Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Mar 23:9:850028.
doi: 10.3389/fcvm.2022.850028. eCollection 2022.

Genotype-Guided Use of P2Y12 Inhibitors: A Review of Current State of the Art

Abdullah Al-Abcha  1 , Yasser Radwan  1 , Danielle Blais  2 , Ernest L Mazzaferri Jr  2 , Konstantinos Dean Boudoulas  2 , Essa M Essa  3 , Richard J Gumina  2
Affiliations
Review

Genotype-Guided Use of P2Y12 Inhibitors: A Review of Current State of the Art

Abdullah Al-Abcha et al. Front Cardiovasc Med. .

Abstract

The pharmacodynamics of the purinergic receptor type Y, subtype 12 (P2Y12) inhibitors has evolved. Our understanding of the metabolism of P2Y12 inhibitors has revealed polymorphisms that impact drug metabolism and antiplatelet efficacy, leading to genetic testing guided therapy. In addition, assays of platelet function and biochemistry have provided insight into our understanding of the efficacy of "antiplatelet" therapy, identifying patients with high or low platelet reactivity on P2Y12 therapy. Despite the data, the implementation of these testing modalities has not gained mainstream adoption across hospital systems. Given differences in potency between the three clinically available P2Y12 inhibitors, the balance between thrombotic and bleeding complications must be carefully considered, especially for the large proportion of patients at higher risk for bleeding. Here we review the current data for genetic and functional testing, risk assessment strategies, and guidelines for P2Y12 inhibitors guided therapy.

Keywords: P2Y12; function; genotype; guided therapy; platelet.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Overview of the biotransformation of P2Y12 inhibitors. Clopidogrel and prasugrel are prodrugs that require bioactivation via cytochrome P450 (CYP) to their active metabolite that can inhibit the P2Y12 receptor in a competitive manner. The two steps of bioactivation of clopidogrel are CYP dependent, while only one step of prasugrel bioactivation is CYP dependent. Ticagrelor undergoes biotransformation to another metabolite via CYP but both ticagrelor and its metabolite can inhibit the P2Y12 receptor in a non-competitive manner. CYP enzymes highlighted in red have more significant roles in each of the steps. Created with BioRender.com. CYP, cytochrome P450, P2Y12 R, P2Y12 receptor.
Figure 2
Figure 2
Cytochrome P450 genotypes and phenotypes. The Clinical Pharmacogenetics Implementation Consortium categorized the level of CYP2C19 function into five different phenotypes; poor metabolizers (PM), intermediate metabolizers (IM), normal metabolizers (NM), rapid metabolizers (RM), and ultrarapid metabolizers (UM).
Figure 3
Figure 3
Therapeutic window of different platelet function testing assays. An expert consensus statement has defined the therapeutic window of platelet reactivity using different platelet function testing assays. Measurements higher than the therapeutic window are defined as high platelet reactivity (HPR), and patients with HPR are associated with high ischemic risk while measurements lower than the therapeutic window are defined as low platelet reactivity (LPR), and patients with LPR are at high bleeding risk. Created with BioRender.com. HPR, high platelet reactivity; LPR, low platelet reactivity; PRU, platelet reactivity unit; PRI, platelet reactivity index; TEG, thromboelastography; U, unit; VASP, vasodilator-stimulated phosphoprotein.
Figure 4
Figure 4
ABCD-Gene scoring system. The ABCD-GENE scoring system was developed to predict patients who are on P2Y12 inhibitors and at risk of high platelet reactivity (HPR). The scoring system was internally and externally validated. Patients with ABCD-Gene score ≥ 10 are at higher risk of all-cause death and major cardiovascular adverse events (MACE) at 1-year compared to those with a score <10. Created with BioRender.com (99). CKD, chronic kidney disease; CYP2C19, cytochrome P450 2C19; GFR, glomerular filtration rate; LOF, loss of function.
See this image and copyright information in PMC

References

    1. Levine GN, Bates ER, Bittl JA, Brindis RG, Fihn SD, Fleisher LA, et al. . 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. (2016) 134:e123–55. 10.1161/CIR.0000000000000453 - DOI - PubMed
    1. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, et al. . Prasugrel versus clopidogrel in patients with acute coronary syndromes: commentary. N Engl J Med. (2007) 357:2001–15. 10.1056/NEJMoa0706482 - DOI - PubMed
    1. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. . Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes. N Engl J Med. (2009) 361:1045–57. 10.1056/NEJMoa0904327 - DOI - PubMed
    1. Neumann FJ, Sousa-Uva M, Ahlsson A, Alfonso F, Banning AP, Benedetto U, et al. . 2018 ESC/EACTS Guidelines on myocardial revascularization. Euro Heart J. (2019) 40:87–165. 10.1093/eurheartj/ehy855 - DOI - PubMed
    1. Kumbhani DJ, Cannon CP, Beavers CJ, Bhatt DL, Cuker A, Gluckman TJ, et al. . 2020 ACC expert consensus decision pathway for anticoagulant and antiplatelet therapy in patients with atrial fibrillation or venous thromboembolism undergoing percutaneous coronary intervention or with atherosclerotic cardiovascular disease: a report of Journal of the American College of Cardiology. J Am Coll Cardiol. (2021) 77:629–58. 10.1016/j.jacc.2020.09.011 - DOI - PubMed