Genetic testing in patients undergoing percutaneous coronary intervention: rationale, evidence and practical recommendations

Abstract

Introduction: Clopidogrel is the most frequently utilized P2Y₁₂ inhibitor and is characterized by broad interindividual response variability resulting in impaired platelet inhibition and increased risk of thrombotic complications in a considerable number of patients. The potent P2Y₁₂ inhibitors, prasugrel and ticagrelor, can overcome this limitation but at the expense of an increased risk of bleeding. Genetic variations of the cytochrome P450 (CYP) 2 C19 enzyme, a key determinant in clopidogrel metabolism, have been strongly associated with clopidogrel response profiles prompting investigations of genetic-guided selection of antiplatelet therapy.

Areas covered: The present manuscript focuses on the rationale for the use of genetic testing to guide the selection of platelet P2Y₁₂ inhibitors among patients undergoing percutaneous coronary intervention (PCI). Moreover, a comprehensive appraisal of the available evidence and practical recommendations is provided.

Expert commentary: Implementation of genetic testing as a strategy to guide the selection of therapy can result in escalation (i.e. switching to prasugrel or ticagrelor) or de-escalation (i.e. switching to clopidogrel) of P2Y₁₂ inhibiting therapy. Most recent investigations support the clinical benefit of a genetic guided selection of antiplatelet therapy in patients undergo PCI. Integrating the results of genetic testing with clinical and procedural variables represents a promising strategy for a precision medicine approach for the selection of antiplatelet therapy among patients undergoing PCI.

Keywords: Genetics; antiplatelet therapy; bleeding; p2y12 inhibitors; percutaneous coronary intervention; thrombosis.

Figure 1:. Mechanisms of action of oral platelet P2Y₁₂ inhibitors

P2Y₁₂ is a chemoreceptor for adenosine diphosphate that belongs to the Gi class of a group of G protein-coupled purinergic receptors. The G protein’s α subunit, causes a decrease in cAMP and PKA that leads to an increase of VASP and a decrease of VASP-P levels. VASP stimulates and VASP-P inhibits platelet activation and stabilization. G protein’s β subunit increases PI3K that promotes granule secretion and increases PKB/akt resulting in platelet activation and stabilization. Thus, inhibition of the P2Y₁₂ receptor suppresses platelet activation. Three oral platelet P2Y₁₂ inhibitors (clopidogrel, prasugrel and ticagrelor) are primarily used in clinical practice. P-glycoprotein (P-gp) in an efflux pump that can return some of the thienopyridine compound to the intestinal lumen. After intestinal absorption, 85% of the oral prodrug clopidogrel is hydrolyzed in the blood and liver by esterases (carboxylase) to an inactive metabolite while the remaining 15% is converted to the active metabolite by hepatic CYP isoenzymes, through a two-step oxidation process. By contrast, esterases are part of prasugrel’s activation pathway, and prasugrel is oxidized more efficiently to its active metabolite via a single CYP- dependent step. Ticagrelor is a direct acting agent which reversibly inhibits platelet activation by allosteric modulation of the P2Y₁₂ receptor; 20-30% of ticagrelor induced antiplatelet effects are attributed to a CYP-derived compound with similar potency compared to the parent drug. Abbreviations: AC: adenylyl cyclase; CYP: cytochrome P450; gp: glycoprotein; PKA: protein kinase A; VASP: vasodilator-stimulated phosphoprotein; P: phosphorylated; PI3K: Phosphoinositide 3-kinase; PKB/akt: protein kinase B.

Figure 2:. Clinical outcomes with unguided P2Y₁₂ inhibitor selection (i.e. clopidogrel versus prasugrel or ticagrelor) and with guided clopidogrel versus unguided prasugrel or ticagrelor.

Randomized controlled trials comparing potent P2Y₁₂ inhibitors versus clopidogrel showed reduced ischemic events but increased bleeding (blue). Genetic testing allows to stratify patients into two groups: CYP2C19 LoF allele carriers (left) and noncarriers (right). Among CYP2C19 LoF allele carriers, selective use of potent P2Y₁₂ inhibitors would result in similar outcomes as compared to a default potent P2Y₁₂ inhibitor strategy (green) while guided use of clopidogrel among CYP2C19 LoF allele noncarriers would result in reduced bleeding and similar ischemic events (yellow). Abbreviations: LoF: loss of function; CYP: cytochrome P450.

Figure 3:. Escalation or de-escalation strategies following genetic testing

According to the P2Y₁₂ inhibitor used in the conventional therapy arm, the guided selection of P2Y₁₂ inhibitor can result in a strategy of escalation (left) or de-escalation (right) of therapy. Abbreviations: LoF: loss of function; CYP: cytochrome P450.

Figure 4:. Integrated approach towards personalized selection of antiplatelet therapy

Integrating the results of genetic testing with clinical and procedural variables represents a promising strategy for a precision medicine approach for the selection of antiplatelet therapy among patients undergoing percutaneous coronary interventions. Abbreviations: ultrarapid (UM), rapid (RM), normal (NM), intermediate (IM), and poor (PM) metabolizers.