长效β-激动剂哮喘安全性试验的联合分析。
Combined Analysis of Asthma Safety Trials of Long-Acting β-Agonists.
机构信息
From the Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine and Public Health, Madison (W.W.B.); the Pulmonary Division, Department of Medicine, University of Cape Town, Cape Town, South Africa (E.D.B.); the Division of Medical Ethics, Department of Population Health, New York University School of Medicine, New York (A.L.C.); the Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque (H.W.K.); the Department of Medicine, McMaster University, Hamilton, ON, Canada (P.M.O.); LungenClinic Grosshansdorf and Christian Albrechts University Kiel, Kiel, and Airway Research Center North, German Center for Lung Research, Grosshansdorf - both in Germany (K.F.R.); and the Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA (V.M.C.).
出版信息
N Engl J Med. 2018 Jun 28;378(26):2497-2505. doi: 10.1056/NEJMoa1716868.
BACKGROUND
Safety concerns regarding long-acting β-agonists (LABAs) in asthma management were initially identified in a large postmarketing trial in which the risk of death was increased. In 2010, the Food and Drug Administration (FDA) mandated that the four companies marketing LABAs for asthma perform prospective, randomized, controlled trials comparing the safety of combination therapy with a LABA plus an inhaled glucocorticoid with that of an inhaled glucocorticoid alone in adolescents (12 to 17 years of age) and adults. In conjunction with the FDA, the manufacturers harmonized their trial methods to allow an independent joint oversight committee to provide a final combined analysis of the four trials.
METHODS
As members of the joint oversight committee, we performed a combined analysis of the four trials comparing an inhaled glucocorticoid plus a LABA (combination therapy) with an inhaled glucocorticoid alone. The primary outcome was a composite of asthma-related intubation or death. Post hoc secondary outcomes included serious asthma-related events and asthma exacerbations.
RESULTS
Among the 36,010 patients in the intention-to-treat study, there were three asthma-related intubations (two in the inhaled-glucocorticoid group and one in the combination-therapy group) and two asthma-related deaths (both in the combination-therapy group) in 4 patients. In the secondary analysis of serious asthma-related events (a composite of hospitalization, intubation, or death), 108 of 18,006 patients (0.60%) in the inhaled-glucocorticoid group and 119 of 18,004 patients (0.66%) in the combination-therapy group had at least one composite event (relative risk in the combination-therapy group, 1.09; 95% confidence interval [CI], 0.83 to 1.43; P=0.55); 2100 patients in the inhaled-glucocorticoid group (11.7%) and 1768 in the combination-therapy group (9.8%) had at least one asthma exacerbation (relative risk, 0.83; 95% CI, 0.78 to 0.89; P<0.001).
CONCLUSIONS
Combination therapy with a LABA plus an inhaled glucocorticoid did not result in a significantly higher risk of serious asthma-related events than treatment with an inhaled glucocorticoid alone but resulted in significantly fewer asthma exacerbations.
背景
最初在一项大型上市后试验中发现，长效β-激动剂（LABA）在哮喘管理中的安全性令人担忧，该试验中死亡风险增加。2010 年，食品和药物管理局（FDA）要求四家销售 LABA 治疗哮喘的公司进行前瞻性、随机、对照试验，比较 LABA 加吸入性糖皮质激素联合治疗与单独使用吸入性糖皮质激素治疗青少年（12 至 17 岁）和成人的安全性。作为与 FDA 合作的一部分，制造商协调了他们的试验方法，允许一个独立的联合监督委员会对四项试验的最终联合分析进行联合分析。
方法
作为联合监督委员会的成员，我们对四项比较吸入性糖皮质激素加 LABA（联合治疗）与单独吸入性糖皮质激素的试验进行了联合分析。主要结局是哮喘相关插管或死亡的综合结果。事后次要结局包括严重哮喘相关事件和哮喘加重。
结果
在意向治疗研究的 36010 名患者中，4 名患者中有 3 例与哮喘相关的插管（吸入性糖皮质激素组 2 例，联合治疗组 1 例）和 2 例与哮喘相关的死亡（均为联合治疗组）。在严重哮喘相关事件的次要分析中（住院、插管或死亡的综合结果），吸入性糖皮质激素组 18006 例患者中有 108 例（0.60%）和联合治疗组 18004 例患者中有 119 例（0.66%）至少有一个复合事件（联合治疗组的相对风险，1.09；95%置信区间[CI]，0.83 至 1.43；P=0.55）；吸入性糖皮质激素组有 2100 名患者（11.7%）和联合治疗组有 1768 名患者（9.8%）至少有一次哮喘加重（相对风险，0.83；95%CI，0.78 至 0.89；P<0.001）。
结论
与单独使用吸入性糖皮质激素相比，LABA 加吸入性糖皮质激素联合治疗并未显著增加严重哮喘相关事件的风险，但显著减少了哮喘加重的次数。
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