American Heart Association Advocates Genetic Testing to Personalize Oral P2Y12 Inhibitor Therapy for CV patients

Published in Circulation journal, the statement underscores the importance of personalized medicine in managing cardiovascular diseases, particularly in the context of antiplatelet therapy. The CYP2C19 gene plays a crucial role in metabolizing clopidogrel and other P2Y12 inhibitors, influencing their effectiveness in preventing blood clots and reducing the risk of adverse cardiovascular events.

Clopidogrel, a primary oral P2Y12 inhibitor, undergoes activation through metabolism by the enzyme CYP2C19 from its prodrug form. However, a significant portion of the population, with varying prevalence across different racial and ethnic groups, carries a genetic variation in the CYP2C19 gene that reduces its enzyme function. This genetic variant has long been associated with increased platelet aggregation and higher rates of ischemic events among patients undergoing clopidogrel therapy.

Despite these findings, current guidelines in the US and Europe concerning antiplatelet therapy for coronary artery disease (CAD) have not universally recommended routine genetic testing. However, selective use of genetic testing has been acknowledged in specific scenarios such as dual antiplatelet therapy (DAPT) adjustment following percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS).

Dr. Naveen L. Pereira, chair of the writing group from Mayo Clinic in Rochester, MN, highlighted that the motivation behind the new American Heart Association (AHA) statement stems from the need to incorporate findings from recent clinical trials (POPular Genetics, TAILOR-PCI, PHARMCLO, and IAC-PCI), observational studies, and meta-analyses into guideline updates. These studies have provided crucial insights into the clinical implications of CYP2C19 genetic testing on treatment outcomes in CAD patients.

Loss-of-function genetic variants in CYP2C19 are prevalent and can lead to reduced levels of active metabolites, resulting in increased platelet aggregation during treatment with clopidogrel and higher rates of ischemic events. Genetic testing for CYP2C19 allows the identification of patients with these variants who may benefit from alternative therapies.

Conversely, guidelines suggest considering potent oral P2Y12 inhibitors like ticagrelor or prasugrel universally, as they do not rely on CYP2C19 for activation. However, these alternatives have been associated with a higher risk of bleeding. Recent clinical trials and meta-analyses indicate that a personalized medicine approach, where individuals with loss-of-function variants receive ticagrelor or prasugrel and noncarriers receive clopidogrel, can reduce ischemic events without increasing bleeding complications.

The evidence strongly supports the integration of CYP2C19 genetic testing into clinical practice before initiating oral P2Y12 inhibitor therapy in patients undergoing acute coronary syndromes or percutaneous coronary intervention.

Dr. Pereira emphasized that adopting genetic testing will hinge on several factors, including the timely availability of results, acceptance of preemptive genetic testing strategies, clear and actionable result reporting with treatment recommendations, and seamless integration into electronic health records. These considerations are crucial for the successful implementation of precision medicine in cardiovascular care.

Reference:

Pereira NL, Cresci S, Angiolillo DJ, Batchelor W, Capers Q 4th, Cavallari LH, Leifer D, Luzum JA, Roden DM, Stellos K, Turrise SL, Tuteja S; American Heart Association Professional/Public Education and Publications Committee of the Council on Genomic and Precision Medicine; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Peripheral Vascular Disease; and Stroke Council. CYP2C19 Genetic Testing for Oral P2Y12 Inhibitor Therapy: A Scientific Statement From the American Heart Association. Circulation. 2024 Jun 20. doi: 10.1161/CIR.0000000000001257. Epub ahead of print. PMID: 38899464.