張萌萌 徐曉涵 翟所迪

（北京大學第三醫(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)生技術評估

張萌萌 徐曉涵 翟所迪

（北京大學第三醫(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、適用性和經濟性，針對阿瑞匹坦在中國的應用，為臨床實踐與準入決策者提供循證證據(jù)。方法：按照衛(wèi)生技術評估的方法，系統(tǒng)檢索Pubmed、Embase、CNKI和CBM等數(shù)據(jù)庫，以及國內外衛(wèi)生技術評估（HTA）機構官方網站，對納入的研究進行系統(tǒng)評價與meta分析。結果：與標準二聯(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）。兩組間安全性結局無顯著差異。阿瑞匹坦三聯(lián)方案具有顯著的經濟學優(yōu)勢。結論：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、安全性和經濟性。

阿瑞匹坦；化療所致惡心嘔吐（CINV）；衛(wèi)生技術評估

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，以結直腸癌為例，50%～70%的晚期患者在術前或術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，可嚴重影響患者的生命質量，甚至導致患者中斷有效的藥物治療[4,5]。同時，CINV相關的直接成本與間接成本也給醫(yī)療衛(wèi)生系統(tǒng)帶來沉重負擔[6]。

它的發(fā)生與包括5-羥色胺、P物質在內的多種神經遞質及其受體有關。阿瑞匹坦是人神經激肽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，與其它止吐藥物聯(lián)合給藥，用于預防高度催吐風險腫瘤化療的初次和重復治療過程中出現(xiàn)的急性和遲發(fā)性惡心和嘔吐。我國當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、適用性和經濟性，針對阿瑞匹坦在中國的應用，為臨床實踐與準入決策者提供循證證據(jù)。

1 資料與方法

1.1 納入與排除標準：按照PICO-S原則設計

1.1.1 研究人群（P）：接受高度催吐風險化療（HEC）或中度催吐風險化療（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的預防；

1.1.4 結局指標（O）：

有效性結局指標：

主要終點指標：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：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；患者生命質量評分（FLIE評分）；

安全性結局指標：發(fā)生 ≥1例不良事件的患者比例；嚴重不良事件的發(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）；

適用性結局指標：人群適用性分析結果；

經濟性結局指標：節(jié)省/增加的花費、治療成本、患者延長的質量調整生命年（QALY）、增量成本效果比（ICER）等；

1.1.5 研究類型（S）：

衛(wèi)生技術評估（HTA）、系統(tǒng)評價及meta分析、隨機對照試驗（RCT）及經濟學評價研究（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，同時檢索國內外HTA機構官方網站及相關數(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列表。

1.3 文獻篩選、數(shù)據(jù)提取與質量評價

由2名研究者（張萌萌，徐曉涵）通過閱讀文獻標題和摘要獨立進行文獻篩選。按照預先設計的數(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標準[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報告及經濟學研究進行數(shù)據(jù)提取，并進行質量評價，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軟件進行統(tǒng)計分析。二分類資料采用比值比（OR）為效應指標，連續(xù)性變量采用均數(shù)差（MD）為效應指標，各效應指標均給出其點估計值和95%CI。對于有效性結局指標，當OR值＞1時，則說明針對該結局指標，阿瑞匹坦組優(yōu)于對照組；對于安全性結局指標，當OR值＜1時，說明針對該結局指標，阿瑞匹坦組優(yōu)于對照組。納入研究結果間的異質性采用χ2檢驗進行分析（檢驗水準設為P=0.1），并結合I2定量判斷異質性的大小。若各研究結果間無統(tǒng)計學異質性，采用固定效應述性分析，對其他類型的研究進行定性分析。模型進行 Meta 分析；若各研究結果間存在統(tǒng)計學異質性，在排除明顯臨床異質性的影響后，采用隨機效應模型進行 Meta分析。明顯的臨床異質性采用亞組分析或敏感性分析等方法進行處理，或只進行描

圖1 文獻篩選流程圖

表1 Meta分析有效性結果

表2 阿瑞匹坦在中國、歐盟、美國獲批的適應證

2 結果

2.1 文獻檢索結果

初檢并查重后獲得2547篇文獻，經過初篩，將得到的57篇文獻進行全文閱讀復篩，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]與藥物經濟學研究[53-59]分別為1、5、36、7，整體質量良好。文獻篩選流程及結果見圖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)方案較標準二聯(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濟性。

35篇RCT研究中，對符合標準的21篇RCT的Meta分析結果顯示，主要及次要終點指標結果均顯示阿瑞匹坦三聯(lián)方案較標準二聯(lián)方案有顯著優(yōu)勢（見表1）。亞組分析結果顯示，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。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，導致研究效能下降至62%。

表3 納入經濟學研究的結果

2.3 安全性

納入的HTA及現(xiàn)有的SR/Meta分析均顯示，兩組之間安全性結局無顯著差異；35篇RCT研究中，對符合標準的24篇RCT的Meta分析結果顯示，阿瑞匹坦三聯(lián)方案組與標準二聯(lián)方案組的常見和嚴重不良事件發(fā)生率無顯著差異。

2.4 適用性

美國及歐盟于2003年批準阿瑞匹坦用于CINV的預防[60,61]，中國于2015年6月30日批準該適應證[62]，詳細的適應證信息見表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 經濟性

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防性使用該藥的成本更高。其他研究[55-59]結果均表明，雖然阿瑞匹坦的使用與更高的藥物成本相關，但其可節(jié)省嘔吐管理、患者入院和解救藥物使用相關的醫(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)方案與標準二聯(lián)方案、甲氧氯普胺+5-HT3RA + DEX相比是具有經濟性的（見表3）。

3 討論

本技術評估納入的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研究進行系統(tǒng)評價和Meta分析顯示，阿瑞匹坦三聯(lián)方案較標準二聯(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。與既往研究結果一致[5]。

亞組分析的結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。既往研究結果顯示，患者年齡越低，則發(fā)生CINV的風險越高[65]，本研究的結果與這些研究的結果一致，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)計學意義，這與在中國開展的Hu等人和Yeo等人研究的結果一致[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結果一致，也顯示了阿瑞匹坦在該種族中的有效性。

所有的安全性結局中， 阿瑞匹坦三聯(lián)方案與標準二聯(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。

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

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）針對阿瑞匹坦的經濟性評價，檢索到的研究均來自中國大陸以外的國家或地區(qū)。

4 結論

與標準二聯(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的預防具有有效性、安全性和經濟性。

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