Anderson Debbie E, Kew Kayleigh M, Boyter Anne C
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.
Cochrane Database Syst Rev. 2015 Aug 24;2015(8):CD011397. doi: 10.1002/14651858.CD011397.pub2.
Despite the availability of several evidence-based therapies and non-pharmacological strategies to improve control of symptoms and prevent exacerbations of asthma, patients with asthma continue to be at risk for mortality and morbidity.Previous trials have demonstrated the potentially beneficial effects of the long-acting muscarinic antagonist (LAMA) tiotropium on lung function in patients with asthma; however, a definitive conclusion on the benefit of LAMA in asthma is lacking, as is information on where in the current step-wise management strategy they would be most beneficial.
To assess the efficacy and safety of a LAMA added to any dose of an inhaled corticosteroid (ICS) compared with the same dose of ICS alone for adults whose asthma is not well controlled.
We searched the Cochrane Airways Group Specialised Register (CAGR) from inception to April 2015, and we imposed no restriction on language of publication. We also searched clinicaltrials.gov, the World Health Organization (WHO) trials portal and drug company registries to identify unpublished studies.
We searched for parallel and cross-over randomised controlled trials in which adults whose asthma was not well controlled by ICS alone were randomly assigned to receive LAMA add-on or placebo (both combined with ICS) for at least 12 weeks.
Two review authors independently screened the searches and extracted data from study reports. We used Covidence for duplicate screening, extraction of study characteristics and numerical data and risk of bias ratings. Pre-specified primary outcomes included exacerbations requiring oral corticosteroids, quality of life and all-cause serious adverse events.
We identified five studies that met the inclusion criteria. All studies applied a double-blind, double-dummy design, and the population of all studies totalled 2563 adult participants. Study duration ranged from 12 weeks to 52 weeks, and risk of bias across domains in all studies was low. Trials included more women than men (33% to 47% male), and mean age of participants ranged from 41 to 48 years. Participants generally had a long history of asthma, and mean baseline predicted forced expiratory volume in one second (FEV1) was between 72% and 75% in three studies reporting pre-bronchodilator values.The rate of exacerbations requiring oral corticosteroids (OCS) was lower in patients prescribed an LAMA add-on than in those receiving the same dose of ICS alone (odds ratio (OR) 0.65, 95% confidence interval (CI) 0.46 to 0.93; 2277 participants; four studies; I(2) = 0%; high-quality evidence), meaning that 27 fewer people per 1000 would have an exacerbation over 21 weeks requiring OCS with LAMA compared with ICS alone (95% CI 42 fewer to 6 fewer).All-cause serious adverse events (SAEs) and exacerbations requiring hospital admission were rare and the effects too imprecise to permit firm conclusions, but effects suggested that LAMA add-on may be associated with fewer of both compared with ICS alone (SAEs: OR 0.60, 95% CI 0.23 to 1.57; 2532 participants; four studies; low-quality evidence; exacerbations requiring hospital admission: OR 0.42, 95% CI 0.12 to 1.47; 2562 participants; five studies; moderate-quality evidence). Additional therapy with a LAMA showed no clear benefit in terms of quality of life compared with ICS given alone; high-quality evidence showed only a small mean improvement in quality of life as measured on the Asthma Quality of Life Questionnaire (AQLQ), which was not statistically significant. The same was true for asthma control as measured on the Asthma Control Questionnaire (ACQ), which was based on moderate-quality evidence. LAMA combined with ICS showed consistent benefit in a range of lung function measures compared with the same dose of ICS alone, and LAMA was not associated with significantly higher rates of adverse events than were reported with placebo.
AUTHORS' CONCLUSIONS: For adults taking ICS for asthma without a long-acting beta₂-agonist (LABA), LAMA given as add-on treatment reduces the likelihood of exacerbations requiring treatment with OCS and improves lung function. The benefits of LAMA combined with ICS for hospital admissions, all-cause serious adverse events, quality of life and asthma control remain unknown.Results of this review, along with findings of related reviews conducted to assess the use of LAMA in other clinical scenarios involving asthma, can help to define the role of LAMA in the management of asthma. Trials of longer duration (up to 52 weeks) would provide a better opportunity to observe rare events such as serious adverse events and exacerbations requiring hospital admission.
尽管有多种循证疗法和非药物策略可用于改善哮喘症状控制和预防哮喘发作，但哮喘患者仍面临死亡和发病风险。既往试验已证明长效毒蕈碱拮抗剂（LAMA）噻托溴铵对哮喘患者肺功能具有潜在有益作用；然而，关于LAMA在哮喘治疗中的益处尚无定论，且在当前的阶梯式管理策略中，LAMA在何处最有益也缺乏相关信息。
评估在任何剂量吸入性糖皮质激素（ICS）基础上加用LAMA与单用相同剂量ICS相比，对哮喘控制不佳的成年人的疗效和安全性。
我们检索了Cochrane Airways Group专业注册库（CAGR）自创建至2015年4月的资料，且对发表语言未设限制。我们还检索了ClinicalTrials.gov、世界卫生组织（WHO）试验平台和制药公司注册库以识别未发表的研究。
我们检索了平行和交叉随机对照试验，其中单用ICS无法良好控制哮喘的成年人被随机分配接受加用LAMA或安慰剂治疗（均与ICS联合使用），治疗时间至少为12周。
两位综述作者独立筛选检索结果并从研究报告中提取数据。我们使用Covidence进行重复筛选、提取研究特征和数值数据以及偏倚风险评级。预先设定 的主要结局包括需要口服糖皮质激素的发作、生活质量和全因严重不良事件。
我们纳入了5项符合纳入标准的研究。所有研究均采用双盲、双模拟设计，所有研究的总样本量为2563名成年参与者。研究持续时间从12周 至52周不等，所有研究各领域的偏倚风险均较低。试验纳入的女性多于男性（男性占33%至47%），参与者的平均年龄在41至48岁之间。参与者通常有较长的哮喘病史，在三项报告支气管扩张剂使用前值的研究中，平均基线预计第1秒用力呼气容积（FEV1）在72%至75%之间。加用LAMA治疗的患者中，需要口服糖皮质激素（OCS）的发作率低于单用相同剂量ICS的患者（比值比（OR）0.65，95%置信区间（CI）0.46至0.93；2277名参与者；4项研究；I² = 0%；高质量证据），这意味着与单用ICS相比，每1000人中使用LAMA治疗21周时，因OCS导致发作的人数少27人（95%CI为少42人至少6人）。全因严重不良事件（SAEs）和需要住院治疗的发作很少见，其影响过于不精确，无法得出确切结论，但结果表明，与单用ICS相比，加用LAMA可能与两者的发生率较低有关（SAEs：OR 0.60，95%CI 0.23至1.57；2532名参与者；4项研究；低质量证据；需要住院治疗的发作：OR 0.42，95%CI 0.12至1.47；2562名参与者；5项研究；中等质量证据）。与单用ICS相比，加用LAMA在生活质量方面未显示出明显益处；高质量证据表明，根据哮喘生活质量问卷（AQLQ）测量，生活质量仅略有改善，且无统计学意义。基于中等质量证据的哮喘控制问卷（ACQ）测量结果也显示同样情况。与单用相同剂量ICS相比，LAMA与ICS联合使用在一系列肺功能指标上均显示出持续的益处，且LAMA与安慰剂相比，不良事件发生率并未显著更高。
对于使用ICS治疗哮喘但未使用长效β₂受体激动剂（LABA）的成年人，加用LAMA治疗可降低需要OCS治疗的发作可能性并改善肺功能。LAMA与ICS联合使用对住院治疗、全因严重不良事件、生活质量和哮喘控制的益处尚不清楚。本综述结果以及为评估LAMA在其他哮喘临床场景中的应用而进行的相关综述结果，有助于明确LAMA在哮喘管理中的作用。持续时间更长（长达52周）的试验将为观察严重不良事件和需要住院治疗的发作等罕见事件提供更好的机会。
