Impact of CYP2C19 Genotype-guided Clopidogrel and Ticagrelor Treatment on Platelet Function Test and Metabolomics Profile

Impact of CYP2C19 Genotype-guided Clopidogrel and Ticagrelor Treatment on Platelet Function Test and Metabolomics Profile Among Coronary Artery Disease (CAD) Patients Undergoing Percutaneous Coronary Intervention (PCI)

Several studies have shown that pharmacodynamic (PD) response varies between patients treated with clopidogrel and that individuals with reduced response have an increased risk of recurrent ischemic events, particularly in patients undergoing percutaneous coronary intervention. This is due to several factors influencing the response to clopidogrel, including genetic variations of the cytochrome P450 (CYP) 2C19 enzyme. Loss of function (LOF) carriers of the CYP2C19 gene are associated with the decreased generation of the active metabolite clopidogrel and decreased platelet inhibition, which translates to an increased rate of adverse cardiovascular events, particularly in the setting of percutaneous coronary intervention (PCI). Thus, drug regulatory authorities have cautioned about the decreased efficacy of clopidogrel among individuals with CYP2C19 LOF carriers and suggested using alternative therapies to inhibit p2Y12. Ticagrelor is a new generation P2Y12 receptor inhibitor with greater efficacy for PD and reduced rates of ischemic events compared with clopidogrel and are not affected by the CYP2C19 LOF polymorphism. However, in clinical practice, the genotype-guided selection strategy for the oral P2Y12 inhibitor has been limited despite intensive research efforts. This is due to the interaction of cardiovascular risk factors and molecular and biochemical complications that lead to poor response to platelet inhibitor therapy, which impedes physicians' ability to prescribe a more effective and personalized antiplatelet therapy. Therefore, we must move away from traditional approaches and use integrated systems biology study designs and disciplines to bridge the gap between genotype, phenotype, disease manifestation and/or recurrence. Pharmacometabolomics is a rapidly developing field that takes advantage of a systems pharmacology approach to probe the molecular pathways involved in drug response variability to understand metabolic changes and identify novel biomarkers that can be used to predict response more comprehensively. Using profiles of changes in metabolites can help establish drug exposure fingerprints and clarify the determinants of drug response. This study aims to investigate the Impact of pharmacogenetics-guided clopidogrel and ticagrelor treatment on platelet function test and its association with metabolomics in Coronary Artery Disease (CAD) patients undergoing PCI in Malaysia

Study Overview

• Status: Completed
• Conditions: Coronary Artery Disease (CAD)
• Intervention / Treatment: Drug: Clopidogrel; Drug: Ticagrelor

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 4

Contacts and Locations

Study Locations

• Malaysia
  • Penang
    • George Town, Penang, Malaysia, 10990
      • Department of Cardiology, Penang General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Males or females.
• Age more than 18 and below 80 years.
• Patients with stable CAD planned for elective PCI.
• Thienopyridine naive for at least two weeks before admission.

Exclusion Criteria:

• Pregnant
• Any urgent/emergent coronary angiography procedure that would not allow for genetic testing to be performed before PCI
• Considered at high risk for bleeding
• History of ischemic or hemorrhagic stroke or transient ischemic attack
• . Current treatment with drugs interfering with CYP3A4 metabolism (to avoid interaction with Ticagrelor): ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, and telithromycin
• History of ACS within 12 months of screening or need for revascularization
• Any acute or chronic unstable condition.
• Liver disease.
• Have increased bleeding risk, e.g., recent gastrointestinal bleed, uncontrolled high blood pressure, low platelet count.
• History of intolerance or allergy to ticagrelor or clopidogrel
• Patient on dialysis.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Clopidogrel; The primary endpoint is the non-inferiority in platelet reactivity of clopidogrel versus ticagrelor among CYP2C19*2 or *3 allele carriers.	Drug: Clopidogrel; Comparison of platelet reactivity between clopidogrel and ticagrelor; Other Names: Plavix; Drug: Ticagrelor; Comparison of platelet reactivity between clopidogrel and ticagrelor; Other Names: Brilinta
Experimental: Ticagrelor; The primary endpoint is the non-inferiority in platelet reactivity of clopidogrel versus ticagrelor among CYP2C19 CYP2C19*2 or *3 allele carriers.	Drug: Clopidogrel; Comparison of platelet reactivity between clopidogrel and ticagrelor; Other Names: Plavix; Drug: Ticagrelor; Comparison of platelet reactivity between clopidogrel and ticagrelor; Other Names: Brilinta

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Platelet Reactivity	The primary endpoint is a Platelet reactivity index (PRI) measured by the ELISA-Based Vasodilator-Associated Stimulated Phosphoprotein Phosphorylation Assay 4hours/hospital discharge post randomization to clopidogrel vs ticagrelor. Vasodilator-stimulated phosphoprotein (VASP) measurement is the most specific approach to evaluate the extent to which P2Y12 receptors are functionally blocked by a P2Y12 antagonist.	4 hours post loading dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Participants With Any Event From the Composite of All-cause Mortality, and MI	Participants with death from any cause or MI. If no event, censoring occurs at the earliest of patient withdrawal of consent or date of the scheduled withdrawal from therapy	Randomization up to 30 days
Participants With MI Event	Participants with MI event. If no event, censoring occurs at the earliest of patient withdrawal consent or date of scheduled withdrawal from therapy	Randomization up to 30 days
Participants With Major or Minor Bleeding	Participants with major (fatal/life-threatening or other) or minor bleed based on need for treatment, number of transfusions, hemoglobin decrease, and other factors	First dosing up to 30 days

Collaborators and Investigators

• Sponsor: Universiti Sains Malaysia
• Investigators: Principal Investigator: Baharudin Ibrahim, Faculty of Pharmacy, University of Malaya, Kuala Lumpur 50603, Federal Territory Malaysia; Principal Investigator: Nur Aizati Athirah Daud, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang 11800, Malaysia; Principal Investigator: Mohammed Ahmed Akkaif, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang 11800, Malaysia; Principal Investigator: Muhammed Ali Sk Abdul Kader, Department of Cardiology, Penang General Hospital, Penang 10990, Malaysia

Publications and helpful links

General Publications

• Akkaif MA, Daud NAA, Sha'aban A, Ng ML, Abdul Kader MAS, Noor DAM, Ibrahim B. The Role of Genetic Polymorphism and Other Factors on Clopidogrel Resistance (CR) in an Asian Population with Coronary Heart Disease (CHD). Molecules. 2021 Apr 1;26(7):1987. doi: 10.3390/molecules26071987.
• Akkaif MA, Sha'aban A, Daud NAA, Yunusa I, Ng ML, Sk Abdul Kader MA, Noor DAM, Ibrahim B. Coronary Heart Disease (CHD) in Elderly Patients: Which Drug to Choose, Ticagrelor and Clopidogrel? A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Cardiovasc Dev Dis. 2021 Sep 30;8(10):123. doi: 10.3390/jcdd8100123.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2019
• Primary Completion (Actual): August 22, 2022
• Study Completion (Actual): August 22, 2022

Study Registration Dates

• First Submitted: August 23, 2022
• First Submitted That Met QC Criteria: August 23, 2022
• First Posted (Actual): August 26, 2022

Study Record Updates

• Last Update Posted (Actual): September 1, 2022
• Last Update Submitted That Met QC Criteria: August 26, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary 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: 56795

Drug and device information, study documents

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