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

July 31, 2014 updated by: RenJi Hospital

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）

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.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Anticipated)

444

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • China
    • Shanghai
      • Shanghai, Shanghai, China, 200127
        • Ren Ji Hospital Afflited to School of Medicine, Shanghai Jiao Tong University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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;

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / 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 Names:
  • BRILINTA
Drug: Aspirin
300mg loading dose aspirin and followed by 100mg once daily
Other Names:
  • 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: Aspirin
300mg loading dose aspirin and followed by 100mg once daily
Other Names:
  • Aspirin Enteric Coated Tablets
Procedure: PCI
PCI is performed according to indication for early PCI according to 2012 Chinese NSTE-ACS guideline recommendation
Drug: clopidogrel
300-mg loading dose followed by 75mg once daily for 30 days.
Other Names:
  • Plavix

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Within 0 to 24 hours after randomization

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Within 0 to 48 hours after enrollment
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.
At 30th day after randomization
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
At 30th day after randomization

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Within 0 to 30 dys after randomization
Other adverse events
Time Frame: Within 0 to 30 days after randomization
Including any other adverse events (AEs) during the study.
Within 0 to 30 days after randomization

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

RenJi Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

August 1, 2014

Primary Completion (ANTICIPATED)

August 1, 2016

Study Completion (ANTICIPATED)

October 1, 2016

Study Registration Dates

First Submitted

July 24, 2014

First Submitted That Met QC Criteria

July 24, 2014

First Posted (ESTIMATE)

July 28, 2014

Study Record Updates

Last Update Posted (ESTIMATE)

August 4, 2014

Last Update Submitted That Met QC Criteria

July 31, 2014

Last Verified

July 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ISSBRIL0208

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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