Ticagrelor and Intracoronary Morphine in Patients Undergoing Primary Percutaneous Coronary Intervention

Study Overview
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Brief Summary
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A 2 by 2 factorial, multicenter, prospective, randomized, open-label, blinded endpoint trial. Patients undergoing primary PCI for STEMI will be eligible. Enrolled patients will be randomly assigned to the ticagrelor group or the clopidogrel group in a 1:1 ratio. After emergent coronary angiography, patients who have thrombolysis in myocardial infarction (TIMI) flow grade <2 in coronary angiogram will be randomized again, to either bolus intracoronary injection of morphine sulfate or saline in a 1:1 ratio. Randomization will be stratified by infarct location (anterior vs. non-anterior), and morphine use for pain control before study enroll (for only intracoronary morphine).

Detailed Description
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1.1. Ticagrelor versus Clopidogrel In spite of timely and successful reperfusion with primary percutaneous coronary intervention (PCI), the mortality rate still remains high1 and substantial numbers of patients suffer from subsequent left ventricular dysfunction or heart failure after ST-segment elevation myocardial infarction (STEMI). One of limitations of primary PCI is distal embolization and effective antiplatelet therapy is needed in patients with STEMI. Clopidogrel is a representative P2Y12 receptor antagonist and has shown consistent efficacy in patients with acute coronary syndromes. However, clopidogrel is a prodrug and has to be converted to an active metabolite to inhibit P2Y12 receptor. Therefore, onset of effect is relatively slow, antiplatelet effect is moderate, and response to clopidogrel shows wide individual variability. Ticagrelor is a new, direct, reversible P2Y12 receptor antagonist, which has rapid and potent antiplatelet effect. In patients who have an acute coronary syndrome with or without ST-segment elevation, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding. However, there has been no data whether ticagrelor can reduce infarct size compared with clopidogrel in patients undergoing primary PCI. 1.2. Intracoronary morphine administration Lethal reperfusion injury accounts for up to 50% of the final size of a myocardial infarct.5,6 Therefore, adjunctive therapy that is effective in preventing lethal reperfusion injury is needed to potentiate the benefits of primary PCI. During the past few decades, a large number of animal studies demonstrated that commonly used opioids could provide cardioprotection against ischemia-reperfusion injury. Opioid-induced preconditioning or postconditioning mimics ischemic preconditioning or ischemic postconditioning. Recent small clinical trial demonstrated the cardioprotective effect of remote ischemic preconditioning and morphine during primary PCI. But this study was small and did not demonstrate the separate effect of morphine-induced cardioprotection. 2. Study Objective To investigate the effects of ticagrelor on myocardial infarct size in patients with STEMI undergoing primary PCI compared with clopidogrel To investigate the effects of morphine-induced cardioprotection during primary PCI in patients with STEMI

Official Title
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Effects of Ticagrelor and Intracoronary Morphine on Myocardial Salvage in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention

Conditions
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ST-Segment Elevation Myocardial Infarction

Intervention / Treatment
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* Drug: Ticagrelor
* Drug: Clopidogrel
* Drug: Morphine Sulfate
* Drug: Saline


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Subject must be at least 20 years of age. Patients undergoing primary PCI for STEMI Diagnosis of STEMI: ST-segment elevation >0.1 millivolt in ≥2 contiguous leads or (presumably) new left bundle branch block Presence of symptoms less than 12 hours Additional inclusion criteria for intracoronary morphine TIMI flow grade 0 or 1 of infarct related arteries Exclusion Criteria: Known hypersensitivity or contraindication to study medications or contrast Female of childbearing potential, unless a recent pregnancy test is negative, who possibly plan to become pregnant any time after enrollment into this study. Rescue PCI after thrombolysis or facilitated PCI Cardiogenic shock or cardiopulmonary resuscitation before randomization Known chronic hepatic disease Known renal dysfunction (creatinine level 3.0mg/dL or dependence on dialysis). Decompensated chronic obstructive pulmonary disease or active asthma at inclusion Mechanical ventilation at inclusion Brain injury or intracranial hypertension Acute alcohol intoxication Known ulcerative colitis Active epilepsy Contraindications to undergo MRI imaging include any of the following A cardiac pacemaker or implantable defibrillator; any implanted or magnetically activated device; or any history indicating contraindication to MRI including claustrophobia or allergy to gadolinium Current use of oral anticoagulant An increased risk of bradycardia Sinus node dysfunction, atrioventricular dysfunction, or heart rate <40/min Patients receiving clopidogrel 300 mg or more before randomization One of followings history of intracranial bleeding intracranial tumor, arteriovenous malformation or aneurysm stroke within past 3 months Active bleeding of internal organ or bleeding diathesis Acute aortic dissection

Ages Eligible for Study
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Minimum Age: 20 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: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ticagrelor + Intracoronary Morphine<br>180 mg loading pre-PCI followed by 90 mg bid for 5 days. Intracoronary Morphine Sulfate 3 mg + Saline 3 ml mix. | Drug: Ticagrelor<br> <br> * Other names: Brilinta;Drug: Morphine Sulfate<br> <br> * Other names: Morphine;|
| Experimental: Ticagrelor + Intracoronary Saline<br>180 mg loading pre-PCI followed by 90 mg bid for 5 days. Saline 3 ml intracoronary injection. | Drug: Ticagrelor<br> <br> * Other names: Brilinta;Drug: Saline<br> <br> * Other names: Normal Saline;|
| Experimental: Clopidogrel + Intracoronary Morphine<br>600 mg loading pre-PCI followed by 75 mg qd for 5 days. Morphine Sulfate 3 mg + Saline 3 ml mix intracoronary injection. | Drug: Clopidogrel<br> <br> * Other names: Plavix;Drug: Morphine Sulfate<br> <br> * Other names: Morphine;|
| Active Comparator: Clopidogrel + Intracoronary Saline<br>600 mg loading pre-PCI followed by 75 mg qd for 5 days. Saline 3 ml intracoronary injection. | Drug: Clopidogrel<br> <br> * Other names: Plavix;Drug: Saline<br> <br> * Other names: Normal Saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Myocardial infarct size measured by magnetic resonance imaging (MRI) at 3-5 days after the index procedure |  | Post-PCI 3-5 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of complete ST-segment resolution on ECG obtained 30 minutes after the procedure |  | 30 min after completion of PCI | 
| Enzymatic Infarct size by creatine kinase-MB (area under curve) |  | 1 month later | 
| Myocardial salvage index measured by MRI |  | Post-PCI 3-5 days | 
| Major adverse cardiac events (a composite of death, myocardial infarction, severe heart failure, or stent thrombosis) |  | 1Month later | 
| The extent of microvascular obstruction measured by MRI |  | post-PCI 3-5days | 
| The number of segments with >75% of infarct transmurality measured by MRI |  | post-PCI 3-5 days | 
| The presence of myocardial hemorrhage measured by MRI |  | post-PCI 3-5 days |