In China, with the ageing of society and acceleration of urbanisation, unhealthy lifestyles have become increasingly prevalent. As a result, cardiovascular disease (CVD) risk factors have increased, showing rapid growth and individual aggregation trends particularly in younger, lower-income groups. At present, CVD is the top cause of total deaths in China, accounting for 45.01% of deaths in rural areas and 42.61% of deaths in urban areas. With the burden of CVD increasing, the CVD mortality rate among rural residents has increased significantly . P2Y12 platelet receptor inhibitor drugs play an important role in the prevention and treatment of cardiovascular diseases . Of these, clopidogrel is the most widely used drug to prevent antiplatelet aggregation. Its use in combination with aspirin is the standard therapy for the prevention and treatment of ischemic events in cardiovascular patients with acute coronary syndrome (ACS), percutaneous coronary intervention (PCI) and acute myocardial infarction in China . With the expansion of clinical use and research of these drugs, several large multi-centre clinical trials have reported individual differences in the outcomes of antiplatelet therapy with clopidogrel . Specifically, some patients with cardiovascular disease or PCI have experienced adverse events such as haemorrhage and thrombus re-formation while taking the standard therapeutic dose of clopidogrel. Studies have shown that the occurrence of these adverse events is related to the absorption and metabolism rate of clopidogrel . Patients with fast absorption and metabolism of clopidogrel are prone to bleeding events, and so adverse events like thrombosis re-formation are more likely to occur in patients with slow absorption and metabolism .
Clopidogrel is an inactive thienopyridine prodrug that is absorbed by regulating P-glycoprotein in the intestine. It is metabolised by the hepatic cytochrome P450 (CYP) system to form the active product, and its active metabolite selectively and irreversibly binds to the platelet P2Y12 receptor, thereby exerting anti-platelet activity [8,9]. In the CYP metabolic system, clopidogrel is first metabolized by CYP1A2, CYP2B6 and CYP2C19 into 2-O-clopidogrel, and then catalysed by CYP2C19, CYP2C9, CYP3A4 and CYP2B6 to generate thiol derivatives that have drug activity. These thiol derivatives can cause irreversible antagonism of the ADP receptor P2Y12 platelet membrane, cannot make fibrinogen glycoprotein Ⅱ b/Ⅲ a combine with receptors and inhibit platelet activation and aggregation. The CYP2C19 gene is thought to play an important role in this transformation process .
Like many other CYP450 superfamily members, the CYP2C19 gene is highly polymorphic and has more than 25 known variant alleles. Different CYP2C19 genotypes can lead to an inconsistent conversion of clopidogrel . CYP2C19 polymorphisms are mainly caused by two types of mutations: one type reduces enzyme activity, such as CYP2C19*2, CYP2C19*3, CYP2C19*4, CYP2C19*5, CYP2C19*7 and CYP2C19*8; the other type enhances enzyme activity, and CYP2C19*17 is the only know mutant allele of this type . The most common CYP2C19 loss-of-function allele is *2 (c.681G > A; rs4244285), with allele frequencies of 15% in Caucasians and Africans and 29–35% in Asians. Other CYP2C19 variant alleles with reduced or absent enzymatic activity have been identified (e.g.,*3-*8); however, their allele frequencies are typically < 1%, with the exception of CYP2C19*3(c.636G > A; rs4986893) which is present in Asians at 2–9% . Correspondingly, in Asian populations there are four metabolic rate types for clopidogrel: poor metabolizers (PM), intermediate metabolizers (IM), extensive metabolizers (EM) and ultrarapid metabolizers (UM). PM individuals carry two loss-of-function alleles (*2-*8), e.g., CYP2C19*2/*2, CYP2C19*2/*3 and CYP2C19*3/*3; IM individuals carry one functional allele (*1) plus one loss-of-function allele (*2–*8), e.g., CYP2C19*1/*2 and CYP2C19*1/*3; EM individuals carry two functional (*1) alleles, e.g., CYP2C19*1/*1; and UM individuals carry two increased-activity alleles (*17) or one functional allele (*1) plus one increased-activity allele (*17), e.g., CYP2C19*1/*17, CYP2C19*17/*17 [14,15].
In clinical practice, it has been found that the use of clopidogrel for the prevention and treatment of cardiovascular disease can lead to adverse events, such as haemorrhage and thrombosis, leading to stroke, acute myocardial infarction and revascularisation, ultimately resulting in treatment instability and uncontrollability . On March 2, 2010, the US Food and Drug Administration (FDA) issued a warning to guide anti-platelet therapy using clopidogrel by assessing CYP2C19 genotype . A correlation between CYP2C19 genetic polymorphisms and adverse events caused by clopidogrel has been reported in Asian Han patients with cardiovascular disease. However, whether CYP2C19 genotyping can be used as a basis for guiding anti-platelet therapy with clopidogrel remains to be determined. To address this question, we performed a single-centre, non-blinded, non-randomised and open-label study to assess CYP2C19 genetic polymorphisms and adverse events caused by clopidogrel in patients with cardiovascular disease.