What Is Clopidogrel Resistance?

Clopidogrel (CPG) is a new type of adenosine diphosphate (ADP) receptor antagonist, which belongs to thiophene pyridine drugs. In 1997, it was approved by the US FDA for secondary prevention of myocardial infarction, stroke, and peripheral arterial disease. It has become one of the main therapeutic drugs for patients with coronary heart disease and percutaneous coronary intervention (PCI) and patients with acute coronary syndrome. It was first listed in the United States in June 1998 and in China in August 2001. Because of its good safety and rapid inhibition of platelet (PLT) aggregation, CPG has basically replaced ticlopidine as one of the most widely used anti-PLT drugs. However, its anti-PLT effect is very individual and unpredictable. The emergence of clopidogrel resistance (CPG resistance) has affected its effectiveness and it is worth further research and discussion.

Clopidogrel resistance

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Clopidogrel (CPG) is a new type of adenosine diphosphate (ADP) receptor antagonist, which belongs to thiophene pyridine drugs. In 1997, it was approved by the US FDA for secondary prevention of myocardial infarction, stroke, and peripheral arterial disease. It has become one of the main therapeutic drugs for patients with coronary heart disease and percutaneous coronary intervention (PCI) and patients with acute coronary syndrome. It was first listed in the United States in June 1998 and in China in August 2001. Because of its good safety and rapid inhibition of platelet (PLT) aggregation, CPG has basically replaced ticlopidine as one of the most widely used anti-PLT drugs. However, its anti-PLT effect is very individual and unpredictable. The emergence of clopidogrel resistance (CPG resistance) has affected its effectiveness and it is worth further research and discussion.

Clopidogrel (CPG) is a new type of adenosine diphosphate (ADP) receptor antagonist, which belongs to thiophene pyridine drugs. In 1997, it was approved by the US FDA for secondary prevention of myocardial infarction, stroke, and peripheral arterial disease. It has become one of the main therapeutic drugs for patients with coronary heart disease and percutaneous coronary intervention (PCI) and patients with acute coronary syndrome. It was first listed in the United States in June 1998 and in China in August 2001. Because of its good safety and rapid inhibition of platelet (PLT) aggregation, CPG has basically replaced ticlopidine as one of the most widely used anti-PLT drugs. However, its anti-PLT effect is very individual and unpredictable. The emergence of clopidogrel resistance (CPG resistance) has affected its effectiveness and it is worth further research and discussion.

1 Definition of CPGR

Basic and clinical studies have confirmed the existence of CPGR. Generally speaking, PLT responds differently to CPG, and lacks or decreases in response to them, which is called CPGR ^[1] [1]. However, there is a lack of internationally recognized standards of consistency. The definitions used in different studies are mostly empirical. Muller et al. [2] defined CPGR as meaning that when administered with a 600 mg loading dose of CPG 4 hours, ADP-induced PLT aggregation was reduced by <10% from baseline, and a 10% to 29% reduction was defined as semi-resistance and inhibition> 30 % Is the normal response. Gurbel et al. [3] defined it as the calculation of PLT aggregation using percentages, using 5 mol / L ADP as an agonist, and the difference between the baseline value and the maximum PLT aggregation using CPG <10% was defined as CPGR. Barragan et al. [4] defined it as relatively high PLT reactivity (> 50%) at any time during treatment. Recently, some scholars [5] suggested that CPGR should be that CPG cannot achieve the expected pharmacodynamic effect, and patients still have clinical events while receiving CPG treatment, which should be called CPG treatment failure. CPGR is also known as CPG nonresponse, CPG low response and so on. Some scholars [6] suggested that in order to standardize terminology and avoid confusion, it is recommended to use CPGR uniformly.

2 Incidence of CPGR

The incidence of CPGR fluctuates from 4.2% to 31% [3, 7]. The reports are not consistent, and may be related to the following factors: (1) lack of universally recognized standards; (2) different judgment standards and research samples; (3) different detection methods for PLT aggregation; (4) the existence of the patients themselves Factors that increase the baseline value of the PLT response. Muller et al. [2] reported that the incidence of CPG non-response was about 10%, and the incidence of low response was about 20%. Matetzky et al. [8] reported that the incidence of CPGR in patients with ST-elevation myocardial infarction was 25%. However, Serebrunuan et al. [9] found that the PLT inhibition curve after normal CPG treatment was normally distributed. With a cut-off value of less than "mean-2 standard deviations", only 4.2% of patients had CPGR. Combined use of aspirin and CPG may cause aspirin and CPG dual resistance at the same time. Lev et al. [10] found that the probability of aspirin resistance and CPGR in patients after PCI was 12.7% and 24%, while 47.4% of aspirin resistance patients occurred. CPGR.

3 possible mechanisms of CPGR

The cause and exact mechanism of CPGR are unclear. Under the premise of good compliance of the drug users, it may be related to the following factors.

3.1 Genetic factors Individual differences in response to anti-PLT drugs stem from hereditary or acquired factors, of which the former plays a decisive role [11]. Bliden et al. [12] also believed that the existence of CPGR is gene-dependent, which may be related to the genetic polymorphism of PLT P2Y12 receptor or the defect of the receptor signal expression system. The effect of ADP on PLT is mediated by two receptors, P2Y1 and P2Y12. ADP activates both of these receptors during PLT agglutination. Hechler et al. [13] studied transgenic mice and found that overexpression of P2Y1 receptor caused high reactivity of PLT, which could reduce the efficacy of CPG. GPa subunit PIA polymorphisms regulate the function of PLT, especially the PIA2 allele is related to the high reactivity of PLT. Studies have confirmed that [14] GPa gene PIA polymorphism (especially PIA2) affects PLT response to CPG . Analysis of the variability of the P2Y12 gene sequence revealed that 86% of the haploids were named H1 haploids and 14% of the haploids were H2 haploids, the latter being related to the downregulation of the cAMP amount of PLT, leading to thrombotic events Increasing incidence, H2 allele carriers are susceptible to atherosclerosis, and the effect on CPG is reduced [15].

3.2 CPG dose factors The anti-PLT effect of CPG is dose-dependent. Tests have shown that CPG given a loading dose> 6 h before PCI can significantly reduce the incidence of early events. Increasing loading (> 300 mg) or maintenance (> 75 mg) of CPG in patients with baseline PLT activation can reduce CPGR [3]. A recent study [16] found that CPG at a 600 mg loading dose had lower non-reactivity and PLT aggregation rates than 300 mg loading dose. Increasing the loading and maintenance doses of CPG may obtain faster and stronger anti-PLT effect and reduce the incidence of CPGR [17].

3.3 CPG absorption and biotransformation CPG becomes an active metabolite through the action of CYP450. The metabolic activity of CYP3A4 is related to CPGR. Any abnormality in any link can lead to changes in the anti-PLT aggregation effect of CPG. Insufficient doses and gastrointestinal malabsorption will cause changes in the amount of drugs entering the liver. Taubert et al. [17] found that the degree of PLT inhibition and the pharmacokinetics of various metabolites of CPG between different individuals are very significant. The variability is related to drug absorption.

3.4 Drug interaction factors Any drug that can inhibit CYP3A4 or use CYP3A4 as a substrate can block the biological transformation of CPG to form active metabolites. In this regard, statins are the most common, and most fat-soluble statins are mainly metabolized by CYP3A4 It is a hydrophilic compound excreted from the kidney. Studies have shown [18] that 40 mg atorvastatin reduces the anti-PLT effect of CPG in a dose-dependent manner, but pravastatin without the CYP3A4 metabolic pathway has no such effect. However, the study by Wienbergen et al. [19] showed that different statins did not significantly affect the efficacy of CPG. Zhao Weiping et al. [20] thought that although the atorvastatin and CPG metabolites are related to CYP3A4, due to the abundant expression of CYP3A4 in the liver of humans, the blood concentrations of atorvastatin and CPG at clinical doses are far below CYP450. Saturated concentrations of 3A4, but they are not specific strong agonists or inhibitors of the latter. On the other hand, CPG can be activated by a variety of CYP450 isoenzyme systems, not limited to CYP450 3A4. The results of subsequent studies also showed that the anti-PLT effect of CPG was not affected by statins [21]. At present, there is no consensus on the interaction between statins and CPG.

3.5 Mechanisms related to biological characteristics of platelets [6]: (1) Increased ADP release: (2) Increased number of P2Y12 receptors; (3) Alternative pathways for PLT activation: Cannot inhibit catecholamine-mediated PLT activation; ADP via P2Y1 Receptor-induced increase in PLT aggregation; P2Y1 receptor and Cq- linked to induce PLT aggregation through Ca2 + to initiate ADP, CPG only blocks P2Y12 receptor without affecting P2Y1 receptor; P2Y12-dependent pathway (thrombin, thromboxane A2, collagen ) Increase [5].

4 Clinical significance

CPG is widely used in coronary heart disease, cerebrovascular disease, and peripheral arterial thrombotic diseases due to its rapid onset, strong effect and good tolerance. However, not all patients respond well to it. The presence of CPGR in some patients suggests that The high-risk nature of these patients has a high incidence of endpoint events (cardiovascular death, reinfarction, or severe bleeding). Research by Matezky et al. [6] linked CPGR with clinical adverse events, and believed that the emergence of CPGR may be a sign of increasing the risk of recurrent cardiovascular adverse events. A considerable part of the patients receiving CPG are after PCI, especially those who receive stent implantation. If CPGR does cause cardiovascular events such as thrombus in the stent, the consequences will be very serious. Therefore, correct identification Early treatment of CPGR has important clinical significance.

In short, with the in-depth understanding of CPG and the further development of basic and clinical research, the prospect of effective prevention and treatment of CPGR is very bright, and it will benefit patients who use CPG.