Study of Effects of Ticagrelor on Microparticles and Micro-RNA in NSTE-ACS (TIGER-M)

Effects of TIcaGREloR on Circulating Microparticles and Micro-RNAs in Patients With Non ST Elevation Acute Coronary Syndromes

The aim of the study is to learn more about the pathophysiology of acute coronary syndrome (ACS) and to evaluate the mechanisms responsible of the action and benefits of ticagrelor.

Ticagrelor is an oral and reversible inhibitor of P2Y12 receptor. Few information is available about the action of ticagrelor on the molecules involved in thrombogenesis and platelets activation in ACS.

The aim of this study is to evaluate the mechanisms of ticagrelor action in vivo.

It was observed that patients with myocardial infarction have higher blood levels of microparticles than patients with unstable angina or stable angina.

The investigators assumed that ticagrelor benefits are represented by a reduction of microparticle levels, a marker of endothelial dysfunction in patients with cardiovascular disease, and by a modification in microRNAs pattern, fragments of mRNA that have a regulatory action in various cellular processes (such as proliferation, differentiation, growth and cellular death) and represent new biomarkers in ACS.

Study Overview

• Status: Terminated
• Conditions: Non ST Segment Elevation Acute Coronary Syndrome
• Intervention / Treatment: Drug: Ticagrelor; Drug: Clopidogrel

Detailed Description

Ticagrelor is an oral, reversibly binding P2Y12 receptor inhibitor that yields, in a dose-dependent fashion, greater and more consistent inhibition of platelet aggregation than standard regimens of clopidogrel in patients with stable atherosclerotic disease and ACS. However, little information is available regarding its complex effect on thrombogenesis and platelet activation in acute coronary syndromes setting. It has been widely demonstrated the potential role of MP in several biologic processes known to take part to pathophysiology of coronary syndromes, such as inflammation, coagulation and apoptosis. Recent studies focused on miRNAs' regulatory activity of several cellular processes, such as proliferation, differentiation, development, and cell death, and on their role as biomarkers in ACS. The investigators suppose that the observed major efficacy of ticagrelor is related to its actions on MP and microRNAs. Considering the major clinical effectiveness shown by ticagrelor in comparison with clopidogrel, the investigators hypothesize a more pronounced MP levels reduction as a possible mechanism for ticagrelor clinical benefits. Moreover, on the basis of the last evidences of microRNA involvement in the ACS pathophysiology, the investigators aim to assess the effect of ticagrelor on microRNA expression, in order to provide evidences for pleiotropic actions of this drug, which could partially explain its major efficacy in reduction of cardiovascular events in ACS patients.

In summary, principal hypothesis of the study are:

• Considering that ticagrelor is a stronger P2Y12 receptor inhibitor than clopidogrel, the investigators suppose that an increased inhibition of P2Y12 receptor by ticagrelor could reduce circulating levels of platelet and endothelial MP.
• In consideration of the observed role of microRNAs in expression of P2Y12 receptor, the investigators speculate that patient's susceptibility to P2Y12 receptor inhibitors could be influenced by microRNAs levels. Moreover, the investigators suppose that ticagrelor could influence microRNAs levels, considered as marker of cardiovascular risk

Aims of the study are:

• to assess MP levels variation in Non ST-Elevation Acute Coronary Syndromes (NSTE-ACS) patients treated with ticagrelor in addition to low or high acetyl-salicylic acid (ASA), in comparison with clopidogrel+ASA treatment, to demonstrate that major clinical efficacy of ticagrelor could be partially attributed to its influence on release of MP, that have an important role in coronary instability.
• to evaluate microRNAs levels variation in Non ST-Elevation Acute Coronary Syndromes (NSTE-ACS) patients treated with ticagrelor in addition to low or high ASA, in comparison with clopidogrel+ASA treatment, and to study possible correlations between microRNAs and MP levels, supposing that the ability of ticagrelor in reduced MP level could be related with microRNAs expression.

• Study Type: Interventional
• Enrollment (Anticipated): 55
• Phase: Phase 4

Contacts and Locations

Study Locations

• Italy
  • Rome, Italy, 00168
    • Policlinico "A.Gemelli"

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• NSTE-ACS
• Male, 50-80 years old
• Female, postmenopausal age

Exclusion Criteria:

• Female, premenopausal age
• autoimmune disease
• infectious disease
• neoplasms
• diabetes
• chronic renal failure
• moderate or severe liver insufficiency
• GRACE risk score>140
• ACS or cerebrovascular accidents in previous three months
• in-stent restenosis
• surgery or trauma in previous three months
• active bleeding
• fibrinolytic therapy within 24 hours before randomization
• need for oral anticoagulation therapy
• an increased risk of bradycardia
• drugs study hypersensitivity (including aspirin)
• co-administration of ticagrelor or clopidogrel with strong CYP3A4 inhibitors

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Ticagrelor; Ticagrelor: oral, 180 mg once for the first dose then 90 mg twice a day	Drug: Ticagrelor; Comparison of Ticagrelor with another anti-platelet drug (Clopidogrel); Other Names: Brilique
Active Comparator: Clopidogrel; Clopidogrel: oral, 300 or 600 mg once for the first dose, 75 mg once a day	Drug: Clopidogrel; Comparison of Clopidogrel with another anti-platelet drug (Ticagrelor); Other Names: Plavix

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Micro-RNA and microparticles	up to three months

Collaborators and Investigators

• Sponsor: Catholic University of the Sacred Heart
• Investigators: Principal Investigator: Luigi M Biasucci, Professor, Catholic University of the Sacred Heart

Study record dates

Study Major Dates

• Study Start: November 1, 2012
• Primary Completion (Actual): December 1, 2015
• Study Completion (Anticipated): November 1, 2016

Study Registration Dates

• First Submitted: February 21, 2014
• First Submitted That Met QC Criteria: February 25, 2014
• First Posted (Estimate): February 26, 2014

Study Record Updates

• Last Update Posted (Estimate): July 26, 2016
• Last Update Submitted That Met QC Criteria: July 25, 2016
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Keywords: Micro-RNA, Microparticles, Ticagrelor, NSTE-ACS
• Additional Relevant MeSH Terms: Pathologic Processes; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Disease; Syndrome; Acute Coronary Syndrome; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Ticagrelor; Clopidogrel
• Other Study ID Numbers: D5130L00028