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

Official title

Pharmacogenomic Markers of Clopidogrel Resistance in Malaysian CAD Patients: Clinical Efficacy and Economic Evaluation of CYP2C19 Genotype-Guided Therapy

Overview

The goal of this clinical trial is to learn if the pilot intervention of CYP2C19 genotype-guided antiplatelet therapy works to reduce the occurrence of cardiovascular events after Percutaneous Coronary Intervention (PCI) done in coronary artery disease patients. It will also learn about the comparison between clopidogrel and ticagrelor. The main questions it aims to answer are: To compare the impact of CYP2C19 genotype-guided antiplatelet therapy, universal use of clopidogrel and ticagrelor treatment on platelet reactivity. To compare the impact of CYP2C19 genotype-guided antiplatelet therapy, universal use of clopidogrel and ticagrelor treatment on the risk of major adverse cardiovascular events (MACE) among newly recruited stable CAD patients. Participants will: Take drug clopidogrel or ticagrelor, based on the random group allocation every day for 1 month. One group of patients will undergone CYP2C19 genetic test for genotype-guided antiplatelet therapy, whether clopidogrel or ticagrelor. Visit the clinic post 30 days of PCI for follow-ups and platelet function tests.

Detailed description

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.

Interventions

• Genetic CYP2C19 genotype-guided antiplatelet therapy
  A panel of genes including CYP2C19\*2 (rs4244285) and CYP2C19\*3 (rs4986893) will be genotyped using the real-time PCR and the expected turnover time will be 48 hours. Patients who are identified to have reduced function CYP2C19 allele will receive 90 mg ticagrelor and patients with wild-type CYP2C19 allele will receive clopidogrel 75 mg in the next scheduled dose. The switching done from clopidogrel to ticagrelor is supported by Antiplatelet Therapy Switching Clinician Guideline, whereby in the

Primary outcome measures

• Major adverse cardiovascular events (MACE) [Time frame: From enrollment to 30 days post PCI]

Secondary outcome measures (1)

• Platelet Reactivity Index (PRI) [Time frame: From enrollment to at least 2 weeks of maintenance dose]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Health services research

Study locations

Malaysia · 1 center

• Hospital Pakar Universiti Sains Malaysia — Kota Bharu

Identifiers

NCT: NCT06759272 · 311224

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗