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Review
. 2024 Sep 17;84(12):1107-1118.
doi: 10.1016/j.jacc.2024.06.038.

Genotype-Guided Antiplatelet Therapy: JACC Review Topic of the Week

Wout W A van den Broek  1 , Brenden S Ingraham  2 , Naveen L Pereira  2 , Craig R Lee  3 , Larisa H Cavallari  4 , Jesse J Swen  5 , Dominick J Angiolillo  6 , Jurriën M Ten Berg  7
Affiliations
Review

Genotype-Guided Antiplatelet Therapy: JACC Review Topic of the Week

Wout W A van den Broek et al. J Am Coll Cardiol. .

Abstract

The clinical efficacy and safety of antiplatelet agents vary among patients. Consequently, some patients are at increased risk of recurrent ischemic events during treatment. This interindividual variability can be a result of genetic variants in enzymes that play a role in drug metabolism. The field of pharmacogenomics explores the influence of these genetic variants on an individual's drug response. Tailoring antiplatelet treatment based on genetic variants can potentially result in optimized dosing or a change in drug selection. Most evidence supports guiding therapy based on the CYP2C19 allelic variants in patients with an indication for dual antiplatelet therapy. In ticagrelor-treated or prasugrel-treated patients, a genotype-guided de-escalation strategy can reduce bleeding risk, whereas in patients treated with clopidogrel, an escalation strategy may prevent ischemic events. Although the clinical results are promising, few hospitals have implemented these strategies. New results, technological advancements, and growing experience may potentially overcome current barriers for implementation in the future.

Keywords: antiplatelet therapy; coronary artery disease; genotype-guided therapy; percutaneous coronary intervention; personalized medicine; pharmacogenomics.

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Conflict of interest statement

Funding Support and Author Disclosures Drs Lee, Cavallari, and Angiolillo are supported by National Institutes of Health grant R01 HL149752. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Dr Pereira has received grants from the National Heart, Lung, and Blood Institute. Dr Lee has received grants from the National Heart, Lung, and Blood Institute; and has received support from Werfen. Dr Cavallari has received grants from the National Heart, Lung, and Blood Institute; and has received support from Werfen. Dr Angiolillo has received consulting fees or honoraria from Abbott, Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, CSL Behring, Daiichi-Sankyo, Eli Lilly, Faraday, Haemonetics, Janssen, Merck, Novo Nordisk, PhaseBio, PLx Pharma, Pfizer, and Sanofi; and his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Faraday, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co, Merck, Novartis, Osprey Medical, Renal Guard Solutions, and the Scott R. MacKenzie Foundation. Dr ten Berg has received grants from the Netherlands Organization for Health Research and Development, a Dutch government institution called ZonMw, and AstraZeneca; and has received personal fees from AstraZeneca, Boehringer Ingelheim, Bayer, Ferrer, Pfizer, and Merck, outside the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

Figure 1.
Figure 1.. Biotransformation and metabolization of the different P2Y12-inhibitors agents.
After absorption, ticagrelor is a direct-acting drug, and is partially metabolized by CYP3A4. Prasugrel is a prodrug that requires a one-step cytochrome (CYP) P450-based (mainly by CYP3A4 and CYP2B6) conversion to its active metabolite. Clopidogrel is a prodrug that necessitates a two-step oxidation process by multiple CYP-enzymes to become active, of which CYP2C19 has the greatest contribution.
Figure 2.
Figure 2.. Flow diagram illustrating the genotype guided escalation and de-escalation P2Y12-inhibitor strategies
The escalation strategy aims to reduce ischemic events by identifying clopidogrel-treated patients with a loss-of-function (LOF) allele and switching them to a more potent P2Y12 inhibitor. The de-escalation strategy seeks to minimize bleeding by identifying CYP2C19 normal metabolizers among prasugrel or ticagrelor-treated patients and switching them to clopidogrel, which is associated with a lower bleeding risk.
Figure 3.
Figure 3.. Forest plot of genotype guided de-escalation and escalation strategies vs. standard DAPT for MACE in patients with CAD.
This forest plot illustrates the impact of both genotype guided de-escalation and genotype guided escalation strategies on major adverse cardiovascular events (MACE) based on studies comparing a genotype guided group with a group of patients treated with standard dual antiplatelet therapy (DAPT). To illustrate the uptake of the genotype guided intervention, the columns in grey provide additional information on the use of clopidogrel and the distribution of CYP2C19 loss-of-function (LOF) allele carriers in both groups, if available. CI, confidence interval; Con., control arm; Inv., intervention arm; HR, hazard ratio. *the hazard ratio is based on the subgroup analysis in acute coronary syndrome patients only **the p-value was not provided in the publication
Figure 4.
Figure 4.. Forest plot of genotype guided de-escalation and escalation strategies vs. standard DAPT for bleeding outcomes in patients with CAD.
This forest plot illustrates the impact of both genotype guided de-escalation and genotype guided escalation strategies on non-major clinically relevant or major bleeding based on studies comparing a genotype guided group with a group of patients treated with standard dual antiplatelet therapy (DAPT). To illustrate the uptake of the genotype guided intervention, the columns in grey provide additional information on the use of clopidogrel and the distribution of CYP2C19 loss-of-function (LOF) allele carriers in both groups, if available. CI, confidence interval; Con., control arm; Inv., intervention arm; HR, hazard ratio.
Central Illustration.
Central Illustration.. Therapeutic Recommendations for Genotype Guided Antiplatelet Therapy in Patients with Coronary Artery Disease.
This flow diagram outlines the therapeutic recommendations for acute coronary syndrome (ACS) patients and chronic coronary syndrome (CCS) patiensts undergoing percutaneous coronary intervention (PCI) based on current guidelines. For ACS patients, the initial treatment determines if a genotype-guided de-escalation or escalation strategy is advised. Special considerations below illustrate the settings where each strategy offers the highest value. 1 Based on a Class IIb Level of Evidence A recommendation in the 2020 ESC Guidelines for the management of ACS in patients presenting without persistent ST-segment elevation 2 Recommendation is classified as strong 3 Based on a Class IIb recommendation (weak) 4 Based on the 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease and 2017 International Expert Consensus on Switching Platelet P2Y12 Receptor Inhibiting Therapies ESC, European Society of Cardiology; NM, normal metabolizers; IM, intermediate metabolizers; PM, poor metabolizers; CPIC, Clinical Pharmacogenetics Implementation Consortium; DPWG, Dutch Pharmacogenetics Working Group; ACC/AHA, American College of Cardiology/American Heart Association
See this image and copyright information in PMC

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