替格瑞洛治疗氯吡格雷低反应患者的有效性及安全性分析

目的 观察替格瑞洛对氯吡格雷低反应急性冠状动脉综合征(acute coronary syndromes,ACS)患者治疗的有效性及安全性。方法 选择2013年1月至2014年6月应用氯吡格雷75 mg/d治疗的ACS经皮冠状动脉介入治疗(PCI)术后患者493例,用血栓弹力图测定血小板聚集率,根据血小板聚集率筛选出氯吡格雷低反应患者173例,采用数字随机法分为氯吡格雷组(n=87)和替格瑞洛组(n=86)。氯吡格雷组继续服用氯吡格雷(75 mg/d),替格瑞洛组将氯吡格雷替换为替格瑞洛(90 mg,2次/d)。主要终点事件为治疗3天、7天、30天二磷酸腺苷(ADP)诱导的血小板聚集率变化情况,次要终点事件为主要不良心脑血管事件(MACCE)及出血的发生率。结果 替格瑞洛组3天、7天、30天血小板聚集率分别为(56.7±12.5)%、(54.1±12.3)%、(53.2±15.3)%显著低于氯吡格雷组(87.7±14.3)%、(85.4±12.7)、(84.9±10.7)%,差异有统计学意义(P<0.01)。对所有患者随访12个月,替格瑞洛组MACCE及出血的发生率显著低于氯吡格雷组(P<0.05)。而两组出血发生率差异无统计学意义(P＞0.05)。结论 对于经皮冠状动脉介入治疗的氯吡格雷低反应患者接受替格瑞洛治疗后能获得理想的抗血小板效果,且替格瑞洛是有效、安全可信赖的药物。     

Inter-patient variability of platelet reactivity in patients treated with prasugrel and ticagrelor

The aim of this study was to evaluate the distribution of platelet reactivity values in patients treated with prasugrel and ticagrelor. This prospective observational study enrolled 200 patients treated with prasugrel or ticagrelor. Platelet aggregation was determined by multiple electrode aggregometry after stimulation with adenosine diphosphate (ADP) in the maintenance phase of treatment with prasugrel or ticagrelor. Only 3% of patients in the prasugrel group and 2% of study participants in the ticagrelor group had high on treatment platelet reactivity (HTPR). The majority of patients displayed low on treatment platelet reactivity (LTPR; prasugrel: 69%; ticagrelor: 64%). The pharmacodynamic effect was similar in patients treated with prasugrel and ticagrelor: the median level of ADP-induced platelet aggregation was 15U (interquartile range IQR 9-21U) under prasugrel treatment and 17U (IQR 8–24U) under ticagrelor treatment (p=0.370). In conclusion, our study suggests that there is some degree of variability in ADP-induced platelet aggregation under treatment with prasugrel and ticagrelor.     

Comparison of half- and standard-dose ticagrelor in Chinese patients with NSTE-ACS

Ticagrelor is a novel direct-acting P2Y₁₂ receptor antagonist used for preventing atherothrombotic events in patients with acute coronary syndromes (ACS). The current recommended dose is 90 mg bid, but a low dose of ticagrelor has not been previously studied in Chinese ACS patients. Therefore, we performed this study to observe the different effects of half- and standard-dose ticagrelor on platelet aggregation in Chinese patients with NSTE-ACS. Sixty-two NSTE-ACS subjects were assigned to half-dose ticagrelor (n = 20), standard-dose ticagrelor (n = 22) and clopidogrel (n = 20) groups. Five days after drug administration, VerifyNow P2Y₁₂ assay was performed to test P2Y₁₂ reaction units (PRU) and inhibition of platelet aggregation (IPA). High-platelet reactivity (HPR) was defined as a PRU > 208. The adverse events, including bleeding events and dyspnoea, were monitored throughout the study. PRU values in the half-dose (44.55 ± 32.88) and standard-dose (39.10 ± 40.02) ticagrelor were dramatically lower than those in the clopidogrel group (189.20 ± 65.22; P < 0.0001). The half-dose (84% ± 10%) and standard-dose (86% ± 13%) ticagrelor both showed greater IPA than clopidogrel (33% ± 20%; P < 0.0001). There were no significant differences in PRU and IPA between the two ticagrelor groups (P = 0.3085 and 0.4028, respectively). HPR rates were significantly lower in the two ticagrelor groups (0% for both) than those in the clopidogrel group (35%). In conclusion, half-dose ticagrelor had a similar inhibitory effect on platelet aggregation as standard-dose ticagrelor in Chinese patients with NSTE-ACS, which was significantly stronger than that of clopidogrel.     

Response variability to clopidogrel: is tailored treatment,based on laboratory testing,the right solution?

Summary. Clopidogrel is an antithrombotic prodrug, whose active metabolite inhibits platelet function by irreversibly binding to the platelet receptor for adenosine diphosphate, P2Y₁₂. Wide inter‐individual variability of response to clopidogrel has been reported in several studies: a significant proportion of treated patients (about one‐third) exhibit a suboptimal inhibition of platelet function. Genetic and environmental factors that influence the absorption and/or the extent of metabolism of clopidogrel to its active metabolite account for the observed variability of response. Tailored treatment based on the results of laboratory tests of platelet function has been proposed as a solution to this problem, which has important clinical implications. Although it is often considered a desirable evolution of modern medicine, tailored treatment based on laboratory tests is actually an old remedy (of yet unproven efficacy, in the case of antiplatelet therapy) for the problem of response variability to antithrombotic drugs with unpredictable bioavailability. When possible, the use of alternative drugs with more uniform and predictable bioavailability, and with favourable profiles in terms of risk/benefit and cost‐benefit ratios should be preferred. Moreover, tailored treatment with laboratory tests must be validated in randomized clinical trials before its implementation can be recommended. We still need to identify and standardize the laboratory test for this purpose, as well as answer basic questions on its clinical utility and cost‐effectiveness, before tailoring clopidogrel therapy based on laboratory tests can be recommended in clinical practise.     

Ticagrelor binds to human P2Y12 independently from ADP but antagonizes ADP-induced receptor signaling and platelet aggregation

Summary. Background: P2Y₁₂ plays an important role in regulating platelet aggregation and function. This receptor is the primary target of thienopyridine antiplatelet agents, the active metabolites of which bind irreversibly to the receptor, and of newer agents that can directly and reversibly modulate receptor activity. Objective: To characterize the receptor biology of the first reversibly binding oral P2Y₁₂ antagonist, ticagrelor (AZD6140), a member of the new cyclopentyltriazolopyrimidine (CPTP) class currently in phase III development. Methods: Ticagrelor displayed apparent non‐competitive or insurmountable antagonism of ADP‐induced aggregation in human washed platelets. This was investigated using competition binding against [³H]ADP, [³³P]2MeS‐ADP and the investigational CPTP compound [¹²⁵I]AZ11931285 at recombinant human P2Y₁₂. Functional receptor inhibition studies were performed using a GTPγS‐binding assay, and further binding studies were performed using membranes prepared from washed human platelets. Results: Radioligand‐binding studies demonstrated that ticagrelor binds potently and reversibly to human P2Y₁₂ with K_on and K_off of (1.1 ± 0.2) × 10^?4 nm ^?1 s^?1 and (8.7 ± 1.4) × 10^?4 s^?1, respectively. Ticagrelor does not displace [³H]ADP from the receptor (K_i > 10 μm ) but binds competitively with [³³P]2MeS‐ADP (K_i = 4.3 ± 1.3 nm ) and [¹²⁵I]AZ11931285 (K_i = 0.33 ± 0.04 nm ), and shows apparent non‐competitive inhibition of ADP‐induced signaling but competitive inhibition of 2MeS‐ADP‐induced signaling. Binding studies on membranes prepared from human washed platelets demonstrated similar non‐competitive binding for ADP and ticagrelor. Conclusions: These data indicate that P2Y₁₂ is targeted by ticagrelor via a mechanism that is non‐competitive with ADP, suggesting the existence of an independent receptor‐binding site for CPTPs.     

替格瑞洛致心律失常不良反应文献分析

目的： 分析替格瑞洛致心律失常不良反应的发生情况及临床特点，为合理用药提供参考。方法： 检索Cochrane图书馆、PubMed、Web of science、Springer link、Embase、Scopus、中国知网（CNKI）、万方期刊论文数据库、维普期刊数据库、中国生物医学文献数据库（CBM）中收载的替格瑞洛致心律失常不良反应文献进行统计分析，检索时间为2011年1月-2019年7月。结果： 检索到14篇共15例关于替格瑞洛致心律失常不良反应个案报道，以男性为主（10例，66.67%），年龄50岁及以上患者12例（80%）。心律失常不良反应发生时间最短的是负荷剂量1 h后；最长为用药后2个月。其中10例（66.67%）患者在用药后10 h内出现不良反应。不良反应发生后有3例患者植入临时起搏器，1例患者在出院前植入永久性双腔起搏器，其他11例患者分别通过停药、继续用药、换用其他药物及对症治疗后，症状得到缓解或消失。结论： 替格瑞洛可能通过抑制红细胞对腺苷的摄取，升高细胞外液腺苷的浓度，而引起心律失常的不良反应。对于传导系统已经受损的患者，临床上在联合用药时需注意药物的相互作用。临床合理使用替格瑞洛的同时，应加强用药监测，以减少不良反应的发生。     

替格瑞洛辅助急诊PCI治疗STEMI对患者心室重构影响情况分析

目的 探讨ST段抬高型心肌梗死(ST-segment elevation myocardial infarction,STEMI)行急诊经皮冠脉介入术(percutaneous coronary intervention,PCI)患者加用替格瑞洛治疗的临床效果及对患者心室重构的影响.方法 选取我院急诊PCI手术治疗的STEMI患者120例(2014年1月至2016年8月)进行回顾性分析,患者均急诊PCI手术,根据治疗药物分为两组,60例患者术前及术后均给予替格瑞洛(替格瑞洛组)、60例患者术前及术后均给予氯吡格雷(氯吡格雷组),对比两组患者术后心室重构指标、心电图等指标.结果 术后12周,替格瑞洛组LVEDd (49.1±5.4)mm、LVESD (40.6±4.6)mm、LVMI(112.8±11.0) g/m2、LVMW(140.7 ±18.5)g低于氯吡格雷组患者LVEDd(53.1±4.6) mm、LVESD (43.9±4.7) mm、LVMI(118.2 ±9.4)g/m2、LVMW(153.0±21.3) g(t =4.638、t=3.887、t=2.891、t =2.198,P均＜0.05),两组患者的LVEF值差异无统计学意义(t=1.064,P ＞0.05);术后12周,替格瑞洛组Tp-e(114.2±12.7) ms、Tp-e/QTc(0.20±0.05)低于氯吡格雷组患者Tp-e(120.6±13.9)ms、Tp-e/QTc (0.25±0.07)(t=2.633、t=4.502,P ＜0.05);替格瑞洛组的不良心血管事件发生率6.67％与氯吡格雷组的13.33％比较,差异无统计学意义(x2=1.481,P＞0.05).讨论 STEMI行PCI患者加用替格瑞洛治疗能有效减轻心室重构,改善心电图指标.     

替格瑞洛的晶体结构研究

替格瑞洛是针对P2Y12受体开发成功的具有高效治疗急性冠状动脉综合症的药物,是一种非常有效的药物。本文主要对合成的替格瑞洛进行单晶X-射线衍射分析,应用SHELXTL-97晶体软件程序包通过直接法和最小二乘法来确定晶体结构和每一个手性碳原子的绝对构型。该晶体属于正交晶系,F₂₂₂空间群, a = 22.172(4) ?, b =34.185(9) ?,c =14.312(3) ?,V = 10848(4) ?₃,R₁ = 0.0811, wR₂ = 0.1978,Flack参数为-0.16(16)。     

替格瑞洛联合阿托伐他汀和阿司匹林对急性ST段抬高型心肌梗死PCI术后心肌血流灌注的影响

目的 探讨替格瑞洛联合阿托伐他汀和阿司匹林对急性ST段抬高型心肌梗死（STEMI）经皮冠状动脉介入术（PCI）术后心肌血流灌注的影响,为其临床诊治提供参考。方法 选择2015年5月-2019年3月郑州市第一人民医院收治的100例行PCI手术的STEMI的患者作为研究对象,按照治疗方法将患者分为对照组和观察组,各50例。对照组口服阿托伐他汀钙片,20 mg/次,1次/d;阿司匹林肠溶片,100 mg/次,1次/d。观察组患者在对照组治疗基础上口服替格瑞洛片,180 mg/次为初始剂量,之后90 mg/次,2次/d。共治疗2个月,随访半年。比较两组患者PCI术后即刻冠状动脉血流及心肌血流灌注指标,分析两组患者住院期间及随访6个月的心功能指标及主要不良心血管事件（MACE）。比较两组患者治疗前后血清心肌肌钙蛋白I（cTnI）、血管性血友病因子（vWF）、肌酸激酶同工酶（CK-MB）及血管内皮生长因子（VEGF）水平变化。结果 治疗后,观察组患者PCI术后ST段回落率、TIMI血流分级3级以及TMPG3级患者均明显高于对照组,而cTFC值比对照组降低（P<0.05）。两组患者治疗后LVEF、E/A明显升高,LVEDD明显降低（P<0.05）;且观察组患者治疗后上述指标改善更为显著（P<0.05）。治疗后,两组患者的血清CK-MB水平明显降低,血清VEGF、vWF及cTnI水平均明显升高（P<0.05）。治疗后,观察组患者CK-MB水平显著低于对照组,VEGF、vWF和cTnI水平显著高于对照组（P<0.05）。观察组住院期间及术后随访MACE发生率低于对照组（P<0.05）。结论 替格瑞洛联合阿托伐他汀和阿司匹林可以更好改善PCI术后STEMI患者的凝血纤溶系统和心肌血流灌注,保护心功能,减少预后MACE事件的发生率,具有一定的临床应用价值。