | 1 Participants | — |
| Vorapaxar 40 mg Loading Dose PCI | Number of Participants Who Did Not Undergo PCI That Had Clinically Important Bleeding Events | Bleeding requiring transfusion | 2 Participants | 0.83 |
| Placebo/Placebo PCI | Number of Participants Who Did Not Undergo PCI That Had Clinically Important Bleeding Events | Major TIMI bleeding | 0 Participants | — |
| Placebo/Placebo PCI | Number of Participants Who Did Not Undergo PCI That Had Clinically Important Bleeding Events | Bleeding requiring transfusion | 0 Participants | 4.64 |
| Placebo/Placebo PCI | Number of Participants Who Did Not Undergo PCI That Had Clinically Important Bleeding Events | Bleeding requiring hospitalization | 0 Participants | — |
| Placebo/Placebo PCI | Number of Participants Who Did Not Undergo PCI That Had Clinically Important Bleeding Events | Intracranial hemorrhage | 0 Participants | 4.06 |
Secondary
Number of Participants Who Underwent PCI With Clinically Important Bleeding Events During Treatment and After Hospital Discharge
Clinically important bleeding events were defined as intracranial hemorrhage, bleeding requiring hospitalization, or TIMI major bleeding. Analysis of data was by loading/maintenance dose group.
Time frame: Up to Day 121
Population: The population included all participants who received at least 1 dose of study drug, underwent PCI, and had bleeding event data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vorapaxar 20 mg Loading Dose PCI | Number of Participants Who Underwent PCI With Clinically Important Bleeding Events During Treatment and After Hospital Discharge | Post-Hospital Discharge | 1 Participants |
| Vorapaxar 20 mg Loading Dose PCI | Number of Participants Who Underwent PCI With Clinically Important Bleeding Events During Treatment and After Hospital Discharge | Treatment Phase | 3 Participants |
| Vorapaxar 40 mg Loading Dose PCI | Number of Participants Who Underwent PCI With Clinically Important Bleeding Events During Treatment and After Hospital Discharge | Post-Hospital Discharge | 0 Participants |
| Vorapaxar 40 mg Loading Dose PCI | Number of Participants Who Underwent PCI With Clinically Important Bleeding Events During Treatment and After Hospital Discharge | Treatment Phase | 0 Participants |
| Placebo/Placebo PCI | Number of Participants Who Underwent PCI With Clinically Important Bleeding Events During Treatment and After Hospital Discharge | Treatment Phase | 2 Participants |
| Placebo/Placebo PCI | Number of Participants Who Underwent PCI With Clinically Important Bleeding Events During Treatment and After Hospital Discharge | Post-Hospital Discharge | 2 Participants |
| Vorapaxar 40 mg/2.5 mg PCI | Number of Participants Who Underwent PCI With Clinically Important Bleeding Events During Treatment and After Hospital Discharge | Treatment Phase | 0 Participants |
| Vorapaxar 40 mg/2.5 mg PCI | Number of Participants Who Underwent PCI With Clinically Important Bleeding Events During Treatment and After Hospital Discharge | Post-Hospital Discharge | 0 Participants |
| Placebo/Placebo PCI | Number of Participants Who Underwent PCI With Clinically Important Bleeding Events During Treatment and After Hospital Discharge | Post-Hospital Discharge | 0 Participants |
| Placebo/Placebo PCI | Number of Participants Who Underwent PCI With Clinically Important Bleeding Events During Treatment and After Hospital Discharge | Treatment Phase | 0 Participants |
Secondary
Number of Participants Who Underwent PCI With Inhibition of Platelet Aggregation By Study Visit
Blood samples were collected from participants at Baseline and Days 30, 60, 74, 90, and 121 to determine the extent of inhibition of platelet aggregation induced by thrombin-receptor agonist peptide (TRAP). Analysis of data was by maintenance dose group.
Time frame: Baseline, Day 30, Day 60, Day 74, Day 90, Day 121
Population: The population consisted of all enrolled participants who received at least 1 dose of study drug and underwent PCI with inhibition of platelet aggregation data available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vorapaxar 20 mg Loading Dose PCI | Number of Participants Who Underwent PCI With Inhibition of Platelet Aggregation By Study Visit | Baseline | 5 Participants |
| Vorapaxar 20 mg Loading Dose PCI | Number of Participants Who Underwent PCI With Inhibition of Platelet Aggregation By Study Visit | Day 90 (follow-up period) | 5 Participants |
| Vorapaxar 20 mg Loading Dose PCI | Number of Participants Who Underwent PCI With Inhibition of Platelet Aggregation By Study Visit | Day 60 | 3 Participants |
| Vorapaxar 20 mg Loading Dose PCI | Number of Participants Who Underwent PCI With Inhibition of Platelet Aggregation By Study Visit | Day 74 (follow-up period) | 5 Participants |
| Vorapaxar 20 mg Loading Dose PCI | Number of Participants Who Underwent PCI With Inhibition of Platelet Aggregation By Study Visit | Day 121 (follow-up period) | 5 Participants |
| Vorapaxar 20 mg Loading Dose PCI | Number of Participants Who Underwent PCI With Inhibition of Platelet Aggregation By Study Visit | Day 30 | 5 Participants |
| Vorapaxar 40 mg Loading Dose PCI | Number of Participants Who Underwent PCI With Inhibition of Platelet Aggregation By Study Visit | Day 60 | 3 Participants |
| Vorapaxar 40 mg Loading Dose PCI | Number of Participants Who Underwent PCI With Inhibition of Platelet Aggregation By Study Visit | Day 74 (follow-up period) | 4 Participants |
| Vorapaxar 40 mg Loading Dose PCI | Number of Participants Who Underwent PCI With Inhibition of Platelet Aggregation By Study Visit | Baseline | 4 Participants |
| Vorapaxar 40 mg Loading Dose PCI | Number of Participants Who Underwent PCI With Inhibition of Platelet Aggregation By Study Visit | Day 30 | 4 Participants |
| Vorapaxar 40 mg Loading Dose PCI | Number of Participants Who Underwent PCI With Inhibition of Platelet Aggregation By Study Visit | Day 90 (follow-up period) | 4 Participants |
| Vorapaxar 40 mg Loading Dose PCI | Number of Participants Who Underwent PCI With Inhibition of Platelet Aggregation By Study Visit | Day 121 (follow-up period) | 4 Participants |
| Placebo/Placebo PCI | Number of Participants Who Underwent PCI With Inhibition of Platelet Aggregation By Study Visit | Day 30 | 3 Participants |
| Placebo/Placebo PCI | Number of Participants Who Underwent PCI With Inhibition of Platelet Aggregation By Study Visit | Day 121 (follow-up period) | 3 Participants |
| Placebo/Placebo PCI | Number of Participants Who Underwent PCI With Inhibition of Platelet Aggregation By Study Visit | Day 90 (follow-up period) | 3 Participants |
| Placebo/Placebo PCI | Number of Participants Who Underwent PCI With Inhibition of Platelet Aggregation By Study Visit | Baseline | 3 Participants |
| Placebo/Placebo PCI | Number of Participants Who Underwent PCI With Inhibition of Platelet Aggregation By Study Visit | Day 60 | 1 Participants |
| Placebo/Placebo PCI | Number of Participants Who Underwent PCI With Inhibition of Platelet Aggregation By Study Visit | Day 74 (follow-up period) | 3 Participants |
Secondary
Number of Participants With Major, Minor, and Non-Thrombolysis in Myocardial Infarction Cooperative Group (TIMI) Bleeding Events Among Participants Who Underwent PCI
Major TIMI bleeding was defined as any intracranial bleeding (excluding microhemorrhages \<10 mm evident only on gradient-echo magnetic resonance imaging \[MRI\]), clinically overt signs of hemorrhage associated with a drop in hemoglobin of ≥5 g/dL, or fatal bleeding (bleeding that directly results in death within 7 days). Minor TIMI bleeding was defined as any clinically overt bleeding resulting in hemoglobin drop of 3 to \<5 g/dL. Non-TIMI bleeding included all bleeding events not covered under Major TIMI bleeding or Minor TIMI bleeding. Analysis of data was by maintenance dose group.
Time frame: Up to Day 60
Population: The population included all enrolled participants who received at least 1 dose of study drug and underwent PCI with TIMI bleeding data available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vorapaxar 20 mg Loading Dose PCI | Number of Participants With Major, Minor, and Non-Thrombolysis in Myocardial Infarction Cooperative Group (TIMI) Bleeding Events Among Participants Who Underwent PCI | Minor TIMI Bleeding Events | 5 Participants |
| Vorapaxar 20 mg Loading Dose PCI | Number of Participants With Major, Minor, and Non-Thrombolysis in Myocardial Infarction Cooperative Group (TIMI) Bleeding Events Among Participants Who Underwent PCI | Major TIMI Bleeding Events | 2 Participants |
| Vorapaxar 20 mg Loading Dose PCI | Number of Participants With Major, Minor, and Non-Thrombolysis in Myocardial Infarction Cooperative Group (TIMI) Bleeding Events Among Participants Who Underwent PCI | Non-TIMI Bleeding Events | 22 Participants |
| Vorapaxar 40 mg Loading Dose PCI | Number of Participants With Major, Minor, and Non-Thrombolysis in Myocardial Infarction Cooperative Group (TIMI) Bleeding Events Among Participants Who Underwent PCI | Minor TIMI Bleeding Events | 3 Participants |
| Vorapaxar 40 mg Loading Dose PCI | Number of Participants With Major, Minor, and Non-Thrombolysis in Myocardial Infarction Cooperative Group (TIMI) Bleeding Events Among Participants Who Underwent PCI | Major TIMI Bleeding Events | 0 Participants |
| Vorapaxar 40 mg Loading Dose PCI | Number of Participants With Major, Minor, and Non-Thrombolysis in Myocardial Infarction Cooperative Group (TIMI) Bleeding Events Among Participants Who Underwent PCI | Non-TIMI Bleeding Events | 17 Participants |
| Placebo/Placebo PCI | Number of Participants With Major, Minor, and Non-Thrombolysis in Myocardial Infarction Cooperative Group (TIMI) Bleeding Events Among Participants Who Underwent PCI | Major TIMI Bleeding Events | 0 Participants |
| Placebo/Placebo PCI | Number of Participants With Major, Minor, and Non-Thrombolysis in Myocardial Infarction Cooperative Group (TIMI) Bleeding Events Among Participants Who Underwent PCI | Non-TIMI Bleeding Events | 11 Participants |
| Placebo/Placebo PCI | Number of Participants With Major, Minor, and Non-Thrombolysis in Myocardial Infarction Cooperative Group (TIMI) Bleeding Events Among Participants Who Underwent PCI | Minor TIMI Bleeding Events | 2 Participants |
Secondary
Number of Participants With Major, Minor, and Non-TIMI Bleeding Events Among Participants Who Did Not Undergo PCI
Major TIMI bleeding was defined as any intracranial bleeding (excluding microhemorrhages \<10 mm evident only on gradient-echo MRI), clinically overt signs of hemorrhage associated with a drop in hemoglobin of ≥5 g/dL, or fatal bleeding (bleeding that directly results in death within 7 days). Minor TIMI bleeding was defined as any clinically overt bleeding resulting in hemoglobin drop of 3 to \<5 g/dL. Non-TIMI bleeding included all bleeding events not covered under Major TIMI bleeding or Minor TIMI bleeding. Analysis of data was by loading dose group.
Time frame: Up to Day 60
Population: The population consisted of all enrolled participants who received at least 1 dose of study drug, did not undergo PCI, and had TIMI bleeding data available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vorapaxar 20 mg Loading Dose PCI | Number of Participants With Major, Minor, and Non-TIMI Bleeding Events Among Participants Who Did Not Undergo PCI | Minor TIMI Events | 0 Participants |
| Vorapaxar 20 mg Loading Dose PCI | Number of Participants With Major, Minor, and Non-TIMI Bleeding Events Among Participants Who Did Not Undergo PCI | Major TIMI Events | 1 Participants |
| Vorapaxar 20 mg Loading Dose PCI | Number of Participants With Major, Minor, and Non-TIMI Bleeding Events Among Participants Who Did Not Undergo PCI | Non-TIMI Bleeding Events | 1 Participants |
| Vorapaxar 40 mg Loading Dose PCI | Number of Participants With Major, Minor, and Non-TIMI Bleeding Events Among Participants Who Did Not Undergo PCI | Minor TIMI Events | 0 Participants |
| Vorapaxar 40 mg Loading Dose PCI | Number of Participants With Major, Minor, and Non-TIMI Bleeding Events Among Participants Who Did Not Undergo PCI | Major TIMI Events | 2 Participants |
| Vorapaxar 40 mg Loading Dose PCI | Number of Participants With Major, Minor, and Non-TIMI Bleeding Events Among Participants Who Did Not Undergo PCI | Non-TIMI Bleeding Events | 8 Participants |
| Placebo/Placebo PCI | Number of Participants With Major, Minor, and Non-TIMI Bleeding Events Among Participants Who Did Not Undergo PCI | Major TIMI Events | 0 Participants |
| Placebo/Placebo PCI | Number of Participants With Major, Minor, and Non-TIMI Bleeding Events Among Participants Who Did Not Undergo PCI | Non-TIMI Bleeding Events | 1 Participants |
| Placebo/Placebo PCI | Number of Participants With Major, Minor, and Non-TIMI Bleeding Events Among Participants Who Did Not Undergo PCI | Minor TIMI Events | 0 Participants |