Inclusion Criteria
Before entering the study, informed consent must be signed by the study participant according to local rules and regulations. Subjects are eligible to be entered in the study (that is, sign informed consent) only if they are of a legal age (at least 18 years of age) and competent mental condition to provide written informed consent, and meet all of the following criteria:
[1] Have had a UA/NSTEMI index, event within 7 days (168 hours) prior to randomization (based on the disease diagnostic criteria in Section 4.1.1).
[2] Have had a medical management strategy decision made with reasonable certainty; that is, neither PCI nor CABG is planned for treatment of the index event.
- For subjects whose medical management strategy decision and randomization occurs no later than 24 hours following onset of the index event, prior clopidogrel treatment is not a consideration for eligibility.
- For subjects with a medical management decision who are randomized beyond 24 hours of onset of the index event, commercial clopidogrel must have been received according to standard of care practice guidelines no later than 24 hours following the onset of the index event (as defined in Section 4.1.2).
[3] Have had at least 1 of the following 3 high-risk features at the time of the UA/NSTEMI event:
- Age 60 years or less
- Prior MI evidenced by pre-existing Q waves, or demonstration of infarction on imaging studies, or prior documentation of elevated cardiac markers.
- Diabetes Mellitus – defined by concomitant treatment with an oral hypoglycemic agent and/or insulin.
[4] Have at least 1 native coronary artery stenosis >50% (applies only to those subjects who undergo diagnostic coronary antiography within 7 days of the onset of the index event but do not undergo PCI or CABG after angiography is performed).
- Disease Diagnostic Criteria
- Definition of UA/NSTEM
For purposes of this study, recent UA/NSTEMI will be defined as follows:
- NSTEMI is defined as a history of chest discomfort or equivalent ischemic symptoms of ≥10 minutes duration at rest within 24 hours prior to the index event, with no evidence of persistent ST-segment elevation. Subjects must also have a CK-MD or troponin T or I greater than the upper limit of normal (ULN) defined by the local laboratory assay. If CK-MB or troponin are not available, total CK ≥2 times ULN is acceptable.
- UA is defined as a history of chest discomfort or equivalent ischemic symptoms of ≥10 minutes duration at rest wthin 24 hours prior to the index event, with ST-segment depression > 1 min in at least two or more ECG leads without elevation of CK-MB, troponin T, or troponin I.
The onset for the index event will be the first medical contact for evaluation of UA/NSTEMI symptoms. First medical contact is defined as the date and time of first contact with medical personnel for the index event including Emergency Medical Systems (EMS) responders for pre-hospital evaluation, Emergency Room personnel for the initial hospital evaluation, or other medical personnel for other locations of first evaluation. If the subject was already hospitalized at the time of the UA/NSTEMI symptoms, the onset of the index event will be the date and time when the subject is initially evaluated for UA/NSTEMI (that is, when ECG or biomarkers for myocardial damage are first obtained), provided that the subject meets all other inclusion and exclusion criteria.
- Decision for Medical Management
The information upon which the medical management decision is made will be at the discretion of the investigator. Any testing, which may include acute coronary angiography or other coronary diagnostic evaluations, must be performed within 7 days of the onset of the index event (that is, first medical contact for evaluation of UA/NSTEMI symptoms).
- Standard of Care for Commercial Ciopidogrel Use in UA/NSTEMI Subjects
Standard of care for the use of commercial clopidogtel in UA/NSTEMI subjects in this study is defined as:
- For clopidogrel-naïve subjects, treatment with a 300 to 600-mg clopidogrel loading dose within 24 hours following the onset of the index event followed by once-daily 75-mg maintenance dose until randomization.
- For subjects on commercial clopidogrel treatment prior to the index event, continue the once-daily 75-mg maintenance dose until randomization.
Exclusion Criteria
Subjects may not be entered into the study if they meet any of the following criteria:
Cardiovascular Exclusion Criteria:
[5] Decision for medical management >24 hours after the onset of the index event without commercial clopidogrel treatment within 24 hours following the onset of the index event (Note: commercial clopidogrel treatment must continue daily thereafter until randomization).
[6] Previous or planned (during the index hospitalization or thereafter) PCI or CABG as treatment for the index event.
[7] PCI or CABG within the previous 30 days.
[8] STEMI as the index event.
[9] Cardiogenic shock within the previous 24 hours (defined as a systolic blood pressure <90 mm Hg associated with clinical evidence of end-organ hypoperfusion, or hypotension requiring vasopressors to maintain systolic blood pressure over 90 mm Hg and associated with clinical evidence of end-organ hypoperfusion).
[10] Refractory ventricular arrhythmias thin the previous 24 hours.
[11] Symptoms of New York Heart Association (NYHA) Class IV congestive heart failure (CHF) within the previous 24 hours (see Attachment TABY.4 for NYHA CHF classifications).
Exclusion Criteria Related to Bleeding
[12] Contraindicated for antiplatelet therapy.
[13] Received fibrinolytic therapy as initial treatment for the index event.
[14] Any history of bleeding diathesis.
[15] Clinical findings associated, in the judgment of the investigator, with an unacceptably high risk of bleeding.
[16] Any of the following:
- History of ischemic or hemorrhagic stroke
- Intracranial neoplasm, arteriovenous malformation, or aneurysm
- History of any TIA symptoms.
[17] International Normalized Ratio (INR) known to be >1.5 at the time of screening.
[18] Platelet count of ,100,000/mm3 at the time of screening.
[19] Anenda (hemoglobin [Hgb] ,10 gm/dL) at the time of screening.
[20] History of spontaneous gastrointestinal bleeding requiring in-hospital treatment.
[21] History of spontaneous non-gastrointestinal internal bleeding requiring in-hospital treatment.
[22] Currently receiving hemodialysis or peritoneal dialysis.
Prior/Concomitant Therapy Exclusion Criteria
[23] History of intolerance or allergy to aspirin or approved thienopyridines (ticlopidine or clopidogrel).
[24] Treated with ticlipidine within 5 days of randomization.
[25] Receiving prasugrel treatment at the time of screening.
[26] Receiving oral anticoagulants at the time of screening or are anticipated to require oral anticoagulants therapy during the course of the study.
[27] Receiving daily treatment with nonsteroidal anti-inflammatory drugs (NSAIDS) or cyclooxygenase-2 (COX2) inhibitors that cannot be discontinued or are anticipated to require .2 weeks of daily treatment with NSAIDS or COX2 inhibitors during the study.
General Exclusion Criteria
[28] Unwilling to provide or not sufficiently mentally competent to provide written informed consent.
[29] Study site personnel directly affiliated with the study or are immediate family of study site personnel directly affiliated with the study. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
[30] Employed by Eli Lilly and Company, Ube Industries Limited, Daiichi Sankyo Pharma Inc, the academic research organization (ARO), or the contract research organization (CRO) (that is, employees, temporary contract workers, or designees responsible for the conduct of the study). Immediate family of Lilly employees may participate in Lilly-sponsored clinical studies, but are not permitted to participate at a Lily facility. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
[31] Previously completed or withdrawn from this study or any other study investigating prasugrel.
[32] Received treatment within the last 30 days with a drug or device that has not received regulatory approval for any indication at the time of study entry or are presently enrolled in another interventional drug or device study.
[33] Females who are known to be pregnant, who have given birth within the past 90 days, or who are breastfeeding.
[34] Females of childbearing potential (that is, females who are not surgically or chemically sterilized and who are between menarche and 1-year post menopause) and do not agree to use a reliable method of birth control during the study.
[35] Concomitant medical illness (for example, terminal malignancy) that, in the opinion of the investigator, is associated with reduced survival over the expected treatment period.
[36] Known severe hepatic dysfunction (that is, with cirrhoasis or portal hypertension).
[37] Conditions associated with poor treatment compliance, including alcoholism, mental illness, or drug dependence.
[38] Unable to cooperate with protocol requirements and follow-up procedures.
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