Low-dose of Ticagrelor and Standard-dose Clopidogrel on Platelet Effects in Chinese Patients With Stable CAD.

Low-dose of Ticagrelor and Standard-dose Clopidogrel on Platelet Effects in Chinese Patients With Stable Coronary Artery Disease: a Randomized, Single-blind, Crossover Clinical Study

Ticagrelor has been demonstrated to provide a more rapid and more powerful inhibition of platelet aggregation compared with clopidogrel in coronary artery disease (CAD) patients. However, current guidelines recommend ticagrelor 90 mg twice daily might not be suitable for patients of Chinese. Therefore, the investigators performed this study to observe the efficacy of 60-mg ticagrelor in comparison to 75-mg clopidogrel in Chinese patients with stable CAD.

Study Overview

• Status: Completed
• Conditions: Platelet Reactivity
• Intervention / Treatment: Drug: low-dose ticagrelor; Drug: Clopidogrel

Detailed Description

Dual antiplatelet therapy with aspirin and a P2Y12 receptor antagonist is the established standard of care in ACS patients. Although a popular P2Y12 receptor inhibitor, clopidogrel is not the most potent antiplatelet agent due to its metabolic activation. Metabolic activation of clopidogrel depends on multiple cytochrome P450 (CYP) enzymes, including CYP2C19, which can delay the onset of its activity; in addition, some populations carry a reduced-function allele of the CYP2C19 gene. Notably, poor drug metabolism of clopidogrel is more common in Asian populations compared with other international regions, due to the prevalence of CYP2C19 reduced-function alleles in these patients. A recent study indicated that Asians might have different adverse event profiles (thrombophilia and bleeding) and "therapeutic window" compared with white subjects, suggesting that regional differences may influence the altered response of clopidogrel to the onset of thrombotic events.

Ticagrelor is an orally administered, reversibly-binding, direct-acting P2Y12 receptor antagonist used clinically for the prevention of atherothrombotic events in patients with ACS. Guidelines give a recommendation on the use of dual antiplatelet therapy (DAPT) support ticagrelor 90 mg twice daily over clopidogrel 75 mg daily in addition to aspirin in ACS patients with or without ST-segment elevation. Increasing evidence indicated that Asian patients showed higher active metabolite exposure rates and stronger pharmacodynamic responses than their Caucasian subjects when treated with the same oral doses of prasugrel .In Korea and Japan, it has been reported that low doses of ticagrelor might have a more potent inhibition of platelet aggregation (IPA) than clopidogrel in healthy subjects and patients with stable coronary artery disease, respectively .In our previous study, the investigators found that half-dose ticagrelor produced similar inhibitory effects on platelet aggregation as standard-dose ticagrelor and exerted significantly stronger effects than clopidogrel in patients with ACS and one-quarter standard-dose ticagrelor provided greater degree of platelet inhibition than clopidogrel in patients with stable CAD. Furthermore, standard-dose ticagrelor (180mg loading dose [LD], then 90mg twice daily) has a significant increase in the risk of bleeding and incidence rate of dyspnea, and that higher discontinuation rates due to adverse effects compared to clopidogrel. A recent study demonstrated that maximum plasma concentration and area under the plasma concentration-time curve of ticagrelor (90 mg twice daily) and its active metabolite (AR-C124910XX) tended to be approximately 40% higher in healthy Chinese volunteers compared with Caucasian subjects. Notably, poor drug metabolism of clopidogrel is more common in Asian populations compared with other international regions, due to the prevalence of CYP2C19 reduced-function alleles. The data suggested that a low dose of ticagrelor might be more appropriate for Chinese patients.

The objectives of this study were to evaluate the effects of ticagrelor (60.0mg daily) in comparison to clopidogrel (75mg daily) on platelet reactivity in Chinese patients with stable CAD.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • California
    • Harbin, California, China, 150001
      • VerifyNow

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients were eligible to participate if they were aged ≥18 years and ≤ 75 Years
• Subjects had documented stable CAD (defned as stable angina pectoris and objective evidence of CAD, a previous MI, or previous revascularization with percutaneous coronary intervention or coronary artery bypass grafting)
• Women were required to be postmenopausal or surgically sterile
• Patients who were taking clopidogrel or ticagrelor were required to discontinue these agents at least 14 days before randomization

Exclusion Criteria:

• Acute coronary syndrome (ACS)
• planned use of glycoprotein IIb/IIIa receptor inhibitors, adenosine diphosphate (ADP) receptor antagonists other than the study medication, or anticoagulant therapy during the study period
• platelet count <10*10^4/ul
• creatinine clearance rate < 30ml/min
• diagnosed as respiratory or circulatory instability (cardiac shock, severe congestive heart failure NYHA II-IV or left ventricular ejection fraction < 40%)
• a history of bleeding tendency
• allergy to aspirin, ticagrelor or clopidogrel
• diabetes patients

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: low-dose ticagrelor; To observe the safety and efficacy of low-dose ticagrelor in Chinese patients with Stable Coronary Artery Disease	Drug: low-dose ticagrelor; low-dose ticagrelor (60.0 mg once daily) for 7 days,followed by a 2-week washout period then a 7 days crossover phase of clopidogrel (75mg once daily).; Drug: Clopidogrel; clopidogrel (75mg once daily) for 7 days,followed by a 2-week washout period then a 7 days crossover phase of low-dose ticagrelor (60.0 mg once daily).
Active Comparator: clopidogrel; To observe the safety and efficacy between low-dose ticagrelor and standard-dose clopidogrel.	Drug: low-dose ticagrelor; low-dose ticagrelor (60.0 mg once daily) for 7 days,followed by a 2-week washout period then a 7 days crossover phase of clopidogrel (75mg once daily).; Drug: Clopidogrel; clopidogrel (75mg once daily) for 7 days,followed by a 2-week washout period then a 7 days crossover phase of low-dose ticagrelor (60.0 mg once daily).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The platelet inhibition ratio.	Verifynow was used to measure platelet inhibition ratio.	up to 2 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The platelet aggregation ratio.	Light transmission aggregometry method was used to measure platelet aggregation ratio.	up to 2 months

Collaborators and Investigators

• Sponsor: First Affiliated Hospital of Harbin Medical University
• Investigators: Principal Investigator: Yue Li, professor, First Affiliated Hospital of Harbin Medical University

Study record dates

Study Major Dates

• Study Start (Actual): August 29, 2018
• Primary Completion (Actual): February 28, 2019
• Study Completion (Actual): February 28, 2019

Study Registration Dates

• First Submitted: September 4, 2018
• First Submitted That Met QC Criteria: September 18, 2018
• First Posted (Actual): September 20, 2018

Study Record Updates

• Last Update Posted (Actual): December 21, 2021
• Last Update Submitted That Met QC Criteria: December 20, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: Ticagrelor; coronary artery disease; clopidogrel; platelet reactivity
• Additional Relevant MeSH Terms: Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Disease; Coronary Artery Disease; 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: CHD-201845

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No