Impact of CYP2C19 Genotype-guided Approach in Antiplatelet Therapy on Platelet Reactivity Index Among Coronary Artery Disease (CAD) Patients

Clopidogrel, a prodrug that inhibits platelet aggregation, is widely used in patients undergoing percutaneous coronary interventions to prevent recurrent cardiovascular events. However, clopidogrel resistance has emerged as a great concern, whereby it causes inadequate platelet inhibition and leads to antiplatelet treatment failure with prevalence as high as 44% in Asian population. Due to various established evidence from pharmacogenomics studies, US FDA has issued a black-box warning notifying that CYP2C19 polymorphisms may impaired the ability of a patient to convert clopidogrel into its active metabolite. Currently, the availability of newer P2Y12 receptor inhibitors has prompted medical professionals to consider genotype-guided treatment, which may include escalation or de-escalation of the antiplatelet based on CYP2C19 genetic result. We hypothesize that CYP2C19 genotype guided therapy will reduce the occurrence of MACE and improve platelet reactivity to prevent clopidogrel resistance. The estimated sample size required for pilot intervention study is 120 patients. Knowledge of potential pharmacogenetic markers for clopidogrel resistance, clinical efficacy and cost evaluation of genotype-guided antiplatelet therapy will provide a comprehensive insight into adopting such approach in a real routine clinical setting.

Inclusion criteria

• Males or females
• Aged between 18 to 80 years old
• Patients presents with stable CAD or acute coronary syndrome (ACS)
• Eligible for percutaneous coronary intervention (PCI)
• Willing to provide DNA sample via blood drawn for genotyping and platelet reactivity assessment
• Willing and able to provide informed written consent

Exclusion criteria

• Primary PCI or rescue PCI
• Any urgent/emergent coronary angiography procedure that would not allow for genetic testing to be performed before PCI
• Failure of index PCI
• Patient or physician refusal to enroll in the study
• Patient with known CYP2C19 genotype prior to randomization
• Planned revascularization of any vessel within 30 days post-index procedure and/or of the target vessel(s) within 12 months post-procedure
• Anticipated discontinuation of clopidogrel or ticagrelor within the 12 months follow up period (e.g. for elective surgery)
• History of ischaemic or haemorrhagic stroke
• History of allergies to aspirin, ticagrelor, or clopidogrel
• Suffering from HIV or any blood transmitted disease.
• Considered at high risk of bleeding*
• Stage 5 chronic kidney disease (CKD) based on the National Kidney Foundation, Kidney disease quality outcome initiative (KDQOI) definition (Levey et al., 2005), or those who were on haemodialysis
• Pre-existing liver cirrhosis
• Pregnant women at any stage of gestation
• Patient is receiving immunosuppressive therapy or has known immunosuppressive or autoimmune disease (e.g. human immunodeficiency virus, systemic lupus erythematous, etc.)
• Patient is receiving chronic anticoagulation therapy (i.e. vitamin K antagonist, direct thrombin inhibitor, Factor Xa inhibitor)
• Concomitant use of simvastatin/lovastatin >40 mg qd
• Concomitant use of potent CYP3A4 inhibitors (atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole) or inducers (carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, and rifapentine)
• Non-cardiac condition limiting life expectancy to less than a year, per judgement of physician