Diagnosis
Detection of SNPs or mutations can be performed using a wide range of techniques. This methods should be highly specific and sensitive to be able to distinguish one nucleotide substitution. On this subject, polymerase chain reaction (PCR) is a tool that has facilitated the molecular analysis of various polymorphisms due to its analytical performance. \cite{Matsuda_2017} TaqMan SNP genotyping assay is based on the allelic discrimination by Real-Time PCR in a TaqMan system that uses a dual-labeled fluorogenic probe. Through the degradation of the probes by the Taq DNA polymerase (with 5'-3' exonuclease activity) during amplification, a specific fluorescence is released. \cite{antoniu2015} This method have been used to evaluate the role of the CYP2C19*2 polymorphism in patients that are treated with clopidogrel. \cite{García-Lagunar2017,antoniu2015}
Therapy Considerations
As mentioned before clopidogrel is a second-generation thienopyridine, introduced in 1988. Historically, ticlopidine was the first member of this class. However, its not insignificant, risk of neutropenia and thrombotic thrombocytopenic purpura led to its predominant replacement by clopidogrel in routine clinical practice.\cite{Kastrati_2004} Currently third-generation P2Y12 inhibitors, prasugrel and ticagrelor gain relevance. This were developed to address the slow onset and heterogeneous platelet inhibitory properties of clopidogrel. Clinical trials show greater benefits from these two in comparison to clopidogrel. \cite{Wallentin_2009,Wallentin_2007,Gurbel_2009,Wiviott_2007}
Initially guidelines like the 2018 European guidelines on myocardial revascularization recommend the use of prasugrel and ticagrelor over clopidogrel.\cite{2019} Nevertheless Clopidogrel is still use and prescribe. \cite{Tscharre_2017,Collet_2020}Mainly cause in the past decade concern has arisen regarding increase bleeding risk with third-generation thienopyridines, greater costs and other adverse effects (e.g., dyspnea with ticagrelor use).\cite{De_Luca_2016,Patti_2020}Also there is an important need for real-world studies, there have been contradictory results in for example CHANGE DAPT study that favored clopidogrel over ticagrerol in percutaneous coronary intervention (PCI) therapy.\cite{Zocca_2017} On the other side th PLATO trial shows the contrary results in adverse effects.\cite{Wallentin_2009}
All this led to the DAPT “deescalation”\cite{Patti_2020} which is a medium-to long-term bleeding reduction strategy in patients with high bleeding risk or low socioeconomic status, and it has showed benefit in clinical trials of patients with ACS.\cite{Cuisset_2017,Sibbing_2017}
Clopidogrel is far from be totally replace, remaining as a pilar in cardiovascular arena. Thienopyridines application covers the wide spectrum of patients with stable angina (SA), ACSs, and/or those undergoing PCI.\cite{Testa_2010} However in in the context of patients with CYP2C19* 2 polymorphism and treatment with CLO there are specific indications or considerations on the previous diseases. In 2017 the US Food and Drug Administration (FDA) issued a statement warning about the diminished antiplatelet effect of clopidogrel in CYP2C19 poor metabolizers.\cite{httpsdailymednlmnihgovdailymeddruginfocfmsetida9a3c560-2408-4dd0-9f83-ee3e3a549c7b}
Acute Coronary Syndrome
The FDA has stated that poor metabolizers taking higher doses of clopidogrel (ie, 600 mg loading dose followed by 150 mg once daily) show an increased antiplatelet response and that alternative treatment strategies can be considered in these patients. However, it also states that an appropriate dose regimen for this patient population has not been established in clinical outcome trials.
Because carriers of *2 alleles demonstrate no CYP2C19 enzymatic activity with normal dosing of clopidogrel, 2 potential alternative treatment strategies for carriers of *2 are to use higher doses of clopidogrel or to use alternative P2Y12 inhibitors. Higher loading and maintenance doses (eg, 1200 mg loading and 150 mg maintenance) appear, in part, to overcome the genetic deficiency of the *2 allele, although maintenance doses of up to 300 mg/day might be required to achieve adequate platelet inhibition. \cite{Pena2009,Gladding_2008,Mega_2011}
Posible alternative treatment could be other kinds of thienopyridine ticlopidine, prasugrel and ticagrelor which are not metabolised by CYP2C19 (or to a lesser extent). Prasugrel, is also a prodrug, but it is unique in that its bioactivation appears to be less dependent on CYP2C19 activity. \cite{Mega_2009}Ticlopidine, is also a prodrug, but there little information about it effect in the context of CYP2C9*2 polymorphism. Ticagrelor is a nonprodrug P2Y12 inhibitor thus is not sensitive to the effects of the CYP2C9*2 allele.\cite{Xi_2020}(Fig. \ref{719341})
The effects and relation within CYP2C19 loss-of-function and clopidogrel can vary between populations, as shown in a substudy of the CHARISMA clinical trial, were patients with function decrease CYP2C19 variants had no reduction in antiplatelet our outcome response to clopidogrel in this population of stable cardiovascular disease patients with no recent ACS or PCI.\cite{Bhatt_2004}