Clinical trial NCT05516784: Impact of CYP2C19 Genotype-guided Clopidogrel and Ticagrelor Treatment on Platelet Function Test and Metabolomics Profile
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Coronary Artery Disease (CAD)
Lead sponsor: Universiti Sains Malaysia
Sponsor class: OTHER
First posted: 2022-08-26
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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


Eligibility criteria: 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.

Primary outcomes:
measure: Platelet Reactivity
timeFrame: 4 hours post loading dose
Secondary outcomes:
measure: Participants With Any Event From the Composite of All-cause Mortality, and MI
timeFrame: Randomization up to 30 days
measure: Participants With MI Event
timeFrame: Randomization up to 30 days
measure: Participants With Major or Minor Bleeding
timeFrame: First dosing up to 30 days
Other outcomes:
Locations:
city: George Town
country: Malaysia
facility: Department of Cardiology, Penang General Hospital
state: Penang
Study officials:
affiliation: Faculty of Pharmacy, University of Malaya, Kuala Lumpur 50603, Federal Territory Malaysia
name: Baharudin Ibrahim
role: PRINCIPAL_INVESTIGATOR
affiliation: School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang 11800, Malaysia
name: Nur Aizati Athirah Daud
role: PRINCIPAL_INVESTIGATOR
affiliation: School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang 11800, Malaysia
name: Mohammed Ahmed Akkaif
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Cardiology, Penang General Hospital, Penang 10990, Malaysia
name: Muhammed Ali Sk Abdul Kader
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.