Cates Christopher J, Lasserson Toby J
Community Health Sciences, St George's, University of London, Cranmer Terrace, London, UK, SW17 0RE.
Cochrane Database Syst Rev. 2010 Jan 20(1):CD007694. doi: 10.1002/14651858.CD007694.pub2.
An increase in serious adverse events with both regular formoterol and regular salmeterol in chronic asthma has been demonstrated in comparison with placebo in previous Cochrane reviews. This increase was significant in trials that did not randomise participants to an inhaled corticosteroid, but less certain in the smaller numbers of participants in trials that included an inhaled corticosteroid in the randomised treatment regimen.
We set out to compare the risks of mortality and non-fatal serious adverse events in trials which have randomised patients with chronic asthma to regular formoterol versus regular salmeterol, when each are used with an inhaled corticosteroid as part of the randomised treatment.
Trials were identified using the Cochrane Airways Group Specialised Register of trials. Manufacturers' web sites of clinical trial registers were checked for unpublished trial data and Food and Drug Administration (FDA) submissions in relation to formoterol and salmeterol were also checked. The date of the most recent search was July 2009.
Controlled clinical trials with a parallel design, recruiting patients of any age and severity of asthma were included 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 authors independently selected trials for inclusion in the review and extracted outcome data. Unpublished data on mortality and serious adverse events were sought from the sponsors and authors.
Eight studies met the eligibility criteria of the review recruiting 6,163 adults and adolescents. There were seven studies (involving 5,935 adults and adolescents) comparing formoterol and budesonide to salmeterol and fluticasone. All but one study administered the products as a combined inhaler, and most used formoterol 50 mcg and budesonide 400 mcg twice daily versus salmeterol 50 mcg and fluticasone 250 mcg twice daily. There were two deaths overall (one on each combination) and neither were thought to be related to asthma.There was no significant difference between treatment groups for non-fatal serious adverse events, either all-cause (Peto OR 1.14; 95% CI 0.82 to 1.59, I(2) = 26%) or asthma-related (Peto OR 0.69; 95% CI 0.37 to 1.26, I(2) = 33%). Over 23 weeks the rates for all-cause serious adverse events were 2.6% on formoterol and budesonide and 2.3% on salmeterol and fluticasone, and for asthma-related serious adverse events, 0.6% and 0.8% respectively.There was one study (228 adults) comparing formoterol and beclomethasone to salmeterol and fluticasone, but there were no deaths or hospital admissions.No studies were found in children.
AUTHORS' CONCLUSIONS: The seven identified studies in adults did not show any significant difference in safety between formoterol and budesonide in comparison with salmeterol and fluticasone. Asthma-related serious adverse events were rare, and there were no reported asthma-related deaths. There was a single small study comparing formoterol and beclomethasone to salmeterol and fluticasone in adults, but no serious adverse events occurred in this study. No studies were found in children.Overall there is insufficient evidence to decide whether regular formoterol and budesonide or beclomethasone have equivalent or different safety profiles from salmeterol and fluticasone.
在以往的Cochrane综述中，与安慰剂相比，慢性哮喘患者规律使用福莫特罗和沙美特罗时严重不良事件有所增加。在未将参与者随机分配至吸入性糖皮质激素的试验中，这种增加具有显著性，但在随机治疗方案中包含吸入性糖皮质激素的试验中，参与者数量较少，情况不太确定。
我们旨在比较将慢性哮喘患者随机分配至规律使用福莫特罗与规律使用沙美特罗的试验中，当二者均与吸入性糖皮质激素作为随机治疗的一部分联合使用时，死亡风险和非致命严重不良事件的差异。
通过Cochrane Airways Group专业试验注册库识别试验。检查了临床试验注册库的制造商网站以获取未发表的试验数据，还检查了与福莫特罗和沙美特罗相关的美国食品药品监督管理局（FDA）提交资料。最近一次检索日期为2009年7月。
纳入具有平行设计的对照临床试验，招募任何年龄和哮喘严重程度的患者，若试验将患者随机分配至规律使用福莫特罗与规律使用沙美特罗（均联合随机使用吸入性糖皮质激素），且持续时间至少为12周。
两位作者独立选择纳入综述的试验并提取结局数据。向赞助商和作者寻求关于死亡率和严重不良事件的未发表数据。
八项研究符合综述的纳入标准，共招募了6163名成人和青少年。有七项研究（涉及5935名成人和青少年）比较了福莫特罗和布地奈德与沙美特罗和氟替卡松。除一项研究外，所有研究均将产品作为联合吸入器给药，大多数使用福莫特罗50微克和布地奈德400微克每日两次，对比沙美特罗50微克和氟替卡松250微克每日两次。总体有两例死亡（每种联合用药各一例），均被认为与哮喘无关。治疗组之间非致命严重不良事件无显著差异，无论是全因性（Peto比值比1.14；95%置信区间0.82至1.59，I² = 26%）还是哮喘相关性（Peto比值比0.69；95%置信区间0.37至1.26，I² = 33%）。在23周内，福莫特罗和布地奈德组的全因严重不良事件发生率为2.6%，沙美特罗和氟替卡松组为2.3%，哮喘相关性严重不良事件发生率分别为0.6%和0.8%。有一项研究（228名成人）比较了福莫特罗和倍氯米松与沙美特罗和氟替卡松，但未出现死亡或住院情况。未发现儿童相关研究。
已识别的七项成人研究未显示福莫特罗和布地奈德与沙美特罗和氟替卡松在安全性上有任何显著差异。哮喘相关性严重不良事件罕见，且未报告与哮喘相关的死亡。有一项在成人中比较福莫特罗和倍氯米松与沙美特罗和氟替卡松的小型研究，但该研究未发生严重不良事件。未发现儿童相关研究。总体而言，没有足够证据来判定规律使用福莫特罗和布地奈德或倍氯米松与沙美特罗和氟替卡松的安全性相当还是不同。
