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ENGLISH ABSTRACT
噻托溴铵喷雾剂治疗慢性阻塞性肺疾病的有效性与安全性荟萃分析
蔡华丹
侯均
吕永宁
熊亮
路明忠
伍三兰
作者及单位信息
·
DOI： 10.3760/cma.j.issn.1001-0939.2017.08.011
Efficacy and safety of tiotropium Respimat in the treatment of chronic obstructive pulmonary disease: systematic review
Cai Huadan
Hou Jun
Lyu Yongning
Xiong Liang
Lu Mingzhong
Wu Sanlan
Authors Info & Affiliations
Cai Huadan
Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
Hou Jun
Lyu Yongning
Xiong Liang
Lu Mingzhong
Wu Sanlan
·
DOI： 10.3760/cma.j.issn.1001-0939.2017.08.011
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摘要

目的系统评价噻托溴铵喷雾剂治疗慢性阻塞性肺疾病(慢阻肺)的疗效和安全性。

方法以"tiotropium respimat"、"tiotropium bromide spray"、"chronic obstructive pulmonary disease"、"COPD"、"randomized"、"controlled"、"randomly"为英文检索词，"噻托溴铵喷雾剂"、"慢阻肺"、"慢性阻塞性肺疾病"、"随机对照"为中文检索词，分别检索Cochrane Library、PubMed、EMbase、中国知网、维普数据、中国生物医学文献数据库和万方数据，各数据库检索时间均从建库至2016年10月。按照Cochrane系统评价方法检索噻托溴铵喷雾剂治疗慢阻肺的所有随机对照试验(RCT)，2名研究者按照纳入排除标准进行数据提取和质量评价，采用RevMan 5.3软件进行统计分析。

结果共纳入11个RCT研究，对文献进行不同指标分析：在改善患者FEV 1水平方面，噻托溴铵喷雾剂组(5 μg/吸)优于安慰剂组[ MD＝0.12，95% CI(0.10～0.14)， P<0.01]。不同剂量噻托溴铵喷雾剂组均与粉吸入剂组疗效相似[5 μg: MD＝0.00，95% CI(－0.04～0.04)， P＝0.94；2.5 μg： MD＝－0.04，95% CI(－0.10～0.01)， P＝0.12；10 μg： MD＝0.02，95% CI(－0.06～0.09)， P＝0.66]。在改善患者FVC水平方面，噻托溴铵喷雾剂组(5 μg/吸)优于安慰剂组[ MD＝0.18，95% CI(0.09～0.28)， P<0.01]。不同剂量噻托溴铵喷雾剂组与粉吸入剂组疗效相似[2.5 μg： MD＝－0.06，95% CI(－0.16～0.04)， P＝0.24；5 μg： MD＝－0.00, 95% CI(－0.08～0.08)， P＝1.00；10 μg： MD＝0.02，95% CI(－0.14～0.19)， P＝0.78]。在急性加重风险方面，噻托溴铵喷雾剂组(5 μg/吸)发生急性加重的风险较安慰剂组低[ OR＝0.72, 95% CI(0.60～0.86)， P<0.01]。噻托溴铵喷雾剂组(5 μg/吸)和粉吸入剂组发生急性加重风险相似[ OR＝1.01, 95% CI(0.94～1.09)， P＝0.71]。圣乔治呼吸问卷评分上，噻托溴铵喷雾剂组(5 μg/吸)优于安慰剂组[ MD＝－3.6, 95% CI(－3.88～－3.32)， P<0.01]。噻托溴铵喷雾剂组(5 μg/吸)和粉吸入剂组在稳态时的最大血药浓度、血药浓度-时间曲线下面积均相似[ MD＝0.2, 95% CI(－5.1～5.5)， P＝0.94]； MD＝－1.01, 95% CI(－11.78～9.77)， P＝0.85]。安全性部分纳入9项RCT研究，噻托溴铵喷雾剂组(5 μg/吸)与安慰剂组及粉吸入剂组的不良反应发生率均相似[ RR＝0.95, 95% CI(0.89～1.00)， P＝0.05， OR＝1.07, 95% CI(1.00～1.16)， P＝0.06]。

结论噻托溴铵喷雾剂与粉吸入剂具有相似的疗效，均能有效改善慢阻肺患者肺功能及临床症状，且安全性较好；但其远期疗效及安全性有待长期随访的RCT研究结果验证。

噻托溴铵;肺疾病，慢性阻塞性;系统评价;随机对照试验
ABSTRACT

ObjectiveTo evaluate the efficacy and safety of tiotropium Respimat in the treatment of chronic obstructive pulmonary disease (COPD) according to the Cochrane systematic evaluation.

MethodsThe Cochrane Library, PubMed, EMbase, CNKI, VIP and CBM, Wanfang Data were searched(from the foundation date to Jan. 2016) for the randomized controlled trials (RCTs) of tiotropium Respimat in the treatment of patients with COPD. Two reviewers independently retrieved the RCTs according to the inclusion and exclusion criteria, assessed the methodological quality of the included trials.and performed statistical analysis on the data using RevMan 5.3 software.

ResultsTotally 11 RCTs on efficacy were finally included.The results of the combined analysis showed that FEV 1 was significantly improved in the tiotropium Respimat group than that in the placebo group[ MD=0.12, 95% CI(0.10-0.14), P<0.000 01], while FEV 1 was similar between the tiotropium Respimat group and the tiotropium HandiHaler group[5 μg: MD=0.00, 95% CI(-0.04-0.04), P=0.94; 2.5 μg: MD=-0.04, 95% CI(-0.10-0.01), P=0.12; 10 μg: MD=0.02, 95% CI(-0.06-0.09), P=0.66]. FVC was significantly improved in the tiotropium Respimat group than that in the placebo group[ MD=0.18, 95% CI(0.09-0.28), P=0.0002], while FVC was similar between the tiotropium Respimat group and the HandiHaler group[2.5 μg: MD=-0.06, 95% CI(-0.16-0.04), P=0.24; 5 μg: MD=-0.00, 95% CI(-0.08-0.08), P=1.00; 10 μg: MD=0.02, 95% CI(-0.14-0.19), P=0.78]. The risk of acute exacerbations was lower in the tiotropium Respimat group (5 μg / kg) than in the placebo group [ OR=0.72, 95% CI(0.60-0.86), P=0.000 3]. It was similar in the tiotropium Respimat group (5 μg) and the HandiHaler group[ OR=1.01, 95% CI(0.94-1.09), P=0.71]. The SGRQ total score of the tiotropium Respimat group (5 μg) was significantly different from that of the placebo group[ MD=-3.6, 95% CI(-3.88--3.32), P<0.000 01]. C max, ss and AUC 0-6 h, ss were also similar between the tiotropium Respimat group and the HandiHaler group[ MD=0.2, 95% CI(-5.1-5.5), P=0.94]; MD=-1.01, 95% CI(-11.78-9.77), P=0.85]. Nine RCTs were included in the evaluation of the incident rates of adverse drug reactions(ADR). There was no significant difference between the tiotropium Respimat group HandiHaler group and the placebo group[ RR=0.95, 95% CI(0.89-1.00), P=0.05], [ OR=1.07, 95% CI(1.00-1.16), P=0.06].

ConclusionsThe efficacy and safety of tiotropium Respimat was similar to tiotropium HandiHaler in the treatment of COPD. They can effectively improve the pulmonary function and clinical symptoms of patients. But the long-term efficacy and safety of tiotropium Respimat still need to be confirmed by higher quality and larger RCTs with long-term follow-up.

Tiotropium Respimat;Pulmonary disease, chronic obstructive;Systematic review;Randomized controlled trial
Wu Sanlan, Email: mocdef.3ab610002nalnas
National Key Technologies R&D Program of China During the 12th Five-Year Plan Period (2013BAl06804Y041)
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引用本文

蔡华丹,侯均,吕永宁,等. 噻托溴铵喷雾剂治疗慢性阻塞性肺疾病的有效性与安全性荟萃分析[J]. 中华结核和呼吸杂志,2017,40(8)：596-603.

DOI:10.3760/cma.j.issn.1001-0939.2017.08.011

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慢性阻塞性肺疾病(慢阻肺)是一种具有气流受限特征的肺部疾病，其气流受限不完全可逆，呈进行性发展。世界卫生组织(WHO)全球疾病负担研究的流行病学数据显示：1990—2013年，慢阻肺已上升至全球疾病负担的第5位；2013年，中国慢阻肺所致死亡人数已超过90万，所致疾病负担超过1 600万人/年，位居我国单病种第4位，预计2020年慢阻肺将位居全球死亡原因的第3位 [ 1 ]，对人类身心健康的危害形势日趋严峻，对其发病机制及治疗药物的探索已成为生命科学领域的研究重点。慢阻肺全球策略指出，其药物治疗旨在减少症状、降低急性加重发生频率、减轻急性加重的严重程度和改善健康状况与运动耐量，而长效抗胆碱能药物(LAMA)已被证明能够降低急性加重风险、改善慢阻肺症状，被推荐为B/C/D类慢阻肺患者的治疗基础。
噻托溴铵是一种新型长效抗胆碱能药物，可有效舒张支气管，抑制气道黏液分泌和气道炎症反应，具有改善肺功能、气道重塑、缓解呼吸困难症状等功能，作用可维持长达24 h，是ATS和ERS的慢阻肺指南中推荐的首选用药，并推荐长期规律使用 [ 2 ]。自2004年被美国食品药品监督管理局(FDA)批准上市以来，噻托溴铵一直以粉吸入剂型被广泛应用。噻托溴铵喷雾剂作为一种新的给药剂型，2014年在中国上市，尽管有噻托溴铵不同剂型比较的单项研究报告，但其总体临床疗效及安全性尚存在争议。本研究采用系统评价方法探讨噻托溴铵喷雾剂治疗慢阻肺的疗效和安全性，以期为其临床应用提供循证医学证据。
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A
伍三兰，Email： mocdef.3ab610002nalnas
B
"十二五"国家科技支撑计划 (2013BAl06804Y041)
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