CYP2C19 Genetic Testing for Oral P2Y12 Inhibitor Therapy: A Scientific Statement From the American Heart Association

Abstract

There is significant variability in the efficacy and safety of oral P2Y12 inhibitors, which are used to prevent ischemic outcomes in common diseases such as coronary and peripheral arterial disease and stroke. Clopidogrel, a prodrug, is the most used oral P2Y12 inhibitor and is activated primarily after being metabolized by a highly polymorphic hepatic cytochrome CYP2C219 enzyme. Loss-of-function genetic variants in CYP2C219 are common, can result in decreased active metabolite levels and increased on-treatment platelet aggregation, and are associated with increased ischemic events on clopidogrel therapy. Such patients can be identified by CYP2C19 genetic testing and can be treated with alternative therapy. Conversely, universal use of potent oral P2Y12 inhibitors such as ticagrelor or prasugrel, which are not dependent on CYP2C19 for activation, has been recommended but can result in increased bleeding. Recent clinical trials and meta-analyses have demonstrated that a precision medicine approach in which loss-of-function carriers are prescribed ticagrelor or prasugrel and noncarriers are prescribed clopidogrel results in reducing ischemic events without increasing bleeding risk. The evidence to date supports CYP2C19 genetic testing before oral P2Y12 inhibitors are prescribed in patients with acute coronary syndromes or percutaneous coronary intervention. Clinical implementation of such genetic testing will depend on among multiple factors: rapid availability of results or adoption of the concept of performing preemptive genetic testing, provision of easy-to-understand results with therapeutic recommendations, and seamless integration in the electronic health record.

Keywords: AHA Scientific Statements; genetic testing; platelet inhibitors.

Figure 1.. Reported race and ethnicity data from selected major clinical outcome trials using clopidogrel and in which CYP2C19 status was reported.

This figure compares the relative percent distribution of reported race and ethnicity from study participants included in major retrospective and prospective clinical outcome studies of CYP2C19 genotype-guided antiplatelet therapy. For reference, the demographic characteristics of each study were compared with data obtained from the NCDR (National Cardiovascular Data Registry). The race and ethnicity distribution of patients who underwent percutaneous coronary intervention (PCI) in the United States was as follows: 86.5% White or European, 8.8% Black or African American, 2.8% Asian, 0.7% Native American, 0.3% Pacific Islander, and 5.8% Hispanic or Latino ethnicity. GIANT indicates Genotyping Infarct Patients to Adjust and Normalize Thienopyridine Treatment; IAC-PCI, Individual Applications of Clopidogrel After Percutaneous Coronary Intervention; IGNITE, Implementing Genomics in Practice; PHARMCLO, Pharmacogenetics of Clopidogrel in Patients With Acute Coronary Syndromes; PHARM-ACS, Registry Study on Drug Therapy and Clinical Outcomes in Patients With Acute Coronary Syndrome; PLATO, Platelet Inhibition and Patient Outcomes; TAILOR-PCI, Tailored Antiplatelet Initiation to Lessen Outcomes Due to Decreased Clopidogrel Response After Percutaneous Coronary Intervention; and TRITON-TIMI 38, Therapeutic Outcomes by Optimizing Platelet Inhibition by Prasugrel–Thrombolysis in Myocardial Infarction 38. Reprinted from Nguyen et al. Copyright © 2022 Nguyen, Cavallari, Rossi, Stouffer and Lee. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Figure 2.. A proposed algorithm using CYP2C19 pharmacogenetic testing to individualize oral P2Y₁₂ inhibitor therapy in patients with coronary artery disease on the basis of meta-analysis results.

LOF indicates loss of function. Modified from Pereira et al with permission from Elsevier. Copyright © 2021.