Pharmacogenetics of P2Y₁₂ receptor inhibitors

Abstract

Oral P2Y12 inhibitors are commonly prescribed for cardiovascular disease and include clopidogrel, prasugrel, and ticagrelor. Each of these drugs has its strengths and weaknesses. Prasugrel and ticagrelor are more potent inhibitors of platelet aggregation and were shown to be superior to clopidogrel in preventing major adverse cardiovascular events after an acute coronary syndrome and percutaneous coronary intervention (PCI) in the absence of genotyping. However, both are associated with an increased risk for non‐coronary artery bypass‐related bleeding. Clopidogrel is a prodrug requiring bioactivation, primarily via the CYP2C19 enzyme. Approximately 30% of individuals have a CYP2C19 no function allele and decreased or no CYP2C19 enzyme activity. Clopidogrel‐treated carriers of a CYP2C19 no function allele have decreased exposure to the clopidogrel active metabolite and lesser inhibition of platelet aggregation, which likely contributed to reduced clopidogrel efficacy in clinical trials. The pharmacogenetic data for clopidogrel are most robust in the setting of PCI, but evidence is accumulating for other indications. Guidance is available from expert consensus groups and regulatory agencies to assist with integrating genetic information into P2Y12 inhibitor prescribing decisions, and CYP2C19 genotype‐guided antiplatelet therapy after PCI is one of the most common examples of clinical pharmacogenetic implementation. Herein, we review the evidence for pharmacogenetic associations with clopidogrel response and outcomes with genotype‐guided P2Y12 inhibitor selection and describe guidance to assist with pharmacogenetic implementation. We also describe processes for applying genotype data for P2Y12 inhibitor therapy selection and remaining gaps in the field. Ultimately, consideration of both clinical and genetic factors may guide selection of P2Y12 inhibitor therapy that optimally balances the atherothrombotic and bleeding risks.

Pharmacogenomics of Cardiovascular Drugs for Atherothrombotic, Thromboembolic and Atherosclerotic Risk

“…Therefore, most of the benefit related to tailored antiplatelet therapy is achieved in the first few months after PCI, which is consistent with previous studies that have shown a shorter DAPT as potential optimal management [20,21]. It is reasonable to assume that the efficacy and safety of DAPT may be maximized beyond a one-size-fits-all strategy by switching patients who are poor metabolizers to novel P2Y12 inhibitors, which can be effective regardless of the CYP2C19 genotype [22], and switching patients who are efficient metabolizers back to clopidogrel. Nevertheless, experts in the field have recognized the usefulness of genotype-guided strategies without endorsing its use in routine clinical practice.…”

Effect of cytochrome P450 2C19 (CYP2C19) gene polymorphism and clopidogrel reactivity on long term prognosis of patients with coronary heart disease after PCI

“…The presence of CYP2C19*2 and/or CYP2C19*3 mutation genes in patients with intermediate metabolizer and poor metabolizer suggested an impact on clopidogrel responsiveness, res-ulting in clopidogrel resistance. [30,31] Previous studies have also identified CYP2C19 gene polymorphism as predictors of clopidogrel resistance. [32][33][34] Application of Antiplatelet Drugs in Patients with Coronary Heart Disease in the Real World Currently, the prognostic benefit of dual antiplatelet therapy (aspirin and clopidogrel) following acute coronary syndromes (ACS) has been well established.…”

Dual Antiplatelet Therapy: A Concise Review for Clinicians

“…Ticagrelor, a non-prodrug, binds reversibly to the adenosine diphosphate (ADP) P2Y12 receptor, inhibiting platelets without demanding metabolic activation [18]. It has a shorter half-life and needs to be taken twice daily.…”