急性冠脉综合征患者替格瑞洛与氯吡格雷 相互转换治疗的现状调查分析

目的：调查分析急性冠脉综合征（ACS）急性期或早期的患者在住院期间替格瑞洛与氯吡格雷相互转换的应用现状。方法：分析2019年6月~12月本院急性期或早期ACS患者院内替格瑞洛与氯吡格雷相互转换的发生率、一般临床特征、转换给药时间和给药剂量。结果：ACS患者替格瑞洛与氯吡格雷转换治疗的比率为12.9%（208/1607）,最终纳入的182例患者中,63.2%（115例）由氯吡格雷换为替格瑞洛（升阶治疗组）,36.8%（67例）由替格瑞洛换为氯吡格雷（降阶治疗组）。升阶组和降阶组的一般临床特征存在一定的差异;两组患者均在造影术后当天至术后第一天的时间段发生转换的人数最多,且组间存在差异（58.4% vs 40.0%,P=0.018）;降阶组仅有35.5%的患者在最后一剂替格瑞洛给药24 h后给予首剂氯吡格雷;仅有37.4%的患者在转换时给予所换用P2Y12受体拮抗剂的负荷剂量。结论：“指南”推荐的P2Y12受体拮抗剂转换策略尚未得到广泛认可,临床实践中转换策略的制定须结合患者情况作个体化选择。     

替格瑞洛在中国急性冠脉综合征患者中的早期疗效及安全性观察

目的 探讨替格瑞洛在中国急性冠脉综合征（ACS）患者中的早期疗效及总结治疗经验。方法 2012年9月～2013年7月入我院心内科诊断为ACS的患者199例,其中服用替格瑞洛患者96例,服用氯吡格雷患者103例。替格瑞洛组给予180 mg负荷剂量口服,后90 mg每日2次维持。氯吡格雷组给予300/600 mg口服,后服用氯吡格雷维持剂量75 mg每日1次,所有患者均给予阿司匹林。比较两组的基础临床资料,观察两组服药10天、30天、90天的不良事件,并对两组90天的心血管事件和出血情况进行比较。结果 两组间基础临床资料无统计学差异（P〉0.05）。替格瑞洛组心血管死亡（1%：1.9%）、心肌梗死（0%：1%）、卒中（0%：1.9%）、支架内血栓（0%：1%）、再发心绞痛（2.1%：4.9%）少于氯吡格雷组,呼吸困难（2.1%：0%）、次要出血（3.1%：1.0%）和轻微出血（5.2%：2.9%）多于氯吡格雷组,但均无统计学意义（P〉0.05）。替格瑞洛组主要心血管不良事件总和低于氯吡格雷组（3.1%：10.7%）,差异有统计学意义（P=0.037）。两组均无主要出血。替格瑞洛组次要出血和轻微出血总和高于氯吡格雷组（8.3%：3.9%）,但差异无统计学意义（P=0.188）。结论 替格瑞洛在中国患者中的早期疗效与PLATO（血小板抑制和患者预后研究）研究结果 基本一致,临床疗效确切,具有良好的安全性和耐受性。     

氯吡格雷抵抗患者应用替格瑞洛治疗的血小板凝集状况分析

目的：对氯吡格雷抵抗患者应用替格瑞洛治疗的血小板凝集状况研究分析。方法：对2015年1月～2016年12月在我院行经皮冠状动脉介入治疗术的540例患者进行血小板聚集率的测定,筛选出氯吡格雷抵抗患者97例,随机分为对照组（48例）、观察组（49例）,观察组改用替格瑞洛进行治疗,对照组继续进行氯吡格雷治疗,对比分析两组治疗前后的血小板聚集率。结果：观察组经替格瑞洛治疗后血小板聚集率降低值高于对照组（P<0.05）,观察组的血小板聚集率达标率（83.7%）高于对照组（4.2%,P<0.05）。结论：用替格瑞洛治疗PCI术后氯吡格雷抵抗,可增加血小板抑制率,降低血小板聚集率,出血事件并未显著增加,所以,替格瑞洛是氯吡格雷抵抗患者进行抗血小板治疗的选择之一。     

新型P2Y12受体抑制剂替格瑞洛临床研究进展

抗血小板药物是急性冠脉综合征（Acute Coronary Syndrome,ACS）治疗的基石,对防治心肌缺血和介入并发症是有益的。目前治疗ACS和经皮冠状动脉介入治疗（percutaneous coronary intervention,PCI）指南推荐使用的口服抗血小板药物包括氯吡格雷、替格瑞洛、普拉格雷联合阿司匹林双重抗血小板治疗预防复发性缺血事件。本文对新型P2Y12受体抑制剂替格瑞洛的药代动力学和药效学特点以及在ACS患者中的循证医学证据作一介绍。     

抗血小板药物替格瑞洛药代药效动力学及遗传药理学研究进展

替格瑞洛是2010年批准上市的抗血小板新药,属于新型环戊基三唑嘧啶类（CPTP）口服P2Y12受体拮抗剂。替格瑞洛口服后迅速吸收,中位达峰时间约1．5h。与已有P2Y12受体拮抗剂氯吡格雷和普拉格雷相比,替格瑞洛具有显著优势：无需代谢激活故起效迅速;与P2Y12受体呈可逆性结合,故停药后血小板功能恢复较快。此外,替格瑞洛可以通过抑制非血小板细胞表面的P2Y12受体从而产生其他药理学作用。替格瑞洛的药动学特征不受年龄、性别、饮食以及对氯吡格雷反应性的影响。替格瑞洛主要经CYP3A4代谢,可迅速产生血药浓度依赖的血小板抑制作用,且对氯吡格雷抵抗的患者同样有效。更重要的是,替格瑞洛的抗血小板作用不受具有多态性的药物转运体（ABCBl）和代谢酶（CYP2C19）基因型的影响。本文主要概述替格瑞洛药动学、药效学以及遗传药理学方面的研究进展。     

替格瑞洛与氯吡格雷在CYP2C19等位基因功能缺失患者中的抗血小板疗效比较

目的比较替格瑞洛与氯吡格雷在细胞色素P450 C19(CYP2C19)等位基因功能缺失的行冠状动脉介入治疗(PCI)的急性冠状动脉综合征(ACS)患者中应用的抗血小板疗效。方法选取行PCI的ACS患者,筛选CYP2C19等位基因功能缺失患者,包括*2/*2、*2/*3以及*3/*3。共入选患者52例,随机分为两组,每组26例。替格瑞洛组于PCI术前给予替格瑞洛180 mg负荷量后90 mg,po,bid;氯吡格雷组术前给予氯吡格雷300 mg负荷量后75 mg,po,qd。若是急诊PCI手术,替格瑞洛组于术前给予替格瑞洛180 mg负荷量后90 mg,po,bid;氯吡格雷组术前给予氯吡格雷600 mg负荷量后75 mg,po,qd维持。观察患者术后1年的主要心脑血管不良事件(MACCE)、出血情况及其他药物不良反应。结果两组患者基线资料无显著差异(P>0.05),应用血管紧张素转换酶抑制药/血管紧张素受体拮抗药、肾上腺素β受体阻滞药比例无显著差异(P>0.05)。术后1年,替格瑞洛组MACCE发生率为8%(2/26),低于氯吡格雷组(31%,8/26,P<0.05)。两组出血事件发生率分别为12%和8%,组间差异无显著意义(P>0.05)。结论 CYP2C19等位基因功能缺失患者给予替格瑞洛治疗可改善临床预后,基于CYP2C19基因型的个体化方案可考虑在行PCI术的ACS患者中实施。     

氯吡格雷和替格瑞洛对老年冠心病患者PCI术后血小板功能、炎性反应及主要不良心血管事件的影响

目的：比较氯吡格雷和替格瑞洛对老年冠心病（CHD）患者经皮冠状动脉介入（PCI）术后血小板功能、炎性反应及主要不良心血管事件（MACE）的影响。方法：采用回顾性分析方法,抽取2019年3月-2020年8月在我院实施PCI术的100例老年CHD患者信息,根据药物治疗方式分组,给予替格瑞洛联合阿司匹林的患者为观察组,给予氯吡格雷联合阿司匹林的患者为对照组。比较治疗前后两组的最大血小板聚集率（MPAR）、P2Y12反应单位（PRU）、IL-6、TNF-α、CRP、出血事件、主要不良心血管事件以及不良反应。结果：治疗后两组的MPAR、PRU、IL-6、TNF-α及CRP水平均较治疗前明显降低（P <0.05）,观察组上述指标均明显低于对照组（P <0.05）;观察组MACE发生率为20.00%,明显低于对照组（38.00%）,P <0.05。两组不良反应发生率及出血事件无显著性差异（P> 0.05）。结论：替格瑞洛与氯吡格雷均能够明显改善老年CHD患者PCI术后的血小板功能,降低炎性反应及MACE发生率,但替格瑞洛的效果优于氯吡格雷。     

替格瑞洛与氯吡格雷在急性冠状动脉综合征经皮冠状动脉介入术治疗中的对比研究

<正>相关研究已证实,血小板活化在急性冠状动脉综合征(ACS)发病与进展中具有关键作用~([1])。以往临床常以阿司匹林、氯吡格雷联合用药预防ACS患者经皮冠状动脉介入术(PCI)后心源性猝死、ACS再发等不良事件,但氯吡格雷是前体药物,其个体反应差异、起效时间延迟等问题不容忽视~([2])。替格瑞洛是新型抗血小板药,近年被逐渐应用于临床。本研究选取我院ACS患者102例,旨在分析替格瑞洛与氯吡格雷于PCI中的临床应用效果。现报告如下。     

基于FAERS的替格瑞洛及氯吡格雷相关出血事件信号挖掘

目的 为替格瑞洛及氯吡格雷的临床合理应用提供指导与依据。方法 利用美国食品和药物管理局（FDA）不良事件报告系统（FAERS）获取替格瑞洛和氯吡格雷从上市起至2021年9月30日的药品不良事件（ADE）报告数据，采用标准MedDRA查询（SMQ）检索其中的出血事件报告，采用报告比值比（ROR）法进行信号挖掘。结果 分别获得两药相关出血报告3 326例和25 538例，严重不良事件（SAE）发生率均较高（66.36%,67.22%），均以住院/住院时间延长为主（40.56%,45.83%）。替格瑞洛[ROR=4.02,95%CI(3.86,4.18)]出血信号值低于氯吡格雷[ROR=6.32,95%CI(6.22,6.42)]。替格瑞洛相关出血事件涉及17个系统器官分类（SOC）,85个可疑信号；氯吡格雷涉及18个SOC,198个可疑信号。出血事件多分布于胃肠系统（33.98%,43.08%）以及血管与淋巴管系统（20.42%,14.03%）。结论 替格瑞洛与氯吡格雷均可诱发多个系统的出血事件，其中胃肠系统较多见，临床应加强对此两种药物的出血事件监护。     

血栓弹力图法和VerifyNow P2Y12法评估CYP2C19基因多态性对氯吡格雷反应性的影响

目的：通过血栓弹力图法（TEG）和VerifyNow P2Y12法检测来评估CYP2C19基因多态性对急性冠脉综合征（ACS）患者服用氯吡格雷疗效的影响，并比较2种方法检测结果的差异。方法：入选2017年10月至2018年10月因ACS入院且服用氯吡格雷（75 mg·d^-1）和阿司匹林（100 mg·d^-1）的患者230例，使用焦磷酸测序检测其CYP2C19基因型，并在服用氯吡格雷7 d后，使用TEG法检测其二磷酸腺苷（ADP）诱导的血小板聚集抑制率和VerifyNow P2Y12法检测其血小板反应单位（PRU）。结果：TEG法结果显示CYP2C19快代谢型、中间代谢型和慢代谢型患者出现氯吡格雷抵抗的比例分别为8.9%、40.2%和59.4%。VerifyNow P2Y12法检测结果显示各代谢型患者出现氯吡格雷抵抗的比例分别为6.9%、29.9%和50.0%。慢代谢型及中间代谢型患者出现氯吡格雷抵抗的概率明显高于快代谢组（P<0.05）。2种方法氯吡格雷抵抗检出率差异无显著性（P>0.05），检测结果显著相关（r=-0.719，P<0.001）。结论：CYP2C19基因多态性显著影响ACS患者服用氯吡格雷的疗效。TEG法和VerifyNow P2Y12法检测抗血小板聚集结果具有相关性。     

新型抗血小板药替卡格雷

替卡格雷为第一个可逆结合的、直接起效的、口服给药的血小板二磷酸腺苷P2Y12受体拮抗剂,比氯吡格雷起效更快,对血小板凝集的抑制作用更强。2011年7月20日,美国FDA批准替卡格雷用于降低急性冠脉综合征(acute coronary syndrome,ACS)患者的血栓性心血管事件的发生率。与氯吡格雷相比,替卡格雷起效更快,对血小板聚集的抑制作用更强,能显著降低心血管死亡、心肌梗死或卒中的发生率。在有效治疗的同时,替卡格雷并未显著增加主要出血事件的发生率。联合用药时,阿司匹林的维持剂量应为75～100 mg.d-1。本文对替卡格雷药理学特性、临床价值及不良反应进行综述。     

Ticagrelor: a review of its use in the management of acute coronary syndromes

Ticagrelor (Brilique?; Brilinta?), a cyclopentyl-triazolo-pyrimidine antiplatelet agent, is the first oral antagonist of the P2Y(12) receptor to offer reversible receptor binding. It is indicated in the EU for the prevention of atherothrombotic events in adults with acute coronary syndromes (ACS) [unstable angina pectoris, ST-segment elevation myocardial infarction [STEMI] or non-STEMI), including those managed medically or with percutaneous coronary intervention or coronary artery bypass grafting (CABG). Ticagrelor provides selective and reversible inhibition of adenosine diphosphate-induced platelet aggregation, with a faster onset and offset of action than that of clopidogrel, and is effective in the treatment of patients with ACS, with or without ST-segment elevation. In the large, randomized, double-blind, multicentre PLATO trial conducted in this patient population, ticagrelor was more effective than clopidogrel in terms of preventing ischaemic events over 12 months, providing a significantly lower risk of the primary composite endpoint of myocardial infarction, stroke or death from vascular causes, and was associated with an overall mortality benefit. The risk of major bleeding with ticagrelor, including bleeds related to CABG, did not differ from that seen with clopidogrel in this study, although ticagrelor was associated with more non-CABG-related major bleeds and fatal intracranial bleeding, albeit the latter bleeding events were rare. Further long-term and comparative efficacy and tolerability data are required to definitively position ticagrelor with respect to other antiplatelet agents, including prasugrel. However, the clinical data currently available indicate that ticagrelor is a promising option for the treatment of patients with ACS and may be of particular use in those at high risk of ischaemic events or unresponsive to clopidogrel.     

根据血小板活性检测指导个体化用药的成本-效用分析

目的：评估急性冠状动脉综合征（acute coronary syndrome,ACS）患者接受经皮冠状动脉介入治疗（percutaneous coronary intervention,PCI）术后使用血小板活性检测系统——VerifyNow P2Y12指导氯吡格雷或替格瑞洛应用的成本-效用。方法：患者年龄≥ 55岁,部分接受氯吡格雷或替格瑞洛联合阿司匹林治疗1年,部分在双联抗血小板治疗（dual antiplatelet therapy,DAPT）前接受VerifyNow P2Y12检测,并根据活性检测结果再选择氯吡格雷或替格瑞洛联合阿司匹林治疗1年。由此建立决策树及Markov模型并进行成本-效用分析,评价开展血小板活性检测的成本-效用。结果：与直接使用氯吡格雷相比,指导下的DAPT每年可以在每1 000名患者中减少5次心梗和4次死亡。指导下的个体化治疗,每名患者的总成本预测值比所有患者都使用替格瑞洛时低32%。单因素敏感性分析与概率敏感性分析的结果与基础分析的结果一致。结论：制订DAPT方案前,使用VerifyNow P2Y12评估血小板活性以实施个体化用药是一种具备成本-效用的策略,与直接使用替格瑞洛相比可减轻经济负担。     

Pharmacokinetic, pharmacodynamic and pharmacogenetic profile of the oral antiplatelet agent ticagrelor

Acute coronary syndromes (ACS) remain life-threatening disorders associated with high morbidity and mortality, despite advances in treatment over the last decade. Adenosine diphosphate-induced platelet activation via P2Y(12) receptors plays a pivotal role in the pathophysiology of ACS. The current standard of treatment involves dual antiplatelet therapy with aspirin (acetylsalicylic acid) and the thienopyridine clopidogrel. Numerous studies and wide use in clinical practice have established the value of this approach in the treatment of ACS. However, clopidogrel treatment has a number of limitations, including a delayed onset of action due to the need for metabolic activation, variable and reduced antiplatelet effects in patients with certain genotypes, and prolonged recovery of platelet function due to irreversible P2Y(12) receptor binding. Prasugrel, a new thienopyridine, has demonstrated more consistent inhibition of platelet aggregation (IPA) than clopidogrel, although this thienopyridine also requires metabolic activation and treatment is associated with a significantly increased risk of life-threatening and fatal bleeding. The recently approved oral antiplatelet agent ticagrelor has the potential to overcome some of the limitations of current therapy due to its unique pharmacokinetic and pharmacodynamic profiles. It is a member of a new chemical class, the cyclopentyltriazolopyrimidines, and is a potent P2Y(12) receptor antagonist. Ticagrelor is rapidly absorbed, with a median time to maximum concentration of 1.3-2.0 hours. Ticagrelor does not require metabolic activation to an active form and binds rapidly and reversibly to the P2Y(12) receptor. As well as exerting effects via platelet P2Y(12) receptors, ticagrelor may confer additional benefits via inhibition of non-platelet P2Y(12) receptors. The pharmacokinetic profile of ticagrelor is not significantly affected by age, gender or administration with food, nor by prior treatment with, or responsiveness to, clopidogrel. Ticagrelor is primarily metabolized via the cytochrome P450 (CYP) 3A4 enzyme, rapidly produces plasma concentration-dependent IPA that is greater and more consistent than that observed with clopidogrel, and can also enhance platelet inhibition and overcome non-responsiveness in patients previously treated with clopidogrel. Importantly, the pharmacodynamic characteristics of ticagrelor are not influenced by CYP2C19 and ABCB1 genotypes. This article summarizes our current knowledge regarding the pharmacokinetic, pharmacodynamic and pharmacogenetic profile of ticagrelor.     

Review of clopidogrel dose escalation in the current era of potent P2Y12 inhibitors

Dual anti-platelet therapy with aspirin and a P2Y12 inhibitor is the standard of care for patients with acute coronary syndromes (ACS) and for patients undergoing percutaneous coronary intervention (PCI). Clopidogrel is associated with increased risk of high on-treatment platelet reactivity (HTPR) compared to ticagrelor and prasugrel. Investigators have therefore sought to “escalate” clopidogrel dosing to overcome HTPR to reduce ischemic/thrombotic events. In this review, we will summarize the evidence for dose escalation in the context of genetic determinants of resistance and platelet function data. We will review contemporary clinical trials that have sought to improve delivery of dual antiplatelet therapy to patients with coronary artery disease and discuss the potential of clopidogrel dose escalation in specific populations.     

Efficacy and safety of ticagrelor in patients with acute coronary syndrome: A meta‐analysis of randomized controlled trials

Acute coronary syndrome (ACS) is a dangerous and urgent clinical pattern of coronary artery disease. Aspirin and adenosine diphosphate P2Y₁₂ receptor antagonists are the standard dual anti‐platelet therapy for patients with ACS. Ticagrelor is a new oral antagonist of the adenosine diphosphate P2Y₁₂ receptor. Randomized controlled trials (RCTs) have evaluated the efficacy and safety of ticagrelor compared to clopidogrel or prasugrel in patients with ACS, obtaining conflicting results. Thus, we conducted a meta‐analysis of these RCTs to determine the efficacy and safety of ticagrelor in patients with ACS. Results of the meta‐analysis indicate that ticagrelor decreased the risk of major adverse cardiovascular events (MACE) and all‐cause death, but increased the risk of bleeding events. In Asiatic patients, analysis indicates that ticagrelor did not decrease the risk of MACE and all‐cause death, while increasing the risk of bleeding events. Together, this meta‐analysis suggests that ticagrelor was more effective, but less safe than clopidogrel and prasugrel in patients with ACS. Subgroup analysis indicates that ticagrelor was not more effective, although less safe than clopidogrel in Asiatic patients, thus more evidence is needed to further evaluate the efficacy and safety of ticagrelor in Asiatic patients.     

替格瑞洛对急性冠脉综合征经皮冠状动脉介入治疗围术期血小板聚集率的影响

目的 探讨替格瑞洛对急性冠脉综合征(ACS)经皮冠状动脉介入治疗(PCI)围术期血小板聚集率(MPAR)的影响.方法 80例确诊为ACS行PCI术患者为研究对象,术前采用随机数字表法分为替格瑞洛治疗组(观察组)和氯吡格雷治疗组(对照组),每组40例.所有研究对象入院前已连续服用氯吡格雷(泰嘉) 75 mg·d-1持续7 d以上者维持原剂量,未曾服用过氯吡格雷者予以300 mg负荷剂量后75 mg·d-1维持.观察组入院前已连续服用替格瑞洛每次90 mg,2次/天,持续7 d以上者维持原剂量,未曾服用过替格瑞洛者予以180 mg负荷剂量后改标准剂量替格瑞洛(每次90 mg,2次/天)治疗.分别于治疗前、术后5 d抽取空腹外周血标本进行MPAR的测定.结果 治疗前观察组和对照组患者MPAR比较,差异无统计学意义 (P>0.05);术后5 d外周血MPAR均明显低于治疗前(P<0.05);观察组MPAR明显低于对照组(P<0.05).结论 替格瑞洛较氯吡格雷能更好地抑制ACS血管病变患者PCI围术期MPAR,降低早中期不良心血管事件的发生率,对重度冠状动脉血管病变的患者具有更好抗血小板聚集的治疗效果.     

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。     

P2Y12 receptor inhibitors: an evolution in drug design to prevent arterial thrombosis

Introduction: P2Y12 inhibitors are a critical component of dual antiplatelet therapy (DAPT), which is the superior strategy to prevent arterialthrombosis in patients with acute coronary syndromes (ACS) and undergoing stent implantation..

Areas covered: Basic science articles, clinical studies, and reviews from 1992–2017 were searched using Pubmed library to collet impactful literature. After an introduction to the purinergic receptor biology, this review summarizes current knowledge on P2Y12 receptor inhibitors. Furthermore, we describe the subsequent improvements of next-generation P2Y12 receptor inhibitors facing the ambivalent problem of bleeding events versus prevention of arterial thrombosis in a variety of clinical settings. Therefore, we summarize data from relevant preclinical and clinical trials of currently approved P2Y12 receptor inhibitors (clopidogrel, prasugrel, ticagrelor, cangrelor) and provide strategies of drug switching and management of bleeding events.

Expert opinion: An enormous amount of pharmacologic and clinical data is available for the application of P2Y12 receptor inhibitors. Today prasugrel, ticagrelor and clopidogrel are the standard of care drugs during dual antiplatelet therapy for ACS patients, but have considerable rates of bleeding. Recent and future clinical trials will provide evidence for subsequent escalation and de-escalation strategies of P2Y12 receptor inhibition. These data may pave the way for an evidence-based, individualized P2Y12 receptor inhibitor therapy.