Firestone Institute for Respiratory Health, St Joseph's Healthcare and Department of Medicine, Michael G DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada.
Centre for Lung Health, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, BC, Canada.
Lancet Respir Med. 2021 Feb;9(2):149-158. doi: 10.1016/S2213-2600(20)30416-1. Epub 2020 Oct 1.
In mild asthma, as-needed budesonide-formoterol reduces long-term exacerbation risk compared with as-needed short-acting β-agonist (SABA), with a similar or increased reduction versus maintenance with budesonide plus as-needed SABA, despite a lower budesonide dose. In this post-hoc analysis of the SYmbicort Given as needed in Mild Asthma (SYGMA) 1 study, we investigated the short-term risk of severe exacerbations after a single day with various levels of reliever use.
SYGMA 1 was a 52-week, double-blind, randomised, controlled, phase 3 trial, in which patients aged 12 years or older with mild asthma were randomly assigned (1:1:1) to placebo twice daily plus as-needed terbutaline 0·5 mg, placebo twice daily plus as-needed budesonide-formoterol 200-6 μg, or budesonide 200 μg twice daily plus as-needed terbutaline (ie, budesonide maintenance group). In this post-hoc analysis, we assessed the frequency of reliever use and the risk of a severe exacerbation in the 21 days after first use of more than two, four, six, or eight reliever inhalations in 24 h. SYGMA 1 is registered with ClinicalTrials.gov, NCT02149199, and is now complete.
Of 5721 patients enrolled in SYGMA 1, 3849 were randomly assigned to as-needed terbutaline (n=1280), as-needed budesonide-formoterol (n=1279), or budesonide maintenance (n=1290), of whom 3836 had evaluable data (n=1277 as-needed terbutaline, n=1277 as needed budesonide-formoterol, and n=1282 budesonide maintenance). Median reliever use was 0·32 (IQR 0·08-0·91) inhalations per day for the as-needed terbutaline group, 0·29 (0·07-0·72) for the as-needed budesonide-formoterol group, and 0·16 (0·04-0·52) for the budesonide maintenance group. Compared with as-needed terbutaline, after adjustment for age, sex, randomly assigned treatment, pre-study treatment group, baseline % predicted post-bronchodilator FEV, and severe exacerbation in the 12 months before enrolment in the study, the hazard ratio (HR) for severe exacerbation in the 21 days after a single day with more than two as-needed inhalations was 0·27 (95% CI 0·12-0·58; p=0·0008) with as-needed budesonide-formoterol and 0·39 (0·19-0·79; p=0·0091) with budesonide maintenance; after a single day of more than four as-needed inhalations the HR was 0·24 (0·10-0·62; p=0·0030) with as-needed budesonide-formoterol and 0·30 (0·13-0·72; p=0·0065) with budesonide maintenance; and after a single day of more than six as-needed inhalations the HR was 0·14 (0·02-1·06; p=0·057) with as-needed budesonide-formoterol and 0·43 (0·14-1·26; p=0·12) with budesonide maintenance. HRs were not calculated for more than eight as-needed inhalations due to the small number of events.
In mild asthma, as-needed budesonide-formoterol reduces the short-term risk of severe exacerbations after a single day of higher use (more than two as-needed inhalations), even when overall use is infrequent. Use of an anti-inflammatory reliever might reduce the risk of short-term severe exacerbations by the timely provision of increased doses of as-needed inhaled corticosteroids and formoterol when symptoms occur. These findings should be further assessed in prospective randomised clinical trials.
AstraZeneca.
在轻度哮喘中，按需使用布地奈德福莫特罗与按需使用短效β-激动剂（SABA）相比，可降低长期加重的风险，与布地奈德加按需使用 SABA 维持治疗相比，其降低风险或更高，尽管布地奈德剂量较低。在轻度哮喘中按需给予 Symbicort（SYGMA）1 研究的这一事后分析中，我们研究了在各种缓解药物使用水平下，单次用药后 21 天内发生严重加重的短期风险。
SYGMA 1 是一项为期 52 周、双盲、随机、对照、3 期临床试验，其中年龄在 12 岁及以上的轻度哮喘患者按 1:1:1 的比例随机分配（双盲）至安慰剂每日 2 次加按需特布他林 0.5mg、安慰剂每日 2 次加按需布地奈德福莫特罗 200-6μg或布地奈德 200μg每日 2 次加按需特布他林（即布地奈德维持组）。在这项事后分析中，我们评估了首次使用 24 小时内超过 2、4、6 或 8 次缓解吸入器后，缓解药物的使用频率和严重加重的风险。SYGMA 1 在 ClinicalTrials.gov 上注册，NCT02149199，现已完成。
在 SYGMA 1 中纳入的 5721 例患者中，3849 例患者被随机分配至按需特布他林（n=1280）、按需布地奈德福莫特罗（n=1279）或布地奈德维持治疗（n=1290），其中 3836 例患者有可评估的数据（n=1277 例按需特布他林，n=1277 例按需布地奈德福莫特罗，n=1282 例布地奈德维持治疗）。按需特布他林组的中位缓解药物使用率为每日 0.32 次（IQR 0.08-0.91），按需布地奈德福莫特罗组为 0.29（0.07-0.72），布地奈德维持组为 0.16（0.04-0.52）。与按需特布他林相比，在调整年龄、性别、随机分组治疗、研究前治疗组、基线支气管扩张剂后 FEV1 预计百分比和研究前 12 个月内严重加重后，每日使用超过 2 次缓解药物的 21 天内严重加重的风险比（HR）为 0.27（95%CI 0.12-0.58；p=0.0008），按需布地奈德福莫特罗组为 0.39（0.19-0.79；p=0.0091），布地奈德维持组为 0.39（0.19-0.79；p=0.0091）；每日使用超过 4 次缓解药物的 21 天内严重加重的 HR 为 0.24（0.10-0.62；p=0.0030），按需布地奈德福莫特罗组为 0.30（0.13-0.72；p=0.0065），布地奈德维持组为 0.30（0.13-0.72；p=0.0065）；每日使用超过 6 次缓解药物的 21 天内严重加重的 HR 为 0.14（0.02-1.06；p=0.057），按需布地奈德福莫特罗组为 0.43（0.14-1.26；p=0.12），布地奈德维持组为 0.43（0.14-1.26；p=0.12）。由于事件数量较少，未计算每日使用超过 8 次缓解药物的 HR。
在轻度哮喘中，按需使用布地奈德福莫特罗可降低单次高剂量使用（每日使用超过 2 次缓解药物）后的短期严重加重风险，即使整体使用频率较低。使用抗炎性缓解药物可能会通过在症状出现时及时提供增加剂量的按需吸入性皮质激素和福莫特罗，从而降低短期严重加重的风险。这些发现应在前瞻性随机临床试验中进一步评估。
阿斯利康。
