Introduction
Methods
Target population
Inclusion criteria | • Age ≥ 18 and < 85. • Non-ST elevated acute coronary syndrome (unstable angina, non-ST elevated myocardial infarction), with an onset of symptoms during the previous 24 h and positive troponin-I or troponin-T. • An initial invasive strategy is chosen (the patient is expected to undergo coronary angiography within 72 h from admission). • Subject is able to start therapy with a new P2Y12 inhibitor (prasugrel or ticagrelor) or is on a maintenance dose of clopidogrel or ticlopidine and is able to switch to a new P2Y12 inhibitor (prasugrel or ticagrelor). • Subject is able to verbally confirm understanding of risks and benefits of dual antiplatelet therapy in coronary acute syndromes, and he/she or his/her legally authorized representative provides written informed consent prior to any clinical investigation related procedure, as approved by the appropriate Ethics Committee. • Patient agrees to comply with follow-up evaluations. |
Exclusion criteria | General exclusion criteria • Known hypersensitivity/contraindication to aspirin, clopidogrel, prasugrel, ticagrelor, heparin, or bivalirudin, or sensitivity to contrast media, which cannot be adequately pre-medicated. • Platelet count < 100,000 cells/mm3 or > 700,000 cells/mm3, or a white blood cell (WBC) count < 3000 cells/mm3 within 7 days prior to index procedure. • Shock. • Have severe hepatic impairment defined as Child-Pugh class C. • Pregnant or nursing subjects and those who plan pregnancy in the period up to 3 years following screening (female subjects of child-bearing potential must have a negative pregnancy test done within 28 days prior to enrollment). • Other medical illness (e.g., cancer or congestive heart failure) or known history of substance abuse (alcohol, cocaine, heroin, etc.) as per physician judgment that may cause non-compliance with the protocol or confound the data interpretation or is associated with a limited life expectancy. • Subject is belonging to a vulnerable population (per investigator’s judgment, e.g., subordinate hospital staff or sponsor staff) or subject unable to read or write. • Currently participating in investigational drug or device trial that has not completed the primary endpoint or that clinically interferes with current trial endpoints. Subject must agree not to participate in any other clinical investigation for a period of 3 years following the index procedure, including clinical trials of medication and invasive procedures. Questionnaire-based studies or other studies that are non-invasive and do not require medication are allowed. Bleeding risk exclusion criteria • Prior history of hemorrhagic or ischemic stroke, a transient ischemic attack (TIA), or sub-arachnoid hemorrhage. • History of intracranial neoplasm, arteriovenous malformation, or aneurysm. • Have received fibrinolytic therapy within 48 h of entry or randomization into the study. • Have active pathological bleeding or history of bleeding diathesis. • Have clinical findings, in the judgment of the investigator, associated with an increased risk of bleeding. • Have had recent surgery (within 4 weeks of entry into the study) or are scheduled to undergo surgery within the next 2 months. Prior/concomitant therapy exclusion criteria • Have received a loading dose of a thienopyridine (ticlopidine, clopidogrel, or prasugrel) or a maintenance dose of prasugrel or ticlopidine or ticagrelor within 7 days of entry into the study. • Are receiving a GPIIb/IIIa inhibitor (eptifibatide, tirofiban, or abciximab). • Are receiving warfarin or other coumarin derivatives. • Are receiving or will receive oral anticoagulation or other oral antiplatelet therapy (except aspirin [ASA]) that cannot be safely discontinued within the next 3 months. • Are 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 NSAID or COX2 inhibitors during the study. • Concomitant therapy with a strong cytochrome P-4503A inhibitor or inducer. |
Screening for eligibility
Consenting and randomization
Study drugs administration
Outcome measures
Type 3 | |
Type 3a | |
Overt bleeding plus hemoglobin drop of 3 to < 5 g/dL (provided hemoglobin drop is related to bleed) | |
Any transfusion with overt bleeding | |
Type 3b | |
Overt bleeding plus hemoglobin drop ≥ 5 g/dL (provided hemoglobin drop is related to bleed) | |
Cardiac tamponade | |
Bleeding requiring surgical intervention for control (excluding dental/nasal/skin/hemorrhoid) | |
Bleeding requiring intravenous vasoactive agents | |
Type 3c | |
Intracranial hemorrhage (does not include microbleeds or hemorrhagic transformation, does include intraspinal) | |
Subcategories confirmed by autopsy or imaging or lumbar puncture | |
Intraocular bleed compromising vision | |
Type 4: CABG-related bleeding | |
Perioperative intracranial bleeding within 48 h | |
Reoperation after closure of sternotomy for the purpose of controlling bleeding | |
Transfusion of ≥ 5 U whole blood or packed red blood cells within a 48-h period | |
Chest tube output ≥ 2 L within a 24-h period | |
Type 5: fatal bleeding | |
Type 5a | |
Probable fatal bleeding; no autopsy or imaging confirmation but clinically suspicious | |
Type 5b | |
Definite fatal bleeding; overt bleeding or autopsy or imaging confirmation |
Primary and secondary endpoints
Single digit and composite of death from vascular causes (death from cardiovascular causes or cerebrovascular causes and any death without another known cause), MI, stroke, TIA, severe recurrent ischemia, recurrent ischemia, or other arterial thrombotic event | |
Death from any cause | |
Any stent thrombosis according to the ARC criteria | |
Target vessel revascularization (TVR) | |
Target lesion revascularization (TLR) | |
NACE (net adverse cardiac events) occurred in the period between admission and coronary revascularization defined as a composite of death from vascular causes (death from cardiovascular causes or cerebrovascular causes and any death without another known cause), non-fatal MI, or non-fatal stroke, and BARC type 2, 3, 4, and 5 bleeding | |
Compliance to mandated antiplatelet therapy | |
BARC type 2, 3, 4, and 5 bleeding (single digit and composite) | |
All TIMI major, major life-threatening, and minor bleeding | |
All CABG surgery-related TIMI major, minor, and composite of TIMI major or minor bleeding | |
Non-CABG surgery-related TIMI major, minor, and composite of TIMI major or minor bleeding |