茚达特罗-格隆溴铵vs沙美特罗-氟替卡松治疗COPD-随机、双盲、双模拟研究（FLAME试验）
2016/07/07
摘要
背景：大多数指南推荐长效β受体激动剂（LABA）联合吸入糖皮质激素（ICS）或长效毒蕈碱拮抗剂（LAMA）作为慢性阻塞性肺疾病（COPD）且有急性加重高风险患者的首选治疗方案。 LABA-LAMA联合治疗方案在这些患者中的作用尚不清楚。
方法：研究者进行了一项52周的随机、双盲、双模拟、非劣效性试验。患有COPD并且前一年至少有一次急性加重史的患者被随机分配接受 “LABA茚达特罗（110 μg）+ LAMA 格隆溴铵（50 μg），1次/日” 或 “LABA沙美特罗（50 μg）+ICS氟替卡松（500 μg），2次/日”的吸入治疗。主要观察终点为所有COPD急性加重的年发生率。
结果：共计1680例患者被分配到茚达特罗-格隆溴铵组，1682例被分配到沙美特罗-氟替卡松组。茚达特罗-格隆溴铵在降低所有COPD急性加重年发生率方面不劣于且优于沙美特罗-氟替卡松；茚达特罗-格隆溴铵组的年发生率比沙美特罗-氟替卡松组降低11%（3.59 vs 4.03；率比，0.89；95% CI，0.83-0.96；P=0.003）。茚达特罗-格隆溴铵组至第一次急性加重的时间长于沙美特罗-氟替卡松组(71天[95%CI，60-82] vs 51天[95%CI，46-57]；风险比，0.84 [95%CI：0.78-0.91]，表示风险降低16%； P<0.001)。茚达特罗-格隆溴铵组中度或重度急性加重的年发生率低于沙美特罗-氟替卡松组(0.98 vs 1.19；率比，0.83； 95%CI，0.75-0.91；P<0.001)，且与沙美特罗-氟替卡松组相比，茚达特罗-格隆溴铵组至第一次中度或重度急性加重的时间更长(风险比，0.78；95%CI，0.70-0.86； P<0.001)，至第一次严重恶化的时间也更长(危险比，0.81；95%CI，0.66-1.00；P=0.046)。茚达特罗-格隆溴铵 vs 沙美特罗-氟替卡松对COPD急性发作率的影响独立于基线外周血嗜酸性粒细胞计数。两组不良事件和死亡的发生率相似。肺炎的发生率在茚达特罗-格隆溴铵组为3.2%，在沙美特罗-氟替卡松组为4.8%(P=0.02)。
结论：对于在前一年有急性加重史的患者，茚达特罗-格隆溴铵在预防COPD急性加重比沙美特罗-氟替卡松更有效。
评论： 大多数指南推荐LABA联合ICS或LAMA作为高风险患者COPD的首选治疗方案。FLAME研究发现茚达特罗-格隆溴铵在预防COPD急性加重比沙美特罗-氟替卡松更有效，且不良事件无明显增加。提示LABA联合LAMA治疗可能成为有高风险病情加重的COPD患者的首选治疗方案。未来将使用其它LABA来验证这一发现。
那么这是否意味着可以根据病人肺功能改善及减少急性加重次数由ICS+LABA调整为LABA+LAMA方案。实际上在早期有观察性研究发现在外周血嗜酸性粒细胞>2%患者，ICS相比LAMA其发作比率更低。本研究虽然不能排除其中有一些病人从ICS获益，结果提示外周血嗜酸性粒细胞>2%或更高并未发现更可能从ICS+LABA中获益。这与Wisdom (Withdrawal of Inhaled Steroids during Optimized Bronchodilator Management) post hoc 分析也不一致，其结果示外周血嗜酸性粒细胞>4%或绝对值超过300个/ul，ICS撤退会增加中重度COPD急性加重率。因此目前基于外周血嗜酸性粒细胞判断ICS治疗价值尚需进一步临床验证。
那么是否FLAME研究提供了足够证据支持C或D级COPD优先考虑LABA+LAMA治疗，来预防急性加重，看起来答案是肯定的。但在此之前，尚需要更多的临床研究，尤其是更长期试验，包括更多的重症和存在合并症病人纳入及检测其它的生物标志物来评估。
Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD.
Abstract
BACKGROUND:Most guidelines recommend either a long-acting beta-agonist (LABA) plus an inhaled glucocorticoid or a long-acting muscarinic antagonist (LAMA) as the first-choice treatment for patients with chronic obstructive pulmonary disease (COPD) who have a high risk of exacerbations. The role of treatment with a LABA-LAMA regimen in these patients is unclear.
METHODS:We conducted a 52-week, randomized, double-blind, double-dummy, noninferiority trial. Patients who had COPD with a history of at least one exacerbation during the previous year were randomly assigned to receive, by inhalation, either the LABA indacaterol (110 μg) plus the LAMA glycopyrronium (50 μg) once daily or the LABA salmeterol (50 μg) plus the inhaled glucocorticoid fluticasone (500 μg) twice daily. The primary outcome was the annual rate of all COPD exacerbations.
RESULTS:A total of 1680 patients were assigned to the indacaterol-glycopyrronium group, and 1682 to the salmeterol-fluticasone group. Indacaterol-glycopyrronium showed not only noninferiority but also superiority to salmeterol-fluticasone in reducing the annual rate of all COPD exacerbations; the rate was 11% lower in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group (3.59 vs. 4.03; rate ratio, 0.89; 95% confidence interval [CI], 0.83 to 0.96; P=0.003). The indacaterol-glycopyrronium group had a longer time to the first exacerbation than did the salmeterol-fluticasone group (71 days [95% CI, 60 to 82] vs. 51 days [95% CI, 46 to 57]; hazard ratio, 0.84 [95% CI, 0.78 to 0.91], representing a 16% lower risk; P<0.001). The annual rate of moderate or severe exacerbations was lower in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group (0.98 vs. 1.19; rate ratio, 0.83; 95% CI, 0.75 to 0.91; P<0.001), and the time to the first moderate or severe exacerbation was longer in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group (hazard ratio, 0.78; 95% CI, 0.70 to 0.86; P<0.001), as was the time to the first severe exacerbation (hazard ratio, 0.81; 95% CI, 0.66 to 1.00; P=0.046). The effect of indacaterol-glycopyrronium versus salmeterol-fluticasone on the rate of COPD exacerbations was independent of the baseline blood eosinophil count. The incidence of adverse events and deaths was similar in the two groups. The incidence of pneumonia was 3.2% in the indacaterol-glycopyrronium group and 4.8% in the salmeterol-fluticasone group (P=0.02).
CONCLUSIONS:Indacaterol-glycopyrronium was more effective than salmeterol-fluticasone in preventing COPD exacerbations in patients with a history of exacerbation during the previous year. (Funded by Novartis; FLAME ClinicalTrials.gov number, NCT01782326.).
背景：大多数指南推荐长效β受体激动剂（LABA）联合吸入糖皮质激素（ICS）或长效毒蕈碱拮抗剂（LAMA）作为慢性阻塞性肺疾病（COPD）且有急性加重高风险患者的首选治疗方案。 LABA-LAMA联合治疗方案在这些患者中的作用尚不清楚。
方法：研究者进行了一项52周的随机、双盲、双模拟、非劣效性试验。患有COPD并且前一年至少有一次急性加重史的患者被随机分配接受 “LABA茚达特罗（110 μg）+ LAMA 格隆溴铵（50 μg），1次/日” 或 “LABA沙美特罗（50 μg）+ICS氟替卡松（500 μg），2次/日”的吸入治疗。主要观察终点为所有COPD急性加重的年发生率。
结果：共计1680例患者被分配到茚达特罗-格隆溴铵组，1682例被分配到沙美特罗-氟替卡松组。茚达特罗-格隆溴铵在降低所有COPD急性加重年发生率方面不劣于且优于沙美特罗-氟替卡松；茚达特罗-格隆溴铵组的年发生率比沙美特罗-氟替卡松组降低11%（3.59 vs 4.03；率比，0.89；95% CI，0.83-0.96；P=0.003）。茚达特罗-格隆溴铵组至第一次急性加重的时间长于沙美特罗-氟替卡松组(71天[95%CI，60-82] vs 51天[95%CI，46-57]；风险比，0.84 [95%CI：0.78-0.91]，表示风险降低16%； P<0.001)。茚达特罗-格隆溴铵组中度或重度急性加重的年发生率低于沙美特罗-氟替卡松组(0.98 vs 1.19；率比，0.83； 95%CI，0.75-0.91；P<0.001)，且与沙美特罗-氟替卡松组相比，茚达特罗-格隆溴铵组至第一次中度或重度急性加重的时间更长(风险比，0.78；95%CI，0.70-0.86； P<0.001)，至第一次严重恶化的时间也更长(危险比，0.81；95%CI，0.66-1.00；P=0.046)。茚达特罗-格隆溴铵 vs 沙美特罗-氟替卡松对COPD急性发作率的影响独立于基线外周血嗜酸性粒细胞计数。两组不良事件和死亡的发生率相似。肺炎的发生率在茚达特罗-格隆溴铵组为3.2%，在沙美特罗-氟替卡松组为4.8%(P=0.02)。
结论：对于在前一年有急性加重史的患者，茚达特罗-格隆溴铵在预防COPD急性加重比沙美特罗-氟替卡松更有效。
评论： 大多数指南推荐LABA联合ICS或LAMA作为高风险患者COPD的首选治疗方案。FLAME研究发现茚达特罗-格隆溴铵在预防COPD急性加重比沙美特罗-氟替卡松更有效，且不良事件无明显增加。提示LABA联合LAMA治疗可能成为有高风险病情加重的COPD患者的首选治疗方案。未来将使用其它LABA来验证这一发现。
那么这是否意味着可以根据病人肺功能改善及减少急性加重次数由ICS+LABA调整为LABA+LAMA方案。实际上在早期有观察性研究发现在外周血嗜酸性粒细胞>2%患者，ICS相比LAMA其发作比率更低。本研究虽然不能排除其中有一些病人从ICS获益，结果提示外周血嗜酸性粒细胞>2%或更高并未发现更可能从ICS+LABA中获益。这与Wisdom (Withdrawal of Inhaled Steroids during Optimized Bronchodilator Management) post hoc 分析也不一致，其结果示外周血嗜酸性粒细胞>4%或绝对值超过300个/ul，ICS撤退会增加中重度COPD急性加重率。因此目前基于外周血嗜酸性粒细胞判断ICS治疗价值尚需进一步临床验证。
那么是否FLAME研究提供了足够证据支持C或D级COPD优先考虑LABA+LAMA治疗，来预防急性加重，看起来答案是肯定的。但在此之前，尚需要更多的临床研究，尤其是更长期试验，包括更多的重症和存在合并症病人纳入及检测其它的生物标志物来评估。
(南方医科大学南方医院 彭显如 赵海金审校)
Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD.
Abstract
BACKGROUND:Most guidelines recommend either a long-acting beta-agonist (LABA) plus an inhaled glucocorticoid or a long-acting muscarinic antagonist (LAMA) as the first-choice treatment for patients with chronic obstructive pulmonary disease (COPD) who have a high risk of exacerbations. The role of treatment with a LABA-LAMA regimen in these patients is unclear.
METHODS:We conducted a 52-week, randomized, double-blind, double-dummy, noninferiority trial. Patients who had COPD with a history of at least one exacerbation during the previous year were randomly assigned to receive, by inhalation, either the LABA indacaterol (110 μg) plus the LAMA glycopyrronium (50 μg) once daily or the LABA salmeterol (50 μg) plus the inhaled glucocorticoid fluticasone (500 μg) twice daily. The primary outcome was the annual rate of all COPD exacerbations.
RESULTS:A total of 1680 patients were assigned to the indacaterol-glycopyrronium group, and 1682 to the salmeterol-fluticasone group. Indacaterol-glycopyrronium showed not only noninferiority but also superiority to salmeterol-fluticasone in reducing the annual rate of all COPD exacerbations; the rate was 11% lower in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group (3.59 vs. 4.03; rate ratio, 0.89; 95% confidence interval [CI], 0.83 to 0.96; P=0.003). The indacaterol-glycopyrronium group had a longer time to the first exacerbation than did the salmeterol-fluticasone group (71 days [95% CI, 60 to 82] vs. 51 days [95% CI, 46 to 57]; hazard ratio, 0.84 [95% CI, 0.78 to 0.91], representing a 16% lower risk; P<0.001). The annual rate of moderate or severe exacerbations was lower in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group (0.98 vs. 1.19; rate ratio, 0.83; 95% CI, 0.75 to 0.91; P<0.001), and the time to the first moderate or severe exacerbation was longer in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group (hazard ratio, 0.78; 95% CI, 0.70 to 0.86; P<0.001), as was the time to the first severe exacerbation (hazard ratio, 0.81; 95% CI, 0.66 to 1.00; P=0.046). The effect of indacaterol-glycopyrronium versus salmeterol-fluticasone on the rate of COPD exacerbations was independent of the baseline blood eosinophil count. The incidence of adverse events and deaths was similar in the two groups. The incidence of pneumonia was 3.2% in the indacaterol-glycopyrronium group and 4.8% in the salmeterol-fluticasone group (P=0.02).
CONCLUSIONS:Indacaterol-glycopyrronium was more effective than salmeterol-fluticasone in preventing COPD exacerbations in patients with a history of exacerbation during the previous year. (Funded by Novartis; FLAME ClinicalTrials.gov number, NCT01782326.).
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