阿瑞匹坦用于化療所致惡心嘔吐的衛(wèi)生技術(shù)評估

張萌萌 徐曉涵 翟所迪

（北京大學(xué)第三醫(yī)院藥劑科 北京 100191）

阿瑞匹坦用于化療所致惡心嘔吐的衛(wèi)生技術(shù)評估

張萌萌 徐曉涵 翟所迪

（北京大學(xué)第三醫(yī)院藥劑科 北京 100191）

目的：全面評價阿瑞匹坦用于化療所致惡心嘔吐（CINV）的有效性、安全性、適用性和經(jīng)濟(jì)性，針對阿瑞匹坦在中國的應(yīng)用，為臨床實踐與準(zhǔn)入決策者提供循證證據(jù)。方法：按照衛(wèi)生技術(shù)評估的方法，系統(tǒng)檢索Pubmed、Embase、CNKI和CBM等數(shù)據(jù)庫，以及國內(nèi)外衛(wèi)生技術(shù)評估（HTA）機(jī)構(gòu)官方網(wǎng)站，對納入的研究進(jìn)行系統(tǒng)評價與meta分析。結(jié)果：與標(biāo)準(zhǔn)二聯(lián)方案相比，阿瑞匹坦三聯(lián)方案可顯著改善全程完全控制率（CR）（OR=1.92, 95% CI =1.73 ～ 2.14, P ＜ 0.001）、急性期CR（OR= 1.82, 95% CI = 1.59 ～ 2.07, P ＜ 0.001）和延遲期CR（OR = 2.00, 95% CI = 1.69 ～ 2.37, P ＜ 0.001）。兩組間安全性結(jié)局無顯著差異。阿瑞匹坦三聯(lián)方案具有顯著的經(jīng)濟(jì)學(xué)優(yōu)勢。結(jié)論：與其他止吐方案相比，阿瑞匹坦三聯(lián)方案具有良好的有效性、安全性和經(jīng)濟(jì)性。

阿瑞匹坦；化療所致惡心嘔吐（CINV）；衛(wèi)生技術(shù)評估

在我國，癌癥已超過心血管疾病，成為我國疾病死因的第一位[1]?；熓前┌Y治療的手段之一，以結(jié)直腸癌為例，50%～70%的晚期患者在術(shù)前或術(shù)后接受化療或化療聯(lián)合放療[2]?；熕聬盒膰I吐（Chemotherapy-induced nausea and vomiting，CINV）是腫瘤患者化療過程中最常見、最痛苦的不良反應(yīng)之一[3]。隨著新型止吐劑的使用，如5-羥色胺3受體拮抗劑（5-HT3RAs），患者嘔吐的發(fā)生率下降，但惡心、嘔吐仍然是化療過程中令患者感到痛苦的不良事件，可嚴(yán)重影響患者的生命質(zhì)量，甚至導(dǎo)致患者中斷有效的藥物治療[4,5]。同時，CINV相關(guān)的直接成本與間接成本也給醫(yī)療衛(wèi)生系統(tǒng)帶來沉重負(fù)擔(dān)[6]。

它的發(fā)生與包括5-羥色胺、P物質(zhì)在內(nèi)的多種神經(jīng)遞質(zhì)及其受體有關(guān)。阿瑞匹坦是人神經(jīng)激肽1（NK1）受體的選擇性高親和力拮抗劑。于2003年獲美國食品藥品管理局批準(zhǔn)用于CINV，2015年6月通過中國國家食品藥品監(jiān)督管理局批準(zhǔn)，與其它止吐藥物聯(lián)合給藥，用于預(yù)防高度催吐風(fēng)險腫瘤化療的初次和重復(fù)治療過程中出現(xiàn)的急性和遲發(fā)性惡心和嘔吐。我國當(dāng)前尚缺乏阿瑞匹坦用于CINV的綜合評價證據(jù)。

本衛(wèi)生技術(shù)評估旨在全面評價阿瑞匹坦用于CINV的有效性、安全性、適用性和經(jīng)濟(jì)性，針對阿瑞匹坦在中國的應(yīng)用，為臨床實踐與準(zhǔn)入決策者提供循證證據(jù)。

1 資料與方法

1.1 納入與排除標(biāo)準(zhǔn)：按照PICO-S原則設(shè)計

1.1.1 研究人群（P）：接受高度催吐風(fēng)險化療（HEC）或中度催吐風(fēng)險化療（MEC）的惡性腫瘤患者（腫瘤類型不限，患者年齡不限，化療天數(shù)不限）；

1.1.2 干預(yù)措施（I）：阿瑞匹坦單藥或與其他類止吐藥物聯(lián)合用于CINV的預(yù)防；

1.1.3 對照措施（C）：安慰劑或其他陽性對照藥物與其他類止吐藥物聯(lián)合用于CINV的預(yù)防；

1.1.4 結(jié)局指標(biāo)（O）：

有效性結(jié)局指標(biāo)：

主要終點指標(biāo)：全程完全控制率（CR，即未發(fā)生嘔吐，也不需要解救治療的患者比例）；

次要終點指標(biāo)：急性期與延遲期CR；全程未發(fā)生嘔吐的患者比例；全程未發(fā)生惡心的患者比例；全程未發(fā)生明顯惡心的患者比例；全程未使用解救藥物的患者比例；患者生命質(zhì)量評分（FLIE評分）；

安全性結(jié)局指標(biāo)：發(fā)生 ≥1例不良事件的患者比例；嚴(yán)重不良事件的發(fā)生率；由于不良事件停用阿瑞匹坦的患者比例；發(fā)熱性中性粒細(xì)胞減少癥的發(fā)生率；其他常見不良事件的發(fā)生率（虛弱/無力、便秘、腹瀉、惡心、頭痛、呃逆）；

適用性結(jié)局指標(biāo)：人群適用性分析結(jié)果；

經(jīng)濟(jì)性結(jié)局指標(biāo)：節(jié)省/增加的花費、治療成本、患者延長的質(zhì)量調(diào)整生命年（QALY）、增量成本效果比（ICER）等；

1.1.5 研究類型（S）：

衛(wèi)生技術(shù)評估（HTA）、系統(tǒng)評價及meta分析、隨機(jī)對照試驗（RCT）及經(jīng)濟(jì)學(xué)評價研究（成本效果分析、成本效益分析、最小成本分析等）；

1.2 檢索策略

計算機(jī)檢索Pubmed、Embase、the Cochrane Library等英文數(shù)據(jù)庫，CNKI和CBM等中文數(shù)據(jù)庫，同時檢索國內(nèi)外HTA機(jī)構(gòu)官方網(wǎng)站及相關(guān)數(shù)據(jù)庫，收集阿瑞匹坦用于CINV的HTA報告、系統(tǒng)評價（SR）與Meta分析、隨機(jī)對照試驗（RCT）研究，檢索時限均為從建庫至2015年8月。中文檢索詞使用“阿瑞匹坦”或“阿瑞吡坦”或“意美”，英文檢索詞使用“aprepitant OR Emend”，進(jìn)行全文檢索或者主題詞檢索。同時手工檢索納入研究的參考文獻(xiàn)列表。

1.3 文獻(xiàn)篩選、數(shù)據(jù)提取與質(zhì)量評價

由2名研究者（張萌萌，徐曉涵）通過閱讀文獻(xiàn)標(biāo)題和摘要獨立進(jìn)行文獻(xiàn)篩選。按照預(yù)先設(shè)計的數(shù)據(jù)提取表以及Cochrane 系統(tǒng)評價員手冊[7]、AMSTAR工具[8]、HTA核查表[9]和CHEERS標(biāo)準(zhǔn)[10]，由2名研究者（張萌萌、徐曉涵）獨立對納入的RCT研究、SR與Meta分析、HTA報告及經(jīng)濟(jì)學(xué)研究進(jìn)行數(shù)據(jù)提取，并進(jìn)行質(zhì)量評價，上述過程如遇分歧，與第3名研究者（翟所迪）討論后決定是否納入。

1.4 數(shù)據(jù)分析與合成

對納入的RCT研究采用 RevMan 5.3軟件進(jìn)行統(tǒng)計分析。二分類資料采用比值比（OR）為效應(yīng)指標(biāo)，連續(xù)性變量采用均數(shù)差（MD）為效應(yīng)指標(biāo)，各效應(yīng)指標(biāo)均給出其點估計值和95%CI。對于有效性結(jié)局指標(biāo)，當(dāng)OR值＞1時，則說明針對該結(jié)局指標(biāo)，阿瑞匹坦組優(yōu)于對照組；對于安全性結(jié)局指標(biāo)，當(dāng)OR值＜1時，說明針對該結(jié)局指標(biāo)，阿瑞匹坦組優(yōu)于對照組。納入研究結(jié)果間的異質(zhì)性采用χ2檢驗進(jìn)行分析（檢驗水準(zhǔn)設(shè)為P=0.1），并結(jié)合I2定量判斷異質(zhì)性的大小。若各研究結(jié)果間無統(tǒng)計學(xué)異質(zhì)性，采用固定效應(yīng)述性分析，對其他類型的研究進(jìn)行定性分析。模型進(jìn)行 Meta 分析；若各研究結(jié)果間存在統(tǒng)計學(xué)異質(zhì)性，在排除明顯臨床異質(zhì)性的影響后，采用隨機(jī)效應(yīng)模型進(jìn)行 Meta分析。明顯的臨床異質(zhì)性采用亞組分析或敏感性分析等方法進(jìn)行處理，或只進(jìn)行描

圖1 文獻(xiàn)篩選流程圖

表1 Meta分析有效性結(jié)果

表2 阿瑞匹坦在中國、歐盟、美國獲批的適應(yīng)證

2 結(jié)果

2.1 文獻(xiàn)檢索結(jié)果

初檢并查重后獲得2547篇文獻(xiàn)，經(jīng)過初篩，將得到的57篇文獻(xiàn)進(jìn)行全文閱讀復(fù)篩，最終納入49個可獲得全文的研究，HTA[11]、SR/ Meta分析[12-16]、RCT研究及其匯總分析[17-52]與藥物經(jīng)濟(jì)學(xué)研究[53-59]分別為1、5、36、7，整體質(zhì)量良好。文獻(xiàn)篩選流程及結(jié)果見圖1。

2.2 有效性

納入的HTA及現(xiàn)有的SR/Meta分析均顯示，阿瑞匹坦三聯(lián)方案較標(biāo)準(zhǔn)二聯(lián)方案可顯著改善CINV的控制情況，尤其是延遲期CR，均未評價阿瑞匹坦的經(jīng)濟(jì)性。

35篇RCT研究中，對符合標(biāo)準(zhǔn)的21篇RCT的Meta分析結(jié)果顯示，主要及次要終點指標(biāo)結(jié)果均顯示阿瑞匹坦三聯(lián)方案較標(biāo)準(zhǔn)二聯(lián)方案有顯著優(yōu)勢（見表1）。亞組分析結(jié)果顯示，在兒童和青少年患者中（全程OR=2.87，95%CI=1.74～4.72，P＜0.001）、亞裔患者中（全程OR =1.86，95%CI=1.50～2.31，P＜ 0.001），阿瑞匹坦三聯(lián)方案均具有顯著優(yōu)勢；此外，無論患者接受的是HEC還是MEC，無論阿瑞匹坦組的地塞米松（DEX）劑量有無調(diào)整，阿瑞匹坦均可顯著改善全程、急性期及延遲期CR；阿瑞匹坦給患者帶來的CR獲益，可在多個化療周期后持續(xù)，且阿瑞匹坦組FLIE評分顯示治療對患者生命質(zhì)量無影響或影響微小的患者比例顯著高于對照組；

三項研究分別將陽性對照藥物與阿瑞匹坦進(jìn)行了對比。其中一項研究[32]發(fā)現(xiàn)奧氮平與單劑帕洛諾司瓊及單劑地塞米松合用時，其全程、急性期及延遲期CR與阿瑞匹坦三聯(lián)方案相比均無顯著差異，但該藥可增加患者摔倒風(fēng)險，且為超說明書用藥；另外兩項研究[37,38]發(fā)現(xiàn)，地塞米松或甲氧氯普胺用于延遲期與阿瑞匹坦效果相當(dāng)。但前者阿瑞匹坦單藥用于延遲期的方案與臨床實踐不符，結(jié)果存在假陰性可能；后者因入組困難未按原計劃招募足夠的受試者，導(dǎo)致研究效能下降至62%。

表3 納入經(jīng)濟(jì)學(xué)研究的結(jié)果

2.3 安全性

納入的HTA及現(xiàn)有的SR/Meta分析均顯示，兩組之間安全性結(jié)局無顯著差異；35篇RCT研究中，對符合標(biāo)準(zhǔn)的24篇RCT的Meta分析結(jié)果顯示，阿瑞匹坦三聯(lián)方案組與標(biāo)準(zhǔn)二聯(lián)方案組的常見和嚴(yán)重不良事件發(fā)生率無顯著差異。

2.4 適用性

美國及歐盟于2003年批準(zhǔn)阿瑞匹坦用于CINV的預(yù)防[60,61]，中國于2015年6月30日批準(zhǔn)該適應(yīng)證[62]，詳細(xì)的適應(yīng)證信息見表2。對阿瑞匹坦膠囊過敏的患者禁用該藥品，同時，由于藥物相互作用，禁止將阿瑞匹坦與匹莫齊特、特非那定、阿司咪唑、西沙比利合用。

2.5 經(jīng)濟(jì)性

一項來自比利時的研究[53]發(fā)現(xiàn)阿瑞匹坦的使用在提高療效的同時還可使成本下降；另一項研究[54]發(fā)現(xiàn)，嘔吐后解救性使用阿瑞匹坦的成本較預(yù)防性使用該藥的成本更高。其他研究[55-59]結(jié)果均表明，雖然阿瑞匹坦的使用與更高的藥物成本相關(guān)，但其可節(jié)省嘔吐管理、患者入院和解救藥物使用相關(guān)的醫(yī)療資源和成本，根據(jù)ICER及各個地區(qū)的成本效果閾值，阿瑞匹坦三聯(lián)方案與標(biāo)準(zhǔn)二聯(lián)方案、甲氧氯普胺+5-HT3RA + DEX相比是具有經(jīng)濟(jì)性的（見表3）。

3 討論

本技術(shù)評估納入的1項HTA及 5項SR/Meta均顯示阿瑞匹坦三聯(lián)方案安全、有效。

對納入的35篇RCT研究進(jìn)行系統(tǒng)評價和Meta分析顯示，阿瑞匹坦三聯(lián)方案較標(biāo)準(zhǔn)二聯(lián)方案可顯著改善全程、急性期和延遲期CR，尤其是延遲期CR。與既往研究結(jié)果一致[5]。

亞組分析的結(jié)果給我們帶來更多啟示。針對兒童和青少年患者群體的研究較少，僅有2項，但與成人組結(jié)果一致，阿瑞匹坦同樣可顯著改善其全程、急性期和延遲期CR，尤其是延遲期CR，且兒童和青少年組的效應(yīng)值要高于成人組，但全程、急性期和延遲期CR率均低于成人組。既往研究結(jié)果顯示，患者年齡越低，則發(fā)生CINV的風(fēng)險越高[65]，本研究的結(jié)果與這些研究的結(jié)果一致，同時提示，在這些患者中，使用阿瑞匹坦的獲益將更顯著。

對于亞裔人群，阿瑞匹坦可顯著改善急性期和延遲期CR，而對急性期CR的改善不具有統(tǒng)計學(xué)意義，這與在中國開展的Hu等人和Yeo等人研究的結(jié)果一致[27,46]。但亞裔人群全程、急性期和延遲期的CR率均高于整體人群，與其在亞洲人群中吸收程度更高的藥代動力學(xué)結(jié)果一致，也顯示了阿瑞匹坦在該種族中的有效性。

所有的安全性結(jié)局中， 阿瑞匹坦三聯(lián)方案與標(biāo)準(zhǔn)二聯(lián)方案均無顯著差異。但對于便秘的發(fā)生率，阿瑞匹坦組較對照組有發(fā)生率更低的趨勢。

納入的經(jīng)濟(jì)學(xué)研究中有6項研究結(jié)果表明，雖然阿瑞匹坦的使用與更高的藥物成本相關(guān)，但其可節(jié)省嘔吐管理、患者入院和解救藥物使用相關(guān)的醫(yī)療資源和成本，根據(jù)各納入研究的ICER結(jié)果及各個地區(qū)的成本效果閾值，阿瑞匹坦的使用是具有經(jīng)濟(jì)性的。

本研究存在一定的局限性：（1）針對亞洲人群的分析，我們假定那些在中國、日本等東亞國家進(jìn)行的研究所納入患者的種族均為亞裔；（2）針對阿瑞匹坦的經(jīng)濟(jì)性評價，檢索到的研究均來自中國大陸以外的國家或地區(qū)。

4 結(jié)論

與標(biāo)準(zhǔn)二聯(lián)方案相比，阿瑞匹坦三聯(lián)方案可有效改善接受HEC或MEC患者的CINV控制情況，與對照組相比，常見和嚴(yán)重不良事件的發(fā)生率無顯著差異；阿瑞匹坦可安全、有效地用于亞裔患者人群、兒童和青少年患者。阿瑞匹坦用于CINV具有成本效果優(yōu)勢。因此，阿瑞匹坦用于CINV的預(yù)防具有有效性、安全性和經(jīng)濟(jì)性。

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Health Technology Assessment on Aprepitant to Control Chemotherapy Induced Nausea and Vomiting

Zhang Mengmeng,Xu Xiaohan, Zhai Suodi Department of Pharmacy, Peking University Third Hospital, Beijing, 100191)

Objectives: To provide evidence to healthcare providers and insurance decision makers by comprehensive evaluation of the effectiveness, safety, applicability and economic efficiency of aprepitant for chemotherapy induced nausea and vomiting. Methods: Databases including Pubmed, Embase, CNKI, CBM and health technology assessment (HTA) organization websites were searched. The included studies were analyzed by systematic review or meta-analysis. Results: 49 studies were included. Compared with the combination of 5-hydroxytryptamine-3 receptor antagonists (5-HT3RAs) and corticosteroids, the addition of aprepitant improved the complete response (CR) in overall (OR=1.92, 95% CI =1.73 ～ 2.14, P ＜ 0.001), acute (OR= 1.82, 95% CI = 1.59～ 2.07, P ＜ 0.001) and delayed phase. Both regimens were tolerable. The addition of aprepitant was more economic. Conclusion: Compared with other antiemetic regimens, the regimen with addition of aprepitant has favorable eff ectiveness, safety and economic efficiency.

Aprepitant, Chemotherapy-induced nausea and vomiting (CINV), health technology assessment

F840.684 C913.7

A

1674-3830（2016）11-50-7

10.369/j.issn.1674-3830.2016.11.012

2016-7-18

張萌萌，理學(xué)碩士，北京大學(xué)第三醫(yī)院藥劑科藥師，主要研究方向：腫瘤藥學(xué),循證藥學(xué)。