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

  1. Christopher J Cates1,*,
  2. Roman Jaeschke2,
  3. Stefanie Schmidt3,
  4. Montse Ferrer3

Editorial Group: Cochrane Airways Group

Published Online: 7 JUN 2013

Assessed as up-to-date: 1 AUG 2012

DOI: 10.1002/14651858.CD006924.pub3


How to Cite

Cates CJ, Jaeschke R, Schmidt S, Ferrer M. Regular treatment with formoterol and inhaled steroids for chronic asthma: serious adverse events. Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD006924. DOI: 10.1002/14651858.CD006924.pub3.

Author Information

  1. 1

    St George's University of London, Population Health Sciences and Education, London, UK

  2. 2

    McMaster University, Department of Medicine and Department of Clinical Epidemiology and Biostatistics, Hamilton, Ontario, Canada

  3. 3

    IMIM (Hospital del Mar Medical Research Institute), Health Services Research Unit, Barcelona, Spain

*Christopher J Cates, Population Health Sciences and Education, St George's University of London, Cranmer Terrace, London, SW17 0RE, UK. ccates@sgul.ac.uk.

Publication History

  1. Publication Status: New search for studies and content updated (conclusions changed)
  2. Published Online: 7 JUN 2013

SEARCH

 

Summary of findings    [Explanations]

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

 
Summary of findings for the main comparison. Regular formoterol and ICS compared to ICS in adults with asthma

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 ICSRegular formoterol and ICS

All-cause mortality
Follow-up: mean 28 weeks
0 per 10001 per 1000
(0 to 4)
OR 3.56
(0.79 to 16.03)
10578
(22 studies)
⊕⊕⊝⊝
low1

All-cause non-fatal serious adverse events
Follow-up: mean 28 weeks
26 per 100025 per 1000
(20 to 32)
OR 0.98
(0.76 to 1.27)
10578
(22 studies)
⊕⊕⊕⊝
moderate2

Asthma-related non-fatal serious adverse events
Follow-up: mean 28 weeks
7 per 10003 per 1000
(2 to 6)
OR 0.49
(0.28 to 0.88)
10208
(21 studies)
⊕⊕⊕⊝
moderate3

*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.

 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.

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

 

Background

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

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 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.

 FigureFigure 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).

 FigureFigure 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.

 

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.

 FigureFigure 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).

 FigureFigure 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.

 FigureFigure 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).

 FigureFigure 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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

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.

 FigureFigure 7. All-cause serious adverse events in children given regular formoterol (with or without ICS).

 

Authors' conclusions

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

 

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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
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 mortality29Peto Odds Ratio (Peto, Fixed, 95% CI)Subtotals only

    1.1 Adults and Adolescents
2210578Peto Odds Ratio (Peto, Fixed, 95% CI)3.56 [0.79, 16.03]

    1.2 Children and Adolescents
72788Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 All-cause non-fatal serious adverse events29Peto Odds Ratio (Peto, Fixed, 95% CI)Subtotals only

    2.1 Adults and Adolescents
2210578Peto Odds Ratio (Peto, Fixed, 95% CI)0.98 [0.76, 1.27]

    2.2 Children and Adolescents
72788Peto Odds Ratio (Peto, Fixed, 95% CI)1.62 [0.80, 3.28]

 3 Asthma mortality29Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected

    3.1 Adults and Adolescents
22Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.2 Children and Adolescents
7Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

 4 Asthma-related non-fatal serious adverse events28Peto Odds Ratio (Peto, Fixed, 95% CI)Subtotals only

    4.1 Adults and Adolescents
2110208Peto Odds Ratio (Peto, Fixed, 95% CI)0.49 [0.28, 0.88]

    4.2 Children and Adolescents
72788Peto Odds Ratio (Peto, Fixed, 95% CI)1.49 [0.48, 4.61]

 

Appendices

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

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


DatabaseFrequency 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


ConferenceYears 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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Last assessed as up-to-date: 1 August 2012.


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 performedThe 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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

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.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. Abstract摘要Résumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to ongoing studies
  22. Additional references
  23. References to other published versions of this review
Brown 2012 {published data only}
  • AstraZeneca. A comparison of SYMBICORT pMDI with budesonide HFA pMDI in African American subjects with asthma. http://www.astrazenecaclinicaltrials.com/_mshost800325/content/clinical-trials/resources/pdf/D5896C00022 (accessed 15 October 2012).
  • Brown RW, O'Brien CD, Martin UJ, Uryniak T, Lampl KL. Long-term safety and asthma control measures with a budesonide/formoterol pressurized metered-dose inhaler in African American asthmatic patients: a randomized controlled trial. Journal of Allergy and Clinical Immunology 2012;130(2):362-7 e9. [1097-6825: (Electronic)]
  • Brown RW, Uryniak T, Lampl KL. Long-term safety of budesonide/formoterol pressurized metered-dose inhaler (PMDI) and budesonide PMDI In African-American patients with asthma: asthma exacerbations and adverse events [Abstract]. American Journal of Respiratory and Critical Care Medicine 2011; Vol. 183, issue Meeting Abstracts:A1294.
Buhl 2003 {published data only}
  • AstraZeneca. Symbicort high dose once daily in mild to moderate asthmatic patients (SD-039-0666). http://www.astrazenecaclinicaltrials.com/sites/133/imagebank/typeArticleparam528362/SD-039-0666.pdf (accessed 26 November 2008).
  • Buhl R, Creemers JP, Vondra V, Martelli NA, Naya IP, Ekstrom T. Once-daily budesonide/formoterol in a single inhaler in adults with moderate persistent asthma. Respiratory Medicine. 2003/04/16 2003; Vol. 97, issue 4:323-30. [0954-6111: (Print)]
  • Buhl R, Creemers JPHM, Vondra V, Martelli NA. Improved and maintained asthma control with once-daily budesonide/formoterol single inhaler in mild-to-moderate persistent asthma. European Respiratory Journal 2001;18(Suppl 33):21s.
  • Buhl R, Creemers JPHM, Vondra V, Martelli NA. Once daily symbicort (budesonide/eformoterol in a single inhaler) is effective in moderate-persistent asthma. Thorax 2001;56(Suppl 3):iii62.
  • Buhl R, Creemers JPHM, Vondra V, Martelli NA. Once-daily budesonide/formoterol via a single inhaler is effective in mild-to-moderate persistent asthma. European Respiratory Journal 2001;18(Suppl 33):21s.
  • Buhl R, Creemers JPHM, Vondra V, Martelli NA. Symbicort® budesonide and formoterol in a single inhaler administered once daily is effective in mild to moderate asthma. Annual Thoracic Society 97th International Conference; May 18-23, 2001; San Francisco CA 2001:D31.
Chuchalin 2002 {published data only}
  • Chuchalin A G, Svensson K, Stahl E, Ovcharenko S I, Goriachkina L A, Sidorenko I V, et al. A health-related quality-of-life comparison of formoterol (Oxis) Turbuhaler plus budesonide (Pulmicort) Turbuhaler with budesonide Turbuhaler alone and noncorticosteroid treatment in asthma: a randomized clinical study in Russia. Respiration 2002;69(5):427-33.
  • Chuchalin A, Stahl E, Svensson K, Ovcharenko S, Goriachkina L, Sidorenko I, et al. Formoterol (oxis(r)) turbuhaler(r) plus budesonide turbuhaler(r) and budesonide alone improve health-related quality of life vs non-steroid therapy in mild to moderate asthma in Russia [abstract]. American Journal of Respiratory and Critical Care Medicine 2001;163(5 Suppl):A506.
  • Chuchalin AG, Ovcharenko SI, Goriachkina LA, Sidorenko IV, Tsoi AN. Formoterol Oxis® Turbuhaler® plus budesonide turbuhaler® is more effective than current non-steroid therapy and budesonide alone in mild to moderate asthma in Russia. Annual Thoracic Society 97th International Conference; May 18-23, 2001; San Francisco CA..
  • Chuchalin AG, Ovcharenko SI, Goriachkina LA, Sidorenko IV, Tsoi AN, Epoch Study G. The safety and efficacy of formoterol OxisRTurbuhalerR plus budesonide PulmicortRTurbuhaler in mild to moderate asthma: a comparison with budesonide Turbuhaler alone and current non-corticosteroid therapy in Russia. International Journal of Clinical Practice 2002; Vol. 56, issue 1:15-20.
Corren 2007 {published data only}
  • AstraZeneca. SD-039-0716. A twelve-week, randomized, double-blind, double-dummy, placebo-controlled trial of SYMBICORT® pMDI (80/4.5 μg) versus its monoproducts (budesonide andformoterol) in children (≥6 years of age) and adults with asthma-SPRUCE 80/4.5. http://www.astrazenecaclinicaltrials.com/sites/133/imagebank/typeArticleparam528362/SD-039-0716.pdf (accessed November 2008).
  • Corren J, Korenblat PE, Miller CJ, O'Brien CD, Mezzanotte WS. Twelve-week, randomized, placebo-controlled, multicenter study of the efficacy and tolerability of budesonide and formoterol in one metered-dose inhaler compared with budesonide alone and formoterol alone in adolescents and adults with asthma. Clinical Therapeutics 2007; Vol. 29, issue 5:823-43.
  • Murphy K, Nelson H, Parasuraman B, Boggs R, Miller C, O'Dowd L. Patient satisfaction with budesonide and formoterol in one pressurized metered-dose inhaler in adults with mild to moderate persistent asthma [Abstract]. American Thoracic Society International Conference; May 18-23, 2007; San Francisco, California, USA. Poster #928..
  • Murphy K, Nelson H, Parasuraman B, Boggs R, Miller C, O'Dowd L. The effect of budesonide and formoterol in one pressurized metered-dose inhaler on patient-reported outcomes in adults with mild-to-moderate persistent asthma. Current Medical Research and Opinion 2008; Vol. 24, issue 3:879-94.
D5896C00001 {published data only}
  • AstraZeneca. A randomized, double-blind, active-controlled, parallel-group, single dummy, multicenter, 12 week study to assess the efficacy and safety of SYMBICORT® pMDI 160/4.5 μg × 2 actuations once-daily (qd) compared to SYMBICORT pMDI 80/4.5 μg × 2 actuations qd, SYMBICORT pMDI80/4.5 μg × 2 actuations twice-daily (bid) and to budesonide pMDI 160 μg × 2 actuations qd in asthmatic subjects 12 years of age and older. [D5896C00001]. http://www.astrazenecaclinicaltrials.com/sites/133/imagebank/typeArticleparam528362/D5896C00001.pdf (accessed 11 November 2008).
  • Kerwin EM, Oppenheimer JJ, LaForce C, Miller CJ, O'Dowd L, Goldman M. Effects on pulmonary function of once-daily (qd) budesonide and formoterol administered via one pressurized metered-dose inhaler (pMDI) in adults and adolescents with asthma previously stable with twice-daily (bid) budesonide/formoterol pMDI. Journal of Allergy and Clinical Immunology 2008;121(2 Suppl 1):S152-3.
  • LaForce C, Kerwin EM, Oppenheimer JJ, Miller CJ, Vervaet P, O'Dowd L, et al. Safety of once-daily (qd) budesonide and formoterol administered via one pressurized metered-dose inhaler (pMDI) in adults and adolescents with asthma previously stable With twice-daily (bid) budesonide/formoterol pMDI. Journal of Allergy and Clinical Immunology 2008;121(2 Suppl 1):S153.
  • Oppenheimer JJ, Kerwin EM, LaForce C, Miller CJ, O'Dowd L, Goldman M. Asthma control with once-daily (qd) budesonide/formoterol pressurized metered-dose inhaler (pMDI) in adults and adolescents with asthma previously stable with twice-daily (bid) budesonide/formoterol pMDI. Journal of Allergy and Clinical Immunology 2008;121(2 Suppl 1):S8.
Jenkins 2006 {published data only}
  • AstraZeneca. Efficacy and safety of Symbicort® (budesonide/ formoterol) 1280/36 mcg daily delivered dose compared to Pulmicort® (budesonide) 1600 mcg metered dose and Pulmicort (budesonide) 1600 mcg metered dose plus Oxis® (formoterol) 36 mcg delivered dose all delivered via Turbuhaler® in steroid-using asthmatic adolescents and adults: a double-blind, double-dummy, randomized, parallel group, phase III, multicentre study. (SD-039-0689). http://www.astrazenecaclinicaltrials.com/sites/133/imagebank/typeArticleparam528362/SD-039-0689.pdfs (accessed 26 November 2008).
  • Jenkins C, Kolarikova R, Kuna P, Caillaud D, Sanchis J, Popp W, et al. Efficacy and safety of high-dose budesonide/formoterol (Symbicort) compared with budesonide administered either concomitantly with formoterol or alone in patients with persistent symptomatic asthma. Respirology 2006; Vol. 11, issue 3:276-86.
  • Jenkins C, Kolarikova R, Kuna P, Caillaud D, Sanchis J, Popp W, et al. Symbicort® turbuhaler® offers an effective and well tolerated treatment for patients with moderate to severe asthma [abstract] American Thoracic Society 99th International Conference; 2003 May 16-21; Seattle. Seattle, 2003:D034 Poster C37.
Kuna 2006 {published data only}
  • AstraZeneca. Symbicort low dose once daily in mild to moderate asthmatic patients (SD-039-0665). http://www.astrazenecaclinicaltrials.com/sites/133/imagebank/typeArticleparam528362/SD-039-0665.pdf (accessed 26 November 2008).
  • Kuna P, Chuchalin A, Ringdal N, De la Padilla EA, Black P, Lindqvist A, et al. Low-dose single-inhaler budesonide/formoterol administered once daily is effective in mild-persistent asthma. European Respiratory Journal 2001;18(Suppl 33):158s.
  • Kuna P, Creemers J, Vondra V, Black PN, Lindqvist A, Nihlen U, et al. Once-daily dosing with budesonide/formoterol compared with twice-daily budesonide/formoterol and once-daily budesonide in adults with mild to moderate asthma. Respiratory Medicine 2006; Vol. 100, issue 12:2151-9.
Meltzer 2012 {published data only}
  • Meltzer E, Nolte H, LaForce C. Efficacy and safety of combined mometasone furoate/formoterol 100/10?g twice daily in subjects with asthma inadequately controlled on low-dose inhaled corticosteroids [Abstract]. European Respiratory Society Annual Congress; September 18-22, 2010; Barcelona, Spain. Poster 1203.
  • Meltzer E, Nolte H, Laforce C. Low-dose mometasone furoate/formoterol therapy: safety and tolerability findings from a study investigating the effects of a new combination treatment for asthma [Abstract]. Annals of Allergy, Asthma, and Immunology 2009:A66.
  • Meltzer EO, Kuna P, Nolte H, Nayak AS, Laforce C. Mometasone furoate/formoterol reduces asthma deteriorations and improves lung function. European Respiratory Journal. 2011/08/11 2012; Vol. 39, issue 2:279-89. [1399-3003: (Electronic)]
  • Meltzer EO, Nolte H, LaForce C. Treatment of moderate asthma with mometasone furoate and formoterol (MF/F) 100/10 1/4g twice-daily administered via a pressurized metered-dose inhaler: efficacy and safety characteristics in subjects 12 years of age and older [Abstract]. American Journal of Respiratory and Critical Care Medicine 2010; Vol. 181, issue Meeting Abstracts:A5661.
Morice 2007 {published data only}
  • AstraZeneca. A randomised, double-blind, parallel-group, multicentre phase-III study to compare the efficacy and safety of Symbicort pMDI (budesonide/formoterol 160/4.5 mcg 2 actuations b.i.d., delivered dose) with that of Pulmicort pMDI (budesonide 200 mcg 2 actuations b.i.d., metered dose) and Symbicort Turbuhaler (budesonide/formoterol 160/4.5 mcg 2 inhalations b.i.d., delivered dose) in adolescents and adults with asthma.. http://www.astrazenecaclinicaltrials.com/search/?itemId=8574676 (accessed 26 November 2008).
  • Morice AH, Hochmuth L, Puterman A, Artheden L, Beckman O. Comparable safety of a novel budesonide/formoterol pMDI versus budesonide/formoterol Turbuhaler in adolescents and adults with asthma [Abstract]. Journal of Allergy & Clinical Immunology 2005; Vol. 115, issue 2 Suppl:S3.
  • Morice AH, Peterson S, Beckman O, Osmanliev D. Therapeutic comparison of a new budesonide/formoterol pMDI with budesonide pMDI and budesonide/formoterol DPI in asthma. International Journal of Clinical Practice. 2007/09/25 2007; Vol. 61, issue 11:1874-83. [1368-5031: (Print)]
Morice 2008 {published data only}
  • AstraZeneca. A 12-week randomised, double-blind, parallel-group, multicentre phase-III study to compare the efficacy and safety of Symbicort® pMDI (budesonide/formoterol 80/4.5 µg 2 actuations b.i.d., delivered dose) with that of Pulmicort® pMDI (budesonide 100 µg 2 actuations b.i.d., metered dose) and Symbicort Turbuhaler® (budesonide/formoterol 80/4.5 µg 2 actuations b.i.d., delivered dose) in children with asthma (SD-039-0682). http://www.astrazenecaclinicaltrials.com/sites/133/imagebank/typeArticleparam528362/SD-039-0682.pdf (accessed 26 November 2008).
  • Morice AH, Peterson S, Beckman O, Kukova Z. Efficacy and safety of a new pressurised metered-dose inhaler formulation of budesonide/formoterol in children with asthma: a superiority and therapeutic equivalence study. Pulmonary Pharmacology and Therapeutics. 2007/03/23 2008; Vol. 21, issue 1:152-9. [1094-5539: (Print)]
Nathan 2010 {published data only}
  • Effects of mometasone furoate/formoterol combination versus mometasone furoate alone in persistent asthmatics (Study P04334AM1) (COMPLETED). http://clinicaltrials.gov/ct2/show/NCT00383240 (accessed 15 October 15 2012).
  • FDA. Clinical review of Dulera (NDA 22-518). http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM224593.pdf (accessed 3 October 2012):1-99.
  • Nathan R, Pearlman D, Nayak A, Nolte H. Safety and tolerability of medium-dose mometasone furoate/formoterol treatment versus mometasone furoate or formoterol monotherapies in persistent asthmatics who previously used medium-dose inhaled corticosteroids (alone or with long-acting beta2-agonist). Chest 2009; Vol. 136, issue 4:8S.
  • Nathan R, Pearlman D, Nolte H, Nayak A. Efficacy and safety of combined medium-dose mometasone furoate/formoterol (MF/F) in persistent asthmatics [Abstract]. Journal of Allergy and Clinical Immunology 2010; Vol. 125, issue 2 Suppl 1:AB195. [: 0091-6749]
  • Nathan R, Pearlman D, Nolte H, Nayak A. Efficacy and safety of combined mometasone furoate/formoterol 200/10mcg in persistent asthmatics [Abstract]. European Respiratory Society Annual Congress, Barcelona, Spain, September 18-22 2010:[E5489].
  • Nathan R, Pearlman D, Nolte H, Nayak A. Safety and tolerability of mometasone furoate/formoterol for persistent asthma subjects who previously were treated with medium-dose inhaled corticosteroids (alone or with a long-acting beta2-agonist) [Abstract]. Annual Scientific Meeting of the American College of Allergy, Asthma and Immunology; 2009; Miami, FL, USA.
  • Nathan RA, Nolte H, Pearlman DS. Twenty-six-week efficacy and safety study of mometasone furoate/formoterol 200/10 mug combination treatment in patients with persistent asthma previously receiving medium-dose inhaled corticosteroids. Allergy and Asthma Proceedings 2010; Vol. 31, issue 4:269-79.
  • Nathan RA, Pearlman D, Nolte H, Nayak A. Efficacy and safety of mometasone furoate and formoterol (MF/F) 200/10 mcg twice-daily administered via a pressurized metered-dose inhaler in subjects 12 years of age and older with moderate-to-severe asthma [Abstract]. American Journal of Respiratory and Critical Care Medicine 2010; Vol. 181, issue Meeting Abstracts:A5412.
  • Nathan RA, Weinstein SF, Nolte H. Lung function improvements over time with combined mometasone furoate/formoterol administered via a pressurized metered-dose inhaler [Abstract]. Annals of Allergy, Asthma and Immunology 2010; Vol. 105, issue 5 Suppl.
Noonan 2006 {published data only}
  • AstraZeneca. A twelve-week, randomized, double-blind, double-dummy, placebo-controlled trial of SYMBICORT® (160/4.5 mcg) versus its mono-products (budesonide and formoterol) in adolescents (> 12 years of age) and adults with asthma, international (SD-039-0717). http://www.astrazenecaclinicaltrials.com/sites/133/imagebank/typeArticleparam528362/SD-039-0717.pdf (accessed 26 November 2008).
  • Baker J, Martin P, Parasuraman B. Patient satisfaction with budesonide and formoterol in one pressurized metered-dose inhaler in patients with asthma. Chest 2007;132(4):509b-510.
  • Noonan M, Rosenwasser LJ, Martin P, O'Brien CD, O'Dowd L. Efficacy and safety of budesonide and formoterol in one pressurised metered-dose inhaler in adults and adolescents with moderate to severe asthma: a randomised clinical trial. Drugs 2006; Vol. 66, issue 17:2235-54.
  • Noonan MJ, Eid NS, Uryniak T, O'Brien CD. Safety of once daily (qd) budesonide/formoterol pressurized metered dose inhaler (BUD/FM pMDI) in children and adolescents with asthma previously stable on twice daily (bid) BUD/FM pMDI [Abstract]. American Thoracic Society International Conference; May 16-21, 2008; Toronto, Ontario, Canada. Abstract 711 [#K71]..
  • Rosenwasser LJ, Noonan MJ, Martin P, O'Dowd L, O'Brien CD. Safety of budesonide and formoterol administered via one pressurized metered dose inhaler (budesonide/formoterol pMDI) in patients (>12 years) with moderate to severe persistent asthma [Abstract]. Journal of Allergy and Clinical Immunology 2007; Vol. 119, issue 1 Suppl:S5 [17].
O'Byrne 2001 {published data only}
  • Barnes PJ, O'Byrne PM, Rodriguez Roisin R, Runnerstrom E, Sandstrom T, Svensson K, et al. Treatment of mild persistent asthma with low doses of inhaled budesonide alone or in combination with formoterol. Thorax 2000;55(Suppl 3):A4.
  • Grosser D, Smith B. Low-dose budesonide improved asthma control in mild asthma: adding formoterol improved control in corticosteroid-treated patients. ACP Journal Club. 2002;137(1):19.
  • Jonsson B, Berggren F, Svensson K, O'Byrne PM. An economic evaluation of combination treatment with budesonide and formoterol in patients with mild-to-moderate persistent asthma. Respiratory Medicine 2004;98(11):1146-54.
  • Jönsson BG, Berggren FE, Svensson K, O'Byrne PM. Budesonide and formoterol in mild persistent asthma compared with doubling the dose of budesonide-a cost-effectiveness analysis. European Respiratory Journal 2001;18(Suppl 33):517s.
  • Jönsson BG, Berggren FE, Svensson K, O'Byrne PM. Economic results of adding formoterol to budesonide in mild persistent asthma. European Respiratory Journal 2001;18(Suppl 33):331s.
  • O'Byrne PM, Barnes PJ, Rodriguez-Roisin R, Runnerstrom EVA, Sandstrom T, Svensson K, et al. Low dose inhaled budesonide and formoterol in mild persistent asthma. The OPTIMA randomized trial. American Journal of Respiratory and Critical Care Medicine 2001; Vol. 164, issue 8:1392-7.
  • O'Byrne PM, Barnes PJ, Rodriguez-Roisin R, Sandtröm T, Tattersfield AE, Runnerström EM, et al. Addition of formoterol Turbuhaler(r) to budesonide Tubuhaler(r) is safe and well tolerated in the long-term treatment of mild asthma: results from the OPTIMA trial. European Respiratory Journal 2001;18(Supp 33):330s.
O'Byrne 2001a {published data only}
  • O'Byrne PM, Barnes PJ, Rodriguez-Roisin R, Runnerstrom EVA, Sandstrom T, Svensson K, et al. Low dose inhaled budesonide and formoterol in mild persistent asthma. The OPTIMA randomized trial. American Journal of Respiratory and Critical Care Medicine 2001; Vol. 164, issue 8:1392-7.
Pauwels 1997 {published data only}
  • Juniper EF, Svensson K, O'Byrne PM, Barnes PJ, Bauer CA, Lofdahl CGA, et al. Asthma quality of life during 1 year of treatment with budesonide with or without formoterol. European Respiratory Journal 1999;14(5):1038-43.
  • Pauwels R. Additive effects of inhaled formoterol and budesonide in reducing asthma exacerbations. [Review]. Allergy 1998;53(42 Suppl):20-3.
  • Pauwels RA, Lofdahl CG, Postma DS, Tattersfield AE, O'Byrne P, Barnes PJ, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. New England Journal of Medicine. 1997/11/14 1997; Vol. 337, issue 20:1405-11. [0028-4793: (Print)]
  • Tattersfield AE, Postma DS, Barnes PJ, Svensson K, Bauer CA, O'Byrne PM, et al. Exacerbations of asthma: a descriptive study of 425 severe exacerbations. The FACET International Study Group. American Journal of Respiratory and Critical Care Medicine 1999;160(2):594-9.
Pauwels 1997a {published data only}
  • Pauwels RA, Lofdahl CG, Postma DS, Tattersfield AE, O'Byrne P, Barnes PJ, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group [New England Journal of Medicine]. New England Journal of Medicine. 1997/11/14 1997; Vol. 337, issue 20:1405-11. [0028-4793: (Print)]
Peters 2008 {published and unpublished data}
  • AstraZeneca. A 52-week, randomized, double-blind, single-dummy, parallel-group, multicenter Phase III study comparing the long-term safety of SYMBICORT® pMDI 160/4.5 mcg × 4 actuations twice daily to SYMBICORT® pMDI 160/4.5 mcg × 2 actuations twice daily and budesonide HFA pMDI 160 mcg × 4 actuations twice daily in adult and adolescent subjects with asthma (SD-039-0728). http://www.astrazenecaclinicaltrials.com/sites/133/imagebank/typeArticleparam528362/SD_039_0728.pdf (accessed 26 November 2008).
  • Lawrance R, Ambrose H, Goldman M. Effect of gly16arg beta2-adrenergic receptor variation on the long-term safety of formoterol (FM) in combination with budesonide (BUD) and of BUD alone, delivered via one pressurized metered-dose inhaler (pMDI) in patients with moderate to severe asthma [Abstract]. American Thoracic Society International Conference; May 18-23, 2007; San Francisco, CA, USA. Poster #420..
  • O'Brien CD, Peters SP, Prenner BM, Martin P. Long-term safety of budesonide/formoterol pressurized metered-dose inhaler (BUD/FM pMDI) in asthma patients: adverse events and asthma exacerbations [Abstract]. American Thoracic Society International Conference; May 18-23, 2007; San Francisco, CA, USA. Poster #L57..
  • O'Brien CD, Peters SP, Prenner BM, Martin P. Resource use with budesonide/formoterol pressurized metered-dose inhaler (BUD/FM pMDI) versus BUD pMDI in asthma patients [Abstract]. American Thoracic Society International Conference; May 18-23, 2007; San Francisco, CA, USA. Poster #L58..
  • Peters SP, Prenner BM, Martin P, O'Brien CD. Long-term effects on lung function of budesonide (BUD) and formoterol (FM) in one pressurized metered-dose inhaler (BUD/FM pMDI) and BUD pMDI in patients with asthma [Abstract]. American Thoracic Society International Conference; May 18-23, 2007; San Francisco, CA, USA. Poster #K5..
  • Peters SP, Prenner BM, Mezzanotte WS, Martin P, O'Brien CD. Long-term safety and asthma control with budesonide/formoterol versus budesonide pressurised metered-dose inhaler in asthma. Alllergy and Asthma Proceedings 2008;29:1-18.
  • Prenner BM, Peters SP, Martin P, O'Brien CD. Long-term control of asthma symptoms with budesonide/formoterol pressurized metered-dose inhaler (BUD/FM pMDI) versus BUD pMDI [Abstract]. American Thoracic Society International Conference; May 18-23, 2007; San Francisco, CA, USA. Poster #L67.
  • Prenner BM, Peters SP, Martin P, O'Brien CD. Safety pharmacodynamics (PD) of budesonide/formoterol (BUD/FM) pMDI in asthma patients [Abstract]. American Thoracic Society International Conference; May 18-23, 2007; San Francisco, CA, USA. Poster #L66.
Pohunek 2006 {published data only}
  • AstraZeneca. Efficacy and safety of Symbicort® (budesonide/formoterol 80/4.5 µg, 2 inhalations b.i.d.) compared to Pulmicort® (budesonide 100 mcg, 2 inhalations b.i.d.) and Pulmicort (budesonide 100 µg, 2 inhalations b.i.d.) plus Oxis® (formoterol 4.5 µg, 2 inhalations b.i.d.) all delivered via Turbuhaler® in steroid using asthmatic children: a double-blind, double-dummy, randomised, parallel-group, phase III, multicentre 12-week study (SD-039-0688). http://www.astrazenecaclinicaltrials.com/sites/133/imagebank/typeArticleparam528362/SD-039-0688.pdf (accessed 26 November 2008)..
  • Pohunek P, Kuna P, De Boeck K. Budesonide/formoterol improves lung function compared with budesonide alone in children with asthma [Abstract]. European Respiratory Journal 2004;24(Suppl 48):379s.
  • Pohunek P, Kuna P, Jorup C, De Boeck K. Budesonide/formoterol improves lung function compared with budesonide alone in children with asthma. Pediatric Allergy & Immunology 2006; Vol. 17, issue 6:458-65.
  • Pohunek P, Matulka M, Rybnicek O, Kopriva F, Honomichlova H, Svobodova T. Dose-related efficacy and safety of formoterol (Oxis) Turbuhaler compared with salmeterol Diskhaler in children with asthma. Pediatric Allergy & Immunology 2004;15(1):32-9.
Price 2002 {published data only}
  • Price D, Dutchman D, Mawson A, Bodalia B, Duggan S, Todd P. Early asthma control and maintenance with eformoterol following reduction of inhaled corticosteroid dose. Thorax. 2002/08/30 2002; Vol. 57, issue 9:791-8. [0040-6376: (Print)]
  • Price MJ, Briggs AH. Development of an economic model to assess the cost effectiveness of asthma management strategies. Pharmacoeconomics. 2002;20(3):183-94.
  • Price MJ, Sondhi S, Yan S, Nyth A, House K. Salmeterol/fluticasone propionate combination inhaler is more cost effective than fluticasone propionate in patients with asthma. European Respiratory Society; Oct 9-13, 1999; Madrid, Spain. Poster #2459..
SD-039-0714 {unpublished data only}
  • AstraZeneca. Efficacy and safety of budesonide/formoterol Turbuhaler® (160/4.5 mg b.i.d.delivered dose) compared to budesonide Turbuhaler® (200 mg b.i.d. metered dose) in steroid-using asthmatic adolescent patients: a double-blind, double dummy,randomised, parallel group, phase III, multicentre study. (ATTAINSTUDY). http://www.astrazenecaclinicaltrials.com/sites/133/imagebank/typeArticleparam528362/SD-039-0714.pdf (accessed 14 November 2008).
SD-039-0718 {unpublished data only}
  • AstraZeneca. A twelve-week, randomized, double-blind, double-dummy trial of Symbicort® (40/4.5 mcg) versus its mono-products (budesonide and formoterol) in asthmatic children aged six to fifteen years. http://www.astrazenecaclinicaltrials.com/sites/133/imagebank/typeArticleparam528362/SD-039-0718.pdf (accessed 14 November 2008).
  • Pearlman DS, Murphy KR, Uryniak T, O'Brien CD, Mezzanotte WS, Denver M. Safety of budesonide/formoterol pressurized metered dose inhaler (BUD/FM pMDI) in children with asthma previously treated with inhaled corticosteroids (ICSs) [Abstract]. American Thoracic Society International Conference; May 16-21, 2008; Toronto, Ontario, Canada. Abstract #A710 (#K67)..
SD-039-0719 {unpublished data only}
  • AstraZeneca. A six-month, randomized, open-label safety study of SYMBICORT® (160/4.5 μg) compared to PULMICORT Turbuhaler® in asthmatic children aged 6 to 11 years. http://www.astrazenecaclinicaltrials.com/sites/133/imagebank/typeArticleparam528362/SD-039-0719.pdf (accessed 14 November 2008).
  • Berger WE, Bleecker ER, O'Dowd L, Miller CJ, Mezzanotte W. Efficacy and safety of budesonide/formoterol pressurized metered-dose inhaler: randomized controlled trial comparing once- and twice-daily dosing in patients with asthma. Allergy and Asthma Proceedings 2010; Vol. 31, issue 1:49-59.
  • Berger WE, Leflein JG, Geller DE, Parasuraman B, Miller CJ, O'Brien CD, et al. The safety and clinical benefit of budesonide/formoterol pressurized metered-dose inhaler versus budesonide alone in children. Allergy and Asthma Proceedings 2010; Vol. 31, issue 1:26-39.
  • Berger WE, Leflein JG, Uryniak T, O'Brien CD, O'Dowd L. Long-term efficacy and resource utilization after treatment with budesonide and formoterol administered via one pressurized metered-dose inhaler (pMDI) compared with budesonide dry powder inhaler (DPI) alone in children with asthma. Journal of Allergy and Clinical Immunology 2008;121(2 Suppl 1):S8.
  • Leflein JG, Berger WE, Uryniak T, Vervaet P, O'Dowd L, O'Brien CD. Long-term safety and systemic effects of budesonide and formoterol administered via one pressurized metered-dose inhaler (pMDI) in children with asthma. Journal of Allergy and Clinical Immunology 2008;121(2 Suppl 1):S155.
  • O'Dowd L, Berger WE, Leflein JG, Uryniak T, Parasuraman B, O'Brien CD. Health-related quality of life (HRQL) and asthma control after long-term treatment with budesonide and formoterol administered via one pressurized metered-dose inhaler (pMDI) compared with budesonide dry powder inhaler (DPI) alone in children with asthma. Journal of Allergy and Clinical Immunology 2008;121(2 Suppl 1):S152.
SD-039-0725 {unpublished data only}
  • AstraZeneca. A twelve-week, randomized, 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. http://www.astrazenecaclinicaltrials.com/sites/133/imagebank/typeArticleparam528362/SD_039_0725.pdf (accessed 18 November 2008).
  • Eid NS, Noonan MJ, Chipps B, Parasuraman B, Miller CJ, O'Brien CD. Once- vs twice-daily budesonide/formoterol in 6- to 15-year-old patients with stable asthma. Pediatrics 2010; Vol. 126, issue 3:e565-75.
SD-039-0726 {unpublished data only}
  • AstraZeneca. A twelve-week, randomized, double-blind, double-dummy, placebo- and active-controlled study of SYMBICORT® pMDI administered once daily in adults and adolescents with asthma. http://www.astrazenecaclinicaltrials.com/sites/133/imagebank/typeArticleparam528362/SD-039-0726.pdf (accessed 14 November 2008).
Spector 2012 {published data only}
  • AstraZeneca. A 12-week, randomized, double-blind, double-dummy, multi-center,phase IV study comparing the efficacy and safety of SYMBICORT® pMDI160/4.5 μg × 2 actuations twice daily versus budesonide inhalation powderDPI 180 μg × 2 inhalations twice daily, in adult and adolescent (≥12 years) African American subjects with asthma. http://www.astrazenecaclinicaltrials.com/_mshost800325/content/clinical-trials/resources/pdf/D589BL00003 (accessed 19 October 2012). [: D589BL00003]
  • Spector SL, CD OB, Uryniak T, Martin UJ. Safety and tolerability of a budesonide/formoterol (BUD/FM) pressurized metered-dose inhaler (pMDI) in black adolescents and adults with moderate to severe persistent asthma [Abstract]. Chest 2010; Vol. 138, issue 4:705A.
  • Spector SL, Martin UJ, Uryniak T, O'Brien CD. Budesonide/formoterol pressurized metered-dose inhaler versus budesonide: a randomized controlled trial in black patients with asthma. J Asthma. 2011/12/03 2012; Vol. 49, issue 1:70-7. [1532-4303: (Electronic)]
  • Spector SL, Martin UJ, Uryniak T, O'Brien CD. Effect of budesonide/formoterol pressurized metered-dose inhaler versus budesonide dry powder inhaler on asthma control in black adolescents and adults with moderate to severe persistent asthma [Abstract]. Annals of Allergy, Asthma and Immunology 2010; Vol. 105, issue 5 Suppl.
Tal 2002 {published data only}
  • AstraZeneca. Efficacy and safety of budesonide/formoterol Turbuhaler® in a fixed combination in steroid-using asthmatic children - COMIC (SD-039-0353). http://www.astrazenecaclinicaltrials.com/sites/133/imagebank/typeArticleparam528362/SD-039-0353.pdf (accessed 26 November 2008).
  • Tal A, Simon G, Vermeulen JH. Symbicort® Budesonide and formoterol in a single inhaler is effective and well tolerated in children with asthma. Annual Thoracic Society 97th International Conference; May 18-23, 2001; San Francisco CA, USA. Poster D29..
  • Tal A, Simon G, Vermeulen JH, Petru V, Cobos N, Everard ML, et al. Budesonide/formoterol in a single inhaler versus inhaled corticosteroids alone in the treatment of asthma. Pediatric Pulmonology 2002; Vol. 34, issue 5:342-50.
  • Tal A, Simon G, Vermeulen JH, Petru V, Cobos N, Everard ML, et al. Rapid and sustained improvements in lung function and symptom control with budesonide/ formoterol in adolescent asthma. European Respiratory Journal 2001;18(Suppl 33):494s.
  • Tal A, Simon G, Vermeulen JH, Petru V, Cobos N, Everard ML, et al. Symbicort budesonide and formoterol in a single inhaler is more effective that budesonide alone in children with asthma. International Paediatric Respiratory and Allergy Congress; April 1-4, 2001; Prague. Poster 84-5..
  • Tal A, Simon G, Vermeulen JH, Vit P, Cobos N, Everard ML, et al. The benefit of the new single inhaler product containing both budesonide and formoterol in asthmatic children. European Respiratory Journal 2000;16(Suppl 31):384s.
  • Vermeulen JH, Simon G, Tal A. Symbicort® Budesonide and formoterol in a single inhaler improves lung function in asthmatic children aged 4-17 years. Annual Thoracic Society 97th International Conference; May 18-23, 2001; San Francisco CA, USA. Poster D29..
Weinstein 2010 {published data only}
  • Schering-Plough. Effects of mometasone furoate/formoterol combination versus mometasone furoate alone in persistent asthmatics (Study P04431AM2) (COMPLETED). http://clinicaltrials.gov/ct2/show/NCT00381485 (accessed 19 October 2012). [: NCT00381485]
  • Weinstein S, Murphy K, Corren J, Nolte H, White M. Efficacy and safety of medium and high doses of mometasone furoate/formoterol (MF/F) combination treatment in subjects with severe persistent asthma [Abstract]. Journal of Allergy and Clinical Immunology 2010; Vol. 125, issue 2 Suppl 1:AB196. [: 0091-6749]
  • Weinstein S, Murphy K, Corren J, Nolte H, White M. Efficacy and safety of medium and high doses of mometasone furoate/formoterol combination treatment in subjects with severe asthma. European Respiratory Society Annual Congress; September 18-22, 2010; Barcelona, Spain. Poster E5482..
  • Weinstein S, Murphy K, White M, Nolte H, Corren J. The safety and tolerability of high and medium doses of mometasone furoate/formoterol combination treatment in subjects with severe persistent asthma [Abstract]. Annual Scientific Meeting of the American College of Allergy, Asthma and Immunology; 2009; Miami, FL, USA.
  • Weinstein S, Murphy K, White M, Nolte H, Corren J. Treatment of severe asthma with a new mometasone furoate and formoterol (MF/F) combination administered with a pressurized metered-dose inhaler device. American Journal of Respiratory and Critical Care Medicine 2010; Vol. 181, issue Meeting Abstracts:A5411.
  • Weinstein S, White M, Corren J, Nolte H. Mometasone furoate/formoterol (MF/F) combination for the treatment of asthma: safety and tolerability findings from a clinical trial in severe asthma patients [Abstract]. European Respiratory Society Annual Congress; September 12-16, 2009; Vienna, Austria. Poster E280.
  • Weinstein SF, Corren J, Murphy K, Nolte H, White M. Twelve-week efficacy and safety study of mometasone furoate/formoterol 200/10 mug and 400/10 mug combination treatments in patients with persistent asthma previously receiving high-dose inhaled corticosteroids. Allergy and Asthma Proceedings 2010; Vol. 31, issue 4:280-9.
  • Weinstein SF, White M, Corren J, Nolte H. Safety and tolerability of medium and high doses of mometasone furoate/formoterol (MF/F) combination treatment administered via a metered-dose inhaler (MDI), in severe asthma patients previously treated with high-dose inhaled corticosteroids (ICS). American Thoracic Society International Conference; May 15-20, 2009; San Diego, CA, USA. Poster #J53..
Zangrilli 2011 {published data only}
  • AstraZeneca. An efficacy study comparing SYMBICORT® pressurised metered dose inhaler (pMDI) with budesonide jydrofluoroalkanes (HFA) pMDI, in Hispanic subjects with ICS dependent asthma. http://clinicaltrials.gov/ct2/show/study/NCT00419757?sect=X3015 (accessed 22 October 2012). [: NCT00419757]
  • Zangrilli J, Mansfield LE, Uryniak T, O'Brien CD. Efficacy of budesonide/formoterol pressurized metered-dose inhaler versus budesonide pressurized metered-dose inhaler alone in Hispanic adults and adolescents with asthma: a randomized, controlled trial. Annals of Allergy, Asthma, and Immunology 2011; Vol. 107:258-65.
Zetterstrom 2001 {published data only}
  • AstraZeneca. Efficacy and safety of a fixed combination of budesonide/formoterol Turbuhaler® in inhaled steroid-using asthmatic adults. (SD-039-0349). http://www.astrazenecaclinicaltrials.com/sites/133/imagebank/typeArticleparam528362/SD-039-0349.pdf (accessed 26 November 2008).
  • Buhl R, Zetterstrom O, Mellem H, Perpina M, Hedman J, O'Neill S, et al. Improved asthma control with budesonide/formoterol via a single inhaler compared with budesonide alone, in moderate persistent asthma. European Respiratory Journal 2001;18(Suppl 33):48s.
  • Zetterstrom O, Buhl R, Mellem H. Efficacy and safety of Symbicort® budesonide and formoterol in a single inhaler in adults with asthma. Annual Thoracic Society 97th International Conference; May 18-23, 2001; San Francisco CA.
  • Zetterstrom O, Buhl R, Mellem H, Perpina M, Hedman J, O'Neill S, et al. Improved asthma control with budesonide/formoterol in a single inhaler, compared with budesonide alone. European Respiratory Journal 2001; Vol. 18, issue 2:262-8.
  • Zetterström O, Buhl R, Mellem H, Perpiñá M, Hedman J, O'Neill S, et al. Efficacy and safety of a new single inhaler product containing both budesonide and formoterol in adult asthma. European Respiratory Journal 2000;16(Suppl 31):455s. Abstract P3198.
  • Zetterström O, Buhl R, Mellem H, Perpiñá M, Hedman J, O'Neill S, et al. The new single inhaler product containing both budesonide/formoterol improves asthma control in adults. European Respiratory Journal 2000;16(Supp 31):455s. Abstract P3199.

References to studies excluded from this review

  1. Top of page
  2. Abstract摘要Résumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to ongoing studies
  22. Additional references
  23. References to other published versions of this review
Ankerst 2003 {published data only}
  • Ankerst J, Persson G, Weibull E. Tolerability of a high dose of budesonide/formoterol in a single inhaler in patients with asthma. Pulmonary Pharmacology & Therapeutics 2003; Vol. 16, issue 3:147-51.
AstraZeneca 2005 {published data only}
  • AstraZeneca. Efficacy & safety of Symbicort Turbuhaler 160/4.5 µg twice daily & Pulmicort Turbuhaler 200 µg twice daily + Theolong tablet 200 mg twice daily in Japanese asthmatic patients. clinicaltrials.gov 2005.
AstraZeneca 2005a {published data only}
  • AstraZeneca. SHARE - symbicort and health economics in a real life evaluation. clinicaltrials.gov 2005.
AstraZeneca 2005b {published data only}
  • AstraZeneca. SOLO-symbicort in the treatment of persistent asthma in adolescents & adults. clinicaltrials.gov 2005.
AstraZeneca 2005c {published data only}
  • AstraZeneca. STYLE - symbicort single inhaler therapy vs. conventional therapy in treatment of persistent asthma. clinicaltrials.gov 2005.
AstraZeneca 2005d {published data only}
  • AstraZeneca. SYMPHONIE -a comparison of symbicort single inhaler and conventional best practice for the treatment of persistent asthma in adolescents and adults. clinicaltrials.gov 2005.
AstraZeneca 2006 {published data only}
  • AstraZeneca. A comparison of the control of asthma inflammation provided by Symbicort turbuhaler 160/4.5 mcg/inhalation bid plus as-needed versus symbicort turbuhaler 320/9 ug/inhalation bid plus pulmicort turbuhaler 400mcg/dose bid plus terbutaline turbuhaler 0.4mg/inhalation as-needed. clinicaltrials.gov 2006.
AstraZeneca 2006a {published data only}
  • AstraZeneca. MONO: Symbicort single inhaler therapy and conventional best standard treatment for the treatment of persistent asthma in adolescents and adults. clinicaltrials.gov 2006.
AstraZeneca 2006b {published data only}
  • AstraZeneca. SALTO - symbicort single inhaler therapy use in adolescent adults and adults with persistent asthma. clinicaltrials.gov 2006.
Balanag 2006 {published data only}
  • Balanag VM, Yunus F, Yang PC, Jorup C. Efficacy and safety of budesonide/formoterol compared with salbutamol in the treatment of acute asthma. Pulmonary Pharmacology & Therapeutics 2006; Vol. 19, issue 2:139-47.
Bateman 2003 {published data only}
  • Bateman ED, Bantje TA, Gomes MJ, Toumbis MG, Huber RM, Naya I, et al. Combination therapy with single inhaler budesonide/formoterol compared with high dose of fluticasone propionate alone in patients with moderate persistent asthma. American Journal of Respiratory Medicine 2003; Vol. 2, issue 3:275-81.
Bateman 2006 {published data only}
  • Bateman ED, Fairall L, Lombardi DM, English R. Budenoside/formoterol and formoterol provide similar rapid relief in patients with acute asthma showing refractoriness to salbutamol. Respiratory Research 2006; Vol. 7:13.
Bodzenta-Lukaszyk 2011 {published data only}
  • Bodzenta-Lukaszyk A, Pulka G, Dymek A, Bumbacea D, McIver T, Schwab B, et al. Efficacy and safety of fluticasone and formoterol in a single pressurized metered dose inhaler. Respiratory Medicine 2011; Vol. 105, issue 5:674-82.
Bouros 1999 {published data only}
  • Bouros D, Bachlitzanakis N, Kottakis J, Pfister P, Polychronopoulos V, Papadakis E, et al. Formoterol and beclomethasone versus higher dose beclomethasone as maintenance therapy in adult asthma. European Respiratory Journal 1999; Vol. 14, issue 3:627-32.
Buhl 2004 {published data only}
  • Buhl R, Kardos P, Richter K, Meyer-Sabellek W, Bruggenjurgen B, Willich SN, et al. The effect of adjustable dosing with budesonide/formoterol on health-related quality of life and asthma control compared with fixed dosing. Current Medical Research & Opinion 2004; Vol. 20, issue 8:1209-20.
Bumbacea 2010 {published data only}
  • Bumbacea D, Dymek A, Mansikka H. Fluticasone propionate/formoterol fumarate combination therapy has an efficacy and safety profile similar to that of its individual components administered concurrently: a randomised controlled trial [Abstract]. Thorax 2010; Vol. 65, issue Suppl 4:P16.
Burgess 1998 {published data only}
  • Burgess C, Ayson M, Rajasingham S, Crane J, Della Cioppa G, Till MD. The extrapulmonary effects of increasing doses of formoterol in patients with asthma. European Journal of Clinical Pharmacology 1998; Vol. 54, issue 2:141-7.
Canonica 2004 {published data only}
  • Canonica GW, Castellani P, Cazzola M, Fabbri LM, Fogliani V, Mangrella M, et al. Adjustable maintenance dosing with budesonide/formoterol in a single inhaler provides effective asthma symptom control at a lower dose than fixed maintenance dosing. Pulmonary Pharmacology & Therapeutics 2004; Vol. 17, issue 4:239-47.
Ceylan 2004 {published data only}
  • Ceylan E, Mehmet G, Sahin A. Addition of formoterol or montelukast to low-dose budesonide: an efficacy comparison in short- and long-term asthma control. Respiration 2004; Vol. 71, issue 6:594-601.
Dhillon 2006 {published data only}
  • Dhillon S, Keating GM. Beclometasone dipropionate/formoterol in an HFA-propelled pressurised metered-dose inhaler. Drugs 2006; Vol. 66, issue 11:1475-83.
FitzGerald 1999 {published data only}
  • FitzGerald JM, Chapman KR, Della Cioppa G, Stubbing D, Fairbarn MS, Till MD, et al. Sustained bronchoprotection, bronchodilatation, and symptom control during regular formoterol use in asthma of moderate or greater severity. Journal of Allergy & Clinical Immunology 1999; Vol. 103, issue 3 I:427-35.
FitzGerald 2003 {published data only}
  • FitzGerald JM, Sears MR, Boulet LP, Becker AB, McIvor AR, Ernst P, et al. Adjustable maintenance dosing with budesonide/formoterol reduces asthma exacerbations compared with traditional fixed dosing: a five-month multicentre Canadian study. Canadian Respiratory Journal 2003; Vol. 10, issue 8:427-34.
Haahtela 2006 {published data only}
  • Haahtela T, Tamminen K, Malmberg LP, Zetterstrom O, Karjalainen J, Yla-Outinen H, et al. Formoterol as needed with or without budesonide in patients with intermittent asthma and raised NO levels in exhaled air: a SOMA study. European Respiratory Journal 2006; Vol. 28, issue 4:748-55.
Ind 2004 {published data only}
  • Ind PW, Haughney J, Price D, Rosen JP, Kennelly J. Adjustable and fixed dosing with budesonide/formoterol via a single inhaler in asthma patients: the ASSURE study. Respiratory Medicine 2004; Vol. 98, issue 5:464-75.
Jakopovic 2009 {published data only}
  • Jakopovic M, Pavicic F, Redzepi G, Plestina S, Jankovic M, Franic Z, et al. Efficacy and safety of budesonide/formeterol combination therapy in asthma patients. Collegium Antropologicum 2009; Vol. 33, issue 2:587-91. [: 0350-6134]
Kozlik-Feldmann 1996 {published data only}
  • Kozlik-Feldmann R, von Berg A, Berdel D, Reinhardt D. Long-term effects of formoterol and salbutamol on bronchial hyperreactivity and beta-adrenoceptor density on lymphocytes in children with bronchial asthma. European Journal of Medical Research 1996; Vol. 1, issue 10:465-70.
Lalloo 2003 {published data only}
  • Lalloo UG, Malolepszy J, Kozma D, Krofta K, Ankerst J, Johansen B, et al. Budesonide and formoterol in a single inhaler improves asthma control compared with increasing the dose of corticosteroid in adults with mild-to-moderate asthma. Chest 2003; Vol. 123, issue 5:1480-7.
Lemanske 2010 {published data only}
  • Lemanske RF, Jr, Mauger DT, Sorkness CA, Pharm D, Jackson DJ, Boehmer SJ, et al. Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids. New England Journal of Medicine 2010; Vol. 362, issue 11:975-85.
Leuppi 2003 {published data only}
  • Leuppi FD, Salzberg M, Meyer L, Bucher SE, Nief M, Brutsche MH, et al. An individualized, adjustable maintenance regimen of budesonide/formoterol provides effective asthma symptom control at a lower overall dose than fixed dosing. Swiss Medical Weekly 2003; Vol. 133, issue 21-22:302-9.
Lotvall {published data only}
  • Lötvall J, Langley S, Woodcock A. Inhaled steroid/long-acting beta2 agonist combination products provide 24 hours improvement in lung function in adult asthmatic patients. Respiratory Research 2006; Vol. 7:110.
Lundborg 2006 {published data only}
  • Lundborg M, Wille S, Bjermer L, Tilling B, Lundgren M, Telg G, et al. Maintenance plus reliever budesonide/formoterol compared with a higher maintenance dose of budesonide/formoterol plus formoterol as reliever in asthma: an efficacy and cost-effectiveness study. Current Medical Research and Opinion 2006; Vol. 22, issue 5:809-21.
Maspero 2010 {published data only}
  • Maspero JF, Nolte H, Cherrez-Ojeda I. Long-term safety of mometasone furoate/formoterol combination for treatment of patients with persistent asthma. Journal of Asthma 2010; Vol. 47, issue 10:1106-15.
Mitchell 2003 {published data only}
  • Mitchell C, Jenkins C, Scicchitano R, Rubinfeld A, Kottakis J. Formoterol (Foradil) and medium-high doses of inhaled corticosteroids are more effective than high doses of corticosteroids in moderate-to-severe asthma. Pulmonary Pharmacology and Therapeutics 2003; Vol. 16, issue 5:299-306.
Molimard 2001 {published data only}
  • Molimard M, Bourcereau J, Le Gros V, Bourdeix I, Leynadier F, Duroux P, et al. Comparison between formoterol 12 microg b.i.d. and on-demand salbutamol in moderate persistent asthma. Respiratory Medicine 2001; Vol. 95, issue 1:64-70.
Nayak 2010 {published data only}
  • Nayak A, LaForce C, Nathan RA, Nolte H, Weinstein SF. Mometasone furoate/formoterol administered via a pressurized metered-dose inhaler improves proportions of saba-free days and nights in subjects with persistent asthma [Abstract]. Annals of Allergy, Asthma and Immunology 2010;105:5 Suppl.
Novartis 2005 {published data only}
  • Novartis. A 12-month multicenter, randomized, double-blind, double-dummy trial to examine the long-term tolerability of formoterol 10µg via the multiple dose dry powder inhaler (MDDPI), both as twice daily maintenance therapy and as on-demand use in addition to maintenance in patients with persistent asthma. http://pharma.us.novartis.com/.
O'Byrne 2005 {published data only}
  • O'Byrne PM, Bisgaard H, Godard PP, Pistolesi M, Palmqvist M, Zhu Y, et al. Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma.[see comment]. American Journal of Respiratory & Critical Care Medicine 2005; Vol. 171, issue 2:129-36.
Ohta 2008 {published data only}
  • Ohta K, Adachi M. Efficacy and safety of budesonide/formoterol comparing with budesonide and theophylline in Japanese adult patients with asthma [Abstract]. European Respiratory Society Annual Congress; October 4-8, 2008; Berlin, Germany. Poster 3626..
Overbeek 2005 {published data only}
  • Overbeek SE, Mulder PG, Baelemans SM, Hoogsteden HC, Prins JB. Formoterol added to low dose budesonide has no additional anti-inflammatory effect in asthmatic patients. Chest 2005;128:1121-7.
Papi 2007 {published data only}
  • Papi A, Paggiaro PL, Nicolini G, Vignola AM, Fabbri LM, Zarkovic J, et al. Beclomethasone/formoterol versus budesonide/formoterol combination therapy in asthma. European Respiratory Journal 2007; Vol. 29, issue 4:682-9.
Pauwels 2003 {published data only}
  • Pauwels RA, Sears MR, Campbell M, Villasante C, Huang S, Lindh A, et al. Formoterol as relief medication in asthma: a worldwide safety and effectiveness trial. European Respiratory Journal 2003; Vol. 22, issue 5:787-94.
Peters 2008a {published data only}
  • Peters SP, Rosenwasser LJ, Vervaet P, O'Brien CD. Cardiac safety of budesonide (BUD)/formoterol (FM) pressurized metered dose inhaler (pMDI) pooled data from clinical studies of children, adolescents and adults with asthma [Abstract]. Journal of Allergy and Clinical Immunology 2008; Vol. 121, issue 2 Suppl 1:S155 [595].
Pleskow 2003 {published data only}
  • Pleskow W, LaForce CF, Yegen U, Matos D, Della Cioppa G. Formoterol delivered via the dry powder Aerolizer inhaler versus albuterol MDI and placebo in mild-to-moderate asthma: a randomized, double-blind, double-dummy trial. Journal of Asthma 2003; Vol. 40, issue 5:505-14.
Pohl 2006 {published data only}
  • Pohl WR, Vetter N, Zwick H, Hrubos W. Adjustable maintenance dosing with budesonide/formoterol or budesonide: double-blind study. Respiratory Medicine 2006; Vol. 100, issue 3:551-60.
Rabe 2006 {published data only}
  • Rabe KF, Pizzichini E, Stallberg B, Romero S, Balanzat AM, Atienza T, et al. Budisonide/formoterol in a single inhaler for maintenance and relief in mild-to-moderate asthma: a randomized, double-blind trial. Chest 2006; Vol. 129, issue 2:246-56.
Rosenhall 2002 {published data only}
  • Rosenhall L, Heinig JH, Lindqvist A, Leegaard J, Stahl E, Bergqvist PB. Budesonide/formoterol (Symbicort) is well tolerated and effective in patients with moderate persistent asthma. International Journal of Clinical Practice. 2002; Vol. 56, issue 6:427-33.
Rosenhall 2003 {published data only}
  • Rosenhall L, Borg S, Andersson HF, Ericsson K. Budesonide/formoterol in a single inhaler (Symbicort) reduces healthcare costs compared with separate inhalers in the treatment of asthma over 12 months. International Journal of Clinical Practice 2003; Vol. 57, issue 8:662-7.
Rosenhall 2003a {published data only}
  • Rosenhall L, Elvstrand A, Tilling B, Vinge I, Jemsby P, Stahl E, et al. One-year safety and efficacy of budesonide/formoterol in a single inhaler (Symbicort Turbuhaler) for the treatment of asthma. Respiratory Medicine 2003; Vol. 97, issue 6:702-8.
Rosenwasser 2008 {published data only}
  • Rosenwasser LJ, Peters SP, Vervaet P, O'Brien CD. Tolerability of budesonide (BUD)/formoterol (FM) pressurized metered dose inhaler (pMDI) pooled adverse event (AE) data from clinical studies of children, adolescents and adults with asthma [Abstract]. Journal of Allergy and Clinical Immunology 2008; Vol. 121, issue 2 Suppl 1:S154 [591].
Saito 2011 {published data only}
  • Saito T, Hasunuma T. Safety and tolerability of high-dose budesonide/formoterol via Turbuhaler in Japanese patients with asthma: phase III study results.. American Journal of Respiratory and Critical Care Medicine 2011;183(Meeting Abstracts):A4489.
Scicchitano 2004 {published data only}
  • Scicchitano R, Aalbers R, Ukena D, Manjra A, Fouquert L, Centann S, et al. Efficacy and safety of budesonide/formoterol single inhaler therapy versus a higher dose of budesonide in moderate to severe asthma. Current Medical Research & Opinion 2004; Vol. 20, issue 9:1403-18.
Stelmach 2007 {published data only}
  • Stelmach I, Grzelewski T, Bobrowska-Korzeniowska M, Stelmach P, Kuna P. A randomized, double-blind trial of the effect of anti-asthma treatment on lung function in children with asthma. Pulmonary Pharmacology and Therapeutics. 2006/10/19 2007; Vol. 20, issue 6:691-700. [1094-5539: (Print)]
van der Molen 1997 {published data only}
  • van der Molen T, Postma DS, Turner MO, Jong BM, Malo JL, Chapman K, et al. Effects of the long acting beta agonist formoterol on asthma control in asthmatic patients using inhaled corticosteroids. The Netherlands and Canadian Formoterol Study Investigators. Thorax 1997; Vol. 52, issue 6:535-9.
Villa 2002 {published data only}
  • Villa J, Kuna P, Egner J, Brander R. A 6-month comparison of the safety profiles of formoterol (Oxis®) turbuhaler® as needed and terbutaline (Bricanyl®) turbuhaler® as needed in asthmatic children on anti-inflammatory medication [abstract]. American Journal of Respiratory and Critical Care Medicine 2002; Vol. 165, issue 8 Suppl:A746.
Von Berg 2003 {published data only}
  • Von Berg A, Papageorgiou Saxoni F, Wille S, Carrillo T, Kattamis C, Helms PJ. Efficacy and tolerability of formoterol turbuhaler in children. International Journal of Clinical Practice 2003; Vol. 57, issue 10:852-6.
Weinstein 2010a {published data only}
  • Weinstein S, Nathan RA, Meltzer E, Nolte H, Maspero J. Treatment of persistent asthma with mometasone furoate/formoterol combination therapy is associated with a low incidence of oral candidiasis and dysphonia [Abstract]. Congress of the Asian Pacific Society of Respirology; 2010; Manila, Philippines.
White 2010 {published data only}
  • White M, Meltzer EO, Nathan RA, Nolte H. Improved asthma control with mometasone furoate/formoterol: a new combination treatment for persistent asthma [Abstract]. Annals of Allergy, Asthma and Immunology 2010; Vol. 105, issue 5 Suppl.
Worth 2005 {published data only}
  • Worth H. DESOLO - SiT Peri-Launch: a comparison of symbicort single inhaler therapy and conventional best practice for the treatment of persistent asthma in adults. clinicaltrials.gov (accessed 3rd September 2008).
Zetterström 2000 {published data only}
  • Zetterström O, Buhl R, Mellem H, Perpiñá M, Hedman J, O'Neill S, et al. Efficacy and safety of a new single inhaler product containing both budesonide and formoterol in adult asthma. European Respiratory Journal 2000; Vol. 16, issue Suppl 31:455s. Abstract P3198.
Zetterstrom 2001a {published data only}
  • Zetterstrom O, Buhl R, Mellem H. Efficacy and safety of symbicort® budesonide and formoterol in a single inhaler in adults with asthma. Annual Thoracic Society 97th International Conference; May 18-23, 2001; San Francisco CA, USA..

References to ongoing studies

  1. Top of page
  2. Abstract摘要Résumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to ongoing studies
  22. Additional references
  23. References to other published versions of this review
NCT01444430 {published data only}
  • AstraZeneca. A 6 month safety study comparing Symbicort with inhaled corticosteroid only in asthmatic adults and adolescents. ClinicalTrials.gov 2012 (accessed June 2012).
NCT01471340 {published data only}
  • Merck. A serious asthma outcome study with mometasone furoate/formoterol versus mometasone furoate in asthmatics 12 years and over (P06241 AM3) (SPIRO). ClinicalTrials.gov (accessed June 2012).

Additional references

  1. Top of page
  2. Abstract摘要Résumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to ongoing studies
  22. Additional references
  23. References to other published versions of this review
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