Thienopyridines and statins: assessing a potential drug-drug interaction

Clopidogrel and statins are frequently administered in patients with ischemic heart disease or other atherothrombotic manifestations and are effective in the prevention of cardiovascular disease. The thienopyridine clopidogrel is a pro-drug metabolised in the liver via the cytochrome P450 (CYP) 3A4 system to the active compound which inhibits the P2Y(12) ADP platelet receptor. The assumption exists that the effect of clopidogrel in inhibiting platelet aggregation is attenuated by co-administration of lipophilic statins such as atorvastatin or simvastatin which are metabolised by the CYP3A4 system to inactive substrates. Assessing a possible drug-drug interaction ex-vivo, inconclusive studies have been published: In an aggregometer study, a strong and dose-dependent interference between atorvastatin and the inhibitory effect of clopidogrel on platelet function was observed. Another study, measuring the effect of clopidogrel by flow cytometry, found a significant attenuation of the clopidogrel effect by lipophilic statins, predominantly in the loading phase. In contrast a recent study, which used 600 mg clopidogrel for loading, found no significant interference between various statins and clopidogrel on ADP-induced platelet aggregation and in addition another study revealed no attenuation of the clopidogrel effect despite statin co-medication after 5 weeks. Additionally, retrospective analysis of clinical studies (CREDO-study) or registries (MITRA-PLUS) revealed no significant influence of different statins on the clinical outcome in patients treated with clopidogrel. However, these clinical studies showed a trend towards a diminishing effect of clopidogrel on those treated with cytochrome CYP3A4 metabolised statins. Even more important seems to be the considerable variability in the response of the antiplatelet effect of clopidogrel. A certain percentage of patients apparently do not respond adequately to clopidogrel treatment. This effect of clopidogrel resistance seems to be more important as the potential interference between CYP3A4 metabolized statins and clopidogrel. Finally, up until now sufficient evidence has not been gained to prefer hydrophil statins on patients receiving clopidogrel co-medication or when to discontinue the use of statins in clopidogrel treatment. Prospective studies are necessary in order to evaluate the magnitude of clopidogrel resistance and the impact of clopidogrel co-medication as well as to redefine antithrombotic therapy for this subgroup.     

The basis of platelets: platelets and atherothrombosis: an understanding of the lack of efficacy of aspirin in peripheral arterial disease (PAD) and diabetic patients

Platelet activation subsequent to the adhesion of platelets to the vascular wall results in the release of mediators that promote platelet aggregation, which plays a pivotal role in the development of the polyvascular atherosclerotic disease that can be referred to by the acronym 'ATIS' (AtheroThrombosIS). The currently available antiplatelet drugs used to prevent vascular events in patients with cardiovascular disease, including peripheral arterial disease (PAD), include aspirin and thienopyridines such as clopidogrel. These drugs decrease platelet aggregability, each of them by inhibiting a different pathway of platelet activation and recruitment. Aspirin acts by inhibiting thromboxane A2 (TXA2) formation through the inhibition (acetylation) of cyclo-oxygenase. On the other hand, thienopyridines suppress the platelet aggregation adenosine diphosphate (ADP) pathway by inhibiting the platelet P2Y12 subtype of the ADP receptor. The results of the large ATT (Antithrombotic Trialists' Collaboration) meta-analysis of published clinical studies on aspirin, reported in 2002, confirmed the previous meta-analysis and major trials that treatment with aspirin (mixed with other antiplatelet agents in these large meta-analyses) can prevent vascular events in high-risk patients with cardiovascular disease. However, it must be stressed that specifically in PAD patients no significant effect of aspirin was demonstrated in a more recent meta-analysis. This was also the case for primary and secondary prevention in diabetic patients. In keeping with these observations, neither a five-year follow-up study of Japanese diabetic patients in the JPAD (Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes) study, a seven-year follow-up study of UK diabetic patients with PAD in the POPADAD (Prevention of Progression of Arterial Disease and Diabetes) study, nor a very recent Scottish study in the same population of diabetics with PAD revealed a significant beneficial effect for aspirin in preventing ischaemic events. This failure may be a consequence of more rapid recovery of platelet aggregability following each dose of aspirin in these PAD or diabetic populations, with the accelerated platelet turnover resulting in a condition of aspirin resistance. Results of the large scale CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events) trial that evaluated clopidogrel in patients with cerebral infarction, myocardial infarction or PAD have found clopidogrel to be significantly more effective than aspirin in preventing ischaemic events in patients with PAD. Furthermore, a subgroup analysis of the study has confirmed the efficacy of clopidogrel in diabetic patients with PAD, showing a significant reduction of events in clopidogrel-treated, compared with aspirin-treated, diabetic patients. These results are also likely to be attributable to the greater frequency of aspirin resistance in aspirin-treated patients in these populations (diabetics and/or PAD). Platelets, through activation and aggregation, have an important role in ATIS. However, although antiplatelet therapy with low-dose aspirin has been reported to prevent vascular events in high-risk patients with cardiovascular disease, recent studies in patients with PAD or diabetes mellitus have failed to support the efficacy of aspirin in preventing vascular events in these patient populations. In contrast, clopidogrel appears to be a useful antiplatelet agent in the prevention of vascular events in patients with PAD or diabetes.     

Old and New Molecular Mechanisms Associated with Platelet Resistance to Antithrombotics

Current available data show that about 5 to 40% of coronary patients treated with conventional doses of antithrombotic drugs do not display adequate antiplatelet response. Nowadays, aspirin remains the main antiplatelet therapy. However, a significant number of patients show platelet resistance to aspirin therapy, and recurrent thrombotic events occur. Combined antithrombotic therapies with thienopyridines, such as clopidogrel have been used to resolve this problem. However, clopidogrel treatment has been also associated with wide response variability, and non-responsiveness to clopidogrel also occurs in some patients. Therefore, the main question arising about the antithrombotic therapy is why particular patients do not benefit from the therapy and how they might be identified to improve their treatment. Different hypotheses have been suggested, including genetic factors, platelet heterogeneity, non-compliance and others. However, it is probably that many molecular mechanisms involved in platelet resistance to antithrombotic therapies still remains unknown. New technologies, such as proteomics and genetic, are beginning to show new unknown biological biomarkers and molecular mechanisms which may be associated with platelet antithrombotic drug resistance.     

Interindividual variability in the laboratory response to the aspirin-clopidogrel combination: are patients with stent occlusion "resistant" to treatment?

Interindividual variability of biological response to antiplatelet agents is an opened question, which constitute the purpose of recent publications. Indeed, a wide interindividual variability in the laboratory response to antiplatelet agents such as aspirin and/or clopidogrel has been shown. However, only few clinical data are available to demonstrate the relationship between a poor laboratory response to antiplatelet treatment and the occurrence of stent thrombosis. The aim of this study is to compare photometric platelet aggregation profiles of two groups of patients who had undergone percutaneous coronary intervention with stent implantation (one group with at least one subacute thrombotic event following stent implantation and one historical control group free of thrombotic events) to determine whether there is a parameter which could be useful in identifying patients with a risk of having a thrombotic event related to poor response to antiplatelet treatment. We found some differences between the two groups regarding the maximal light transmission after stimulation with arachidonic acid (1,39 mM) or collagen at low concentration (Horm, 2 microg/mL) but not after stimulation with ADP irrespective of the concentration studied (10, 5 and 2,5 microM). However, platelet inhibition response to ADP could be assessed with another parameter, the disaggregation percentage, which was significantly lower in patients with than without thrombosis, and may be used as marker to distinguish patients with a higher risk of thrombosis.     

Clopidogrel and aspirin in cardiovascular medicine: responders or not--current best available evidence

Dual antiplatelet therapy represents an important advance for patients with established coronary artery disease. It is an important strategy for patients with acute coronary syndromes and those undergoing percutaneous transcatheter coronary interventions. Clopidogrel effectively inhibits ADP-induced platelet activation and aggregation by selectively and irreversibly blocking the P2Y(12) receptor on the platelet membrane. Aspirin works by irreversibly acetylating the cyclooxygenase (COX-1) enzyme, thus suppressing the production of thromboxane A(2) (TxA(2)) and inhibiting platelet activation and aggregation. Variable platelet response and potential resistance to therapy has emerged with aspirin and clopidogrel. The definitions of antiplatelet agents variability in responsiveness and nonresponsiveness are discussed. Clopidogrel and aspirin responsiveness as they are measured in the laboratory by various techniques (platelet aggregometry and point-of-care assays such as platelet function analyzer [PFA-100] and rapid platelet function assay [RPFA]) are evaluated. The mechanisms responsible for variations in responsiveness to antiplatelet agents such as clinical, cellular and genetic factors are defined. Aspirin and clopidogrel resistance are emerging clinical entities with potentially severe consequences such as myocardial infarction, stroke or death. The therapeutic interventions to deal with nonresponsiveness are reported, although specific recommendations are not clearly established. In the future, routine measurement of platelet function in patients with cardiovascular disease may become the standard of care. Personalized antithrombotic treatment strategies may be determined by ex-vivo measurements that identify critical pathways influencing thrombotic risk in the individual patient.     

Clopidogrel: a selective inhibitor of platelet ADP receptors

Platelets play a key role in the development of ischemic complications in the arterial circulation. Antiplatelet therapy has proven effective in the treatment and prevention of ischemic events. Numerous clinical studies have confirmed the therapeutic efficacy of aspirin to such a point that this antiplatelet agent has become the gold standard in clinical practice. Clopidogrel is a thienopyridine compound that inhibits platelet aggregation by selectively binding to adenylate cyclase-coupled ADP receptors. Results of a large, double-blind, randomized study (CAPRIE) confirm that administration of clopidogrel to patients with atherosclerotic vascular disease is more effective than aspirin in reducing the combined risk of ischemic stroke, myocardial infarction or vascular death. The present article highlights the importance of activation of platelets through ADP receptors and reviews the pharmacology and clinical studies of clopidogrel, a selective inhibitor of these mechanisms.     

Does glycoprotein IIIa gene (Pl(A)) polymorphism influence clopidogrel resistance? : a study in older patients

BACKGROUND: Clopidogrel is a potent antiplatelet drug used for secondary prevention after ischaemic cardiovascular or cerebrovascular events. In patients with aspirin (acetylsalicylic acid) intolerance or resistance, it is used as monotherapy. Recent data report that Pl(A) polymorphism of the glycoprotein IIIa gene may account for differences in aspirin-induced antiplatelet effects. An increased degree of platelet reactivity was also reported in Pl(A2) carriers compared with Pl(A1/A1) patients after administration of a clopidogrel 300mg loading dose. OBJECTIVES: The aim of this study was to assess the modulatory effect of the Pl(A2) allele on platelet aggregation in patients taking long-term clopidogrel. M ETHODS: The prevalence of the Pl(A2) allele was assessed in 38 (21 males, 17 females; mean age 63 +/- 13 years) clopidogrel-resistant and 59 (26 males, 33 females; mean age 63 +/- 11 years) clopidogrel-responsive patients. The polymerase chain reaction-restriction fragment length polymorphism method was utilised to evaluate Pl(A) polymorphism. A Carat TX4 optical platelet aggregometer (Carat Diagnostics Ltd, Budapest, Hungary) was used to measure 5 and 10 micromol/L adenosine diphosphate-induced platelet aggregation. RESULTS: Significantly more patients were taking combination antiplatelet therapy in the clopidogrel-resistant group than in the clopidogrel-responsive group (50% vs 30%, respectively). The prevalence of the Pl(A2) allele did not differ significantly between the two groups (0.09 vs 0.13), even after adjustment for combination therapy and various risk factors. CONCLUSIONS: Our results show that carriers of the Pl(A2) allele do not have an increased risk of clopidogrel resistance. These findings and data from our previous studies suggest that patients with a Pl(A2) allele homozygosity may benefit from antiplatelet therapy based on clopidogrel rather than aspirin.     

Platelets in atherothrombosis--diagnostic and prognostic value of platelet activation in patients with atherosclerotic diseases

Platelets and their activation have a pivotal role in the development of atherosclerotic diseases such as acute myocardial infarction (AMI), stroke and peripheral arterial occlusion. Biomarkers of platelet activation are making inroads into clinical studies and may serve as promising agents upstream to established downstream markers of myocardial necrosis such as troponin and creatin kinase. Targeting the degree of platelet activation assessed by the key collagen receptor of platelet activation, glycoprotein VI (GPVI), may have diagnostic and prognostic value for the assessement of high-risk groups of patients with symptomatic coronary artery disease and ischemic stroke and may be worthwhile to help to facilitate clinical decision-making and to rapidly initiate adequate therapy. The concert of platelet count, platelet activation, platelet aggregation and subsequent inflammation has had a significant impact on the clinical outcome in patients with atherosclerotic diseases. For a therapeutical approach to ameliorate prognosis, the use of antiplatelet treatment in particular in AMI patients with low response to clopidogrel has partly been overcome by novel second antiplatelet drugs on top of aspirin such as prasugrel and ticagrelor. Antiplatelet therapy may be adapted according to a GPVI-based platelet activity monitoring along with aggregometry of residual platelet aggregation. Other approaches using protease-activated receptor- 1 antagonists vorapaxar or atopaxar, which inhibit the platelet thrombin receptor, soluble GPVI called Revacept?, which blocks the collagen binding sites at the vascular lesion and anopheline saliva protein derived from the malaria vector mosquito, a platelet adhesion inhibitor independent of a GPVI mechanism, still wait for their breakthrough.     

Recent advances in antiplatelet agents

Platelet aggregation plays a key role in the pathogenesis of thromboembolic diseases such as myocardial infarction, stroke, unstable angina and peripheral artery disease. Until recently, aspirin was the only antiplatelet agent available to prevent or treat these events. Over the past several years, there has been a substantial expansion in the antiplatelet armamentarium as well as in the understanding of the clinical importance of antiplatelet therapy in limiting the complications of thrombosis. Aspirin was one of the first agents to be adopted and it remains as the standard therapy with the higher amount of available clinical information. Following aspirin, ADP receptor antagonists like ticlopidine and clopidogrel as well as phosphodiesterase inhibitors dipyridamole and cilostazol have been introduced. Glycoprotein (GP) IIb/IIIa receptor antagonists like eptifibatide, tirofiban and abciximab are the newer antiplatelet agents which act at the end of the common pathway of platelet aggregation. Although results of clinical studies with the first oral GPIIb/IIIa antagonists were disappointing, agents of the new generation might expand the potential application of GPIIb/IIIa targeted therapy. This review will highlight recent advances in the development of aspirin, phosphodiesterase inhibitors, ADP receptor antagonists and the platelet glycoprotein IIb/IIIa inhibitors. The emphasis of this paper has been placed on the chemical aspects of these agents.     

Platelet function and antiplatelet therapy in cardiovascular disease: implications of genetic polymorphisms

Platelets play a crucial role in thrombosis, inflammation, immunity and atherogenesis. Antiplatelet agents are widely used in patients with acute coronary syndrome and other cardiovascular disorders. Aspirin and clopidogrel are the most commonly prescribed antiplatelet agents, with a relatively safe profile and efficiency in a variety of clinical conditions. Numerous prospective studies have revealed variability of antiplatelet efficacy. The so called "antiplatelet resistance" prompted a search for mechanisms implicated in poor responsiveness to aspirin and clopidogrel therapy. In this regard, genetic polymorphisms in the platelet receptor genes attracted considerable interest. Specific genetic variants in platelet receptors such as the P2Y12, glycoprotein (GP) IIb/IIIa, GPIa/IIa, GPIb/IX/V and the cytochrome P450 (CYP) family of genes are associated with variable response to antiplatelet therapy and cardiovascular events. Genetic polymorphisms and haplotypes that comprehensively capture the genetic information encoded within the platelet receptor genes can, to some extent, predict response to the antiplatelet drug better than any single genotype. Genotyping for multiple receptor variants in patients on antiplatelet therapy, complemented by standardized quantification of platelet function, can provide useful information for future drug design studies and possibly for personalized antiplatelet therapy and prevention of thrombotic events. Additional information is, however, needed to evaluate the cost-effectiveness of complex genetic and platelet function testing.     

氯吡格雷抵抗原因及对策的研究进展

众所周知,血小板在动脉血栓形成中起到了关键的作用,抗血小板治疗已成为急性冠脉综合征患者预防和治疗动脉血栓的基石。氯吡格雷作为一种新型抗血小板药物,对心血管病的重要辅助治疗作用已得到证实。但研究发现,大约有11%～44%患者对氯吡咯雷表现为低反应甚至无反应,定义为氯吡格雷抵抗。而导致此种抵抗现象的可能原因是氯吡格雷给药剂量不足,个体的基因多态性和药物之间的相互作用等。其主要对策有提高氯吡格雷的给药剂量,联用其它抗血小板药物,减少药物的不良相互作用和采用新型药物等。     

Ticagrelor: Positive,negative and misunderstood properties as a new antiplatelet agent

相似文献   

Resistance to antiplatelet drugs: what progress has been made?

Introduction: Despite well-documented efficacy, recurrent thrombotic event occurrences, particularly stent thrombosis, have been repeatedly demonstrated in stented patients treated with aspirin and clopidogrel. The latter observation stimulated the close scrutiny of the pharmacodynamic effects of clopidogrel and revealed the ‘wide variability’ and the phenomenon of ‘antiplatelet resistance’. High on-treatment platelet reactivity to ADP (HPR) during clopidogrel therapy is an independent risk factor for ischemic event occurrences in post-percutaneous coronary intervention (post-PCI) patients. Recent observational studies demonstrated a link between low on-treatment platelet reactivity to bleeding. The concept of a ‘therapeutic window’ of P2Y₁₂ receptor reactivity associated with both ischemic event occurrence (upper threshold) and bleeding risk (lower threshold) has been proposed.

Areas covered: An update on and a brief review of the current knowledge on antiplatelet resistance were presented. Evidence available from studies evaluating aspirin resistance and high and low on-treatment platelet reactivity to ADP during P2Y₁₂ receptor blocker therapy was collected from a selective literature search.

Expert opinion: The available evidence indicates that HPR is an independent risk factor for post-PCI ischemic event occurrences. The therapeutic window concept for the P2Y₁₂ receptor blocker therapy may facilitate the balance between reducing ischemic events and avoiding bleeding events, thereby improving net clinical outcome.     

Genetics of platelet inhibitor treatment

Dual antiplatelet therapy with aspirin and a P2Y₁₂ receptor antagonist is the standard of care in patients undergoing percutaneous coronary intervention (PCI) and in patients with acute coronary syndromes (ACS) because this regimen has markedly decreased the rate of cardiovascular events. The substantial variability in pharmacodynamic response as well as the moderate antiplatelet efficacy of clopidogrel has raised major concerns, since high on-clopidogrel platelet reactivity has consistently been associated with increased risk for ischaemic events in PCI patients. Baseline demographic and clinical variables contributing to the observed variability have been identified. Besides this, research within the past decade has focused on the impact of genetic polymorphisms encoding transport systems or enzymes involved in the absorption and metabolism of these drugs. Loss-of-function polymorphisms in CYP2C19 are the strongest individual variables affecting pharmacokinetics and antiplatelet response to clopidogrel, but explain no more than 5 to 12% of the variability in adenosine diphosphate-induced platelet aggregation on clopidogrel. No genetic variables contributing to clinical outcomes of patients treated with the newer P2Y₁₂ receptor antagonists, prasugrel or ticagrelor, have been identified so far. This review aims to provide an update on the current status of genotype-based personalized therapy with clopidogrel.     

Fish oil: what is the role in cardiovascular health?

Fish and fish oil supplements are often used to lower triglycerides; however, recent studies suggest the beneficial use of fish oil for other cardiovascular reasons. Studies have shown that in addition to decreasing triglycerides, fish oil has shown benefit in providing antiplatelet activity, improving heart failure, and improving vascular function in diabetes. Fish oil was shown to improve triglycerides in combination with other lipid-lowering therapy such as a statin or fibrate. Fish oil also had effects on lowering total cholesterol, very-low-density lipoprotein (VLDL), and increasing high-density lipoprotein (HDL). In terms of its antiplatelet activity, fish oil was shown to lower platelet aggregation when given in combination with clopidogrel and aspirin therapy during PCI, thus fish oil appears to enhance platelet response to clopidogrel. Fish oil has a role in heart failure as well.Fish oil was shown to slightly decrease morbidity and mortality in patients with class II-IV heart failure compared to placebo.Finally, fish oil showed benefit in patients with type II diabetes in terms of improving micro- and macrovascular function.     

氯吡格雷对二磷酸腺苷诱导的血小板聚集的影响

目的 :探讨氯吡格雷对血小板聚集率的影响。方法 :血小板聚集率增高病人 2 4例 ,男性 1 4例 ,女性 1 0例 ,年龄 (5 9±s 1 0 )a。给予氯吡格雷5 0mg ,po,qd×4wk。在服药后 8d,4wk后用光学法测定血小板聚集率 (ADP诱导法 ) ,Duke法测定出、凝血时间 ,凝血因子Ⅰ及血小板计数。结果 :高血小板聚集率的病人使用氯吡格雷后血小板聚集率明显下降 ,治疗后 8d,4wk分别下降 (3 1±2 5 ) % ,(3 2± 2 1 ) % ,(P <0 .0 1 )。但出、凝血时间 ,血小板计数及凝血因子Ⅰ含量在使用氯吡格雷后无明显变化。结论 :氯吡格雷可有效拮抗ADP诱导的血小板聚集作用     

氯吡格雷对不同体重的急性缺血性脑卒中患者的疗效观察

目的：研究标准剂量的氯吡格雷对正常体重指数范围内不同体重的急性缺血性脑卒中患者的防治效果。方法入组2012年9月至2013年5月,在南京市第一医院神经内科住院的正常体重指数范围内诊断为 AIS的患者126例,将其分性别取体重中位数等量分为高、低体重组各63例,给予标准剂量氯吡格雷抗血小板治疗,检测服药前及服药7 d 后的血小板聚集率,随访患者1年内卒中再发率及不良事件发生率。结果两组患者服用氯吡格雷前血小板聚集率为低体重组74．1％±13．2％,高体重组74．7％±13．6％,P ＝0．802,无统计学差异,服药7 d 后低体重组34．4％±9．8％,高体重组39．1％±14．4％,P ＝0．034,有显著的统计学差异。随访1年,两组卒中再发率及不良事件发生率无统计学差异。结论正常体重指数范围内,较低体重的患者在服用氯吡格雷7 d 后有更好的抗血小板作用。但此作用是否会减少缺血性卒中再发率或增加出血等不良事件发生率,仍需进一步研究。     

Clopidogrel: a review of its use in the prevention of thrombosis

Clopidogrel (Plavix), Iscover) selectively and irreversibly inhibits adenosine diphosphate (ADP)-induced platelet aggregation. Long-term administration of clopidogrel was associated with a modest but statistically significant advantage over aspirin in reducing adverse cardiovascular outcomes in patients with established cardiovascular disease in the CAPRIE trial. In other large well designed multicentre trials, such as CURE, COMMIT and CLARITY-TIMI 28, the addition of clopidogrel to aspirin therapy improved outcomes in patients with acute coronary syndromes. However, some issues regarding the use of clopidogrel remain unresolved, such as the optimal loading dose in patients undergoing percutaneous coronary interventions (PCI) and the optimal treatment duration following drug-eluting intracoronary stent placement. Results of several large randomised trials, therefore, have established clopidogrel as an effective and well tolerated antiplatelet agent for the secondary prevention of ischaemic events in patients with various cardiovascular conditions, including those with ischaemic stroke or acute coronary syndromes. In addition, treatment guidelines from the US and Europe acknowledge the importance of clopidogrel in contemporary cardiovascular medicine.     

雷贝拉唑和泮托拉唑对氯吡格雷抗血小板作用的影响

目的 探讨冠心病病人使用雷贝拉唑或泮托拉唑对氯吡格雷的抗血小板作用的影响.方法 148例冠心病病人在给予阿司匹林和氯吡格雷基础上,分成雷贝拉唑组(雷贝拉唑10 mg·d-1,n=50)、泮托拉唑组(泮托拉唑40 mg·d-1,n=48)和对照组(n=50).比较3 d后血小板聚集率.结果 三组平均血小板最大聚集率分别为雷贝拉唑组(44.4±21.1)、泮托拉唑组(39.4±21.4)、对照组(45.3±15.2),P=0.274,三组之间差异无统计学意义,三组间的氯吡格雷抵抗发生率分别为雷贝拉唑组(46.0%)、泮托拉唑组(41.7%)、对照组(38.0%),P=0.719,差异无统计学意义.结论 雷贝拉唑和泮托拉唑对氯吡格雷的抗血小板活性短期内无明显影响.     

CYP2C19、P2Y12基因多态性与缺血性脑卒中患者氯吡格雷抵抗的相关性研究

目的：考察CYP2C19、P2Y12受体的基因多态性与氯吡格雷抵抗的相关性研究.方法：96例中国缺血性脑卒中患者持续服用氯吡格雷75 mg,收集全血提取DNA,采用Sequenom MassARRAY iPLEX（R）基因型分析技术进行CYP2C19＊ 2（681G＞A,rs4244285）、CYP2C19＊3（636 G＞A,rs4986893）及P2Y12受体（52G＞T,rs6809699） （744T＞C,rs2046934）4个SNPs的基因型分析.采用二磷酸腺苷（ADP）诱导光比浊法测定血小板聚集功能.采用Chi-square检验或Fisher确切概率法分析相关性.结果：患者分为氯吡格雷抵抗（CR）组与非抵抗组,CYP2C19＊ 2（rs4244285）及P2Y12受体（rs2046934）基因型分布在两组间的差异有统计学意义（P=0.027,P=0.034）.其中,CYP2C19＊2 GA＋ AA基因型为CR发生的风险因素（OR=2.607,95％CI：1.062～6.399）.CYP2C19＊3（rs4986893）及P2Y12受体（rs6809699）基因型分布在两组比较中差异无统计学意义（P＞0.05）.结论：在中国缺血性脑卒中患者中,CYP2C19＊2（rs4244285） GA＋ AA型与氯吡格雷抵抗的发生密切相关,该基因型检测将有助于指导氯吡格雷的临床合理应用.