Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, New York.
LungenClinic Grosshansdorf and Christian-Albrechts University Kiel, Airway Research Center North, Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany.
Am J Respir Crit Care Med. 2021 Mar 1;203(5):553-564. doi: 10.1164/rccm.202006-2618OC.
In the phase III, 52-week ETHOS (Efficacy and Safety of Triple Therapy in Obstructive Lung Disease) trial in chronic obstructive pulmonary disease (COPD) (NCT02465567), triple therapy with budesonide/glycopyrrolate/formoterol fumarate (BGF) significantly reduced all-cause mortality compared with glycopyrrolate/formoterol fumarate (GFF). However, 384 of 8,509 patients were missing vital status at Week 52 in the original analyses. To assess the robustness of the ETHOS mortality findings after additional data retrieval for patients missing Week 52 vital status in the original analyses. Patients with moderate to very severe COPD and prior history of exacerbation received twice-daily dosing with 320/18/9.6 μg of BGF (BGF 320), 160/18/9.6 μg of BGF (BGF 160), 18/9.6 μg of GFF, or 320/9.6 μg of budesonide/formoterol fumarate (BFF) (all delivered via a single metered-dose Aerosphere inhaler). Time to death (all-cause) was a prespecified secondary endpoint. In the final retrieved dataset, which included Week 52 vital status for 99.6% of the intent-to-treat population, risk of death with BGF 320 was significantly lower than GFF (hazard ratio, 0.51; 95% confidence interval, 0.33-0.80; unadjusted = 0.0035). There were no significant differences in mortality when comparing BGF 320 with BFF (hazard ratio, 0.72; 95% confidence interval, 0.44-1.16; = 0.1721), nor were significant differences observed when comparing BGF 160 against either dual comparator. Results were similar when the first 30, 60, or 90 days of treatment were excluded from the analysis. Deaths from cardiovascular causes occurred in 0.5%, 0.8%, 1.4%, and 0.5% of patients in the BGF 320, BGF 160, GFF, and BFF groups, respectively. Using final retrieved vital status data, triple therapy with BGF 320 reduced the risk of death compared with GFF, but was not shown to significantly reduce the risk of death compared with BFF, in patients with COPD. Triple therapy containing a lower dose of inhaled corticosteroid (BGF 160) was not shown to significantly reduce the risk of death compared with the dual therapy comparators.
在 III 期 ETHOS（阻塞性肺病三联疗法的疗效和安全性）试验中，慢性阻塞性肺疾病（COPD）（NCT02465567）中，布地奈德/格隆溴铵/福莫特罗富马酸盐（BGF）三联疗法与格隆溴铵/福莫特罗富马酸盐（GFF）相比，显著降低了全因死亡率。然而，在原始分析中，8509 名患者中有 384 名在第 52 周时的生存状况缺失。为了评估在原始分析中对缺失第 52 周生存状况的患者进行额外数据检索后，ETHOS 死亡率结果的稳健性。中度至重度 COPD 且有加重病史的患者每天接受两次 320/18/9.6μg 的 BGF（BGF 320）、160/18/9.6μg 的 BGF（BGF 160）、18/9.6μg 的 GFF 或 320/9.6μg 的布地奈德/福莫特罗富马酸盐（BFF）（均通过单一计量吸入器 Aerosphere 给药）治疗。死亡时间（全因）是预先指定的次要终点。在最终检索的数据集中，包含了意向治疗人群中 99.6%的第 52 周生存状况，与 GFF 相比，BGF 320 的死亡风险显著降低（风险比，0.51；95%置信区间，0.33-0.80；未调整的=0.0035）。与 BFF 相比，BGF 320 与死亡率无显著差异（风险比，0.72；95%置信区间，0.44-1.16；=0.1721），与 BGF 160 相比也无显著差异。当从分析中排除治疗的前 30、60 或 90 天时，结果相似。BGF 320、BGF 160、GFF 和 BFF 组的患者分别有 0.5%、0.8%、1.4%和 0.5%发生心血管原因导致的死亡。使用最终检索到的生存状况数据，与 GFF 相比，BGF 320 三联疗法降低了死亡风险，但与 BFF 相比，并未显示显著降低死亡风险，在 COPD 患者中。与双重治疗比较剂相比，含有较低剂量吸入皮质激素的三联疗法（BGF 160）并未显示出显著降低死亡风险。
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