<p>Clinical Utility of CYP2C19 Genotype-Guided Antiplatelet Therapy in Patients at Risk of Adverse Cardiovascular and Cerebrovascular Events: A Review of Emerging Evidence</p>

Abstract

In patients undergoing percutaneous coronary intervention (PCI), the standard of care is dual antiplatelet therapy with a P2Y 12 inhibitor (clopidogrel, prasugrel, or ticagrelor) and aspirin. Current clinical practice guidelines now recommend more potent P2Y 12 inhibitors (prasugrel or ticagrelor) over clopidogrel in acute coronary syndrome (ACS). However, clopidogrel remains the most commonly prescribed P2Y 12 inhibitor in the setting of PCI and is also the preferred agent in the treatment and secondary prevention of stroke. Clopidogrel is a prodrug that requires bioactivation by the CYP2C19 enzyme. It has been shown that clopidogrel use in patients who are CYP2C19 no function allele carriers are associated with impaired antiplatelet inhibition and a higher risk of major adverse cardiovascular and cerebrovascular events. Compared to clopidogrel, prasugrel and ticagrelor clinical response is not impacted by CYP2C19 genotype. Even with a demonstrated increased risk of adverse outcomes in CYP2C19 no function allele carriers treated with clopidogrel, routine implementation of CYP2C19 genotyping to guide antiplatelet therapy selection has remained controversial and has not been widely adopted. Recent results from multiple prospective randomized and nonrandomized clinical trials investigating the use of CYP2C19 genotypeguided antiplatelet therapy following PCI have advanced the evidence base demonstrating the clinical utility of this strategy. Multiple recent studies have examined the effects of CYP2C19 genotype on clopidogrel outcomes in the setting of stroke and neurointerventional procedures. In this review, we discern the clinical utility of using CYP2C19 genotype testing to guide antiplatelet therapy prescribing by evaluating the impact of CYP2C19 genotypeguided selection of antiplatelet therapy on clinical outcomes, summarizing emerging data from cardiovascular and neurology clinical studies, and discussing implications for clinical practice guidelines, remaining knowledge gaps and future research directions.

Use of Clopidogrel and Proton Pump Inhibitors Alone or in Combinations in Persons with Diabetes in Denmark; Potential for CYP2C19 Genotype-Guided Drug Therapy

“…This treatment is widely used among the elderly and in persons with diabetes having a well-known high risk for cardiovascular diseases and increased platelet reactivity, i.e., secondary prophylaxis in cerebral infarction and acute coronary syndrome, respectively [ 3 , 5 , 6 , 7 ]. The treatments have been shown to inhibit blood clots in coronary artery disease, peripheral vascular disease and cerebrovascular disease, and to prevent myocardial infarction [ 3 , 8 , 9 ]. Although clinical practice guidelines now recommend prasugrel and ticagrelor over clopidogrel, in acute coronary syndrome patients undergoing percutaneous coronary interventions (PCI), clopidogrel remains the most widely used P2Y12 inhibitor [ 3 , 9 ].…”

“…The treatments have been shown to inhibit blood clots in coronary artery disease, peripheral vascular disease and cerebrovascular disease, and to prevent myocardial infarction [ 3 , 8 , 9 ]. Although clinical practice guidelines now recommend prasugrel and ticagrelor over clopidogrel, in acute coronary syndrome patients undergoing percutaneous coronary interventions (PCI), clopidogrel remains the most widely used P2Y12 inhibitor [ 3 , 9 ]. Clopidogrel is a prodrug that requires cytochrome P450 biotransformation, primarily by CYP2C19, to form an active metabolite that selectively and irreversibly inhibits the purinergic P2Y12 receptor and, thus, platelet aggregation for the life span of the platelet [ 3 , 9 ].…”

“…The concomitant use of clopidogrel and PPIs exhibit the Achilles’ heel of personalized medicine, referred to as phenoconversion, which describes the overlapping of DDI and DGI [ 31 , 32 ], also denoted to as drug–drug–gene interaction (DDGI). In spite of a strong association between CYP2C19 gene variants and outcomes related to antiplatelet therapy [ 9 , 33 ], only a few studies have actually dealt with DDGI in relation to concomitant use of PPIs [ 34 , 35 ]. Altogether, this warrants the need for special caution when it comes to the use of clopidogrel alone or in combination with PPIs to balance overall risk and benefits.…”

MicroRNAs as Novel Biomarkers for P2Y12 – Inhibitors Resistance Prediction

“…Currently, the genotype-based strategy in prescription of P2Y12-inhibitors lowers the risk of high on-platelet reactivity and MACE. 39 Currently the genotype-based strategy in the prescription of P2Y12-inhibitors is only recommended in patients at high risk of thrombotic events and not suitable for all comers as the trials have shown the conflicting results. 40 There is an unmet need for a novel complex biomarker that can combine genetic profile and platelet laboratory parameters.…”

Effects of aging on clinical outcomes in patients receiving genotype‐guided P2Y12 inhibitor selection after percutaneous coronary intervention

“…6 Moreover, numerous observational studies have shown that CYP2C19 no function allele carriers prescribed clopidogrel after PCI have higher rates of major adverse cardiovascular and cerebrovascular events (MACCE) compared to patients with no function alleles treated with prasugrel or ticagrelor. 4,7 CYP2C19 genotype-guided P2Y12 inhibitor selection after PCI, wherein patients with no function alleles are prescribed prasugrel or ticagrelor, has been increasingly adopted to guide treatment of patients undergoing PCI. 8,9 The average age of patients undergoing PCI has increased from 2003 to 2016 with about half of patients currently being over 65 years of age.…”