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Efficacy of Ticagrelor vs Clopidogrel in High-risk NSTE-ACS Patients Undergoing Early PCI

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ClinicalTrials.gov Identifier: NCT02201667
Recruitment Status : Unknown
Verified July 2014 by RenJi Hospital.
Recruitment status was:  Not yet recruiting
First Posted : July 28, 2014
Last Update Posted : August 4, 2014
Sponsor:
Information provided by (Responsible Party):
RenJi Hospital

Study Description
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Brief Summary:

The goal of acute coronary syndrome (ACS) therapy is to successfully restore both epicardial blood flow and myocardial perfusion. Percutaneous coronary intervention (PCI) has been documented as being the most effective method for restoration of epicardial blood flow. However, epicardial blood flow does not necessarily equate to myocardial perfusion. Clopidogrel binds irreversibly to platelet P 2 Y 12 receptors to inhibit platelet aggregation, with main limitations of slow onset, prevention of recovery of platelet functions, and interindividual variability. Clinical pharmacology and early dose-finding studies suggested a faster onset and greater and more consistent inhibition of platelet aggregation (IPA) with ticagrelor compared with clopidogrel. Two currently main methods of angiographic assessment of myocardial perfusion includes thrombolysis in myocardial infarction(TIMI) myocardial perfusion grading (TMPG) and myocardial blush grading (MBG). These established myocardial perfusion parameters have been widely used in various important trials and are reported to be highly useful in predicting clinical outcomes. However, visual assessment of these methods is categorical, subjective, and operator dependent of contrast in the myocardium using cine-angiographic frame-counting, was developed by the investigators' center to quantify myocardial tissue- level perfusion and was proved to be a predictive value on clinical prognosis.

Thus, the investigators aim to initiate an open-label study evaluating the acute efficacy of treatment with ticagrelor versus clopidogrel on myocardial tissue-level perfusion assessed by Myocardial Perfusion Frame Count(TMPFC) and magnetic resonance imaging (MRI) in patients with high-risk non-ST elevation acute coronary syndrome (NSTE-ACS) undergoing early percutaneous coronary intervention (PCI) .

The investigators hypothesize that compared with clopidogrel, ticagrelor can significantly improve myocardial perfusion assessed by Myocardial Perfusion Frame Count(TMPFC) in high-risk non-ST elevation acute coronary syndrome (NSTE-ACS) patients undergoing early percutaneous coronary intervention (PCI), without additional increased major bleeding.


Condition or disease Intervention/treatment Phase
Acute Coronary Syndrome Drug: Ticagrelor Drug: clopidogrel Drug: Aspirin Procedure: PCI Phase 4

Detailed Description:

The goal of acute coronary syndrome (ACS) therapy is to successfully restore both epicardial blood flow and myocardial perfusion. Percutaneous coronary intervention (PCI) has been documented as being the most effective method for restoration of epicardial blood flow. However, epicardial blood flow does not necessarily equate to myocardial perfusion; not every patient with thrombolysis in myocardial infarction(TIMI) 3 flow after successful percutaneous coronary intervention (PCI) achieves effective myocardial tissue-level perfusion. Although epicardial thrombolysis in myocardial infarction(TIMI) 3 flow could be restored in >90% of acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) , normalization of myocardial perfusion was achieved less frequently, with detrimental impacts on survival.

Clopidogrel, the most widely used antiplatelet agent in acute coronary syndrome (ACS), is a thienopyridine prodrug, which is inactive until in undergoes biotransformation into its active metabolite, which then binds irreversibly to platelet P 2 Y 12 receptors. This irreversible binding means that the receptors are inhibited for the lifespan of the platelet. The main limitations of clopidogrel administration include slow onset, prevention of recovery of platelet functions, and interindividual variability.

Clinical pharmacology and early dose-finding studies suggested a faster onset and greater and more consistent inhibition of platelet aggregation (IPA) with ticagrelor compared with clopidogrel. ONSET/OFFSET study showed that in patients with stable coronary artery disease on aspirin, ticagrelor demonstrates a rapid onset of pharmacological effect, as demonstrated by a mean platelet aggregation (IPA) for ticagrelor at 0.5 h after 180 mg loading dose of about 41%, with the maximum platelet aggregation (IPA) effect of 87.9-89.6% by 2-4 hours post dose. A total of 90% of patients had final extent Inhibition of platelet aggregation (IPA) >70% by 2 h post-dose. The high inhibition of platelet aggregation (IPA) effect of ticagrelor (between 87% and 89%) was maintained for 2-8 hours. Ticagrelor might overcome the slow-onset limitation of clopidogrel and bring extra benefit for improving myocardial perfusion in the acute phase of acute coronary syndrome (ACS) when undergoing early percutaneous coronary intervention (PCI).

Currently, there are two main methods of angiographic assessment of myocardial perfusion: Thrombolysis in myocardial infarction (TIMI) myocardial perfusion grading (TMPG), described by Gibson et al. and myocardial blush grading (MBG), described by Van't Hof et al. These established myocardial perfusion parameters, myocardial perfusion grading (TMPG), and myocardial blush grading (MBG), have been widely used in various important trials and are reported to be highly useful in predicting clinical outcomes. However, visual assessment of these methods is categorical, subjective, and operator dependent. Thrombolysis in myocardial infarction(TIMI) Myocardial Perfusion Frame Count (TMPFC), a novel and objective method that measures the filling and clearance of contrast in the myocardium using cine-angiographic frame-counting, was developed by the investigators' center to quantify myocardial tissue- level perfusion and was proved to be a predictive value on clinical prognosis.

Thus, the investigators aim to initiate an open-label study evaluating the acute efficacy of treatment with ticagrelor versus clopidogrel on myocardial tissue-level perfusion assessed by Myocardial Perfusion Frame Count (TMPFC) and magnetic resonance imaging (MRI) in patients with high-risk non-ST elevation acute coronary syndrome (NSTE-ACS) undergoing early percutaneous coronary intervention (PCI).

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 444 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-label Study Evaluating the Acute Efficacy of Treatment With Ticagrelor Versus Clopidogrel on Myocardial Tissue-level Perfusion Assessed by TMPFC and MRI in Patients With High-risk NSTE-ACS Undergoing Early PCI（EARLY-MYO II）
Study Start Date : August 2014
Estimated Primary Completion Date : August 2016
Estimated Study Completion Date : October 2016

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Arms and Interventions
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Arm Intervention/treatment
Experimental: Ticagrelor group
Patients wil be given 180 mg loading dose of ticagrelor and 300mg loading dose of aspirin followed by PCI, then will receive 90 mg ticagrelor twice daily with aspirin maintenance dose to 30 days after randomization.
 Drug: Ticagrelor
180-mg loading dose followed by 90mg twice daily for 30 days
Other Name: BRILINTA

Drug: Aspirin
300mg loading dose aspirin and followed by 100mg once daily
Other Name: Aspirin Enteric Coated Tablets

Procedure: PCI
PCI is performed according to indication for early PCI according to 2012 Chinese NSTE-ACS guideline recommendation
Active Comparator: Clopidogrel group
Patients will be given clopidogrel 300mg loading dose and 300mg loading dose of aspirin followed by PCI, then will receive 75mg clopidogrel once with aspirin maintenance dose to 30 days after randomization.
 Drug: clopidogrel
300-mg loading dose followed by 75mg once daily for 30 days.
Other Name: Plavix

Drug: Aspirin
300mg loading dose aspirin and followed by 100mg once daily
Other Name: Aspirin Enteric Coated Tablets

Procedure: PCI
PCI is performed according to indication for early PCI according to 2012 Chinese NSTE-ACS guideline recommendation


Outcome Measures
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Primary Outcome Measures :
  1. TIMI Myocardial Perfusion Frame Count (TMPFC) [ Time Frame: Within 0 to 24 hours after randomization ]
    The Myocardial Perfusion Frame Count (TMPFC) is developed to standardize and quantify myocardial perfusion by timing the filling and clearance of contrast in the myocardium using cine-angiographic frame-counting. The first frame of Myocardial Perfusion Frame Count (TMPFC) is defined as the frame that clearly demonstrates the first appearance of myocardial blush beyond the infarct-related artery (IRA) (F1). The last frame of Myocardial Perfusion Frame Count (TMPFC) is then defined as the frame where contrast or myocardial blush disappears (F2). TMPFC is therefore F2-F1 frame counts at filming rate of 15frames/sec.


Secondary Outcome Measures :
  1. Cardiac Magnetic Resonance Imaging [ Time Frame: At 30th day after randomization ]
    Cardiovascular MRI will be performed at 30th day, to detect microvascular obstruction (MO) and intramyocardial hemorrhage (IMH). Infarct size and myocardial strain will also be measured by the method previously described.

  2. Echocardiography [ Time Frame: At 30th day after randomization ]
    echocardiography will be performed within 24h post PCI and at 30th day to assess changes in left ventricular size and function

  3. Myocardial-specific isoenzyme of creatine kinase (CK-MB) enzyme levels peri-PCI [ Time Frame: Within 0 to 48 hours after enrollment ]
    Infarct size is measured by the myocardial-specific isoenzyme of creatine kinase (CK-MB) area under the curve, calculated by the linear-trapezoidal method. If the baseline or last value is missing, the corresponding value will be set to zero. For missing values of intermediate time points, linear interpolation is used.


Other Outcome Measures:
  1. Bleeding events: Incidence of bleeding events [ Time Frame: Within 0 to 30 dys after randomization ]
    Incidence of bleeding events, classified by TIMI criteria and GUSTO severity criteria.

  2. Other adverse events [ Time Frame: Within 0 to 30 days after randomization ]
    Including any other adverse events (AEs) during the study.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

For inclusion in the study subjects should fulfill the following criteria:

  1. Provision of informed consent prior to any study specific procedures;
  2. Men or women > 18 years of age, with documented evidence of non-ST segment elevation Acute Coronary Syndrome(ACS) in the 24 hours before randomisation;
  3. Hospitalized for high-risk non-ST segment elevation Acute Coronary Syndrome(ACS)(GRACE risk score>140) with indication for early percutaneous coronary intervention (PCI) according to 2012 Chinese non-S T segment elevation Acute Coronary Syndrome(ACS) guideline recommendation.

Exclusion Criteria:

Subjects should not enter the study if any of the following exclusion criteria are fulfilled:

  1. Evidence of cardiac rupture;
  2. History of major hemorrhage (intracranial, gastrointestinal, etc.);
  3. Active pathological bleeding;
  4. Acute or chronic hematologic disorder including a Hemoglobin less than 10 g/L or a platelet count less than 10×109/L before procedure;
  5. Contraindication against the use of clopidogrel and ticagrelor;
  6. Subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.
  7. Severe complication 7.1 Other diseases with life expectancy ≤12 months; 7.2 Any history of Severe renal or hepatic dysfunction(hepatic failure, cirrhosis, portal hypertension and active hepatitis); Neutropenia, thrombocytopenia ; Known acute pancreatitis; 7.3 Arterial aneurysm, arterial/venous malformation and aorta dissection;
  8. Complex heart condition 8.1 PCI within previous 1 month or Previous coronary-artery bypass surgery(CABG); 8.2 History of myocardial infarction; 8.3 Previously known multivessel coronary artery disease not suitable for percutaneous coronary intervention (PCI);
  9. Previous enrolment in this study or treatment with an investigational drug or device under another study protocol in the past 30 days;
  10. Treatment with anticoagulants;
  11. Pregnancy or lactating;
  12. Body weight <40kg or >125kg;
  13. Known hypersensitivity to any drug that may appear in the study;
  14. Inability to follow the protocol and comply with follow-up requirements or any other reason that the investigator feels would place the patient at increased risk;
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02201667


Contacts
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Contact: Ben He, MD,PhD 68383609 heben1025@hotmail.com

Locations
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China, Shanghai
Ren Ji Hospital Afflited to School of Medicine, Shanghai Jiao Tong University
Shanghai, Shanghai, China, 200127
Contact: Ben He, MD,PhD    68383609    heben1025@hotmail.com   
Sponsors and Collaborators
RenJi Hospital
Investigators
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Principal Investigator: Ben He, MD,PhD Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University
More Information
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Publications:

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Responsible Party: RenJi Hospital
ClinicalTrials.gov Identifier: NCT02201667    
Other Study ID Numbers: ISSBRIL0208
First Posted: July 28, 2014    Key Record Dates
Last Update Posted: August 4, 2014
Last Verified: July 2014
Keywords provided by RenJi Hospital:
non-ST elevation acute coronary syndrome
myocardial perfusion
magnetic Resonance Imaging
antiplatelet
Additional relevant MeSH terms:
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Acute Coronary Syndrome
Myocardial Ischemia
Heart Diseases
Cardiovascular Diseases
Vascular Diseases
Aspirin
Clopidogrel
Ticagrelor
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
 Anti-Inflammatory Agents
Antirheumatic Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Platelet Aggregation Inhibitors
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Antipyretics
Purinergic P2Y Receptor Antagonists
Purinergic P2 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents