CYP2C19基因多态性指导下的抗血小板个体化治疗急性脑梗死的临床观察

目的 探讨CYP2C19基因多态性指导下的抗血小板个体化治疗对急性脑梗死病人疗效的影响.方法 前瞻性纳入非心源性急性脑梗死的病人100例,根据CYP2C19基因多态性分为常规治疗组、慢代谢个体化治疗组和慢代谢常规治疗组,常规治疗组和慢代谢常规治疗组给予阿司匹林+氯吡格雷治疗,慢代谢个体化治疗组给予阿司匹林+氯吡格雷+西洛他唑治疗.三组病人疗程均为15 d,比较各组病人疗效、美国国立卫生院卒中量表(NIHSS)评分及主要出血事件的发生率.结果 各组病人性别、年龄、原发性高血压、糖尿病、高脂血症等方面,均差异无统计学意义(P>0.05);常规治疗组与慢代谢个体化治疗组的有效率分别为84.00%和76.67%,差异无统计学意义(P>0.05),两组的出血事件及其他不良反应均差异无统计学意义(P>0.05);慢代谢常规治疗组对血小板的抑制率低于慢代谢个体化治疗组,差异有统计学意义(P<0.05).结论 联合使用西洛他唑可以克服氯吡格雷抵抗,根据基因指导抗血小板治疗急性脑梗死的疗效良好.     

CYP2C19基因多态性与氯吡格雷ADP抑制率的临床研究

目的探讨CYP2C19基因多态性与氯吡格雷ADP抑制率间的临床关系,以期为个体化的抗血小板治疗方案提供用药参考。方法选取本院2014年10月至2015年10月收治的120例急性冠状动脉综合征患者作为临床研究对象,患者术前均进行CYP2C19基因型测定并完成经皮冠状动脉介入术治疗,患者按基因型分为慢代谢组、中等代谢组及快代谢组,每组40例。入院当天给予患者过量氯吡格雷和标准剂量阿司匹林,之后按规律常规给予氯吡格雷75 mg/d,于第1天和第7天测定患者ADP抑制率,并根据结果筛选出抗氯吡格雷患者,加大氯吡格雷用量后7 d再次测定患者ADP抑制率,并进行前后差异比对。结果与服用前相比,服用氯吡格雷7 d后3组患者的血小板聚集率均明显下降,其中快代谢型患者显著优于中间代谢型和慢代谢型者(P<0.05)。氯吡格雷抵抗患者增加药物剂量后7 d,ADP抑制率无明显改变,差异无显著性(P>0.05)。结论针对急性冠状动脉综合征患者,采用适时的CYP2C19基因多态性检测对于指导选用药物治疗具有一定临床意义,但仅通过基因分型还无法完全预测氯吡格雷的给药剂量,对于氯吡格雷抵抗患者单纯增加氯吡格雷剂量不能同时达到提高血小板抑制率的效果,治疗方案还需进一步探讨和深入研究。     

缺血性脑卒中患者CYP2C19基因代谢型、联用药物与氯吡格雷抵抗关系的研究

目的 探讨CYP2C19基因代谢型、联用药物与氯吡格雷抵抗的关系.方法 选择缺血性脑卒中患者102例,连续口服氯吡格雷75 mg/d,共7d.检测患者CYP2C19各基因型及血小板聚集率,以1年内发生缺血性脑卒中复发终点事件为观察指标.结果 CYP2C19基因弱代谢型15例,中间代谢型39例,强代谢型48例,氯吡格雷抵抗发生率在弱代谢型较中间代谢型高,中间代谢型较强代谢型发生率高,差异均有统计学意义(P＜0.05);氯吡格雷联用阿司匹林、他汀类药可明显减少卒中复发事件(P＜0.05).结论 采用基因分型法可预测缺血性脑卒中患者氯吡格雷疗效,指导临床个体化给药.氯吡格雷联用阿司匹林、他汀类药的应用效果较好.     

西洛他唑治疗经皮冠脉内介入术后对阿司匹林致上消化道出血患者的随访研究

目的观察经皮冠脉内介入术(percutaneous coronary intervention,PCI)后使用西洛他唑对阿司匹林致上消化道出血患者的外周血血小板聚集率、PGE2及心血管事件发生率的影响。方法 64例确诊冠心病并行PCI术后的患者,服用阿司匹林和氯吡格雷双重抗血小板治疗出现阿司匹林相关上消化道出血,其中32例患者改用西洛他唑加氯吡格雷,而另外32例患者出血治疗后继续原抗血小板治疗方案,随访比较两组患者血小板聚集率、PGE2及心血管事件发生率。结果平均随访(0.9±0.1)年,两组患者血小板聚集率均明显下降,西洛他唑组的血小板聚集率显著低于阿司匹林组(P<0.05),外周血PGE2的浓度高于阿司匹林组(P<0.05),但两组患者临床不良事件发生率差异无统计意义。结论对PCI术后上消化道出血患者,应用西洛他唑替代阿司匹林,联用氯吡格雷进行抗血小板治疗,经过短期的临床观察,其血小板聚集率优于阿司匹林,升高外周血PGE2的浓度,且安全性与阿司匹林相当,可用于预防上消化道出血的复发。     

CYP2C19基因型功能缺失患者介入术后抗血小板治疗

目的：评价CYP2C19基因型功能缺失患者介入术后不同抗血小板治疗方案的安全性及有效性。方法：纳入择期冠脉支架植入术后行CYP2C19基因型检测的患者,按其表型分为快代谢组,中代谢组及慢代谢组,将中代谢组随机分为氯吡格雷双倍剂量组和氯吡格雷常规剂量联用西洛他唑组,慢代谢组随机分为替格瑞洛组和氯吡格雷常规剂量联用西洛他唑组,另设快代谢氯吡格雷常规剂量组为对照组,连续用药6个月,随访其临床事件。结果：所有患者中CYP2C19基因快、中、慢代谢型的比例分别为25%,60%, 15%;中代谢型患者使用氯吡格雷双倍剂量方案或氯吡格雷常规剂量联用西洛他唑方案、慢代谢患者使用替格瑞洛方案,可取得与快代谢型患者常规剂量氯吡格雷方案相似的疗效,但慢代谢患者使用氯吡格雷常规剂量联用西洛他唑预防心脏缺血的获益不佳,劣于替格瑞洛方案。结论：择期冠脉支架植入术后的中代谢患者在服用阿司匹林的基础上,采用氯吡格雷双倍剂量或氯吡格雷常规剂量联用西洛他唑的方案可能有益;慢代谢型患者建议使用替格瑞洛。     

质子泵抑制剂与氯吡格雷药物相互作用研究进展

对2010年Mdeline收载的关于质子泵抑制剂(PPIs)与氯吡格雷相互作用的研究文献进行综述分析,PPIs对氯吡格雷抗血小板聚集活性的影响与多个因素相关:氯吡格雷和阿司匹林合用时,PPIs与氯吡格雷之间无临床意义的药物相互作用;当单用氯吡格雷抗血小板聚集时,PPIs对其药效的影响显著,而且不同的PPIs之间的作用强度有差异;以微观指标(如ADP或花生四烯酸诱导的血小板聚集度)为标准,则氯吡格雷和PPIs之间存在不良药物相互作用,但以宏观指标(如一级事件发生率)为标准则无临床意义的不良药物相互作用;PPIs对氯吡格雷的影响与CYP2C19基因多态性有关:快代谢型患者PPIs对氯吡格雷的抗血小板聚集作用影响显著,慢代谢型无明显影响;与单用氯吡格雷相比,PPI+阿司匹林可以显著降低胃肠道出血事件,对心血管系统没有不良影响。因此,对于PCI术后短期内行氯吡格雷和阿司匹林双抗血小板聚集患者,临床可以根据情况选择任何一个PPIs;对于单用氯吡格雷抗血小板聚集的患者,应该首选与泮托拉唑合用;PPIs合用阿司匹林能有效抗血小板聚集,而且显著减少胃肠道出血事件,因此在必须应用PPIs的情况下,阿司匹林是氯吡格雷的一个有效替代药物。     

CYP2C19基因多态性及患者主要临床资料与氯吡格雷药物抵抗的相关性研究

目的观察药物代谢酶系统中CYP2C19基因多态性及患者主要临床资料与服用氯吡格雷前后血小板聚集率变化(氯吡格雷药物抵抗)的相关性。方法入选拟行冠脉造影检查或支架植入治疗患者35例,根据围手术期应用氯吡格雷前后血小板聚集率变化,将患者分为氯吡格雷抵抗组和非抵抗组。检测CYP2C19基因型,并记录患者年龄、性别、烟酒史、高血压、糖尿病等主要临床资料,分析基因水平及临床水平各因素对血小板聚集及氯吡格雷药物抵抗的影响。结果检测出氯吡格雷抵抗的患者15例,CYP2C19慢代谢基因型患者4例,Logistic回归分析显示,CYP2C19基因型是氯吡格雷抵抗的危险因素(OR=1.236,95%CI:0.273~5.599,P=0.049)。结论 CYP2C19基因型在基因水平与氯吡格雷抵抗相关,临床水平资料未见明显相关性。     

氯吡格雷联合阿司匹林在急性轻度脑梗死治疗中的临床应用分析

<正>急性脑梗死属于一种脑血管疾病,在临床较为常见,诱发因素为局部脑组织缺血缺氧或坏死,极易引发语言、运动等神经功能障碍,发病率、致残率、病死率均较高[1]。相关医学研究表明[2],要想对急性轻度脑梗死患者神经功能及预后进行改善,关键是要对血小板聚集与活化进行有效控制。阿司匹林、氯吡格雷、西洛他唑等均属于抗血小板聚集药物,在临床均较为常用,但是单独用药缺乏理想的效果[3]。本研究分析了氯吡格雷联合阿司匹林在急性轻度脑梗死治疗中的临     

回顾性分析氯吡格雷弱代谢患者的抗血小板治疗现状

目的筛查氯吡格雷弱代谢型急性冠脉综合征患者,回顾性分析其抗血小板治疗现状。方法选取医院收治的285例陕西汉族急性冠脉综合征患者,通过焦磷酸测序技术检测CYP2C19*2和CYP2C19*3基因多态性筛查氯吡格雷弱代谢患者,分析其抗血小板治疗现状。结果在285例患者中,快代谢型占38.6%,中间代谢型占49.1%,慢代谢型占12.3%,后两者为弱代谢型(61.4%)。中间代谢型患者,53.6%应用氯吡格雷75mg·d~(-1);46.4%调整治疗方案,如氯吡格雷剂量加倍至150mg·d~(-1),更换替格瑞洛或三联疗法(加用西洛他唑)。慢代谢型患者,54.3%应用氯吡格雷75mg·d~(-1),45.7%调整为上述治疗方案,其中28.5%更换替格瑞洛。结论在陕西汉族急性冠脉综合征患者中,氯吡格雷弱代谢型发生率高,目前个体化抗血小板治疗方案并无统一规范。     

通心络和西洛他唑对脑梗死患者阿司匹林抵抗现象的影响

目的探讨通心络和西洛他唑对脑梗死阿司匹林抵抗(AR)患者血小板聚集率、血栓素B2(TXB2)的影响。方法选择60例脑梗死阿司匹林抵抗(AR)患者,随机分为3组,A组常规治疗组,B组通心络组,C组西洛他唑组;分别在治疗前和治疗后1个月测定血小板聚集率、TXB2;比较3组治疗前后及治疗后不同组别上述指标的差异。结果①通心络和西洛他唑均可使脑梗死阿司匹林抵抗患者血小板聚集率下降,西洛他唑对ADP诱导的血小板聚集率的下降更明显。②通心络和西洛他唑治疗后均可使脑梗死患者TXB2下降,与治疗前比较有显著性差异;同时与常规组治疗后比较也有显著性差异。而尽管西洛他唑组使TXB2下降更明显,但与通心络组比较无统计学差异。结论通心络和西洛他唑对脑梗死阿司匹林抵抗患者有抗血小板聚集作用,一定程度上可改善脑梗死患者的AR。     

Clopidogrel hydrogen sulphate for atrial fibrillation

Introduction: Atrial fibrillation is a common cardiac rhythm abnormality with a considerable cardiovascular disease burden worldwide. It is an independent major risk factor for stroke. Stroke prevention with anticoagulation or antiplatelet agents has been an important area of clinical research. Warfarin is the most widely used antithrombotic therapy for stroke prophylaxis for last several years, and now dabigatran (150 mg b.i.d.) is more effective than warfarin in stroke prevention in individuals at increased of stroke. In addition, several studies have evaluated the efficacy of clopidogrel for stroke prophylaxis either alone or in combination with aspirin.

Areas covered: This review summarizes the key findings of the trials looking at the efficacy of clopidogrel in stroke prevention. A literature search was performed using PubMed and Google Scholar. The trials that evaluated the efficacy of clopidogrel in preventing atherothrombotic events or stroke were also included.

Expert opinion: Clopidogrel prevents more vascular events, including stroke, in patients with a recent myocardial infarction, stroke or peripheral vascular disease than aspirin. Combination of clopidogrel and aspirin provides a greater reduction of stroke than aspirin or clopidogrel monotherapy, but at an increased risk of bleeding. Dual antiplatelet therapy (clopidogrel and aspirin) is inferior to warfarin in primary stroke prevention for patient with atrial fibrillation and thus should be considered for stroke prophylaxis only in patients ineligible for warfarin. However, with the advent of newer agents, like direct thrombin inhibitors and Factor Xa inhibitors, the role of antiplatelet therapy for stroke prevention in atrial fibrillation remains unclear.     

The safety of clopidogrel

Importance of the field: Clopidogrel is an antiplatelet prodrug widely used in acute coronary syndromes and after intravascular stent placement. Acute or chronic use can cause bleeding, a major adverse effect, which can lead to drug discontinuation or noncompliance with therapy.

Areas covered in this review: The mechanism of action of clopidogrel, safety of different loading doses of clopidogrel, its use as a solitary antiplatelet agent and concomitant use with other antiplatelet agents such as aspirin and warfarin are discussed. Thrombotic thrombocytopenic purpura, a rare but important adverse event, has also been reviewed. Literature searches including randomized controlled trials were conducted in Medline.

What the reader will gain: Clinicians will be able to understand the safety profile of using different doses of clopidogrel and the incidence of bleeding when used alone or in combination with other antiplatelet agents.

Take home message: Compared to aspirin, clopidogrel when taken alone causes less severe bleeding and less intracranial hemorrhage. Higher loading dose of clopidogrel is associated with increased bleeding. When combined with other antiplatelet agents, risk of bleeding increases, but like any other drug, the risks have to be weighed against potential benefits.     

Low‐dose adjunctive cilostazol in patients with complex lesions undergoing percutaneous coronary intervention

Patients with complex coronary lesions undergoing percutaneous coronary intervention (PCI) have more major adverse cardiac events (MACE) than do those with simpler cases. Therefore, intensive antiplatelet therapy might be needed in these patients. A total of 127 patients with complex lesions undergoing PCI in the Second Hospital of Tianjin Medical University from October 2012 to April 2014 were randomized to receive either dual (aspirin plus clopidogrel, DAPT, n = 66), or triple antiplatelet therapy (aspirin plus clopidogrel plus cilostazol; TAPT, n = 61). Patients in the TAPT group received low‐dose cilostazol (100 mg loading, followed with 50 mg twice per day) for 3–6 months. The primary endpoint was composite MACE. The complex coronary target lesions were defined as at least one of the following: left main disease; severe 3‐vessel disease; chronic total occlusion lesions; true bifurcation lesion; ostial lesions; severe calcified lesions; and highly thrombotic lesions. The two groups had similar baseline clinical and angiographic characteristics. One‐year clinical outcomes showed that the TAPT group had significantly lower incidences of myocardial infarction (1.6% vs 13.6%, P = 0.018) and MACE (1.6% vs 16.7%, P = 0.004) than DAPT group. The DAPT group had two cases of stent thrombosis, while the TAPT group did not. Furthermore, adjunctive low‐dose cilostazol didn't significantly increase the incidence of bleeding events (26.2% vs 19.7%, P = 0.381) regardless of major (4.9% vs 4.5%, P = 0.921) or minor (21.3% vs 15.2%, P = 0.368) bleeding events. In conclusion, low‐dose adjunctive cilostazol seems superior to dual antiplatelet therapy in reducing recurrent ischemic events in patients with complex coronary lesions and the two test groups have a similar incidence of bleeding events.     

Comment and reply on: Evaluation of injection force of three insulin delivery pens

Importance of the field: The use of clopidogrel and aspirin has become standard therapy in patients with acute coronary syndromes and stent implantation. However, concern arises because about 25% of subjects are nonresponders to clopidogrel. This nonresponsiveness is associated with a threefold increase in adverse outcomes. Clopidogrel resistance is multifactorial, but genetic polymorphisms in clopidogrel's metabolic activation (e.g., cytochrome P450 2C19) and drug–drug interactions at this level (e.g., between proton pump inhibitors (PPIs) and clopidogrel) are both associated with decreased clopidogrel efficacy. Despite all PPIs being potent inhibitors of CYP2C19, evidence about their clinical impact is controversial.

Areas covered in this review: Pharmacogenomic and pharmacokinetic aspects of clopidogrel nonresponsiveness were considered in detail.

What the reader will gain: The reader will gain an exhaustive review of the current state of the controversial issues regarding genetic polymorphisms and drug–drug interactions affecting clopidogrel efficacy.

Take home message: It is important to consider clopidogrel resistance in some patients and establish strategies to handle this problem (e.g., genotyping, platelet aggregability tests, new antiplatelet drugs). The combined use of PPIs and clopidogrel is at present regulated by the FDA and EMEA; however, the risk/benefit balance should be made for each patient individually.     

2017—2020年天津市10家医院心血管疾病患者住院期间抗血小板药应用分析

目的:了解天津市心血管疾病患者住院期间抗血小板药使用情况,以期为规范合理用药提供依据。方法:以2017—2020年天津市10家医院心血管科住院患者为研究对象,应用Epidata软件进行数据录入,应用SPSS 26.0软件进行统计分析。结果:共纳入1178例患者,其中心绞痛患者499例(占42.4%),急性心肌梗死患者158例(占13.4%),冠心病患者390例(占33.1%),其他类型疾病患者131例(占11.1%);抗血小板药各药品选用率由高至低依次为阿司匹林、氯吡格雷、替格瑞洛、替罗非班和西洛他唑;负荷剂量联合用药方式主要为阿司匹林与氯吡格雷联合应用,但负荷剂量应用率较低;维持剂量联合用药方式主要为阿司匹林与氯吡格雷联合应用;不同疾病用药行为特点存在差异,同一疾病用药行为特点亦存在不一致性。结论:天津市心血管疾病住院患者在抗血小板药的品种选用、负荷剂量、维持剂量和联合应用方式上存在用药行为差异,科学规范的治疗策略仍需大样本真实世界研究加以确证。     

血府逐瘀胶囊对重度血瘀证患者经皮冠状动脉介入治疗术后氯吡格雷抵抗的调节作用

目的 观察血府逐瘀胶囊联合氯吡格雷治疗氯吡格雷抵抗患者的效果,评价其改善氯吡格雷抵抗作用的效果。方法 经皮冠状动脉介入治疗（PCI）术后氯吡格雷抵抗患者80人,随机分组,分别给予3种药物治疗方案：A组用国产氯吡格雷（泰嘉）加用血府逐瘀胶囊;B组使用进口氯吡格雷（波立维）;C组用国产氯吡格雷（泰嘉）加用西洛他唑,连续3个月,采用血栓弹力图法检测干预后血小板抑制率。并随访患者半年,观察临床不良事件的发生率。结果 治疗3个月后,各组抑制率均有所提高,且均有显著差异（P<0.05）。A组对血小板抑制的有效率达40%,优于C组（33.33%）,与B组相当（40.74%）。对阿司匹林、氯吡格雷均不敏感的患者换用进口波立维对提高血小板抑制效果更佳;仅对氯吡格雷不敏感的患者加用血府逐瘀胶囊对血小板抑制有协同作用。随访半年后发现,联合使用血府逐瘀胶囊的时间延长可能会增强血小板抑制的效果,但并不增加出血及凝血功能异常等风险。结论 血府逐瘀胶囊对提高血小板抑制率有一定的作用,同时对出血风险影响较小。     

Antiplatelet Drug Resistance and Drug-Drug Interactions: Role of Cytochrome P450 3A4

Antiplatelet therapy provided pivotal advances in the treatment of cardiovascular disease. Aspirin and thienopyridine, clopidogrel, is currently the treatment of choice in acute coronary syndromes and the prevention of thrombosis after coronary stent implantation. Despite the efficacy of this dual antiplatelet therapy in reduction of adverse coronary events in patients with acute coronary syndromes, complications persist in a subgroup of these patients. Emerging causes of aspirin and clopidogrel resistance may translate to increase risk for recurrent myocardial infarction, stroke, or cardiac related mortality. However, the mechanism of antiplatelet drug resistance remains incompletely characterized, and a sensitive and specific assay of aspirin and clopidogrel effect that reliably predicts treatment failure has not emerged. To date, evidence supporting antiplatelet drug resistance are pharmacokinetic response variability, drug-drug interaction through competitive inhibition a specific enzymatic pathway, genetic variability, and variability in the induction of enzymatic pathway in metabolic activation of prodrugs, like clopidogrel. Further investigation or guidelines are needed to optimize antiplatelet treatment strategies to identify and treat patients resistant to aspirin and/or clopidogrel.     

泮托拉唑对氯吡格雷治疗急性脑梗死疗效的影响小于奥美拉唑

目的比较中国徐州地区汉族人群泮托拉唑+氯吡格雷+拜阿司匹林与奥美拉唑+氯吡格雷+拜阿司匹林治疗急性脑梗死的疗效差异,初步探讨泮托拉唑对氯吡格雷治疗急性脑梗死疗效的影响。方法选取400例发病3 d内的急性脑梗死患者(均常规予氯吡格雷75 mg和阿司匹林200 mg口服),随机分为奥美拉唑组(n=200,加用奥美拉唑40 mg/d,静脉用药)和泮托拉唑组(n=200,加用泮托拉唑60 mg/d,静脉用药),分别于入院时、治疗后14 d对其进行美国国立卫生研究院卒中量表(NIHSS)评分,并在治疗14 d时对患者进行疗效评价。数据处理采用SPSS13.0软件包进行统计学分析。结果两组患者入院时的一般资料、NIHSS评分比较无明显差异(P均<0.05);治疗后两组患者的NIHSS评分均低于入院时,两组NIHSS评分比较显示泮托拉唑组低于奥美拉唑组(P<0.05),使用泮托拉唑组的疗效高于使用奥美拉唑组(P均<0.05)。结论泮托拉唑对氯吡格雷治疗急性脑梗死疗效的影响小于奥美拉唑,临床治疗急性脑梗死可优先选用泮托拉唑。     

PCI术后患者抗血小板治疗方案的药物经济学评价

目的 从医疗保险角度,对经皮冠脉支架置入（percutaneous coronary intervention,PCI）术后3种抗血小板药物治疗方案进行经济学评价。方法 3种治疗方案为在使用阿司匹林基础上,经验性给予国产氯吡格雷,或经验性给予替格瑞洛,或根据CYP2C19基因型指导选择国产氯吡格雷或替格瑞洛,由此建立决策树模型并进行成本效果分析,预测该3种方案避免主要心血管事件的发生率以及成本,研究时间为1年。结果 经验性给予国产氯吡格雷联合阿司匹林治疗方案为成本最低方案,但直接给予替格瑞洛联合阿司匹林治疗方案的经济性最好。结论 对于PCI术后的患者,最推荐直接采用替格瑞洛联合阿司匹林的治疗方案。