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。     

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。     

CYP2C19基因指导冠心病患者经皮冠状动脉介入术后抗血小板药合理应用

目的 探索CYP2C19基因指导冠心病患者经皮冠状动脉介入（PCI）术后抗血小板药物的合理使用。方法 利用医院管理信息系统,收集2015年12月至2016年12月在心内科住院的冠心病患者2 836例,从中选取符合标准的CYP2C19 IM和PM基因型患者480例,根据患者是否根据基因型改变治疗方案,将患者分为常规剂量氯吡格雷组（常规治疗组）、氯吡格雷剂量加倍组和替格瑞洛组,观察各组患者血小板聚集抑制率和1年内主要不良心血管（MACE）及出血事件发生率。结果 最终入选468例患者,替格瑞洛组和剂量加倍组的血小板聚集抑制率均高于常规治疗组（P<0.05）,且替格瑞洛组又明显高于剂量加倍组（P<0.05）。MACE事件发生率方面,各组患者均是再发心肌梗死发生率最高,且替格瑞洛组及剂量加倍组明显低于常规治疗组（P<0.017）,其余MACE各事件及出血发生率各组之间无差异性（P>0.017）。结论 CYP2C19基因指导下冠心病患者PCI术后抗血小板治疗临床效果较好,临床应根据患者基因特点进行个体化合理用药。     

服用氯吡格雷或替格瑞洛患者的血小板最大聚集率差异研究

摘 要 目的：研究经皮冠脉介入术（PCI）后服用氯吡格雷的患者与服用替格瑞洛的患者血小板最大聚集率（MAR）的差异和出血情况,为临床使用抗血小板药物提供参考。方法: 选取因急性冠状动脉综合征(ACS)入院行PCI后服用氯吡格雷或者替格瑞洛的患者,在出院前对其MAR值进行检测,随访3个月内出血事件的发生情况,并比较两组患者MAR值以及随访结果的差异。结果: 服用氯吡格雷的患者出院时MAR为（51.1±13.7）%（n=76）,服用替格瑞洛的患者MAR为（32.6±15.7）%（n=76）,两组差异有统计学意义（P<0.001）。随访结果显示氯吡格雷组出血事件低于替格瑞洛组（P<0.05）。结论: 服用替格瑞洛的患者出院后出血的倾向可能比服用氯吡格雷的患者更大。     

老年急性冠脉综合征患者PCI围手术期应用替格瑞洛的效果

目的 探讨老年急性冠脉综合征患者经皮冠脉介入治疗（PCI）围手术期阿司匹林联合替格瑞洛抗血小板聚集的有效性和安全性。方法 选取2014年1月至2017年1月就诊于芜湖市第一人民医院心内科,年龄≥65岁且通过临床表现、冠脉造影确诊为急性冠脉综合征（ACS）的患者80例,根据PCI围术期治疗药物选择不同分为两组,接受阿司匹林联合替格瑞洛治疗的为替格瑞洛组（40例）,接受阿司匹林联合氯吡格雷治疗的为氯吡格雷组（40例）,PCI术后随访1年。比较两组患者手术前后心肌梗死溶栓试验（TIMI）血流分级,及术后随访期内主要不良心血管事件、出血事件及药物不良反应等情况。结果 两组患者均顺利完成手术。替格瑞洛组PCI术后TIMI血流改善程度较氯吡格雷组好（替格瑞洛组术后TIMI血流3级增加22例,氯吡格雷组术后TIMI血流3级仅增加5例）,差异有统计学意义（P<0.05）;替格瑞洛组术后1年内主要不良心血管事件发生4例,少于氯吡格雷组的12例,肌酐值升高发生1例少于氯吡格雷组的8例,差异有统计学意义（P<0.05）;两组患者术后出血风险和其他不良反应发生率差异无统计学意义（P>0.05）。结论 阿司匹林联合替格瑞洛在老年ACS患者PCI围手术期中抗血小板聚集的有效性和安全性较好。     

临床药师参与1例氯吡格雷抵抗患者的个体化用药分析

摘 要 目的：探讨临床药师参与氯吡格雷抵抗患者的药物治疗。方法：临床药师参与1例CYP2C19未突变的氯吡格雷抵抗患者的治疗。氯吡格雷基因多态性测定与血栓弹力图（TEG）检测结果不一致,TEG示：氯吡格雷抑制率25.2%,MADP 57 mm。氯吡格雷治疗基因预测示：CYP2C19*2 GG,CYP2C19*3 GG,CYP2C19*17 CC,ABCB1 3435 TT,PON1 576 AA,结论为氯吡格雷抵抗低风险。综合分析患者病情,临床药师为患者制定个体化用药方案,调整抗血小板治疗方案,同时考虑到患者的经济情况,建议将氯吡格雷替换为替格瑞洛。结果：医师采纳临床药师建议,患者出院后随访1年,无心血管不良事件、胃肠道出血等不良反应。结论：临床药师参与氯吡格雷抵抗患者的个体化给药方案的制定,分析两种检验方法结果不一致的现象,为患者调整抗血小板治疗方案、提供用药教育,保证了临床合理用药。     

血栓弹力图评价替格瑞洛对氯吡格雷低反应患者血小板抑制的影响

目的探讨经皮冠状动脉介入(PCI)术后,经血栓弹力图(TEG)检测的氯吡格雷药物低反应患者,换用替格瑞洛治疗后的血小板抑制情况。方法因冠心病不稳定型心绞痛行PCI术的患者常规氯吡格雷联合阿司匹林抗栓,经TEG筛选出53例氯吡格雷抑制不敏感、阿司匹林抑制正常的患者,换用替格瑞洛联合阿司匹林治疗。使用TEG比较换药前后花生四烯酸(AA)诱导的血小板抑制率及二磷酸腺苷(ADP)诱导的血小板抑制率。结果经TEG检测的氯吡格雷药物低反应患者,在换用替格瑞洛后,由ADP诱导的血小板抑制率明显升高[(41±8)%与(70±11)%],差异有统计学意义(P<0.01)。换用替格瑞洛前后由AA诱导的血小板抑制率变化差异无统计学意义(P>0.05)。结论对于血小板高反应性的患者,每天75mg氯吡格雷不能满足血小板抑制效果,换用替格瑞洛能够有效减低药物低反应的发生率,明显改善血小板抑制效果。     

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。     

CYP2C19基因中间代谢型ACS患者双倍剂量氯吡格雷和标准剂量替格瑞洛疗效与安全性评价

目的：探讨CYP2C19中间代谢型急性冠脉综合征（ACS）患者双倍剂量氯吡格雷和标准剂量替格瑞洛的疗效与安全性。方法：就诊的ACS患者,排除未行PCI手术、重度肝功能不全患者,对568例患者进行CYP2C19基因检测,其中CYP2C19中间代谢型患者252例（占比44.37%）,22例因各种原因（包括经济因素等）未接受PCI治疗,最终将230例CYP2C19中间代谢型患者（占比40.49%）随机分配至双倍剂量氯吡格雷组和标准剂量替格瑞洛组,并对2组患者进行长达12个月的随访,统计分析2组患者主要终点事件、出血事件和呼吸困难事件发生率差异。结果：随访1,6,12个月时2组患者主要终点事件发生率方面无显著差异（P＞0.05）。出血事件发生率替格瑞洛组稍高于氯吡格雷组,但无显著性差异（P＞0.05）。替格瑞洛组有2例发生致命颅内出血事件,可能原因是患者为出血高风险人群。呼吸困难发生率标准剂量替格瑞洛组显著高于双倍剂量氯吡格雷组（P<0.05）。替格瑞洛组6例患者发生显著的呼吸困难,导致患者无法耐受均转换成氯吡格雷。结论：CYP2C19基因中间代谢型ACS患者双倍剂量氯吡格雷和标准剂量替格瑞洛疗效无显著性差异。安全性方面,2组患者出血事件无显著性差异,但替格瑞洛组严重出血事件高于氯吡格雷组;呼吸困难发生率标准剂量替格瑞洛组显著高于双倍剂量氯吡格雷组。基于本研究结果,谨慎建议对于CYP2C19基因中间代谢型患者,无出血风险高危因素时,双倍剂量氯吡格雷和标准剂量替格瑞瑞洛均可选择;出血高风险人群,建议选择氯吡格雷。对于使用替格瑞洛过程中发生呼吸困难,建议及时更换为双倍剂量氯吡格雷。     

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。     

经皮冠状动脉介入治疗术后亚急性支架内血栓形成并发肝功能异常患者的药学服务

目的 通过临床药师参与经皮冠状动脉介入治疗（PCI）术后亚急性支架内血栓形成并发肝功能异常患者的临床治疗和药学服务,探讨临床药师所起的作用。方法 临床药师通过分析患者PCI术后亚急性支架内血栓形成及发生肝功能异常的原因,根据患者病情、基因型、合并用药、相互作用、不良反应等,及时调整患者抗血小板治疗药物为替格瑞洛90 mg,po,bid,同时减少瑞舒伐他汀剂量为10 mg,po,qn,并行药学监护和用药教育。结果 医师采纳临床药师建议,患者病情好转。结论 临床药师应发挥自身专业所长,协助医师调整患者药物治疗方案,保证患者用药安全、有效。     

Beyond efficacy: pharmacokinetic differences between clopidogrel,prasugrel and ticagrelor

Introduction: Clinical nonresponse to clopidogrel has been associated with variability in response. This has led to the development of other P2Y12 receptor inhibitors, such as prasugrel and ticagrelor, with different pharmacokinetic characteristics that influence their pharmacodynamics.

Areas covered: Clopidogrel response variability is attributable to its complex pharmacokinetics and is vulnerable to genetic polymorphisms in genes involved in absorption, metabolism and drug–drug interactions (i.e., proton pump inhibitors). Prasugrel which has a simpler metabolism, leading to greater bioavailability, seems to be less affected by genetic or drug–drug interactions and achieves a greater antiplatelet effect. Ticagrelor is the most novel compound approved with a simpler metabolism. Both prasugrel and ticagrelor reached their antiplatelet effect faster and to a much greater extent than clopidogrel. All these differences observed in kinetics explain, to some degree, the efficacy and safety profile observed in clinical trials for these molecules associated with other antiplatelet agents (aspirin, gpIIb/IIIa inhibitors) and anticoagulants.

Expert opinion: Clopidogrel is still the best standard of care. However, the pharmacokinetic advantages of both prasugrel and ticagrelor allow clinicians to center patient management by selecting the best drug for the appropriate subject.     

Pharmacokinetics and pharmacodynamics of ticagrelor in the treatment of cardiac ischemia

Introduction: After acute coronary syndromes (ACS), the so-called dual antiplatelet therapy (DAPT), which usually consists of low-dose of aspirin in combination with a thienopyridine (clopidogrel, prasugrel) or with a cyclopentyltriazolopyrimidine (ticagrelor), reduces the risk of ischemic events. Ticagrelor, un particular, is an effective drug as it isn’ a prodrug, doesn’t require metabolic activation and demonstrates a rapid onset and faster offset of action.

Areas covered: This article evaluates the pharmacokinetics, efficacy, safety and tolerability of ticagrelor during DAPT after ACS and its potential use beyond the canonical twelve months after PCI. The review discusses studies comparing: ticagrelor and clopidogrel (DISPERSE, DISPERSE-2, PLATO, RESPOND Trial, ONSET/OFFSET Trials), ticagrelor and placebo (PEGASUS TIMI 54 Trial).

Expert opinion: For ACS patients, the PLATO trial showed that ticagrelor was superior to clopidogrel in the reduction of cardiovascular death, myocardial infarction and stroke. PEGASUS TIMI 54 showed that patients in whom ischemic events and cardiovascular death outweigh the risk of life-threatening bleeding, may benefit from prolonged ticagrelor-based dual antiplatelet therapy, over 12 months. This strategy has been recently approved by the ACC/AHA guidelines. Further studies are needed to evaluate and eventually validate the role of the prolonged DAPT in patients treated with new generation stents.     

1例PCI术后支架内血栓形成患者的药学监护

1例40岁男性患者,因发作性胸痛3年,加重6h入院。入院诊断为：冠心病,急性前壁心肌梗死,陈旧性下壁心肌梗死,PCI＋支架置入术后。入院后急行冠状动脉造影＋PCI术,并给予抗血小板、抗凝、调脂、稳定斑块、改善心肌缺血等治疗。考虑到辛伐他汀可能与氯吡格雷存在代谢酶竞争,从而导致氯吡格雷抗栓效果不充分,临床药师建议将辛伐他汀调整为经CYP2C9代谢的氟伐他汀,或极少经CYP2C19代谢的瑞舒伐他汀;同时,对患者服用的双联抗血小板药物可能引起的胃肠道不适或出血症状,以及他汀类药物相关不良反应进行监测。并分析患者PCI术后支架内血栓形成的原因是抗血小板药物治疗不充分及不健康的生活方式,并据此对患者进行用药教育,督促患者遵循健康的生活方式,保障患者用药安全、有效。     

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.     

Treating acute coronary syndromes with new antiplatelet drugs: the mortality issue with prasugrel and ticagrelor

Abstract

Acute coronary syndromes (ACS) are the leading cause of mortality in Western countries. Until a few years ago, the antiplatelet drug to be administered in association with aspirin was indisputably clopidogrel. Recent data from randomized trials conducted in ACS patients have shown that the new oral antiplatelet regimens, prasugrel and ticagrelor, are associated with a significant reduction in cardiovascular events, as compared to clopidogrel. Moreover ticagrelor reduced both all-cause and cardiovascular mortality as compared to clopidogrel in the PLATO trial. However, there are intrinsic differences between the trials design and among the enrolled ACS populations, that make complex the generalization of the mortality results in the whole spectrum of ACS patients. We aimed to provide further insights into the unresolved mortality issues raised in the PLATO and TRITON–TIMI 38 trials, by analysing the effects of ticagrelor and prasugrel in the ACS populations included in the respective trials.     

Ticagrelor in modern cardiology - an up-to-date review of most important aspects of ticagrelor pharmacotherapy

Introduction: Ticagrelor is a first drug of a new chemical class cyclopentyltriazolopyrimidines. It is an antiplatelet agent with a unique mechanism of action, allowing a direct and reversible competitive inhibition of P2Y₁₂ receptor. According to newest guidelines, it is recommended for prevention of thrombotic events in patients with acute coronary syndromes. Moreover, it is preferred over clopidogrel, an older generation antiplatelet drug, and therefore gains more interest in modern cardiology and vascular medicine.

Areas covered: This review is a comprehensive and thorough summary of the most important findings on ticagrelor. Pharmacokinetics, pharmacogenetics, drug-drug interactions, adverse effects, efficacy in specific patient populations and off-label properties of ticagrelor are discussed in this paper. Moreover, the results from pivotal clinical trials are presented.

Expert opinion: Introduction of ticagrelor, a first directly-acting and reversible P2Y₁₂ inhibitor, gave some new possibilities as the efficacy of older drugs was often insufficient. Despite some drawbacks, such as a risk of bleeding events or dyspnea, a rapid onset of action, consistency in the antiplatelet effect and reports on pleiotropic properties make this drug a promising candidate for a first-choice antiplatelet agent in patients with acute coronary events.     

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.