长效β2-激动剂治疗哮喘的安全性试验综合分析
2018/07/09
摘要
长效β2-兴奋剂（LABA）在哮喘管理中的安全性问题最初是在一项大的药物上市后试验中被指出的，该试验认为长效β2-兴奋剂使哮喘患者死亡风险增加。2010年食品药品监督管理局（FDA）规定，四家公司销售长效β2-兴奋剂的实验室进行前瞻性随机对照试验，比较LABA联合吸入糖皮质激素及单独应用吸入糖皮质激素治疗哮喘在青少年（12至17岁）和成人哮喘患者的安全性。在与FDA的合作中，制造商协调他们的试验方法，允许独立的联合监督委员会提供四个试验的最终综合分析。方法是作为联合监督委员会的成员，我们进行了四项试验的综合分析，比较吸入糖皮质激素加LABA（联合疗法）和单独吸入糖皮质激素。主要结果包括哮喘相关插管或死亡。次要结果包括严重哮喘相关事件和哮喘恶化。结果为在36010例意向性治疗中，4名哮喘患者中有3例哮喘相关插管（2例吸入糖皮质激素组，1例为联合治疗组），2例哮喘相关死亡（均为联合治疗组）。在严重哮喘相关事件的二次分析中（住院、插管或死亡的综合），吸入糖皮质激素组的18006例患者中有108例（0.60%），联合治疗组18004例中有119例（0.66%）至少有一项综合事件（联合治疗组的相对危险度为1.09；95%可信区间[CI]，0.83～1.43；P＝0.55）；吸入糖皮质激素组2100例（11.7%），联合治疗组1768例（9.8%）有至少1例哮喘发作（相对危险度0.83，95% CI，0.78～0.78；P＜0.01）。结论为使用LABA联合吸入糖皮质激素并没有导致严重哮喘相关事件的风险显著高于单独吸入糖皮质激素的治疗，但哮喘恶化明显减少。
Combined Analysis of Asthma Safety Trials of Long-Acting β2-Agonists.
Busse WW, Bateman ED, Caplan AL, Kelly HW, O'Byrne PM, Rabe KF, Chinchilli VM.
Abstract
Background Safety concerns regarding long-acting β2-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.
长效β2-兴奋剂（LABA）在哮喘管理中的安全性问题最初是在一项大的药物上市后试验中被指出的，该试验认为长效β2-兴奋剂使哮喘患者死亡风险增加。2010年食品药品监督管理局（FDA）规定，四家公司销售长效β2-兴奋剂的实验室进行前瞻性随机对照试验，比较LABA联合吸入糖皮质激素及单独应用吸入糖皮质激素治疗哮喘在青少年（12至17岁）和成人哮喘患者的安全性。在与FDA的合作中，制造商协调他们的试验方法，允许独立的联合监督委员会提供四个试验的最终综合分析。方法是作为联合监督委员会的成员，我们进行了四项试验的综合分析，比较吸入糖皮质激素加LABA（联合疗法）和单独吸入糖皮质激素。主要结果包括哮喘相关插管或死亡。次要结果包括严重哮喘相关事件和哮喘恶化。结果为在36010例意向性治疗中，4名哮喘患者中有3例哮喘相关插管（2例吸入糖皮质激素组，1例为联合治疗组），2例哮喘相关死亡（均为联合治疗组）。在严重哮喘相关事件的二次分析中（住院、插管或死亡的综合），吸入糖皮质激素组的18006例患者中有108例（0.60%），联合治疗组18004例中有119例（0.66%）至少有一项综合事件（联合治疗组的相对危险度为1.09；95%可信区间[CI]，0.83～1.43；P＝0.55）；吸入糖皮质激素组2100例（11.7%），联合治疗组1768例（9.8%）有至少1例哮喘发作（相对危险度0.83，95% CI，0.78～0.78；P＜0.01）。结论为使用LABA联合吸入糖皮质激素并没有导致严重哮喘相关事件的风险显著高于单独吸入糖皮质激素的治疗，但哮喘恶化明显减少。
(中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校)
(N Engl J Med. 2018 Jun 28;378(26):2497-2505. )
(N Engl J Med. 2018 Jun 28;378(26):2497-2505. )
Combined Analysis of Asthma Safety Trials of Long-Acting β2-Agonists.
Busse WW, Bateman ED, Caplan AL, Kelly HW, O'Byrne PM, Rabe KF, Chinchilli VM.
Abstract
Background Safety concerns regarding long-acting β2-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.
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25-羟维生素D和儿童早期哮喘的卫生服务利用
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非嗜酸细胞性哮喘患者吸入糖皮质激素的降级治疗：现实世界的前瞻性试验
