【Cochrane简语概要】定期服用福莫特罗联合吸入类固醇治疗慢性哮喘的严重不良事件

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系统综述问题 

对患有哮喘的成人或儿童，在吸入类固醇（ICS）治疗上加用福莫特罗是否安全？

研究背景 

哮喘是一种肺部疾病。症状（主要）包括气喘、呼吸困难和胸闷。哮喘的两个主要特征是基础炎症反应和支气管收缩（肺内小气管周边的肌肉收缩）。每日吸入类固醇可以治疗炎症反应。支气管收缩则可以使用β2受体激动放松肌肉来治疗。从而扩张呼吸道，使呼吸变得更容易。β2受体激动剂有两种使用方式：短效β2受体激动剂可以缓解胸闷症状，长效β2受体激动剂（LABA）可以预防（哮喘）症状发作。

对接受每日低剂量ICS治疗但症状得不到控制的哮喘患者，许多哮喘（治疗）指南中建议每日增加使用LABA，如福莫特罗。我们相信LABA可以改善肺功能、缓解症状、改善生活质量、并防止病情恶化。然而，这些药物对哮喘患者的安全性一直存在争议。这是我们想在此次系统综述中探讨的问题，聚焦于（有关此种治疗的）罕见和严重的危害。（我们将罕见和严重的危害）定义为：危及生命、需要入院治疗或延长住院时间、造成永久性或重大残疾（能力丧失）或新生儿先天缺陷。

主要结果 

我们分析了29项涉及35751位成人的研究，和10项涉及4035位17岁以下儿童的研究。受试者的哮喘严重程度不一，大多数都接受常规ICS治疗（但剂量不一致，且分布广）。由于这些研究参与的儿童过少，我们无法确定对儿童的影响。

在35751位成人中，有30人死亡。其中17人是接受福莫特罗联合ICS治疗，13人只接受ICS治疗。接受福莫特罗联合ICS治疗的成人中，有3人死于哮喘；但只接受ICS治疗的人中，无人因哮喘死亡。17岁以下的儿童中没有报告死亡病例。

无论使用福莫特罗与否，任何原因引起成人严重伤害的人数是相似的。尽管在成年人中，无论在ICS基础上联合常规福莫特罗与否，严重伤害的风险都没有差异，但与只接受ICS相比，我们没有信心排除这些风险增加或减少（的可能）。

证据质量 

我们对有关成年人的数据有中等程度的信心（中等质量证据），但对于使用ICS的儿童，联合福莫特罗的影响则不确定。因为这些研究中发生死亡的案例较少，我们没有足够的数据衡量福莫特罗联合ICS能否增加死亡的风险。

几乎所有的试验均接受了来自药厂的资金支持。

出于其他考量，严重不良反应的原因（如：试验者判断不良反应是否与哮喘相关）并没有被独立评估，但可能猜测出发生不良反应的受试者来自哪个治疗组。虽然试验的受试者并不知道他们接受的为假药（安慰药）或积极治疗（试验药），但福莫特罗对症状的影响非常大。这意味着他们（受试者们）可以猜测到那些人是接受了福莫特罗治疗。我们无法判断这种事情是否发生，这就是为什么我们要关注所有原因造成的不良事件，而非针对原因进行评估。

结论 

我们没有十足的信心宣称接受ICS治疗的患者添加福莫特罗后不会增加死亡风险。另一方面，我们没有发现严重伤害增加的明确证据。在12777名接受ICS联合福莫特罗治疗的成年人中，有3人发生于哮喘相关的死亡事件。没有明确的证据表明，接受ICS治疗的成年人在添加福莫特罗后会增加非致命性的严重不良反应的风险。

此简语概要的更新时间为2019年2月。

结论: 

我们没有发现福莫特罗联合ICS与单独使用ICS相比，死亡风险（全因或哮喘相关的死亡）上具有差异。在儿童和青少年中没有报告死亡病例。使用这两种治疗方法的死亡风险非常低，但我们不能确定在服用ICS时添加福莫特罗对死亡率是否有影响（低质量证据）。

在成人中，我们没有发现任何原因造成的非致命性SAEs风险的差异（高质量证据）。在先前版本的系统综述中，接受福莫特罗联合ICS的成人发生与哮喘有关的SAE风险较低；然而，纳入新研究后，不再显示不同治疗间的风险存在差异（中等质量证据）。

报告中发生SAEs的儿童和青少年人数很少，故这一年龄组的结论仍是不确定的。

我们纳入FDA授权的大型研究的结果。向患者提供使用福莫特罗联合ICS的临床决策和消息之前，需权衡福莫特罗联合ICS的已知获益与潜在伤害，以及此伤害与用药之间不明确的关联程度。

【Cochrane Plain Language Summary】Regular treatment with formoterol and inhaled steroids for chronic asthma: serious adverse events

Review question

Is it safe to add regular formoterol to inhaled corticosteroid (ICS) for adults or children with asthma?

Background

Asthma is a disease of the lungs. Symptoms include wheezing, breathlessness, and chest tightness. Two main features of asthma are underlying inflammation and bronchoconstriction (tightening of the muscles around small tubes in the lungs). The inflammation can be treated with daily steroid inhalers. The bronchoconstriction can be treated with a beta2-agonist to relax the muscles. This opens up the airways and makes it easier to breathe. Beta2-agonists can be used two ways: to provide relief from symptoms of chest tightness ('short-acting beta2-agonists') and to help prevent symptoms from occurring ('long-acting beta2-agonists', or LABAs).

When asthma is not controlled by daily low-dose ICS, many asthma guidelines recommend additional daily LABA, such as formoterol. We are confident that LABA improves lung function, symptoms, quality of life, and exacerbations. However, there is long-standing controversy about how safe these drugs are for people with asthma. This is what we wanted to explore in this review by focusing on rare and serious harms. These are defined as events that are life-threatening, require admission to hospital or prolongation of existing hospitalisation, or result in persistent or significant disability/incapacity or a birth defect.

Key results

We analysed data from 29 studies in 35,751 adults and 10 studies in 4035 children aged up to 17 years. The participants in the studies had a range of asthma severity, with most having been previously treated with regular ICS (over a wide range of doses). There were too few children in the studies to allow us to be certain about the effects in children.

Thirty deaths were reported in 35,751 adults. Seventeen of these deaths were reported in participants taking formoterol and ICS, and 13 deaths in participants who were taking ICS alone. Three deaths reported in adults taking formoterol and ICS were due to asthma, but there were no deaths due to asthma with ICS alone. No deaths were reported in children up to 17 years age.

The number of people experiencing serious harms of any cause was similar in adults with and without formoterol. Although there was no difference in the risk of serious harms in adults with asthma taking regular formoterol in combination with ICS compared to ICS alone, we could not confidently exclude a reduced or increased risk of events compared to taking ICS alone.

Quality of the evidence

We were moderately certain regarding the data in adults, but less certain about the effects of adding formoterol to ICS in children. Given the low number of deaths that occurred in the studies, we do not yet have enough information to be able to measure accurately the risk of adding formoterol to ICS on number of deaths.

Almost all trials were sponsored by drug manufacturers.

Other concerns were that the cause of serious adverse events (i.e. whether they were judged by the trialists to be asthma-related or not) were not independently assessed, and it may have been possible to guess which treatment group the person experiencing the adverse event was from. Although the people in the trial did not know whether they had been given a dummy drug or the active treatment, formoterol has quite a large effect on symptoms. This meant that they might have been able to guess who was taking formoterol. It was not possible for us to tell whether this occurred or not, which is why we primarily look at the all-cause events, which do not require assessment of cause.

Conclusions

We are not able to state confidently that adding formoterol to ICS carries no risk of increasing the number of deaths in comparison with ICS alone. On the other hand, we found no conclusive evidence of an increase in serious harm. Three asthma-related deaths occurred in a total of 12,777 adults treated with formoterol in combination with ICS. We found no conclusive evidence of risk of non-fatal serious harms attributed to asthma when formoterol was combined with ICS in adults.

This Plain language summary is current as of February 2019.

Authors' conclusions: 

We did not find a difference in the risk of death (all-cause or asthma-related) in adults taking combined formoterol and ICS versus ICS alone (moderate- to low-certainty evidence). No deaths were reported in children and adolescents. The risk of dying when taking either treatment was very low, but we cannot be certain if there is a difference in mortality when taking additional formoterol to ICS (low-certainty evidence).

We did not find a difference in the risk of non-fatal SAEs of any cause in adults (high-certainty evidence). A previous version of the review had shown a lower risk of asthma-related SAEs in adults taking combined formoterol and ICS; however, inclusion of new studies no longer shows a difference between treatments (moderate-certainty evidence).

The reported number of children and adolescents with SAEs was small, so uncertainty remains in this age group.

We included results from large studies mandated by the FDA. Clinical decisions and information provided to patients regarding regular use of formoterol and ICS need to take into account the balance between known symptomatic benefits of formoterol and ICS versus the remaining degree of uncertainty associated with its potential harmful effects.

译者：姜若文，黑龙江中医药大学；审校：李迅，北京中医药大学循证医学中心；编辑排版：张晓雯，北京中医药大学循证医学中心

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