Antithrombotic Effects of Ticagrelor Versus Clopidogrel

Phase 4

Completed

Conditions: Acute Coronary Syndrome

Interventions: Drug: Clopidogrel + ASA + Bivalirudin
Drug: Ticagrelor + ASA + Bivalirudin

Registration Number: NCT01642238

Lead Sponsor: Juan J Badimon

Brief Summary: The purpose of this study is to determine whether treatment with ticagrelor (plus aspirin and bivalirudin) is more effective than treatment with clopidogrel (plus aspirin and bivalirudin).

Detailed Description: The HORIZONS-AMI Trial compared the effectiveness of heparin plus a glycoprotein IIb/IIIa inhibitor (GPI) versus bivalirudin in acute myocardial infarction (AMI) patients undergoing stent deployment 1. Overall the data showed benefits associated with the bivalirudin treatment with lower rates of all-cause mortality, cardiac mortality, re-infarction and non-CABG related major bleeding; However, the data seems to indicate a non-significant increase in acute stent thrombosis in the bivalirudin group. This observation seems to suggest the potential benefits of adding an antiplatelet agent to bivalirudin. A study by Dangas G et al found that in the HORIZONS-AMI patients, the group receiving 600 mg loading-dose of clopidogrel had significantly lower 30-day unadjusted rates of mortality, reinfarction and stent thrombosis than the 300 mg loading-dose group, without increase in bleeding rate. Furthermore, even though the benefits of bivalirudin were independent of the clopidogrel loading dose; the 600mg LD was associated with more benefits with both anticoagulation regimens. Similar observations have been reported in the ARMYDA-6 MI study.

It is our hypothesis that using ticagrelor instead of clopidogrel, given its more potent and faster activity, would have greater antithrombotic activity and therefore may reduce the rate of acute stent thrombosis when administered in combination with bivalirudin + ASA in AMI patients. To investigate this hypothesis, we will compare the antithrombotic effects of ticagrelor with clopidogrel, when administered in combination with ASA and bivalirudin, in healthy human volunteers using a cross-over study design. The antithrombotic activity will be assessed pre-treatment and 2-hours and 24-hours post treatment, using methodologies including Badimon Perfusion chamber, VerifyNow P2Y12 assay, platelet aggregation with Multiplate Analyzer and Thromboelastography.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 15

Inclusion Criteria

Male or female volunteers between 18 and 65 years old.
Body mass index (BMI) 18 - 30 kg/m2 inclusive.
Healthy as assessed by a detailed medical history and physical examination.
Laboratory est results within the normal range.
Ability to provide signed informed consent.

Exclusion Criteria

History of clinically relevant disease, bleeding, acute infectious disease or signs of acute illness.
Allergy or hypersensitivity to aspirin or thienopyridines, or atopy diagnosed by a physician.
Use of medication within one month prior to study drug administration.
History of drug abuse or alcohol consumption >20 g/day.
Inability to abstain from intensive muscular effort or sport competition.
Loss of >400 mL blood or blood donation within 3 months.
Positive serology for hepatitis B (HBs Ag) or hepatitis C.
Conditions associated with hemorrhagic risk.
Positive pregnancy test.

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Clopidogrel + ASA + Bivalirudin	Clopidogrel + ASA + Bivalirudin	Single loading dose of Clopidogrel (600 mg given as two 300 mg tablets), plus single dose of ASA (one 81 mg tablet) + bivalirudin administered as 0.75 mg/kg IV bolus followed by 1.75 mg/kg/hour for 1 hour.
Ticagrelor + ASA + Bivalirudin	Ticagrelor + ASA + Bivalirudin	Single loading dose of Ticagrelor (180 mg given as two 90 mg tablets), plus single dose of ASA (one 81 mg tablet) + bivalirudin administered as 0.75 mg/kg IV bolus followed by 1.75 mg/kg/hour for 1 hour.

Primary Outcome Measures

Name	Time	Method
Platelet-thrombus Formation in an ex Vivo Model of Thrombosis	Pre-treatment baseline and 24 hrs post treatment	Change in thrombus size at 24 hours as compared to Pre-treatment baseline, where a positive change represents a decrease in thrombus size.

Secondary Outcome Measures

Name	Time	Method
Platelet Reactivity	24-hours post-treatment	Platelet reactivity measured by VerifyNowP2Y12 assay measuring percent inhibition
Blood Thrombogenicity	24-hours post-treatment	Coagulation times, assessed using the ROTEM thromboelastometry