Top Things to Know: CYP2C19 Genetic Testing for Oral P2Y12 Inhibitor Therapy
Prepared by Prepared by: Naveen Pereira, MD and Katherine Sheehan, PhD.
- Clopidogrel, the most prescribed oral P2Y12 inhibitor, is a prodrug that is primarily metabolized by the hepatic cytochrome P450 system enzyme CYP2C19, which activates its ability to inhibit blood platelet aggregation.
- Loss of CYP2C19 enzymatic function due to genetic variation in the CYP2C19 gene that encodes it reduces the amount of clopidogrel activated. Carriers of the variation are common, with higher prevalence in some racial and ethnic populations.
- When carriers of the CYP2C19 loss of function (LOF) gene variant are treated with clopidogrel they have lower levels of active drug, increased platelet aggregation, and increased ischemic events compared to non-carriers, especially during percutaneous coronary intervention, acute coronary syndromes, and stroke.
- Ticagrelor or prasugrel are not dependent on the CYP2C19 enzyme for activation, thus when treated with these oral P2Y12 inhibitors, CYP2C19 LOF gene carriers experience reduced ischemic events compared to those carriers treated with clopidogrel.
- CYP2C19 genetic guided therapy consists of LOF carriers receiving ticagrelor or prasugrel and non-carriers receiving clopidogrel. Clinical results have shown this to be non-inferior to universal ticagrelor or prasugrel use by reducing major adverse cardiovascular events along with reducing bleeding episodes.
- The FDA has approved point-of-care commercial assays of CYP2C19 genotype that provide results with short turnaround times and high accuracy, sensitivity, specificity, and reproducibility.
- Clinical implementation of CYP2C19 genetic testing to guide the selection of oral P2Y12 inhibitors will be dependent on additional trial results, and factors such as adoption of point-of-care genetic testing yielding timely results, integration of these results into the electronic health record, education to support the understanding and interpretation of these results, and reimbursement by insurance companies.
Citation
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; on behalf of the 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 inhibitortherapy: a scientific statement from the American Heart Association. Circulation. Published June 20, 2024. doi: 10.1161/CIR.0000000000001257