替格瑞洛药物利用评价标准的构建和应用

目的 建立替格瑞洛药物利用评价(drug use evaluation,DUE)标准,为临床合理应用替格瑞洛提供参考。方法 以替格瑞洛说明书为基础,参考相关指南、专家共识和文献,并通过专家咨询法,从用药指征、用药过程和用药结果3个方面建立替格瑞洛的DUE标准。采用回顾性研究法,对某三甲医院2021年1月—12月使用替格瑞洛的病历进行合理用药评价。结果 建立的替格瑞洛DUE标准分为三级,包括一级指标3项,二级指标14项,三级指标60项。共纳入使用替格瑞洛的病例263例,其中不合理率为72.62%,不合理情况主要为超适应证用药(60.08%)、药物转换(14.83%)和用法用量(5.70%)等方面。结论 建立的替格瑞洛DUE标准有较强的科学性、实用性和可行性,可为临床合理用药和处方点评提供参考依据。     

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。     

替格瑞洛和氯吡格雷在老年冠心病患者抗血小板治疗中有效性及安全性的Meta分析

目的：探讨替格瑞洛和氯吡格雷在老年冠心病患者抗血小板治疗中的疗效及安全性,阐明更合理的抗血小板治疗策略。方法：应用计算机检索Cochrane试验资料库、Ovid-Medline全文数据库、EMBase数据库、PubMed数据库、中国学术文献总库（CNKI）、万方数字化期刊库、维普数据库（VIP）及中国生物医学文献数据库（CBM）,收集分为替格瑞洛组和氯吡格雷组治疗老年冠心病的随机对照试验（RCT）,2组患者分别给予替格瑞洛联合其他药物及氯吡格雷联合其他药物治疗,应用RevMan5.3统计软件进行Meta分析,观察抗血小板治疗有效性相关不良事件[即主要心血管不良事件（MACE）、心肌梗死（MI）、支架内血栓、全因死亡及卒中]和安全性相关不良事件（出血事件）的发生情况。结果：按照纳入和排除标准,共纳入15篇符合入选标准的RCT。Meta分析,与氯吡格雷组比较,替格瑞洛组MACE发生率（RR=0.59,95% CI：0.46~0.76,Z=4.08,P<0.01）、MI发生率（RR=0.48,95% CI：0.28~0.81,Z=2.74,P=0.006）、支架内血栓发生率（RR=0.16,95% CI：0.06~0.48,Z=3.30,P=0.001）和全因死亡发生率（RR=0.52,95% CI：0.30~0.89,Z=2.41,P=0.02）均明显降低,卒中发生率（RR=0.76,95% CI：0.39~1.47,Z=0.81,P=0.42）差异无统计学意义,出血发生率（RR=1.57,95% CI：1.20~2.05,Z=3.28,P=0.001）明显增加。结论：对于老年冠心病患者,替格瑞洛抗血小板治疗的有效性优于氯吡格雷,但可增加出血发生率。     

New drugs for the treatment of coronary artery syndromes: otamixaban and ticagrelor

Acute coronary syndromes are a major cause of mortality and morbidity. The objective of this evaluation is to review the clinical trials of two new drugs being developed for the treatment of acute coronary syndromes. The first drug is the anticoagulant otamixaban, and the trial compared otamixaban with unfractionated heparin and eptifibatide in acute coronary syndromes. The second drug is the antiplatelet ticagrelor, and the trial compared ticagrelor with clopidogrel in acute coronary syndromes. In the SEPIA-ACS1 TIMI 42 trial, the primary efficacy endpoint occurred in 6.2% of subjects treated with unfractionated heparin and eptifibatide, and to a significantly lesser extent with otamixaban. In the PLATO trial, the primary efficacy endpoint had occurred less in the ticagrelor group (9.8%) than in the clopidogrel group (11.7%) at 12 months. Two new drugs for acute coronary syndromes, otamixaban and ticagrelor, have recently been shown to have benefits in subjects undergoing percutaneous interventions compared to the present standard regimens for this condition.     

P2Y12 receptor inhibitors for secondary prevention of ischemic stroke

Introduction: Ischemic stroke (IS) is a major cause of death and disability worldwide. The P2Y₁₂ receptor plays a critical role in the formation of a stable thrombus leading to ischemic complications. Therefore, P2Y₁₂ receptor inhibitors constitute a major antiplatelet strategy in the secondary prevention of IS.

Areas covered: We searched articles about P2Y₁₂ receptor inhibitors and stroke in PubMed published until December 2014. This is a comprehensive review of the role of P2Y₁₂ receptor inhibitors alone and in combination with aspirin in the secondary prevention of noncardioembolic stroke.

Expert opinion: The potential benefit of more potent antiplatelet therapy for secondary stroke prevention must be weighed against the risk of bleeding in patients with IS. Short-term (≤ 3 months) dual antiplatelet therapy with clopidogrel and aspirin that is initiated early after IS or transient ischemic attack due to large artery atherosclerosis appears most efficient.     

Aspirin withdrawal in patients treated with ticagrelor presenting with non‐ST elevation myocardial infarction

Essentials

• Strong P2Y₁₂ blockade may cause platelet inhibition that is only minimally enhanced by aspirin.
• We evaluated aspirin withdrawal on platelet reactivity in ticagrelor treated patients.
• Aspirin withdrawal resulted in increased platelet reactivity to arachidonic acid.
• Aspirin withdrawal caused little difference in adenosine diphosphate‐induced platelet aggregation.

Summary

Background

Recent studies have shown that the thromboxane A₂‐dependent pathway is dependent on the ADP–P2Y₁₂ pathway, and that strong P2Y₁₂ receptor blockade alone causes inhibition of platelet aggregation that is minimally enhanced by aspirin. Data from the PLATO trial suggested that, among ticagrelor‐treated patients, high‐dose versus low‐dose (< 100 mg day^?1) aspirin is associated with an increased risk fof ischemic events.

Objectives

To evaluate the impact of aspirin withdrawal on platelet reactivity in acute coronary syndrome (ACS) patients treated with a potent P2Y₁₂ blocker.

Patients/Methods

This was a current prospective, randomized, placebo‐controlled, double‐blind, cross‐over study. The study population comprised 22 consecutive ACS patients who underwent percutaneous coronary intervention and were treated with aspirin (100 mg day^?1) and ticagrelor. Thirty days post‐ACS, open‐label aspirin was stopped, and patients were randomized to either blinded aspirin or placebo for 2 weeks, with each patient crossing over to the other arm for an additional 2 weeks. Platelet reactivity to arachidonic acid and ADP determined with light‐transmission aggregometry (LTA) and VerifyNow was evaluated at baseline, and 2 weeks and 4 weeks later.

Results

Aspirin withdrawal resulted in an increase in arachidonic‐acid induced platelet reactivity as determined with both LTA (77.0% ± 11.3% versus 20.8% ± 4.4%) and VerifyNow (607.7 ± 10.6 aspirin reaction units [ARU] versus 408.5 ± 14.4 ARU). Platelet response to ADP, as determined with both LTA and VerifyNow, did not differ with either aspirin or placebo (32.9% ± 2.6% versus 35.8% ± 3.6%, and 33.5 ± 6.4 P2Y₁₂ reaction units (PRU) versus 29.6 ± 5.7 PRU, respectively).

Conclusions

Aspirin withdrawal early post‐ACS results in increased platelet reactivity in response to arachidonic acid, despite concomitant treatment with the potent P2Y₁₂ blocker ticagrelor.

     

替格瑞洛在老年STEMI患者急诊PCI中的疗效与安全性分析

目的观察替格瑞洛在老年急性ST段抬高型心肌梗死(ST-segment elevated myocardial infarction,STEMI)患者急诊经皮冠状动脉介入治疗术(percutaneous coronary artery intervention,PCI)中的疗效和安全性。方法 2013年4月至2014年10月行急诊PCI术的60岁以上STEMI患者113例,采用数字表法随机分为负荷量替格瑞洛组(57例)和氯吡格雷组(56例),分别给予300 mg阿司匹林和180 mg替格瑞洛嚼服及300 mg阿司匹林和600 mg氯吡格雷嚼服。观察并比较2组患者急诊PCI术后无复流情况及术后1个月内主要心脏不良事件(major adverse cardiovascular events,MACE)发生率及出血、呼吸困难及恶性心律失常的发生率。结果替格瑞洛组无复流发生率以及术后1个月MACE的发生率均低于氯吡格雷组(P<0.05);而2组主要出血、恶性心律失常的发生率差异无统计学意义(P>0.05)。结论在老年STEMI患者的急诊PCI治疗中,应用替格瑞洛抗栓疗效显著,且安全性较好。     

CYP2 C19基因多态性联合血小板功能检测指导PCI术后患者抗血小板药物选择的效果观察

目的 探讨 CYP2C19基因多态性联合血小板功能检测指导下的抗血小板药物选择对经皮冠状动脉介入术(percutaneous transluminal coronary intervention,PCI) 治疗后患者临床预后的影响。方法 选取2017 年10月至 2018年2月因冠状动脉粥样硬化性心脏病就诊并成功完成PCI的患者200例,最终纳入符合条件并完成随访的患者190例。根据基因型将患者分为氯吡格雷正常代谢型(超快代谢型和快代谢型)和异常代谢型(中间代谢型和慢代谢型)两组。根据治疗后血小板聚集率将患者分为氯吡咯雷正常反应型(clopidogrel normal reaction,NCR,最大血小板聚集率＜46)和氯吡咯雷抵抗型(clopidogrel low reaction,LCR,最大血小板聚集率≥46)。结合基因型及血小板聚集率的检测结果,将基因型为正常代谢型+氯吡咯雷正常反应型患者分为A组,正常代谢型+氯吡咯雷抵抗型或异常代谢型+氯吡咯雷正常反应型患者归为B组,异常代谢型+氯吡咯雷抵抗型患者为C组。A组及B组给予阿司匹林+氯吡格雷抗血小板治疗,C组给予阿司匹林+替格瑞洛抗血小板治疗。随访3组12个月内主要不良心血管事件及出血事件的发生率。结果 3组患者一般临床资料(性别、年龄、吸烟、饮酒、高血压、糖尿病、高脂血症),临床用药[血管紧张素受体转换酶抑制剂(angiotensin converting enzyme inhibitor,ACEI)/血管紧张素受体阻滞剂(angiotension receptor blocker,ARB)、β受体阻滞剂、钙离子拮抗剂(calcium-channel antagonist,CCB)、质子泵抑制剂、硝酸酯类药物],随访1年时常规血液生物化学指标(肌酐、尿酸、转氨酶),PCI基本特征(多支病变、支架植入数量、支架直径、支架长度)等方面,差异均无统计学意义(P均>0.05);3组总不良心血管事件(major adverse cardiovascular event, MACE)发生率差异有统计学意义(P<0.05),其中靶血管再次血运重建,C组发生率降低,主要出血事件均为0;3组呼吸困难不良反应发生率,C组较A、B两组升高,但差异无统计学意义(P>0.05)。结论 通过CYP2C19基因型联合血小板功能检测共同筛选出的氯吡咯雷低反应患者给予阿司匹林联合替格瑞洛抗血小板治疗可以降低不良心血管事件的发生,并不增加出血事件的发生率,能够改善患者的预后。     

氯吡格雷抵抗的临床处理

急性冠状动脉综合征的患者尽管接受了标准剂量的氯吡格雷治疗,仍有部分患者发生缺血性心血管事件,称为氯吡格雷抵抗。氯吡格雷抵抗引起的广泛关注使个体化抗血小板药物成为这些患者改善预后的治疗策略。在遗传学检测的辅助下,新型P2Y12受体拮抗剂普拉格雷、替卡格雷和坎格雷拉以及糖蛋白Ⅱb/Ⅲa受体拮抗剂和高剂量氯吡格雷是可能的应对措施。就现有的临床试验研究证据对氯吡格雷抵抗患者的个体化治疗做一综述。     

Effects of ticagrelor pretreatment on electrophysiological properties of stellate ganglion neurons following myocardial infarction

Higher sympathetic activity predisposes to malignant ventricular arrhythmias in the context of myocardial infarction (MI). This is, in part, mediated by the electrical activity of the stellate ganglion (SG). The aim of this study is to examine the effects of ticagrelor pretreatment on the electrophysiological properties of SG neurons following MI in rabbits. MI was induced by isoproterenol (ISO) of 150 mg kg^-1 d^-1 (twice at an interval of 24 hours). Ticagrelor pretreatment was administered at low- (10 mg kg^-1 d^-1) or high-dose (20 mg kg^-1 d^-1). Protein and RNA expression were determined by immunohistochemical analysis and real-time PCR, respectively. The activity of sodium channel current (I_Na), delayed rectifier potassium current (I_KDR), M-type potassium current (I_KM) as well as action potentials (APs) from SG neurons were measured by whole-cell patch-clamp. Intracellular calcium concentrations were measured by confocal microscopy. Compared with the control group, the MI group exhibited a greater amplitude of I_Na, I_KDR and I_KM, significantly altered activation and inactivation characteristics of I_Na, no significant alterations in protein or mRNA expression of sodium and M-type potassium channels, along with higher AP amplitude and frequency and intracellular calcium concentrations. Most of these abnormalities were prevented by pretreatment with low- or high-dose ticagrelor. Our data suggest that ticagrelor exerts cardioprotective effects, potentially through modulating the activity of different ion channels in SG neurons.