宋 敏，姚朱華，門劍龍，曹明英，黎文婷，陳 穎

·論著·

經(jīng)皮冠狀動(dòng)脈介入治療術(shù)6個(gè)月后應(yīng)用低劑量替格瑞洛的有效性及安全性研究

宋 敏1，2，姚朱華2*，門劍龍3，曹明英2，黎文婷2，陳 穎2

目的 探討經(jīng)皮冠狀動(dòng)脈介入治療(PCI)術(shù)6個(gè)月后應(yīng)用低劑量替格瑞洛的有效性及安全性。方法 選取2015年7月—2016年2月在天津市人民醫(yī)院行PCI術(shù)6個(gè)月后復(fù)查的患者95例，根據(jù)術(shù)后服用的二磷酸腺苷受體(P2Y12受體)拮抗劑類型，將其分為替格瑞洛組(n=33)和氯吡格雷組(n=62)。其中，替格瑞洛組患者術(shù)后服用標(biāo)準(zhǔn)劑量替格瑞洛(90 mg/次，2次/d)、6個(gè)月后改為低劑量替格瑞洛(45 mg/次，2次/d)，氯吡格雷組患者術(shù)后持續(xù)服用氯吡格雷(75 mg/次，1次/d)，兩組均聯(lián)合服用阿司匹林(100 mg/次，1次/d)。比較兩組患者PCI術(shù)6個(gè)月后服藥1周、3個(gè)月時(shí)采用光比濁(LTA)法檢測的血小板聚集率，以及隨訪6個(gè)月的主要不良心血管事件(MACE)和不良反應(yīng)發(fā)生率。結(jié)果 PCI術(shù)6個(gè)月后服藥1周、3個(gè)月，替格瑞洛組患者血小板聚集率均低于氯吡格雷組，差異有統(tǒng)計(jì)學(xué)意義(P<0.05)；服藥3個(gè)月，兩組患者血小板聚集率與服藥1周比較，差異無統(tǒng)計(jì)學(xué)意義(P>0.05)。隨訪期間，替格瑞洛組患者M(jìn)ACE發(fā)生率低于氯吡格雷組，差異有統(tǒng)計(jì)學(xué)意義(P<0.05)；但兩組患者輕度出血、呼吸困難發(fā)生率比較，差異無統(tǒng)計(jì)學(xué)意義(P>0.05)。結(jié)論 PCI術(shù)后6個(gè)月應(yīng)用低劑量替格瑞洛的抗血小板聚集作用強(qiáng)于氯吡格雷，可有效減少PCI術(shù)后患者的缺血事件發(fā)生，且不增加出血風(fēng)險(xiǎn)。

血管成形術(shù)，氣囊，冠狀動(dòng)脈；替格瑞洛；氯吡格雷；治療結(jié)果

宋敏，姚朱華，門劍龍，等.經(jīng)皮冠狀動(dòng)脈介入治療術(shù)6個(gè)月后應(yīng)用低劑量替格瑞洛的有效性及安全性研究[J].中國全科醫(yī)學(xué)，2017，20(16)：1973-1977.[www.chinagp.net]

SONG M,YAO Z H,MEN J L,et al.Efficacy and safety of low-dose ticagrelor in patients at six months after percutaneous coronary intervention[J].Chinese General Practice，2017，20(16)：1973-1977.

雙聯(lián)抗血小板療法(dual antiplatelet therapy，DAPT)是指阿司匹林聯(lián)合一種二磷酸腺苷受體(P2Y12受體)拮抗劑可以降低血小板反應(yīng)性，是急性冠脈綜合征(acute coronary syndromes，ACS)和經(jīng)皮冠狀動(dòng)脈介入治療(percutaneous coronary intervention，PCI)術(shù)后患者防止缺血事件發(fā)生的有效治療方案[1-2]。氯吡格雷是應(yīng)用廣泛的P2Y12受體拮抗劑，替格瑞洛是一種新型P2Y12受體拮抗劑，與氯吡格雷相比，替格瑞洛具有起效快、作用強(qiáng)的特點(diǎn)，且不增加患者的主要出血發(fā)生風(fēng)險(xiǎn)，但可增加次要出血發(fā)生風(fēng)險(xiǎn)[3-4]。越來越多的數(shù)據(jù)表明，亞洲人群的血栓形成、出血等不良事件的形成及抗血小板藥物治療窗與白種人不同[5]；且近期研究結(jié)果顯示，在我國非ST段抬高型(non-ST-elevation，NSTE)ACS患者中，低劑量替格瑞洛的抗血小板聚集作用強(qiáng)于氯吡格雷[6]。因此，低劑量替格瑞洛可能更適合我國人群。本研究旨在探討行PCI術(shù)6個(gè)月后應(yīng)用低劑量替格瑞洛的臨床有效性及安全性，從而得出替格瑞洛在我國人群中的合適劑量。

1 對象與方法

1.1 研究對象 選取2015年7月—2016年2月在天津市人民醫(yī)院行PCI術(shù)6個(gè)月后復(fù)查的患者95例。納入標(biāo)準(zhǔn)：(1)年齡18～75歲；(2)符合美國心臟協(xié)會(huì)(AHA)等制定的ACS診斷標(biāo)準(zhǔn)[7]，成功行PCI術(shù)；(3)植入藥物洗脫支架為Xience V、BuMA或吉威EXSEL，植入支架后心肌梗死溶栓治療(TIMI)血流分級為3級；(4)術(shù)后服用標(biāo)準(zhǔn)劑量替格瑞洛(倍林達(dá)，英國阿斯利康公司，90 mg/片，90 mg/次，2次/d)、6個(gè)月后改為服用低劑量替格瑞洛(45 mg/次，2次/d)，或術(shù)后持續(xù)服用氯吡格雷(泰嘉，深圳信立泰有限公司，25 mg/片，75 mg/次，1次/d)，聯(lián)合服用阿司匹林(拜耳醫(yī)藥保健有限公司，100 mg/次，1次/d)。排除標(biāo)準(zhǔn)：(1)服用華法林、達(dá)比加群酯等抗凝藥物；(2)服用中醫(yī)活血藥物；(3)伴嚴(yán)重感染、免疫系統(tǒng)疾病、腫瘤或血液系統(tǒng)疾??；(4)貧血(血紅蛋白<100 g/L)；(5)肝腎功能異常；(6)血小板計(jì)數(shù)<100×109/L或>450×109/L。根據(jù)服用P2Y12受體拮抗劑類型，將納入患者分為替格瑞洛組(n=33)和氯吡格雷組(n=62)。本研究通過天津市人民醫(yī)院倫理委員會(huì)批準(zhǔn)，納入患者均知情同意。

1.2 研究方法

1.2.1 一般資料收集 通過查閱病歷的方法收集患者的一般資料，包括性別、年齡、體質(zhì)量、吸煙史、合并癥、ACS類型、病變程度、用藥情況及植入支架數(shù)量。其中，以吸煙≥1支/d、持續(xù)時(shí)間≥1年，或長期吸煙而戒煙時(shí)間<6個(gè)月為有吸煙史。

1.2.2 血小板聚集率檢測 分別于PCI術(shù)6個(gè)月后服藥1周、3個(gè)月時(shí)，抽取患者空腹靜脈血3 ml置于真空管(包含質(zhì)量分?jǐn)?shù)為3.2%的枸櫞酸鈉)中，2 h內(nèi)由天津醫(yī)科大學(xué)總醫(yī)院醫(yī)學(xué)檢驗(yàn)科專業(yè)人員采用普利生PRECIL LBY-NJ四通道血小板聚集儀檢測血小板聚集率，檢測方法為光比濁(LTA)法，以10 μmol/L二磷酸腺苷為誘導(dǎo)劑。LTA法具體操作方法參照參考文獻(xiàn)[8]，血小板聚集率以相對數(shù)表示。

1.2.3 主要不良心血管事件(MACE)和不良反應(yīng)記錄 通過電話隨訪的方式對患者進(jìn)行為期6個(gè)月的隨訪，記錄其MACE和不良反應(yīng)發(fā)生情況。MACE包括心源性死亡、非致死性心肌梗死、靶血管再次血運(yùn)重建、支架內(nèi)血栓形成、不穩(wěn)定型心絞痛(UA)、心力衰竭等；不良反應(yīng)包括出血、呼吸困難。其中出血分級評估采用全球梗死相關(guān)動(dòng)脈開通策略(GUSTO)分級標(biāo)準(zhǔn)：(1)嚴(yán)重出血，包括顱內(nèi)出血或?qū)е卵鲃?dòng)力學(xué)不穩(wěn)定且需及時(shí)干預(yù)的出血；(2)中度出血，需輸血治療但尚未引起血流動(dòng)力學(xué)不穩(wěn)定的出血；(3)輕度出血，未達(dá)到中度出血標(biāo)準(zhǔn)的少量出血[9]。

2 結(jié)果

2.1 兩組患者一般資料 兩組患者性別、年齡、體質(zhì)量、吸煙史、合并高血壓發(fā)生率、合并糖尿病發(fā)生率、合并血脂異常發(fā)生率、ACS類型、病變程度、β-受體阻滯劑使用率、血管緊張素轉(zhuǎn)換酶抑制劑(ACEI)/血管緊張素Ⅱ受體阻滯劑(ARB)使用率、鈣通道拮抗劑(CCB)使用率、質(zhì)子泵抑制劑(PPI)使用率、他汀類藥物使用率、植入支架數(shù)量比較，差異無統(tǒng)計(jì)學(xué)意義(P>0.05，見表1)。

2.2 兩組患者PCI術(shù)6個(gè)月后服藥1周、3個(gè)月血小板聚集率比較 PCI術(shù)6個(gè)月后服藥1周、3個(gè)月，兩組患者血小板聚集率比較，差異有統(tǒng)計(jì)學(xué)意義(P<0.05)；服藥3個(gè)月，兩組患者血小板聚集率與服藥1周比較，差異無統(tǒng)計(jì)學(xué)意義(P>0.05，見表2)。

2.3 兩組患者隨訪期間MACE和不良反應(yīng)發(fā)生率比較 隨訪期間，兩組患者M(jìn)ACE發(fā)生率比較，差異有統(tǒng)計(jì)學(xué)意義(P<0.05)；兩組患者均無中、重度出血，輕度出血、呼吸困難發(fā)生率比較，差異無統(tǒng)計(jì)學(xué)意義(P>0.05，見表3)。

3 討論

支架內(nèi)血栓形成是PCI術(shù)嚴(yán)重的并發(fā)癥，國際指南推薦方案為阿司匹林聯(lián)合一種P2Y12受體拮抗劑[1]。氯吡格雷是應(yīng)用最為廣泛的P2Y12受體拮抗劑，但因CYP2C19基因多態(tài)性及CYP2C19、CYP3A4水平上的藥物相互作用，使得氯吡格雷的抗血小板作用出現(xiàn)了個(gè)體差異性，增加了發(fā)生支架內(nèi)血栓的風(fēng)險(xiǎn)[10-11]。替格瑞洛是一種新型P2Y12受體拮抗劑，其母體藥物及活性代謝產(chǎn)物(AR-C124910XX)均有抗血小板作用，起效快、作用強(qiáng)，不受基因型的影響，不增加主要出血發(fā)生風(fēng)險(xiǎn)，但可增加次要出血發(fā)生風(fēng)險(xiǎn)[3-4]。國際指南推薦，對于NSTE-ACS或STEMI藥物洗脫支架植入術(shù)后患者，替格瑞洛90 mg/次、2次/d服用1年為一線治療方案[12-15]。國外研究表明，低劑量替格瑞洛(60 mg/次，2次/d)的心血管獲益情況與標(biāo)準(zhǔn)劑量替格瑞洛相似，但低劑量替格瑞洛可略減少出血事件的發(fā)生[16]。

與西方人群相比，亞洲人群具有較低的血栓形成傾向和較高的出血傾向[16]，抗血小板藥物的治療窗也不同于西方人群[5]，低劑量的替格瑞洛可能更適合亞洲人群。LI等[17]通過研究發(fā)現(xiàn)，服用90 mg/次、2次/d替格瑞洛在達(dá)穩(wěn)態(tài)時(shí)，我國健康受試者替格瑞洛及AR-C124910XX的最大濃度及血藥濃度-時(shí)間曲線下面積較西方人群高40%左右。一項(xiàng)近期藥動(dòng)學(xué)及藥效學(xué)研究，選取了118例日本穩(wěn)定型冠狀動(dòng)脈粥樣硬化性心臟病(coronary artery disease，CAD)患者，發(fā)現(xiàn)替格瑞洛45 mg/次、2次/d對血小板聚集的抑制強(qiáng)于氯吡格雷75 mg/次，1次/d[18]。XUE等[6]選取我國NSTE-ACS患者進(jìn)行臨床試驗(yàn)，發(fā)現(xiàn)半數(shù)劑量的替格瑞洛(45 mg/次，2次/d)的血小板抑制作用與標(biāo)準(zhǔn)劑量替格瑞洛相似，明顯強(qiáng)于氯吡格雷組。HE等[19]通過研究發(fā)現(xiàn)，在中國穩(wěn)定型CAD患者中，1/4劑量替格瑞洛(22.5 mg/次，2次/d)的血小板抑制作用強(qiáng)于標(biāo)準(zhǔn)劑量的氯吡格雷。

Table 2 Platelet aggregation rate in ticagrelor group and clopidogrel group measured at different time points following the reviewing

組別例數(shù)服藥1周服藥3個(gè)月t值P值氯吡格雷組6229.1±9.527.3±7.1-2.030.06替格瑞洛組3319.2±8.818.3±7.9-0.690.50t值-4.99-5.71P值<0.01<0.01

注：PCI術(shù)=經(jīng)皮冠狀動(dòng)脈介入治療術(shù)

表3 兩組患者隨訪期間MACE和不良反應(yīng)發(fā)生率比較〔n(%)〕

Table 3 Incidence of MACE and adverse reactions in ticagrelor group and clopidogrel group during the follow-up period

組別例數(shù)MACE輕度出血呼吸困難氯吡格雷組6214(22.6)7(11.3)0替格瑞洛組331(3.0)4(12.1)2(6.1)χ2值4.810.00-P值0.031.000.12

注：MACE=主要不良心血管事件；-代表采用Fisher確切概率法

表1 兩組患者一般資料比較

注：ACS=急性冠脈綜合征，UA=不穩(wěn)定型心絞痛，NSTEMI=非ST段抬高型心肌梗死，STEMI=ST段抬高型心肌梗死，ACEI=血管緊張素轉(zhuǎn)換酶抑制劑，ARB=血管緊張素Ⅱ受體阻滯劑，CCB=鈣通道拮抗劑，PPI=質(zhì)子泵抑制劑；a為t值

本研究結(jié)果顯示，PCI術(shù)6個(gè)月后應(yīng)用替格瑞洛45 mg/次、2次/d對血小板的抑制作用大于氯吡格雷75 mg/次、1次/d，與上述研究相符。隨訪6個(gè)月，服用低劑量替格瑞洛患者的MACE發(fā)生率低于氯吡格雷，出血和呼吸困難發(fā)生率與氯吡格雷無差異。本研究納入患者的植入支架為Xience V、BuMA及吉威EXSEL支架。其中，Xience V、BuMA支架采用光學(xué)相干斷層成像系統(tǒng)(OCT)技術(shù)，植入3個(gè)月后可在支架小梁上形成很好的內(nèi)膜覆蓋[20]；而吉威EXSEL支架植入6個(gè)月后停用雙抗具有可行性[21]，可為臨床上PCI術(shù)后替格瑞洛的服用提供借鑒資料。但本研究也存在一定的局限性，如：(1)樣本量較??；(2)采用LTA法檢測血小板聚集率用以評價(jià)血小板功能，LTA法應(yīng)用廣泛，被認(rèn)為是血小板功能檢測的金標(biāo)準(zhǔn)，但目前LTA法檢測血小板聚集率的影響因素較多且重復(fù)性差，很難標(biāo)準(zhǔn)化[22-23]。因此，對于PCI術(shù)后服用低劑量替格瑞洛的有效性及安全性仍需大樣本、多中心、長期及多種血小板功能檢測方法的臨床研究予以驗(yàn)證，以尋求適合我國人群的替格瑞洛合適劑量。

作者貢獻(xiàn)：宋敏參與研究的實(shí)施與可行性分析、數(shù)據(jù)收集，負(fù)責(zé)數(shù)據(jù)整理和統(tǒng)計(jì)學(xué)處理、結(jié)果的分析與解釋、撰寫論文和中英文修訂，對文章整體負(fù)責(zé)，監(jiān)督管理；姚朱華負(fù)責(zé)文章的構(gòu)思與設(shè)計(jì)、患者入組；門劍龍參與研究的實(shí)施與可行性分析；曹明英參與數(shù)據(jù)收集，負(fù)責(zé)文章的質(zhì)量控制及審校；黎文婷、陳穎參與數(shù)據(jù)收集。

本文無利益沖突。

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(本文編輯：王鳳微)

Efficacy and Safety of Low-dose Ticagrelor in Patients at Six Months after Percutaneous Coronary Intervention

SONGMin1,2,YAOZhu-hua2*,MENJian-long3,CAOMing-ying2,LIWen-ting2,CHENYing2

1.GraduateSchool,TianjinMedicalUniversity,Tianjin300070,China2.DeparmentofCardiology,TianjinPeople′sHospital,Tianjin300121,China3.MedicalLaboratory,TianjinMedicalUniversityGeneralHospital,Tianjin300052,China*Correspondingauthor:YAOZhu-hua,Chiefphysician,Mastersupervisor;E-mail:tjyzhpci@163.com

Objective To evaluate the efficacy and safety of low-dose ticagrelor in patients at six months after percutaneous coronary intervention(PCI).Methods Nine-five patients underwent postoperative review at 6 months after PCI in Tianjin People′s Hospital between July 2015 and February 2016 were selected as the participants and divided into the ticagrelor group(n=33) and clopidogrel group(n=62) based on the P2Y12 adenosine diphosphate-receptor antagonist type that the postoperatively orally taken drug belongs to.Patients in the ticagrelor group

standard dose of ticagrelor(90 mg,twice daily),and those in the clopidogrel group took clopidogrel(75 mg,once daily) after PCI.At six months after PCI,the ticagrelor group changed to low-dose ticagrelor(45 mg,twice daily),but the clopidogrel group continued to take the same dose of clopidogrel.Both groups were given aspirin(100 mg,once daily).Light transmission aggregometry(LTA) was used to measure the platelet aggregation rate at the time that they completed 1-week,and 3-month administration following the reviewing.Comparisons were made between the two groups′ two measurement results of platelet aggregation rate,major adverse cardiac events(MACE) and adverse reactions occurred during the 6-month follow-up.Results The platelet aggregation rates measured at the time that the patients completed 1-week,and 3-month administration following the reviewing in ticagrelor group were all dramatically lower than those in clopidogrel group(P<0.05).In both groups,little difference was observed between the two measurement results of platelet aggregation rate(P>0.05).The follow-up results showed that,the incidence of MACE was significantly lower in the ticagrelor group than that in the clopidogrel group(P<0.05),but there were no significant difference in the incidence of mild hemorrhage and dyspnea between the two groups(P>0.05).Conclusion Inhibitory effect on platelet aggregation of low-dose ticagrelor administered at 6 months after PCI was significantly stronger than that of clopidogrel.Low-dose ticagrelor can reduce the incidence of ischemic events in the patients after PCI,without increasing the risk of bleeding.

Angioplasty,balloon,coronary;Ticagrelor;Clopidogrel;Treatment outcome

R 543.3

A

10.3969/j.issn.1007-9572.2017.16.014

2017-01-10；

2017-04-17)

1.300070 天津市，天津醫(yī)科大學(xué)研究生院

2.300121 天津市人民醫(yī)院心內(nèi)科

3.300052 天津市，天津醫(yī)科大學(xué)總醫(yī)院醫(yī)學(xué)檢驗(yàn)科

*通信作者：姚朱華，主任醫(yī)師，碩士生導(dǎo)師；E-mail：tjyzhpci@163.com