CYP2C19 genotype and adverse cardiovascular outcomes after stent implantation in clopidogrel-treated Asian populations: A systematic review and meta-analysis

The effect of CYP2C19 gene polymorphism on clinical outcomes of patients with coronary artery disease (CAD) treated with clopidogrel remains controversial. Ethnicity has been proposed to influence clopidogrel response following stent implantation in CAD patients with different CYP2C19 genotypes. Furthermore, Asian populations are reported to have a relatively greater prevalence of CYP2C19 loss-of-function (LOF) alleles. We aimed to evaluate the impact of CYP2C19 gene polymorphism on clinical outcomes in Asian populations who underwent percutaneous coronary interventions (PCI) and received clopidogrel therapy. We conducted a comprehensive search in PubMed, EMBASE, and Cochrane Library from their inceptions to January 20, 2017. Studies that reported clopidogrel therapy information, clinically relevant outcomes (adverse cardiovascular events, stent thrombosis and bleeding), and CYP2C19 genotypes among Asian populations were included. The primary endpoint was major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death and myocardial infarction. The safety endpoint was any kind of bleeding. We retrieved 20 studies of 15056 patients reporting 1301 cardiovascular events. The primary analysis showed at least one CYP2C19 LOF allele (*2 and/or *3) carriers were at an increased risk of MACE compared with non-carriers (10.58% vs. 6.07%, OR: 1.99, 95% CI: 1.64 to 2.42, p < .001). Stent thrombosis (ST) was also more frequent in LOF allele carriers (2.22% vs. 0.44%, OR: 4.77, 95% CI: 2.84 to 8.01, p < .001). Inversely, the risk of bleeding was lower in LOF allele carriers (OR: 0.66, 95% CI: 0.46 to 0.96, p < .001). Subgroup analysis was performed to assess differences by high (600 mg) or routine (300 mg) loading dose of clopidogrel and by different nationalities. The risk of MACE in LOF allele carriers remained significantly higher even in high loading dose group (high loading dose: OR 1.72, 95% CI: 1.37 to 2.16, and routine loading dose: OR 2.22, 95% CI: 1.68 to 2.94, p for subgroup heterogeneity = 0.16). Subgroup analysis between three nationalities of China, Korea, and Japan demonstrated that the risk of MACE among Chinese LOF allele carriers was the greatest (OR: 2.28; 95% CI:1.91 to 2.73). In conclusion, among Asian populations with CAD undergoing stent implantation, CYP2C19 LOF allele carriers are at greater risk of adverse cardiovascular events and lower risk of bleeding compared with non-carriers. Genetic testing may be helpful for clinicians to personalize antiplatelet therapy especially in Asian population.     

CYP2C19功能缺失性等位基因与老年冠心病患者支架植入术后氯吡格雷抗血小板反应性和疗效的药物基因组学研究

目的：探讨编码CYP2C19酶的基因（CYP2C19）功能缺失性（LOF）等位基因与老年冠心病患者支架植入术后氯吡格雷抗血小板反应性和临床心血管终点事件的关联性。方法连续募集2011年9月1日至2012年12月1日期间在解放军总医院住院拟行经皮冠状动脉介入术（PCI）、年龄≥65岁的老年冠心病患者,术前给予氯吡格雷负荷剂量（300mg）治疗,手术当日测定血小板聚集率,采用SNaPshot法进行CYP2C19 LOF等位基因型（CYP2C19＊2和CYP2C19＊3）检测,并记录在院临床资料。所有患者均在PCI术后1年规律服用阿司匹林和氯吡格雷,随访1年内主要心血管缺血和出血事件的发生率。结果在436例符合入选标准的老年冠心病患者中,CYP2C19＊2携带者与氯吡格雷负荷剂量治疗后的抗血小板反应性之间存在显著相关性（P＝0.001）,但在CYP2C19＊3携带者中未见上述相关性（P＝0.884）。CYP2C19＊2和至少一个CYP2C19 LOF携带者1年内心血管终点事件的发生率较非携带者均明显增加（P＜0.05）。与非携带者相比,CYP2C19＊2携带者因心绞痛再入院的发生率明显增加[校正比值比（OR）：1.67,95%可信区间（CI）：1.05～2.65,P＝0.010]。至少一个CYP2C19 LOF携带者的联合心血管事件（校正OR：1.22,95%CI：1.03～1.98,P＝0.049）和因心绞痛再入院（校正OR：1.67,95%CI：1.04～2.68,P＝0.032）的发生率较非携带者明显增加。结论 CYP2C19 LOF等位基因与老年冠心病患者PCI术后的氯吡格雷抗血小板反应性密切相关,并可明显削弱PCI术后双联抗血小板的治疗效果,导致PCI术后1年内的心血管终点事件发生风险明显增加。     

Variant recurrent risk among stroke patients with different CYP2C19 phenotypes and treated with clopidogrel

Polymorphisms of CYP2C19 have been associated with variant risk of subsequent cardiovascular events in survivors of myocardial infarction (MI) receiving clopidogrel. This study evaluated the impacts of CYP2C19 polymorphisms on stroke recurrence and other vascular events in a cohort of Chinese patients receiving clopidogrel. From Nanjing Stroke Registry Program, 625 consecutive patients with ischemic stroke were enrolled between May 2008 and April 2010. CYP2C19 variants (*2, *3, and *17) were genotyped. Clinical outcomes were determined with three monthly follow-up. The primary endpoint was a composite of vascular death, non-fatal ischemic stroke, and non-fatal MI. The second endpoint was bleeding events. The median exposure to clopidogrel was 13.2 (interquartile range, 8.9–18.0) months. Primary endpoint was observed in 85 (13.6%) patients and secondary endpoint in 13 (2.1%) patients. Frequencies of CYP2C19*1, *2, *3, and *17 alleles were 61.2, 34.0, 3.8, and 1.0%, respectively, in this patient cohort. CYP2C19 loss-of-function allele (*2 and *3, LOF) carriers were observed with higher risk of subsequent vascular events compared with non-carriers (17.2 versus 8.1%, HR?=?2.16, 95% CI: 1.31–3.56, p?=?0.003). After adjusted for age, sex, major cardiovascular risk factors, and drug agent, CYP2C19 LOF carrier was independently associated with primary endpoint (HR?=?2.31, 95% CI: 1.39–3.84, p?=?0.001). No significant association between CYP2C19 gain-of-function (*17, GOF) and clinical events was detected. In Chinese stroke survivors treated with clopidogrel, carriers of CYP2C19 LOF allele may have increased risk of recurrence.     

High on-treatment platelet reactivity by ADP and increased risk of MACE in good clopidogrel metabolizers

High on-treatment platelet reactivity (HPR) by ADP, which primarily reflects the effect of thienopyridines, has been found to be an independent predictor of ischemic events in patients with acute coronary syndrome (ACS) on dual antiplatelet therapy. CYP2C19*2 is associated with HPR by ADP. The aim of our study was to evaluate if high on-clopidogrel platelet reactivity (HPR) by ADP is associated with an increased risk of major adverse coronary events (MACE) after ACS independent of CYP2C19*2 allele, i.e. whether genotyping patients for CYP2C19*2 polymorphism is sufficient to identify those to be switched to novel antiplatelets. A total of 1187 patients were included (CYP2C19 *1/*1 n?=?892; *1/*2 n?=?264; *2/*2 n?=?31); 76 MACE (CV death and non-fatal MI) were recorded in non-carriers of CYP2C19*2 (8.5%) and 39 in carriers of CYP2C19*2 (13.2%). At the landmark analysis in the first 6 months, HPR by ADP and CYP2C19*2 allele were both significantly and independently associated with MACE [HPR by ADP: HR?=?2.0 (95% CI 1.2–3.4), p?=?0.01; CYP2C19*2 allele: HR?=?2.3 (95% CI 1.3–3.9), p?=?0.003]. At the land mark analysis from 7 to 12 months, only HPR by ADP remained significantly associated with the risk of MACE [HPR by ADP: HR?=?2.7 (95% CI 1.4–5.3), p?=?0.003; CYP2C19*2: HR?=?0.8 (95% CI 0.2–1.1), p?=?ns]. CYP2C19*2 allele and HPR by ADP are both independently associated with an increased risk of MACE in the first 6 months after ACS. HPR by ADP is associated with an increased risk until 12 months of follow-up. Therefore, both phenotype and genotype are clinically relevant for the evaluation of the antiplatelet effect of clopidogrel and for the prognostic stratification of ACS patients.     

Multisite Investigation of Outcomes With Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention

Objectives

This multicenter pragmatic investigation assessed outcomes following clinical implementation of CYP2C19 genotype–guided antiplatelet therapy after percutaneous coronary intervention (PCI).

The relationship between CYP2C19 polymorphisms and ischaemic and bleeding outcomes in stable outpatients: the CHARISMA genetics study

Aims Clinical trials have established the value of clopidogrel therapy in a wide spectrum of patients with cardiovascular diseases. Both loss- and gain-of-function single nucleotide variants of CYP2C19 genes have been identified that affect clopidogrel metabolism and anti-platelet response. We sought to determine the impact of CYP2C19 polymorphisms on ischaemic and bleeding events. Methods and results A subset of patients from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial who consented to genotyping was analysed. Patients with clinically evident cardiovascular disease or multiple risk factors were enrolled in the trial. The rates of ischaemic and bleeding events were compared between carriers and non-carriers of loss-of-function and gain-of-function alleles in patients randomized to clopidogrel vs. placebo. A total of 4819 patients were genotyped and available for the analysis. Carriers of CYP2C19 loss-of-function alleles did not have an increased rate of ischaemic events. However, clopidogrel-treated patients did have a significantly lower rate of any bleeding in carriers: 36.1% (240/665) vs. 42.5% (681/1601) in non-carriers, HR: 0.80, 95% CI: 0.69-0.93, P = 0.003 (genotype/treatment interaction, P-value = 0.023). The CYP2C19 gain-of-function alleles did not affect ischaemic or bleeding endpoints. Conclusion No relationship was seen between CYP2C19 status and ischaemic outcomes in stable patients treated with clopidogrel. There was, however, significantly less bleeding with clopidogrel in carriers of the loss-of-function allele, suggesting less anti-platelet response. Although several prior studies, including mainly stented patients, have emphasized the relationship between CYP2C19 loss-of-function alleles and efficacy of clopidogrel, this study of stable patients establishes a potential link with reduced bleeding complications. Clinical Trial Registration: This study is registered with ClinicalTrials.gov number, NCT00050817.     

CYP2C19基因多态性与氯吡格雷抵抗的研究进展

氯吡格雷是治疗急性冠脉综合征的一种经典抗血小板药物,但是临床观察到部分患者不能从氯吡格雷的治疗中获益,从而提出了氯吡格雷抵抗（CR）的问题。目前研究认为,CR受多因素影响,其中CYP2C19基因的多态性是最重要的内部因素。CYP2C19基因变异者,氯吡格雷的活性代谢产物减少,抗血小板效应减弱,不良心血管事件增加。而CYP2C19＊2和CYP2C19＊3是亚洲人最常见类型,因此,探讨CYP2C19基因的多态性对氯吡格雷疗效的影响具有临床意义。     

老年冠状动脉支架植入术后患者CYP2C19基因681G＞A单核苷酸多态性与氯吡格雷抵抗的相关性

目的拟通过该项研究,探讨在中国汉族老年冠心病患者植入药物洗脱支架后,CYP2C19基因681G〉A位点单核苷酸多态性与氯吡格雷抵抗（CR）之间的关系。方法2010年6月至2011年4月,连续入选在沈阳军区总医院心血管内科住院治疗并成功接受经皮冠状动脉药物洗脱支架植入术的老年（年龄≥60岁）冠心病患者614例。所有人选患者全部接受双联抗血小板治疗（氯吡格雷＋阿司匹林）,均给予负荷剂量氯吡格雷600mg及阿司匹林300mg,并于服药24h后采静脉血测定20μmol／L的ADP诱导的残余血小板聚集率（RPA）。定义RPA≥70％为CR,RPA〈70％为氯吡格雷非抵抗（NCR）。使用酚．氯仿法提取全血中白细胞基因组DNA标本,并通过聚合酶链反应．限制性片段长度多态性（PCR-RFLP）方法测定CYP2C19基因681G〉A位点单核苷酸多态类型。结果在所有入选的614例老年冠心病患者中,CR的发生率为20．5％（126例）,NCR为79．5％（488例）。CYP2C19基因681G〉A多态位点的三种基因型（GGGA,AA）的频率,在CR组中分别为32．6％、47．6％和19．8％,在NCR组中分别为47．9％,45．1％和7．0％。其中,AA型纯合子在CR组中的频率显著高于NCR组（OR=3．03,95％CI：1．889-5．784,P=0．003）。A等位基因的携带者较G等位基因携带者更易发生CR（OR=1．85,95％CI：1．392-2．459,P：0．002）。结论在中国汉族老年冠心病患者中,CYP2C19基因681G〉A位点单核苷酸多态性与氯吡格雷抵抗的发生存在相关性,其A等位基因可能是氯吡格雷抵抗的遗传易感因素之一。     

CYP2C19＊2基因多态性与经皮冠状动脉介入治疗后氯吡格雷抗血小板临床疗效的相关性

目的探讨CYP2C19＊2（c．681G〉A,rs4244285）基因多态性与经皮冠状动脉介入（percutaneouscoronaryintervention,PCI）治疗后氯吡格雷抗血小板临床疗效的相关性。方法选择478例接受PCI治疗的急性冠脉综合征（acutecoronarysyndrome,ACS）患者,采用TaqMan基因分型技术检测其CYP2C19＊2的基因多态性。患者术后均采用氯吡格雷抗血小板治疗并定期随访,分析不同基因型与PCI治疗后支架内血栓、主要心血管事件（majoradversecardiacevents,MACE）发生率及生存时间的相关性。采用COX单因素分析检测PCI治疗后发生MACE的相关因素,采用COX多因素分析检测PCI治疗后MACE的危险因素。结果本研究人群中的CYP2C19＊2的基因型分布符合Hardy—Weinberg平衡。478例患者纯合野生型（GG）238例（49．8％）,杂合型（GA）加纯合突变型（AA）240例（50．2％）。分析结果显示,对于支架内血栓（P=0．025）及MACE（P=0．09）,携带681GG基因型的患者预后较携带681A等位基因（AA／AG基因型）的好。单因素COX回归结果显示,CYP2C19＊2的基因型、糖尿病病史、原发性高血压（高血压）病史[RR（95％CI）为2．796（1．245—6．281）、2．157（1．039—4．478）和3．564（1．364-9．312）]是发生MACE的相关因素。多因素COX回归分析结果显示,CYP2C19＊2的基因型、高血压病史是发生MACE的危险因素。结论CYP2C19＊2的基因多态性与PCI治疗后氯吡格雷抗血小板临床疗效有关,CYP2C19＊2基因突变能够降低氯吡格雷抗血小板效果,增加PCI治疗后发生支架内血栓、MACE的风险。     

Polymorphisms in xenobiotic-metabolizing genes and the risk of chronic lymphocytic leukemia and non-Hodgkin's lymphoma in adult Russian patients

Polymorphisms in genes coding xenobiotic-metabolizing enzymes are considered as risk factors modifying susceptibility to cancer. We developed a biochip for the analysis of 18 mutations in 10 genes of metabolizing system: CYP1A1, CYP2D6, GSTT1, GSTM1, MTHFR, MTRR, NQO1, CYP2C9, CYP2C19, and NAT2. Using allele-specific hybridization on the biochip 76 T-cell non-Hodgkin's lymphoma (NHL) patients, 83 B-cell chronic lymphocytic leukemia (B-CLL) patients, and 177 healthy donors were tested. Polymorphic CYP1A1 alleles were more frequent in B-CLL patients relative to normal controls, for example, a combination of polymorphic variants 4887C > A, 4889A > G, and 6235T > C (OR = 1.76, 95% CI = 1.0-3.1). The GSTM1 null genotype was more frequent in NHL patients relative to controls (OR = 1.82, 95% CI = 1.1-3.1). The combination of unfavorable polymorphic CYP1A1 variants and GSTM1 null genotype was found more frequently in B-CLL patients relative to controls (OR = 2.52, 95% CI = 1.3-4.9). In addition, male B-CLL patients demonstrated a significantly increased occurrence of heterozygous and homozygous allele *2 of CYP2C9 gene (OR = 2.38, 95% CI = 1.1-5.2) as well as a combination of alleles *2 and *3 of the gene (OR = 2.09, 95% CI = 1.1-3.9). Thus, our findings show the association between polymorphic alleles of CYP1A1, GSTM1, and CYP2C9 genes and the risk to develop NHL or B-CLL. The developed biochip can be considered as a convenient analytical tool for research studies and predictive analysis in oncohematology.     

CYP2C19基因多态性与氯吡格雷抵抗的研究现状

氯吡格雷是目前治疗急性冠状动脉综合征的一种经典抗血小板药物,能降低冠心病患者尤其是支架术后患者的主要不良心血管事件的风险。但是部分患者存在氯吡格雷抵抗。研究认为,氯吡格雷抵抗受多因素影响,CYP2C19基因多态性是最重要的内部因素。CYP2C19*2和CYP2C19*3是亚洲人群最常见类型,CYP2C19基因变异者,氯吡格雷抗血小板效应减弱,不良心血管事件增加。因此,常规检测CYP2C19基因多态性可指导临床上氯吡格雷个性化用药。     

Risk of stroke in CYP2C19 LoF polymorphism carrier coronary artery disease patients undergoing clopidogrel therapy: An ethnicity-based updated meta-analysis

BackgroundAntiplatelet agent clopidogrel has been widely used for stroke management for many years, although resistance to clopidogrel may increase the chance of stroke recurrence. CYP2C19 loss-of-function (LoF) polymorphism is assumed to be responsible for the poor metabolism of clopidogrel that ultimately turns to resistance. Previous publications could not provide firm evidence due to highly conflicting and heterogeneous outcomes.AimTo get clear evidence from an updated meta-analysis on CYP2C19 LoF polymorphism association with stroke risk in clopidogrel treated patients, this study has been performed.MethodsWe conducted a meta-analysis with 72 selected studies from authentic databases, including 40,035 coronary artery disease patients treated with clopidogrel.ResultsThis analysis showed that the worldwide carrier of one or more CYP2C19 LoF alleles had a significantly higher risk of stroke and composite events than the non-LoF carriers (RR=1.78, 95% CI=1.52-2.07, p<0.00001 and RR=1.39, 95% CI=1.26-1.54, p<0.00001, respectively). Besides, subgroup analysis showed that Asian CYP2C19 LoF carriers had a significantly increased risk of stroke (RR=1.91, 95% CI=1.60-2.28, p<0.00001) while the risk of composite events was significantly higher in all ethnic populations (Asian: RR=1.58, 95% CI=1.32-1.89, p<0.00001; Caucasian: RR=1.27, 95% CI=1.08-1.50, p=0.003; Hispanic and others: RR=1.21, 95% CI=1.09-1.34, p=0.0003).ConclusionOur meta-analysis confirmed that the presence of CYP2C19 LoF alleles increases the risk of stroke and composite events recurrence in the worldwide population, especially in Asians undergoing clopidogrel treatment. Alternative antiplatelet therapy should be investigated thoroughly for the intermediate and poor metabolizers.     

Antithrombotic Regimens for Patients Taking Oral Anticoagulation After Coronary Intervention: A Meta‐analysis of 16 Clinical Trials and 9185 Patients

The optimal antithrombotic regimen remains controversial in patients taking oral anticoagulation (OAC) undergoing coronary stenting. This study sought to compare efficacy and safety outcomes of triple therapy (OAC, aspirin, and clopidogrel) vs dual therapy (clopidogrel with aspirin or OAC) in these patients. We hypothesize OAC plus clopidogrel could be the optimal regimen for patients with indications for OAC receiving stent implantation. Medline, the Cochrane Library, and other Internet sources were searched for clinical trials comparing the efficacy and safety of triple vs dual therapy for patients taking OAC after coronary stenting. Sixteen eligible trials including 9185 patients were identified. The risks of major adverse cardiac events (odds ratio [OR]: 1.06, 95% confidence interval [CI]: 0.82‐1.39, P = 0.65), all‐cause mortality (OR: 0.98, 95% CI: 0.76‐1.27, P = 0.89), myocardial infarction (OR: 1.01, 95% CI: 0.77‐1.31, P = 0.97), and stent thrombosis (OR: 0.91, 95% CI: 0.49‐1.69, P = 0.75) were similar between triple and dual therapy. Compared with dual therapy, triple therapy was associated with a reduced risk of ischemic stroke (OR: 0.57, 95% CI: 0.35‐0.94, P = 0.03) but with higher major bleeding (OR: 1.52, 95% CI: 1.11‐2.10, P = 0.01) and minor bleeding (OR: 1.59, 95% CI: 1.05‐2.42, P = 0.03). Subgroup analysis indicated there were similar ischemic stroke and major bleeding outcomes between triple therapy and therapy with OAC plus clopidogrel. Treatment with OAC and clopidogrel was associated with similar efficacy and safety outcomes compared with triple therapy. Triple therapy could be replaced by OAC plus clopidogrel without any concern about additional risk of thrombotic events.     

Factors determining clinical effectiveness of clopidogrel and prognosis of patients with stable ischemic heart disease

Aim of the study was to elucidate genetic and drug factors affecting efficacy of clopidogrel in patients with ischemic heart disease - inhabitants of central region of Russian Federation. We included 399 patients with IHD (79% men, mean age 58.3+/-9 years) receiving long term therapy with clopidogrel 75 mg/day (during stable manifestations of the disease) or 75-150 mg/day in combination with aspirin (in relation with recent elective percutaneous interventions). We studied carriage of polymorphisms of genes controlling intestinal absorption of clopidogrel (ABCB1 C3435T), activation of clopidogrel in the liver (CYP2C19 *1 *2), and also registered concomitant administration of proton pump inhibitors (PPI). Then we determined relationship of these factors to development of vascular complications (vascular death/myocardial infarction/requirement in revascularization) during 18 months followup. Among studied genetic factors carriage of allele variants CYP2C19 *1/*2 and *2/* (found in 25.5 and 1.8% of patients, respectively), possessed prognostic significance. In the group of clopidogrel monotherapy carriage of at least one *2 allele was associated with increased rate of vascular complications (33.3% vs. 11.3%) including thrombotic complications (27.7% vs. 3.2%; =0.01). In patients receiving 75 mg/day of clopidogrel in combination with aspirin total rate of thrombotic complications as well as of all adverse unfavorable outcomes was higher in *2 carriers compared with wild type homozygotes (14.0% vs.8.7% and 21.0% vs. 15.8%, respectively). In patients receiving double dose clopidogrel in combination with aspirin we found no worsening of outcomes associated with CYP2C19*2 carriage. In the multifactorial risk model independent predictors of vascular complications turned out to be CYP2C19 *2/*2 homozygosity (RR 4.9; =0.02) and concomitant PPI administration ( 1.8; p=0.05).     

<Emphasis Type="Italic">CYP2C19</Emphasis> LOF and GOF-Guided Antiplatelet Therapy in Patients with Acute Coronary Syndrome: A Cost-Effectiveness Analysis

Purpose

This study aimed to examine the cost-effectiveness of CYP2C19 loss-of-function and gain-of-function allele guided (LOF/GOF-guided) antiplatelet therapy in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI).

Methods

A life-long decision-analytic model was designed to simulate outcomes of three strategies: universal clopidogrel (75 mg daily), universal alternative P2Y₁₂ inhibitor (prasugrel 10 mg daily or ticagrelor 90 mg twice daily), and LOF/GOF-guided therapy (LOF/GOF allele carriers receiving alternative P2Y₁₂ inhibitor, wild-type patients receiving clopidogrel). Model outcomes included clinical event rates, quality-adjusted life-years (QALYs) gained and direct medical costs from perspective of US healthcare provider.

Results

Base-case analysis found nonfatal myocardial infarction (5.62%) and stent thrombosis (1.2%) to be the lowest in universal alternative P2Y₁₂ inhibitor arm, whereas nonfatal stroke (0.72%), cardiovascular death (2.42%), and major bleeding (2.73%) were lowest in LOF/GOF-guided group. LOF/GOF-guided arm gained the highest QALYs (7.5301 QALYs) at lowest life-long cost (USD 76,450). One-way sensitivity analysis showed base-case results were subject to the hazard ratio of cardiovascular death in carriers versus non-carriers of LOF allele and hazard ratio of cardiovascular death in non-carriers of LOF allele versus general patients. In probabilistic sensitivity analysis of 10,000 Monte Carlo simulations, LOF/GOF-guided therapy, universal alternative P2Y₁₂ inhibitor, and universal clopidogrel were the preferred strategy (willingness-to-pay threshold = 50,000 USD/QALY) in 99.07%, 0.04%, and 0.89% of time, respectively.

Conclusions

Using both CYP2C19 GOF and LOF alleles to select antiplatelet therapy appears to be the preferred antiplatelet strategy over universal clopidogrel and universal alternative P2Y₁₂ inhibitor therapy for ACS patients with PCI.

     

PEAR1基因多态性对冠心病患者预后的影响

目的分析血小板内皮聚集受体-1(PEAR1)基因多态性对冠心病患者临床预后的影响。方法连续纳入2016年12月至2018年12月于北京大学人民医院心血管内科行冠状动脉介入诊疗并接受阿司匹林和氯吡格雷双联抗血小板治疗的冠心病患者。检测患者PEAR1基因(rs822441、rs12041331)以及CYP2C19基因(rs4986893、rs4244285)单核苷酸多态性(SNP)。临床随访2年,主要终点是全因死亡、非致死性心肌梗死、缺血性卒中和不稳定型心绞痛(UA)导致再次住院的复合事件。在校正CYP2C19功能缺失型(LOF)等位基因及其他混杂因素后,利用Cox回归分析研究PEAR1基因多态性对冠心病患者临床预后的影响。结果共纳入411例冠心病患者,平均随访时间(737.7±0.7)d,共有22例发生主要终点事件。将年龄、总胆固醇、肌酐、左主干病变、CYP2C19 LOF等位基因携带状态作为协变量纳入多因素Cox回归分析中,结果显示PEAR1基因SNP rs822441、rs12041331与主要终点事件风险无相关性,但rs822441突变型等位基因携带者发生UA导致再次住院事件风险升高(校正HR 5.084,95%CI 1.071~24.131,P=0.041)。结论PEAR1基因SNP rs822441与冠心病患者临床预后具有相关性。     

Comparison of ticagrelor and clopidogrel in the treatment of patients with coronary heart disease carrying CYP2C19 loss of function allele

BackgroundClopidogrel is a traditional P2Y12 receptor inhibitor that is widely used in clinical practice, but there are significant individual differences in its therapeutic effect. Carriers of the CYP2C19 deletion allele have a higher risk of adverse cardiovascular events than non-carriers.MethodsIn this study, 170 patients diagnosed with coronary heart disease (CHD) and on regular oral clopidogrel or ticagrelor antiplatelet therapy in the Department of Cardiology of Wuxi Second People’s Hospital from August to December 2019 were screened. Baseline patient data were collected, percutaneous coronary angiography (CAG) or coronary computed tomography angiography (CTA) results were recorded, CYP2C19 gene type was detected, and prognosis/outcome was assessed by telephone/outpatient/inpatient follow-up for 12 months.Results(I) Of the 170 patients, 0.66% were the fast metabolic type, 41.45% were the normal metabolic type, 42.76% were the intermediate metabolic type, and 15.13% were the poor metabolic type. CYP2C19*2 mutation accounted for 89.29% of all mutations, CYP2C19*3 mutation accounted for 9.82%, and CYP2C19*17 mutation accounted for only 0.89%. (II) Among the patients with CHD who regularly took clopidogrel, the risk in the intermediate metabolic group was 5.208-fold higher than that of normal metabolic group, and that of the poor metabolic group was 3.75-fold higher than that of normal metabolic group; there was no significant difference between the intermediate and poor metabolic groups. (III) Prognosis was significantly associated with regular use of ticagrelor or clopidogrel by patients in the intermediate metabolic group. There was no significant correlation between poor metabolism (PM) and normal metabolism (NM). Prognosis was significantly associated with regular use of ticagrelor or clopidogrel in patients undergoing percutaneous coronary intervention (PCI), but not in patients who did not undergo PCI.ConclusionsCYP2C19 polymorphism was associated with the prognosis of patients with CHD administered antiplatelet therapy with oral clopidogrel. The incidence of poor prognosis was significantly increased with CYP2C19*2 and/or CYP2C19*3 mutations, and patients undergoing PCI or carrying a single CYP2C19 deletion allele had a better prognosis with ticagrelor as replacement therapy.     

Relation of cytochrome P450 2C19 gene 681G&gt;A single nucleotide polynmrphism to clopidogrel resistance after PCI in Chinese

Objectives Clopidogrel is a prodrug that has to be converted to an active metabolite by hepatic cytochrome P450(CYP) isoenzymes to inhibit platelet aggregation.Individualvariability of platelet inhibition by clopidogrel suggests a possibility for genetic factors having a significant influence on clopidogrel responsiveness.In this study,we sought to determine the association between the single nucleotide polymorphism of CYP 2C19 681G>A and the occurrence of clopidogrel resistance(CR) in Chinese.Methods The study enrolled 614 hospitalized patients who underwentsuccessful percutaneouscoronary intervention with drug-eluting stents were received the treatmentwith dual antiplatelet regimen(aspirin plus clopidogrel).All patients received loading doses of 600 mg clopidogrel and 300 mg aspirin.20μmol/L ADP-induced platelet aggregation ratio(PAR ) was assessed 24 h after clopi- dogrel administration.The maximum residual PAR≥70%was defined as CR.Genomic DNA was extracted from whole blood samples according to standard protocols,the single nucleotide polymorphism of the CYP2C19 681G>A was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in all the patients.Results CR was found in 126 patients(20.5%).There was CYP2C19 681G>A polymorphism in the study population.The frequencies of the three kinds of genotypes(GG,GA,A A) in CR group and non-CR (NCR)group were 32.5%,47.6%,19.8%and 48.0%, 45.0%,7.0%,respectively.The frequency of AA genotype was significantly higher in NCR group than that in CR group (OR =3.03,95%CI:1.889～5.784,P=0.003).The A allele carriers were more likely to develop clopidogrel resistance compared with that of G allele carriers(OR=1.85,95%CI: 1.392～2.459,P=0.002).Conclusions CYP2C19 681G/A polymorphism is associated with the risk of CR,and the A allele carriers may be a possible genetic susceptibility factor for patients with CR.     

Genetic susceptibility to nonsteroidal anti-inflammatory drug-related gastroduodenal bleeding: role of cytochrome P450 2C9 polymorphisms

BACKGROUND AND AIMS: Several nonsteroidal anti-inflammatory drugs (NSAIDs) are metabolized by the cytochrome P450 2C9 (CYP2C9). Two common variants of the CYP2C9 gene (CYP2C9*2 and *3) were reported to significantly affect the activity of the CYP2C9 enzyme. The aim of this study was to evaluate the impact of CYP2C9 polymorphisms on the risk of gastroduodenal bleeding in acute NSAID users. METHODS: This case-control study included 26 patients with endoscopically documented NSAID-related gastroduodenal bleeding lesions and 52 age-, sex- and NSAID use-matched controls with no lesions at endoscopy. Both cases and controls were Helicobacter pylori negative and acute users of an NSAID or cycloxygenase-2 inhibitor that undergoes CYP2C9 metabolism (ie, celecoxib, diclofenac, ibuprofen, naproxen, or piroxicam). Two marker single nucleotide polymorphisms in the CYP2C9 gene, identifying the CYP2C9 *2 and *3 allele, were evaluated in all subjects. RESULTS: Setting the CYP2C9*1/*1 wild type as reference, significantly higher frequencies of CYP2C9*1/*3 (34.6% vs 5.8%; P < .001; odds ratio [OR], 12.9; 95% confidence interval [CI], 2.917-57.922) and CYP2C9*1/*2 (26.9% vs 15.4%; P = .036; OR, 3.8; 95% CI, 1.090-13.190) were identified in bleeding versus control patients, whereas no differences between bleeding and controls were observed in the distribution of CYP2C9*2/*3 heterozygotes. Considering allele carriers, the presence of CYP2C9*3 allele was associated with a significant high risk of bleeding (adjusted OR, 7.3; 95% CI, 2.058-26.004). CONCLUSIONS: CYP2C9 genotyping may identify subgroups of persons who potentially are at increased risk of gastroduodenal bleeding when treated with NSAIDs metabolized by CYP2C9. Further studies that evaluate the effectiveness of a strategy using CYP2C9 genotyping in NSAID users are needed before genotyping is introduced into clinical practice.