Regular treatment with formoterol and inhaled steroids for chronic asthma: serious adverse events

  • Conclusions changed
  • Review
  • Intervention

Authors


Abstract

Background

Epidemiological evidence has suggested a link between beta2-agonists and increases in asthma mortality. Much debate has surrounded possible causal links for this association and whether regular (daily) long-acting beta2-agonists are safe when used alone or in conjunction with inhaled corticosteroids. This is an updated Cochrane Review.

Objectives

To assess the risk of fatal and non-fatal serious adverse events in people with chronic asthma given regular formoterol with inhaled corticosteroids versus the same dose of inhaled corticosteroids alone.

Search methods

Trials were identified using the Cochrane Airways Group Specialised Register of trials. Web sites of clinical trial registers were checked for unpublished trial data; Food and Drug Administration (FDA) submissions in relation to formoterol were also checked. The date of the most recent search was August 2012.

Selection criteria

Controlled clinical trials with a parallel design were included if they randomly allocated people of any age and severity of asthma to treatment with regular formoterol and inhaled corticosteroids for at least 12 weeks.

Data collection and analysis

We used standard methodological procedures expected by The Cochrane Collaboration. Unpublished data on mortality and serious adverse events were obtained from the sponsors. We assessed the quality of evidence using GRADE recommendations.

Main results

Following the 2012 update, we have included 20 studies on 10,578 adults and adolescents and seven studies on 2788 children and adolescents. We found data on all-cause fatal and non-fatal serious adverse events for all studies, and we judged the overall risk of bias to be low.

Six deaths occurred in participants taking regular formoterol with inhaled corticosteroids, and one in a participant administered regular inhaled corticosteroids alone. The difference was not statistically significant (Peto odds ratio (OR) 3.56, 95% confidence interval (CI) 0.79 to 16.03, low-quality evidence). All deaths were reported in adults, and one was believed to be asthma-related.

Non-fatal serious adverse events of any cause were very similar for each treatment in adults (Peto OR 0.98, 95% CI 0.76 to 1.27, moderate-quality evidence), and weak evidence suggested an increase in events in children on regular formoterol (Peto OR 1.62, 95% CI 0.80 to 3.28, moderate-quality evidence).

In contrast with all-cause serious adverse events, the addition of new trial data means that asthma-related serious adverse events associated with formoterol are now significantly fewer in adults taking regular formoterol with inhaled corticosteroids (Peto OR 0.49, 95% CI 0.28 to 0.88, moderate-quality evidence). Although a greater number of asthma-related events were reported in children receiving regular formoterol, this finding was not statistically significant (Peto OR 1.49, 95% CI 0.48 to 4.61, low-quality evidence).

Authors' conclusions

From the evidence in this review, it is not possible to reassure people with asthma that regular use of inhaled corticosteroids with formoterol carries no risk of increasing mortality in comparison with use of inhaled corticosteroids alone. On the other hand, we have found no conclusive evidence of serious harm, and only one asthma-related death was registered during more than 4200 patient-years of observation with formoterol.

In adults, no significant difference in all-cause non-fatal serious adverse events was noted with regular formoterol with inhaled corticosteroids, but a significant reduction in asthma-related serious adverse events was observed in comparison with inhaled corticosteroids alone.

In children the number of events was too small, and consequently the results too imprecise, to allow determination of whether the increased risk of all-cause non-fatal serious adverse events found in a previous meta-analysis on regular formoterol alone is abolished by the additional use of inhaled corticosteroids.

We await the results of large ongoing surveillance studies mandated by the Food and Drug Administration (FDA) for more information. Clinical decisions and information provided to patients regarding regular use of formoterol have to take into account the balance between known symptomatic benefits of formoterol and the degree of uncertainty associated with its potential harmful effects.

摘要

背景

規律使用formoterol和吸入式類固醇治療慢性氣喘:嚴重不良事件

流行病學證據顯示beta2agonists可能與氣喘死亡率有關,不過目前對於相關原因、以及規律使用(每天使用)長效型beta2agonists(單獨使用或是合併吸入型類固醇使用)的安全性還是有所爭議。

目標

本文旨在評估隨機慢性氣喘病患規律使用formoterol併用ICS治療,和單獨使用相同劑量ICS進行治療,引發產生致命性和非致命性不良事件的風險。

搜尋策略

利用Cochrane Airways Group Specialised Register of trials篩選試驗,也會確認臨床試驗登錄中心的網頁中以獲得未公開的試驗數據,並檢視食品藥物管理局(Food and Drug Administration,FDA)對於formoterol的意見書,最近一次的檢索時間為2008年10月。

選擇標準

納入任何年齡患有氣喘疾病患者設計的對照性平行臨床試驗,只要這個試驗是隨機選取患者進行規律formoterol和ICS治療即可,治療時間至少要持續12週。

資料收集與分析

有2位獨立作者挑選適合納入研究的試驗,並由這2位作者分別摘錄結果數據,並透過贊助者取得死亡率和嚴重不良事件的未公開數據。

主要結論

本文獻回顧納入了14個以成人及青少年為受試者(共8028人)的試驗,另外有7個試驗則是針對幼童及青少年為受試對象(共2788人)。所有試驗中都有揭露全原因致命和非致命嚴重不良事件的數據,整體來說發生偏誤(bias)的風險很低。 規律服用formoterol和ICS的組別中出現了4個死亡案例,但是單獨規律使用ICS的組別則沒有出現死亡案例。所有的死亡個案都是成人,並且有1個個案的死亡原因與氣喘有關。這樣的差異性不具統計顯著,出現在成人身上的全原因非致命嚴重不良事件都十分相似(Peto OR值為0.99,95%的CI 介於0.74至1.33之間),規律使用formoterol的幼童在不良事件發生率增加上也不具有統計上顯著(Peto OR值為0.62,95%的CI 介於0.80至3.28之間)。 在使用formoterol的組別中,成人較少出現與氣喘有關的嚴重不良事件((Peto OR值為0.53,95%的CI 介於0.28至1.00之間),而幼童出現與氣喘有關的不良事件機率較高((Peto OR值為1.49,95%的CI 介於0.48至4.61之間),但是這些結果上的差異在統計學上並不具有顯著性。

作者結論

本文獻回顧的數據並無法確認與僅使用吸入性類固醇組別相較,氣喘患者在使用吸入性類固醇時搭配規律使用formoterol不會增加死亡率的風險,因為在6594名受試者使用吸入性類固醇搭配規律使用formoterol,只有出現4個死亡案例。另一方面,也沒有決定性的證據指出具有危害,此外觀察3000病人年(patient year),也只有出現1個與氣喘有關的死亡個案。 ■對於成人來說,使用formoterol和吸入性類固醇,雖然可以降低與氣喘有關的嚴重不良事件發生率,不過並無法降低全原因嚴重不良事件發生率。 ■在幼童這組,由於不良事件過少,因此結果不夠精確,無法確認常規單獨使用formotero與全原因非致死不良事件增加的狀況(之前統合分析發現的)是否會因為添加使用吸入型類固醇而減少。提供給患者有關於規律使用formoterol的臨床決策和資訊之前,必須先考量使用formoterol對症狀的益處,以及不確定性及所帶來的害處之間的平衡。

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

對於氣喘患者進行formoterol、LABA治療後,嚴重不良事件發生機率增加而引發疑慮。我們分析了147個以成人為受試者及7個以幼童為受試者的試驗數據。試驗中的死亡個案過少,所以對於規律使用formoterol和ICS是否會降低死亡風險或是不會增加死亡風險(在6594個搭配使用formoterol和ICS的患者中,發生有4個死亡案例,包括1個與氣喘有關的死亡案例)尚無法獲得確切的再確認結果。不論是否使用formoterol,發生在成人身上的嚴重不良事件都十分相似,使用formoterol對於幼童會引發較多的不良事件,但這樣的差異不夠明顯到足以說明這樣的結果是否只是一個意外發現。相同的,成人患者發生與氣喘有關的嚴重不良事件風險也會降低,但是幼童患者服用formoterol後發生與氣喘有關不良事件的風險卻增加了,這樣的結果也是意外的發現。

Résumé scientifique

Traitement de fond de formotérol et de stéroïdes inhalés contre l'asthme chronique: événements indésirables graves

Contexte

Des preuves épidémiologiques ont suggéré un lien entre les bêta2-agonistes, et l'augmentation de la mortalité liée à l'asthme. Il existe de nombreux débats autour des liens de causalité possibles pour cette association, et sur la question de la sécurité autour des bêta2-agonistes à longue durée d'action (en traitement de fond) utilisés seuls ou en association à des corticoïdes inhalés.

Objectifs

Le but de cette revue est d'évaluer le risque d'événements indésirables graves mortels ou non, dans les essais qui ont randomisé les patients souffrant d'asthme chronique avec du salmétérol et des corticoïdes inhalés par rapport à la même dose de corticoïdes inhalés seuls.

Stratégie de recherche documentaire

Les essais ont été identifiés en examinant le registre Cochrane des groupes spécialisés d'essais sur les voies respiratoires. Les sites Internet des registres des essais cliniques ont été vérifiés, les données d'essais non publiées et les soumissions à la Food and Drug Administration (FDA) en rapport au formotérol ont aussi été vérifiées. La recherche la plus récente est datée d'octobre 2008.

Critères de sélection

Les essais cliniques contrôlés parallèles sur les patients de tout âge et de différentes gravités d'asthme ont été inclus s'ils randomisaient les patients sous traitement de fond de formotérol et de corticoïdes inhalés, et s'ils étaient d'une durée d'au moins 12 semaines.

Recueil et analyse des données

Deux auteurs ont sélectionné indépendamment des essais à inclure dans la revue. Les données de pronostic ont été extraites indépendamment par deux auteurs. Les données non publiées sur la mortalité et les événements indésirables graves ont été obtenues des sponsors.

Résultats principaux

La revue a inclus 14 études sur les adultes et les adolescents (8 028 participants) et sept études sur les enfants et les adolescents (2 788 participants). Les données sur les événements indésirables graves mortels et non mortels toutes causes confondues ont été trouvées pour toutes les études, et le risque général de biais était bas.

Quatre décès sont survenus sous formotérol en traitement de fond avec des corticoïdes inhalés, et aucun sous corticoïdes inhalés seuls. Tous les décès étaient chez les adultes, et un a été rapporté comme étant lié à l'asthme. La différence n'était pas statistiquement significative.

Des événements indésirables non mortels toutes causes confondues étaient très similaires chez les adultes [Rapport des cotes Peto 0,99 (IC à 95% entre 0,74 et 1,33)], et une augmentation des événements chez les enfants sous formotérol en traitement de fond n'était pas statistiquement significative [Rapport des cotes Peto 1,62 (IC à 95% entre 0,80 et 3,28)].

Les événements indésirables graves liés à l'asthme sous formotérol étaient plus bas chez les adultes [Rapport des cotes Peto 0,53 (IC à 95% entre 0,28 et 1,00)] et bien qu'ils fussent plus hauts chez les enfants [Rapport des cotes 1,49 (IC à 95% entre 0,48 et 4,61)], cela n'était pas statistiquement significatif.

Conclusions des auteurs

Il n'est pas possible, en se basant sur les données de cette revue, de rassurer les personnes souffrant d'asthme sur le fait que les corticoïdes inhalés liés au formotérol en traitement de fond, ne présentent aucun risque d'augmentation du taux de mortalité en comparaison aux corticoïdes inhalés seuls car les quatre décès sont survenus parmi 6 594 personnes utilisant des corticoïdes inhalés avec du formotérol. Cependant, nous n'avons trouvé aucune preuve concluante d'effets délétères et un seul décès lié à l'asthme a été enregistré sur chez plus de 3 000 patients-années d’observation sous formotérol. Chez les adultes, la réduction des événements indésirables graves liés à l'asthme sous formotérol avec corticoïdes inhalés n'était pas accompagnée d'une réduction de graves événements indésirables toute cause confondue. Chez l'enfant le nombre d'événements était trop limité, et en conséquence les résultats trop imprécis pour déterminer si l'augmentation des événements indésirables graves non mortels toutes causes confondues trouvés dans les méta-analyses précédentes autour du formotérol en traitement de fond seul puisse être annulée par l'utilisation supplémentaire de corticoïdes inhalés. Les décisions cliniques et les informations aux patients concernant l'utilisation en traitement de fond du formotérol doivent prendre en compte l'équilibre entre les bénéfices symptomatiques connus et les degrés d'incertitude et d'inquiétude associés à ses effets néfastes potentiels.

Plain language summary

Regular treatment with formoterol and inhaled steroids for chronic asthma: serious adverse events

Background
Asthma is a disease of the lungs. Symptoms include wheezing, breathlessness and chest tightness. Two main features of asthma have been identified: underlying inflammation, which can be treated with daily steroids, and bronchoconstriction (tightening of the muscles around small tubes in the lungs), which can be treated with a beta2-agonist to relax the muscles.

When asthma is not controlled by daily low-dose inhaled steroids, many asthma guidelines recommend additional daily long-acting beta2-agonists (such as formoterol). Although we know that long-acting beta2-agonists are beneficial for lung function, symptoms, quality of life, and exacerbations, long-standing controversy surrounds the safety of regular use of beta2-agonists in people with asthma. This is the topic we sought to explore in this review.

Review question
We assessed the risk of death and of non-fatal serious adverse events in clinical trials comparing regular formoterol and inhaled steroids with the same dose of inhaled steroids in adults and children with asthma.

Key results
We analysed data from 20 studies in adults and 7 in children; these studies included participants with a range of asthma severity, and most participants had been previously treated with regular inhaled steroids (over a wide range of doses). The number of children studied was insufficient to allow a solid conclusion. However, a large trial in children is now in progress.

Seven deaths were reported among 13,366 participants. Six of these deaths, including one related to asthma, were reported in adults taking formoterol and inhaled steroids, and one death occurred in a participant who was taking inhaled steroids alone. Because few deaths were reported in these trials, we cannot conclusively state whether taking formoterol and inhaled steroids reduces or increases the risk of death compared with taking inhaled steroids alone.

The number of people experiencing serious adverse events of any cause was very similar in adults with and without formoterol. A significant reduction in serious adverse events was noted in adult participants with asthma who were taking regular formoterol in combination with inhaled corticosteroids.

Quality of the evidence
The quality of the data was moderate for adults but low in children because data in children were insufficient. All trials were sponsored by drug manufacturers. We were therefore concerned that bias might have been introduced in the attribution of asthma as the cause of serious events, as this was not independently assessed. The trials were double-blind; however, formoterol can have a big impact on asthma symptoms, and those who decided on the cause of the events may have guessed which treatment was being given.

Bottom line
We are not able to confidently state that adding formoterol to inhaled steroids carries no risk of increasing the number of deaths in comparison with inhaled steroids alone. On the other hand, we found no conclusive evidence of serious harm, and only one asthma-related death was reported over 4200 patient-years of observation of those treated with formoterol. With the addition of new studies in 2012, we have found a lower risk of non-fatal serious adverse events attributed to asthma when formoterol is combined with inhaled steroids.

Glossary: serious adverse events: events that are life threatening, require inpatient hospitalisation or prolongation of existing hospitalisation, or result in persistent or significant disability/incapacity or a birth defect.

This Cochrane plain language summary is current as of August 2012.

Résumé simplifié

Événements indésirables graves sous formotérol et corticoïdes inhalés en traitement de fond

Certaines inquiétudes ont été soulevées sur la possibilité d'une augmentation des événements indésirables suivant l'administration de formotérol, un bêta-agoniste à longue durée d'action chez les asthmatiques. Nous avons analysé les données de 14 études chez l'adulte et sept chez l'enfant. Trop peu de décès sont survenus dans les essais pour pouvoir conclure de façon rassurante que le formotérol en traitement de fond avec des corticoïdes inhalés réduit le risque de mortalité ou ne l'augmente pas (les quatre décès survenus, dont celui lié à de l'asthme, étaient parmi 6 594 patients sous formotérol avec corticoïdes inhalés.) Des événements indésirables graves étaient très similaires chez les adultes avec ou sans formotérol. Bien qu'il se soit produit plus d'événements sous formotérol chez les enfants, la différence n'était pas assez importante pour écarter l'idée d'une coïncidence. De même, la diminution du risque d'événements indésirables graves liés à l'asthme chez les adultes et le risque accru parmi les enfants sous formotérol pourrait aussi être une coïncidence.

Notes de traduction

Traduit par: French Cochrane Centre 1st October, 2012
Traduction financée par: Ministère du Travail, de l'Emploi et de la Santé Français

Summary of findings(Explanation)

Summary of findings for the main comparison. Regular formoterol and ICS compared to ICS in adults with asthma
  1. 1 Imprecision (-2): very wide confidence interval.
    2 Imprecision (-1): wide confidence interval.
    3 Risk of bias (-1): no independent assessment of causation of SAEs.

Regular formoterol and ICS compared to ICS in adults with asthma
Patient or population: adults with asthma
Settings: community
Intervention: regular formoterol and ICS
Comparison: same dose ICS
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Same dose ICS Regular formoterol and ICS
All-cause mortality
Follow-up: mean 28 weeks
0 per 1000 1 per 1000
(0 to 4)
OR 3.56
(0.79 to 16.03)
10578
(22 studies)
⊕⊕⊝⊝
low 1
 
All-cause non-fatal serious adverse events
Follow-up: mean 28 weeks
26 per 1000 25 per 1000
(20 to 32)
OR 0.98
(0.76 to 1.27)
10578
(22 studies)
⊕⊕⊕⊝
moderate 2
 
Asthma-related non-fatal serious adverse events
Follow-up: mean 28 weeks
7 per 1000 3 per 1000
(2 to 6)
OR 0.49
(0.28 to 0.88)
10208
(21 studies)
⊕⊕⊕⊝
moderate 3
 
*The basis for the assumed risk is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio.
GRADE Working Group grades of evidence:
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 2 Regular formoterol and ICS compared to ICS in children with asthma

Summary of findings 2. Regular formoterol and ICS compared to ICS in children with asthma
  1. 1No deaths in children were reported.
    2Imprecision (-1): wide confidence interval.
    3Risk of bias (-1): no independent assessment of causation of SAEs.
    4Unexplained heterogeneity between trial results.

Regular formoterol and ICS compared to ICS in children with asthma
Patient or population: children with asthma
Settings: community
Intervention: regular formoterol and ICS
Comparison: same dose ICS
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Same dose ICS Regular formoterol and ICS
All-cause mortality
Follow-up: mean 13 weeks
See commentSee commentNot estimable2788
(7 studies)
⊕⊝⊝⊝
very low 1
There were no deaths in children
All-cause non-fatal serious adverse events Follow-up: mean 13 weeks 8 per 1000 14 per 1000
(7 to 27)
OR 1.62
(0.8 to 3.28)
2788
(7 studies)
⊕⊕⊕⊝
moderate 2
 
Asthma-related non-fatal serious adverse events Follow-up: mean 13 weeks 4 per 1000 6 per 1000
(2 to 17)
OR 1.49
(0.48 to 4.61)
2788
(7 studies)
⊕⊕⊝⊝
low 2,3,4
 
*The basis for the assumed risk is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio.
GRADE Working Group grades of evidence:
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

When asthma is not controlled by low-dose inhaled corticosteroids alone, many asthma guidelines recommend the use of additional long-acting beta2-agonists (LABA). Several Cochrane reviews have addressed the efficacy of long-acting beta2-agonists in addition to inhaled corticosteroids (Ni Chroinin 2009a; Ni Chroinin 2010) in comparison with placebo (Walters 2007), short-acting beta2-agonists (Walters 2002) and leukotriene-receptor antagonists (Ducharme 2011a) and have assessed their use against increased doses of inhaled corticosteroids (Ducharme 2010a). The beneficial effects of long-acting beta2-agonists on lung function, symptoms, quality of life and exacerbations requiring oral steroids have been demonstrated.

However, long-standing controversy over the regular use of beta2-agonists in asthma is ongoing. Sears 1986 suggested that excessive use of short-acting beta2-agonists might have contributed directly or indirectly to an increase in asthma deaths in New Zealand between 1960 and 1980. The authors comment that "most deaths were associated with poor assessment, underestimation of severity and inappropriate treatment (over-reliance on bronchodilators and under-use of systemic corticosteroids), and delays in obtaining help."

Concern remains that the symptomatic benefit derived from treatment with long-acting beta2-agonists might lead to underestimation of attack severity in acute asthma, and could lead to an increase in asthma-related deaths. Furthermore, regular treatment with beta2-agonists can lead to tolerance of their bronchodilator effects, and this phenomenon might be more marked with longer-acting as opposed to shorter-acting compounds (Lipworth 1997). A number of molecular mechanisms have been proposed to explain the possible detrimental effects of long-term beta2-agonists in patients with asthma, including receptor downregulation and desensitisation (Giembycz 2006).

Two long-acting beta2-agonists are currently available: salmeterol and formoterol (also known as eformoterol). These two drugs have shown differences in speed of onset and receptor activity and are used in different ways (e.g. salmeterol has a slower onset of action than salbutamol (Beach 1992) and therefore is unsuitable for use as a reliever). 'The Fenoterol Story' is a reminder that all beta2-agonists may not carry the same risks (Pearce 2007), so in view of the potential differences in adverse effects between salmeterol and formoterol, we have considered the two drugs separately. Two recently updated systematic reviews have addressed the impact of long-acting beta2-agonists on all-cause mortality and serious adverse events: Cates 2008 (salmeterol) and Cates 2012 (formoterol). Both reviews considered long-acting beta2-agonists that were randomly assigned without additional inhaled corticosteroids and described increased risks of non-fatal serious adverse events.

Much debate has focused on the interaction between inhaled corticosteroids and long-acting beta2-agonists in relation to serious adverse events since the publication of SMART 2006. This study did not randomly assign participants to inhaled corticosteroids, but nevertheless a subgroup analysis of the results was carried out on the basis of inhaled corticosteroid use at baseline. It is tempting to find reassurance from the fact that no statistically significant increase in asthma-related mortality was observed in the subgroup using inhaled corticosteroids, but this is not the correct way to test for interaction (Altman 2003), and no assessment was carried out during the trial in relation to the actual use of inhaled corticosteroids during the course of the study.

Counfounding by severity has been shown by Sears 2008 in data from the RELIEF study, where the rate of asthma-related SAEs was significantly higher in both arms of the study among participants taking ICS in comparison with those not taking ICS. This is a serious threat to any conclusions drawn from observational data when the interaction between ICS and formoterol is assessed. Therefore, there is a need to systematically review all available data from controlled trials that randomly assigned participants to regular formoterol in combination with inhaled corticosteroids, and to consider all serious adverse events (fatal and non-fatal), whether or not these are deemed by the investigators to be related to trial medication.

The focus of this review is therefore on regular formoterol randomly assigned in combination with inhaled corticosteroids (in a single inhaler or in separate inhalers) and compared with inhaled corticosteroids alone. Because of the difficulty involved in deciding whether adverse events are asthma-related, this review focusses on studies that capture mortality and serious adverse events and records both all-cause outcomes and those considered by trial investigators to be asthma-related events.

A review comparing regular salmeterol randomly assigned in combination with inhaled corticosteroids (in a single inhaler or in separate inhalers) versus inhaled corticosteroids alone is currently being updated (Cates 2009), and an overview of the safety of regular formoterol or salmeterol in children has been published (Cates 2012a).

Objectives

To assess the risks of mortality and non-fatal serious adverse events in trials that randomly assign participants with chronic asthma to regular formoterol and inhaled corticosteroid versus the same dose of inhaled corticosteroid.

Methods

Criteria for considering studies for this review

Types of studies

Controlled parallel-design clinical trials, with or without blinding, in which formoterol and inhaled corticosteroid were randomly assigned to participants with chronic asthma for comparison with outcomes in those given the same dose of inhaled corticosteroid alone. Studies on acute asthma and exercise-induced bronchospasm have not been included.

Types of participants

Participants with a clinical diagnosis of asthma of any age group, unrestricted by disease severity or previous or current treatment.

Types of interventions

Inhaled corticosteroids and formoterol given regularly once or twice daily for a period of at least 12 weeks at any dose and delivered by any single or separate devices (CFC-MDI, HFA-MDI, DPI). Studies that randomly assigned participants to formoterol and inhaled corticosteroids for intermittent use as a reliever have not been included in this review, and studies that compared different doses of formoterol or different delivery devices or propellants without a placebo arm were also not included. Studies in which formoterol was randomly assigned without an inhaled steroid have been considered in a separate review (Cates 2012). Studies that use comparison groups given the same dose and type of inhaled corticosteroid in the control arm will be included in this review, and co-intervention with leukotriene-receptor antagonists, cromones or theophylline will be allowed as long as they are not part of the randomly assigned intervention and therefore are not systematically different between groups. Studies comparing formoterol with salmeterol will be subject to another review and were not included in this review. We have also excluded from this review studies in which inhaled corticosteroids were used in all participants as background treatment (rather than as a randomised intervention).

Types of outcome measures

Primary outcomes
  • All-cause mortality.

  • All-cause non-fatal serious adverse events.

Secondary outcomes
  • Asthma-related mortality.

  • Asthma-related non-fatal serious adverse events.

  • Respiratory-related mortality.

  • Respiratory-related non-fatal serious adverse events.

  • Cardiovascular-related mortality.

  • Cardiovascular-related non-fatal serious adverse events.

  • Asthma-related non-fatal life-threatening events (intubation or admission to intensive care).

  • Respiratory-related non-fatal life-threatening events (intubation or admission to intensive care).

Outcomes were not subdivided according to whether the trial investigators considered them related to trial medication.

Search methods for identification of studies

Electronic searches

Trials were identified using the Cochrane Airways Group Specialised Register of trials, which is derived from systematic searches of bibliographic databases, including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED and PsycINFO and from handsearching of respiratory journals and meeting abstracts (see Appendix 3 for additional details). All records in the Specialised Register coded as 'asthma' were searched using the following terms:

(((beta* and agonist*) and (long-acting or "long acting")) or ((beta* and adrenergic*) and (long-acting or "long acting")) or (bronchodilat* and (long-acting or "long acting")) or (salmeterol or formoterol or eformoterol or advair or symbicort or serevent or seretide or oxis)) AND (serious or safety or surveillance or mortality or death or intubat* or adverse or toxicity or complications or tolerability)

Searches were conducted up to August 2012 with no restriction on language of publication.

Searching other resources

Reference lists of all primary studies and review articles were checked for additional references. Web sites of clinical trial registers were checked for unpublished trial data; Food and Drug Administration (FDA) submissions in relation to formoterol were also checked.

Data collection and analysis

Selection of studies

Two review authors independently assessed studies identified in the literature searches by examining title, abstract and keywords fields. Studies that potentially fulfilled the inclusion criteria were obtained in full text. These were independently assessed for inclusion by CJC, with a second assessment by Toby Lasserson for the original review and by Marta Oleszczuk for the 2012 update. Disagreements were resolved by consensus.

Data extraction and management

Data were extracted using a prepared checklist before they were entered into Rev Man 5.0 by one reviewer (CJC), and data extraction and entry were checked by a second reviewer (Toby Lasserson,MF or SS). Outcome data were independently extracted by the third reviewer (RJ, MF or SS) and discrepancies resolved by correspondence with the sponsors, when necessary. Data included characteristics of included studies (methods, participants, interventions, outcomes) and results of the included studies. Sponsors of included studies were contacted for unpublished adverse event data, and the sponsor's Web site was searched for further details of adverse events. All-cause serious adverse events (fatal and non-fatal) were recorded, and in view of the difficulty involved in deciding whether events were asthma related, details of the cause of death and of serious adverse events were noted when available. The definition of serious adverse events was recorded, and further information was sought if this was not clear (particularly in relation to hospital admissions and serious adverse events).

Assessment of risk of bias in included studies

One review author (CJC) assessed all included studies for bias protection (including sequence generation for randomisation, allocation concealment, blinding of participants and assessors, loss to follow-up and selective outcome reporting) with assistance from Susan Hansen for the original version of the review and from MF or SS for the 2012 update.

Unit of analysis issues

We confined our analysis to participants with one or more serious adverse event, rather than focusing on the number of events that occurred (as the latter are not independent when one patient suffers multiple events).

Assessment of heterogeneity

Heterogeneity was assessed using I2 to indicate how much of the total heterogeneity found was between, rather than within, studies.

Data synthesis

The outcomes of this review were dichotomous, and we recorded the numbers of participants with at least one outcome event by allocated treated group. Pooled odds ratio (ORs) and risk difference (RDs) were calculated. The Peto OR provides advantages when events are rare as no adjustment for zero cells is required (Bradburn 2007). We considered this specific property to be more important than potential problems with unbalanced treatment arms and large effect sizes associated with this method in view of the low number of events and the high proportion of zero cells. The primary analysis of results for serious adverse event outcomes was conducted in RevMan 5.2 using the Peto method, and the Mantel-Haenszel method was used as a sensitivity analysis. Funnel plots were inspected for assessment of possible publication bias.

Subgroup analysis and investigation of heterogeneity

Subgroup analyses were conducted on the basis of participant age (adults vs children) and the dose of formoterol used (usual dose vs high dose). Subgroups were compared with the use of tests for interaction (Altman 2003).

Sensitivity analysis

Sensitivity analysis was carried out to assess the impact of the method used to combine study events (risk difference, Peto OR and Mantel-Haenszel OR). The degree of bias protection included in the study design was also included in the of sensitivity analysis.

Summary of findings tables

We assessed the quality of the evidence for all-cause mortality, all-cause non-fatal serious adverse events and asthma-related serious adverse events. Assessments were conducted according to recommendations put forth by the GRADE working group and are presented in our reviews in separate Summary of Findings tables for adults and children.

Results

Description of studies

Results of the search

A total of 523 abstracts were found from the search of the Cochrane Airways Group Specialised Register of trials in October 2008. For this review, 59 abstracts were identified as potentially relevant, and of these, 48 were subsequently excluded (see Characteristics of excluded studies) and 11 were included in the review. Ten additional trials were identified primarily from the AstraZeneca register of controlled trials (Buhl 2003; D5896C00001; Morice 2007; Morice 2008; Peters 2008; SD-039-0714; SD-039-0718; SD-039-0719; SD-039-0725; SD-039-0726). No additional trials were found from the Novartis Website or the FDA Website. A submission from Novartis to the FDA in December 2008 indicated that no trials in the Novartis database were trials of Foradil in which participants had also been randomised to inhaled corticosteroids (Novartis 2008).

The August 2012 search update found another 199 abstracts, from which 55 were identified as potentially relevant to this review. The full papers identified 25 reports of six new trials of 2550 adults and adolescents given regular formoterol in combination with budesonide or mometasone (Brown 2012; Meltzer 2012; Nathan 2010; Spector 2012; Weinstein 2010; Zangrilli 2011). Twelve additional citations were identified for six trials already included in the review (D5896C00001; Noonan 2006; Peters 2008; SD-039-0718; SD-039-0719; SD-039-0725). Twelve studies (with 18 reports) were excluded as documented in the Characteristics of excluded studies.

No new studies on children were identified.

Included studies

The 27 trials included in this review are described in detail in Characteristics of included studies, and a summary of the daily dose of budesonide and formoterol that was used in each trial is provided in Table 1). To avoid confusion, all delivered doses have been converted to an equivalent metered dose (so Symbicort 320/9 mcg is a delivered dose that is equivalent to a metered dose of budesonide 400 mcg and formoterol 12 mcg).

Table 1. Dose and delivery of budesonide and formoterol
Study IDAge (YearsN on F&ICSN on ICS AloneDaily dose of budesonide or mometasone (mcg metered dose)Daily Dose of Formoterol (mcg metered dose)Once dailyTwice dailyCombined inhalersSeparate inhalersDPIpMDIDuration weeks
Brown 201212+37736480024   52
Buhl 200318+35217140012  12
Chuchalin 200218+11111440024   12
Corren 200712+12312140024   12
D5896C0000112+31215340012/24  12
Jenkins 200612+341115160048  24
Kuna 200618+40920720012  12
Meltzer 201212+182188200 (mometasone)20    26
Morice 200712+46221780024  12
Morice 20086 to 1141520720024  12
Nathan 201012+191192400 (mometasone)20   26
Noonan 200612+23910940024 12
O'Byrne 200118+55455040012   52
O'Byrne 2001a18+31531280012   52
Pauwels 199718+21021320024   52
Pauwels 1997a18+21521480024   52
Peters 200812+443133160048   52
Pohunek 20064 to 1141721340024  12
Price 200212+25025580024   24
SD-039-071411 to 1713613440012   12
SD-039-07186 to 1512814520024   12
SD-039-07196 to 111236340024  26
SD-039-07256 to 1535216920012/24  12
SD-039-072616+30114520012/24  12
Spector 201212+15615580024  12
Tal 20024 to 1714813840024   12
Weinstein 201012+255240800 (mometasone)20   12
Zangrilli 201112+12712380024   12
Zetterstrom 200118+23812480024  12

Table 1 also indicates whether each study randomly assigned participants to once- or twice-daily formoterol, used combined or separate inhalers and delivered the medication using dry powder inhaler (DPI) or pressurised metered-dose inhalers (pMDIs). Some trials had more than two arms so featured more than one option in each of these cases. Because OPTIMA (O'Byrne 2001; O'Byrne 2001a) and FACET (Pauwels 1997; Pauwels 1997a) randomly assigned participants to higher and lower doses of budesonide, each has been considered as two separate comparisons and has been given two identifiers. The review therefore lists a total of 29 studies, drawn from the 27 trials that have been conducted.

All the trials on budesonide and formoterol have been sponsored or supported by AstraZeneca, and all the trials on mometasone and formoterol have been sponsored by Merck or Schering-Plough (Meltzer 2012; Nathan 2010; Weinstein 2010).

Adults

After the 2012 update, a total of 10,578 adults and adolescents were randomly assigned in 13 trials enrolling participants over the age of 12 years (Brown 2012; Corren 2007; D5896C00001; Jenkins 2006; Meltzer 2012; Morice 2007; Nathan 2010; Noonan 2006; Peters 2008; Price 2002; Spector 2012; Weinstein 2010; Zangrilli 2011), a further six trials that enrolled adults over the age of 18 years (Buhl 2003; Chuchalin 2002; Kuna 2006; O'Byrne 2001; Pauwels 1997; Zetterstrom 2001) and a single trial that enrolled those older than 16 years of age (SD-039-0726). All participants in these studies had a mean age of greater than 18 years.

The weighted mean duration of the adult and adolescent studies was 28 weeks. The daily metered dose of formoterol used was 12 to 24 mcg, with the exception of Jenkins 2006 and Peters 2008, who used 48 mcg daily (which remains within the licensed daily dose range). The daily metered dose of budesonide ranged from 200 to 1600 mcg, and for mometasone from 200 to 800 mcg (see Table 1).

Children

The seven trials in children included 2788 participants in the following age ranges: Morice 2008, 6 to 11 years old; Pohunek 2006, 4 to 11; SD-039-0714, 11 to 17; SD-039-0718, 6 to 15; SD-039-0719, 6 to 11; SD-039-0725, 6 to 15 and Tal 2002 (4 to 17). In all studies, the mean age of participants was younger than 18 years.

The weighted mean duration of the studies of children and adolescents was 13 weeks. The daily metered dose of formoterol was 12 to 24 mcg. The daily metered dose of budesonide was 200 to 400 mcg (see Table 1).

Risk of bias in included studies

An overview of the risk of bias in individual studies is shown in Figure 1; individual judgements can be viewed in Characteristics of included studies.

Figure 1.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

Allocation

Very little information is available from the paper publications or from Web reports on sequence generation or allocation concealment, but this is unlikely to be a source of bias in view of the fact that all the studies are sponsored, and standard methodology is likely to have been used to minimise the risk of selection bias. We therefore regarded the risk of selection bias as low, although sequence generation and allocation concealment are marked as unclear in most studies in Figure 1.

Blinding

All of the studies were double-blind with the exception of SD-039-0719, which was an open study. We regard the overall risk of performance and detection bias as low for the all-cause events. We were concerned that bias might have been introduced in the attribution of asthma as the cause of serious events, as this was not independently assessed. Although the trials were double-blind, formoterol can have a big impact on asthma symptoms, and those who decided on the cause of the events may have guessed which treatment was being given.

Incomplete outcome data

The rate of withdrawals and dropouts was clearly reported and was generally less than 20% for randomly assigned participants; these rates were similar in the arms of each study. However, Spector 2012 reported more withdrawals on budesonide alone (34% compared with 24% on combination treatment), so we judged this study to be at high risk of attrition bias.

Selective reporting

Data have been found or provided from the sponsor for fatal and non-fatal serious adverse events by treatment group and causation for all studies, except for Brown 2012, which does not include details of asthma-related serious adverse events. We have therefore obtained data from all trials in relation to the primary outcomes of all-cause mortality and all-cause serious adverse events, and we regard the overall risk of reporting bias as low.

Effects of interventions

See: Summary of findings for the main comparison Regular formoterol and ICS compared to ICS in adults with asthma; Summary of findings 2 Regular formoterol and ICS compared to ICS in children with asthma

Primary Outcomes

All-cause mortality

No deaths were reported in the trials on children and adolescents (2788 participants). In the adult and adolescent studies (10,578 participants), seven deaths occurred. Six deaths were reported in 6163 participants taking formoterol with inhaled corticosteroids, and one death occurred out of 4415 participants taking inhaled corticosteroids alone. These trials were combined with the use of the Peto odds ratio (OR; as no continuity correction for zero cells is required). The increased odds of all-cause mortality with formoterol did not reach statistical significance (Peto OR 3.56, 95% confidence interval (CI) 0.79 to 16.03, P = 0.1) and I2 was zero (Figure 2). When analysed is performed with the use of risk differences (RD) with a fixed-effect model, the RD is 0.0009 (95% CI -0.0012 to 0.0030, P = 0.42) for adults and adolescents treated for an average of 28 weeks, and the RD is zero (95% CI -0.0042 to 0.0042, P = 1) in trials on children and adolescents treated for an average of 13 weeks (in which no deaths were reported).

Figure 2.

Forest plot of comparison: 1 Formoterol and ICS versus same dose ICS, outcome: 1.1 All-cause mortality.

Reports on the cause of each death are documented in Table 2.

Table 2. Mortality by cause of death
Study IDTreatment givenCause of death
Buhl 2003Formoterol and budesonideCardiac arrest
O'Byrne 2001Formoterol and budesonide (separate inhalers)Status asthmaticus, followed by septic shock
Pauwels 1997aFormoterol and budesonide (separate inhalers)Suicide
Zetterstrom 2001Formoterol and budesonideSuicide
Brown 2012Formoterol and budesonideCerebrovascular accident
Brown 2012BudesonideHomicide
Nathan 2010Formoterol and mometasoneUterine leiomyosarcoma
Jenkins 2006Formoterol and budesonidePulmonary embolus (but the death occurred after the control budesonide arm was discontinued so was not included in the meta-analysis)
Serious adverse events (non-fatal all-cause)

A non-fatal serious adverse event is defined as an event that falls into any of the following categories:

  • Is life-threatening.

  • Requires inpatient hospitalisation or prolongation of existing hospitalisation.

  • Results in persistent or significant disability/incapacity.

  • Is a congenital anomaly/birth defect.

This is further explained in Appendix 4, and AstraZeneca has confirmed that this definition was used in its included trials (even though this often was not made explicit in the paper reports).

Adults and adolescents

The number of participants experiencing one or more non-fatal serious adverse events was very similar when formoterol was randomly assigned with inhaled corticosteroids (ICS) in comparison with ICS alone. In 142 out of 6163 (2.3%) participants on regular formoterol with ICS and in 113 out of 4415 (2.6%) on ICS alone, such events occurred. The Peto OR was close to 1 (0.98, 95% CI 0.76 to 1.27, P = 0.87), and I2 was zero (Figure 3). The pooled RD was -0.0005 (95% CI -0.0066 to 0.0056, P = 0.87) over an average of 28 weeks of treatment, and I2 was again zero.

Figure 3.

Forest plot of comparison: 1 Formoterol and ICS versus same dose ICS, outcome: 1.2 All-cause non-fatal serious adverse events.

Children and adolescents

In trials of participants who were younger than 18 years of age, the results were more heterogeneous, and more non-fatal serious adverse events occurred with formoterol. A total of 25 such events were reported amongst young people out of 1719 (1.5%) on regular formoterol with ICS, and nine events occurred amongst 1069 (0.8%) participants taking ICS alone. The increased odds of serious adverse events with formoterol did not reach statistical significance: Peto OR: 1.62 (95% CI 0.80 to 3.28, P = 0.18); I2: 32%. The pooled RD for children was 0.0058 (95% CI -0.0028 to 0.0144, P = 0.19). When Tal 2002 is removed from the analysis, the I2 measurement is reduced to 0. In this study, events were reported in seven children on formoterol and in none on ICS alone.

The test for interaction between adults and children did not find a significant impact of age on treatment effect during analysis as Peto OR (test for subgroup differences: Chi² = 1.72, df = 1, P = 0.19, I² = 41.9%; see Figure 3).

Secondary Outcomes

Mortality by cause of death

None of the seven deaths in adults were reported as being due to asthma in the original trial reports, but the death in O'Byrne 2001 (OPTIMA) was subsequently attributed to status asthmaticus and septic shock in a recent meta-analysis (Sears 2008). The full report on the cause of death provided by the sponsors stated, "One of the deaths occurred in a 35 year old female after an 8 day hospitalisation for a severe asthma attack leading to intubation, ventilation, and nosocomial pneumonia with septic shock." This is the only death that has been reported as related to asthma and it occurred in a patient taking budesonide/formoterol Figure 4. Two deaths were reported as due to suicide, one as homicide, and one as cerebrovascular accident; one patient died of a uterine leiomyosarcoma and one from cardiac arrest (see Table 2).

Figure 4.

Forest plot of comparison: 1 Formoterol and ICS versus same dose ICS, outcome: 1.3 Asthma mortality.

Serious adverse events related to asthma
Adults and adolescents

The number of adults experiencing one or more asthma-related non-fatal serious adverse events was lower when formoterol was randomly assigned with ICSs in comparison with ICSs alone, and after the 2012 update, the difference reached statistical significance when both the Peto OR and the RD were used. A total of 17 out of 5981 (0.3%) participants on regular formoterol and ICS suffered an asthma-related serious adverse event, as well as 30 out of 4227 (0.7%) on ICS alone. The Peto OR was 0.49 (95% CI 0.28 to 0.88), and I2 was zero (see Figure 5). The pooled RD was -0.0034 (95% CI -0.0067 to -0.0001). This represents a reduction of three adults per thousand treated with combination therapy over 28 weeks, with a 95% CI of six fewer to less than one per thousand fewer.

Figure 5.

Forest plot of comparison: 1 Formoterol and ICS versus same dose ICS, outcome: 1.4 Asthma-related non-fatal serious adverse events.

Children and adolescents

In trials in participants who were younger than 18 years of age, the results were again more heterogeneous. Nine young people out of 1719 (0.5%) on regular formoterol and ICS suffered an asthma-related serious adverse event (SAE), as did four out of 1069 (0.4%) on ICS alone. The increased odds of SAEs related to asthma was imprecise and was not statistically significant (Peto OR 1.49, 95% CI 0.48 to 4.61, P = 0.49), and I2 was 60% (see Figure 5). The pooled RD was 0.002 (95% CI -0.005 to 0.009).

The difference between children and adults was not statistically significant (test for subgroup differences: Chi² = 2.94, df = 1, P = 0.09, I² = 66.0%). The data retrieved were insufficient to allow assessment of the other proposed secondary outcomes (such as intensive care unit (ICU) admission and intubation). One intubation (ICS only group; O'Byrne 2001) was reported.

Sensitivity analyses
Risk of bias

No deaths occurred in children in the unblinded study (SD-039-0719), so exclusion of this study resulted in no difference in mortality outcomes. When this study was excluded for non-fatal SAEs, the Peto OR for children was 1.69 (95% CI 0.81 to 3.54) and I2 was 45%. A funnel plot did not suggest obvious asymmetry related to publication bias (Figure 6).

Figure 6.

Funnel plot of comparison: 1 Formoterol and ICS versus same dose ICS, outcome: 1.2 All-cause non-fatal serious adverse events.

Methods of analysis

Primary outcomes were also analysed using Mantel-Haenszel fixed-effect and random-effects models. The result of a fixed-effect model for mortality was OR 1.95, 95% CI 0.56 to 6.82. This method uses a correction for zero cells, which means that the pooled OR is smaller than the Peto OR, because the addition of 0.5 to all cells when the arms have similar numbers randomly assigned will generate an OR of 3 when only one event is reported. When outcomes are very sparse (as for mortality), the results are entirely dependent on the size of the zero cell adjustment and whether the treatment arms are balanced. For all-cause SAEs in adults, the Mantel-Haenszel fixed-effect (OR 0.97, 95% CI 0.75 to 1.26) and random-effects models (OR 0.93, 95% CI 0.71 to 1.21) yielded results almost identical to those obtained by the Peto method. Similarly for asthma-related SAEs in adults, the fixed-effect (OR 0.52, 95% CI 0.30 to 0.90) and random-effects Mantel-Haenszel models (OR 0.53, 95% CI 0.30 to 0.95) provided very similar to results to those obtained when the Peto model was used.

Dose of formoterol

The dose of formoterol used in all studies was within the licensed daily dose, so no sensitivity analysis was required to exclude unlicensed doses.

Subgroup analyses

Mortality data were too sparse for any subgroup analyses to be carried out.

Although the results for adults and children showed opposite directions of effect for non-fatal SAEs (both all-cause and asthma-related), the test for interaction did not show a significant interaction of treatment effect and age.

Discussion

Summary of main results

All-cause mortality

The CIs for all-cause mortality in adults indicate that for every thousand patients treated with regular formoterol and ICS in comparison with ICS alone, we can expect something between three additional deaths and one less death in adults over 28 weeks of treatment, and at most four additional deaths to four fewer deaths in children over 13 weeks of treatment (the average duration of treatment in the respective trials). The pooled Peto OR for adults was 3.56 (95% CI 0.79 to 16.03) and could not be calculated for children because no deaths in children were reported.

All-cause non-fatal SAEs

For non-fatal SAEs, the limits of the pooled CI are six more to seven fewer adults and ten more to three fewer children for every thousand treated over the period of time represented in the trials. The Peto OR was 0.98 (95% CI 0.76 to 1.27) for adults, and 1.62 (95% CI 0.80 to 3.28) for children, with heterogeneity noted in the results of studies in children.

Asthma-related mortality

Only one death was attributed to asthma, so evidence was insufficient to allow assessment of impact on asthma-related mortality in adults or children.

Asthma-related non-fatal SAEs

Since six new trials in adults were added, a significant reduction in asthma-related non-fatal events has been reported in adults (Peto OR 0.49, 95% CI 0.28 to 0.88). This represents a reduction of three adults per thousand treated with combination therapy over 28 weeks, with a 95% CI of six fewer to less than one per thousand fewer. The results in children do not show a significant difference (Peto OR 1.49, 95% CI 0.48 to 4.61), and although the direction of the effect in children contrasts with that in adults, the difference between results in children and those in adults is not significant (test for subgroup differences: Chi² = 2.94, df = 1, P = 0.09, I² = 66.0%).

Overall completeness and applicability of evidence

Two large studies have examined the use of regular salmeterol (SMART 2006, SNS 1993), but the only large surveillance study on formoterol (Pauwels 2003; RELIEF) investigated its use as a reliever rather than as maintenance therapy and therefore has not been included in this review. This means that data in this review are insufficient to allow investigation of the impact of formoterol on SAEs in comparison with our previous review on salmeterol (Cates 2008).

The small number of events in this review results in low precision of the estimates of relative risk between formoterol and control. However, outcome data for all-cause events were obtained from all included studies, and a funnel plot did not suggest publication bias (Figure 6).

Two of the new trials included in the 2012 update focused on African American adults (Brown 2012; Spector 2012), and one studied Hispanic adults (Zangrilli 2011), so the diversity of ethnic groups represented is now greater. However, there remains very little in the way of separate data on adolescent participants recruited in any of the adult or adolescent trials. Separate data on adolescents must be reported in large ongoing trials initiated by the FDA (Chowdhury 2011).

Quality of the evidence

Risks of bias in the studies included in this review are thought to be low, as almost all of the studies were double-blind, and although allocation concealment was not well reported, it is likely to have been adequate, as all trials were sponsored or supported by product manufacturers. Because the trials were carried out for regulatory purposes, the collection of SAE data will have been assessed with the use of uniform definitions across studies.

Whilst we judged the risks of bias to be low in relation to all-cause fatal and non-fatal SAEs, this is not necessarily the case for asthma-related events. No independent assessment of the causation of events was undertaken, so bias may have been introduced if the investigators had a high threshold for classifying events as asthma-related. However, we would expect such a bias to decrease any differences observed in asthma-related events.

The level of heterogeneity within the subgroup of paediatric trials is significant (I2 = 60%), and cannot be explained easily. The CIs from two studies do not overlap (Morice 2008; Tal 2002), and observed results indicate protection (Morice 2008) and harm (Tal 2002).

The 2012 update of this review includes three new trials that are examining the combination of formoterol and mometasone in 1248 adults (Meltzer 2012; Nathan 2010; Weinstein 2010). The number of participants is insufficient to allow investigators to compare and contrast the safety of this new combination versus the combination of formoterol and budesonide used in the other studies. However, a large ongoing trial on formoterol and mometasone is designed to recruit 11,000 adults and adolescents (NCT01471340) and will enable better safety comparison of various products in the future.

Despite the addition of new evidence to this updated review, we have downgraded the quality of evidence across a number of outcomes for imprecision (Summary of findings for the main comparison; Summary of findings 2). The very low power of studies in children to detect any differences in SAEs means that we will have to await the results of the large ongoing study in children (NCT01471340) before we can determine whether the different directions of effect in asthma-related SAEs between children and adults are confounded or conflicting for another reason.

Potential biases in the review process

Selection of the best method to combine studies with rare events is contentious when event rates are low, not least because of the corrections required to calculate ORs with zero events (Sweeting 2004). It became apparent in the course of the review that the pooled ORs were heavily dependent on the zero adjustment used in the Mantel-Haenszel and inverse variance methods; therefore, we used the Peto OR and RDs to report results of this review. The imbalance between trial arms is never greater than two to one; therefore, the likely bias with use of the Peto OR is small (Sweeting 2004).

Similarly, the included studies were influenced by the decision to restrict the review to trials that randomly assigned participants to formoterol and ICS, but this decision reduces the risk of bias that arises when patients discontinue their usual inhaled steroid medication if they feel better while receiving the randomly assigned treatment. This presupposes a similar risk of SAEs when formoterol and budesonide are delivered via a single inhaler, and when formoterol is introduced to ICS therapy via a separate inhaler, when both are randomly assigned treatments in a controlled trial.

Agreements and disagreements with other studies or reviews

Mortality

Comparison of the results of this review with those of the review on regular formoterol without randomly assigned ICS (Cates 2012) indicates that nine out of 10 deaths in the trials comparing formoterol with placebo or comparing formoterol with ICS versus the same dose of ICS were performed in participants who were randomly assigned to formoterol (with or without ICS). This is a cause for concern because although it may seem that many of the deaths were not related to asthma, it is often difficult to be sure of the exact cause of death, and the classification of cause of death is not straightforward. For example, the participant who died during the OPTIMA trial (O'Byrne 2001) was recorded by authors as dying from septic shock but was listed in Sears 2008 as dying from status asthmaticus and septic shock, whereas the 13-year-old boy who died in Von Berg 2003 is listed in Sears 2008 as dying of respiratory failure, although the article reported that the cause of death was subarachnoid haemorrhage. Sears 2008 does not report all-cause mortality in the subgroup of trials in participants receiving regular formoterol and maintenance ICS; the primary analysis on all-cause mortality included the RELIEF study, which allowed regular long-acting beta2-agonists in both arms and therefore was not included in this review. The adjusted all-cause mortality in Sears 2008 is relative risk (RR) 1.79 (95% CI 0.80 to 4.00) when studies with any baseline ICS are considered; the conditional logistic regression was adjusted for trial effect (data on file provided by AstraZeneca).

Only one asthma-related death was reported in this review, but the overview of Sears 2008 identified two additional asthma-related deaths from the AstraZeneca database of trials in which participants were receiving maintenance ICS; all three deaths occurred amongst participants who had been randomly assigned to regular formoterol.

Six additional deaths were reported when formoterol and ICS were compared with higher doses of ICS-three deaths in each arm (Jaeschke 2008).

We agree with the conclusion of Sears 2008 that "the power is insufficient to conclude no increased mortality with formoterol" when regular formoterol is used in conjunction with ICS.

All-cause non-fatal SAEs

Sears 2008 did not present data on all-cause SAEs, but Jaeschke 2008 reported that a reduction in asthma-related SAEs and in hospitalisations does not seem to translate into similar reductions in all-cause SAEs (which are about four times more common). Jaeschke 2008 and Jaeschke 2008a did not include trials in children. Information derived from trials in children in this review is insufficient to allow us to determine whether the increased risk of non-fatal SAEs found with formoterol alone in Cates 2012 (Peto OR 2.48, 95% CI 1.27 to 4.83) is abolished by the addition of randomised ICS (Peto OR 1.62, 95% CI 0.80 to 3.28), as a large degree of overlap in CIs led to negative test findings for interaction (test for subgroup differences: Chi² = 0.74, df = 1, P = 0.39, I² = 0%) (see Figure 7). This is discussed more fully in the overview of the safety of regular formoterol or salmeterol in children (Cates 2012a) and is in agreement with the findings of McMahon 2011, who reported a significant association between younger age and increased risk of formoterol or salmeterol monotherapy, but no significant age association with combination inhalers.

Figure 7.

All-cause serious adverse events in children given regular formoterol (with or without ICS).

Authors' conclusions

Implications for practice

From the evidence provided in this review, it is not possible to reassure people with asthma that regular use of ICS with formoterol carries no risk of increasing mortality in comparison with ICS alone. On the other hand, we have found no conclusive evidence of harm, and only one asthma-related death was registered over more than 4200 patient-years of observation of individuals taking formoterol. In adults, the decrease in asthma-related SAEs seen amongst those receiving regular formoterol with ICS was not accompanied by a similar decrease in all-cause SAEs. In children, the number of events was too small to allow determination of whether the increase in all-cause non-fatal SAEs previously found among those taking regular formoterol alone is abolished by the additional use of ICS. Clinical decisions and information provided to patients regarding regular use of formoterol must take into account the balance between known symptomatic benefits of formoterol and the degree of uncertainty associated with its potential harmful effects.

Implications for research

Future research should clearly specify the number of patients with fatal and non-fatal SAEs by treatment group and cause. New large surveillance studies on combination therapies that are licensed in the United States have been mandated by the FDA; these aim to recruit 11,000 adults and adolescents to compare regular formoterol with budesonide against budesonide alone, and a similar number to compare regular formoterol with mometasone against mometasone alone, but trial investigators will not report results until 2017.

Acknowledgements

We thank Susan Hansen, Elizabeth Stovold and Emma Jackson of the Cochrane Airways Group for assistance in searching for trials and obtaining the abstracts and full reports and for extracting data on trial characteristics. We also thank Toby Lasserson for his contribution to previous versions of the review. We acknowledge the assistance of Matthew Cates in relation to the physiology of beta-agonist receptors and co-writing of the protocol, and of Marta Oleszczuk for assessing studies for inclusion in the 2012 update. We thank Joe Gray, Finn Radner and Anders Ottosson of AstraZeneca, and Davis Gates from Merck, for obtaining data on file for SAEs in these studies.

Data and analyses

Download statistical data

Comparison 1. Formoterol and ICS versus same dose ICS
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 All-cause mortality29 Peto Odds Ratio (Peto, Fixed, 95% CI)Subtotals only
1.1 Adults and Adolescents2210578Peto Odds Ratio (Peto, Fixed, 95% CI)3.56 [0.79, 16.03]
1.2 Children and Adolescents72788Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]
2 All-cause non-fatal serious adverse events29 Peto Odds Ratio (Peto, Fixed, 95% CI)Subtotals only
2.1 Adults and Adolescents2210578Peto Odds Ratio (Peto, Fixed, 95% CI)0.98 [0.76, 1.27]
2.2 Children and Adolescents72788Peto Odds Ratio (Peto, Fixed, 95% CI)1.62 [0.80, 3.28]
3 Asthma mortality29 Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected
3.1 Adults and Adolescents22 Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]
3.2 Children and Adolescents7 Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]
4 Asthma-related non-fatal serious adverse events28 Peto Odds Ratio (Peto, Fixed, 95% CI)Subtotals only
4.1 Adults and Adolescents2110208Peto Odds Ratio (Peto, Fixed, 95% CI)0.49 [0.28, 0.88]
4.2 Children and Adolescents72788Peto Odds Ratio (Peto, Fixed, 95% CI)1.49 [0.48, 4.61]
Analysis 1.1.

Comparison 1 Formoterol and ICS versus same dose ICS, Outcome 1 All-cause mortality.

Analysis 1.2.

Comparison 1 Formoterol and ICS versus same dose ICS, Outcome 2 All-cause non-fatal serious adverse events.

Analysis 1.3.

Comparison 1 Formoterol and ICS versus same dose ICS, Outcome 3 Asthma mortality.

Analysis 1.4.

Comparison 1 Formoterol and ICS versus same dose ICS, Outcome 4 Asthma-related non-fatal serious adverse events.

Appendices

Appendix 1. Pharmacology of beta2-agonists

Beta-agonists are thought to cause bronchodilatation primarily through binding of beta2-adrenoceptors on airways smooth muscle (ASM), with subsequent activation of both membrane-bound potassium channels and a signalling cascade involving enzyme activation and changes in intracellular calcium levels following a rise in cyclic adenosine monophosphate (cAMP) (Barnes 1993). However, beta2-adrenoceptors are also expressed on a wide range of cell types where beta2-agonists may have a clinically significant effect, including airway epithelium (Morrison 1993), mast cells, postcapillary venules, sensory and cholinergic nerves and dendritic cells (Anderson 2006). Beta2-agonists will also cross-react to some extent with other beta-adrenoceptors, including beta1-adrenoceptors on the heart. 

The in vivo effect of any beta2-agonist will depend on a number of factors related to both the drug and the patient. The degree to which a drug binds to one receptor over another is known as selectivity, which can be defined as absolute binding ratios to different receptors in vitro, whilst functional selectivity is measured from downstream effects of drugs in different tissue types in vitro or in vivoAll of the beta2-agonists described thus far are more beta2 selective than their predecessor isoprenaline in vitro. However, because attempts to differentiate selectivity between the newer agents are confounded by so many factors, it is difficult to draw conclusions about in vitro selectivity studies and is probably best to concentrate on specific adverse effects in human participants at doses that cause the same degree of bronchodilatation. The potency of a drug refers to the concentration that achieves half the maximal receptor activation of which that drug is capable. but it is not very important clinically, as for each drug, manufacturers will alter the dose to try to achieve a therapeutic ratio of desired to undesired effects. In contrast, efficacy refers to the ability of a drug to activate its receptor independent of drug concentration. Drugs that fully activate a receptor are known as full agonists. and those that partially activate a receptor are known as partial agonists. Efficacy also is very much dependent on the system in which it is being tested and is affected by factors such as the number of receptors available and the presence of other agonists and antagonists. Thus whilst salmeterol acts as a partial agonist in vitro, it causes a similar degree of bronchodilatation to the strong agonist formoterol in stable asthmatic patients (vanNoord 1996), presumably because an abundance of well-coupled beta2-adrenoceptors are available with few downstream antagonising signals. In contrast, with repetitive dosing, formoterol is significantly better than salmeterol at preventing methacholine-induced bronchoconstriction (Palmqvist 1999). These differences have led to attempts to define the “intrinsic efficacy” of a drug independent of tissue conditions (Hanania 2002), as shown in Table 1. The clinical significance of intrinsic efficacy remains unclear.

Appendix 2. Possible mechanisms of increased asthma mortality with beta-agonists

Direct toxicity

This hypothesis states that direct adverse effects of beta2-agonists are responsible for an associated increase in mortality, and most research in the area has concentrated on effects detrimental to the heart. Whilst it is often assumed that cardiac side effects of beta2-agonists are due to cross-reactivity with beta1-adrenoceptors (i.e. poor selectivity), it is worth noting that human myocardium also contains an abundance of beta2-adrenoceptors capable of triggering positive chronotropic and inotropic responses (Lipworth 1992). Indeed, good evidence suggests that cardiovascular side effects of isoprenaline (Arnold 1985) and of beta2-agonists including salbutamol (Hall 1989) are mediated predominantly via cardiac beta2-adrenoceptors, thus making the concept of in vitro selectivity less relevant. Generalised beta2-adrenoceptor activation can also cause hypokalaemia (Brown 1983), and it has been proposed that, through these and other actions, beta2-agonists may predispose to life-threatening dysrhythmias or may cause other adverse cardiac effects.

During the 1960s epidemic, most deaths occurred in patients with severe asthma, and it was originally assumed that asthma and its sequelae, including hypoxia, were the primary cause of death. However, mucus plugging and hypoxia do not preclude a cardiac event as the final cause of death, and one might expect those with severe asthma to take additional doses of a prescribed inhaler. As noted by Speizer and Doll, most deaths in the 1960s were in the 10- to 19-year age group, and “at these ages children have begun to act independently and may be particularly prone to misuse a self-administered form of treatment” (Speizer 1968). If toxicity were related to increasing doses of beta2-agonists, one might expect most deaths to occur in hospital, where high doses are typically used, but this was not the case. One possible explanation for this anomaly was provided by animal experiments in which large doses of isoprenaline caused little ill effect in anaesthetised dogs with normal arterial oxygenation, whereas much smaller doses caused fatal cardiac depression and asystole (although no obvious dysrhythmia) when hypoxic (Collins 1969; McDevitt 1974). It has been hypothesised therefore that such events would be less likely in hospital, where supplemental oxygen is routinely given. The clinical relevance of these studies remains unclear, although some evidence suggests a synergistic effect between hypoxia and salbutamol use in asthmatic patients in reducing total peripheral vascular resistance (Burggraaf 2001)-another beta2-mediated effect that could be detrimental to the heart during an acute asthma attack through a reduction in diastolic blood pressure. Other potential mechanisms of isoprenaline toxicity include a potential increase in mucus plugging and worsening of ventilation-perfusion mismatch despite bronchodilatation (Pearce 1990).

Additional concerns about a possible toxic effect of beta2-agonists were raised during the New Zealand epidemic in the 1970s. In 1981, Wilson et al, who first reported the epidemic, reviewed 22 fatal cases of asthma and noted, “In 16 patients, death was seen to be sudden and unexpected. Although all were experiencing respiratory distress, most were not cyanosed, and the precipitate nature of their death suggested a cardiac event, such as an arrest, inappropriate to the severity of their respiratory problem” (Wilson 1981). In humans, fenoterol causes significantly greater chronotropic, inotropic and electrocardiographic side effects than are produced by salbutamol in asthmatic patients (Wong 1990). It is interesting to note that across the same parameters, fenoterol also causes more side effects than are produced by isoprenaline (Burgess 1991). 

In patients with mild asthma and without a bronchoconstrictor challenge, salmeterol and salbutamol cause a similar degree of near-maximal bronchodilation at low doses (Bennett 1994). However, whilst as a one-off dose salbutamol is typically used at 2 to 4 times the concentration of salmeterol, the dose equivalences for salmeterol versus salbutamol in increasing heart rate and decreasing potassium concentration and diastolic blood pressure were 17.7, 7.8 and 7.6, respectively (i.e. salmeterol had a greater effect across all parameters). Given the lower intrinsic efficacy of salmeterol (Table 2), these results highlight the importance of in vivo factors; one possible explanation for the difference is the increased lipophilicity of salmeterol compared with salbutamol, contributing to higher systemic absorption (Bennett 1994).    

When increasing actuations of standard doses of formoterol and salmeterol inhalers are compared in stable asthmatic patients, relatively similar cardiovascular effects are seen at lower doses (Guhan 2000). However, at highest doses (above those recommended by the manufacturers), trends towards an increase in systolic blood pressure were noted with formoterol; in comparison, a trend towards a decrease in diastolic blood pressure and an increase in QTc interval was seen with salmeterol, although no statistical analysis of the difference was performed. In contrast, in asthmatic patients with methacholine-induced bronchoconstriction, no significant difference was noted between salmeterol and formoterol in causing increased heart rate and QTc interval, although formoterol caused significantly greater bronchodilatation and hypokalaemia (Palmqvist 1999). Whilst good evidence of cardiovascular and metabolic side effects has been observed with increasing doses of beta2-agonists, it is a little difficult to envisage serious adverse effects of this nature when LABAs are used at manufacturer-recommended preventative doses. However, it is possible that some patients choose to use repeated doses of LABAs during exacerbations. 

Tolerance

In this setting, the term tolerance refers to an impaired response to beta2-agonists in patients who have been using regular beta2-agonist treatment previously (Haney 2006). Tolerance is likely to result from a combination of reduced receptor numbers secondary to receptor internalisation and reduced production and also uncoupling of receptors from downstream signalling pathways following repeated activation (Barnes 1995). This phenomenon is likely to explain the beneficial reduction in systemic side effects seen with regular use of beta2-agonists including salbutamol after 1 to 2 weeks (Lipworth 1989). However, the same effect on beta2-adrenoceptors in the lung might be expected to produce a diminished response to the bronchodilating activity of beta2-agonists following regular use. In patients with stable asthma, whilst some evidence shows tolerance to both salbutamol (Nelson 1977) and terbutaline (Weber 1982), other studies have been less conclusive (Harvey 1982; Lipworth 1989). However, evidence of tolerance to short- and long-acting beta2-agonists in both protecting against and reducing bronchoconstriction is much stronger in the setting of an acute bronchoconstrictor challenge with chemical, allergen and 'natural' stimuli (Haney 2006; Lipworth 1997). 

Studies comparing salmeterol and formoterol have shown that both cause tolerance compared with placebo, but no significant difference was noted between the drugs (van der Woude 2001). There also appears to be little difference in the tolerance induced by regular formoterol and regular salbutamol treatment (Hancox 1999; Jones 2001). To the review authors' knowledge, no studies have looked specifically at the degree of tolerance caused by isoprenaline and fenoterol in the setting of acute bronchoconstriction. Tolerance to bronchodilatation has clearly been shown to occur with addition of inhaled corticosteroids to salmeterol and formoterol (Lee 2003) and terbutaline (Yates 1996). Evidence as to whether high-dose steroids can reverse tolerance in the acute setting is conflicting (Lipworth 2000; Jones 2001).

At first glance, the toxicity and tolerance hypotheses might appear incompatible, as systemic and cardiovascular tolerance ought to protect against toxicity in the acute setting, and good evidence suggests that such tolerance occurs in stable asthmatic patients (Lipworth 1989). However, whilst this study showed that changes in heart rate and potassium levels were blunted by previous beta2-agonist use, they were not abolished; furthermore, at the doses studied, these side effects appear to follow an exponential pattern (Lipworth 1989). In contrast, in the presence of bronchoconstrictor stimuli, the bronchodilator response to beta2-agonists follows a flatter curve (Wong 1990; Hancox 1999), and as was previously discussed, this curve is shifted downwards by previous beta2-agonist exposure (Hancox 1999). Thus, it is theoretically possible that in the setting of an acute asthmatic attack and strong bronchoconstricting stimuli, bronchodilator tolerance could lead to repetitive beta2-agonist use and ultimately to more systemic side effects than would otherwise have occurred. Of course, other sequelae of inadequate bronchodilation including airway obstruction will be detrimental in this setting.

Whilst the tolerance hypothesis is often cited as contributing towards the asthma mortality epidemics, it is difficult to argue that reduced efficacy of a drug can cause increased mortality relative to a time when that drug was not used at all. However, tolerance to the bronchodilating effect of endogenous circulating adrenaline is theoretically possible, and evidence has revealed rebound bronchoconstriction when fenoterol is stopped (Sears 1990), which may be detrimental. Furthermore, it appears that regular salbutamol treatment can actually increase airway responsiveness to allergen (Cockcroft 1993)-a potentially important effect that could produce a variant of the toxicity hypothesis. Differences between beta2-agonists in this regard are unclear, but the combination of rebound hyperresponsiveness and tolerance of the bronchodilator effect with regular beta2-agonist exposure has been recently advocated as a possible mechanism to explain the association between beta2-agonists and asthma mortality (Hancox 2006).

Other explanations

Confounding by severity

Historically, this hypothesis has been used extensively to try to explain the association between mortality and the use of fenoterol during the 1970s New Zealand epidemic (see Pearce 2007), and it is still quoted today. The hypothesis essentially relies on the supposition that patients with more severe asthma are more likely to take higher doses of beta2-agonists or a particular beta2-agonist (such as fenoterol), thereby explaining the association. This hypothesis was carefully ruled out in the three case-control studies by comparison of the association between fenoterol and mortality in patients with varying severity of disease (Crane 1989; Pearce 1990; Grainger 1991). Furthermore, the hypothesis cannot explain the overall increase in mortality in the 1960s and 1970s, nor can it explain any significant increase in mortality (whether or not inhaled steroids are taken) based on randomised controlled trial data.

The delay hypothesis

This hypothesis accepts that beta2-agonists or a particular beta2-agonist can cause increased risk of mortality, but indirectly, by causing patients to delay before getting medical help and further treatments, including high-dose steroids and oxygen. Evidence indicates that both salmeterol and formoterol can reduce awareness of worsening underlying inflammation (Bijl-Hofland 2001; McIvor 1998). It is difficult to rule out the delay hypothesis in explaining or contributing towards both the asthma mortality epidemics and an association with regular use of LABAs. Evidence shows that beta2-agonists with higher intrinsic efficacy are more effective in relieving bronchoconstriction in the acute setting (Hanania 2007) and could paradoxically cause patients to further delay seeking medical help. For the delay hypothesis to explain the increase in mortality during the 1960s and 1970s, one has to imply that hospital treatment of asthma when mortality rates were low during the earlier years of the 20th century was effective. It is difficult to say exactly how effective such treatment is likely to have been.   

Reduced corticosteroid treatment

A slight but significant variation of the delay hypothesis suggests that patients who have separate beta2-agonists and corticosteroid inhalers may choose to take less corticosteroid because of better symptom control from the inhaled beta2-agonists, and it is reduced corticosteroid treatment that contributes to a rise in mortality. It is rather difficult to see how this hypothesis explains the epidemics of asthma deaths in the 1960s and 1970s relative to the 1920s and 1930s (Figure 1), given that corticosteroids were not used for the treatment of asthma in the earlier decades. If this hypothesis were to explain increased mortality based on more recent randomised controlled trial data, one would not expect to see an increase in mortality in those taking LABAs alone. 

Appendix 3. Sources and search methods for the Cochrane Airways Group Specialised Register (CAGR)

Electronic searches: core databases

Database Frequency of search
CENTRAL (T he Cochrane Library)Monthly
MEDLINE (Ovid)Weekly
EMBASE (Ovid)Weekly
PsycINFO (Ovid)Monthly
CINAHL (EBSCO)Monthly
AMED (EBSCO)Monthly

 

Handsearches: core respiratory conference abstracts

Conference Years searched
American Academy of Allergy, Asthma and Immunology (AAAAI)2001 onwards
American Thoracic Society (ATS)2001 onwards
Asia Pacific Society of Respirology (APSR)2004 onwards
British Thoracic Society Winter Meeting (BTS)2000 onwards
Chest Meeting2003 onwards
European Respiratory Society (ERS)1992, 1994, 2000 onwards
International Primary Care Respiratory Group Congress (IPCRG)2002 onwards
Thoracic Society of Australia and New Zealand (TSANZ)1999 onwards

 

MEDLINE search strategy used to identify trials for the CAGR

Asthma search

1. exp Asthma/

2. asthma$.mp.

3. (antiasthma$ or anti-asthma$).mp.

4. Respiratory Sounds/

5. wheez$.mp.

6. Bronchial Spasm/

7. bronchospas$.mp.

8. (bronch$ adj3 spasm$).mp.

9. bronchoconstrict$.mp.

10. exp Bronchoconstriction/

11. (bronch$ adj3 constrict$).mp.

12. Bronchial Hyperreactivity/

13. Respiratory Hypersensitivity/

14. ((bronchial$ or respiratory or airway$ or lung$) adj3 (hypersensitiv$ or hyperreactiv$ or allerg$ or insufficiency)).mp.

15. ((dust or mite$) adj3 (allerg$ or hypersensitiv$)).mp.

16. or/1-15

Filter to identify RCTs

1. exp "clinical trial [publication type]"/

2. (randomised or randomised).ab,ti.

3. placebo.ab,ti.

4. dt.fs.

5. randomly.ab,ti.

6. trial.ab,ti.

7. groups.ab,ti.

8. or/1-7

9. Animals/

10. Humans/

11. 9 not (9 and 10)

12. 8 not 11

The MEDLINE strategy and RCT filter are adapted to identify trials in other electronic databases.

Appendix 4. Definition of Serious Adverse Events

The Expert Working Group (Efficacy) of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) defines serious adverse events as follows (ICHE2a 1995):

"A serious adverse event (experience) or reaction is any untoward medical occurrence that at any dose:

  • Results in death.

  • Is life threatening.

  • Requires inpatient hospitalisation or prolongation of existing hospitalisation.

  • Results in persistent or significant disability/incapacity.

  • Is a congenital anomaly/birth defect.

NOTE: The term 'life threatening' in the definition of 'serious' refers to an event in which the participant was at risk of death at the time of the event; it does not refer to an event that hypothetically might have caused death if it were more severe."

What's new

DateEventDescription
29 October 2012New citation required and conclusions have changedWith the addition of data from six new trials in adults, we have found a significant reduction in asthma-related serious adverse events on regular formoterol with inhaled corticosteroids, but this does not translate into a similar reduction in all-cause serious adverse events.
22 October 2012New search has been performed

The 2012 update of this review includes six new trials, which recruited 2550 adults and adolescents given regular formoterol in combination with budesonide or mometasone (Brown 2012; Meltzer 2012; Nathan 2010; Spector 2012; Weinstein 2010; Zangrilli 2011).

There were no new studies in children, but two large ongoing studies have been identified in adults and adolescents, each intending to recruit 11,000 participants. They are expected to report in 2017 (NCT01444430; NCT01471340).

Contributions of authors

CJC: Conception of the idea and co-writing of protocol with MJC. Trial selection, data extraction and co-writing the original review and the 2012 update.

RJ: Trial selection, data extraction and co-writing the review.

MF & SS: Data-extraction and co-writing the 2012 update.

Declarations of interest

None known for CJC. RJ received on one occasion honorarium and travel support from GlaxoSmtihKline for a lecture related to the topic of this review and is a deputy editor of a medical journal that is financed in part by advertising of drugs, including medications for asthma.

Sources of support

Internal sources

  • NHS R&D, UK.

External sources

  • NIHR, UK.

    Programme Grant (10/4001/01)

  • European Union (FP7) Health, Not specified.

    ASTROLAB project (EC HEALTH-F5-2011-282593)

Differences between protocol and review

Peto OR was used for primary meta-analysis of ORs, as otherwise the results are largely dependent on the zero correction adopted. Single-inhaler therapy and adjustable maintenance dosing were not included in the review, nor was comparison with higher-dose ICS. This was done because we decided to restrict our attention to the question of regular use of formoterol, in addition to the same ICS regimen, in both active and control arms. Subgroup analysis was not attempted on the basis of asthma severity or dose of ICS.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Brown 2012

Methods Study Design: a  randomised, double-blind, parallel-group study over 52 weeks in 122 centers in America, between February 2007 and November 2009. Two-week single-blind run-in on budesonide 320 µg BD.
Participants

Population: 742 African American adults (aged 12 years or older) with asthma (ATS definition). 

Baseline Characteristics: mean age 37 years. FEV1 78% predicted. Concomitant ICS used by 100% of participants (with or without LABA). 

Inclusion Criteria: stable asthma for at least 6 months. FEV1 % predicted ri at least 50%, bronchodilator reversibility at least 12% in FEV1 or 0.2 litres. 

Exclusion Criteria: smoking history of greater than 10 pack-years, use of oral corticosteroids within 30 days or beta-blockers (including eye drops) during the study. Pregnancy, breast-feeding or malignancy in the past five years.

Interventions
  • Budesonide/formoterol 160/9 µg BD.

  • Budesonide 160 µg BD.                                                                               

Delivery was pMDI.

Outcomes

Safety variables included asthma exacerbations (oral/systemic corticosteroid use or an asthma-related hospitalisation or emergency room/urgent care visit) and adverse events (AEs).

No published data found on asthma-related non-fatal SAEs, so we used hospitalisation for asthma exacerbation as a proxy measure.

NotesSponsored by AstraZeneca.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation occurred with the use of computer-generated sequential allocation; approximately equal distribution of participants per treatment group at each site was ensured by the use of balanced blocks.
Allocation concealment (selection bias)Low riskAllocation concealment was maintained by packaging the study medications identically, with the exception of the computer-generated randomisation number.
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind.
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk

Number of reported withdrawals reasonably balanced, but high proportions of total:

  • 149/377 (intervention group).

  • 125/365 (control group).

Selective reporting (reporting bias)Unclear riskNo reporting of asthma-related SAEs, so there may be high risk for this outcome.

Buhl 2003

Methods Study Design:  a  randomised, double-blind, double-dummy, active-controlled, multi-centre, parallel-group study over 12 weeks from October 1999 to June 2000 at 56 centres in 9 countries: Argentina (5), Belgium (5), the Czech Republic (14), Germany (6), Mexico (4), Russia (6), Spain (5), the Netherlands (7) and the United Kingdom (4). Run-in 2 weeks (budesonide 200 mcg twice daily).
Participants

Population: 523 adults (18 to 78 years) with moderate persistent asthma.

Baseline Characteristics: mean age 44 years. FEV1 77% predicted. Concomitant ICS used by 100% of participants (400-1000 mcg/day), and condition not fully controlled on this dose.

Inclusion Criteria:outpatients aged 18 years and older with perennial asthma (ATS) with a minimum duration of 6 months. Used any ICS at a constant daily dose of 400 to 1000 µg for at least 30 days before entry and still had sub-optimal asthma control. FEV1 % predicted between 60% and 90%, bronchodilator reversibility by an increase of at least 12% in FEV1 over baseline at 15 minutes after inhalation of a short-acting beta2-agonist.

Exclusion Criteria: use of oral, parenteral or rectal GCS within 30 days before visit 1; seasonal asthma, significant respiratory infection within 30 days of visit 1, severe cardiovascular disorder or any other significant disease or disorder, pregnant or planning a pregnancy, breast-feeding, not using acceptable contraceptives, not surgically sterile, hypersensitivity to study drugs and tobacco smokers or previous smokers if greater than 10 pack-years.

Interventions
  • Budesonide/formoterol 320/9 µg daily.

  • Budesonide/formoterol 160/4.5 µg twice daily. 

  • Budesonide 400 µg daily (equivalent daily dose of budesonide).

Delivery was DPI.

Outcomes

The primary efficacy variable was morning peak expiratory flow (am PEF, L/min).

Paper reports five SAEs: one in the once-daily BDF group and two each in the other groups. One death due to cardiac arrest and four other events were reported. (No details given by treatment group in article or in Web report.)

Jaeschke 2008 reports one death on combined treatment and two participants with non-fatal SAE on combined treatment and two on budesonide. One SAE on BDF was asthma-related.

NotesSponsored by AstraZeneca.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported.
Allocation concealment (selection bias)Unclear riskNot reported.
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind.
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed.
Incomplete outcome data (attrition bias)
All outcomes
Low risk480 of 523 (92%) completed the study.
Selective reporting (reporting bias)Low riskSAE data not attributable to treatment groups in article but obtained from Jaeschke 2008.

Chuchalin 2002

Methods Study Design:  a  randomised, double-blind, parallel-group study over 12 weeks in Russia. Run-in 2 weeks.
Participants

Population: 338 adults (18 to 66 years) with mild to moderate asthma. 

Baseline Characteristics: mean age 45 years. FEV1 unknown % predicted. Concomitant ICS used by 0% of participants. 

Inclusion Criteria: diagnosed at least 6 months. FEV1 % predicted between 50% and 85%, bronchodilator reversibility at least 15% in FEV1 over baseline after inhalation of terbutaline. Female participants to be postmenopausal or surgically sterile or using medically approved contraceptive measures. 

Exclusion Criteria: smoking history of greater than 10 pack-years, current or recent users of inhaled, oral or parenteral corticosteroids, oral leukotriene antagonists, nedocromil sodium or sodium cromoglycate, beta-blockers (including eye drops).

Interventions
  • Budesonide and formoterol 200 and 9 µg BD.

  • Budesonide 200 µg BD.                                                                              

Delivery was DPI.

Outcomes

The primary efficacy variable was change in peak expiratory flow (PEF) in the morning before any study medication was taken.

Article reports no deaths and two serious adverse events (aggravated asthma and hypertension) in the budesonide-only group that required hospitalisation.

NotesSupported by AstraZeneca.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported.
Allocation concealment (selection bias)Unclear risk "Allocated a randomised number (identifying which of the three treatments they would receive) in consecutive order, per centre, at the second visit."
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind.
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed.
Incomplete outcome data (attrition bias)
All outcomes
Low risk316 of 338 (93%) completed the study.
Selective reporting (reporting bias)Low riskSAE data reported in the article.

Corren 2007

MethodsRandomised, double-blind, double-dummy, multi-centre, placebo-controlled  study over 12 weeks at 56 US centres from July 2002 to September 2003. Run-in 7 to 21 days, in which usual asthma therapy was withdrawn.
Participants

Population: 480 adolescents and adults (12 to 78 years) with mild to moderate persistent asthma. 123 randomly assigned to BDF and 121 to budesonide. The Web report also includes 13 children in these treatment groups aged 6 to 11 years, but they were not separately analysed.

Baseline Characteristics: mean age 36 years. FEV1 75% predicted. Concomitant ICS used by 100% of participants at baseline but withdrawn for the formoterol and placebo arms of this study.

Inclusion Criteria:  mild to moderate persistent asthma for at least 6 months, treated with ICS for at least 4 weeks before screening, FEV1 between 60% and 90% predicted on ICS at screening and between 50% and 85% predicted after discontinuation of ICS during the run-in period. Bronchodilator reversibility of at least 12% and 0.20 L in FEV1 over baseline within 15 to 30 minutes after administration of  albuterol pMDI (2 to 4 inhalations [90 µg per inhalation]).

Exclusion Criteria: reasons for exclusion from the study included severe:

asthma (as judged by the investigator), asthma requiring hospitalisation once or emergency treatment more than once within the 6 months before the study or requiring treatment with systemic corticosteroids within the 4 weeks before screening, and/or a > 10-pack-year smoking history at screening. Pregnant or breast-feeding.

Interventions
  • Budesonide/formoterol 160/9 µg (DPI) twice daily.

  • Budesonide 160 µg (DPI) twice daily.

The Symbicort and budesonide arms of this study are included in this review.

Outcomes

The co-primary efficacy variables were changes from baseline in morning predose FEV1 and 12-hour mean FEV1 (from serial spirometry) after administration of the morning dose of study medication.

Two serious adverse events in the BDF group (lobar pneumonia and facial bone fracture) were reported in the article. No cardiac-related SAEs were reported in any group. No deaths occurred in any group (Website data).

Jaeschke 2008 reports no asthma-related SAEs.

NotesStudy sponsored by AstraZeneca.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskBy study site, computer-generated allocation schedule using balanced blocks of four.
Allocation concealment (selection bias)Unclear riskNo information.
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-dummy. Participants received both a pMDI and a DPI containing active treatment or placebo of the alternative active treatment as appropriate.
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed.
Incomplete outcome data (attrition bias)
All outcomes
Low risk18 of 123 discontinued on BDF and 18 of 121 on budesonide.
Selective reporting (reporting bias)Low riskSAEs reported in paper publication.

D5896C00001

Methods Study Design: a randomised, double-blind, single-dummy, active-controlled, multi-centre, parallel-group study over 12 weeks from October 2003 to February 2005 at 143 centres in the United States. Run-in 4 to 5 weeks.
Participants

Population: 619 adolescents and adults (12 to 79 years) with asthma. 

Baseline Characteristics: mean age 35 years. FEV1 76% predicted. Concomitant ICS used by 100% of participants. 

Inclusion Criteria: 12 years of age and older, had a documented clinical diagnosis of asthma for at least 6 months before screening and were in stable condition. Should have received maintenance asthma treatment with IICS for at least 4 weeks before the screening visit. FEV1 % predicted between 60% and 90% measured at least 24 hours after the last dose of long-acting beta2-agonist and 6 hours after the last dose of short-acting beta2-agonist.

Interventions
  • Budesonide/formoterol 160/4.5 µg  2× QD pMDI. 

  • Budesonide/Formoterol  80/4.5 µg  2× QD pMDI (data from this arm not used).

  • Budesonide/formoterol  80/4.5 µg  2× BD pMDI.

  • Budesonide 160 µg  2× QD pMDI.

Outcomes

Primary variable: evening predose FEV1.

No full paper publication for this study. Web report indicated 2 SAEs on BDF 160/4.5 twice daily with a participant who had had a myocardial infarction on the day after the treatment was discontinued. No deaths occurred. No data on asthma SAEs were found in the original review, but 2012 update includes report by Kerwin (no asthma-related SAEs in the arms included in this review).

NotesSponsored by AstraZeneca.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported.
Allocation concealment (selection bias)Unclear riskNot reported.
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind. To maintain blinding with the twice-daily dosing regimen, all participants randomly assigned to receive once-daily dosing were to take the active treatment in the evening and a matched placebo device in the morning.
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed.
Incomplete outcome data (attrition bias)
All outcomes
Low risk12% dropout in each arm.
Selective reporting (reporting bias)Unclear riskNo asthma-related SAE data found

Jenkins 2006

Methods Study Design:  a  randomised, double-blind, double-dummy, reference-controlled, multi-centre, parallel-group study over 24 weeks from July 2001 to June 2002 at 54 centres in 6 countries: Australia (11), Austria (6) Czech Republic (15), France (9), Poland (8) and Spain (5). Run-in 2 weeks (on usual ICS).
Participants

Population: 456 adolescents and adults (12 to 79 years) with persistent symptomatic asthma. 

Baseline Characteristics: mean age 46 years. FEV1 66% predicted. Concomitant ICS used by 100% of participants. 

Inclusion Criteria: outpatients aged 12 years and older with a diagnosis of asthma (minimum duration 6 months), FEV1 % predicted between 40% and 85% and bronchodilator reversibility by an increase of at least 15% in FEV1 over baseline after inhalation of a bronchodilator. For patients aged 18 years and older, an increase in baseline FEV1 of at least 200 mL 15 to 30 minutes post bronchodilator was required at study entry (visit 1). All participants had used ICS for at least 4 months at a constant daily dose of at least 750 mcg for at least 4 weeks before study entry.  

Exclusion Criteria: if asthma deteriorated, resulting in a change in asthma therapy. Total asthma symptom score had to be  > 1 on a scale of 0 to 6 for at least 4 of the last 7 days of run-in. The total asthma symptom score was the sum of daytime and night-time asthma symptom scores, each measured on a scale of 0 to 3 (where 0 = no symptoms and 3 = unable to perform usual activities (or to sleep because of asthma).

Interventions
  • Budesonide/formoterol 320/9 µg two inhalations BD + Placebo BD.

  • Budesonide 400 µg two inhalations BD + Formoterol 9 µg two inhalations BD + Placebo BD.

  • Budesonide 400 µg two inhalations BD + Placebo BD.

This was the treatment for the first 12 weeks, then group three was split between the first two treatments. DPI delivery.

Outcomes

The primary efficacy variable was morning peak expiratory flow (PEF) as registered daily on diary cards.

Article reports five participants with SAE on BDF and two on budesonide. One death occurred in the BDF group from pulmonary embolism, but as this was after 17 weeks, when there was no budesonide control arm, this has not been included in the meta-analysis.

Data from AstraZeneca show 7 participants with SAE on BDF and 3 on budesonide in the first 12 weeks of the study. This has been used in the meta-analysis. It is not clear why the article reports different numbers.

NotesSponsored by AstraZeneca.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskIndividual treatment codes were computer generated in balanced blocks of eight at AstraZeneca R&D, Lund, Sweden.
Allocation concealment (selection bias)Low riskCodes were then assigned to participants and were kept in sealed envelopes until data analysis.
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind.
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed.
Incomplete outcome data (attrition bias)
All outcomes
Low risk400 of 456 (88%) completed the study.
Selective reporting (reporting bias)Low riskSAE data in article, but they did not match final data from sponsors

Kuna 2006

Methods Study design: a  randomised, double-blind, double-dummy, active-controlled, multi-centre, parallel-group study over 12 weeks from November 1999 to July 2000 at 60 centres in 8 countries: Finland (5), Germany (17), Mexico (4), New Zealand (3), Norway (6), Poland (7), Russia (5) and Sweden (13). Run-in 2 weeks in which all participants received budesonide 200 mcg daily (half the previous average dose).
Participants

Population: 616 adults (18 to 80 years) with mild to moderate persistent asthma. 

Baseline Characteristics: mean age 45 years. FEV1 78.5% predicted. Concomitant inhaled corticosteroids used by 100% of participants. 

Inclusion Criteria: 18 years of age and older, a diagnosis of asthma (minimum duration 6 months) that was not optimally controlled despite a daily ICS dose of 200 to 500 mg for at least 30 days before study entry. FEV1 % predicted of 60% to 90%, bronchodilator reversibility by an increase of at least 12% in FEV1 over baseline after inhalation of either 1 mg of terbutaline or salbutamol 0.4 mg. 

Exclusion Criteria: used any systemic corticosteroids within the previous 30 days; seasonal asthma (defined as asthma exacerbated by seasonal increases in aero allergens); respiratory infection in the 4 weeks before study entry; a severe cardiovascular disorder or any other significant disease; used beta-blocker therapy (including eye drops) or had a history of heavy smoking (×10 pack-years), women of child-bearing potential who were pregnant or who failed to use acceptable contraceptive measures.

Interventions
  • Budesonide/formoterol 80/4.5 µg 2× QD.

  • Budesonide/formoterol 80/4.5 µg BD.

  • Budesonide 200 µg QD.

Delivery was DPI, and all arms received equivalent delivered dose of 160 mcg budesonide daily.

Outcomes

The primary variable was morning PEF.

"Seven serious adverse events were reported: two in the once-daily BDF group, one in the twice-daily BDF group and four in the budesonide group." Although the three asthma SAEs were not described by treatment group in the article or the Web report, Jaeschke 2008 indicates one on BDF and two events on budesonide, with one hospitalisation for asthma in each group. No mortality.

NotesSponsored by AstraZeneca.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described.
Allocation concealment (selection bias)Unclear riskNot described.
Blinding (performance bias and detection bias)
All outcomes
Low riskTo ensure treatment blinding, a double-dummy design was used so that participants received four successively numbered Turbuhalers, with the corresponding placebo inhalers identical in appearance to those containing active medication.
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed.
Incomplete outcome data (attrition bias)
All outcomes
Low risk555 of 616 (90%) completed the study.
Selective reporting (reporting bias)Low riskSAEs reported in paper by treatment group.

Meltzer 2012

Methods Study Design: randomised, multi-centre, double-blind, double-dummy, placebo-controlled, parallel-group study over 26 weeks at 172 sites worldwide. Run-in two weeks mometasone fumarate (MF) 100 mcg twice daily.
Participants

Population: 370 adults (in the arms that were eligible for this review) who were aged 12 years or older with asthma (generally moderate uncontrolled asthma). 

Baseline Characteristics: mean age 38 years. FEV1 75% predicted. Concomitant inhaled corticosteroids used by 100% of participants for at least 12 weeks (with or without LABA). 

Inclusion Criteria: asthma for at least 12 months and on a stable ICS regimen for at least 12 weeks. FEV1 60% to 85% predicted, bronchodilator reversibility at least 12% in FEV1 or 0.2 litres; alternatively PEF variability over 20%. 

Exclusion Criteria: unstable asthma, smoking history greater than 10 pack-years, past history or present evidence of oropharyngeal candidiasis.

Interventions
  • Mometasone furoate/formoterol (MF/F)  100/10 mcg twice daily.

  • Mometasone furoate (MF) 100 mcg twice daily.

Delivery was pMDI (the placebo and formoterol arms in this trial were not considered for this review).

OutcomesAll-cause SAE data not reported by treatment group in article but data kindly provided by the authors, four adults with SAE on MF/F and 5 with SAE on MF (one on formoterol and one on placebo). No hospital admissions for asthma exacerbation, so no asthma-related SAEs (confirmed by authors).
NotesSponsored by Merck Sharp & Dohme.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo details.
Allocation concealment (selection bias)Unclear riskNo details.
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind, double-dummy.
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk36 of 182 discontinued on combination and 41/188 on MF alone, but imbalance was noted for treatment failure (2% and 7%, respectively).
Selective reporting (reporting bias)Low riskSAE details obtained from authors.

Morice 2007

Methods

Study Design: a randomised, double-blind, double-dummy, parallel-group study over 12 weeks from April

2002 to February 2003 at 62 centres in Brazil (7), Bulgaria (5), Canada (9), Hungary (9), Mexico (7), the Philippines (6), Thailand (5) and UK (14). Run-in 2 weeks on pre-study ICS, but LABA was withdrawn from the 15% previously treated with LABA and ICS.

Participants

Population: 680 adolescents and adults (12 to 79 years) with asthma. 

Baseline Characteristics: mean age 40 years. FEV1 70% predicted. Concomitant ICS used previously by 100% of participants (mean dose 770 mcg/day). 

Inclusion Criteria: 12 years of age and older with asthma for at least 6 months, who were inadequately controlled on ICS alone, FEV1 % predicted between 50% and 90%, bronchodilator reversibility by an increase of at least 12% in FEV1 after inhalation of terbutaline 1 mg, a history of daily ICS use (stable dose of 500 to 1600 mcg/day within 30 days before enrolment) for at least 3 months. Symptoms must have been present on at least 4 of the last 7 days of run-in.

Exclusion Criteria: not defined.

Interventions
  • Budesonide 200 µg  2× BD pMDI (CFC propellant).

  • Budesonide/formoterol 160/4.5 µg  2× BD DPI.

  • Budesonide/formoterol 160/4.5 µg  2× BD  pMDI (HFA propellant).

All delivered the same daily dose of budesonide.

Outcomes

The primary efficacy endpoint was the change in morning peak expiratory flow (PEF) from baseline (mean of the last 10 days of run-in) to the mean value over the 12-week treatment period.

Article reports: "No deaths occurred. Four participants experienced serious adverse events, two in the budesonide group (joint dislocation, asthma) and two in BDF pMDI (menorrhagia, increased liver enzymes)."

NotesSponsored by AstraZeneca.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskParticipants were randomly assigned sequentially in blocks of six using a computer-generated randomisation schedule.
Allocation concealment (selection bias)Low riskEligible participants were consecutively allocated the lowest available randomisation code. In view of double-dummy design, this is considered satisfactory.
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind, double-dummy. To maintain blinding, each patient also received a placebo device.
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed.
Incomplete outcome data (attrition bias)
All outcomes
Low risk600 of 680 (88%) completed the study.
Selective reporting (reporting bias)Low riskFull SAE data available from article by treatment group and cause.

Morice 2008

Methods

Study Design: a randomised, double-blind, double-dummy, parallel-group study over 12 weeks from June 2002 to May 2003 at 53 centres in Argentina (4), Brazil (6), Denmark (14), Hong Kong (1), Mexico (6), Poland (4), Slovakia (12) and Taiwan (6).

Run-in 2 weeks on previous ICS dose (but previous LABA may have been withdrawn; not made clear in the article).

Participants

Population: 622 children (6 to 11 years) with symptomatic asthma. 

Baseline Characteristics: mean age 8 years. FEV1 82% predicted. Concomitant ICS used by 100% of participants (375 to 100 mcg daily). 

Inclusion Criteria: paediatric outpatients (6 to 11 years) with asthma and a history of clinically important exercise-induced bronchoconstriction, daily use of 375 to 1000 µg of inhaled glucocorticosteroids (GCSs), peak expiratory flow (PEF) at least 50% of predicted normal value (pre-bronchodilator). Had to have a total asthma symptom score (night-time plus daytime) of at least 1 on at least 4 of the last 7 days of the run-in period and a mean morning PEF (mPEF) during the last 7 days of the run-in period of 50% to 85% of post bronchodilatory PEF, measured at Visit 1 (enrolment). 

Exclusion Criteria: inability to use DPI and peak flow meter.

Interventions
  • Budesonide 100 µg  2× BD pMDI.

  • Budesonide/formoterol 80/4.5 µg  2× BD DPI. 

  • Budesonide/formoterol 80/4.5 µg  2× BD  pMDI,

Dose of budesonide was equivalent in each arm (100 metered dose equivalent to 160 delivered doses).

Outcomes

The primary efficacy endpoint was the change in morning peak expiratory flow (PEF) from baseline (mean of the last 10 days of run-in) to the mean value over the 12-week treatment period.

Article reports: "Five patients reported serious adverse events: 3 in budesonide group (asthma aggravation (2), nervousness), 2 BDF DPI (acute sinusitis, migraine). No deaths were reported."

NotesSponsored by AstraZeneca.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskParticipants were randomly assigned sequentially in blocks of six using a computer-generated randomisation schedule.
Allocation concealment (selection bias)Unclear riskNo details.
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind (all participants used a placebo inhaler and an active inhaler).
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed.
Incomplete outcome data (attrition bias)
All outcomes
Low risk583 of 622 (94%) completed the study,
Selective reporting (reporting bias)Low riskSAEs reported by treatment group and cause in paper.

Nathan 2010

Methods Study Design: randomised, multi-centre, double-blind, double-dummy, placebo-controlled, parallel-group study over 26 weeks at 152 sites worldwide. Run-in two or three weeks mometasone fumarate (MF) 200 mcg twice daily.
Participants

Population: 383 adults (in the arms that were eligible for this review) who were aged 12 years or older) with asthma (generally moderate uncontrolled asthma). 

Baseline Characteristics: mean age 42 years. FEV1 73% predicted. Concomitant inhaled corticosteroids used by 100% of participants for at least 12 weeks (with or without LABA). 

Inclusion Criteria: asthma for at least 12 months and on a stable medium dose ICS regimen for at least 12 weeks. FEV1 60% to 85% predicted, bronchodilator reversibility at least 12% in FEV1 or 0.2 litres; alternatively PEF variability over 20%. 

Exclusion Criteria: unstable asthma, smoking history greater than 10 pack-years, past history or present evidence of oropharyngeal candidiasis.

Interventions
  • Mometasone furoate/formoterol (MF/F) 200/10 mcg twice daily.

  • Mometasone furoate (MF) 200 mcg twice daily.

Delivery was pMDI (the placebo and formoterol arms in this trial were not considered for this review).

Outcomes

To evaluate the safety and tolerability of the study drugs, clinical assessment and review of laboratory data included monitoring of adverse events (AEs) and serious AEs (SAEs).

We found no specific reporting of deaths in trial reports, but the FDA report detailed that "in P04334, a 53-year-old female (Patient 0012/Site 12) on MF/F 200/10 BID died from metastatic uterine leiomyosarcoma"

NotesSponsored by Merck & Co.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo details.
Allocation concealment (selection bias)Unclear riskNo details.
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind, double-dummy.
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed.
Incomplete outcome data (attrition bias)
All outcomes
Low risk18% and 17% withdrawals on combination and MF.
Selective reporting (reporting bias)Low riskFull SAE data obtained from publications and FDA report,

Noonan 2006

MethodsRandomised, double-blind, double-dummy, multi-centre, placebo-controlled study over 12 weeks from July 2002 to January 2004 at 84 US centres (respiratory or allergy speciality clinical practice). Run-in 2 weeks.
Participants

Population: 596 adolescents and adults (12 to 87 years) with moderate to severe persistent asthma. BDF 124 participants, BD + F 115 participants, budesonide 109 participants.

Baseline Characteristics: mean age 41 years. FEV1 67% predicted. Concomitant ICS used by 100% of participants. 

Inclusion Criteria: moderate to severe persistent asthma treated long term with a medium to high dose of ICS, FEV1 % predicted within the entrance range of 45% to 85%, bronchodilator reversibility of FEV1 of at least 12% and 0.20 L from the pre-albuterol baseline value within 15 to 30 min after administration of a standard dose of salbutamol. 

Exclusion Criteria: requiring hospitalisation once or emergency treatment more than once in the preceding 6 months, greater than 10-pack-per-year smoking history.

Interventions
  • Budesonide 160 mcg twice daily.

  • Budesonide/formoterol 160/9 mcg pMDI twice daily.

  • Budesonide pMDI and formoterol DPI 160/9 mcg twice daily.

Outcomes

The co-primary efficacy variables were baseline adjusted average 12-hour FEVI and predose FEVI.

"Nine subjects had SAEs during double-blind treatment: 4 on BDF pMDI (asthma -2, urti and ECG T wave inversion), 2 in the formoterol group and 3 in the budesonide + formoterol group (small intestine obstruction, abdominal injury, pneumonia)."

Web data found on AZ clinical trials Website SD-039-0717.

NotesSponsored by AstraZeneca. Jaeschke 2008 excluded this study as it included more than 20% dropouts.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated allocation schedule.
Allocation concealment (selection bias)Low riskIdentical packages shipped to centres.
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind.
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed.
Incomplete outcome data (attrition bias)
All outcomes
Low risk23% withdrawals in combined arms and 28% in budesonide arm.
Selective reporting (reporting bias)Low riskFull SAE data on Website.

O'Byrne 2001

Methods Study design: A randomised, double-blind, parallel-group study over 12 months from January 1998 to February 2000 at 198 centres in 17 countries. Run-in 1 month.
Participants

Population: 1970 adults (18 to 76 years) with mild asthma (Group A  698) and mild to moderate asthma (Group B 1272).

Baseline Characteristics:

(Group A) Mean age 31 years. FEV1 90% predicted. Concomitant ICS used by 0% of participants. 

(Group B) Mean age 37 years. FEV1 87% predicted. Concomitant ICS used by 100% of participants. 

Inclusion Criteria: 12 years of age and older. Diagnosis of stable asthma, according to the American Thoracic Society (ATS). 

(Group A) had used no inhaled corticosteroid for at least 3 months, pre-bronchodilator FEV1 % predicted at least 70% at visit 1. 15 min post bronchodilator FEV1 % predicted of at least 80% at visit 1 (2 × 0.5 mg Bricanyl Turbuhaler). 

(Group B) taking no more than 400 µg of inhaled budesonide or its equivalent

for at least 3 months, pre-bronchodilator FEV1 % predicted at least 50% at visit 1. 15 minutes post bronchodilator FEV1 % predicted at least 70% at visit 1 (2 x 0.5 mg Bricanyl Turbuhaler). 

Exclusion Criteria: use of oral GCS within 3 months before visit 1, beta-blocker therapy (eyedrops included). Pregnant and/or lactating women or women not using acceptable contraceptives as judged by the investigator, participants with a history of smoking greater than 15 pack-years.

Interventions

THIS REPORT RELATES TO PATIENTS GIVEN 200 mcg budesonide twice daily:

(Group A)

  • Budesonide 200 µg.

  • Budesonide and formoterol 200 and 4.5 µg.

Placebo arm from Group A was not included in this review.

(Group B)

  • Budesonide 200 µg.

  • Budesonide and formoterol 200 and 4.5 µg.

  • Budesonide 400 µg.

  • Budesonide and formoterol 400 and 4.5 µg.

Outcomes

Primary variable was time to first severe asthma exacerbation, expressed as the risk for a first severe exacerbation, and rate (proportion) of poorly controlled days.

Serious adverse events are not mentioned at all in the article publication and the Web report (SD-037-0345) gives only total numbers of participants with SAEs for Groups A and B (with no indication of treatment group).

AstraZeneca has provided a breakdown of all-cause SAE and asthma-related SAE (AstraZeneca Data on file 2008).

One death was not reported in the article but was mentioned in the Web report as probably due to 'septic shock' in group A. Sears 2008 indicates that the death was also related to status asthmaticus and occurred in a participant who was taking budesonide/formoterol combination treatment. The full report of the death from the sponsors is as follows: "One of the deaths occurred in a 35 year old female after an 8-day hospitalisation for a severe asthma attack leading to intubation, ventilation, and nosocomial pneumonia with septic shock."

NotesSponsored by AstraZeneca.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated random numbers.
Allocation concealment (selection bias)Low riskOpaque consecutive numbered envelopes containing assignment.
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind. Identical placebo.
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed.
Incomplete outcome data (attrition bias)
All outcomes
Low risk81% in Group A and 87% in Group B completed the study.
Selective reporting (reporting bias)Low riskSAE data provided by sponsors and found from other sources.

O'Byrne 2001a

Methods Study design: a  randomised, double-blind, parallel-group study over 12 months from January 1998 to February 2000 at 198 centres in 17 countries. Run-in 1 month.
Participants

Population: 1970 adults (18 to 76 years) with mild asthma. (Group A  698) and mild to moderate asthma (Group B 1272). 

Baseline Characteristics:

(Group A) Mean age 31 years. FEV1 90% predicted. Concomitant ICS used by 0% of participants. 

(Group B) Mean age 37 years. FEV1 87% predicted. Concomitant ICS used by 100% of participants. 

Inclusion Criteria: 12 years of age and older. Diagnosis of stable asthma, according to the American Thoracic Society (ATS). 

(Group A) had used no inhaled corticosteroid for at least  3 months, pre-bronchodilator FEV1 % predicted at least 70% at visit 1. 15 min post bronchodilator FEV1 % predicted at least 80% at visit 1 (2× 0.5 mg Bricanyl Turbuhaler). 

(Group B) taking no more than 400 µg of inhaled budesonide or its equivalent

for at least 3 months, pre-bronchodilator FEV1 % predicted at least 50% at visit 1. 15 minutes post bronchodilator FEV1 % predicted of at least 70% at visit 1 (2 × 0.5 mg Bricanyl Turbuhaler). 

Exclusion Criteria: use of oral GCS within 3 months before visit 1, beta-blocker therapy (eye drops included).pregnant and/or lactating women or women not using acceptable contraceptives as judged by the investigator, participants with a history of smoking greater than 15 pack-years.

Interventions

THIS REPORT RELATES TO PATIENTS GIVEN 400 mcg budesonide twice daily.

(Group A)

  • Budesonide 200 µg.

  • Budesonide and formoterol 200 and 4.5 µg.

Placebo arm from Group A was not included in this review.

(Group B)

  • Budesonide 200 µg.

  • Budesonide and formoterol 200 and 4.5 µg.

  • Budesonide 400 µg.

  • Budesonide and formoterol 400 and 4.5 µg.

Outcomes

The primary variable was time to first severe asthma exacerbation, expressed as the risk for a first severe exacerbation, and rate (proportion) of poorly controlled days.

SAEs are not mentioned at all in the paper publication, and the Web report (SD-037-0345) gives only total numbers of participants with SAEs for Groups A and B (with no indication of treatment group).

AstraZeneca has provided a breakdown of all-cause SAE and asthma-related SAE that was used in the meta-analysis. (AstraZeneca Data on file 2008)

NotesSponsored by AstraZeneca.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated random numbers.
Allocation concealment (selection bias)Low riskOpaque consecutive numbered envelopes containing assignment.
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind. Identical placebo.
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed.
Incomplete outcome data (attrition bias)
All outcomes
Low risk81% in Group A and 87% in Group B completed the study.
Selective reporting (reporting bias)Low riskSAE data provided by sponsors.

Pauwels 1997

Methods Study Design: a randomised, double-blind, multi-centre, parallel-group study over 12 months at 71 centres in 9 countries. (Belgium, Canada, the Netherlands, Israel, Italy, Luxembourg, Norway, Spain and the United Kingdom). Run-in 4 weeks on 800 mcg twice daily.
Participants

Study Design:  a randomised, double-blind, multi-centre, parallel-group study over 12 months at 71 centres in 9 countries. (Belgium, Canada, the Netherlands, Israel, Italy, Luxembourg, Norway, Spain and the United Kingdom). Run-in 4 weeks on 800 mcg twice daily. 

Population: 852 adults (18 to 70 years) with persistent symptomatic asthma. 

Baseline Characteristics: mean age 42 years. FEV1 76% predicted. Concomitant inhaled corticosteroids used by 100% of participants (mean dose 820 mcg/day).  

Inclusion Criteria: 18 to 70 years old, who had had asthma for at least six months and had been treated with an inhaled glucocorticoid for at least three months. FEV1 % predicted at least 50%, bronchodilator reversibility by an increase of at least 15% in FEV1 over baseline after inhalation of 1 mg of terbutaline. Stable asthma during run-in and compliant with treatment. 

Exclusion Criteria: three or more courses of oral glucocorticoids or had been hospitalised for asthma during the previous six months. Taking more than 2000 mcg of beclomethasone or 1600 mcg of budesonide daily by pressurised metered dose inhaler, 800 mcg of budesonide daily by Turbuhaler dry-powder inhaler or 800 mcg of fluticasone daily.

Interventions

Budesonide 100 µg BD + Placebo.

Budesonide100 µg + Formoterol 12 µg BD (9 µg delivered dose).

Budesonide 400 µg BD + Placebo.

Budesonide 400 µg + Formoterol 12 µg BD (9 µg delivered dose).

Delivery was DPI.

Outcomes

Two primary outcome variables, the rate of severe exacerbations and the rate of mild exacerbations, according to treatment group.

SAE data (all-cause and asthma-related) provided by AstraZeneca from Data on file 2008.

No SAE data given in the paper publication, except asthma admissions, but the sponsors have provided data on file for the numbers of participants with all-cause and asthma-related SAEs.

NotesSponsored by AstraZeneca.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated randomisation schedule (Ni Chroinin 2010).
Allocation concealment (selection bias)Low riskParticipants were randomly assigned to treatment groups in balanced blocks of four at each centre.
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind.
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed.
Incomplete outcome data (attrition bias)
All outcomes
Low risk694 of 852 (81%) completed the study.
Selective reporting (reporting bias)Low riskSAE data provided by sponsors.

Pauwels 1997a

Methods Study Design: a randomised, double-blind, multi-centre, parallel-group study over 12 months at 71 centres in 9 countries (Belgium, Canada, the Netherlands, Israel, Italy, Luxembourg, Norway, Spain and the United Kingdom). Run-in 4 weeks on 800 mcg twice daily.
Participants

Study Design: a randomised, double-blind, multi-centre, parallel-group study over 12 months at 71 centres in 9 countries (Belgium, Canada, the Netherlands, Israel, Italy, Luxembourg, Norway, Spain and the United Kingdom). Run-in 4 weeks on 800 mcg twice daily. 

Population: 852 adults (18 to 70 years) with persistent symptomatic asthma. 

Baseline Characteristics: mean age 42 years. FEV1 76% predicted. Concomitant ICS used by 100% of participants (mean dose 820 mcg/day).  

Inclusion Criteria: 18 to 70 years old, who had asthma for at least six months and had been treated with an inhaled glucocorticoid for at least three months. FEV1 % predicted at least 50%, bronchodilator reversibility by an increase of at least 15% in FEV1 over baseline after inhalation of 1 mg of terbutaline. Stable asthma during run-in and compliant with treatment. 

Exclusion Criteria: three or more courses of oral glucocorticoids or had been hospitalised for asthma during the previous six months. Taking more than 2000 mcg of beclomethasone or 1600 mcg of budesonide daily by pressurised metered dose inhaler, 800 mcg of budesonide daily by Turbuhaler dry-powder inhaler or 800 mcg of fluticasone daily.

Interventions

This report deals with patients on 800 mcg budesonide daily.

Budesonide 100 µg BD + Placebo.

Budesonide100 µg + Formoterol 12 µg BD (9 µg delivered dose).

Budesonide 400 µg BD + Placebo.

Budesonide 400 µg + Formoterol 12 µg BD (9 µg delivered dose).

Delivery was DPI.

Outcomes

Two primary outcome variables, the rate of severe exacerbations and the rate of mild exacerbations, according to treatment group.

SAE data (all-cause and asthma-related) provided by AstraZeneca from Data on file 2008.

No SAE data given in the paper publication, except asthma admissions, but the sponsors have provided data on file for the number of participants with all-cause and asthma-related SAEs. One death (unrelated to asthma) occurred in a participant on budesonide 400 and formoterol 12 twice daily.

NotesSponsored by AstraZeneca.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated randomisation schedule (Ni Chroinin 2010).
Allocation concealment (selection bias)Low riskParticipants were randomly assigned to treatment groups in balanced blocks of four at each centre.
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind.
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed.
Incomplete outcome data (attrition bias)
All outcomes
Low risk694 of 852 (81%) completed the study.
Selective reporting (reporting bias)Low riskSAE data provided by sponsors.

Peters 2008

Methods

Study Design: a randomised, double-blind, single-dummy, multi-centre, phase III, parallel-group study over 52 weeks from August 2003 to February 2005 at 77 centres in the United States.

Run-in 2 weeks on budesonide 320 mcg bd (LABA discontinued).

Participants

Population: 708 adults and adolescents (12 to 81 years) with moderate to severe persistent asthma.

Baseline Characteristics: mean age 40 years. FEV1 72% predicted. Concomitant ICS used by 100% of participants (mean daily dose around 500 mcg).

Inclusion Criteria: 12 years of age and older with a documented clinical diagnosis of moderate to severe asthma for at least 6 months before screening, received maintenance asthma treatment with a stable dose of ICS for at least 4 weeks before the screening visit. FEV1 % predicted of at least 45%, bronchodilator reversibility by an increase of at least 12% in FEV1 and at least 0.20 L from baseline within 15 to 30 minutes after administration of a fast-acting beta2-agonist or have a documented history of this level of reversibility after administration of a fast-acting beta2-agonist while using ICS within 1 year of screening. To require two asthma controller medications or to have had a history of at least two asthma-related night-time awakenings or at least three uses of rescue medication within the week before screening. Required to be nonsmokers, with a less than 20-pack-year smoking history. 

Exclusion Criteria: had a significant disease or disorder (e.g. cardiovascular, pulmonary [other than asthma], hepatic, renal) that, in the opinion of the investigator, may put the participant at risk or influence the results of the study. In addition, those treated with systemic corticosteroids within 30 days before screening or during the period between screening and randomisation were excluded.

Interventions
  • Budesonide/formoterol 640/18 µg BD.

  • Budesonide/formoterol 320/9 µg BD (this arm was not used in the analysis for this review).

  • Budesonide 640 µg BD.

Delivery was pMDI.

Outcomes

Because this study was a safety study, no single variable was considered primary. However, spirometry (predose and 2-hour post-dose FEV1) was conducted at each study visit to detect any untoward decreases in lung function over the 52-week period.

Web report indicates 21 participants with SAE on BDF 640/18 bd and 5 on budesonide 640 bd. No deaths in the study.

Article reports one asthma SAE in the BDF 640/18 bd group.

NotesSponsored by AstraZeneca (SD-039-0728).
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomly assigned using a 3:1:1 overall randomisation scheme and a computer-generated allocation schedule.
Allocation concealment (selection bias)Unclear riskNot reported.
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind.
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed.
Incomplete outcome data (attrition bias)
All outcomes
Low risk579 of 708 (82%) completed the study.
Selective reporting (reporting bias)Low riskSAE data available from paper and Web report.

Pohunek 2006

Methods

Study Design: a randomised, double-blind, double-dummy, active-controlled, multi-centre, parallel-group study over 12 weeks from March 2002 to March 2003 at 80 centres in 8 countries:  Austria (5), Belgium (11), Czech Republic (14), France (11), Hungary (12), Poland (17), Spain (8) and Switzerland (2).

Run-in 2 weeks on previous dose of ICS, but LABA appears to have been withdrawn from the 40% previously taking LABA?

Participants

Population: 630 children (4 to 11 years) with asthma. 

Baseline Characteristics: mean age 8 years. FEV1 92% predicted. Concomitant ICS used by 100% of participants (mean 450 mcg/day), and around 40% had previously being taking LABA. 

Inclusion Criteria: outpatients aged 4 to 11 years who had been diagnosed with asthma (as defined by the American Thoracic Society) for a minimum period of 6 months, to have a pre-bronchodilator PEF at least 50% of predicted normal and to have received treatment with an ICS (any brand) for at least 3 months before entry into the study, with the dose remaining constant (375 to1000 µg/day) during the 30 days immediately before enrolment, had to have a history of an average of more than 1 clinically important exercise-induced bronchoconstriction per week during the 3 months leading up to the study. 

Exclusion Criteria: used oral, parenteral, or rectal corticosteroids within 30 days of inclusion in the study; any respiratory infection affecting asthma control within the 30 days before enrolment; any significant disease or concomitant disorder; known or suspected hypersensitivity to the study medication or inhaled lactose. Use of inhaled anticholinergics, beta-blockers (including eye drops), xanthines, and other anti-asthma products was not permitted during the study.

Interventions
  • Budesonide/formoterol 80/4.5 µg 2× BD.

  • Budesonide 100 µg 2× BD.

  • Budesonide 100 µg 2× BD + Formoterol  4.5 µg 2× BD (separate inhalers).

Equivalent budesonide in each arm (400 mcg metered dose). DPI delivery.

Outcomes

The primary efficacy variable was the change from baseline to treatment (average of the 12-week treatment period) in morning peak expiratory flow (PEF).

Article reports: "Serious adverse events were experienced by a total of 11 participants: 3 BDF (fracture, laryngitis, torticollis), 5 with budesonide and formoterol in separate inhalers (appendicitis (2), vomiting, laryngitis, pneumonia) and 3 with budesonide (gastroenteritis (2) and fracture). No deaths were reported.

NotesSponsored by AstraZeneca.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported.
Allocation concealment (selection bias)Unclear riskNot reported.
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind.
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed.
Incomplete outcome data (attrition bias)
All outcomes
Low risk592 of 630 (94%) completed the study.
Selective reporting (reporting bias)Low riskSAEs reported by treatment group and event type in article.

Price 2002

Methods Study Design: a randomised, double-blind, multi-centre, parallel-group study in 152 general practices in the UK and the Republic of Ireland comprising two parts (4 weeks and  24 weeks). Run-in 7 to 14 days.
Participants

Population: 663 adolescents and adults (12+ years) with mild to moderate asthma (part 1). 505 continued to part 2.

Baseline Characteristics: mean age 38 years. Concomitant ICS used by 67% of participants. 

Inclusion Criteria: 12 years and older with a diagnosis of asthma confirmed in the clinical record for at least 3 months. Current treatment had to include a short-acting beta2-agonist alone or with an ICS (<400 mg/day beclomethasone dipropionate or budesonide via pressurised metered dose inhaler, or <200 mg/day fluticasone or budesonide via Turbohaler) at a constant dose for >4 weeks. Were required to have experienced asthma symptoms (chest tightness, cough, wheeze or shortness of breath) on a minimum of 3 days in the week before enrolment into the study. Either reversibility of peak expiratory flow (PEF)/forced expiratory volume in 1 second (FEV1) of > 12% (or > 9% of predicted normal), or a diurnal variation of > 20% on at least one day during the run in period.

Exclusion Criteria: more severe or recently unstable asthma, PEF < 50% predicted; currently receiving (during 4 weeks before enrolment) nebulised therapy, oral corticosteroids, leukotriene antagonist, or long-acting beta2-agonist; a clinically relevant upper respiratory tract infection in the 4 weeks leading up to enrolment, irreversible chronic airways disease.

Interventions
  • Budesonide 400 µg BD + Eformoterol 9 µg BD.

  • Budesonide 400 µg BD + placebo.

Data from part 2 used after 4 weeks stabilisation of participants on the same treatments in part 1. DPI delivery.

Outcomes

In part 2, the primary outcome measure was time to the first mild asthma exacerbation.

SAE data not reported in article but obtained from Jaeschke 2008.

NotesSupported by grant from AstraZeneca.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated random numbers (Ni Chroinin 2010).
Allocation concealment (selection bias)Low riskNumbered coded solutions supplied by pharmacy (Ni Chroinin 2010).
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind.
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed.
Incomplete outcome data (attrition bias)
All outcomes
Low risk400 of 505 (79%) completed part 2.
Selective reporting (reporting bias)Low riskData on SAEs from Jaeschke 2008.

SD-039-0714

Methods

A  randomised, double-blind, multi-centre, parallel-group study over 12 weeks from August 2001 to September 2002 at 122 centres in the United Kingdom (119 general practice centres and 3 hospital centres). Run-in 2 weeks on budesonide 200 mcg twice daily.

Efficacy and safety of budesonide/formoterol Turbuhaler (160/4.5 mg bid delivered dose) compared with budesonide Turbuhaler (200 mg bid metered dose) in steroid-using asthmatic adolescent participants. A double-blind, double-dummy, randomised, parallel-group, phase III, multicentre study (ATTAIN study).

Participants

Population: 271 steroid-using asthmatic adolescents (11 to 17) years. 

Baseline Characteristics: mean age 14 years. FEV1 75% predicted. Concomitant ICS used by 100% of participants. 

Inclusion Criteria: 12 to 17 years old. FEV1 % predicted 40% to 90%, bronchodilator reversibility of at least 12% in FEV1 and experiencing asthma symptoms. Receiving an ICS for perennial asthma, dose of ICS within or equal to 375 to 1000 mg daily dose within the licensed dose for participants’ age, 

Exclusion Criteria: not obvious.

Interventions
  • Budesonide/formoterol 160/4.5 µg BD.

  • Budesonide 200 µg BD.

Delivery was DPI.

Outcomes

am PEF as recorded in diary daily by participants..

Web report indicates no deaths and one SAE in each group (overdose on BDF and bronchospasm on budesonide).

NotesSponsored by AstraZeneca.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported.
Allocation concealment (selection bias)Unclear riskNot reported.
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind.
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed.
Incomplete outcome data (attrition bias)
All outcomes
Low risk219 of 271 (81%) completed the study.
Selective reporting (reporting bias)Low riskSAE data in Web report.

SD-039-0718

Methods Study Design: a randomised, double-blind, double-dummy, active-controlled study over 12 weeks from July 2002 to October 2003 at 52 centres in the United States. Run-in 2 weeks on 100 mcg budesonide twice daily.
Participants

Population: 411 children (6 to15 years) with mild to moderate asthma. 

Baseline Characteristics: mean age 10 years. FEV1 82% predicted. Concomitant inhaled corticosteroids used by 100% of participants (mean 235 mcg/day). 

Inclusion Criteria: 6 to 15 years of age, treated long term with a low to medium dose of ICS, FEV1 % predicted at least 50% on ICS therapy, older than 12 years, bronchodilator reversibility of at least 12% in FEV1 and at least 0.20 L from the pre-albuterol value within 15 to 30 minutes after administration of a standard dose of a fast-acting beta2-agonist (albuterol pMDI, 2 to 4 actuations [90 µg per actuation], with or without a spacer) or after administration of up to 2.5 mg nebulized albuterol. Younger than 12 years needed to show only reversibility of at least 12%. Alternatively, reversibility of  PEF of at least 15%, but not more than 50%, could be used by any subject to meet the reversibility criterion. 

Exclusion Criteria: not obvious.

Interventions
  • Budesonide/formoterol 40/4.5 µg 2× BD pMDI delivery.

  • Budesonide 40 µg 2× BD pMDI delivery.

  • Formoterol  4.5 µg 2× BD DPI delivery.

Arm three not used in this review.

Outcomes

Primary efficacy variable: morning peak expiratory flow (PEF).

Web report lists no deaths and no participants with SAE in groups one or two.

NotesSponsored by AstraZeneca.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation was stratified by age group (children younger than 8 years of age vs children 8 years and older). Participants were randomly assigned to 1 of the 3 treatment groups.
Allocation concealment (selection bias)Unclear riskNo details.
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind. Treatments were given in double-dummy fashion because of the differences in devices.
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed.
Incomplete outcome data (attrition bias)
All outcomes
Low risk28% dropout on BDF and 35% on budesonide (all randomly assigned participants in safety analysis and no events reported!).
Selective reporting (reporting bias)Low riskSAE data on Web report.

SD-039-0719

Methods Study Design: a randomised, open-label, safety study over 26 weeks from July 2002 to October 2003 at 29 centers in the United States. Run-in 1 week.
Participants

Population: 187 children (6 to 11 years) with ICS-dependent asthma.

Baseline Characteristics: mean age 9 years. FEV1 84% predicted. Concomitant ICS used by 100% of participants.  

Inclusion Criteria: 6 to under 12 years of age with ICS-dependent asthma. FEV1 % predicted at least 50%, documented historic peak expiratory flow (PEF) or FEV1 reversibility at least 12% from a pre-albuterol value within 15 to 30 min after administration of a standard dose of fast-acting beta2-agonist. Participants without a documented history of reversibility must have demonstrated FEV1 reversibility as above at any time before visit 2.  

Exclusion Criteria: not obvious.

Interventions
  • Budesonide/formoterol 160/4.5 µg  2× BD pMDI delivery.

  • Budesonide 160 µg 2× BD TBH delivery.

Outcomes

Outcome: No single variable was considered to be primary. The primary objective of the study was to assess long-term safety.

Web report indicates no deaths. Two SAEs in BDF group (asthma and pneumonia) and one on budesonide (sickle cell anaemia).

NotesSponsored by AstraZeneca.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported.
Allocation concealment (selection bias)Unclear riskNot reported.
Blinding (performance bias and detection bias)
All outcomes
High riskOpen.
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed.
Incomplete outcome data (attrition bias)
All outcomes
Low risk87% completed the study.
Selective reporting (reporting bias)Low riskSAE reported fully.

SD-039-0725

Methods

Study Design: a randomised, double-blind, double-dummy, multi-centre, active-controlled, parallel-group study over 12 weeks from January 2003 to August 2004 at 128 centres in the United States. Run-in 4 to 5 weeks, single-blind (participants had to be stable on budesonide/formoterol 40/4.5 mcg two puffs twice daily).

A 12--week, randomised, double-blind, double-dummy, active-controlled study of SYMBICORT pMDI administered once daily in children and adolescents 6 to 15 years of age with asthma.

Participants

Population: 522 children and adolescents (6 to15 years) with asthma.

Baseline Characteristics: mean age 10 years. FEV1 78% predicted. Concomitant ICS previously used by 100% of participants (mean 245 mcg/day).

Inclusion Criteria: 6 to 15 years with a documented clinical diagnosis of asthma for at least 6 months before screening, and in stable condition. Should have received maintenance asthma treatment with ICS for at least 4 weeks before the screening visit. FEV1 % predicted of between 60% and 90%, as measured approximately 24 hours after the last dose of long-acting beta2- agonist and 6 hours after the last dose of short-acting beta2-agonist. Participants with an FEV1 predicted between 90% and 95% predicted could be included if they had an FEV1/FVC ratio measured on screening spirometry of less than 80%. Bronchodilator reversibility of at least 12% in FEV1 and at least 0.20 L from baseline within 15 to 30 minutes after administration of a standard dose of fast-acting beta2-agonist, except for participants  younger than 11 years of age, who were required to show reversibility of at least 12% but not also a change of at least 0.20 L.  

Exclusion Criteria: Not stated.

Interventions
  • Budesonide/formoterol 80/4.5 µg  2× QD. 

  • Budesonide/formoterol 40/4.5 µg  2× BD. 

  • Budesonide 80 µg 2× QD.

Delivery was pMDI. All groups had 160 mcg budesonide daily.

Outcomes

Primary variable: evening PEF (from daily diary).

"There were no deaths at any time during the study."

"6 subjects had an SAE during the double blind treatment period: 2 on BDF 40 bd (abdominal pain, asthma), 3 in BDF 80 qd group (influenza, asthma 2) and one in the budesonide group (asthma)."

NotesSponsored by AstraZeneca.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomisation was stratified by age (6 to 11 years of age vs 12 to 15 years of age) at the time of screening, to ensure an approximately uniform distribution of participants across treatment groups within each of these 2 strata.
Allocation concealment (selection bias)Unclear riskNo details.
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind. To maintain blinding with the twice-daily dosing regimen, all participants randomly assigned to receive once-daily dosing were to receive the active treatment in the evening and placebo treatment with a matched device in the morning.
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed.
Incomplete outcome data (attrition bias)
All outcomes
Low risk499 of 521 (96%) completed the study.
Selective reporting (reporting bias)Low riskSAEs reported by treatment group and cause.

SD-039-0726

Methods

Study Design: a randomised, double-blind, double-dummy, multi-centre, parallel-group, placebo- and active-controlled study over 12 weeks from April 2003 to June 2004 at 151 centers in the United States. Run-in 4- to 5-week single-blind.

A twelve-week, randomised, double-blind, double-dummy, placebo- and active-controlled study of SYMBICORT pMDI administered once daily in adults and adolescents with asthma.

Participants

Population: 752 adolescents and adults (16 to 79 years) with asthma.

Baseline Characteristics: mean age 38 years. FEV1 75% predicted. Concomitant ICS used by 100% of participants. 

Inclusion Criteria: 16 years of age and older, with a documented clinical diagnosis of asthma for at least 6 months before screening, and in stable condition. Received maintenance asthma treatment with a low to medium dose of ICS for at least 4 weeks before the screening visit.

FEV1 % predicted of between 60% and 90%, measured at least 24 hours after the last dose of long-acting beta2-agonist and 6 hours after the last dose of short-acting beta2-agonist. 

Exclusion Criteria: not obvious.

Interventions
  • Budesonide/formoterol 160/4.5 µg  2× QD.      

  • Budesonide/formoterol 80/4.5 µg 2× QD.   

  • Budesonide/formoterol 80/4.5 µg  2× BD.   

  • Budesonide 160 µg 2× QD.

Placebo arm and arm two not used in this analysis. MDI delivery.

Outcomes

Primary variable: evening PEF (from daily diary).

SAE data obtained from Web report. Five participants suffered an SAE: three on BDF 80 bd (breast cancer in situ, road traffic accident, musculoskeletal chest pain), one on BDF 160 daily (prostate cancer), and one on budesonide (tension headache). No deaths were reported.

NotesSponsored by AstraZeneca.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported.
Allocation concealment (selection bias)Unclear riskNot reported.
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind.
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed.
Incomplete outcome data (attrition bias)
All outcomes
Low risk707 of 751 (94%) completed the study.
Selective reporting (reporting bias)Low riskSAE data on Web report.

Spector 2012

Methods

Study Design: This was a 12-week, randomised, double-blind, double-dummy, phase IV study comparing the efficacy and safety of SYMBICORT pressurized metered dose inhaler (pMDI) 160/4.5 μg × 2 actuations twice daily (BID) with budesonide inhalation powder dry powder inhaler (DPI) 180 μg × 2 inhalations BID in adult and adolescent (≥ 12 years) African American (self-reported) participants with asthma who required a medium to high dose of ICS therapy. Randomisation was stratified by asthma severity, based on daily dosage of ICS at screening (visit 1).

Conducted in 46 US centres from June 2008 to September 2009. Two-week run-in on budesonide DPI 90 mcg (two puffs twice daily) and enrolled if symptomatic on three or more of seven consecutive days.

Participants

Population: 301 adolescents and adults (12+ years old) with moderate to severe persistent asthma. BDF 156 participants, budesonide 155 participants.

Baseline Characteristics: mean age 39 years. FEV1 66% predicted. Concomitant ICS used by 100% of participants. 

Inclusion Criteria: moderate to severe persistent asthma treated long term with a medium to high dose of ICS, FEV1 % predicted within the entrance range of 45% to 85%, bronchodilator reversibility of FEV1 of at least 12% and 0.20 L from the pre-albuterol baseline value within 15 to 30 minutes after administration of a standard dose of salbutamol. 

Exclusion Criteria: requiring hospitalisation once in the preceding 6 months or emergency treatment more than once in the previous 3 months, or systemic corticosteroids in previous 30 days or omalizumab in previous 90 days.

Interventions
  • Budesonide/formoterol 160/9 mcg pMDI two inhalations twice daily.

  • Budesonide DPI 180 mcg two inhalations twice daily.

OutcomesPrimary efficacy variable was pre-dose FEV1. SAEs were those that were immediately life threatening, or resulted in death, significant disability or hospitalisation. No deaths and no SAEs were reported in the article by treatment group and causation.
NotesSponsored by AstraZeneca.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation was generated by computer-derived sequential allocation and stratification by asthma severity using balanced blocks.
Allocation concealment (selection bias)Low riskRandomisation was generated by computer-derived sequential allocation and stratification by asthma severity using balanced blocks.
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind, double-dummy.
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed.
Incomplete outcome data (attrition bias)
All outcomes
High risk38 of 156 withdrawals on combination treatment and 53 of 155 on budesonide alone (high rate and unbalanced).
Selective reporting (reporting bias)Low riskSAE data fully reported.

Tal 2002

Methods

Study Design: a randomised, double-blind, double-dummy, active-controlled, multi-centre, parallel-group study over 12 weeks from November 1998 to June 1999 at 48 centres in 7 countries: Hungary (6), the Czech Republic (7), the United Kingdom (11), Spain (7), Belgium (4), Israel (4) and South Africa (4).

Run-in 2 to 4 weeks on budesonide 400 mcg daily (unclear if previous LABA withdrawn).

Participants

Population: 286 children (4 to 17 years) with asthma. 

Baseline Characteristics: mean age 11 years. FEV1 75% predicted. Concomitant ICS used by 100% of participants (mean 548 mcg/day), previous LABA use not reported.

Inclusion Criteria: between 4 and 17 years of age with a diagnosis of asthma (minimum duration 6 months), FEV1 % predicted of 40% to 90%, bronchodilator reversibility by an increase of at least 15% in FEV1 over baseline within 15 minutes of inhalation of a short-acting beta2-agonist. 

Exclusion Criteria: unstable asthma (defined as the use of oral, parenteral, or rectal corticosteroids within 30 days of study commencement), any respiratory infection affecting disease control within the previous 4 weeks, and known hypersensitivity to study medication or inhaled lactose.

Interventions
  • Budesonide/formoterol 80/4.5 µg 2× BD.

  • Budesonide 100 µg 2× BD.

Delivery was DPI.

Outcomes

The primary efficacy variable was the change in morning PEF from baseline to end of treatment.

"A total of 7 patients in the budesonide/formoterol group had a serious adverse event requiring admission to hospital (asthma (5), larynx edema (1), pneumonia (1)." Deaths are not mentioned, nor are any events in the budesonide group. Further clarification was sought from the sponsors, who have confirmed no SAEs in the budesonide group.

NotesSponsored by AstraZeneca.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated block randomisation list.
Allocation concealment (selection bias)Unclear riskIndividual treatment code envelopes provided for each participant.
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind, double-dummy technique.
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed.
Incomplete outcome data (attrition bias)
All outcomes
Low risk268 of 286 (94%) completed the study.
Selective reporting (reporting bias)Low riskSAEs appear to be fully reported in the article.

Weinstein 2010

Methods Study Design: randomised, multi-centre, double-blind, double-dummy, placebo-controlled, parallel-group study over 12 weeks at 115 sites worldwide. Run-in two weeks mometasone fumarate (MF) 400 mcg twice daily (pMDI).
Participants

Population: 495 adults (in the arms that were eligible for this review) who were 12 years of age or older) with severe asthma. 

Baseline Characteristics: mean age 48 years. FEV1 66% predicted. Concomitant ICS used at high dose by 100% of participants for at least 12 weeks (with or without LABA) . 

Inclusion Criteria: asthma for at least 12 months (with a history of deterioration requiring oral steroids in the previous 2 to 12 months) and on a high-dose ICS regimen (with or without LABA) for at least 12 weeks. FEV1 50% to 85% predicted, bronchodilator reversibility at least 12% in FEV1 or 0.2 litres; alternatively, PEF variability over 20%. 

Exclusion Criteria: unstable asthma between screening and baseline, smoking history more than 10 pack-years (or current smoking), past history of pregnancy or clinically significant abnormality in electrocardiogram.

Interventions
  • Mometasone furoate/formoterol (MF/F) 400/10 mcg twice daily.

  • Mometasone furoate (MF) 400 mcg twice daily.

  • MF/F 200/10 mcg twice daily (not used in this review).

Delivery was pMDI (the placebo and formoterol arms in this trial were not considered for this review).

OutcomesPrimary outcome mean change from baseline in FEV1 (AUC0-12h) up to week 12. SAEs were those that were immediately life threatening or that resulted in death, significant disability or hospitalisation. No deaths and no SAEs were reported with causation on the clinicaltrials.gov Website.
NotesSponsored by Schering-Plough.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk“Randomization was performed in blocks using random numbers generated by SAS.”
Allocation concealment (selection bias)Unclear riskNo details.
Blinding (performance bias and detection bias)
All outcomes
Low risk"Double-blind."
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed.
Incomplete outcome data (attrition bias)
All outcomes
Low risk33 of 240 withdrawals on combination and 27 of 255 on MF.
Selective reporting (reporting bias)Low riskFull SAE data obtained from report of NCT00381485 and from article.

Zangrilli 2011

Methods

Study design: a 12-week, randomised, double-blind, active-controlled, multi-centre, phase IIIB study comparing the efficacy and safety of SYMBICORT pMDI 160/4.5 mg × 2 actuations twice daily versus budesonide HFA pMDI 160 mg × 2 actuations twice daily, in adult/adolescent (> 12 yrs) Hispanic subjects with asthma.

Carried out in 39 US centres between January 2007 and June 2008.

Two-week run-in on BUD pMDI 160 mcg twice daily.

Participants

Population: 250 adults and adolescents (over 12 years of age) with moderate to severe asthma based on historical daily dosing of medium- to high-dose ICS alone or in combination with LABA for 30 days or longer before enrolment.

Baseline characteristics: mean age 38 years. FEV1 68% predicted. Concomitant ICS reported by 91% of participants at a mean dose of 600 mcg per day, but FEV1 rose to 72% predicted after step-down to BUD 160 mcg twice daily during run-in.

Inclusion Criteria:

  • Male or female, Hispanic (self-reported), > 12 years of age.

  • Moderate to severe asthma requiring treatment with an ICS.

  • Diagnosis of asthma for at least 6 months.

  • Participants had pre-bronchodilator forced expiratory volume in 1 second (FEV1) of 45% to 85% of predicted normal and reversibility of 12% or greater and 0.20 L or greater.

  • Randomly assigned participants had documented daytime or night-time asthma symptom scores greater than 0 on 3 or more days within 7 consecutive days during a 2-week run-in period on BUD pMDI 160 μg twice daily.

Exclusion Criteria:

  • Participants requiring treatment with systemic corticosteroids (e.g. oral, parenteral, ocular).

  • Participants who had required hospitalisation once or emergency treatment more than once in the preceding 6 months, used systemic corticosteroids within the previous 30 days, or had a smoking history of 10 or more pack-years.

Interventions
  • Budesonide/formoterol 160/9 mcg pMDI twice daily.

  • Budesonide 160 mcg HFA pMDI twice daily.

Outcomes

Primary outcome: mean change from baseline in morning peak expiratory flow.

SAEs were those that were immediately life threatening, or that resulted in death, significant disability or hospitalisation, or required intervention to prevent one of these outcomes. No deaths and no SAEs were reported in the article by treatment group and causation.

NotesSponsored by AstraZeneca.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Randomization used a computer-generated allocation schedule."
Allocation concealment (selection bias)Unclear riskNo details.
Blinding (performance bias and detection bias)
All outcomes
Low risk"Double-blind (subject, caregiver, investigator, outcomes assessor)."
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed,
Incomplete outcome data (attrition bias)
All outcomes
Low risk18 of 127 and 21 of 123 withdrawals given combination and budesonide, respectively.
Selective reporting (reporting bias)Low riskFull report of SAEs in published article and at clinicaltrials.gov.

Zetterstrom 2001

Methods

Study Design: a randomised, double-blind, double-dummy, active-controlled, parallel-group study over 12 weeks at 63 centres in 6 countries: Finland (7), Germany (12), Ireland (6), Norway (12), Spain (11) and Sweden (15).

Run-in 2 weeks receiving usual ICS (no mention of continuing previous LABA).

Participants

Population: 362 adults (18 to 78 years) with asthma not controlled with inhaled corticosteroids alone.

Baseline Characteristics: mean age 47 years. FEV1 74% predicted. Concomitant ICS used by 100% of participants (mean dose 960 mcg/day). 

Inclusion Criteria: 18 years and older, using inhaled glucocorticosteroids at a constant daily dose of at least 500 µg for at least 30 days before entry, FEV1 % predicted of 50% to 90%, bronchodilator reversibility by an increase of at least 15% in FEV1 over baseline after inhalation of terbutaline sulphate 1 mg (Bricanyl Turbuhaler) or salbutamol 0.4 mg. 

Exclusion Criteria: use of oral, parenteral, or rectal glucocorticosteroids within 30 days before study entry; respiratory infection; seasonal asthma; severe cardiovascular disorder; beta-blocker therapy; a history of heavy smoking (greater than10 pack-years); pregnancy or failure to use acceptable contraceptives in women of child-bearing potential.

Interventions
  • Budesonide/formoterol 160/4.5 µg 2× BD.

  • Budesonide 200 µg + Formoterol 4.5 µg 2× BD.

  • Budesonide 200 µg 2× BD.

Delivery was DPI, equivalent to budesonide 400 mcg bd metered dose in all arms.

Outcomes

The primary efficacy variable was change in average morning PEF from baseline to study end.

Article reports: "There were five serious adverse events in the single inhaler therapy group and one in the budesonide alone group. There was one death by suicide and four hospital admissions (due to pneumonia, liver cysts, ischaemic stroke and intervertebral disc prolapse)." The sponsors have confirmed that the death occurred in a participant who was using a combined budesonide/formoterol inhaler.

NotesSponsored by AstraZeneca.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputerised randomisation occurred on a per country basis.
Allocation concealment (selection bias)Low riskIndividual treatment codes were kept in sealed envelopes until data analysis.
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind; participants successively used three numbered inhalers (identical in appearance to the corresponding placebo) each morning and evening.
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed.
Incomplete outcome data (attrition bias)
All outcomes
Low risk309 of 362 (85%) completed the study.
Selective reporting (reporting bias)Low riskSAE by treatment group in article.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Ankerst 2003Short-term cross-over study.
AstraZeneca 2005Comparison with budesonide and theophylline.
AstraZeneca 2005aOngoing study.
AstraZeneca 2005bComparison of single-inhaler therapy with current best practice.
AstraZeneca 2005cComparison of single-inhaler therapy with current best practice.
AstraZeneca 2005dComparison of single-inhaler therapy with current best practice.
AstraZeneca 2006Comparison of single-inhaler therapy with ICS and terbutaline.
AstraZeneca 2006aComparison of single-inhaler therapy with current best practice.
AstraZeneca 2006bComparison of single-inhaler therapy with current best practice.
Balanag 2006Comparison with salbutamol in acute asthma.
Bateman 2003BDF compared with higher-dose fluticasone.
Bateman 2006Acute asthma.
Bodzenta-Lukaszyk 2011Eight-week duration.
Bouros 1999Formoterol and beclomethasone compared with higher-dose beclomethasone.
Buhl 2004Adjustable versus fixed-dose BDF.
Bumbacea 2010Eight-week duration.
Burgess 1998Short-term cross-over study.
Canonica 2004Adjustable versus fixed-dose BDF.
Ceylan 2004Formoterol in comparison with montelukast in addition to low-dose ICS.
Dhillon 2006Review of beclomethasone/formoterol treatment.
FitzGerald 1999No randomisation to ICS.
FitzGerald 2003Adjustable versus fixed-dose BDF.
Haahtela 2006Formoterol used as needed (with or without budesonide).
Ind 2004Adjustable versus fixed-dose BDF.
Jakopovic 2009Uncontrolled study.
Kozlik-Feldmann 1996No randomisation to ICS.
Lalloo 2003BDF compared with higher-dose ICS.
Lemanske 2010Cross-over design without same-dose ICS comparator group.
Leuppi 2003Adjustable versus fixed-dose BDF.
LotvallShort-term comparison of bronchodilation following FPS and BDF.
Lundborg 2006Cost-effectiveness of single-inhaler therapy.
Maspero 2010No arm with same-dose ICS comparator.
Mitchell 2003Comparison with higher-dose ICS.
Molimard 2001Not randomly assigned to ICS.
Nayak 2010Combined results of other studies.
Novartis 2005No random assignment to ICS.
O'Byrne 2005BDF as single-inhaler therapy or fixed-dose treatment compared with higher-dose budesonide.
Ohta 2008Eight-week duration.
Overbeek 2005Duration of less than 12 weeks on each dose of budesonide.
Papi 2007Delivery device comparison for beclomethasone/formoterol combination inhalers.
Pauwels 2003Comparison of formoterol with salbutamol as relief medication.
Peters 2008aOverview.
Pleskow 2003Not randomly assigned to ICS.
Pohl 2006Adjustable maintenance dosing study.
Rabe 2006BDF single-inhaler therapy compared with higher-dose budesonide.
Rosenhall 2002Combined BDF inhaler compared with both medications given together in separate inhalers.
Rosenhall 2003Combined BDF inhaler compared with both medications given together in separate inhalers.
Rosenhall 2003aCombined BDF inhaler compared with both medications given together in separate inhalers.
Rosenwasser 2008Combined results of other studies.
Saito 2011Cross-over study.
Scicchitano 2004BDF single-inhaler therapy compared with higher-dose budesonide.
Stelmach 20074-Week study.
van der Molen 1997No random assignment to ICS.
Villa 2002Formoterol as needed compared with terbutaline as needed.
Von Berg 2003No random assignment to ICS.
Weinstein 2010aOverview.
White 2010Combined results of other studies.
Worth 2005Single-inhaler therapy compared with current best practice.
Zetterstrom 2001aSingle-inhaler therapy.
Zetterström 2000Single-inhaler therapy.

Characteristics of ongoing studies [ordered by study ID]

NCT01444430

Trial name or titleD5896C00027
MethodsA 26-week, randomised, double-blind, parallel-group, active-controlled, multi-centre, multi-national safety study evaluating the risk of serious asthma-related events during treatment with Symbicort, a fixed combination of inhaled Corticosteroid (ICS) (budesonide) and a long-acting beta2-agonist (LABA) (formoterol) as compared with treatment with ICS (budesonide) alone in adult and adolescent (≥ 12 years of age) patients with asthma
Participants
  • Male or female, ≥ 12 years of age.

  • Documented clinical diagnosis of asthma for at least 1 year before visit 2.

  • Patient must have history of at least 1 asthma exacerbation, including one of the following: requiring treatment with systemic corticosteroids, asthma-related hospitalisation between 4 weeks and 12 months before randomisation.

  • Current asthma therapy: Participants must be appropriately using one of the treatments for asthma listed in the protocol combined with achieving certain results when an asthma control questionnaire is completed.

  • Estimated enrolment 11,700.

Interventions
  • Symbicort pMDI80/4.5 μg ×2 actuations bid (morning and evening), for oral inhalation, 26-week treatment.

  • Symbicort pMDI160/4.5 μg ×2 actuations bid (morning and evening), for oral inhalation, 26-week treatment.

  • budesonide pMDI80 μg ×2 actuations bid (morning and evening), for oral inhalation, 26-week treatment.

  • budesonide pMDI160 μg ×2 actuations bid (morning and evening), for oral inhalation, 26-week treatment.

Outcomes
  • Time to first event in composite endpoint (asthma-related death, asthma-related intubation or asthma-related hospitalisation) [time frame: up to 27 weeks].

  • Time to first event included in the definition of asthma exacerbation [time frame: up to 26 weeks]; asthma exacerbation defined as deterioration of asthma requiring systemic corticosteroids for at least 3 days or an inpatient hospitalisation or emergency room visit as a result of asthma that required systemic corticosteroids.

Starting dateDecember 2011.
Contact informationAstraZeneca.
Notes 

NCT01471340

Trial name or titleP06241.
MethodsA 26-week randomised, double-blinded, active-controlled study comparing the safety of mometasone furoate/formoterol fumarate MDI fixed-dose combination versus mometasone furoate MDI monotherapy in adolescents and adults with persistent asthma (Protocol No. P06241, also known as P202).
Participants
  • Male or female, ≥ 12 years of age.

  • Persistent asthma for at least 1 year.

  • Must use a daily asthma controller medication for at least 4 weeks before randomisation, including an ICS with or without a long-acting beta-agonist (LABA) or other adjunctive asthma therapy OR must be using a leukotriene receptor antagonist (LTRA), xanthine or a short-acting beta-agonist (SABA) as monotherapy.

  • Must be able to discontinue current asthma medication.

  • Must have a history of at least one asthma exacerbation in previous 4 to 52 weeks.

  • Estimated enrolment 11,664.

Interventions
  • Mometasone furoate/formoterol MDI 100/5 mcg two inhalations twice daily (BID); Dulera/Zenhale.

  • Drug: mometasone furoate/formoterol MDI 200/5 mcg two inhalations BID; Dulera/Zenhale.

  • Drug: mometasone furoate MDI 100 mcg two inhalations BID.

  • Drug: mometasone furoate MDI 200 mcg two inhalations BID.

OutcomesPrimary outcome measures: time to first serious asthma outcomes (a composite endpoint defined as asthma-related: hospitalisations, intubations, and deaths) [Time frame: baseline up to 26 weeks].

Secondary outcome measures: time-to-first asthma exacerbation [time frame: baseline up to 26 weeks].
Starting dateJanuary 2012.
Contact informationMerck.
Notes 

Ancillary