Cates Christopher J, Jaeschke Roman, Schmidt Stefanie, Ferrer Montse
Population Health Sciences and Education, St George's University of London, Cranmer Terrace, London, UK, SW17 0RE.
Cochrane Database Syst Rev. 2013 Jun 7(6):CD006924. doi: 10.1002/14651858.CD006924.pub3.
Epidemiological evidence has suggested a link between beta2-agonists and increases in asthma mortality. Much debate has surrounded possible causal links for this association and whether regular (daily) long-acting beta2-agonists are safe when used alone or in conjunction with inhaled corticosteroids. This is an updated Cochrane Review.
To assess the risk of fatal and non-fatal serious adverse events in people with chronic asthma given regular formoterol with inhaled corticosteroids versus the same dose of inhaled corticosteroids alone.
Trials were identified using the Cochrane Airways Group Specialised Register of trials. Web sites of clinical trial registers were checked for unpublished trial data; Food and Drug Administration (FDA) submissions in relation to formoterol were also checked. The date of the most recent search was August 2012.
Controlled clinical trials with a parallel design were included if they randomly allocated people of any age and severity of asthma to treatment with regular formoterol and inhaled corticosteroids for at least 12 weeks.
We used standard methodological procedures expected by The Cochrane Collaboration. Unpublished data on mortality and serious adverse events were obtained from the sponsors. We assessed the quality of evidence using GRADE recommendations.
Following the 2012 update, we have included 20 studies on 10,578 adults and adolescents and seven studies on 2788 children and adolescents. We found data on all-cause fatal and non-fatal serious adverse events for all studies, and we judged the overall risk of bias to be low.Six deaths occurred in participants taking regular formoterol with inhaled corticosteroids, and one in a participant administered regular inhaled corticosteroids alone. The difference was not statistically significant (Peto odds ratio (OR) 3.56, 95% confidence interval (CI) 0.79 to 16.03, low-quality evidence). All deaths were reported in adults, and one was believed to be asthma-related.Non-fatal serious adverse events of any cause were very similar for each treatment in adults (Peto OR 0.98, 95% CI 0.76 to 1.27, moderate-quality evidence), and weak evidence suggested an increase in events in children on regular formoterol (Peto OR 1.62, 95% CI 0.80 to 3.28, moderate-quality evidence).In contrast with all-cause serious adverse events, the addition of new trial data means that asthma-related serious adverse events associated with formoterol are now significantly fewer in adults taking regular formoterol with inhaled corticosteroids (Peto OR 0.49, 95% CI 0.28 to 0.88, moderate-quality evidence). Although a greater number of asthma-related events were reported in children receiving regular formoterol, this finding was not statistically significant (Peto OR 1.49, 95% CI 0.48 to 4.61, low-quality evidence).
AUTHORS' CONCLUSIONS: From the evidence in this review, it is not possible to reassure people with asthma that regular use of inhaled corticosteroids with formoterol carries no risk of increasing mortality in comparison with use of inhaled corticosteroids alone. On the other hand, we have found no conclusive evidence of serious harm, and only one asthma-related death was registered during more than 4200 patient-years of observation with formoterol.In adults, no significant difference in all-cause non-fatal serious adverse events was noted with regular formoterol with inhaled corticosteroids, but a significant reduction in asthma-related serious adverse events was observed in comparison with inhaled corticosteroids alone.In children the number of events was too small, and consequently the results too imprecise, to allow determination of whether the increased risk of all-cause non-fatal serious adverse events found in a previous meta-analysis on regular formoterol alone is abolished by the additional use of inhaled corticosteroids.We await the results of large ongoing surveillance studies mandated by the Food and Drug Administration (FDA) for more information. Clinical decisions and information provided to patients regarding regular use of formoterol have to take into account the balance between known symptomatic benefits of formoterol and the degree of uncertainty associated with its potential harmful effects.
流行病学证据表明β2激动剂与哮喘死亡率增加之间存在关联。围绕这种关联的可能因果关系以及常规（每日）长效β2激动剂单独使用或与吸入性糖皮质激素联合使用是否安全，一直存在诸多争议。这是一篇更新的Cochrane系统评价。
评估慢性哮喘患者规律使用福莫特罗与吸入性糖皮质激素联合治疗相比单独使用相同剂量吸入性糖皮质激素时发生致命和非致命严重不良事件的风险。
通过Cochrane Airways Group专业试验注册库识别试验。检查临床试验注册库网站以获取未发表的试验数据；还检查了美国食品药品监督管理局（FDA）提交的与福莫特罗相关的资料。最近一次检索日期为2012年8月。
纳入采用平行设计的对照临床试验，这些试验将任何年龄和哮喘严重程度的患者随机分配接受规律福莫特罗与吸入性糖皮质激素治疗至少12周。
我们采用了Cochrane协作网期望的标准方法程序。从申办方获取未发表的死亡率和严重不良事件数据。我们使用GRADE推荐评估证据质量。
在2012年更新后，我们纳入了20项针对10578名成人和青少年的研究以及7项针对2788名儿童和青少年的研究。我们获取了所有研究中全因致命和非致命严重不良事件的数据，并且判断总体偏倚风险较低。
接受规律福莫特罗与吸入性糖皮质激素治疗的参与者中有6例死亡，单独接受规律吸入性糖皮质激素治疗的参与者中有1例死亡。差异无统计学意义（Peto比值比（OR）3.56，95%置信区间（CI）0.79至16.03，低质量证据）。所有死亡均报告于成人，其中1例被认为与哮喘相关。
成人中每种治疗的任何原因导致的非致命严重不良事件非常相似（Peto OR 0.98，95%CI 0.76至1.27，中等质量证据），且有微弱证据表明规律使用福莫特罗的儿童不良事件有所增加（Peto OR 1.62，95%CI 0.80至3.28，中等质量证据）。
与全因严重不良事件相反，新试验数据的加入意味着在接受规律福莫特罗与吸入性糖皮质激素治疗的成人中，与福莫特罗相关的哮喘相关严重不良事件现在显著减少（Peto OR 0.49，95%CI 0.28至0.88，中等质量证据）。尽管接受规律福莫特罗治疗的儿童报告了更多哮喘相关事件，但这一发现无统计学意义（Peto OR 1.49，95%CI 0.48至4.61，低质量证据）。
根据本系统评价中的证据，无法向哮喘患者保证规律使用吸入性糖皮质激素与福莫特罗相比单独使用吸入性糖皮质激素不会增加死亡风险。另一方面，我们未发现严重危害的确凿证据 在超过420多年的福莫特罗观察患者年中仅记录到1例与哮喘相关的死亡。
在成人中，规律使用福莫特罗与吸入性糖皮质激素联合治疗时全因非致命严重不良事件无显著差异，但与单独使用吸入性糖皮质激素相比，哮喘相关严重不良事件显著减少。
在儿童中，事件数量过少，因此结果过于不精确，无法确定之前单独关于规律福莫特罗的荟萃分析中发现的全因非致命严重不良事件增加风险是否因额外使用吸入性糖皮质激素而消除。我们等待美国食品药品监督管理局（FDA）要求的正在进行的大型监测研究结果以获取更多信息。关于规律使用福莫特罗的临床决策和向患者提供的信息必须考虑到福莫特罗已知的症状改善益处与其潜在有害影响相关的不确定程度之间的平衡。
