Impact of CYP2C19 Genotype-guided Clopidogrel and Ticagrelor Treatment on Platelet Function Test and Metabolomics Profile
Status:
Completed
Trial end date:
2022-08-22
Target enrollment:
Participant gender:
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 that influence 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 the use of
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 is not affected by the CYP2C19 LOF polymorphism. However, in clinical
practice, the implementation of the genotype-guided selection strategy for the oral P2Y12
inhibitor has been limited despite intensive research efforts in this aspect. 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 impeded physicians' ability
to prescribe a more effective and personalized antiplatelet therapy. Therefore, we need to
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. The aim
of this study is to investigate the Impact of pharmacogenetics-guided clopidogrel and
ticagrelor treatment on platelet function test and its association with metabolomics in CAD
patients undergoing PCI in Malaysia