Ticagrelor and Intracoronary Morphine in Patients Undergoing Primary Percutaneous Coronary Intervention

Condition(s) targeted: ST-Segment Elevation Myocardial Infarction

Intervention: Ticagrelor (Drug); Clopidogrel (Drug); Morphine Sulfate (Drug); Saline (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: Hyeon-Cheol Gwon

Official(s) and/or principal investigator(s):
Hyeon-Cheol Gwon, MD/PhD, Principal Investigator, Affiliation: Samsung Medical Center

Overall contact:
Hyeon-Cheol Gwon, MD/PhD, Phone: 82-2-3410-6653, Email: hcgwon62@gmail.com

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).

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

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Factorial Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Myocardial salvage index measured by magnetic resonance imaging (MRI) at 3-5 days after the index procedure

Secondary outcome:

Rate of complete ST-segment resolution on ECG obtained 30 minutes after the procedure

Enzymatic Infarct size by creatine kinase-MB (area under curve)

Myocardial infarct size measured by MRI

Major adverse cardiac events (a composite of death, myocardial infarction, severe heart failure, or stent thrombosis)

The extent of microvascular obstruction measured by MRI

The number of segments with >75% of infarct transmurality measured by MRI

The presence of myocardial hemorrhage measured by MRI

Detailed description: 1. 1. Ticagrelor versus Clopidogrel 1. 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). 2. One of limitations of primary PCI is distal embolization and effective antiplatelet therapy is needed in patients with STEMI. 3. 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. 4. 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. 5. 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 1. 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. 2. 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. 3. 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 1. To investigate the effects of ticagrelor on myocardial salvage in patients with STEMI undergoing primary PCI compared with clopidogrel 2. To investigate the effects of morphine-induced cardioprotection during primary PCI in patients with STEMI

Minimum age: 20 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

1. 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

2. 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

Hyeon-Cheol Gwon, MD/PhD, Phone: 82-2-3410-6653, Email: hcgwon62@gmail.com

Samsung Medical Center, Seoul, Gang nam-Gu, Ilwon-Dong 135-710, Korea, Republic of; Recruiting
Hyeon-Cheol Gwon, PhD, Phone: 82-2-3410-6653, Email: hcgwon@skku.edu
Joo-Yong Hahn, PhD, Phone: 82-2-3410-6653, Email: jy.hahn@samsung.com

Starting date: September 2012
Last updated: October 19, 2014