London, UK.
Evidence Production and Methods Directorate, Cochrane, London, UK.
Cochrane Database Syst Rev. 2022 Sep 26;9(9):CD007524. doi: 10.1002/14651858.CD007524.pub5.
BACKGROUND: People with asthma may experience exacerbations, or 'attacks', during which their symptoms worsen and additional treatment is required. Written action plans sometimes advocate a short-term increase in the dose of inhaled corticosteroids (ICS) at the first sign of an exacerbation to reduce the severity of the attack and to prevent the need for oral steroids or hospital admission. OBJECTIVES: To compare the clinical effectiveness and safety of increased versus stable doses of ICS as part of a patient-initiated action plan for the home management of exacerbations in children and adults with persistent asthma. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register, which is derived from searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and CINAHL (Cumulative Index to Nursing and Allied Health Literature), and handsearched abstracts to 20 December 2021. We also searched major trial registries for ongoing trials. SELECTION CRITERIA: We included parallel and cross-over randomised controlled trials (RCTs) that allocated people with persistent asthma to take a blinded inhaler in the event of an exacerbation which either increased their daily dose of ICS or kept it stable (placebo). DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed quality, and extracted data. We reassessed risk of bias for all studies at the result level using the revised risk of bias tool for RCTs (Risk of Bias 2), and employed the GRADE approach to assess our confidence in the synthesised effect estimates. The primary outcome was treatment failure, defined as the need for rescue oral steroids in the randomised population. Secondary outcomes were treatment failure in the subset who initiated the study inhaler (treated population), unscheduled physician visits, unscheduled acute care, emergency department or hospital visits, serious and non-serious adverse events, and duration of exacerbation. MAIN RESULTS: This review update added a new study that increased the number of people in the primary analysis from 1520 to 1774, and incorporates the most up-to-date methods to assess the likely impact of bias within the meta-analyses. The updated review now includes nine RCTs (1923 participants; seven parallel and two cross-over) conducted in Europe, North America, and Australasia and published between 1998 and 2018. Five studies evaluated adult populations (n = 1247; ≥ 15 years), and four studies evaluated child or adolescent populations (n = 676; < 15 years). All study participants had mild to moderate asthma. Studies varied in the dose of maintenance ICS, age, fold increase of ICS in the event of an exacerbation, criteria for initiating the study inhaler, and allowed medications. Approximately 50% of randomised participants initiated the study inhaler (range 23% to 100%), and the included studies reported treatment failure in a variety of ways, meaning assumptions were required to permit the combining of data. Participants randomised to increase their ICS dose at the first signs of an exacerbation had similar odds of needing rescue oral corticosteroids to those randomised to a placebo inhaler (odds ratio (OR) 0.97, 95% confidence interval (CI) 0.76 to 1.25; 8 studies; 1774 participants; I = 0%; moderate quality evidence). We could draw no firm conclusions from subgroup analyses conducted to investigate the impact of age, time to treatment initiation, baseline dose, smoking history, and fold increase of ICS on the primary outcome. Results for the same outcome in the subset of participants who initiated the study inhaler were unchanged from the previous version, which provides a different point estimate with very low confidence due to heterogeneity, imprecision, and risk of bias (OR 0.84, 95% CI 0.54 to 1.30; 7 studies; 766 participants; I = 42%; random-effects model). Confidence was reduced due to risk of bias and assumptions that had to be made to include study data in the intention-to-treat and treated-population analyses. Sensitivity analyses that tested the impact of assumptions made for synthesis and to exclude cross-over studies, studies at overall high risk of bias, and those with commercial funding did not change our conclusions. Pooled effects for unscheduled physician visits, unscheduled acute care, emergency department or hospital visits, and duration of exacerbation made it very difficult to determine where the true effect may lie, and confidence was reduced by risk of bias. Point estimates for both serious and non-serious adverse events favoured keeping ICS stable, but imprecision and risk of bias due to missing data and outcome measurement and reporting reduced our confidence in the effects (serious adverse events: OR 1.69, 95% CI 0.77 to 3.71; 2 studies; 394 participants; I² = 0%; non-serious adverse events: OR 2.15, 95% CI 0.68 to 6.73; 2 studies; 142 participants; I² = 0%). AUTHORS' CONCLUSIONS: Evidence from double-blind trials of adults and children with mild to moderate asthma suggests there is unlikely to be an important reduction in the need for oral steroids from increasing a patient's ICS dose at the first sign of an exacerbation. Other clinically important benefits and potential harms of increased doses of ICS compared with keeping the dose stable cannot be ruled out due to wide confidence intervals, risk of bias in the trials, and assumptions that had to be made for synthesis. Included studies conducted between 1998 and 2018 reflect evolving clinical practice and study methods, and the data do not support thorough investigation of effect modifiers such as baseline dose, fold increase, asthma severity and timing. The review does not include recent evidence from pragmatic, unblinded studies showing benefits of larger dose increases in those with poorly controlled asthma. A systematic review is warranted to examine the differences between the blinded and unblinded trials using robust methods for assessing risk of bias to present the most complete view of the evidence for decision makers.
背景:哮喘患者在病情恶化时可能会经历哮喘加重(也称为“发作”),需要额外的治疗。书面行动计划有时提倡在哮喘加重的最初迹象时增加吸入性皮质类固醇(ICS)的剂量短期增加,以减轻发作的严重程度并防止需要口服类固醇或住院治疗。
目的:比较增加与稳定剂量的 ICS 作为患者发起的行动计划的一部分,用于管理儿童和成人持续性哮喘加重的有效性和安全性。
检索方法:我们检索了 Cochrane Airways 组特藏、Cochrane 中央对照试验注册库(CENTRAL)、MEDLINE、Embase 和 Cumulative Index to Nursing and Allied Health Literature(CINAHL),并于 2021 年 12 月 20 日对摘要进行了手工检索。我们还检索了主要的试验注册处,以查找正在进行的试验。
选择标准:我们纳入了平行和交叉随机对照试验(RCTs),这些试验将持续性哮喘患者随机分配使用吸入器,在哮喘加重时增加或保持 ICS 的日常剂量(安慰剂)。
数据收集和分析:两名综述作者独立选择试验、评估质量并提取数据。我们使用修订后的 RCT 偏倚风险工具(偏倚风险 2)重新评估了所有研究的偏倚风险,并使用 GRADE 方法评估了综合效果估计的可信度。主要结局是随机人群中需要抢救性口服类固醇的治疗失败。次要结局是在启动研究吸入器的治疗人群中发生治疗失败、未计划的医生就诊、未计划的急性护理、急诊或住院就诊、严重和非严重不良事件以及发作持续时间。
主要结果:本次更新综述增加了一项新的研究,将原发性分析中的人数从 1520 人增加到 1774 人,并采用了最新的方法来评估荟萃分析中偏倚的可能影响。更新后的综述现在包括 9 项 RCT(1923 名参与者;7 项平行研究和 2 项交叉研究),这些研究在欧洲、北美和澳大拉西亚进行,发表于 1998 年至 2018 年之间。5 项研究评估了成人人群(n = 1247;≥15 岁),4 项研究评估了儿童或青少年人群(n = 676;<15 岁)。所有研究参与者的哮喘均为轻度至中度。研究在维持 ICS 的剂量、哮喘加重时 ICS 的增幅、启动研究吸入器的标准以及允许的药物方面存在差异。大约 50%的随机参与者启动了研究吸入器(范围为 23%至 100%),并且纳入的研究以各种方式报告了治疗失败,这意味着需要进行假设才能合并数据。在哮喘加重的最初迹象时增加 ICS 剂量的随机参与者与接受安慰剂吸入器的随机参与者相比,需要抢救性口服皮质类固醇的可能性相似(比值比(OR)0.97,95%置信区间(CI)0.76 至 1.25;8 项研究;1774 名参与者;I = 0%;中等质量证据)。我们无法从亚组分析中得出明确的结论,这些亚组分析调查了年龄、治疗开始时间、基线剂量、吸烟史和 ICS 增幅对主要结局的影响。对于在启动研究吸入器的治疗人群中发生的相同结局的结果与上一版本相同,由于异质性、不精确性和偏倚风险,提供了不同的点估计值,可信度非常低(OR 0.84,95%置信区间 0.54 至 1.30;7 项研究;766 名参与者;I = 42%;随机效应模型)。由于偏倚和在意向治疗和治疗人群分析中纳入研究数据的假设,置信度降低。对用于综合和排除交叉研究、整体高偏倚风险研究以及有商业资助研究的假设进行的敏感性分析并未改变我们的结论。未计划的医生就诊、未计划的急性护理、急诊或住院就诊以及发作持续时间的汇总效应使得很难确定真正的效果可能在哪里,并且由于数据缺失和结局测量和报告,可信度降低。严重和非严重不良事件的点估计值都倾向于保持 ICS 稳定,但由于数据缺失和结局测量和报告的偏倚和不精确性,降低了对效果的可信度(严重不良事件:OR 1.69,95%置信区间 0.77 至 3.71;2 项研究;394 名参与者;I² = 0%;非严重不良事件:OR 2.15,95%置信区间 0.68 至 6.73;2 项研究;142 名参与者;I² = 0%)。
作者结论:来自轻度至中度哮喘的成人和儿童的双盲试验证据表明,在哮喘加重的最初迹象时增加患者的 ICS 剂量不太可能显著减少对口服类固醇的需求。与保持剂量稳定相比,ICS 剂量增加的其他其他重要临床获益和潜在危害不能排除,因为置信区间较宽、试验偏倚以及综合分析中需要进行假设。纳入的研究在 1998 年至 2018 年间进行,反映了不断发展的临床实践和研究方法,数据不支持对基线剂量、增幅、哮喘严重程度和时间等效应修饰因素进行彻底研究。综述未包括最近来自未盲、务实研究的证据,这些证据显示在控制不佳的哮喘患者中较大剂量增加的益处。需要进行系统评价,使用评估偏倚的稳健方法来检查盲法和非盲法试验之间的差异,以呈现决策者最完整的证据视图。
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