Clopidogrel Therapy and Genotype

Clopidogrel (brand name Plavix) is an antiplatelet medicine that reduces the risk of myocardial infarction (MI) and stroke in individuals with acute coronary syndrome (ACS), and in individuals with atherosclerotic vascular disease (indicated by a recent MI or stroke, or established peripheral arterial disease) (1). Clopidogrel is also indicated in combination with aspirin for individuals undergoing percutaneous coronary interventions (PCI), including stent placement. The effectiveness of clopidogrel depends on its conversion to an active metabolite, which is accomplished by the cytochrome P450 2C19 (CYP2C19) enzyme. Individuals who have 2 loss-of-function copies of the gene are classified as CYP2C19 poor metabolizers (PM). Individuals with a CYP2C19 PM phenotype have significantly reduced enzyme activity and cannot activate clopidogrel via CYP2C19, which means the drug will have a reduced antiplatelet effect. Approximately 2% of Caucasians, 4% of African Americans, 14% of Chinese, and 57% of Oceanians are CYP2C19 PMs (2). The effectiveness of clopidogrel is also reduced in individuals who are CYP2C19 intermediate metabolizers (IM). These individuals have one loss-of-function copy of , with either one normal function copy or one increased function copy. The frequency of the IM phenotype is more than 45% in individuals of East Asian descent, more than 40% in individuals of Central or South Asian descent, 36% in the Oceanian population, approximately 30% in individuals of African descent, 20–26% in individuals of American, European, or Near Eastern descent, and just under 20% in individuals of Latino descent (2). The 2022 FDA-approved drug label for clopidogrel includes a boxed warning on the diminished antiplatelet effect of clopidogrel in CYP2C19 PMs (Table 1). The warning states that tests are available to identify individuals who are CYP2C19 PMs, and to consider the use of another platelet P2Y (purinergic receptor P2Y, G-protein coupled 12) inhibitor in individuals identified as CYP2C19 PMs. The 2022 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for clopidogrel recommends that for individuals with ACS or non-ACS indications who are undergoing PCI, being treated for peripheral arterial disease (PAD), or stable coronary artery disease following MI, an alternative antiplatelet therapy (for example, prasugrel or ticagrelor) should be considered for CYP2C19 PMs if there is no contraindication (Table 2) (3). Similarly, CPIC strongly recommends that CYP2C19 IMs should avoid clopidogrel for ACS or PCI but makes no recommendations for other cardiovascular indications (Table 2). For neurovascular indications, CPIC recommends avoidance of clopidogrel for CYP2C19 PMs and consideration of alternative medications for both IMs and PMs if not contraindicated (Table 3) (3). The Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP) have also made antiplatelet therapy recommendations based on genotype. For individuals with ACS who undergo PCI, they recommend an alternative antiplatelet agent in PMs, and for IMs they recommend choosing an alternative antiplatelet agent or doubling the dose of clopidogrel to 150 mg daily dose, 600 mg loading dose (Table 4) (4).