Addition of long-acting beta2-agonists to inhaled steroids as first line therapy for persistent asthma in steroid-naive adults and children

 

Abstract

Background

Consensus statements recommend the addition of long-acting inhaled ß2-agonists (LABA) only in asthmatic patients who are inadequately controlled on inhaled corticosteroids (ICS). It is not uncommon for some patients to be commenced on ICS and LABA together as initial therapy.

Objectives

To compare the efficacy of combining inhaled corticosteroids with long-acting ß2-agonists (ICS+LABA) with inhaled corticosteroids alone (ICS alone) in steroid-naive children and adults with persistent asthma. We assessed two protocols: (1) LABA + ICS versus a similar dose of ICS (comparison 1) and (2) LABA + ICS versus a higher dose of ICS (comparison 2).

Search methods

We identified randomised controlled trials through electronic database searches (May 2008).

Selection criteria

Randomised trials comparing ICS + LABA with ICS alone in children and adults with asthma who had no inhaled corticosteroids in the preceding 28 days prior to enrolment.

Data collection and analysis

Each author assessed studies independently for risk of bias and extracted data. We obtained confirmation from the trialists when possible. The primary endpoint was rate of patients with one or more asthma exacerbations requiring rescue systemic corticosteroids. Results are expressed as relative risks (RR) for dichotomous data and as mean differences (MD) or standardised mean differences (SMD) for continuous data.

Main results

Twenty-eight study comparisons drawn from 27 trials (22 adult; five paediatric) met the review entry criteria (8050 participants). Baseline data from the studies indicated that trial populations had moderate or mild airway obstruction (FEV1≥65% predicted), and that they were symptomatic prior to randomisation. In comparison 1, the combination of ICS and LABA was not associated with a significantly lower risk of patients with exacerbations requiring oral corticosteroids (RR 1.04; 95% confidence interval (CI) 0.73 to 1.47) or requiring hospital admissions (RR 0.38; 95% CI 0.09 to 1.65) compared to a similar dose of ICS alone. The combination of LABA and ICS led to a significantly greater improvement from baseline in FEV1 (0.12 L/sec; 95% CI 0.07 to 0.17), in symptoms (SMD -0.26; 95% CI -0.37 to -0.14) and in rescue ß2-agonist use (-0.41 puffs/day; 95% CI -0.73 to -0.09) compared with a similar dose of ICS alone. There was no significant group difference in the risk of serious adverse events (RR 1.15; 95% CI 0.64 to 2.09), any adverse events (RR 1.02; 95% CI 0.96 to 1.09), study withdrawals (RR 0.95; 95% CI 0.82 to 1.11), or withdrawals due to poor asthma control (RR 0.94; 95% CI 0.63 to 1.41).

In comparison 2, the combination of LABA and ICS was associated with a higher risk of patients requiring oral corticosteroids (RR 1.24; 95% CI 1 to 1.53) and study withdrawal (RR 1.31; 95% CI 1.07 to 1.59) than a higher dose of ICS alone. For every 100 patients treated over 43 weeks, nine patients using a higher dose ICS compared to 11 (95% CI 9 to 14) on LABA and ICS suffered one or more exacerbations requiring rescue oral corticosteroids. There was a high level of statistical heterogeneity for FEV1 and morning peak flow. There was no statistically significant group difference in the risk of serious adverse events. Due to insufficient data we could not aggregate results for hospital admission, symptoms and other outcomes.

Authors' conclusions

In steroid-naive patients with mild to moderate airway obstruction, the combination of ICS and LABA does not significantly reduce the risk of patients with exacerbations requiring rescue oral corticosteroids over that achieved with a similar dose of ICS alone. However, it significantly improves lung function, reduces symptoms and marginally decreases rescue ß2-agonist use. Initiation of a higher dose of ICS is more effective at reducing the risk of exacerbations requiring rescue systemic corticosteroids, and of withdrawals, than combination therapy. Although children appeared to respond similarly to adults, no firm conclusions can be drawn regarding combination therapy in steroid-naive children, given the small number of children contributing data.

 

Plain language summary

The effect of adding a long-acting beta-agonist to inhaled steroids in people not previously treated with inhaled steroids

In patients with asthma who require daily anti-inflammatory therapy, there is insufficient evidence to support initiating therapy with a combination of inhaled corticosteroids (ICS) and long-acting ß2-agonist (LABA) rather than with inhaled corticosteroids alone. Most consensus statements recommend the addition of LABA as second line therapy, only in asthmatic individuals who remain insufficiently controlled on maintenance inhaled corticosteroids. Yet, many physicians initiate combination therapy in patients with asthma, without a prior trial of inhaled corticosteroids alone. The purpose of this review was to compare the benefit and safety profile of initiating treatment with the combination of ICS and LABA as compared to a (1) similar and (2) higher dose of ICS alone in asthmatic patients who had not received ICS previously. This review identified 28 randomised controlled trials. The combination of ICS and LABA did not reduce the risk of patients with exacerbations requiring rescue oral corticosteroids but improved lung function, symptoms and minimally reduced the use of rescue ß2-agonists as compared to a similar dose of ICS alone. Initiating ICS at a higher dose than that used with LABA in the control group significantly reduced the risk of exacerbations and study withdrawals over that observed with the combination of LABA and a lower dose of ICS; there is insufficient evidence to comment on the impact on lung function, symptoms and use of rescue ß2-agonists. The current evidence does not support use of combination therapy with LABA and ICS as first line treatment in adults and children with asthma, without a prior trial of inhaled corticosteroids.

 

摘要

背景

在患有持續性氣喘、且對類固醇治療無效的成人或幼童身上，添加吸入式長效型β−2增效劑(LABA)至吸入性類固醇(Inhaled steroids，ICS)中，作為第一線的治療用藥

一些共識原則(Consensus statements)建議，若患者無法以ICS進行控制，才添加LABA進行治療。也有某些患者一開始就合併使用ICS和LABA治療。

目標

在持續氣喘且無法用類固醇控制症狀的幼童和成人身上，為了比較單獨使用ICS和並用ICS與LABA的複合式類固醇的療效，我們設計了兩組實驗，(1)第一組：將使用ICS和LABA的混合藥劑與類似劑量的ICS的治療效果進行比較(比較組1)；(2)第二組：將使用ICS和LABA的混合藥劑和較高劑量的ICS的治療效果進行比較(比較組2)。

搜尋策略

搜尋電子資料庫，尋找相關的隨機對照試驗。(2008年5月)

選擇標準

針對在試驗前28天未曾使用ICS的幼年或成年氣喘患者，比較其使用ICS和LABA混合藥物和單獨使用ICS藥物的隨機性試驗都會被納入研究中。

資料收集與分析

每位作者分別針對風險偏差(Risk of bias)和萃取出的數據(Extracted data)進行獨立評估，在可能的狀況下，我們可以由受試者身上獲得一些驗證，試驗的主要結束點是依據患者出現一種以上氣喘症狀惡化至需要使用緊急用全身性皮質類固醇的速率來決定。二元化資訊的研究結果以相對風險(Relative risks，RR)表示，而連續性資訊的結果則以平均數差異(Mean differences，MD)或標準化平均數差異(Standardised mean differences，SMD)表示。

主要結論

由27個試驗(其中22個以成人為受試者的試驗，5個以幼童為受試者的試驗)獲得28個符合本文獻回顧的納入條件(納入規範的人數共8050人)的比較結果。研究獲得的基準數據顯示，受試族群患有輕至中度的呼吸道阻塞(Airway obstruction)(第一秒內用力吐氣量FEV1值約為預期的65％)，且這些患者在進行隨機分組前皆具有相關症狀。在比較組1中，與單獨使用相似劑量ICS的組別相較，將ICS和LABA混合使用的組別，無法明顯降低患者因症狀惡化而需使用口服類固醇(相對風險RR為1.04，95％信賴區間CI介於0.73至1.47之間)或住院治療(相對風險為0.38，95％信賴區間介於0.09至1.65之間)的風險；將ICS和LABA混合使用能使FEV1由基準值大幅改善(每秒0.12公升(L/sec)，95％信賴區間介於0.07至0.17之間)，症狀也有明顯改善(SMD值為−0.26，95％信賴區間介於−0.37至−0.14之間)，更可減少急救時β2增效劑的用量(−0.41puffs天，95％信賴區間介於−0.73至−0.09之間)。各組別間對於嚴重不良事件的風險(相對風險為1.15，95％信賴區間介於0.64至2.09之間)、任何副作用的風險(相對風險為1.02，95％信賴區間介於0.96至1.09之間)、研究終止的風險(相對風險為0.95，95％信賴區間介於0.82至1.11之間)和因為氣喘症狀無法獲得良好控制而停藥(相對風險為0.94，95％信賴區間介於0.63至1.41之間)這些事件上並無顯著差異。在比較組2中，與單獨使用較高劑量ICS的組別相較，將ICS和LABA混合使用，會使需要使用口服類固醇(相對風險為1.24，95％信賴區間介於1至1.53之間)和研究終止(相對風險為1.31，95％信賴區間介於1.07至1.59之間)等事件的風險增加；若治療超過43週，使用較高劑量ICS的患者有9％、混合使用ICS和LABA的患者則有11％的機率(95％信賴區間介於9至14之間)會產生一次以上的症狀惡化現象，需緊急以口服類固醇治療。FEV1值和清晨尖峰氣流量(Morning Peak Flow)等數值都有統計學上的高度異質性；在發生嚴重不良事件的風險上，各組別之間沒有顯著差異。此外，由於數據不足，我們無法聚集有效的結果並針對住院率、症狀和其他可能結果進行探討。

作者結論

對於患有輕至中度氣管阻塞且無法以類固醇控制症狀的患者來說，相對於單獨使用相似劑量ICS，將ICS和LABA並用無法明顯降低患者因為症狀惡化而需緊急口服類固醇的風險，但能改善患者的肺功能指數、緩解症狀，緊急狀況下所需β2增效劑的劑量也可稍微降低。相對於混合療法，使用高劑量的ICS對降低因為症狀惡化而需緊急使用全身性類固醇、或是終止研究的風險，其效果比較理想。雖然幼童研究的結果與成人相似，但因為參與試驗的幼童數較少，無法提供足夠的證據來支持有關對類固醇無效的幼童使用混合藥物療法其療效的結論。

翻譯人

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

對於未曾接受吸入式類固醇治療的病患，在吸入式類固醇內添加長效β增效劑的影響。對於每天都需要抗發炎治療的氣喘患者來說，研究證據無法支持將ICS和LABA進行混合使用，而非單獨使用ICS；多數共識原則也認為只有當氣喘患者無法藉由ICS獲得良好的病情控制時，才需添加LABA作為第二線治療藥物。然而，許多醫師不先單獨使用ICS，而直接給氣喘患者進行混合藥物治療。本文獻回顧的主要目的便是希望建立在治療氣喘初期使用ICS和LABA混合藥物其治療效益和安全性規範，並將此混合藥物在患者未曾接受過ICS治療的前提下與(1)單獨使用相似劑量的ICS；及(2)單獨使用較高劑量ICS的療效進行比較。本文獻回顧挑選出28個隨機性對照試驗。相對於單獨使用相似劑量的ICS，混合使用ICS和LABA無法降低患者因症狀惡化而需緊急口服式類固醇的風險，但是卻可增進肺功能、改善症狀，並且將緊急時所需使用β2增效劑的劑量降低一些。若是使用高劑量的ICS，比與LABA併用的對照組或使用低劑量ICS的組別更能明顯降低症狀惡化和終止研究的風險；但目前沒有足夠的證據顯示肺功能、症狀改善或是緊急時β2增效劑的使用量有所改善。對於患有氣喘且未曾使用吸入式類固醇的幼童或成人，目前的研究證據無法支持施以ICS和LABA的混合性藥劑作為第一線治療用藥。