A Comparison of Prasugrel and Clopidogrel in Acute Coronary Syndrome Subjects

Study Overview
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Brief Summary
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This study will evaluate the relative efficacy and safety of prasugrel and clopidogrel in a medically managed Unstable Angina/Non-ST-Elevation Myocardial Infarction (UA/NSTEMI) acute coronary syndrome (ACS) population (that is, patients who are not managed with acute coronary revascularization).

Detailed Description
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Based upon the significant number of subjects with UA/NSTEMI ACS who are managed medically and their high risk for future cardiovascular events, further exploration of novel treatment strategies for this population, who are under-represented in large clinical trials, is warranted. Potential subjects will be those with a recent UA/NSTEMI event who are to be medically managed. Eligibility for this study will be determined by both the timing of the medical management decision and by prior commercial clopidogrel treatment at the time of randomization. The TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes (TRILOGY ACS) Study will assess the efficacy and safety of prasugrel and aspirin compared to the current standard of care, clopidogrel and aspirin, for long-term treatment of medically managed UA/NSTEMI ACS subjects.

Official Title
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A Comparison of Prasugrel and Clopidogrel in Acute Coronary Syndrome Subjects With Unstable Angina/Non-ST-Elevation Myocardial Infarction Who Are Medically Managed

Conditions
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Acute Coronary Syndrome

Intervention / Treatment
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* Drug: Clopidogrel
* Drug: Prasugrel
* Drug: Commercially-available Aspirin


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Have had a Unstable Angina/Non-ST-Elevation Myocardial Infarction (UA/NSTEMI) index event within 10 days prior to randomization Had a medical management strategy decision made with reasonable certainty that neither percutaneous coronary intervention (PCI) nor coronary artery bypass graft (CABG) is planned for treatment of the index event Had at least 1 of 4 specified high-risk features at the time of the UA/NSTEMI event Key Exclusion Criteria: Decision for medical management greater than 72 hours after onset of index event without commercial clopidogrel treatment within 72 hours following onset of the index event. Insignificant coronary artery disease (CAD) on coronary angiography if performed for Index Event (absence of greater than or equal to 30% stenosis in at least one native vessel) Previous or planned PCI or CABG as treatment for the index event PCI/CABG within previous 30 days ST-segment elevation myocardial infarction (STEMI) as the index event Cardiogenic shock, Refractory ventricular arrhythmias, New York Heart Association (NYHA) Class IV congestive heart failure (CHF) within the previous 24 hours History of ischemic or hemorrhagic stroke, transient ischemic attack (TIA), Intracranial neoplasm, arteriovenous malformation, or aneurysm History of spontaneous gastrointestinal (GI) or non-GI bleeding requiring hospitalization for treatment, unless definitive treatment has occurred and there is low likelihood of recurrence Hemodialysis or peritoneal dialysis

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prasugrel<br>Prasugrel and Low-dose Commercially-available Aspirin | Drug: Prasugrel<br>* 30 milligrams (mg), oral, once as loading dose (in those subjects who initiate study drug with a loading dose); and either 5 mg or 10 mg (based upon weight and age), oral, once daily as maintenance dose through end of study<br>* Other names: CS-747;Drug: Commercially-available Aspirin<br>* Low-dose aspirin, oral, as prescribed by physician through end of study<br>|
| Active Comparator: Clopidogrel<br>Clopidogrel and Low-Dose Commercially-available Aspirin | Drug: Clopidogrel<br>* 300 milligrams (mg), oral, once as loading dose (in those subjects who initiate study drug with a loading dose); and 75 mg, oral, once daily as maintenance dose through end of study<br>Drug: Commercially-available Aspirin<br>* Low-dose aspirin, oral, as prescribed by physician through end of study<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Composite Endpoint of Cardiovascular (CV) Death, Myocardial Infarction (MI), or Stroke | The percentage of participants is the total number of participants experiencing a CV death, nonfatal MI, or nonfatal stroke divided by number of participants in the treatment arm multiplied by 100. Endpoint events were adjudicated by the Clinical Endpoint Committee. | Randomization through end of study (30-month visit) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Composite Endpoint of CV Death and MI | The percentage of participants is the total number of participants experiencing a CV death or nonfatal MI divided by number of participants in the treatment arm. Endpoint events were adjudicated by the Clinical Endpoint Committee. | Randomization through end of study (30-month visit) | 
| Percentage of Participants With a Composite Endpoint of CV Death, MI, Stroke, or Re-hospitalization for Recurrent Unstable Angina (UA) | The percentage of participants is the total number of participants experiencing a CV death, nonfatal MI, nonfatal stroke or re-hospitalization for a recurrent UA divided by number of participants in the treatment arm. Endpoints events were adjudicated by the Clinical Endpoint Committee. | Randomization through end of study (30-month visit) | 
| Percentage of Participants With a Composite Endpoint of All-cause Death, MI, or Stroke | The percentage of participants is the total number of participants experiencing an all-cause death, nonfatal MI, or nonfatal stroke divided by number of participants in the treatment arm. Endpoint events were adjudicated by the Clinical Endpoint Committee. | Randomization through end of study (30-month visit) | 
| Platelet Aggregation Measures | Platelet aggregation was measured by as measured by Accumetrics Verify Now™ P2Y12. Results were reported in P2Y12 Reaction Units (PRU). PRU represents the rate and extent of adenosine (ADP)-stimulated platelet aggregation. Lower values indicate greater P2Y12 platelet inhibition and lower platelet activity and aggregation. ANCOVA Model was used and values were corrected for treatment + baseline value + clopidogrel status at randomization. | Day 30 and 12 Months | 
| Biomarker Measurements of Inflammation/Hemodynamic Stress: Brain Natriuretic Peptide (BNP) | Brain natriuretic peptide (BNP) is secreted by the ventricles of the heart in response to hemodynamic stress and is a biomarker associated with increased CV risk. Results are presented as geometric least squares means (Geometric LS means). Geometric LS means were adjusted for treatment + baseline value + clopidogrel status at randomization. | Day 30 and 6 Months | 
| Biomarker Measurements of Inflammation/Hemodynamic Stress: C-Reactive Protein (CRP) | C-Reactive Protein (CRP) is a biomarker associated with inflammation and increased CV risk. Results are presented as geometric least squares means (Geometric LS means). Geometric LS means were adjusted for treatment + baseline value + clopidogrel status at randomization. | Day 30 and Month 6 | 
| Genotyping Related to Drug Metabolism | Variation in the genes encoding the cytochrome P450 (CYP) enzymes (CYP2C19) can reduce the ability to metabolize clopidogrel and a reduced platelet response and have been associated with increased rates of CV events including CV death. Participants were classified as extensive metabolizers (EM); reduced metabolizers (RM); or unknown (UNK) metabolizers based on their CYP2C19 genotype. Possible extensive metabolizer (EM) phenotypes include EM=extensive metabolizer, UM=ultra-rapid metabolizer, and EM (non-UM) that are not UM. Possible reduced metabolizer (RM) phenotypes include IM=intermediate metabolizer and PM=poor metabolizer. Genotypes associated with each predicted phenotype are presented; predicted phenotype is presented first followed by the genotype. Percentage=(number of participants with the predicted phenotype and genotype divided by the total number of participants per arm) multiplied by 100. | Baseline | 
| Economic and Quality of Life Outcomes | Seattle Angina Questionnaire (SAQ) is a validated, disease-specific questionnaire containing 11 questions (Q) yielding 5 summary scales related to angina: physical limitations, angina stability, angina frequency, treatment satisfaction and disease perception. In this study only angina frequency and the physical limitations scales were assessed. Anginal Frequency was assessed using Q3 and Q4 which consists of a Likert scale ranging from 1 to 6 (higher values equals better quality of life) to assess how often a patient is having symptoms now. Physical limitations was assessed using Q1 which contains 9 items each assessed via Likert scale ranging from 1 to 6 (higher values equals better quality of life) to assess how much a participant's condition is hampering their ability to do what they want to do. Scale scores are transformed to a 0-100 by subtracting the lowest possible score, dividing by the range of the scale, and multiplying by 100. Higher values equal better quality of life. | Baseline and follow-up (24 months) | 
| Summary of All Deaths | All deaths, regardless of possible relatedness, with the exception of 1 event, were adjudicated by the Clinical Endpoint Committee (CEC) and are reported in this table. The 1 event which was not adjudicated was a result of the revocation of consent by the participant prior to their death. Deaths possibly related to study drug in the opinion of the investigator are also contained in the Serious Adverse Event (SAE) module. | Randomization through end of study (30-month visit) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ACS