萬繼業(yè)，馬淑梅

阿司匹林及氯吡格雷雙聯(lián)抗血小板治療對(duì)女性月經(jīng)的影響

萬繼業(yè)，馬淑梅*

目的 觀察女性經(jīng)皮冠狀動(dòng)脈介入治療(Percutaneous coronary intervention，PCI)術(shù)后全程雙聯(lián)抗血小板藥物阿司匹林及氯吡格雷口服治療對(duì)月經(jīng)的影響。方法 我院心內(nèi)科2004年1月至2013年6月診斷為急性冠脈綜合征且行冠狀動(dòng)脈支架植入術(shù)的住院絕經(jīng)前女性患者，采用回顧性研究的方法觀察其口服雙聯(lián)抗血小板藥物治療前及治療后6個(gè)月、1年的月經(jīng)情況，并采用PABC評(píng)分量表對(duì)患者的月經(jīng)量進(jìn)行定量評(píng)分。結(jié)果 絕經(jīng)前女性冠狀動(dòng)脈支架置入術(shù)后雙聯(lián)抗血小板藥物阿司匹林及氯吡格雷口服治療1年的月經(jīng)量較術(shù)前無明顯變化。結(jié)論 絕經(jīng)前女性應(yīng)用雙聯(lián)抗血小板藥物治療1年，月經(jīng)量無明顯變化，是相對(duì)安全的。

阿司匹林；氯吡格雷；月經(jīng)

0 引言

近年來，我國(guó)心血管疾病的發(fā)病率和死亡率呈上升趨勢(shì)，女性患者(尤其是絕經(jīng)前女性患者)冠心病的發(fā)病率逐年增加，服用非甾體抗炎藥物阿司匹林抗血小板治療已經(jīng)成為目前臨床上治療冠心病的基本手段之一。非甾體抗炎藥物能夠減少月經(jīng)過多女性患者的月經(jīng)量已經(jīng)得到許多RCTs研究證實(shí)[1-4]，然而，目前對(duì)于發(fā)生急性冠脈綜合征(Acute coronary syndrome，ACS)的絕經(jīng)前女性患者，口服非甾體抗炎藥物阿司匹林及ADP受體拮抗劑氯吡格雷雙聯(lián)抗血小板藥物治療對(duì)月經(jīng)的影響尚不明確。本文通過回顧性調(diào)查探討這一特定人群冠狀動(dòng)脈支架植入術(shù)后服用阿司匹林及氯吡格雷雙聯(lián)抗血小板藥物1年期間月經(jīng)的變化情況，探討其對(duì)女性月經(jīng)的影響，從而為臨床用藥提供參考。

1 資料與方法

1.1 臨床資料 2004年1月至2013年6月于我院心內(nèi)科住院、診斷為ACS、行冠狀動(dòng)脈支架植入術(shù)的絕經(jīng)前女性患者，排除術(shù)后1年有妊娠計(jì)劃、患有嚴(yán)重肝腎疾病且預(yù)計(jì)生存期不超過1年的患者，平均年齡(44±5.2)歲。術(shù)后嚴(yán)格遵醫(yī)囑每天口服雙聯(lián)抗血小板藥物拜阿司匹林腸溶片100 mg及氯吡格雷片75 mg治療。

1.2 研究方法 對(duì)于符合納入及排除標(biāo)準(zhǔn)的患者統(tǒng)一建立隨訪檔案，記錄患者的住院號(hào)、民族、文化程度、家族史、吸煙史、發(fā)病年齡及住院時(shí)收縮壓、舒張壓、心率、血液生化、冠脈病變情況等一般基線資料；同時(shí)記錄患者住院前2個(gè)月的月經(jīng)周期、經(jīng)期及經(jīng)量情況，并采用PABC(Pictorial blood loss assessment chart)月經(jīng)量評(píng)分量表對(duì)患者的月經(jīng)量統(tǒng)一進(jìn)行半定量評(píng)分[5]；術(shù)后6個(gè)月、1年分別通過門診或電話隨訪的方式獲知患者近2個(gè)月的月經(jīng)周期、經(jīng)期及經(jīng)量情況，亦采用PABC評(píng)分量表對(duì)患者月經(jīng)量進(jìn)行評(píng)分。

1.3 統(tǒng)計(jì)學(xué)分析 應(yīng)用SPSS 13.0軟件統(tǒng)計(jì)錄入數(shù)據(jù)，采用重復(fù)測(cè)量資料的方差分析對(duì)患者術(shù)前及術(shù)后6個(gè)月、1年的月經(jīng)量進(jìn)行統(tǒng)計(jì)分析，P<0.05為差異有統(tǒng)計(jì)學(xué)意義。

2 結(jié)果

2.1 基線情況分析 符合納入及排除標(biāo)準(zhǔn)的患者共27例，失訪3例，有效樣本數(shù)24例。漢族22例，鮮族2例；文化程度：初中以下7例，占29.2%，高中15例，占62.5%，大學(xué)2例，占8.3%；三代以內(nèi)直系親屬有心腦血管疾病病史3例，占12.5%；有吸煙史2例，占8.3%；合并高血壓10例，占41.7%，合并高血壓及糖尿病1例，占4.2%，合并高血壓及腦卒中1例，占4.2%；冠狀動(dòng)脈左前降支置入支架13例，左回旋支置入支架6例，右冠狀動(dòng)脈置入支架9例，人均置入支架1.3個(gè)。樣本人群的血壓、心率及血液生化等一般基線情況見表1。

表1 樣本人群的基線特征

注：*使用Kolmogorov-Smirnov方法的正態(tài)性檢驗(yàn)結(jié)果(下同)

2.2 月經(jīng)情況分析

2.2.1 月經(jīng)周期及經(jīng)期的變化 通過電話隨訪獲知符合條件的24例患者術(shù)前月經(jīng)周期及經(jīng)期較以往無明顯變化，術(shù)后2例患者自覺周期較術(shù)前延長(zhǎng)，4例患者訴經(jīng)期較術(shù)前延長(zhǎng)，其中1例患者訴月經(jīng)周期及經(jīng)期均較術(shù)前延長(zhǎng)。

2.2.2 月經(jīng)量的變化 使用PABC評(píng)分量表對(duì)患者冠狀動(dòng)脈支架植入術(shù)前及術(shù)后6個(gè)月、1年的月經(jīng)量情況進(jìn)行半定量評(píng)分，其基本檢驗(yàn)統(tǒng)計(jì)量見表2。患者術(shù)前及術(shù)后6個(gè)月、1年的PABC評(píng)分分值均分別行Kolmogorov-Smirnov正態(tài)性檢驗(yàn)，P均>0.1，提示樣本人群術(shù)前及術(shù)后6個(gè)月、1年的PABC月經(jīng)量評(píng)分分值均服從正態(tài)性分布。

表2 PCI術(shù)前及術(shù)后6個(gè)月、1年樣本人群月經(jīng)量PABC積分

樣本人群術(shù)前及術(shù)后6個(gè)月、1年的PABC評(píng)分分值樣本Mauchly球?qū)ΨQ檢驗(yàn)結(jié)果：P=0.41(>0.1)，符合球?qū)ΨQ假設(shè)，使用重復(fù)測(cè)量的方差分析法分析患者口服雙聯(lián)抗血小板藥物阿司匹林及氯吡格雷治療前及治療后6個(gè)月、1年月經(jīng)量的變化時(shí)，無需校正自由度，其方差分析的結(jié)果顯示，P=0.6(>0.1)，說明月經(jīng)正常女性冠狀動(dòng)脈支架植入術(shù)前及術(shù)后6個(gè)月、1年的月經(jīng)量無明顯變化。

3 討論

阿司匹林通過不可逆地乙?；傲邢偎丨h(huán)氧化酶，阻止花生四烯酸轉(zhuǎn)化為前列腺素，抑制血栓素A2的生成，從而間接發(fā)揮抗血小板作用。波利維在體內(nèi)水解成無生物活性的藥物前體，通過肝臟細(xì)胞色素P450(包括CYP3A4、CYP2C19、CYP1A2、CYP2B6)氧化成具有生物活性的物質(zhì)，通過抑制ADP與血小板P2Y12受體結(jié)合，從而抑制血小板活化及血栓的形成[6]。

發(fā)生ACS的患者由于冠狀動(dòng)脈粥樣斑塊破裂，內(nèi)皮下組織因子暴露，血小板激活，并介導(dǎo)了血管內(nèi)血栓的形成[7-8]，血液會(huì)在相當(dāng)長(zhǎng)的一段時(shí)間內(nèi)處于高凝狀態(tài)，由此引發(fā)的心臟缺血事件風(fēng)險(xiǎn)增加[9]，加上冠狀動(dòng)脈內(nèi)支架置入后，支架作為外源性異物本身亦導(dǎo)致血小板的過度激活。臨床研究證實(shí)，雙聯(lián)抗血小板藥物阿司匹林及氯吡格雷聯(lián)合治療能大幅度降低缺血事件[8-10]，尤其與單用阿司匹林治療相比，住院再缺血事件、再梗死、中風(fēng)及再次血運(yùn)重建率明顯降低，主要出血事件卻無明顯增加[11-14]，因此雙聯(lián)抗血小板藥物治療已經(jīng)成為支架植入術(shù)后預(yù)防冠脈再狹窄及支架內(nèi)血栓形成的常規(guī)治療措施。

隨著雙聯(lián)抗血小板藥物阿司匹林及氯吡格雷的廣泛應(yīng)用，患者消化道出血及顱內(nèi)出血的發(fā)生率也在增加。研究顯示，PCI術(shù)后口服雙聯(lián)抗血小板藥物胃腸道出血的發(fā)生率均在2%左右，高齡、既往消化潰瘍病史、合并應(yīng)用其他非甾體抗炎藥物或抗凝藥物均能增加消化道出血的發(fā)生率[15-17]。既往有消化道出血病史是服用阿司匹林和/或氯吡格雷藥物后發(fā)生消化道出血的預(yù)測(cè)因子，且消化道出血與近期及遠(yuǎn)期死亡密切相關(guān)[18-23]。Shiotani等[24]認(rèn)為，雙聯(lián)抗血小板藥物治療亦能夠加重小腸的損傷。在使用阿司匹林和氯吡格雷抑制血小板活性的同時(shí)，顱內(nèi)出血事件風(fēng)險(xiǎn)增加，并且部分抵消了抗血小板藥物降低心血管事件風(fēng)險(xiǎn)所帶來的獲益[25-26]。

雖然雙聯(lián)抗血小板治療對(duì)于患者消化道出血及顱內(nèi)出血的影響研究較多，但對(duì)于絕經(jīng)前女性發(fā)生ACS事件后，口服雙聯(lián)抗血小板藥物后月經(jīng)量的變化情況并不清楚。有報(bào)道，在月經(jīng)過多的人群中發(fā)現(xiàn)存在子宮內(nèi)膜環(huán)氧化酶及前列腺素的過度表達(dá)[27-29]，前列腺素類物質(zhì)通過與細(xì)胞膜G蛋白受體偶聯(lián)，通過第二信使途徑使細(xì)胞內(nèi)cAMP濃度增加，調(diào)節(jié)基因的表達(dá)，來發(fā)揮其生物學(xué)作用[30]。尤其是前列腺素E及前列腺素F在月經(jīng)期間對(duì)于調(diào)節(jié)子宮內(nèi)膜的生理功能起重要作用[31-32]，而非甾體抗炎藥物阿司匹林能通過環(huán)氧化酶抑制前列腺素的生成，影響月經(jīng)量。已經(jīng)有臨床研究證實(shí)，服用非甾體抗炎藥物能減少月經(jīng)過多女性患者的月經(jīng)量[1-4]，且不同種類的非甾體抗炎藥物之間療效相似。然而對(duì)于月經(jīng)量正常的女性患者，非甾體抗炎藥物對(duì)月經(jīng)量的影響的研究甚少。

本文通過對(duì)冠脈支架植入術(shù)前未絕經(jīng)女性術(shù)后1年的觀察，并未觀察到患者口服阿司匹林及氯吡格雷后月經(jīng)量較前有所變化，提示對(duì)于月經(jīng)正常的女性，發(fā)生ACS事件后，口服阿司匹林及氯吡格雷治療對(duì)月經(jīng)量影響不大，是相對(duì)安全的。

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Influence of dual anti-platelet therapy of asprin and clopidogrel on menstrual changes

WAN Ji-ye,MA Shu-mei*

(Department of Cardiology,Shengjing Hospital of China Medical University,Shenyang 110004,China)

Objective To observe the influence of dual anti-platelet therapy of aspirin and clopidogrel on the menstruation changes of patients after percutaneous coronary intervention.Methods Twenty-four premenopausal female patients who was diagnosed as ACS(Acute coronary syndrome)and lined of coronary artery stent implantation in our hospital from January 2004 to June 2013 were chosen,all the patients were given dural anti-platelet therapy of aspirin and clopidogrel.The menstruation situation before treatment and at 0.5,1 year after treatment were observed by a retrospective method,and the amount of menstruation was assessed by PABC(pictorial blood loss assessment chart).Results No significant difference was observed in the amount of menstruation in premenopausal female patients before surgery and after one year dual anti-platelet therapy.Conclusion The dual anti-platelet therapy for the premenopausal female patients(lasting one year)has no obvious influence on the amount of menstruation,it is relatively safe.

Aspirin;Clopidogrel;Menstruation

2014-09-24

中國(guó)醫(yī)科大學(xué)附屬盛京醫(yī)院心內(nèi)科，沈陽 110004

*通信作者

10.14053/j.cnki.ppcr.201506013