聂小燕,刘健,扶宇,李俊蕾,覃思蓓,梁广楷,陈敬,周沛,熊玮珏,王伟民,史录文

• 1:北京大学药学院
• 2:北京大学人民医院心血管内科

摘要(Abstract)：

目的观察急性冠状动脉综合征且接受阿司匹林和氯吡格雷双联抗血小板药物治疗的患者联合使用二级预防用药情况及其与血小板反应性的关联性。方法纳入北京大学人民医院心血管内科2014年4月至2015年5月诊断为急性冠状动脉综合征的患者176例,住院期间用血栓弹力图检测患者血小板反应性,检测氯吡格雷药理作用主要效应基因CYP2C19多态性,详细记录患者住院期间及出院带药品种与使用情况、临床特征。用多因素逐步Logistic回归的方法,分析二级预防用药率与血小板反应性的关系。结果 176例急性冠状动脉综合征患者他汀类药物使用率为94.89%、β阻滞药使用率为80.68%;氯吡格雷用药后血小板抑制率平均为(45.33±28.78)%,出现血小板高反应性(high on-treatment platelet reactivity,HTPR)患者66例(37.50%)。在校正CYP2C19基因多态性影响以及其他临床特征干扰后发现,住院期间使用β阻滞药患者比不使用者血小板抑制率显著增高,HTPR风险显著降低(72.73%比85.45%,OR 0.18,95%CI0.06~0.53,P=0.002),而其他药物使用率与血小板反应性的相关性差异无统计学意义。除药物因素和基因多态性因素之外,吸烟、疾病表现、经皮冠状动脉介入治疗(percutaneous coronary intervention,PCI)置入支架长度对HTPR风险有显著影响。结论β阻滞药与氯吡格雷用药后血小板反应性显著相关。

关键词(KeyWords)： β阻滞药;血小板高反应性;急性冠状动脉综合征

Abstract:

Keywords:

基金项目(Foundation):

作者(Author): 聂小燕,刘健,扶宇,李俊蕾,覃思蓓,梁广楷,陈敬,周沛,熊玮珏,王伟民,史录文

参考文献(References)：

• [1]Fitzgerald DJ,Roy L,Catella F,et al.Platelet activation in unstable coronary disease.N Engl J Med,1986,315(16):983–989.
• [2]郑振国,张妍,周旭晨.CYP2C19基因多态性检测指导非ST段抬高急性冠状动脉综合征患者经皮冠状动脉介入治疗术后抗血小板药物应用的临床随访研究.中国介入心脏病学杂志,2015,23(2):94-97.
• [3]Levine GN,Bates ER,Bittl JA,et al.2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease:a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines:an update of the 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention,2011ACCF/AHA guideline for coronary artery bypass graft surgery,2012 ACC/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease,2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction,2014 ACC/AHA guideline for the management of patients with non–ST-elevation acute coronary syndromes,and 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery.Circulation,2016,134(10):e123-e155.
• [4]中华医学会心血管病学分会介入心脏病学组,中国医师协会心血管内科医师分会血栓防治专业委员会,中华心血管病杂志编辑委员会.中国经皮冠状动脉介入治疗指南(2016).中华心血管病杂志,2016,44(5):382-400.
• [5]中国医师协会急诊医师分会,中华医学会心血管病学分会,中华医学会检验医学分会.急性冠脉综合征急诊快速诊疗指南.中华急诊医学杂志,2016,25(4):397-404.
• [6]Liu J,Nie XY,Zhang Y,et al.CYP2C19*2 and Other Allelic Variants Affecting Platelet Response to Clopidogrel Tested by Thrombelastography in Patients with Acute Coronary Syndrome.CMJ,2015,128(16):2183-2188.
• [7]Hochholzer W,Trenk D,Frundi D,et al.Time dependence of platelet inhibition after a 600-mg loading dose of clopidogrel in a large,unselected cohort of candidates for percutaneous coronary intervention.Circulation,2005,111(20):2560-2564.
• [8]Bonello L,Tantry US,Marcucci R,et al.Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate.J Am Coll Cardiol,2010,56(12):919-933.
• [9]Tantry US,Bonello L,Aradi D,et al.Consensus and update on the definition of high on-treatment platelet reactivity to adenosine diphosphate with ischemia and bleeding.J Am Coll Cardiol,2013,62(24):2261-2273.
• [10]Brar SS,Berg J,Marcucci R,et al.Impact of platelet reactivity on clinical outcomes after percutaneous coronary intervention.A collaborative meta-analysis of individual participant data.J Am Coll Cardiol,2011,58(19):1945–1954.
• [11]Wisman PP,Roest M,Asselbergs W,et al.Platelet-reactivity tests identif y patients at risk of secondary cardiovascular events:a systematic review and meta-analysis.J Thromb Haemost,2014,12(5):736–747.
• [12]Lakovou I,Schmidt T,Bonizzoni E,et al.Incidence,predictors,and outcome of thrombosis after successful implantation of drug eluting stents.JAMA,2005,293(17):2126-2130.
• [13]Bonten T.Effect ofβ-blockers on platelet aggregation:a systematic review and meta-analysis.Br J Clin Pharmacol,2014,78(5):940–949.
• [14]Anfossi G,Trovati M.Role of catecholamines in platelet function:pathophysiological and clinical significance.Eur J Clin Invest,1996,26(5):353-370.
• [15]Frishman WH.Beta-adrenoceptor antagonists:new drugs and new indications.N Engl J Med,1981,305(9):500-506.
• [16]Imai S.Pharmacologic characterization of beta blockers with special reference to the significance of nonspecific membrane effects.Am J Cardiol,1991,22,67(10):B8–B12.
• [17]Steer ML,Atlas D.Demonstration of human platelet betaadrenergic receptors using 125I-labeled cyanopindolol and 125I-labeled hydroxybenzylpindolol.Biochim Biophys Acta,1982,686(2):240-244.
• [18]Ark DW,Ahn JM,Song HG,et al.Differential prognostic impact of high on-treatment platelet reactivity among patients with acute coronary syndromes versus stable coronary artery disease undergoing percutaneous coronary intervention.Am Heart J,2013,165(1):34-42.
• [19]Ahn SG,Lee SH,Yoon JH,et al.Different prognostic significance of high on-treatment platelet reactivity as assessed by the Verify Now P2Y12 assay after coronary stenting in patients with and without acute myocardial infarction.JACC Cardiovasc Interv,2012,5(3):259-267.
• [20]Ahn SG,Lee SH,Yoon JH,et al.Different Prognostic Significance of High On-Treatment Platelet Reactivity as Assessed by the Verif y Now P2Y12 Assay After Coronary Stenting in Patients With and Without Acute Myocardial Infarction.J Am Coll Cardiol Intv,2012,5(3):259–267.
• [21]Tantcheva PI,Zaigler M,Rietbrock S,et al.Estimation of cytochrome P-450 CYP1A2 activity in 863 healthy Caucasians using a saliva-based caffeine test.Pharmacogenetics,1999,9(2):131-144.
• [22]Yousef AM,Arafat T,Bulatova NR,et al.Smoking behaviour modulates pharmacokinetics of orally administered clopidogrel.J Clin Pharm Ther,2008,33(4):439-449.
• [23]Bliden KP,Di Chiara J,Lookman L,et al.The association of cigarette smoking with enhanced platelet inhibition by clopidogrel.J Am Coll Cardiol,2008,52(7):531–533
• [24]Berger JS,Bhatt DL,Steinhubl SR,et al.Smoking,clopidogrel,and mortality in patients with established cardiovascular disease.Circulation,2009,120(23):2337–2344.
• [25]Hochholzer W,Trenk D,Mega JL,et al.Impact of smoking on antiplatelet effect of clopidogrel and prasugrel after loading dose and on maintenance therapy.Am Heart J,2011,162(3):518-526.
• [26]Sibbing D,Bernlochner I,Schulz S,et al.The impact of smoking on the antiplatelet action of clopidogrel in non-STelevation myocardial infarction patients:results from the ISARREACT 4 platelet substudy.J Thromb Haemost,2012,10(10):2199-2202.
• [27]Kim JW,Suh SH,Kang,et al.Cigarette smoking does not enhance clopidogrel responsiveness after adjusting Verify Now P2Y12 reaction unit for the influence of hemoglobin level.2016,J Am Coll Cardiol Intv,9(16):1680-1690.