Introduction
According to the Institute of Health Metrics an Evaluation, in 2019, cardiovascular diseases (CVD) were the leading cause of death worldwide and in Mexico, mainly due to ischemic heart disease \cite{compare}. The 2016 Heart Disease and Stroke Statistics update of the American Heart Association (AHA) has recently reported that 15.5 million persons >20 years of age in the USA have a coronary heart disease (CHD)\cite{Mozaffarian_2016}. Approximately, every 42 seconds, a person will suffer for an Myocardial infarctation (MI) in US. Although the absolute numbers of CVD deaths have significantly increased since the 1990, the age-standardized death rate has decreased by 22% over the same period, primarily due to a shift in age demographics and causes of death worldwide \cite{Sanchis_Gomar_2016}. This change this year, 2020, according to preliminary, incomplete data from the CDC deaths from ischaemic heart disease were anywhere from 6% to 29% higher than the norm \cite{Viglione_2020}this can be explain cause indirect deaths to COVID-19 pandemic.
CVD can be subdivided in several diseases like coronary heart disease (CHD), coronary artery disease (CAD), and acute coronary syndrome (ACS). These terms can easily be confused or used interchangeably but they are different.\cite{norrving2011}CHD can be a result of CAD defines by atherosclerosis in coronary arteries, often asymptomatic.\cite{norrving2011} The term ACS encompasses a spectrum of conditions that are usually associated with acute myocardial ischemia, regardless CAD, such as; unstable angina, non-ST-elevation myocardial infarction (NSTEMI) and ST-elevation myocardial infarction (STEMI). \cite{norrving2011,Amsterdam_2014}
Platelets play a central role in the pathogenesis of ACS. Platelets rupture precipitates both the activation and aggregation of platelets with the formation of a thrombus, but this is avoided in patients with acute coronary syndromes as well as in those undergoing percutaneous coronary intervention (PCI) by using antiplatelet drugs to prevent abrupt vessel occlusion.\cite{Viveros_2016}
Sufficient platelet inhibition and (temporary) anticoagulation is essential. Aspirin is considered to be the cornerstone of treatment but current trials and guidelines recommend dual antiplatelet therapy (DAPT), defined as the use of a P2Y12 receptor inhibitor (clopidogrel, ticagrelor or prasugrel) and aspirin.\cite{Collet_2020} Clopidogrel (CLO) also known as Plavix cause of his brand name have lost protagonism in the last years, is characterized by less potent and variable platelet inhibition.\cite{Levine_2016} Clopidogrel should only be used when prasugrel or ticagrelor are contraindicated, not available or cannot be tolerated. Nevertheless is still an important part of antiplatelet treatment for example single oral antiplatelet agent in specific conditions\cite{Collet_2020} or in some guidelines is name as equal to aspirin and the best option if subjects have aspirin hypersensitivity\cite{hbr}, therefore, clopidogrel is far from been replace.
Clopidogrel depends on its conversion to an active metabolite by CY2C19. Poor metabolizers have decrease effectiveness. Individuals who carry 2 non-functional copies of the CYP2C19 gene have no enzyme activity and cannot activate clopidogrel via the CYP2C19 pathway, which means the drug will have no effect.\cite{bookshelf} It has been described that heterozygotes and homozygotes for the CYP2C19*2 polymorphism, which is a reduced-function allele, might present poor metabolism of CLO and, subsequently, lower levels of the active metabolite, decreased platelet inhibition and higher rate of cardiovascular events compared with *1 homozygotes.\cite{Scott_2013} Therefore, it is important to evaluate the impact of this effects when CLO is used as antiplatelet therapy in patients with ACS.
How common is this? What about intermediate metabolizers? Do we need to think in alternative treatment? what is the importance of CYP2C19* 2 polymorphism versus other polymorphism? this and other topics would be addressed in this review.
Pharmacokinetics of Clopidogrel
Clopidogrel is a thienopyridine that blocks the P2Y12 ADP receptor on platelets and has been shown to reduce cardiovascular events\cite{Mega_2015}.