Percutaneous coronary intervention

 A genome-wide association study followed by CYP2C*2 genotyping in patients undergoing PCI suggested a link between the CYP2C*2 genotype and both diminished platelet response to clopidogrel (accounting for 12% of interindividual variation) and cardiovascular ischemic events or death during 1 year of follow-up (hazard ratio 2.42, p = 0.02)\cite{Shuldiner2009}
In 2017 the Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP)  made antiplatelet therapy recommendations based on CYP2C19 genotype. For patients with ACS who receive PCI, they recommend an alternative drug to clopidogrel in poor metabolizers, and for intermediate metabolizers, they recommend choosing an alternative drug, or doubling the dose of clopidogrel to 150 mg daily dose, 600 mg loading dose.
In 2013 the Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for clopidogrel recommends an alternative antiplatelet therapy like prasugrel or ticagrelor for CYP2C19 poor or intermediate metabolizers, if there is no contraindication for patients with ACS who are undergoing PCI.\cite{Scott_2013}

Acute Myocardial Infarction

Combination therapy of clopidogrel with low-dose acetylsalicylic acid is the main oral antiplatelet regimen to prevent recurrent ischemic events after acute coronary syndromes. The functional genetic variant, CYP2C19, is a major contributor to the intervariability of response to treatment.\cite{Collet_2009} 
There is a close association between the risk of subsequent ischemic events and high platelet reactivity, being influenced by CYP2C19. The administration of clopidogrel in high doses does not achieve levels of suppression of platelet reactivity in homozygous of the allele of loss of function CYP2C19, however, such as prasugrel or ticagrelor, they can overcome the high reactivity of platelet to clopidogrel in these patients.\cite{Lee_2015} Current guidelines suggest that a potent alternative P2Y12 inhibitor (eg, Prasugrel or ticagrelor) can be switched to in patients with a CYP2C19 loss of function allele.
Evidence suggests that patients have variable responses to clopidogrel and that a lower response to the drug could be a risk factor for ischemic complications. A meta-analysis demonstrated a significant association between the CYP2C19 loss-of-function allele and major adverse cardiovascular events. \cite{Lee_2015} A study in 2009, demonstrated the relationship between the presence of the gene variant and the risk of our thrombotic vascular events, they observed that patients with an eaves * 2 had a higher risk of cardiovascular recurrence compared to non-carriers. Another study, proposes the effect of gene dose of the CYP2C19 * 2 allele on the pharmacokinetics and pharmacodynamics of proton pump inhibitors, which are also substrates of CYP2C19. In a double-blind, placebo-controlled trial, co-administration of omeprazole with clopidogrel was associated with increased platelet reactivity, and patients receiving chronic proton pump inhibitor therapy were 4.3 times more likely to have an inadequate response in contrast to those treated with clopidogrel alone. However, this remains controversial. \cite{Collet_2009} 
CYP2C19 genotyping is proposed as an alternative method of individualized antiplatelet therapy, although it is not yet recommended due to the few studies conducted to evaluate genotype-directed antiplatelet therapy.\cite{Lee_2015}

Cerebrovascular disease 

Clopidogrel is used for the secondary prevention of cerebrovascular events, reducing the  occurrence of new cerebrovascular accidents in patients with acute ischemic stroke. However, a substantial number of subsequent strokes still occur despite clopidogrel treatment due to interindividual variability in response to treatment. \cite{Pan_2017}\cite{Song_2020} 
Previous studies have shown that the CYP2C19 polymorphism influences the response and efficacy of clopidogrel for the prevention of cardiovascular events.\cite{Pan_2017} It is associated with an increase in cardiovascular risk and mortality in patients with coronary artery disease treated with clopidogrel, however, there are very few patient studies that determine whether the CYP2C19 genotype influences the preventive efficacy of clopidogrel in patients who have had a stroke. \cite{Pan_2017}\cite{Song_2020}\cite{Gower_2020} The recognition of CYP2C19 genotyping is important as it allows us a better selection of secondary prevention strategies. However, before requesting pharmacogenetic tests or platelet function studies, it is important to consider modifiable factors that may influence platelet function studies, such as the patient's dosing regimen, adherence to medication, and potential drug-drug interactions that may decrease the effectiveness of clopidogrel (proton pump inhibitors, lipophilic statins, and calcium blockers). \cite{Lyerly_2018}
Several studies have shown that a dual therapy of clopidogrel with aspirin reduces the appearance of new strokes. Recent studies demonstrated that among patients with transient ischemic attack or mild stroke, the use of aspirin and clopidogrel compared to aspirin alone reduced the risk of recurrent stroke only in patients who were not carriers of the CYP2C19 allele with loss of function. \cite{Pan_2017}\cite{Song_2020} In a genetic substudy (SPS3-genes) it was found that patients with a CYP2C19 loss of function allele had a higher risk of stroke recurrence compared to non-carrier patients. \cite{Lyerly_2018} A meta-analysis found a 1.92-times increased risk of stroke in carriers of the CYP2C19 loss-of-function alleles.\cite{Song_2020} Another meta-analysis proposes that carriers of the CYP2C19 loss-of-function allele may have an attenuated response to clopidogrel.\cite{Pan_2017}
In contrast to studies of patients with coronary artery disease, guideline recommendations regarding the use of the CYP2C19 genotype in the context of stroke are limited due to a lack of prospective evidence. \cite{Song_2020}\cite{Gower_2020} Prasugrel and ticagrelor have been shown to be more potent platelet inhibitors than clopidogrel. Genetic variations in CYP2C19 have little effect on the pharmacokinetics of prasugrel, however, it is contraindicated in patients with a previous stroke due to an increased risk of bleeding complications.\cite{Lyerly_2018} In contrast, ticagrelor may offer clinical utility in the treatment and prevention of stroke, but further studies are required to determine its role and efficacy in treatment. \cite{Gower_2020} Current secondary prevention guidelines from the American Heart Association recommend its use when aspirin is contraindicated. \cite{Lyerly_2018} The American Stroke Association Secondary Stroke Prevention Guide does not provide recommendations on therapeutic alternatives. \cite{Gower_2020} Genetic tests to guide prescription can be useful, however, its use is not yet recommended. \cite{Song_2020,Gower_2020,Lyerly_2018}

Conclusion

P2Y12 inhibitors have become an integral part of treatment for ACS patients. Clopidogrel has been used in clinical practice for more than a decade and has been extensively studied in the management of cardiac patient his tolerability and cost make him the most used thiopyridine however substantial number of patients show an inadequate response to clopidogrel despite a standardized dosing regimen. Several factors can influence the response but CYP2C19 is an important one, a highly polymorphic gene with more than 25 allelic variants catalogued. Current guidelines of American College of Cardiology (ACC), American Heart Association (AHA) and the European Society of Cardiology (ESC) do not recommend routine use of genotype testing. However they recommend it in selected cases.  Further randomized studies are needed to clarify role of CYP2C19 genotype testing in tailoring antiplatelet therapies in clinical practice but recent and early studies show promising outcomes from these practice and the commercial test are available. Standardization and cost reduction of these genotype tests is need it, this would facilitate accessibility, and perhaps saving lives by a change management of patients or suggesting an alternative treatment.