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

NCT ID: NCT02201667

Last Updated: 2014-08-04

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE4
• Total Enrollment: 444 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-08-31
• Study Completion Date: 2016-10-31

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.

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).

Conditions

Acute Coronary Syndrome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Ticagrelor

Intervention Type: DRUG

180-mg loading dose followed by 90mg twice daily for 30 days

Aspirin

Intervention Type: DRUG

300mg loading dose aspirin and followed by 100mg once daily

PCI

Intervention Type: PROCEDURE

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

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.

Group Type: ACTIVE_COMPARATOR

clopidogrel

Intervention Type: DRUG

300-mg loading dose followed by 75mg once daily for 30 days.

Aspirin

Intervention Type: DRUG

300mg loading dose aspirin and followed by 100mg once daily

PCI

Intervention Type: PROCEDURE

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

Interventions

Ticagrelor

180-mg loading dose followed by 90mg twice daily for 30 days

Intervention Type: DRUG

clopidogrel

300-mg loading dose followed by 75mg once daily for 30 days.

Intervention Type: DRUG

Aspirin

300mg loading dose aspirin and followed by 100mg once daily

Intervention Type: DRUG

PCI

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

Intervention Type: PROCEDURE

Other Intervention Names

BRILINTA; Plavix; Aspirin Enteric Coated Tablets

Eligibility 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

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;

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

RenJi Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Ben He, MD,PhD

Role: PRINCIPAL_INVESTIGATOR

Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University

Locations

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

Shanghai, Shanghai Municipality, China

Countries

China

Central Contacts

Ben He, MD,PhD

Role: CONTACT

heben1025@hotmail.com

68383609

Facility Contacts

Ben He, MD,PhD

Role: primary

heben1025@hotmail.com

68383609

References

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Other Identifiers

ISSBRIL0208

Identifier Type: -

Identifier Source: org_study_id