吸入糖皮质激素联合沙美特罗以及不联合沙美特罗治疗哮喘的严重不良事件
2020/01/02
摘要
背景：流行病学证据表明，β2 受体激动剂的使用与哮喘死亡率增加之间存在联系。目前的争论主要围绕上述关联之间的可能因果关系，以及常规（每日）使用长效β2受体激动剂（LABAs），特别是与吸入皮质类固醇（ICS）联合使用是否安全这一话题。本研究主要针对Cochrane综述进行更新，包括两项由美国食品和药物管理局（FDA）授权的大型试验的数据，有11,679名成人和6208名儿童参与其中。
目的：比较随机分组的慢性哮喘患者分别接受常规的沙美特罗加用ICS治疗与相同剂量的ICS治疗后的死亡率和非致命性严重不良事件（SAE）发生的风险。
搜索方法：我们使用Cochrane Airways集团专业实验注册器检索随机试验。我们同时查找了临床试验注册网站的未发表的试验数据。我们还查找了沙美特罗提交给FDA的材料。最近一次检索的日期是2018年10月10日。
对象：我们纳入了患有任何程度哮喘并随机接受至少12周常规沙美特罗和ICS联合治疗（单独使用或采用吸入器）或相同剂量ICS治疗的成人、儿童，或两者均有的平行设计的随机试验。
数据收集和分析：我们根据Cochrane预期的标准程序处理这些综述。我们从赞助商，ClinicalTrials.gov和向FDA提交的数据中获得了未发表的关于死亡率和SAE的数据。我们根据目前GRADE的建议评估了证据的确信性。
主要结果：我们在本综述中纳入了针对成人和青少年的41项研究（共计27,951例参与者），以及针对儿童的8项研究（共计8453例参与者）。我们判断全因事件的总体偏倚风险较低，并从所有研究者那里获得了SAE数据。除了542名成年人（无儿童）外，所有人都通过同一（组合式）吸入器使用沙美特罗和氟替卡松。死亡：11,233名服用常规沙美特罗和ICS的成人中有11人死亡，而服用常规ICS的13,718名患者中有13人死亡。汇总的Peto比值比（OR）为0.80（95％置信区间（CI）为0.36至1.78;参与者 27,951人；研究数41例; I（2）= 0％;中度确定性证据）。换句话说，对于每1000名接受25周治疗的成年人，单独使用ICS的人中仅有1人死亡，而服用沙美特罗合并ICS的人中相应的死亡风险也是1例（95％CI 为0-2人死亡）。没有儿童死亡，并且没有成人或儿童死于哮喘，因此我们仍然不确定儿童的死亡率和各年龄组的哮喘死亡率。非致命的严重不良事件：接受常规沙美特罗合并ICS治疗的332名成人出现了非致命性SAE，而在接受常规ICS的成人中出现SAE的则有282人。汇总的Peto OR为1.14（95％CI 0.97-1.33;参与者=27,951人; 研究41例; I（2）= 0％;中度确定性证据）。在每1000名接受25周治疗的成年人中，单独使用ICS治疗的21名成人患有SAE，而在沙美特罗合并ICS治疗的患者中相应风险为23人（95％CI 20-27）。在4229名使用常规沙美特罗合并ICS治疗的儿童中，有5人出现SAE，而4224名使用常规ICS治疗的儿童中，出现SAE的则为62人。汇总的Peto OR为1.04（95％CI 0.73-1.48;参与者8453人;研究8例; I（2）= 0％;中度确定性证据）。对于每1000名接受23周治疗的儿童，单独使用ICS治疗的儿童中有15人患有SAE，而使用沙美特罗合并ICS治疗的相应风险为15人（95％CI 11-22）。与哮喘相关的严重不良事件：两组中分别有80和67名成年人发生哮喘相关的非致命性SAE。汇总的Peto OR为1.15（95％CI 0.83-1.59;参与者=27951人;研究41例; I（2）= 0％;低确定性证据）。对于每1000名接受25周治疗的成年人，仅有5名接受ICS治疗者患有与哮喘相关的SAE，而在使用沙美特罗合并ICS的患者中相应的风险为6人（95％CI为4-8）。在儿童中，29例服用沙美特罗合并ICS者和23例单独服用ICS者报告了哮喘相关事件。汇总的Peto OR为1.25（95％CI 0.72-2.16;参与者8453人;研究8例; I（2）= 0％;中度确定性证据）。对于每1000名接受23周治疗的儿童，仅接受ICS治疗的儿童中有5名出现哮喘相关SAE，而在接受沙美特罗合并ICS治疗的儿童中相应的风险为7人（95％CI 为4-12）。
结论：我们没有发现在成人与儿童中死亡或严重不良事件的风险存在差异。然而，根据试验者的报告，在平均6个月的时间里中，随机接受常规沙美特罗合并ICS治疗或单独ICS治疗的27,951名成人及8453名儿童没有因哮喘死亡者。因此，采用两种治疗方法死于哮喘的风险都非常低，但我们仍不确定在ICS中添加沙美特罗能否改变死于哮喘的风险。纳入新的试验提高了评估非致命性SAE的准确性。我们现在可以得出结论，按照最坏情况估计，至少在每152名接受沙美特罗与ICS联合治疗6个月的成人和139名接受该治疗的儿童中，与单独使用ICS治疗相比会多出1名患者入院。这些潜在的风险仍然需要与采取联合治疗的人所获得的益处进行权衡。然而，在新的试验中，超过90％的处方治疗被采用，因此观察到的效果可能与沙美特罗联合ICS在日常实践中观察到的效果有所不同。
Inhaled steroids with and without regular salmeterol for asthma: serious adverse events.
Cates, C. J, et al. Cochrane. 2018 Dec.
Abstract
BACKGROUND: Epidemiological evidence has suggested a link between use of beta(2)-agonists and increased asthma mortality. Much debate has surrounded possible causal links for this association, and whether regular (daily) long-acting beta(2)-agonists (LABAs) are safe, particularly when used in combination with inhaled corticosteroids (ICSs). This is an update of a Cochrane Review that now includes data from two large trials including 11,679 adults and 6208 children; both were mandated by the US Food and Drug Administration (FDA).
OBJECTIVES: To assess risks of mortality and non-fatal serious adverse events (SAEs) in trials that randomised participants with chronic asthma to regular salmeterol and ICS versus the same dose of ICS.
SEARCH METHODS: We identified randomised trials using the Cochrane Airways Group Specialised Register of trials. We checked websites of clinical trials registers for unpublished trial data. We also checked FDA submissions in relation to salmeterol. The date of the most recent search was 10 October 2018.
SELECTION CRITERIA: We included parallel-design randomised trials involving adults, children, or both with asthma of any severity who were randomised to treatment with regular salmeterol and ICS (in separate or combined inhalers) versus the same dose of ICS of at least 12 weeks in duration.
DATA COLLECTION AND ANALYSIS: We conducted the review according to standard procedures expected by Cochrane. We obtained unpublished data on mortality and SAEs from the sponsors, from ClinicalTrials.gov, and from FDA submissions. We assessed our confidence in the evidence according to current GRADE recommendations.
MAIN RESULTS: We have included in this review 41 studies (27,951 participants) in adults and adolescents, along with eight studies (8453 participants) in children. We judged that the overall risk of bias was low for all-cause events, and we obtained data on SAEs from all study authors. All except 542 adults (and none of the children) were given salmeterol and fluticasone in the same (combination) inhaler.DeathsEleven of a total of 14,233 adults taking regular salmeterol and ICS died, as did 13 of 13,718 taking regular ICS at the same dose. The pooled Peto odds ratio (OR) was 0.80 (95% confidence interval (CI) 0.36 to 1.78; participants = 27,951; studies = 41; I(2) = 0%; moderate-certainty evidence). In other words, for every 1000 adults treated for 25 weeks, one death occurred among those on ICS alone, and the corresponding risk among those taking salmeterol and ICS was also one death (95% CI 0 to 2 deaths).No children died, and no adults or children died of asthma, so we remain uncertain about mortality in children and about asthma mortality in any age group.Non-fatal serious adverse eventsA total of 332 adults receiving regular salmeterol with ICS experienced a non-fatal SAE of any cause, compared to 282 adults receiving regular ICS. The pooled Peto OR was 1.14 (95% CI 0.97 to 1.33; participants = 27,951; studies = 41; I(2) = 0%; moderate-certainty evidence). For every 1000 adults treated for 25 weeks, 21 adults on ICS alone had an SAE, and the corresponding risk for those on salmeterol and ICS was 23 adults (95% CI 20 to 27).Sixty-five of 4229 children given regular salmeterol with ICS suffered an SAE of any cause, compared to 62 of 4224 children given regular ICS. The pooled Peto OR was 1.04 (95% CI 0.73 to 1.48; participants = 8453; studies = 8; I(2) = 0%; moderate-certainty evidence). For every 1000 children treated for 23 weeks, 15 children on ICS alone had an SAE, and the corresponding risk for those on salmeterol and ICS was 15 children (95% CI 11 to 22).Asthma-related serious adverse eventsEighty and 67 adults in each group, respectively, experienced an asthma-related non-fatal SAE. The pooled Peto OR was 1.15 (95% CI 0.83 to 1.59; participants = 27,951; studies = 41; I(2) = 0%; low-certainty evidence). For every 1000 adults treated for 25 weeks, five receiving ICS alone had an asthma-related SAE, and the corresponding risk among those on salmeterol and ICS was six adults (95% CI 4 to 8).Twenty-nine children taking salmeterol and ICS and 23 children taking ICS alone reported asthma-related events. The pooled Peto OR was 1.25 (95% CI 0.72 to 2.16; participants = 8453; studies = 8; I(2) = 0%; moderate-certainty evidence). For every 1000 children treated for 23 weeks, five receiving an ICS alone had an asthma-related SAE, and the corresponding risk among those receiving salmeterol and ICS was seven children (95% CI 4 to 12).
AUTHORS' CONCLUSIONS: We did not find a difference in the risk of death or serious adverse events in either adults or children. However, trial authors reported no asthma deaths among 27,951 adults or 8453 children randomised to regular salmeterol and ICS or ICS alone over an average of six months. Therefore, the risk of dying from asthma on either treatment was very low, but we remain uncertain about whether the risk of dying from asthma is altered by adding salmeterol to ICS. Inclusion of new trials has increased the precision of the estimates for non-fatal SAEs of any cause. We can now say that the worst-case estimate is that at least 152 adults and 139 children must be treated with combination salmeterol and ICS for six months for one additional person to be admitted to the hospital (compared to treatment with ICS alone). These possible risks still have to be weighed against the benefits experienced by people who take combination treatment. However more than 90% of prescribed treatment was taken in the new trials, so the effects observed may be different from those seen with salmeterol in combination with ICS in daily practice.
背景：流行病学证据表明，β2 受体激动剂的使用与哮喘死亡率增加之间存在联系。目前的争论主要围绕上述关联之间的可能因果关系，以及常规（每日）使用长效β2受体激动剂（LABAs），特别是与吸入皮质类固醇（ICS）联合使用是否安全这一话题。本研究主要针对Cochrane综述进行更新，包括两项由美国食品和药物管理局（FDA）授权的大型试验的数据，有11,679名成人和6208名儿童参与其中。
目的：比较随机分组的慢性哮喘患者分别接受常规的沙美特罗加用ICS治疗与相同剂量的ICS治疗后的死亡率和非致命性严重不良事件（SAE）发生的风险。
搜索方法：我们使用Cochrane Airways集团专业实验注册器检索随机试验。我们同时查找了临床试验注册网站的未发表的试验数据。我们还查找了沙美特罗提交给FDA的材料。最近一次检索的日期是2018年10月10日。
对象：我们纳入了患有任何程度哮喘并随机接受至少12周常规沙美特罗和ICS联合治疗（单独使用或采用吸入器）或相同剂量ICS治疗的成人、儿童，或两者均有的平行设计的随机试验。
数据收集和分析：我们根据Cochrane预期的标准程序处理这些综述。我们从赞助商，ClinicalTrials.gov和向FDA提交的数据中获得了未发表的关于死亡率和SAE的数据。我们根据目前GRADE的建议评估了证据的确信性。
主要结果：我们在本综述中纳入了针对成人和青少年的41项研究（共计27,951例参与者），以及针对儿童的8项研究（共计8453例参与者）。我们判断全因事件的总体偏倚风险较低，并从所有研究者那里获得了SAE数据。除了542名成年人（无儿童）外，所有人都通过同一（组合式）吸入器使用沙美特罗和氟替卡松。死亡：11,233名服用常规沙美特罗和ICS的成人中有11人死亡，而服用常规ICS的13,718名患者中有13人死亡。汇总的Peto比值比（OR）为0.80（95％置信区间（CI）为0.36至1.78;参与者 27,951人；研究数41例; I（2）= 0％;中度确定性证据）。换句话说，对于每1000名接受25周治疗的成年人，单独使用ICS的人中仅有1人死亡，而服用沙美特罗合并ICS的人中相应的死亡风险也是1例（95％CI 为0-2人死亡）。没有儿童死亡，并且没有成人或儿童死于哮喘，因此我们仍然不确定儿童的死亡率和各年龄组的哮喘死亡率。非致命的严重不良事件：接受常规沙美特罗合并ICS治疗的332名成人出现了非致命性SAE，而在接受常规ICS的成人中出现SAE的则有282人。汇总的Peto OR为1.14（95％CI 0.97-1.33;参与者=27,951人; 研究41例; I（2）= 0％;中度确定性证据）。在每1000名接受25周治疗的成年人中，单独使用ICS治疗的21名成人患有SAE，而在沙美特罗合并ICS治疗的患者中相应风险为23人（95％CI 20-27）。在4229名使用常规沙美特罗合并ICS治疗的儿童中，有5人出现SAE，而4224名使用常规ICS治疗的儿童中，出现SAE的则为62人。汇总的Peto OR为1.04（95％CI 0.73-1.48;参与者8453人;研究8例; I（2）= 0％;中度确定性证据）。对于每1000名接受23周治疗的儿童，单独使用ICS治疗的儿童中有15人患有SAE，而使用沙美特罗合并ICS治疗的相应风险为15人（95％CI 11-22）。与哮喘相关的严重不良事件：两组中分别有80和67名成年人发生哮喘相关的非致命性SAE。汇总的Peto OR为1.15（95％CI 0.83-1.59;参与者=27951人;研究41例; I（2）= 0％;低确定性证据）。对于每1000名接受25周治疗的成年人，仅有5名接受ICS治疗者患有与哮喘相关的SAE，而在使用沙美特罗合并ICS的患者中相应的风险为6人（95％CI为4-8）。在儿童中，29例服用沙美特罗合并ICS者和23例单独服用ICS者报告了哮喘相关事件。汇总的Peto OR为1.25（95％CI 0.72-2.16;参与者8453人;研究8例; I（2）= 0％;中度确定性证据）。对于每1000名接受23周治疗的儿童，仅接受ICS治疗的儿童中有5名出现哮喘相关SAE，而在接受沙美特罗合并ICS治疗的儿童中相应的风险为7人（95％CI 为4-12）。
结论：我们没有发现在成人与儿童中死亡或严重不良事件的风险存在差异。然而，根据试验者的报告，在平均6个月的时间里中，随机接受常规沙美特罗合并ICS治疗或单独ICS治疗的27,951名成人及8453名儿童没有因哮喘死亡者。因此，采用两种治疗方法死于哮喘的风险都非常低，但我们仍不确定在ICS中添加沙美特罗能否改变死于哮喘的风险。纳入新的试验提高了评估非致命性SAE的准确性。我们现在可以得出结论，按照最坏情况估计，至少在每152名接受沙美特罗与ICS联合治疗6个月的成人和139名接受该治疗的儿童中，与单独使用ICS治疗相比会多出1名患者入院。这些潜在的风险仍然需要与采取联合治疗的人所获得的益处进行权衡。然而，在新的试验中，超过90％的处方治疗被采用，因此观察到的效果可能与沙美特罗联合ICS在日常实践中观察到的效果有所不同。
(中国医科大学附属一院呼吸与危重症学科 李文扬 摘译 杨冬 审校)
(Cates, C. J, et al. Cochrane. 2018 Dec.)
(Cates, C. J, et al. Cochrane. 2018 Dec.)
Inhaled steroids with and without regular salmeterol for asthma: serious adverse events.
Cates, C. J, et al. Cochrane. 2018 Dec.
Abstract
BACKGROUND: Epidemiological evidence has suggested a link between use of beta(2)-agonists and increased asthma mortality. Much debate has surrounded possible causal links for this association, and whether regular (daily) long-acting beta(2)-agonists (LABAs) are safe, particularly when used in combination with inhaled corticosteroids (ICSs). This is an update of a Cochrane Review that now includes data from two large trials including 11,679 adults and 6208 children; both were mandated by the US Food and Drug Administration (FDA).
OBJECTIVES: To assess risks of mortality and non-fatal serious adverse events (SAEs) in trials that randomised participants with chronic asthma to regular salmeterol and ICS versus the same dose of ICS.
SEARCH METHODS: We identified randomised trials using the Cochrane Airways Group Specialised Register of trials. We checked websites of clinical trials registers for unpublished trial data. We also checked FDA submissions in relation to salmeterol. The date of the most recent search was 10 October 2018.
SELECTION CRITERIA: We included parallel-design randomised trials involving adults, children, or both with asthma of any severity who were randomised to treatment with regular salmeterol and ICS (in separate or combined inhalers) versus the same dose of ICS of at least 12 weeks in duration.
DATA COLLECTION AND ANALYSIS: We conducted the review according to standard procedures expected by Cochrane. We obtained unpublished data on mortality and SAEs from the sponsors, from ClinicalTrials.gov, and from FDA submissions. We assessed our confidence in the evidence according to current GRADE recommendations.
MAIN RESULTS: We have included in this review 41 studies (27,951 participants) in adults and adolescents, along with eight studies (8453 participants) in children. We judged that the overall risk of bias was low for all-cause events, and we obtained data on SAEs from all study authors. All except 542 adults (and none of the children) were given salmeterol and fluticasone in the same (combination) inhaler.DeathsEleven of a total of 14,233 adults taking regular salmeterol and ICS died, as did 13 of 13,718 taking regular ICS at the same dose. The pooled Peto odds ratio (OR) was 0.80 (95% confidence interval (CI) 0.36 to 1.78; participants = 27,951; studies = 41; I(2) = 0%; moderate-certainty evidence). In other words, for every 1000 adults treated for 25 weeks, one death occurred among those on ICS alone, and the corresponding risk among those taking salmeterol and ICS was also one death (95% CI 0 to 2 deaths).No children died, and no adults or children died of asthma, so we remain uncertain about mortality in children and about asthma mortality in any age group.Non-fatal serious adverse eventsA total of 332 adults receiving regular salmeterol with ICS experienced a non-fatal SAE of any cause, compared to 282 adults receiving regular ICS. The pooled Peto OR was 1.14 (95% CI 0.97 to 1.33; participants = 27,951; studies = 41; I(2) = 0%; moderate-certainty evidence). For every 1000 adults treated for 25 weeks, 21 adults on ICS alone had an SAE, and the corresponding risk for those on salmeterol and ICS was 23 adults (95% CI 20 to 27).Sixty-five of 4229 children given regular salmeterol with ICS suffered an SAE of any cause, compared to 62 of 4224 children given regular ICS. The pooled Peto OR was 1.04 (95% CI 0.73 to 1.48; participants = 8453; studies = 8; I(2) = 0%; moderate-certainty evidence). For every 1000 children treated for 23 weeks, 15 children on ICS alone had an SAE, and the corresponding risk for those on salmeterol and ICS was 15 children (95% CI 11 to 22).Asthma-related serious adverse eventsEighty and 67 adults in each group, respectively, experienced an asthma-related non-fatal SAE. The pooled Peto OR was 1.15 (95% CI 0.83 to 1.59; participants = 27,951; studies = 41; I(2) = 0%; low-certainty evidence). For every 1000 adults treated for 25 weeks, five receiving ICS alone had an asthma-related SAE, and the corresponding risk among those on salmeterol and ICS was six adults (95% CI 4 to 8).Twenty-nine children taking salmeterol and ICS and 23 children taking ICS alone reported asthma-related events. The pooled Peto OR was 1.25 (95% CI 0.72 to 2.16; participants = 8453; studies = 8; I(2) = 0%; moderate-certainty evidence). For every 1000 children treated for 23 weeks, five receiving an ICS alone had an asthma-related SAE, and the corresponding risk among those receiving salmeterol and ICS was seven children (95% CI 4 to 12).
AUTHORS' CONCLUSIONS: We did not find a difference in the risk of death or serious adverse events in either adults or children. However, trial authors reported no asthma deaths among 27,951 adults or 8453 children randomised to regular salmeterol and ICS or ICS alone over an average of six months. Therefore, the risk of dying from asthma on either treatment was very low, but we remain uncertain about whether the risk of dying from asthma is altered by adding salmeterol to ICS. Inclusion of new trials has increased the precision of the estimates for non-fatal SAEs of any cause. We can now say that the worst-case estimate is that at least 152 adults and 139 children must be treated with combination salmeterol and ICS for six months for one additional person to be admitted to the hospital (compared to treatment with ICS alone). These possible risks still have to be weighed against the benefits experienced by people who take combination treatment. However more than 90% of prescribed treatment was taken in the new trials, so the effects observed may be different from those seen with salmeterol in combination with ICS in daily practice.
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