呂中華，耿曉雯，程慶強(qiáng)，高 潔，任藝虹

(解放軍總醫(yī)院心血管內(nèi)科，北京 100853)

雙聯(lián)抗血小板治療(dual antiplatelet therapy，DAPT)已經(jīng)成為急性冠脈綜合征(acute coronary syndrome，ACS)和經(jīng)皮冠狀動(dòng)脈介入治療(percutaneous coronary intervention，PCI)患者的標(biāo)準(zhǔn)治療方案，目前主要為阿司匹林(aspirin)聯(lián)合氯吡格雷(clopidogrel)或替格瑞洛(ticagrelor)[1,2]。替格瑞洛憑借其快速、可逆的抗血小板聚集作用，不受代謝酶影響[3-5]，逐漸成為首選推薦藥物。臨床觀察中發(fā)現(xiàn)即使規(guī)律應(yīng)用抗血小板聚集藥物，仍有部分患者再出現(xiàn)心血管事件及血栓彈力圖(thromboelastography，TEG)檢測(cè)血小板抑制率不達(dá)標(biāo)情況。本研究旨在比較年齡<60歲阿司匹林+氯吡格雷組(<60C組)與年齡<60歲阿司匹林+替格瑞洛組(<60T組)、≥75歲阿司匹林+氯吡格雷組(≥75C組)與年齡≥75歲阿司匹林+替格瑞洛組(≥75T組)、<60T組與≥75T組、<60C組與≥75C組主要不良心血管事件(major adverse cardiovascular events,MACE)、出血事件發(fā)生情況，并分析相應(yīng)的危險(xiǎn)因素。

1 對(duì)象與方法

1.1 研究對(duì)象

連續(xù)收集2014年3月至2015年5月于解放軍總醫(yī)院心血管內(nèi)科住院治療的ACS、年齡<60歲及≥75歲、并進(jìn)行TEG檢查的416例患者的臨床資料。根據(jù)年齡及應(yīng)用P2Y12受體拮抗劑類型分為4組：(1)年齡<60歲阿司匹林+氯吡格雷組(<60C組，n=193)，(2)年齡≥75歲阿司匹林+氯吡格雷組(≥75C組，n=58)，(3)年齡<60歲阿司匹林+替格瑞洛組(<60T組，n=129)，(4)年齡≥75歲阿司匹林+替格瑞洛組(≥75T組，n=36)。

1.2 研究方法

臨床醫(yī)師根據(jù)患者病情確定治療藥物。收集4組患者的臨床資料，并隨訪，記錄患者DAPT期間MACE情況、出血情況?；颊咭蛉魏卧蛲Ｖ笵APT，終止隨訪。16人失訪，失訪率3.85%。

1.3 相關(guān)概念

(1)TEG指標(biāo)：最大振幅(maximal amplitude，MA)反映血小板功能；檢測(cè)過(guò)程中分別加入血小板激活劑花生四烯酸(arachidonic acid，AA)、二磷酸腺苷(adenosine diphosphate，ADP)，可測(cè)得相應(yīng)的MA，即：MA-AA、MA-ADP；血小板抑制率(%)分為AA誘發(fā)性血小板聚集(AA-induced platelet aggregation，AA-IPA)和ADP-IPA通路[6,7]。(2)MACE：再次血運(yùn)重建、再次心肌梗死及全因死亡等。(3)出血事件按照出血學(xué)術(shù)研究協(xié)議(Bleeding Academic Research Consortium，BARC)標(biāo)準(zhǔn)定義；Ⅰ型：患者無(wú)需因此就醫(yī)的非活動(dòng)性出血；Ⅱ型：明顯活動(dòng)性出血，需要就醫(yī)干預(yù)，未達(dá)到以下 Ⅲ～Ⅴ型標(biāo)準(zhǔn)；Ⅲ型，分為3個(gè)亞型：3a型，血紅蛋白降低3～5 g/dl；3b型：血紅蛋白降低≥5 g/dl，需要外科干預(yù)的出血；3c型：顱內(nèi)出血，損害視力的眼內(nèi)出血；Ⅳ型：冠狀動(dòng)脈旁路移植術(shù)(coronary artery bypass grafting，CABG)相關(guān)出血；Ⅴ型: 致死性出血。

1.4 統(tǒng)計(jì)學(xué)處理

數(shù)據(jù)應(yīng)用SPSS17.0軟件進(jìn)行分析。計(jì)量資料以均數(shù)±標(biāo)準(zhǔn)差表示，組間比較采用方差分析(正態(tài)分布)或秩和檢驗(yàn)(非正態(tài)分布)。計(jì)數(shù)資料以百分率表示，組間比較采用χ2檢驗(yàn)。應(yīng)用Cox回歸分析MACE危險(xiǎn)因素，logistic回歸分析出血事件危險(xiǎn)因素。以P<0.05為差異具有統(tǒng)計(jì)學(xué)意義。

2 結(jié) 果

2.1 各組基線資料比較

表1結(jié)果表明，<60C組與<60T組比較，各指標(biāo)差異均無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)；≥75C組與≥75T組比較，≥75C組年齡較大(P<0.001)，其余指標(biāo)差異均無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)；與≥75T組比較，<60T組吸煙比例較高(P=0.001)，高血壓患病率較低(P=0.012)，其余指標(biāo)差異均無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)；<60C組與≥75C組比較，<60C組男性比例、體質(zhì)量指數(shù)(body mass index,BMI)、吸煙比例均較高(P<0.001)，eGFR亦較高(P=0.001)，其余指標(biāo)差異均無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)。

2.2 TEG指標(biāo)比較

表2結(jié)果表明，<60C組與<60T組比較，<60T組ADP途徑抑制率較高(P<0.001)，MA-ADP較低(P<0.001)，其余各項(xiàng)指標(biāo)差異均無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)；≥75C組與≥75T組比較，≥75T組ADP途徑抑制率較高(P<0.001)，MA-ADP較低(P<0.001)，其余各項(xiàng)指標(biāo)差異均無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)。

表3結(jié)果表明，<60T組與≥75T組比較，各項(xiàng)指標(biāo)差異均無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)；<60C組與≥75C組比較，≥75C組ADP途徑抑制率較低(P=0.011)，MA-ADP較高(P=0.001)，MA-AA較低(P=0.005)。

2.3 MACE及出血事件比較

4組患者M(jìn)ACE發(fā)生率差異無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05；表4，表5)。應(yīng)用Cox回歸分析總體MACE危險(xiǎn)因素：將心率、性別、年齡、BMI、吸煙、飲酒、血糖、MA值、AA-IPA、ADP-IPA、MA-ADP、MA-AA、eGFR、高血壓、口服血管緊張素轉(zhuǎn)換酶抑制劑/血管緊張素受體拮抗劑情況、口服β-阻滯劑情況、DAPT方案帶入分析，得出MACE相關(guān)因素：血糖(B=0.111，RR=1.117,95%CI：1.014～1.231，P=0.025)，eGFR(B=-0.023，RR=0.977,95%CI：0.961～0.993，P=0.005)，心率(B=0.040，RR=1.041,95%CI：1.013～1.070，P=0.004)。

表1 患者基線資料比較

<60C group: <60 years old patients treated with aspirin combined clopidogrel; ≥75C group: ≥75 years old patients treated with aspirin combined clopidogrel; <60T group: <60 years old patients treated with aspirin combined ticagrelor; ≥75T group: ≥75 years old patients treated with aspirin combined ticagrelor; BMI: body mass index; HR: heart rate; DM: diabetes mellitus; TC: total cholesterol; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; APTT:activated partial thromboplastin time; eGFR: estimated glomerular filtration rate; ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker. Compared with ≥75T group,**P<0.01; compared with ≥75C group,##P<0.01

表2 相同年齡段不同P2Y12拮抗劑TEG指標(biāo)比較

<60C group: <60 years old patients treated with aspirin combined clopidogrel; ≥75C group: ≥75 years old patients treated with aspirin combined clopidogrel; <60T group: <60 years old patients treated with aspirin combined ticagrelor; ≥75T group: ≥75 years old patients treated with aspirin combined ticagrelor; MA: maximal amplitude; AA-IPA: inhibitory rate of arachidonic acid (AA)-induced platelet aggregation; ADP-IPA: inhibitory rate of adenosine diphosphate (ADP)-induced platelet aggregation; MA-ADP: ADP induced maximum amplitude; MA-AA: AA induced maximum amplitude

表3 相同P2Y12拮抗劑不同年齡段TEG指標(biāo)比較

<60C group: <60 years old patients treated with aspirin combined clopidogrel; ≥75C group: ≥75 years old patients treated with aspirin combined clopidogrel; <60T group: <60 years old patients treated with aspirin combined ticagrelor; ≥75T group: ≥75 years old patients treated with aspirin combined ticagrelor; MA: maximal amplitude; AA-IPA: inhibitory rate of arachidonic acid (AA)-induced platelet aggregation; ADP-IPA: inhibitory rate of adenosine diphosphate (ADP)-induced platelet aggregation; MA-ADP: ADP induced maximum amplitude; MA-AA: AA induced maximum amplitude

表4 相同年齡段不同P2Y12拮抗劑MACE、出血事件比較

<60C group: <60 years old patients treated with aspirin combined clopidogrel; ≥75C group: ≥75 years old patients treated with aspirin combined clopidogrel; <60T group: <60 years old patients treated with aspirin combined ticagrelor; ≥75T group: ≥75 years old patients treated with aspirin combined ticagrelor; MACE:major adverse cardiovascular events

表5 相同P2Y12拮抗劑不同年齡段MACE、出血事件比較

<60C group: <60 years old patients treated with aspirin combined clopidogrel; ≥75C group: ≥75 years old patients treated with aspirin combined clopidogrel; <60T group: <60 years old patients treated with aspirin combined ticagrelor; ≥75T group: ≥75 years old patients treated with aspirin combined ticagrelor; MACE: major adverse cardiovascular events

“替格瑞洛”患者出血事件發(fā)生率較“氯吡格雷”患者升高(P<0.05；表4)。<60C組出血1例(0.52%)表現(xiàn)為月經(jīng)過(guò)多；≥75C組出血2例(3.45%)：血尿1例、便血1例；<60T組出血36例(27.91%)：淤斑20例、牙齦出血10例、鼻出血6例；≥75T組出血6例(16.67%)：淤斑3例、牙齦出血1例、鼻出血1例、眼底出血1例。出血事件多為不需要臨床干預(yù)的Ⅰ型出血。應(yīng)用logistic回歸分析出血事件危險(xiǎn)因素：(1)總體：DAPT方案(B=3.527，OR=34.025,95%CI：9.560～121.101，P<0.001)，性別(B=1.126，OR=3.085,95%CI：1.083～8.788，P=0.035)；(2)分別對(duì)<60C與<60T，≥75C與≥75T進(jìn)行l(wèi)ogistic回歸分析，均提示DAPT方案為出血事件危險(xiǎn)因素。

3 討 論

DAPT已經(jīng)成為ACS、PCI患者抗血小板的標(biāo)準(zhǔn)方案，那么如何選擇同為P2Y12受體拮抗劑的氯吡格雷與替格瑞洛，則成為臨床醫(yī)師面臨的問(wèn)題。氯吡格雷作為經(jīng)典的P2Y12受體拮抗劑，仍是目前國(guó)內(nèi)的一線用藥，但存在著如下問(wèn)題：為前體藥物，需要經(jīng)肝酶代謝后形成活性產(chǎn)物；代謝受ABCB1、CYP2C19基因的影響[8,9]，在慢代謝患者體內(nèi)活性代謝物的血藥濃度降低，抗血小板作用降低。替格瑞洛為新型P2Y12受體拮抗劑，已成為首選推薦藥物[10]；半衰期短，不受代謝酶及ABCB1、CYP2C19基因的影響[3-5,11]。多項(xiàng)研究認(rèn)為替格瑞洛能夠更快速、強(qiáng)效地抑制血小板[12,13]。對(duì)氯吡格雷低反應(yīng)性患者應(yīng)用替格瑞洛可得到良好療效[14]。有研究顯示中國(guó)人群中替格瑞洛低反應(yīng)性的比例明顯低于氯吡格雷[15]，且在中國(guó)人群中有良好的療效及安全性[16,17]，但也有研究顯示其出血風(fēng)險(xiǎn)較氯吡格雷增高，且替格瑞洛有呼吸困難等不良反應(yīng)，因不良反應(yīng)停藥的患者中約55.6%源于呼吸困難[18]。

TEG目前常用來(lái)檢測(cè)血小板活性、判斷DAPT的療效。有研究認(rèn)為TEG檢測(cè)的ADP-IPA可作為預(yù)測(cè)支架內(nèi)再狹窄的檢驗(yàn)指標(biāo)之一[7]。TEG檢測(cè)發(fā)現(xiàn)替格瑞洛的ADP-IPA高于氯吡格雷、MA-ADP低于氯吡格雷，但MACE發(fā)生率無(wú)明顯差異。這與替格瑞洛可降低MACE[1,2]不符，考慮與此研究為小樣本、單中心有關(guān)。

綜上所述，本研究顯示替格瑞洛Ⅰ型出血發(fā)生率高于氯吡格雷，但未增加致命性出血風(fēng)險(xiǎn)與文獻(xiàn)報(bào)道相符[3]，出血發(fā)生率在<60T組與≥75T組無(wú)明顯差異。

本研究屬于單中心、小樣本量研究，特別是≥75T組樣本量偏小、口服氯吡格雷的兩組患者僅有3例發(fā)生出血事件，因此需進(jìn)一步行多中心、大樣本量的隨機(jī)對(duì)照研究以明確中國(guó)人群不同DAPT方案的優(yōu)缺點(diǎn)，同時(shí)明確MACE及出血事件的相關(guān)因素，以利于臨床醫(yī)師在充分評(píng)估出血風(fēng)險(xiǎn)及血栓風(fēng)險(xiǎn)的基礎(chǔ)上制定個(gè)體化的DAPT方案。

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