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。     

Antiplatelet options for secondary prevention in acute coronary syndromes

Current guidelines recommend dual antiplatelet therapy, a combination of aspirin and a P2Y₁₂ inhibitor, for 6–12 months after percutaneous coronary intervention with drug-eluting stent implantation in all patients and for 1 year in all patients after an acute coronary syndrome (ACS), irrespective of revascularization strategy. Clopidogrel has a pharmacokinetic and pharmacodynamic profile that results in a delayed and/or subtherapeutic antiplatelet effect, and wide variability in antiplatelet response. New P2Y₁₂ inhibitors, such as prasugrel and ticagrelor, have favorable pharmacodynamics and clinical efficacy over clopidogrel and offer an alternative antiplatelet treatment strategy in specific patients. Prasugrel has more potent, rapid, and consistent effects on inhibiting ADP-induced platelet aggregation than clopidogrel. Ticagrelor also appears to have more rapid and consistent antiplatelet effects than clopidogrel. The higher levels of antiplatelet inhibition provided by prasugrel and ticagrelor compared with standard-dose clopidogrel result in improved ischemic outcomes in patients with ACS. Despite an increase in bleeding risk, prasugrel and ticagrelor appear to have a better net clinical benefit, especially in higher-risk patients with ACS.     

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: Positive,negative and misunderstood properties as a new antiplatelet agent

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Lack of clinically significant pharmacological interactions between ticagrelor and enoxaparin or unfractionated heparin in healthy subjects

What is known and Objective: Patients with acute coronary syndromes (ACS) receive several pharmacological therapies concomitantly, including antiplatelet and anticoagulant agents. As unfractionated heparin (UFH) activates platelets in vitro and in vivo, co‐administration with an antiplatelet agent may lead to decreased clinical effectiveness of the latter. The aim was therefore to determine any potential drug–drug interactions between the new oral antiplatelet agent ticagrelor, and UFH or enoxaparin. Methods: In two open‐label, three‐period, crossover trials, healthy subjects were randomized to receive ticagrelor alone or with enoxaparin (study 1) or UFH (study 2), or enoxaparin or UFH alone. Ticagrelor plasma concentrations, inhibition of platelet aggregation (IPA), anti‐factor Xa levels, activated partial thromboplastin time (aPTT) and activated coagulation time (ACT) were measured. Results: Thirty and 28 subjects completed studies 1 and 2, respectively. Study drugs were generally well tolerated, with no significant bleeding or serious adverse events. Co‐administration with enoxaparin or UFH had no significant effect on ticagrelor pharmacokinetics. The effect of ticagrelor on IPA was unimpaired by co‐administration of enoxaparin, except for a marginal (?2·9%; 908·7%.h, 881·9%.h) reduction in final extent area under the effect curve (AUEC)_2–12 (95% CI: ?51·6%.h, ?2·0%.h). Co‐administering UFH with ticagrelor caused small decreases in IPA_max (?3·8%; 94·6%, 91·0%) and AUEC_2–12 (?6·8%; 888·6%.h, 828·3%.h) vs. ticagrelor alone (95% CI: final extent IPA_max?5·7%, ?1·6%; AUEC_2–12?109·8%.h, ?10·8%.h). Ticagrelor had no clinically significant effects on enoxaparin as assessed by anti‐factor Xa (study 1), or UFH as assessed by aPTT or ACT (study 2). What is new and conclusions: Enoxaparin and UFH had no effect on the pharmacokinetics and no clinically significant effect on the pharmacodynamics of ticagrelor. Ticagrelor had no clinically significant effects on the pharmacodynamics of enoxaparin or UFH.     

替格瑞洛上市后出血不良反应信号检测与分析

目的:检测替格瑞洛上市后出血不良反应信号,并分析其影响因素,为临床合理用药提供参考。方法:采用报告比值比法(ROR)对美国食品药品监督管理局不良事件报告系统(AERS)数据库进行替格瑞洛不良反应信号检测,应用标准MedDRA分析查询(SMQ)检索其中的出血信号,并利用SPSS 17.0分析年龄、性别、用药时长对出血信号的影响。结果:总的药物不良反应报告6806330份,以替格瑞洛为首要怀疑药物的不良反应报告5279份,经ROR法检测,共得到158个替格瑞洛不良反应信号,其中出血信号42个。统计学分析结果显示:维持剂量时,与其他ADR相比,出血ADR在年龄(P=0.003)、用药时长(P=0.026)分布中差异有统计学意义,在性别(P=0.417)分布中差异无统计学意义;负荷剂量时,与其他ADR相比,出血ADR在年龄(P=0.000)分布中差异有统计学意义,在性别(P=0.846)分布中差异无统计学意义。其中,年龄大于75岁负荷剂量时,维持剂量用药半年内,发生出血ADR风险更大。结论:检测到的替格瑞洛不良反应信号和影响因素,有必要进行进一步信号评价和验证,为临床安全用药提供依据。     

老年冠心病患者服用替格瑞洛与氯吡格雷出血风险比较

目的比较≥70岁老年冠心病患者院外服用替格瑞洛与氯吡格雷时发生出血事件的风险。方法本研究连续入选2014年1月至2015年3月期间在解放军总医院心血管内科因急性冠脉综合征(ACS)住院并行冠状动脉支架植入术的患者597例。根据选择的双联抗血小板方案分为两组:替格瑞洛组(同时服用替格瑞洛和阿司匹林,n=99)和氯吡格雷组(同时服用氯吡格雷和阿司匹林,n=498)。随访1年,比较两组患者的出血风险,并分析影响出血事件的危险因素。结果替格瑞洛组患者出血事件的发生率显著高于氯吡格雷组(25.3%vs14.5%),差异具有统计学意义(P=0.008),且两组患者的Ⅰ型出血事件发生率间差异具有统计学意义(P=0.015),而Ⅱ型出血事件发生率间差异无统计学意义(P=0.261)。用药期间共有263例患者行血栓弹力图(TEG)检测,其中替格瑞洛组77例和氯吡格雷组186例。与氯吡格雷组相比,替格瑞洛组患者的二磷酸腺苷(ADP)抑制率显著增加[(80.29±20.67)%vs(61.65±26.81)%,P0.001]、ADP诱导的最大振幅(MA_(ADP))显著降低[(25.28±14.28)vs(36.41±16.20)mm,P0.001]。替格瑞洛组中MA_(ADP)31 mm的患者(68.8%vs40.3%,P0.001)以及此类患者中发生出血事件者(24.5%vs10.7%,P=0.037)均显著高于氯吡格雷组。多因素logistic回归分析表明,低体质量指数(BMI)(OR=0.910,95%CI:0.842~0.984,P=0.018)和高血压病(OR=1.301,95%CI:1.036~1.635,P=0.024)是≥70岁老年冠心病患者服用双联抗血小板药物期间发生出血事件的独立危险因素。结论老年冠心病患者口服替格瑞洛的出血风险比氯吡格雷高,且低BMI与高血压病患者更易发生出血事件,因此选用双联抗血小板治疗方案时应充分考虑危险因素并行TEG监测,以减少出血事件的发生。     

Occurrence,causes, and outcome after switching from ticagrelor to clopidogrel in a real-life scenario: data from a prospective registry

In randomized clinical trials, ticagrelor has been substituted in roughly one-third of the patients during follow-up. To date, there are no studies addressing safety and modalities of switching from ticagrelor to clopidogrel. The aim of our study is to describe the occurrence, causes, and outcome of the switch from ticagrelor to clopidogrel in a real-life scenario. From June 2013 to March 2015, 586 patients were treated with ticagrelor in our centre. Overall, 101 (17%) patients were switched to clopidogrel through a standardized protocol, and they were followed-up for 12 months. Ischemic and bleeding events were prospectively recorded. The switch from ticagrelor to clopidogrel occurred mostly after discharge (69 ± 40 days), and the most frequent cause was the need of oral anticoagulation treatment, followed by bleeding events. Patients requiring ticagrelor discontinuation were older, more frequently female, with lower body mass index and creatinine clearance if compared to the “non-switched” group. In the 10 days after the switch, we did not observe ischemic adverse events. No definite/probable stent thrombosis was recorded. Before the switch, there was a significant higher occurrence of BARC bleedings in the “switched” group, particularly BARC 1 and 2. Our data confirm that the switch from ticagrelor to clopidogrel is common, and it occurs for several reasons. Our analysis did not demonstrate a significant increase in adverse cardiovascular events in the days following the switch from ticagrelor to clopidogrel, although larger studies are needed to validate our findings.