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        抗凝藥物防治癌癥患者靜脈血栓栓塞癥的藥物經(jīng)濟(jì)學(xué)系統(tǒng)評(píng)價(jià)

        2021-05-10 02:29:44周謙高笑男高敬林馮章英王明霞
        中國(guó)藥房 2021年7期
        關(guān)鍵詞:系統(tǒng)評(píng)價(jià)癌癥

        周謙 高笑男 高敬林 馮章英 王明霞

        摘 要 目的:系統(tǒng)評(píng)價(jià)抗凝藥物預(yù)防或治療癌癥患者靜脈血栓栓塞癥(VTE)的藥物經(jīng)濟(jì)性。方法:計(jì)算機(jī)檢索PubMed、Embase、Cochrane圖書館、中國(guó)知網(wǎng)、萬(wàn)方數(shù)據(jù)、維普網(wǎng)、中國(guó)生物醫(yī)學(xué)文獻(xiàn)服務(wù)系統(tǒng)以及The NHS Economic Evaluation Database、The Healthy Technology Assessment Database、EconLit等數(shù)據(jù)庫(kù),并輔以手工檢索,收集不同抗凝藥預(yù)防或治療癌癥患者VTE的經(jīng)濟(jì)學(xué)評(píng)價(jià)研究,檢索時(shí)限為建庫(kù)至2020年11月12日。經(jīng)篩選、提取后,采用衛(wèi)生經(jīng)濟(jì)評(píng)估報(bào)告標(biāo)準(zhǔn)清單評(píng)價(jià)納入文獻(xiàn)的質(zhì)量。采用描述性的方法總結(jié)納入文獻(xiàn)的基本特征,并根據(jù)用藥目的和不同干預(yù)分組歸納其經(jīng)濟(jì)學(xué)結(jié)果。結(jié)果:共納入15篇文獻(xiàn),3篇質(zhì)量?jī)?yōu)秀,10篇質(zhì)量良好,其余2篇質(zhì)量適中。研究分布于中國(guó)(1項(xiàng))、美國(guó)(7項(xiàng))、加拿大(3項(xiàng))、法國(guó)(2項(xiàng))、荷蘭(1項(xiàng))、巴西(1項(xiàng))、奧地利(1項(xiàng))等不同收入水平的國(guó)家。對(duì)于預(yù)防癌癥患者VTE,華法林和低分子肝素(LMWH)的經(jīng)濟(jì)學(xué)評(píng)價(jià)有待更新;在VTE中高風(fēng)險(xiǎn)的癌癥患者中,新型口服抗凝藥(NOACs)在中國(guó)的經(jīng)濟(jì)優(yōu)勢(shì)不如美國(guó),但是其在VTE高風(fēng)險(xiǎn)人群中的經(jīng)濟(jì)優(yōu)勢(shì)卻在增加;阿司匹林對(duì)比依諾肝素預(yù)防骨髓瘤患者VTE具有絕對(duì)經(jīng)濟(jì)優(yōu)勢(shì)。對(duì)于治療癌癥患者VTE,LMWH對(duì)比華法林在美國(guó)不具有成本-效用優(yōu)勢(shì),但是在加拿大和北歐等國(guó)家具有明顯的經(jīng)濟(jì)優(yōu)勢(shì);NOACs對(duì)比LMWH能節(jié)省總成本,但是美國(guó)和巴西的增量效果正負(fù)相反。敏感性分析顯示,經(jīng)濟(jì)學(xué)結(jié)果對(duì)藥物價(jià)格、血栓發(fā)生風(fēng)險(xiǎn)基線率以及不同干預(yù)下的不良事件(血栓復(fù)發(fā)、大出血、死亡)發(fā)生風(fēng)險(xiǎn)敏感,其中藥物價(jià)格和血栓發(fā)生基線率能夠逆轉(zhuǎn)結(jié)論。結(jié)論:對(duì)于預(yù)防癌癥患者VTE,與無(wú)干預(yù)或安慰劑相比,NOACs在不同國(guó)家、不同血栓風(fēng)險(xiǎn)人群中的經(jīng)濟(jì)性不同;華法林、LMWH的經(jīng)濟(jì)性尚未明確;阿司匹林對(duì)比依諾肝素的經(jīng)濟(jì)優(yōu)勢(shì)明顯。對(duì)于治療癌癥患者VTE,LMWH對(duì)比華法林在不同國(guó)家的經(jīng)濟(jì)優(yōu)勢(shì)不同;NOACs對(duì)比LMWH能節(jié)省成本。經(jīng)濟(jì)策略受不同國(guó)家的疾病發(fā)生風(fēng)險(xiǎn)、醫(yī)療體系、藥物價(jià)格、患者偏好和價(jià)值觀以及經(jīng)濟(jì)水平、成本-效用閾值標(biāo)準(zhǔn)等影響較大,最終的經(jīng)濟(jì)決策需要依據(jù)不同國(guó)家背景而定。

        關(guān)鍵詞 抗凝藥物;癌癥;靜脈血栓栓塞癥;藥物經(jīng)濟(jì)學(xué);系統(tǒng)評(píng)價(jià)

        中圖分類號(hào) R956 文獻(xiàn)標(biāo)志碼 A 文章編號(hào) 1001-0408(2021)07-0850-10

        ABSTRACT ? OBJECTIVE: To systematically review the pharmacoeconomics of anticoagulants for the prevention and therapy of venous thromboembolism (VTE) in cancer patients. METHODS: Retrieved from PubMed, Embase, Cochrane library, CNKI, Wanfang database, VIP, SinoMed, The NHS Economic Evaluation Database, The Healthy Technology Assessment Database and EconLit, supplemented by manual retrieval, the economic evaluation studies on the prevention and therapy of VTE in cancer patients with different anticoagulants were collected. The retrieval time was from the inception to Nov. 12th, 2020. After screening and extracting, the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) was used to evaluate the quality of the included literatures. The basic characteristics of the included literatures were summarized by descriptive methods, and the economic results were summarized according to medication purpose and different intervention grouping. RESULTS: A total of 15 literatures were included. Three literatures were of excellent quality; ten were of good quality; and the other two were of moderate quality. Included studies were widely conducted in countries of different economic levels, including China (1 piece), the United States (7 pieces), Canada (3 pieces), France (2 pieces), the Netherlands (1 piece), Brazil (1 piece) and Austria (1 piece). For preventing VTE in cancer patients, the economic evaluation results of warfarin and low-molecular-weight heparin (LMWH) needed to be updated.? Novel oral anticoagulants (NOACs) for the prevention of VTE were less cost-effective among cancer patients with medium- and high-risk venous thrombosis in China than in the United States, but the economic advantage increased among the high-risk patients. Compared to enoxaparin, aspirin was absolutely dominant to preventing VTE in patients with myeloma. For the treatment of VTE in cancer patients, LMWH was not cost-effective, compared to warfarin in the United States; but it was cost-effective in Canada and some countries of Northern Europe. Compared with LMWH, NOACs could save total cost, but the incremental utility in the United States and Brazil were opposite. Sensitivity analysis showed that economic results were sensitive to drug prices, the baseline rate of thrombosis risk, and the risk of adverse events (thrombosis recurrence, major bleeding and death) of different interventions, the first two of which could reverse the conclusions. CONCLUSIONS: For the prevention of VTE in cancer patients, compared with no intervention or placebo, the economic advantages of NOACs were different in different countries or for patients with different thrombosis risk; the economics of warfarin and LMWH were not yet clear. Aspirin had obvious economic advantages compared with enoxaparin. For the treatment of VTE in cancer patients, LMWH had different economic advantages compared with warfarin in different countries; NOACs could save costs compared with LMWH. Economic strategies are greatly affected by the risk of diseases, medical systems, drug price, patient preferences and values, economic levels, cost-utility threshold standards in different countries. Therefore, the final economic strategies need to be based on the contexts of different countries.

        KEYWORDS? ?Anticoagulants; Cancer; Venous thromboembolism; Pharmocoeconomics; Systematic review

        靜脈血栓栓塞癥(VTE)是造成癌癥患者死亡的重要原因之一,主要包括深靜脈血栓(DVT)和肺栓塞(PE)[1]。在癌癥患者中,VTE的累計(jì)發(fā)生率約為1%~8% ,是普通患者血栓風(fēng)險(xiǎn)的4.1倍[2]。同時(shí),癌癥相關(guān)血栓(CAT)患者在抗凝治療期間還面臨復(fù)發(fā)和出血的風(fēng)險(xiǎn)[1]。最近一項(xiàng)研究發(fā)現(xiàn),伴有VTE的癌癥患者住院率是不伴有VTE的癌癥患者的3倍,且醫(yī)療費(fèi)用增加了30 538美元[3]。因此,預(yù)防或治療癌癥患者VTE不僅需要考慮抗凝藥物的安全性和有效性,而且還需要關(guān)注其經(jīng)濟(jì)性。

        目前,用于防治VTE的抗凝藥物包括普通肝素(UFH)、低分子肝素(LMWH)、磺達(dá)肝癸鈉(Fondaparinux)、華法林(Warfarin)、新型口服抗凝劑(NOACs)等。最新國(guó)內(nèi)外指南均建議在血栓高風(fēng)險(xiǎn)(Khorana評(píng)分≥3)的門診化療癌癥患者以及多發(fā)性骨髓瘤患者中進(jìn)行VTE預(yù)防[2,4]。美國(guó)臨床腫瘤協(xié)會(huì)(ASCO)和國(guó)際血栓與止血學(xué)會(huì)(ISTH)相關(guān)指南建議采用利伐沙班(Rivaroxaban)作為癌癥患者VTE的一級(jí)預(yù)防用藥,該藥適用的癌癥患者范圍更廣泛,包括起始化療、血栓中高風(fēng)險(xiǎn)(Khorana評(píng)分≥2)、無(wú)藥物相互作用且無(wú)出血高風(fēng)險(xiǎn)(如胃腸道癌癥)的門診癌癥患者[1,5]。依據(jù)血栓發(fā)生部位和復(fù)發(fā)風(fēng)險(xiǎn),指南建議伴有VTE的癌癥患者的抗凝時(shí)間至少持續(xù)3~12個(gè)月,甚至無(wú)限期抗凝[2,4]。目前,針對(duì)癌癥患者防治VTE的抗凝藥物的有效性和安全性研究較多,但缺乏此類藥物經(jīng)濟(jì)性的相關(guān)研究[5-6]。因此,本文通過(guò)系統(tǒng)檢索、總結(jié)歸納防治癌癥患者VTE的抗凝藥物的經(jīng)濟(jì)學(xué)研究,為臨床合理用藥和醫(yī)藥衛(wèi)生決策提供經(jīng)濟(jì)學(xué)依據(jù)。

        1 資料與方法

        1.1 納入與排除標(biāo)準(zhǔn)

        1.1.1 納入標(biāo)準(zhǔn)

        (1)研究類型:防治癌癥患者VTE的抗凝藥物的經(jīng)濟(jì)學(xué)分析,包括成本-效果分析、成本-效用分析、成本-效益分析和最小成本分析等;(2)語(yǔ)種:限定為中、英文。

        1.1.2 研究對(duì)象

        (1)癌癥患者,伴有或不伴有VTE;(2)非癌癥外科圍手術(shù)期抗凝的患者。

        1.1.3 干預(yù)措施

        美國(guó)國(guó)家綜合癌癥網(wǎng)絡(luò)臨床實(shí)踐指南《癌癥相關(guān)性靜脈血栓栓塞性疾?。?020.V1)》[4]和中國(guó)《腫瘤相關(guān)靜脈血栓栓塞癥預(yù)防與治療指南(2019版)》[2]推薦的預(yù)防或治療VTE用藥,包括UFH、LMWH、磺達(dá)肝癸鈉、華法林、利伐沙班、艾多沙班(Edoxaban)、阿哌沙班(Apixaban)等;對(duì)于預(yù)防用藥,其對(duì)照干預(yù)措施除了上述藥物外,還可以為無(wú)干預(yù)或安慰劑或預(yù)防骨髓瘤患者VTE的阿司匹林(Aspirin)。

        1.1.4 結(jié)局指標(biāo)

        成本、質(zhì)量調(diào)整生命年(QALYs)、增量成本-效果比(ICER)、增量成本-效用比(ICER)等經(jīng)濟(jì)學(xué)評(píng)價(jià)指標(biāo)。

        1.1.5 排除標(biāo)準(zhǔn)

        (1)研究對(duì)象不符合的文獻(xiàn);(2)干預(yù)措施不包括抗凝藥物的文獻(xiàn);(3)經(jīng)濟(jì)學(xué)評(píng)價(jià)指標(biāo)不明確的文獻(xiàn);(4)綜述、摘要以及其他無(wú)法獲取全文的文獻(xiàn)。

        1.2 文獻(xiàn)檢索策略

        計(jì)算機(jī)檢索中外醫(yī)學(xué)、衛(wèi)生技術(shù)評(píng)估、經(jīng)濟(jì)學(xué)數(shù)據(jù)庫(kù),如PubMed、Embase、Cochrane圖書館、中國(guó)知網(wǎng)、萬(wàn)方數(shù)據(jù)、維普網(wǎng)、中國(guó)生物醫(yī)學(xué)文獻(xiàn)服務(wù)系統(tǒng)(SinoMed)以及The NHS Economic Evaluation Database(NHS EED)、The Healthy Technology Assessment Database(HTA)、EconLit等,并對(duì)檢索到的相關(guān)綜述文獻(xiàn)輔以手工檢索;檢索時(shí)限為各數(shù)據(jù)庫(kù)建庫(kù)至2020年11月12日。采用主題詞、關(guān)鍵詞和自由詞相結(jié)合的檢索方式,依具體數(shù)據(jù)庫(kù)調(diào)整。英文檢索主題詞為“Cost-benefit analysis”“Anticoagulants”“Thromboembolism”“Neoplasms”,關(guān)鍵詞及自由詞為“Cost benefit”“Cost utility”“Cost effectiveness”“Cost analysis”“Economic”“Pharmacoeconomic”“Marginal”“Heparin”“Dicumarol”“Coumarins”“NOACs”“DOACs”“UFH”“LMWH”“Enoxaparin”“Dalteparin”“Tinzaparin”“Warfarin”“Vitamin K antagonist”“Fondaparinux”“Rivaroxaban”“Edoxaban”“Apixaban”“Dabigatran”“Aspirin”“Venous”“Thrombosis”“Embolism”“VTE”“DVT”“PE”“Tumor”“Cancer”;中文檢索詞為與之對(duì)應(yīng)詞。以Cochrane圖書館為例,檢索策略如圖1所示。

        1.3 數(shù)據(jù)提取

        按照上述納入與排除標(biāo)準(zhǔn),由2名研究者獨(dú)立收集文獻(xiàn)和提取數(shù)據(jù);若存在分歧,則由第3名研究者進(jìn)行評(píng)審。總結(jié)、提取納入文獻(xiàn)的第一作者、時(shí)間、研究對(duì)象、干預(yù)措施、評(píng)價(jià)方法和經(jīng)濟(jì)學(xué)評(píng)價(jià)結(jié)果等信息。

        1.4 文獻(xiàn)質(zhì)量評(píng)價(jià)

        采用衛(wèi)生經(jīng)濟(jì)評(píng)估報(bào)告標(biāo)準(zhǔn)清單(CHEERS)評(píng)估文獻(xiàn)報(bào)告質(zhì)量[7]。該清單包括“題目與摘要”“介紹”“方法”“結(jié)果”“討論”“其他”等6個(gè)部分——若文獻(xiàn)完全符合標(biāo)準(zhǔn),記1分;若不滿足或不充分,記0分;其他,記“不適用”。對(duì)于“討論”部分,若文獻(xiàn)同時(shí)滿足“結(jié)果”和“局限性”2項(xiàng),且至少滿足“適用性”或“當(dāng)前知識(shí)”中的1項(xiàng),記1分。評(píng)價(jià)結(jié)果以總得分占最大可能得分的百分比表示,分為優(yōu)秀(100%符合)、良好(75%~99%符合)、適中(50%~74%符合)和偏低(不足50%符合)等4個(gè)等級(jí)[7]。由2名研究者打分,存在分歧時(shí)請(qǐng)第3名研究者判斷后打分。為確保研究文獻(xiàn)的質(zhì)量可靠性,剔除質(zhì)量等級(jí)為“偏低”的文獻(xiàn)。

        1.5 數(shù)據(jù)處理

        采用描述性的方法總結(jié)文獻(xiàn)的基本特征,按照用藥目的和不同干預(yù)分組歸納所納入文獻(xiàn)的經(jīng)濟(jì)學(xué)結(jié)果。

        2 結(jié)果

        2.1 文獻(xiàn)檢索結(jié)果

        從各數(shù)據(jù)庫(kù)中共檢索出文獻(xiàn)703篇,去重后剩余550篇;經(jīng)標(biāo)題和摘要初篩后獲得44篇;閱讀全文后最終納入15篇。文獻(xiàn)檢索流程與結(jié)果如圖2所示。

        2.2 納入文獻(xiàn)的基本特征

        共納入15篇文獻(xiàn)[8-22],發(fā)表于1995-2020年;美國(guó)7篇[9-10,12,15,18-19,21],加拿大3篇[8,11,16],法國(guó)2篇[13,17],中國(guó)[20]、荷蘭[14]、巴西[22]、奧地利[17]各1篇。其中,5篇研究分析了預(yù)防癌癥患者VTE的藥物的經(jīng)濟(jì)性[8,12-13,20-21],1篇研究分析了癌癥患者住院治療VTE的短期經(jīng)濟(jì)性[9],其余9篇研究分析了治療癌癥患者VTE并進(jìn)行擴(kuò)展預(yù)防的藥物的經(jīng)濟(jì)性[10-11,14-19,22]。進(jìn)行比較的藥物包括UFH、華法林、LMWH、NOACs和阿司匹林,其中LMWH包括依諾肝素(Enoxaparin)和達(dá)肝素(Dalteparin),NOACs包括利伐沙班、阿哌沙班和艾多沙班。最早發(fā)表的2篇研究的評(píng)價(jià)方法采用的是最小成本分析[8-9],其余13篇文獻(xiàn)均進(jìn)行了成本-效用分析[10-22]。研究時(shí)限為4個(gè)月至終生。納入文獻(xiàn)的基本特征如表1所示。

        2.3 納入文獻(xiàn)的質(zhì)量評(píng)價(jià)

        所有文獻(xiàn)均符合CHEERS清單報(bào)告要求[7]。其中,3篇評(píng)分為100%[11,14,16],質(zhì)量?jī)?yōu)秀;10篇評(píng)分為75%~99%[8-10,12-13,17,19-22],質(zhì)量良好;其余2篇評(píng)分分別為72%和63%[15,18],質(zhì)量適中。所有納入文獻(xiàn)的“前言”和“討論”部分得分均為100%,“方法”部分存在的問(wèn)題主要是未闡述模型、研究角度和研究時(shí)限的選擇理由,對(duì)比較對(duì)象的用法用量、參數(shù)分析方法以及效果來(lái)源的描述不充分。4篇文獻(xiàn)未體現(xiàn)貼現(xiàn)率[9,12,16,18],其中3篇研究時(shí)限不足1年[9,16,18]。“結(jié)果”部分存在的問(wèn)題主要是不確定性分析不夠全面。只有最早發(fā)表的2篇文獻(xiàn)未完全體現(xiàn)“資金來(lái)源”和“利益沖突”條目[8-9]。

        2.4 納入文獻(xiàn)的主要臨床效果

        納入文獻(xiàn)的主要臨床效果來(lái)源如表1所示。

        Avritscher等[9]通過(guò)收集病歷建立回顧性隊(duì)列以獲得臨床效果。該研究通過(guò)匹配試驗(yàn)組和對(duì)照組患者的年齡、腫瘤表現(xiàn)、分期以及VTE病史等因素來(lái)降低組間異質(zhì)性,但由于達(dá)肝素組樣本量過(guò)小,故假設(shè)達(dá)肝素的臨床效果與UFH一致。其余研究的臨床效果主要源于臨床RCT和Meta分析[8,10-22]。當(dāng)研究時(shí)限超出RCT的隨訪時(shí)間后,Li等[19,21]的研究在模型中使用了大型流行病學(xué)研究方法以及美國(guó)生命表數(shù)據(jù)來(lái)模擬隨時(shí)間變化的轉(zhuǎn)移概率[31,36-37]。

        文獻(xiàn)研究結(jié)果顯示,對(duì)于預(yù)防癌癥患者VTE,與安慰劑或無(wú)干預(yù)預(yù)防比較,使用4、6個(gè)月的VLDW、LMWH以及低劑量NOACs均能有效降低VTE發(fā)生率,但不會(huì)明顯降低患者病死率,其中低劑量NOACs的出血風(fēng)險(xiǎn)更高[23,25,34-35]。AVERT研究表明,相比于安慰劑,阿哌沙班能夠明顯提高患者的大出血率[3.5% vs. 1.8%;HR=2.00,95%CI(1.01,3.95),P=0.046],其中胃腸道或婦科癌癥患者的出血風(fēng)險(xiǎn)更高[32]?;贑ASSINI、AVERT研究的Meta分析和累積分析結(jié)果均表明,在具有VTE中高風(fēng)險(xiǎn)(Khorana評(píng)分≥2)的化療癌癥患者中,低劑量NOACs(如阿哌沙班、利伐沙班)較安慰劑有增加出血風(fēng)險(xiǎn)的趨勢(shì),但差異無(wú)統(tǒng)計(jì)學(xué)意義[32-35]。Li等[35]的Meta分析顯示,低劑量NOACs在VTE高風(fēng)險(xiǎn)癌癥患者中的療效優(yōu)于VTE低風(fēng)險(xiǎn)組。在骨髓瘤患者中,阿司匹林與依諾肝素預(yù)防癌癥患者VTE的療效和安全性無(wú)明顯差異[26]。

        對(duì)于治療癌癥患者VTE,CLOT研究以及Meta分析結(jié)果均顯示,與華法林相比,LMWH可明顯降低VTE復(fù)發(fā)率,同時(shí)不提高出血率,其中中重度腎損傷患者療效受益更加明顯(3% vs. 17%;P=0.011)[15,24,27]?;贖okusai VTE cancer和SELECT-D研究的Meta分析顯示,NOACs降低VTE復(fù)發(fā)的療效優(yōu)于達(dá)肝素,但前者可增加大出血的風(fēng)險(xiǎn)[28-29],其中胃腸道癌癥患者的出血風(fēng)險(xiǎn)更高[30]。Raskob等[38]的研究結(jié)果顯示,艾多沙班降低VTE復(fù)發(fā)率的療效不劣于華法林,同時(shí)未提高出血率。上述研究均未能證實(shí)不同干預(yù)下癌癥患者的病死率存在明顯差異。

        2.5 納入文獻(xiàn)的經(jīng)濟(jì)學(xué)評(píng)價(jià)結(jié)果

        2.5.1 癌癥患者VTE預(yù)防用藥

        Rajan等[8]的研究表明,在初始化療的轉(zhuǎn)移性乳腺癌患者中,與使用安慰劑相比,每100名患者連續(xù)使用6個(gè)月VLDW的藥物成本增加了21 854加元,但不良反應(yīng)成本減少了24 297加元,最終總成本減少了2 433加元。

        Pishko等[12]的研究表明,在門診癌癥患者中,當(dāng)死亡相對(duì)風(fēng)險(xiǎn)為0.920時(shí),若選取較高的成本-效用閾值(以下簡(jiǎn)稱“閾值”)即100 000美元,與無(wú)干預(yù)相比,使用依諾肝素4個(gè)月更具有成本-效用優(yōu)勢(shì);但是不建議將干預(yù)時(shí)間延長(zhǎng)至24個(gè)月,除非死亡相對(duì)風(fēng)險(xiǎn)低于0.762。

        Du等[20]和Li等[21]分別基于中國(guó)和美國(guó)背景研究了在具有VTE中高風(fēng)險(xiǎn)(Khorana評(píng)分≥2)的化療癌癥患者中預(yù)防性使用低劑量NOACs 6個(gè)月的長(zhǎng)期經(jīng)濟(jì)性。這2項(xiàng)研究均表明,與安慰劑相比,低劑量NOACs的QALYs更高。在中國(guó),當(dāng)以人均國(guó)內(nèi)生產(chǎn)總值(GDP)的1倍作為閾值時(shí),NOACs不具有成本-效用優(yōu)勢(shì);而在美國(guó),NOACs與安慰劑相比的ICER遠(yuǎn)低于閾值,具有明顯的成本-效用優(yōu)勢(shì);此外,無(wú)論中國(guó)還是美國(guó),NOACs在VTE高風(fēng)險(xiǎn)(Khorana評(píng)分≥3)亞組患者中的成本-效用優(yōu)勢(shì)均明顯增加。鑒于目前NOACs在中國(guó)價(jià)格偏高,Du等[20]的研究并不強(qiáng)烈推薦使用NOACs來(lái)預(yù)防VTE,最終應(yīng)根據(jù)癌癥患者的病死率、血栓和出血風(fēng)險(xiǎn)調(diào)整預(yù)防策略。

        Chalayer等[13]的研究表明,在接受沙利度胺治療的新確診多發(fā)性骨髓瘤患者中,與依諾肝素相比,使用阿司匹林預(yù)防VTE 6個(gè)月不僅能降低成本,而且能夠提高患者的生存質(zhì)量,具有絕對(duì)經(jīng)濟(jì)優(yōu)勢(shì)。

        癌癥患者VTE預(yù)防用藥的經(jīng)濟(jì)學(xué)評(píng)價(jià)結(jié)果如表2所示。

        2.5.2 癌癥患者VTE治療用藥

        (1)LMWH對(duì)比華法林:美國(guó)的2項(xiàng)研究均表明,在伴有VTE的癌癥患者中,LMWH的QALYs較華法林更高;但LMWH的藥物成本過(guò)高,使其與華法林相比的ICER遠(yuǎn)超過(guò)其閾值,因此華法林更加經(jīng)濟(jì)[10,15]。

        然而,Dranitsaris等[11,14,16-17]的系列研究顯示,在加拿大以及荷蘭、法國(guó)和奧地利等北歐國(guó)家,相比華法林,LMWH治療癌癥患者VTE 6個(gè)月的成本-效用優(yōu)勢(shì)更加明顯。在中重度腎損傷癌癥患者中,LMWH具有潛在的絕對(duì)經(jīng)濟(jì)優(yōu)勢(shì)[14,16-17]。Dranitsaris等[11]對(duì)前瞻性臨床試驗(yàn)CLOT研究的患者個(gè)體數(shù)據(jù)進(jìn)行了多因素分析,發(fā)現(xiàn)達(dá)肝素干預(yù)、男性、年齡和癌癥表現(xiàn)狀態(tài)等因素能夠明顯影響藥物治療成本,其中達(dá)肝素干預(yù)、男性均可導(dǎo)致患者治療成本增加;且患者年齡越大、腫瘤表現(xiàn)狀態(tài)評(píng)分越差,其病死率更高,可能導(dǎo)致總成本降低。

        從上述2種策略的成本組成來(lái)看,達(dá)肝素干預(yù)的藥物成本占比最多,遠(yuǎn)遠(yuǎn)超過(guò)華法林(46%~67% vs. 3%~13%)[11,14-15],而華法林的VTE治療成本和實(shí)驗(yàn)室監(jiān)測(cè)成本占比最多[11]。

        LMWH對(duì)比華法林治療癌癥患者VTE的經(jīng)濟(jì)學(xué)評(píng)價(jià)結(jié)果如表3所示。

        (2)NOACs對(duì)比LMWH、華法林以及其他藥物:在美國(guó)和巴西,NOACs較達(dá)肝素治療癌癥患者VTE更能節(jié)省成本[18-19,22]。不同的是,在美國(guó),NOACs的QALYs略低于達(dá)肝素,但由于其成本遠(yuǎn)低于LMWH而具有經(jīng)濟(jì)性[18-19];而在巴西,NOACs的QALYs高于達(dá)肝素,因此NOACs是絕對(duì)經(jīng)濟(jì)策略[22]。無(wú)論是否針對(duì)胃腸道癌癥患者,NOACs均因成本遠(yuǎn)遠(yuǎn)低于LMWH而更經(jīng)濟(jì)[18-19]。胃腸道癌癥患者使用NOACs的總成本因出血風(fēng)險(xiǎn)的增加而增加,但不足以使LMWH對(duì)比NOACs的ICER低于閾值[18]。

        Lopes等[22]的研究表明,當(dāng)以巴西人均GDP的3倍作為閾值時(shí),與華法林比較,艾多沙班治療癌癥患者VTE具有明顯成本-效用優(yōu)勢(shì)。

        Avritscher等[9]的研究表明,在因VTE的住院治療中,與UFH比較,達(dá)肝素能夠通過(guò)縮短癌癥患者住院時(shí)間和減少其監(jiān)測(cè)次數(shù)而具有最小成本。

        NOACs對(duì)比LMWH、華法林以及其他藥物治療癌癥患者VTE的經(jīng)濟(jì)學(xué)評(píng)價(jià)結(jié)果如表4所示。

        2.6 敏感性分析結(jié)果

        納入文獻(xiàn)均進(jìn)行了敏感性分析,結(jié)果如表2~表4所示。其中,14篇文獻(xiàn)進(jìn)行了單因素分析[8-17,19-22],2篇進(jìn)行了雙因素分析[12,18],3篇進(jìn)行了情境分析[19,20-21],6篇進(jìn)行了PSA[10,12,19-22]。

        2.6.1 癌癥患者VTE預(yù)防用藥

        對(duì)于預(yù)防癌癥患者VTE,藥物成本是經(jīng)濟(jì)策略的共同驅(qū)動(dòng)因素[8,12,20-21]。Rajan等[8]的研究顯示,增量成本對(duì)VTE治療成本、華法林療效、大出血等不良事件發(fā)生相對(duì)風(fēng)險(xiǎn)敏感,即當(dāng)不良事件發(fā)生率提高、VTE的治療成本降低時(shí),VLDW的經(jīng)濟(jì)優(yōu)勢(shì)會(huì)進(jìn)一步降低。Pishko等[12]的研究表明,依諾肝素對(duì)比安慰劑的死亡相對(duì)風(fēng)險(xiǎn)是驅(qū)動(dòng)經(jīng)濟(jì)結(jié)果的關(guān)鍵因素,而依諾肝素效果對(duì)其ICER的影響并不明顯。

        無(wú)論在中國(guó)還是美國(guó),低劑量NOACs對(duì)比安慰劑的ICER對(duì)發(fā)生VTE、MB和死亡事件的相對(duì)風(fēng)險(xiǎn)等因素高度敏感,而對(duì)藥物成本、預(yù)防時(shí)間和患者5年生存率變化等因素的敏感程度較小[20-21]。在中國(guó),癌癥人群的VTE風(fēng)險(xiǎn)基線率會(huì)逆轉(zhuǎn)NOACs對(duì)比安慰劑的經(jīng)濟(jì)學(xué)結(jié)論[20]。PSA結(jié)果顯示,NOACs在美國(guó)具有成本-效用優(yōu)勢(shì)的概率明顯高于中國(guó)(94% vs. 42%~55%)[20-21]。除VTE風(fēng)險(xiǎn)基線率外,其他參數(shù)的變化不會(huì)改變低劑量NOACs對(duì)比安慰劑的經(jīng)濟(jì)決策[20-21]。

        2.6.2 癌癥患者VTE治療用藥

        藥物成本始終是美國(guó)治療癌癥患者VTE經(jīng)濟(jì)策略的主要驅(qū)動(dòng)因素[10,15,18-19],而對(duì)其他國(guó)家的影響不明顯。在美國(guó),相比華法林或者NOACs,當(dāng)達(dá)肝素價(jià)格降低或者替換為更便宜的依諾肝素時(shí),LMWH可能逆轉(zhuǎn)原先不經(jīng)濟(jì)的結(jié)論[10,18-19]。LMWH對(duì)比華法林、NOACs的ICER對(duì)干預(yù)下的死亡相對(duì)風(fēng)險(xiǎn)敏感[10,19],當(dāng)死亡相對(duì)風(fēng)險(xiǎn)降低時(shí),經(jīng)濟(jì)策略有利于LMWH。在NOACs對(duì)比LMWH的經(jīng)濟(jì)學(xué)評(píng)價(jià)中,研究時(shí)限(12、60個(gè)月)對(duì)增量成本影響較大,干預(yù)下的死亡相對(duì)風(fēng)險(xiǎn)和相對(duì)效用值對(duì)增量效果影響較明顯[19]。然而,PSA結(jié)果顯示,盡管ICER隨上述參數(shù)(除成本外)變化,但是不會(huì)改變最終的經(jīng)濟(jì)決策[10,18-19]。

        3 討論

        VTE是癌癥的嚴(yán)重并發(fā)癥之一,增加了患者的額外負(fù)擔(dān)[3]。因此,本研究對(duì)抗凝藥物防治癌癥患者VTE的經(jīng)濟(jì)學(xué)研究進(jìn)行了系統(tǒng)評(píng)價(jià),并從經(jīng)濟(jì)學(xué)角度探討了不同抗凝藥物預(yù)防和治療癌癥患者VTE的優(yōu)劣以及影響其經(jīng)濟(jì)性的因素。

        本研究發(fā)現(xiàn),對(duì)于初始化療或具有VTE中高風(fēng)險(xiǎn)(Khorana評(píng)分≥2)的癌癥患者,預(yù)防性抗凝均能改善患者的生存質(zhì)量,并且在合理的預(yù)防時(shí)間內(nèi)具有成本-效用優(yōu)勢(shì)[8,12-13,20-21]。Li等[21]通過(guò)經(jīng)濟(jì)學(xué)研究發(fā)現(xiàn),低劑量NOACs在抗凝結(jié)束(6個(gè)月)與之后5年的臨床結(jié)局相似,提示早期預(yù)防對(duì)癌癥患者具有長(zhǎng)期積極作用。當(dāng)患者血栓風(fēng)險(xiǎn)趨于平穩(wěn)后,若延長(zhǎng)預(yù)防時(shí)間,成本和效果可能同時(shí)增加,但邊際效應(yīng)降低,最終導(dǎo)致方案不再具有經(jīng)濟(jì)性[12,21]。

        相比無(wú)干預(yù)或安慰劑,華法林和LMWH的流行病學(xué)更新數(shù)據(jù)顯示,兩者預(yù)防癌癥患者VTE的出血風(fēng)險(xiǎn)明顯增加,而患者病死率沒(méi)有明顯降低[39-40]。這將降低預(yù)防策略的經(jīng)濟(jì)優(yōu)勢(shì),也提示需要根據(jù)最新證據(jù)和當(dāng)前經(jīng)濟(jì)水平重新評(píng)估華法林和LMWH預(yù)防VTE的經(jīng)濟(jì)性。低劑量NOACs對(duì)比安慰劑預(yù)防癌癥患者VTE的臨床效果源自AVERT研究和CASSINI研究,其對(duì)患者的VTE風(fēng)險(xiǎn)分層均是基于Khorana風(fēng)險(xiǎn)評(píng)估模型[32-33]。該模型存在一定的不足之處,例如在肺癌中表現(xiàn)不佳、未考慮化療方案等[34],因此風(fēng)險(xiǎn)評(píng)估模型的局限性可能會(huì)影響評(píng)價(jià)結(jié)果的適用性。

        對(duì)于治療癌癥患者VTE,LMWH對(duì)比華法林在不同國(guó)家的價(jià)格差異十分明顯,因而經(jīng)濟(jì)策略不同[10-11,14-19,22]。NOACs對(duì)比LMWH的價(jià)格優(yōu)勢(shì)可減少VTE復(fù)發(fā)的療效,抵消NOACs導(dǎo)致的出血成本[28,30]。因此,NOACs對(duì)比LMWH能夠明顯節(jié)省成本。需要注意的是,NOACs在胃腸道癌癥患者中的出血風(fēng)險(xiǎn)較高,因此國(guó)內(nèi)外指南均不推薦將NOACs應(yīng)用于此類患者[2,4]。存在爭(zhēng)議的是,NOACs對(duì)比LMWH的增量QALYs在美國(guó)為負(fù)值,而在巴西為正值,這可能與不同國(guó)家患者用藥偏好和療效偏好的差異有關(guān):首先,NOACs可直接口服,能減少注射帶來(lái)的痛苦;再者,Hokusai-VTE Cancer研究和相關(guān)Meta分析結(jié)果均顯示,NOACs對(duì)比LMWH雖然會(huì)增加出血風(fēng)險(xiǎn),但是也會(huì)降低VTE復(fù)發(fā)率,出血風(fēng)險(xiǎn)和療效對(duì)QALYs的影響恰好相反[28,30]。德國(guó)和英國(guó)的2項(xiàng)研究顯示,無(wú)論是癌癥患者還是護(hù)理者均會(huì)優(yōu)先權(quán)衡抗凝藥物的療效和出血風(fēng)險(xiǎn),并且在血栓和出血風(fēng)險(xiǎn)相似的前提下,才傾向于選擇口服用藥的方式[41-42]。然而,這可能與中低收入國(guó)家(例如巴西)的患者選擇偏好存在差異。目前,尚缺乏相關(guān)研究直接評(píng)估癌癥患者對(duì)NOACs和LMWH的選擇偏好。

        藥物成本是防治癌癥患者VTE經(jīng)濟(jì)策略的主要驅(qū)動(dòng)因素[8,10,12,15,18-21]。對(duì)于預(yù)防癌癥患者VTE,降低藥物成本必然增加預(yù)防策略的經(jīng)濟(jì)性,尤其是對(duì)于VTE高風(fēng)險(xiǎn)(Khorana評(píng)分≥3)的癌癥患者。其中,LMWH的經(jīng)濟(jì)學(xué)評(píng)價(jià)結(jié)果對(duì)價(jià)格高度敏感[10,12,15,18-19]。目前,國(guó)內(nèi)臨床廣泛應(yīng)用的LMWH選擇多、價(jià)格各異,并且不同的LMWH的臨床效果也可能存在差異[43-44]。因此,基于真實(shí)世界的醫(yī)療數(shù)據(jù)對(duì)不同LMWH之間以及LMWH與口服抗凝藥進(jìn)行經(jīng)濟(jì)學(xué)評(píng)價(jià)具有實(shí)際價(jià)值。其他影響評(píng)價(jià)結(jié)果的因素主要是不同干預(yù)下發(fā)生或復(fù)發(fā)VTE、大出血和死亡的相對(duì)風(fēng)險(xiǎn)。當(dāng)試驗(yàn)組對(duì)比對(duì)照組的不良事件發(fā)生率降低時(shí),增量效果增加[8,10,12,19-21]。目前,尚無(wú)臨床證據(jù)確切表明任何抗凝策略能夠明顯降低癌癥患者的病死率[6,27,30,39-40,45]。

        本研究尚存在一定局限性:一是只檢索已發(fā)表的文獻(xiàn),未納入灰色文獻(xiàn);二是納入文獻(xiàn)質(zhì)量不齊;三是經(jīng)濟(jì)學(xué)結(jié)果無(wú)法定量分析。由于研究人群、方法等不一致,并且沒(méi)有華法林、LMWH和NOACs之間的直接比較,所以本研究未能得出何種抗凝藥物預(yù)防癌癥患者VTE最經(jīng)濟(jì)。此外,本研究納入的NOACs 對(duì)比華法林的直接比較研究較少。目前,華法林由于價(jià)格低廉,可能在低收入地區(qū)更常用。隨著NOACs的廣泛應(yīng)用及其在價(jià)格和療效上的優(yōu)勢(shì)逐漸凸顯,該藥相比華法林在低收入地區(qū)可能將更具有經(jīng)濟(jì)優(yōu)勢(shì)。因此,需要進(jìn)一步研究證實(shí)NOACs對(duì)比華法林治療癌癥患者VTE的經(jīng)濟(jì)性。

        綜上,防治癌癥患者VTE的藥物經(jīng)濟(jì)學(xué)評(píng)價(jià)結(jié)果受不同國(guó)家的醫(yī)療體系、藥物價(jià)格、患者偏好和價(jià)值觀以及經(jīng)濟(jì)水平、閾值標(biāo)準(zhǔn)等影響明顯,缺乏一致性和可比性;而且,各國(guó)的疾病發(fā)生風(fēng)險(xiǎn)、治療指南、臨床路徑以及醫(yī)師用藥習(xí)慣等亦存在差異。因此,國(guó)外研究結(jié)果并不完全適用于國(guó)內(nèi),亟需開(kāi)展更多中國(guó)人群防治癌癥患者VTE的藥物經(jīng)濟(jì)學(xué)研究,為我國(guó)臨床決策和藥品政策制定提供可靠證據(jù)。

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        (收稿日期:2020-11-17 修回日期:2021-03-15)

        (編輯:胡曉霖)

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