School of Physiotherapy, Royal College of Surgeons in Ireland, Dublin, Ireland.
Cochrane Airways, Population Health Research Institute, St George's, University of London, London, UK.
Cochrane Database Syst Rev. 2021 Apr 14;4(4):CD007694. doi: 10.1002/14651858.CD007694.pub3.
Asthma is characterised by chronic inflammation of the airways and recurrent exacerbations with wheezing, chest tightness, and cough. Treatment with inhaled steroids and bronchodilators can result in good control of symptoms, prevention of further morbidity, and improved quality of life. However, an increase in serious adverse events with the use of both regular formoterol and regular salmeterol (long-acting beta₂-agonists) compared with placebo for chronic asthma has been demonstrated in previous Cochrane Reviews. This increase was statistically significant in trials that did not randomise participants to an inhaled corticosteroid, but not when formoterol or salmeterol was combined with an inhaled corticosteroid. The confidence intervals were found to be too wide to ensure that the addition of an inhaled corticosteroid renders regular long-acting beta₂-agonists completely safe; few participants and insufficient serious adverse events in these trials precluded a definitive decision about the safety of combination treatments.
To assess risks of mortality and non-fatal serious adverse events in trials that have randomised patients with chronic asthma to regular formoterol and an inhaled corticosteroid versus regular salmeterol and an inhaled corticosteroid.
We searched the Cochrane Airways Register of Trials, CENTRAL, MEDLINE, Embase, and two trial registries to identify reports of randomised trials for inclusion. We checked manufacturers' websites and clinical trial registers for unpublished trial data, as well as Food and Drug Administration (FDA) submissions in relation to formoterol and salmeterol. The date of the most recent search was 24 February 2021.
We included controlled clinical trials with a parallel design, recruiting patients of any age and severity of asthma, if they randomised patients to treatment with regular formoterol versus regular salmeterol (each with a randomised inhaled corticosteroid) and were of at least 12 weeks' duration.
Two review authors independently selected trials for inclusion in the review, extracted outcome data from published papers and trial registries, and applied GRADE rating for the results. We sought unpublished data on mortality and serious adverse events from study sponsors and authors. The primary outcomes were all cause mortality and non-fatal serious adverse events. We chose not to calculate an average result from all the formulations of formoterol and inhaled steroid, as the doses and delivery devices are too diverse to assume a single class effect.
Twenty-one studies in 11,572 adults and adolescents and two studies in 723 children met the eligibility criteria of the review. No data were available for two studies; therefore these were not included in the analysis. Among adult and adolescent studies, seven compared formoterol and budesonide to salmeterol and fluticasone (N = 7764), six compared formoterol and beclomethasone to salmeterol and fluticasone (N = 1923), two compared formoterol and mometasone to salmeterol and fluticasone (N = 1126), two compared formoterol and fluticasone to salmeterol and fluticasone (N = 790), and one compared formoterol and budesonide to salmeterol and budesonide (N = 229). In total, five deaths were reported among adults, none of which was thought to be related to asthma. The certainty of evidence for all-cause mortality was low, as there were not enough deaths to permit any precise conclusions regarding the risk of mortality on combination formoterol versus combination salmeterol. In all, 201 adults reported non-fatal serious adverse events. In studies comparing formoterol and budesonide to salmeterol and fluticasone, there were 77 in the formoterol arm and 68 in the salmeterol arm (Peto odds ratio (OR) 1.14, 95% confidence interval (CI) 0.82 to 1.59; 5935 participants, 7 studies; moderate-certainty evidence). In the formoterol and beclomethasone studies, there were 12 adults in the formoterol arm and 13 in the salmeterol arm with events (Peto OR 0.94, 95% CI 0.43 to 2.08; 1941 participants, 6 studies; moderate-certainty evidence). In the formoterol and mometasone studies, there were 18 in the formoterol arm and 11 in the salmeterol arm (Peto OR 1.02, 95% CI 0.47 to 2.20; 1126 participants, 2 studies; moderate-certainty evidence). One adult in the formoterol and fluticasone studies in the salmeterol arm experienced an event (Peto OR 0.05, 95% CI 0.00 to 3.10; 293 participants, 2 studies; low-certainty evidence). Another adult in the formoterol and budesonide compared to salmeterol and budesonide study in the formoterol arm had an event (Peto OR 7.45, 95% CI 0.15 to 375.68; 229 participants, 1 study; low-certainty evidence). Only 46 adults were reported to have experienced asthma-related serious adverse events. The certainty of the evidence was low to very low due to the small number of events and the absence of independent assessment of causation. The two studies in children compared formoterol and fluticasone to salmeterol and fluticasone. No deaths and no asthma-related serious adverse events were reported in these studies. Four all-cause serious adverse events were reported: three in the formoterol arm, and one in the salmeterol arm (Peto OR 2.72, 95% CI 0.38 to 19.46; 548 participants, 2 studies; low-certainty evidence).
AUTHORS' CONCLUSIONS: Overall, for both adults and children, evidence is insufficient to show whether regular formoterol in combination with budesonide, beclomethasone, fluticasone, or mometasone has a different safety profile from salmeterol in combination with fluticasone or budesonide. Five deaths of any cause were reported across all studies and no deaths from asthma; this information is insufficient to permit any firm conclusions about the relative risks of mortality on combination formoterol in comparison to combination salmeterol inhalers. Evidence on all-cause non-fatal serious adverse events indicates that there is probably little to no difference between formoterol/budesonide and salmeterol/fluticasone inhalers. However events for the other formoterol combination inhalers were too few to allow conclusions. Only 46 non-fatal serious adverse events were thought to be asthma related; this small number in addition to the absence of independent outcome assessment means that we have very low confidence for this outcome. We found no evidence of safety issues that would affect the choice between salmeterol and formoterol combination inhalers used for regular maintenance therapy by adults and children with asthma.
哮喘的特征是气道慢性炎症和喘息、胸闷和咳嗽等反复恶化。使用吸入性皮质类固醇和支气管扩张剂治疗可以很好地控制症状，预防进一步的发病，并改善生活质量。然而，先前的 Cochrane 综述已经证明，与安慰剂相比，常规福莫特罗和常规沙美特罗（长效β₂-激动剂）在慢性哮喘中使用会导致严重不良事件的增加。在未随机分配参与者接受吸入皮质类固醇的试验中，这种增加具有统计学意义，但当福莫特罗或沙美特罗与吸入皮质类固醇联合使用时则没有统计学意义。置信区间太宽，无法确保吸入皮质类固醇的添加完全使常规长效β₂-激动剂安全；这些试验中参与者人数少，严重不良事件不足，无法对联合治疗的安全性做出明确决定。
评估随机分配慢性哮喘患者接受常规福莫特罗和吸入皮质类固醇与常规沙美特罗和吸入皮质类固醇治疗的试验中死亡率和非致命性严重不良事件的风险。
我们检索了 Cochrane 气道试验登记册、CENTRAL、MEDLINE、Embase 和两个试验登记册，以确定纳入的随机试验报告。我们检查了制造商的网站和临床试验登记册，以寻找未发表的试验数据，以及食品和药物管理局 (FDA) 提交的与福莫特罗和沙美特罗有关的信息。最近一次检索日期为 2021 年 2 月 24 日。
我们纳入了具有平行设计的对照临床试验，招募了任何年龄和哮喘严重程度的患者，如果他们将患者随机分配接受常规福莫特罗与常规沙美特罗（均与随机吸入皮质类固醇）治疗，且至少持续 12 周。
两名综述作者独立选择纳入综述的试验，从已发表的论文和试验登记册中提取结局数据，并对结果进行 GRADE 评级。我们从研究赞助商和作者那里寻求关于死亡率和严重不良事件的未发表数据。主要结局是全因死亡率和非致命性严重不良事件。我们选择不计算福莫特罗和吸入类固醇所有制剂的平均结果，因为剂量和输送装置差异太大，不能假设存在单一的类效应。
21 项成人和青少年研究（11572 名参与者）和 2 项儿童研究（723 名参与者）符合综述的纳入标准。有两项研究的数据不可用；因此，这些研究未包括在分析中。在成人和青少年研究中，有 7 项研究比较了福莫特罗和布地奈德与沙美特罗和氟替卡松（N = 7764），6 项研究比较了福莫特罗和倍氯米松与沙美特罗和氟替卡松（N = 1923），2 项研究比较了福莫特罗和莫米松与沙美特罗和氟替卡松（N = 1126），2 项研究比较了福莫特罗和氟替卡松与沙美特罗和氟替卡松（N = 790），1 项研究比较了福莫特罗和布地奈德与沙美特罗和布地奈德（N = 229）。共有 5 名成年人死亡，均与哮喘无关。由于死亡人数不足以确定死亡率的风险，因此所有原因死亡率的证据确定性较低。共有 201 名成年人报告了非致命性严重不良事件。在比较福莫特罗和布地奈德与沙美特罗和氟替卡松的研究中，福莫特罗组有 77 例，沙美特罗组有 68 例（Peto 比值比（OR）1.14，95%置信区间（CI）0.82 至 1.59；5935 名参与者，7 项研究；中等确定性证据）。在福莫特罗和倍氯米松研究中，福莫特罗组有 12 名成年人和沙美特罗组有 13 名成年人发生事件（Peto OR 0.94，95% CI 0.43 至 2.08；1941 名参与者，6 项研究；中等确定性证据）。在福莫特罗和莫米松研究中，福莫特罗组有 18 名成年人和沙美特罗组有 11 名成年人发生事件（Peto OR 1.02，95% CI 0.47 至 2.20；1126 名参与者，2 项研究；中等确定性证据）。在沙美特罗组的福莫特罗和氟替卡松研究中有 1 名成年人发生事件（Peto OR 0.05，95% CI 0.00 至 3.10；293 名参与者，2 项研究；低确定性证据）。在福莫特罗和布地奈德与沙美特罗和布地奈德比较的研究中，福莫特罗组有 1 名成年人发生事件（Peto OR 7.45，95% CI 0.15 至 375.68；229 名参与者，1 项研究；低确定性证据）。只有 46 名成年人报告发生了哮喘相关的严重不良事件。由于事件数量少，且缺乏独立的因果关系评估，证据的确定性为低至非常低。两项针对儿童的研究比较了福莫特罗和氟替卡松与沙美特罗和氟替卡松。这些研究中没有报告死亡和哮喘相关的严重不良事件。报告了 4 例全因严重不良事件：3 例发生在福莫特罗组，1 例发生在沙美特罗组（Peto OR 2.72，95% CI 0.38 至 19.46；548 名参与者，2 项研究；低确定性证据）。
总的来说，对于成人和儿童，福莫特罗联合布地奈德、倍氯米松、氟替卡松或莫米松与沙美特罗联合氟替卡松或布地奈德的安全性证据不足。所有研究中报告了 5 例任何原因的死亡，均与哮喘无关；这一信息不足以得出关于福莫特罗组合吸入器与沙美特罗组合吸入器相比相对死亡率风险的任何明确结论。关于所有原因非致命性严重不良事件的证据表明，福莫特罗/布地奈德和沙美特罗/氟替卡松吸入器之间可能几乎没有差异。然而，其他福莫特罗组合吸入器的事件太少，无法得出结论。只有 46 例非致命性严重不良事件被认为与哮喘有关；由于缺乏独立的结局评估，因此这一数字加上缺乏独立的结局评估，我们对这一结局的信心非常低。我们没有发现任何可能影响成人和儿童使用哮喘的沙美特罗和福莫特罗组合吸入器进行常规维持治疗选择的安全性问题。
