ChiCTR1800015597 版本V1.0 版本创建时间2018/04/20 11:14:33 中国临床试验注册中心

审核状态：

Project audit state：

通过审核

Successful

注册号：

Registration number：

 ChiCTR1800015597 

最近更新日期：

Date of Last Refreshed on：

 2018-04-11 15:01:09 

注册时间：

Date of Registration：

 2018-04-11 00:00:00 

注册号状态：

预注册

Registration Status：

Prospective registration

注册题目：

药物基因导向的氯吡格雷个体化精准用药临床路径的研究

Public title：

Clinical pathway study of drug gene-directed clopidogrel individualized and precise medication

注册题目简写：

English Acronym：

研究课题的正式科学名称：

药物基因导向的氯吡格雷个体化精准用药临床路径的研究

Scientific title：

Clinical pathway study of drug gene-directed clopidogrel individualized and precise medication

研究课题代号(代码)：

Study subject ID：

 1604a0802097

在二级注册机构或其它机构的注册号：

The registration number of the Partner Registry or other register：

申请注册联系人：

栾家杰 

研究负责人：

栾家杰 

Applicant：

Luan Jiajie 

Study leader：

Luan Jiajie 

申请注册联系人电话：

Applicant telephone：

 +86 15855965132

研究负责人电话：

Study leader's
telephone：

+86 15855965132

申请注册联系人传真 ：

Applicant Fax：

研究负责人传真：

Study leader's fax：

申请注册联系人电子邮件：

Applicant E-mail：

 luanjiajie757@163.com

研究负责人电子邮件：

Study leader's E-mail：

 luanjiajie757@163.com

申请单位网址(自愿提供)：

Applicant website(voluntary supply)：

研究负责人网址(自愿提供)：

Study leader's website(voluntary supply)：

申请注册联系人通讯地址：

安徽省芜湖市赭山西路2号

研究负责人通讯地址：

安徽省芜湖市赭山西路2号

Applicant address：

2 Zheshan Road West, Wuhu, Anhui, China

Study leader's address：

2 Zheshan Road West, Wuhu, Anhui, China

申请注册联系人邮政编码：

Applicant postcode：

 241001

研究负责人邮政编码：

Study leader's postcode：

 241001

申请人所在单位：

皖南医学院弋矶山医院

Applicant's institution：

Yijishan Hospital of Wannan Medical College

研究负责人所在单位：

皖南医学院弋矶山医院

Affiliation of the Leader：

Yijishan Hospital of Wannan Medical College

是否获伦理委员会批准：

是

Approved by ethic committee：

Yes

伦理委员会批件文号：

Approved No. of ethic committee：

 2017-24

伦理委员会批件附件：

Approved file of Ethical Committee：

 查看附件View

批准本研究的伦理委员会名称：

皖南医学院弋矶山医院科学研究伦理委员会

Name of the ethic committee：

Scientific research IRB of Wannan Medical College Yijishan Hospital

伦理委员会批准日期：

Date of approved by ethic committee：

 2017-11-09 00:00:00

伦理委员会联系人：

杨春艳

Contact Name of the ethic committee：

Yang Chunyan

伦理委员会联系地址：

安徽省芜湖市赭山西路2号

Contact Address of the ethic committee：

2 Zheshan Road West, Wuhu, Anhui, China

伦理委员会联系人电话：

Contact phone of the ethic committee：

伦理委员会联系人邮箱：

Contact email of the ethic committee：

研究实施负责（组长）单位：

皖南医学院弋矶山医院

Primary sponsor：

Yijishan Hospital of Wannan Medical College

研究实施负责（组长）单位地址：

安徽省芜湖市赭山西路2号

Primary sponsor's address：

2 Zheshan Road West, Wuhu, Anhui, China

试验主办单位(项目批准或申办者)：

Secondary sponsor：

国家：

中国

省(直辖市)：

安徽省

市(区县)：

芜湖市

Country：

China

Province：

Anhui

City：

Wuhu

单位(医院)：

皖南医学院弋矶山医院

具体地址：

安徽省芜湖市赭山西路2号

Institution
hospital：

Yijishan Hospital of Wannan Medical College

Address：

2 Zheshan Road West, Wuhu, Anhui, China

经费或物资来源：

安徽省科技厅

Source(s) of funding：

Anhui provincial science and technology department

研究疾病：

急性冠脉综合症，缺血性脑卒中  

Target disease：

Acute coronary syndromes；Cerebral ischemic stroke

研究疾病代码：

Target disease code：

研究类型：

治疗研究

Study type：

Treatment study

研究所处阶段：

 其它 

Study phase：

N/A

研究设计：

单臂 

Study design：

Single arm 

研究目的：

本项目针对目前临床在使用氯吡格雷中存在问题及基因多态性对药物疗效的影响，提出以急性冠状动脉综合征和缺血性脑血管病需要接受介入治疗的患者为研究对象，以目前抗血小板治疗过程中存在的“药物抵抗”为切入点，对需要接受氯吡格雷治疗的患者进行CYP2C19基因型检测，研究此类基因在人群多态性分布，明确其对氯吡格雷疗效的影响，并在基因分型指导下对患者进行用药风险评估，针对不同风险等级患者实施个体化精准治疗。同时采用药效学、药动学和药物经济学研究指标来评价药物基因导向个体化治疗方案与标准治疗方案的优劣性，阐明药物基因导向的氯吡格雷个体化精准用药对氯吡格雷规范化使用的临床应用价值，旨在最大限度地提高氯吡格雷临床疗效，减少患者不良事件的发生，最终构建药物基因导向的氯吡格雷个体化精准用药的临床路径，力求在氯吡格雷抗血小板规范化治疗领域有所突破，提高临床合理用药水平，保障患者安全用药，也为国内指南的更新提供有力的科学依据。  

Objectives of Study：

The aim of this project is to investigate the problems existing in the clinical use of clopidogrel and the effect of gene polymorphism on the efficacy of clopidogrel. We choose the patients with acute coronary syndrome and ischemic stroke that need interventional therapy as the research object. We identify the drug resistance in the process of antiplatelet therapy as the breakthrough point. Firstly, CYP2C19 genotypes were detected in patients requiring clopidogrel treatment and then the polymorphic distribution of these genes in the population were also studied, which indicate the effect on the efficacy of clopidogrel. Finally, we evaluate the risk of drug use based on the guidance of genotyping and carry out individualized precise treatment for patients with different risk grades. At the same time, pharmacodynamics, pharmacokinetics and pharmacoeconomics indicators were used to evaluate the advantages and disadvantages between drug gene-oriented individualized and standard treatment scheme. These conclusions could elucidate the clinical value of clopidogrel individualized medication directed by drug gene. The aim is to maximize the clinical efficacy of clopidogrel, reduce the incidence of adverse events and ultimately construct the clinical pathway of the drug gene-directed clopidogrel individualized precise medication. We strive to make some breakthroughs in the field of clopidogrel antiplatelet therapy, improving the level of rational use of drugs, ensuring the safe use of drugs for patients, and provide a powerful scientific basis for the renewal of domestic guide.

药物成份或治疗方案详述：

本研究主要分为入组期、第一周期（住院治疗期）和第二周期（出院后随访期）三个阶段，共12个月（其中急性冠状动脉综合征研究周期12个月，缺血性脑血管病研究周期6个月）。入组期：通过入选标准和排除标准筛选入组患者，详细告知患者或（和）家属具体情况，签署知情同意书，建立患者病例记录表；第一周期：患者入组后，按照临床诊疗常规进行与患者疾病相关的实验室检查和临床诊治；第二周期：医学随访期，患者出院后分别在1个月、3个月、6个月及12个月后（从介入手术日开始计算，其中急性冠状动脉综合征随访期12个月，缺血性脑血管病随访期6个月）来到我院随诊，并按要求进行相关医学检查。 1 入组期 1.1人口学基本信息：住院号、姓名、性别、年龄、身高、体重（计算体重指数）、民族、婚姻状况、职业、文化程度、患者及直系亲属联系电话（至少2个）、联系地址（工作单位/家庭住址）。 1.2既往病史：疾病史、传染病史、手术外伤史、输血献血史、药物及其他过敏史。 1.3个人史：有酗酒、嗜烟、药物滥用或吸毒史；有疫区疫水接触史。 1.4体格检查：生命体征（腋下体温、静息坐位血压、脉搏和呼吸频率）；一般状况、皮肤粘膜、淋巴结、头部及其器官、颈部、胸部、腹部、脊柱及四肢、神经反射。 1.5实验室及器械检查：血常规、生化检查（肝功能、肾功能等）、血凝检查；12导联心电图和血管造影检查。 1.6临床诊断：包括主要诊断和其他诊断。 1.7筛选入组：本研究按照入选标准和排除标准筛选患者200例，随机分别进入个体化治疗组或常规治疗组接受治疗。其中个体化治疗组100例（包括50例急性冠脉综合征和50例缺血性脑卒中）和常规治疗组100例（包括50例急性冠脉综合征和50例缺血性脑卒中）。1.8患者入组后当前基本状况评估：①是否患急性疾病？②是否吸烟或接触二手烟？③是否饮酒？④是否饮用含咖啡因饮品？⑤是否剧烈运动？⑥是否饮用西柚汁，葡萄汁类？⑦是否保持良好的生活习惯（如维持每天睡眠时间6~8小时，饮食时间和结构规律：定时饮食，低脂饮食，推荐摄入富含不饱和脂肪酸的食物）？ 患者入组前需对其进行健康宣教，要求其按照上述评估指标执行，其中①-⑥是需要患者尽量避免这些不利于疾病治疗的相关事宜，如有发生请及时记录；⑦是需要尽量遵照执行，此项评估应贯穿研究全程，随访就诊时进行评估。 1.9个体化治疗组患者药物基因检测及机体对氯吡格雷处置（代谢）能力评估 1.9.1 药物基因型检测（化学药物用药指导的基因检测） 患者入组后术前采用EDTA抗凝真空管采集外周静脉血5ml，采用荧光染色原位杂交技术检测CYP2C19*2、CYP2C19*3、CYP2C19*17基因型。 1.9.2机体对氯吡格雷处置（代谢）能力评估 ①机体对氯吡格雷处置能力正常：药物基因检测结果为 CYP2C19*1*1或*1/*17或*17/*17，该患者CYP2C19为快代谢型（RM）或超快代谢型（UM）。 (该类患者无需调整氯吡格雷初始给药剂量，75mg/d) 。 ②机体对氯吡格雷处置能力减弱：药物基因检测结果为 CYP2C19*1/*2或*1/*3，或者为CYP2C19*2/*17或*3/*17，患者为中间代谢型（IM）。(该类患者采用氯吡格雷75mg/d，阿司匹林100mg/d和西洛他唑100mg，bid) ③机体对药物处置能力极低：药物基因检测结果为CYP2C19*2/*2，或CYP2C19*3/*3，或CYP2C19*2/*3，患者属于慢代谢型（PM）。（该类患者采用替格瑞洛90mg，bid和阿司匹林100mg/d） 2 第一周期（住院治疗期） 2.1给药方案：所有患者于手术当日给药，包括术前给予负荷剂量和术后给予维持剂量，用药前10h及服药后4h内禁食。 2.1.1 选用药物 阿司匹林（拜阿司匹林，100mg/片，拜耳医药保健公司，100mg*30片/盒）；氯吡格雷（泰嘉，25mg/片，深圳信立泰制药有限公司，25mg*20片/盒）；替格瑞洛（倍林达，90mg/片，阿斯利康药业股份有限公司，90mg*14片/盒）。 2.1.2给药 所有患者均同时服用阿司匹林（100mg/d）和氯吡格雷两种抗血小板药。氯吡格雷用药剂量需根据具体情况进行调整，调整原则为：常规治疗组患者均采用75mg/d初始维持剂量，个体化治疗组依据患者药物基因型检测及机体对氯吡格雷处置能力给药：①机体处置能力正常：氯吡格雷75mg/d和阿司匹林100mg/d；②机体处置能力减弱：氯吡格雷75mg/d、阿司匹林100mg/d和西洛他唑100mg，bid；③机体处置能力降低（弱代谢）：替格瑞洛90mg，bid和阿司匹林100mg/d。 2.2药动学检测：两组患者连续服用氯吡格雷5d后，第6d清晨空腹采集患者外周静脉血3ml，采用高效液相色谱-质谱联用法（HPLC-MS/MS）分别检测患者体内氯吡格雷酸的浓度（如果患者未服用氯吡格雷，则不需检测）。 2.3药效学检测：主要通过实验室检测相关指标来评估。 （1）血小板功能试验：采用血栓弹力图仪描记血小板图以检测患者服药120h（第5天）后，以二磷酸腺苷（ADP）和花生四烯酸（AA）为诱导剂的血小板聚集抑制率（inhibition of platelet aggregation，IPA），其中IPA（ADP）评估氯吡格雷疗效，IPA（AA）评估阿司匹林疗效。如果IPA≥75%为效果良好，50%~75%为起效，＜50%为效果欠佳。≥50%定义为药物敏感，＜50%则定义为药物不敏感（即对药物抵抗）。 如果患者检测的IPA（ADP）＜50%，则需进一步调整给药方案（如患者初始方案为氯吡格雷75mg/d和阿司匹林100mg/d，则调整方案为氯吡格雷75mg/d、阿司匹林100mg/d和西洛他唑100mg，bid；如初始方案为氯吡格雷75mg/d、阿司匹林100mg/d和西洛他唑100mg，bid，则调整为替格瑞洛90mg，bid和阿司匹林100mg/d。 如果患者调整治疗方案后，IPA（ADP）仍＜50%，则采用阿司匹林100mg/d和替格瑞洛90mg，bid的治疗方案。 （2）其他实验室检查：包括血常规、生化检查（肝功能、肾功能）、血凝检查；器械检查：12导联心电图。 2.4 安全性监测 （1）生命体征监测：患者在给药前和给药后4h、8h、24h、48h、72h、96h、120h进行生命体征的监测（血压、心率、血氧饱和度等）。 （2）不良事件观察：主要观察患者在给药后是否发生与研究相关的不良事件，如发生，则填写不良事件表。 3 第二周期（出院后随访期） 对两组患者分别在服药后第1个月、3个月、6个月和12个月进行医学随访（其中急性冠状动脉综合征随访期12个月，缺血性脑血管病随访期6个月），主要包括实验室检测、不良事件评估及患者依从性调查。如果患者发生不良事件，则随时记录。 3.1 实验室检测： （1）血小板功能试验：两组患者上午空腹采集外周静脉血3ml，采用血栓弹力图仪检测服药后1个月、3个月、6个月和12个月以二磷酸腺苷（ADP）为诱导剂的血小板聚集抑制率IPA-ADP（其中急性冠状动脉综合征在服药后1个月、3个月、6个月和12个月检测，缺血性脑卒中在服药后1个月、3个月和6个月检测）。 （2）其他实验室检查：包括血常规、生化检查（肝功能、肾功能）、血凝检查；器械检查、12导联心电图。 3.2药动学检测：两组患者连续服用氯吡格雷服药后1个月、3个月、6个月和12个月后，次日清晨空腹采集患者外周静脉血3ml，采用高效液相色谱-质谱联用法（HPLC-MS/MS）分别检测患者体内氯吡格雷酸的浓度。如果患者未服用氯吡格雷，则不需检测（其中急性冠状动脉综合征在服药后1个月、3个月、6个月和12个月检测，缺血性脑血管病在服药后1个月、3个月和6个月检测）。 备注：该项检测也可以判断患者是否按医嘱服用氯吡格雷。 3.3 安全性监测：观察患者在随访期间疾病症状是否复发或加重以及是否再住院等不良事件的发生情况，其中病情平稳包括无胸闷胸痛等临床症状，或为稳定性心绞痛，或有心电图显示无动态改变。病情恶化则是指出院后3个月内发生不良心脑血管事件，包括不稳定性心绞痛、急性心肌梗死、支架内再狭窄、心源性猝死以及脑卒中等。 3.3 依从性监测：随访期间患者应按照医嘱服用药物，如发现患者依从性差，则应记录原因，并视为自动退出。 4 药物经济学评价 采用成本-效果分析方法（costeffectivenessanalysis，CEA）定量评价使用药物基因型检测进行个体化精准用药方案的治疗所获取的临床价值结果（即健康效果）。以成本效果比和增量成本效果比（ICER）作为评价指标。 

Description for medicine or protocol of treatment in detail：

This study was divided into three stages, including the period of entry, the first cycle (hospitalization) and the second cycle (follow-up period after discharge), for a total of 12 months (12 months for the study of acute coronary syndromes and 6 months for ischemic stroke). Entry period: screening the patients through admission criteria and exclusion criteria, informing patients or (and) family members in detail, signing informed consent, and setting up a patient's case record table; The first cycle: after entering the group, we should conduct laboratory examination and clinical diagnosis and treatment according to the routine clinical guidance; The second cycle: medical follow-up period, patients were discharged after 1 months, 3 months, 6 months and 12 months, respectively (from the day of intervention operation, of which the acute coronary syndrome was followed up for 12 months, the ischemic stroke was followed up for 6 months) should come to our hospital and complete the related medical examination. 1. Entry period 1.1 Basic demographic information: admission number, name, sex, age, height, weight (calculation of body weight index), nationality, marital status, occupation, education level, patients and direct relatives contact telephone (at least 2), contact address (work unit / home address). 1.2 Past medical history: history of disease, history of infectious diseases, history of surgical trauma, history of blood transfusion, drug and other allergies. 1.3 Personal history: smoking, alcoholism, drug abuse or drug addiction; epidemic area and water contact. 1.4 Physical examination: vital signs (axillary body temperature, resting seat blood pressure, pulse and respiratory frequency); general condition, skin mucous membrane, lymph node, head and organ, neck, chest, abdomen, spine and limbs, nerve reflex. 1.5 Lboratory and instrument examination: blood routine, biochemical examination (liver function, renal function, etc.), blood coagulation examination, 12-lead electrocardiogram and angiography examination. 1.6 Clinical diagnosis: including main diagnosis and other diagnoses. 1.7 Screening group: 200 patients were screened according to the inclusion criteria and exclusion criteria in this study. They were randomly divided into the individualized treatment group or the conventional treatment group. There were 100 cases of individualized treatment group (including 50 cases of acute coronary syndrome and 50 cases of ischemic stroke) and 100 cases of routine treatment group (including 50 cases of acute coronary syndrome and 50 cases of ischemic stroke). 1.8 Current basic situation of patients after admission was evaluated: (1) whether suffering from any acute disease? (2)whether smoking or exposure to second-hand smoke? (3)whether drink alcohol? (4)whether drink caffeine? (5)Whether strenuous exercise? (6)whether the drinking grapefruit or grape juice? (7)Whether to keep good living habits (such as maintaining 6~8 hours of daily sleep, eating time and structural rules: regular diet, low fat diet, and recommended intake of foods rich in unsaturated fatty acids) 1.9 Drug gene testing and assessment of clopidogrel disposition (metabolism) in individualized treatment group. 1.9.1 Drug genotyping detecting (the gene test for the guidance of chemical drugs): collect the peripheral venous blood 5ml by EDTA anticoagulant vacuum tube before operation, and the genotypes of CYP2C19*2, CYP2C19*3 and CYP2C19*17 were detected by fluorescence staining in situ hybridization. 1.9.2 Evaluation of organism's ability to treat clopidogrel (metabolism). (1) the body's ability to treat clopidogrel was normal: the results of the drug gene detection were CYP2C19*1*1 or *1/*17 or *17/*17, and the patient CYP2C19 was fast metabolic (RM) or ultrafast metabolic (UM). (Patients in this group did not need to adjust the initial dose of clopidogrel, 75mg/d). (2) the body's ability to dispose of clopidogrel was weakened: the results of the drug gene detection are CYP2C19*1/*2 or *1/*3, or CYP2C19*2/*17 or *3/*17, and the patients are intermediate metabolic type (IM). (Patients using clopidogrel 75mg/d, aspirin and cilostazol 100mg/d 100mg, bid) (3) the body's ability to dispose of drugs is extremely low: the results of drug gene detection are CYP2C19*2/*2, or CYP2C19*3/*3, or CYP2C19*2/*3, and the patients are slow metabolic type (PM). (Patients are treated by ticagrelor 90mg, bid and aspirin 100mg/d. 2 First cycle (hospitalization period) 2.1 Regimen: all patients were administered on the day of the operation, including the dose of the load before the operation and the maintenance dose after the operation. Fasting is required before 10h and after taking the medicine within 4H. 2.1.1 Selected drug: Aspirin (bayaspirin, 100mg/tablet, Bayer HealthCare Pharmaceuticals Inc, 100mg*30/box); Clopidogrel (taijia, 25mg/tablet, Shenzhen shilitai Pharmaceutical Co., 25mg*20/box); Ticagrelor (belinda, 90mg/tablet, AstraZeneca Pharmaceutical Co., 90mg*14/box). 2.1.2 Drug administration: all patients are treated with the coadministration of two antiplatelet drugs aspirin (100mg/d) and clopidogrel. The dosage of clopidogrel should be adjusted according to the specific conditions. The adjustment principle: the patients in the routine treatment group use the initial 75mg/d maintenance dose. The individualized treatment group is based on the patient's drug genotyping and the body's ability to treat clopidogrel. (1) the capacity of the body is normal: clopidogrel 75mg/d and aspirin 100mg/d; (2) the ability to dispose of the body is weakened: clopidogrel 75mg/d, aspirin 100mg/d and cilostazol 100mg, bid; (3) lower body disposal capacity (weak metabolism): ticagrelor 90mg, bid and aspirin 100mg/d. 2.2 Pharmacokinetic detection: after continuous use of clopidogrel 5d in two groups, the patient's peripheral venous blood 3ml was collected on the morning of 6d early morning. High performance liquid chromatography and mass spectrometry (HPLC-MS/MS) was used to detect the concentration of clopidogrel in the patient's body (if the patient did not take clopidogrel, it was not to be detected). 2.3 Pharmacodynamic detection: it is mainly evaluated by laboratory related indicators. (1) Platelet function test: the inhibition rate of platelet aggregation (IPA) induced by adenosine diphosphate (ADP) and arachidonic acid (AA) after 120h (5d) administration was detected by thromboelastography(TEG) for recording the platelet graph, in which IPA (ADP) was used to evaluate clopidogrel therapy efficacy, IPA (AA) was used to evaluate the efficacy of aspirin. If IPA ≥75%: good effect; 50%~75%: take effect; < 50%, the effect is poor. IPA ≥50% is defined as drug sensitivity, < 50% is defined as drug non-sensitivity (i.e. drug resistance). If the patient IPA (ADP) < 50%, the regimen needed to be further adjusted. If the patient's initial scheme was clopidogrel 75mg/d and aspirin 100mg/d, then the modified regimen was clopidogrel 75mg/d, aspirin 100mg/d, and cilostazol 100mg, bid; if the initial scheme was clopidogrel 75mg/d, aspirin 100mg/d and cilostazol 100mg, bid, then the modified regimen was ticagrelor 90mg, bid and aspirin 100mg/d. If the patient IPA (ADP) is still less than 50% after adjusting the regimen, then the modified regimen was aspirin 100mg/d and ticagrelor 90mg,bid. (2) Other laboratory examinations: including blood routine examination, biochemical examination (liver function, renal function), blood coagulation examination, instrument examination: 12-lead electrocardiogram. 2.4 Safety monitoring (1) Monitoring of vital signs: monitoring the vital signs (blood pressure, heart rate, blood oxygen saturation, etc.) of patients before and after administration: 4h, 8h, 24h, 48h, 72h, 96h and 120h. (2) Observation of adverse events: mainly observe whether there are adverse events related to research after taking medicine, and fill in adverse events table if they happen. 3 Second cycles (follow-up period after discharge) The two groups of patients were followed up for first, third, sixth and twelfth months after taking the medicine (the follow-up period of the acute coronary syndrome for 12 months and the ischemic stroke for 6 months), including laboratory tests, adverse events assessment and patient compliance investigation. If the patient has adverse events, we will record at any time. 3.1 Laboratory detection: (1) Platelet function test: 3ml peripheral venous blood was collected in two groups of patients in the morning. The platelet aggregation inhibition rate (IPA-ADP) induced by adenosine diphosphate(ADP) after the medication 1st , 3rd , 6th and 12th month were detected by thromboelastography(TEG) (acute coronary syndrome should be detected in 1st,3rd,6th,12th months after taking medicine; ischemic stroke was detected at 1st, 3rd and 6th after taking medicine.) (2) Other laboratory examinations: including blood routine examination, biochemical examination (liver function, renal function), blood coagulation examination, instrument examination and 12-lead electrocardiogram. 3.2 Pharmacokinetic test: The 3ml peripheral venous blood in two groups of patients treated with clopidogrel after 1 months, 3 months, 6 months and 12 months was collected on the empty stomach on the next morning.The concentration of clopidogrel acid in the patients was detected by high performance liquid chromatography mass spectrometry (HPLC-MS/MS). If the patient did not take clopidogrel, it was not required to be detected. (The acute coronary syndromes were tested 1, 3, 6 and 12 months after taking the medicine, and the ischemic stroke was detected in 1, 3 and 6 months after taking the medicine). Remarks: this test can also determine whether the patient is taking clopidogrel according to the doctor's advice. 3.3 Safety monitoring: observe the occurrence of adverse events such as relapse or aggravation of the disease symptoms or rehospitalization during follow-up; Steady state of illness including no chest pain or chest pain clinical symptoms, or stable angina, or no dynamic changes in electrocardiogram. Exacerbation of the condition refers to the occurrence of adverse cardiac and cerebrovascular events within 3 months after discharge, including unstable angina, acute myocardial infarction, stent restenosis, sudden cardiac death and moderate stroke. 3.4 Compliance monitoring: during the follow-up period, patients should take medicine according to the doctor's advice. If a patient's compliance is poor, then should record the cause and regard as quit automatically. 4 Pharmacoeconomic evaluation The cost effectiveness analysis (CEA) was used to quantify the clinical value (health effects) of the individualized precise medication regimen based on the drug genotyping. Cost effectiveness ratio and incremental cost effectiveness ratio (ICER) were used as evaluation indicators. 

纳入标准：

①年龄20~70岁；②具有心脑血管介入治疗指征；③具有阿司匹林和氯吡格雷双联抗血小板治疗指征，其中经皮冠状动脉介入患者坚持服药1年，脑血管疾病血管内介入患者坚持服药6个月；④患者在被充分告知临床诊治全过程及可能发生的各种不良事件，明确是否参与本项目与其在接受临床诊治中可能出现的各种状况无关，并签署知情同意书；⑤患者术后住院时间不少于5天。⑥患者依从性较高，可以配合以及完成本项目随访。

Inclusion criteria

(1) aged 20~70 years old;
(2) have the indications of cardiovascular and cerebrovascular interventional therapy;
(3) have the indications of double anti-platelet therapy with aspirin and clopidogrel, of which the patients with percutaneous coronary intervention persist in taking medicine for 1 years, and the patients with cerebrovascular diseases adhere to take the drug for 6 months;
(4) patients are fully informed of the whole process of clinical diagnosis and treatment and potential adverse events. The various conditions that may occur in the clinical diagnosis and treatment, which are not related to this research and sign the informed consent;
(5) the patient's hospitalization time is not less than 5 days after postoperation;
(6) The compliance of patients is higher, which can lead to the completion of this project and follow up.

排除标准：

①对阿司匹林或氯吡格雷过敏或不能耐受者以及通过血栓弹力图检测发现为阿司匹林抵抗的患者；②患有血液系统疾病、出血性疾病或存在出血倾向者；③严重肝肾功能障碍患者；④合并肿瘤、严重免疫系统疾病或其他终末期疾病的患者；⑤半年内有中风或内脏出血性疾病病史者；⑥严重心力衰竭（NYHA IV级）或重度贫血（血红蛋白＜60g/L）的患者；⑦未控制的高血压（收缩压＞180mmHg或舒张压＞120mmHg）；⑧具有抗血小板治疗禁忌证或近期拟行外科手术者；⑨妊娠期和哺乳期妇女；⑩最近3个月内献血或作为志愿者被采样者；

Exclusion criteria：

(1) patients with aspirin or clopidogrel anaphylaxis or intolerance, as well as patients with aspirin resistance detected by thromboelastography (TEG);
(2) patients with hematological diseases, hemorrhagic diseases or bleeding;
(3) patients with severe liver and kidney dysfunction;
(4) combined with tumors, severe immune system diseases, or other end-stage diseases;
(5) patients with a history of apoplexy or visceral hemorrhagic disease in half a year;
(6) patients with severe heart failure (NYHA IV) or severe anemia (hemoglobin < 60g/L);
(7) uncontrolled hypertension (systolic pressure > 180mmHg or diastolic pressure > 120mmHg);
(8) there is a taboo antiplatelet therapy or a recent surgical procedure;
(9) women in pregnancy and lactation;
(10) blood donation or as a volunteer of blood sampling in the last 3 months;

研究实施时间：

Study execute time：

从 From 2018-01-01 00:00:00至 To 2019-12-31 00:00:00  

征募观察对象时间：

Recruiting time：

从 From 2018-05-01 00:00:00 至 To 2019-03-31 00:00:00

干预措施：

Interventions：

组别：

Case series

样本量：

 200

Group：

Case series

Sample size：

干预措施：

氯吡格雷

干预措施代码：

Intervention：

clopidogrel

Intervention code：

研究实施地点：

Countries of recruitment and research settings：

国家：

 中国

省(直辖市)：

 安徽省 

市(区县)：

 芜湖市 

Country：

China

Province：

Anhui

City：

单位(医院)：

 皖南医学院弋矶山医院 

单位级别：

 三级甲等 

Institution
hospital：

Yijishan hospital of wannan medical college

Level of the institution：

Tertiary A hospital

测量指标：

Outcomes：

指标中文名：

血小板聚集抑制率

指标类型：

主要指标

Outcome：

Inhibition of platelet aggregation

Type：

Primary indicator

测量时间点：

患者服药120h，出院后第1月，3月，6月，12月

测量方法：

血栓弹力图仪

Measure time point of outcome：

After admininstration at 120h, post-discharge on 1st, 3rd, sixth, 12th month.

Measure method：

Thromboelastography

指标中文名：

氯吡格雷酸的浓度

指标类型：

主要指标

Outcome：

Concentration of clopidogrel acid

Type：

Primary indicator

测量时间点：

患者服药120h，出院后第1月，3月，6月，12月

测量方法：

高效液相色谱-质谱联用法

Measure time point of outcome：

After admininstration at 120h, post-discharge on 1st, 3rd, sixth, 12th month.

Measure method：

HPLC-MS/MS

指标中文名：

不良事件

指标类型：

主要指标

Outcome：

adverse events

Type：

Primary indicator

测量时间点：

用药后

测量方法：

临床随访

Measure time point of outcome：

After admininstration at any time

Measure method：

Clinical follow-up

采集人体标本：

Collecting sample(s)
from participants：

标本中文名：

血液

组织：

Sample Name：

blood

Tissue：

人体标本去向

 使用后保存  

说明

1年

Fate of sample：

Preservation after use  

Note：

征募研究对象情况：

Recruiting status：

尚未开始

Not yet recruiting

年龄范围：

Participant age：
最小 Min age 20 岁 years
最大 Max age 70 岁 years

性别：

男女均可

Gender：

Both

随机方法（请说明由何人用什么方法产生随机序列）：

本项目将由课题组统计学专家采用随机数字表产生200个随机数字号，并依据患者入院时间先后顺序分别标号。

Randomization Procedure (please state who generates the random number sequence and by what method)：

This project will produce 200 random numbers by the statistics experts based on the random number table, and label them according to the order of patients' admission time.

是否公开试验完成后的统计结果:

Calculated Results after the Study Completed public access:

不公开/Private

盲法：

Blinding：

是否共享原始数据：

IPD sharing

是Yes

共享原始数据的方式（说明：请填入公开原始数据日期和方式，如采用网络平台，需填该网络平台名称和网址）：

试验完成后6个月内公开；中国临床试验注册中心网站

The way of sharing IPD”(include metadata and protocol, If use web-based public database, please provide the url)：

Within six months after the trial complete； Chines clinical trial registry

数据采集和管理（说明：数据采集和管理由两部分组成，一为病例记录表(Case Record Form, CRF)，二为电子采集和管理系统(Electronic Data Capture, EDC)，如ResMan即为一种基于互联网的EDC：

病例记录表和基于互联网的临床研究公共管理平台

Data collection and Management (A standard data collection and management system include a CRF and an electronic data capture：

Case Record Form and ResMan

数据与安全监察委员会：

Data and Safety Monitoring Committee：

有/Yes

注册人：

Name of Registration：

  2018-04-11 15:01:09