Medical Research Institute of New Zealand, Wellington, New Zealand; Capital and Coast District Health Board, Wellington, New Zealand; Division of Respiratory Medicine, School of Clinical Sciences, University of Nottingham, Nottingham, UK.
Lancet Respir Med. 2013 Mar;1(1):32-42. doi: 10.1016/S2213-2600(13)70007-9. Epub 2013 Mar 4.
The Single combination budesonide-formoterol inhaler Maintenance And Reliever Therapy (SMART) regimen reduces severe asthma exacerbations in patients, but whether the high doses of corticosteroid and β agonist increase the risk of adverse effects with both short-term and cumulative exposure is not certain. Our aim was to investigate whether the SMART regimen would reduce the risk of overuse of β agonist, reduce the likelihood of patients to seek medical review when such episodes occurred, and if any reduction in severe asthma exacerbations would be at the cost of a higher burden of systemic corticosteroid.
In this 24-week trial undertaken at four primary health-care practices and one hospital in New Zealand, patients (aged 16-65 years) with a recent asthma exacerbation were randomly assigned in a 1:1 ratio to the SMART or standard fixed-dose regimen. Treatment in the SMART group consisted of two actuations of budesonide-formoterol (200 μg and 6 μg, respectively, per actuation) twice daily, delivered through a combination metered dose inhaler (MDI), with one extra actuation as needed for relief of symptoms; treatment in the standard group consisted of two actuations of budesonide-formoterol (200 μg and 6 μg, respectively, per actuation) twice daily through a combination MDI with one to two actuations of salbutamol (100 μg per actuation) by MDI as needed for relief of symptoms. MDIs were monitored electronically to measure actual use of medication. The allocation sequence for randomisation was computer generated, with a block size of eight per site. Participants, investigators, and the statistician were not masked to group assignment. The primary outcome was the proportion of participants with at least one high-use episode of β agonist (more than eight actuations per day of budesonide-formoterol in addition to the four maintenance doses in the SMART group or more than 16 actuations per day of salbutamol in the standard group). Analysis was by intention to treat. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12610000515099.
303 patients were randomly assigned to the SMART (n=151) or standard group (n=152). No significant difference was noted between the SMART and standard groups in the proportion of participants with at least one high-use episode of β agonist (84 [56%] vs 68 [45%], respectively, relative risk 1·24 [95% CI 0·99-1·56]; p=0·058). There were fewer days of high use in the SMART group (mean 5·1 days [SD 14·3] vs 8·9 days [20·9], relative rate 0·58 [0·39-0·88]; p=0·01). Of the patients who had at least one high-use episode, those in the SMART group had fewer days of high use without medical review (8·5 days [17·8] vs 18·3 days [24·8], 0·49 [0·31-0·75]; p=0·001). The SMART regimen resulted in higher inhaled corticosteroid exposure (943·5 μg budesonide per day [1502·5] vs 684·3 μg budesonide per day [390·5], respectively; ratio of means 1·22 [1·06-1·41]; p=0·006), but reduced oral corticosteroid exposure (77·5 mg prednisone [240·5] vs 126·6 mg prednisone [382·1], respectively; p=0·011), with no significant difference in composite systemic corticosteroid exposure (793·7 mg prednisone equivalent per year [893·1] vs 772·1 mg prednisone equivalent per year [1062·7], respectively; 1·03 [0·86-1·22]; p=0·76). Participants in the SMART group had fewer severe asthma exacerbations (35 [weighted mean rate per year 0·53] vs 66 [0·97]; relative rate 0·54 [0·36-0·82]; p=0·004).
The SMART regimen has a favourable risk-to-benefit profile and can be recommended for use in adults at risk of severe asthma exacerbations.
Health Research Council of New Zealand.
单一组合布地奈德-福莫特罗吸入维持和缓解疗法（SMART）方案可降低患者重度哮喘恶化的风险，但高剂量皮质激素和β激动剂是否会增加短期和累积暴露的不良影响尚不确定。我们的目的是研究 SMART 方案是否会降低β激动剂过度使用的风险，当此类发作发生时，是否会降低患者寻求医疗审查的可能性，以及是否会以更高的系统性皮质激素负担为代价降低重度哮喘恶化的发生率。
在新西兰的四家基层医疗保健机构和一家医院进行的这项 24 周试验中，近期哮喘恶化的患者（年龄 16-65 岁）按 1:1 的比例随机分配至 SMART 或标准固定剂量方案组。SMART 组的治疗包括每天两次使用两个布地奈德-福莫特罗剂量（每次吸入分别为 200μg 和 6μg），通过组合计量吸入器（MDI）给药，需要时可额外使用一次缓解症状；标准组的治疗包括每天两次使用两个布地奈德-福莫特罗剂量（每次吸入分别为 200μg 和 6μg），通过组合 MDI 给药，需要时可额外使用一到两次沙丁胺醇（每次吸入 100μg）缓解症状。通过电子监测 MDI 来测量实际用药量。随机分组的序列是通过计算机生成的，每个站点的块大小为 8。参与者、研究人员和统计学家对分组情况不知情。主要结局是至少发生一次高剂量β激动剂（除 SMART 组每天 4 次维持剂量外，每天布地奈德-福莫特罗超过 8 次，或标准组每天沙丁胺醇超过 16 次）的参与者比例。分析按意向治疗进行。该试验在澳大利亚和新西兰临床试验注册中心注册，编号为 ACTRN12610000515099。
303 名患者被随机分配至 SMART（n=151）或标准组（n=152）。与标准组相比，SMART 组中至少发生一次高剂量β激动剂的参与者比例无显著差异（分别为 84 [56%] vs 68 [45%]，相对风险 1.24 [95%CI 0.99-1.56]；p=0.058）。SMART 组高剂量使用天数较少（平均 5.1 天[SD 14.3] vs 8.9 天[20.9]，相对比率 0.58 [0.39-0.88]；p=0.01）。在至少发生一次高剂量使用的患者中，SMART 组无需医疗审查的高剂量使用天数较少（8.5 天[17.8] vs 18.3 天[24.8]，0.49 [0.31-0.75]；p=0.001）。SMART 方案导致更高的吸入皮质激素暴露（每天布地奈德 943.5μg[1502.5] vs 每天布地奈德 684.3μg[390.5]，比值均数 1.22 [1.06-1.41]；p=0.006），但降低了口服皮质激素暴露（泼尼松 77.5mg[240.5] vs 泼尼松 126.6mg[382.1]，p=0.011），复合全身皮质激素暴露无显著差异（泼尼松等效物每年 793.7mg[893.1] vs 泼尼松等效物每年 772.1mg[1062.7]，比值均数 1.03 [0.86-1.22]；p=0.76）。SMART 组发生重度哮喘恶化的患者较少（35 [加权年发生率 0.53] vs 66 [0.97]，相对率 0.54 [0.36-0.82]；p=0.004）。
SMART 方案具有有利的风险效益比，可推荐用于有发生重度哮喘恶化风险的成年人。
新西兰健康研究委员会。
