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. 2011 Jul 13;2011:1512.

Asthma in adults (chronic)

Rodolfo J Dennis 1,#, Ivan Solarte 2,#
PMCID: PMC3275169  PMID: 21749735

Abstract

Introduction

About 10% of adults have suffered an attack of asthma, and up to 5% of these have severe disease that responds poorly to treatment. Patients with severe disease have an increased risk of death, but patients with mild-to-moderate disease are also at risk of exacerbations. Most guidelines about the management of asthma follow stepwise protocols. This review does not endorse or follow any particular protocol, but presents the evidence about specific interventions.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for chronic asthma? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 54 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding anti-IgE treatment; beta2 agonists (adding long-acting inhaled beta2 agonists when asthma is poorly controlled by inhaled corticosteroids, or short-acting inhaled beta2 agonists as needed for symptom relief); inhaled corticosteroids (low dose and increasing dose); leukotriene antagonists (with or without inhaled corticosteroids); and theophylline (when poorly controlled by inhaled corticosteroids).

Key Points

About 10% of adults have suffered an attack of asthma, and up to 5% of these have severe disease that responds poorly to treatment. These people have an increased risk of death.

Most guidelines about the management of asthma follow stepwise protocols. This review does not endorse or follow any particular protocol, but presents the evidence about specific interventions.

Taking short-acting beta2 agonists as needed is as likely to relieve symptoms and improve lung function as a regular dosing schedule in adults with chronic asthma.

Adding long-acting beta2 agonists to inhaled corticosteroids decreases the number of exacerbations and improves symptoms, lung function, and quality of life in people with mild-to-moderate persistent asthma that is poorly controlled with corticosteroids.

CAUTION: Long-acting beta2 agonists have been associated with increased asthma-related mortality, and should always be used with inhaled corticosteroids.

Low-dose inhaled corticosteroids improve symptoms and lung function in persistent asthma compared with placebo or regular inhaled beta2 agonists.

  • Leukotriene antagonists are more effective than placebo at reducing symptoms, but we don't know if adding leukotriene antagonists to low-dose inhaled corticosteroids is of benefit in people with chronic asthma.

  • CAUTION: Leukotriene antagonists have been associated with a possible increased risk of neuropsychiatric events.

  • Adding theophylline to inhaled corticosteroids may improve lung function in people with mild or moderate chronic asthma that is poorly controlled with inhaled corticosteroids, but we don't know if they are of benefit compared with long-acting beta2 agonists or leukotriene antagonists.

  • Anti-IgE treatment (omalizumab) as an adjunct to treatment with inhaled and oral corticosteroids improves symptom severity, decreases exacerbation frequency, and may decrease hospital admission rates in people with chronic moderate to severe asthma.

About this condition

Definition

Asthma is characterised by variable airflow obstruction and airway hyper-responsiveness. Symptoms include dyspnoea, cough, chest tightness, and wheezing. The normal diurnal variation of PEFR is increased in people with asthma. Chronic asthma is defined here as asthma requiring maintenance treatment to achieve part or total control. In a newly diagnosed person, and when confronted with the first treatment decision, asthma should be classified by severity (intermittent, chronic mild, moderate, or severe). As further classification of disease status depends both on the severity of the disease and the response to treatment, it is now recommended that the terms "controlled", "partly controlled", and 'uncontrolled' are used for people receiving treatment. For details of the US and UK classifications of asthma, see table 1 . Most guidelines about the management of asthma follow stepwise protocols. This review does not endorse or follow any particular protocol, but presents the evidence about specific interventions in no particular order. We assume that most adults will be taking as needed or regular use of short-acting beta2 agonists for symptom relief, and in some cases long-acting beta2 agonists. We have not excluded papers with combinations of any type of beta2 agonists; however, the type of beta2 agonist therapy should be the same in all arms to be included in the review.

Table 1.

Classification of severity for chronic asthma

 
In the USA
Asthma is classified by symptoms of severity. Using this system, even people with mild intermittent asthma can develop severe exacerbations if exposed to appropriate stimuli
Mild intermittent asthma Symptoms less than weekly with normal or near-normal lung function
Mild persistent asthma Symptoms more than weekly but less than daily with normal or near-normal lung function
Moderate persistent asthma Daily symptoms with mild-to-moderate variable airflow obstruction
Severe asthma Daily symptoms and frequent night symptoms, and moderate to severe variable airflow obstruction
In the UK
Chronic asthma in ambulatory settings is graded according to the amount of medication required to keep symptoms controlled. People are classified according to whether, for symptom control, they need:
Step 1 Occasional beta2 agonists for symptomatic relief
Step 2 In addition, regular inhaled anti-inflammatory agents (such as inhaled corticosteroids, cromoglycate, or nedocromil)
Step 3 In addition, high-dose inhaled corticosteroids or low-dose inhaled steroids plus long-acting inhaled beta2 bronchodilator
Step 4 In addition, high-dose inhaled corticosteroids plus regular bronchodilators
Step 5 In addition, regular oral corticosteroids
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Incidence/ Prevalence

The reported prevalence of asthma has been increasing worldwide, but may have currently reached a plateau. About 10% of people have suffered an attack of asthma, but epidemiological studies have also found marked variations in prevalence between and within countries.

Aetiology/ Risk factors

Most people with asthma are atopic. Exposure to certain stimuli initiates inflammation and structural changes in airways causing airway hyper-responsiveness and variable airflow obstruction, which in turn cause most asthma symptoms. There are many such stimuli; the more important include environmental allergens, occupational sensitising agents, and respiratory viral infections.

Prognosis

In people with mild asthma, prognosis is good and progression to severe disease is rare. However, as a group, people with asthma lose lung function faster than those without asthma, although less quickly than people without asthma who smoke. People with chronic asthma can improve with treatment. However, some people (possibly up to 5%) have severe disease that responds poorly to treatment. These people are most at risk of morbidity and death from asthma.

Aims of intervention

To improve current asthma control by minimising or eliminating symptoms, minimising the need for medication, and maximising lung function and current levels of activity. To reduce future risk by preventing symptom worsening, exacerbations, and lung function loss. To minimise adverse effects of treatment. To provide enough information and support to facilitate self-management of asthma.

Outcomes

Symptom severity, daytime and nocturnal, excluding lung function, but including need for rescue medication such as inhaled beta2 agonists, attendance at primary care; lung function, in terms of peak expiratory flow rate (PEFR), forced expiratory volume in 1 second (FEV1), forced vitality capacity (FVC), and variability of flow rates; quality of life, including activities of daily living; hospital admissions, including time in the emergency department; and adverse effects of treatment.

Methods

Clinical Evidence search and appraisal April 2010. The following databases were used to identify studies for this systematic review: Medline 1966 to April 2010, Embase 1980 to April 2010, and The Cochrane Database of Systematic Reviews 2010, April (1966 to date of issue). When editing this review we used The Cochrane Database of Systematic Reviews 2010, Issue 2. An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment (HTA) database. We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews of RCTs and RCTs in any language. Blinded and open RCTs were included. RCTs had to contain 40 or more individuals, of whom 80% or more were followed up. Minimum length of follow-up required to include studies was 12 weeks. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied applying the same study design criteria for inclusion as we did for benefits. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. This was supplemented by additional material assessing harms from the previous authors' own search. We have primarily included RCTs in people aged 13 years or older, but we have also included high-quality studies with people aged 12 years or older if most people in the trial were adults. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table.

GRADE Evaluation of interventions for Asthma in adults (chronic).

Important outcomes Hospital admission, Lung function, Quality of life, Symptom severity (excluding lung function)
Studies (Participants) Outcome Comparison Type of evidence Quality Consistency Directness Effect size GRADE Comment
What are the effects of treatments for chronic asthma?
At least 10 (at least 2922) Symptom severity (excluding lung function) Short-acting inhaled beta2 agonists as needed for symptom relief versus regular short-acting beta2 agonists 4 0 0 −1 0 Moderate Directness point deducted for inclusion of children
11 (2756) Lung function Short-acting inhaled beta2 agonists as needed for symptom relief versus regular short-acting beta2 agonists 4 0 0 −1 0 Moderate Directness point deducted for inclusion of children
1 (225) Quality of life Short-acting inhaled beta2 agonists as needed for symptom relief versus regular short-acting beta2 agonists 4 −2 0 0 0 Low Quality points deducted for wide confidence intervals and incomplete reporting of results
4 (1527) Symptom severity (excluding lung function) Leukotriene antagonists versus placebo 4 0 0 −1 0 Moderate Directness point deducted for inclusion of adolescents
3 (1431) Lung function Leukotriene antagonists versus placebo 4 0 0 −1 0 Moderate Directness point deducted for inclusion of adolescents
1 (454) Quality of life Leukotriene antagonists versus placebo 4 0 0 −1 0 Moderate Directness point deducted for inclusion of adolescents
19 (5190) Symptom severity (excluding lung function) Leukotriene antagonists versus low-dose inhaled corticosteroids 4 0 0 −1 0 Moderate Directness point deducted for inclusion of children and people taking higher doses of inhaled corticosteroids
2 (267) Lung function Leukotriene antagonists versus low-dose inhaled corticosteroids 4 −1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
13 (3189) Hospital admission Leukotriene antagonists versus low-dose inhaled corticosteroids 4 0 0 −1 0 Moderate Directness point deducted for inclusion of children and people taking higher doses of inhaled corticosteroids
2 (855) Symptom severity (excluding lung function) Leukotriene antagonists versus low-dose inhaled corticosteroids plus long-acting beta2 agonists 4 0 0 −1 0 Moderate Directness point deducted for inclusion of adolescents
1 (432) Lung function Leukotriene antagonists versus low-dose inhaled corticosteroids plus long-acting beta2 agonists 4 0 0 −1 0 Moderate Directness point deducted for inclusion of adolescents
at least 15 (at least 4709) Symptom severity (excluding lung function) Low-dose inhaled corticosteroids versus placebo 4 0 0 −1 0 Moderate Directness point deducted for inclusion of children
at least 33 (at least 8574) Lung function Low-dose inhaled corticosteroids versus placebo 4 0 0 −1 0 Moderate Directness point deducted for inclusion of children
1 (7241) Hospital admission Low-dose inhaled corticosteroids versus placebo 4 0 0 −1 0 Moderate Directness point deducted for inclusion of children
3 (704) Quality of life Low-dose inhaled corticosteroids versus placebo 4 0 0 0 0 High
At least 13 (at least 3812) Symptom severity (excluding lung function) Adding long-acting inhaled beta2 agonists to inhaled corticosteroids versus adding placebo to inhaled corticosteroids or versus inhaled corticosteroids alone 4 0 0 −1 0 Moderate Directness point deducted for inclusion of adolescents
11 (3673) Lung function Adding long-acting inhaled beta2 agonists to inhaled corticosteroids versus adding placebo to inhaled corticosteroids or versus inhaled corticosteroids alone 4 0 0 −1 0 Moderate Directness point deducted for inclusion of adolescents
At least 7 (at least 5571) Symptom severity (excluding lung function) Adding long-acting inhaled beta2 agonists to inhaled corticosteroids versus adding leukotriene antagonists to inhaled corticosteroids 4 0 0 −1 0 Moderate Directness point deducted for inclusion of adolescents
At least 10 (at least 5669) Lung function Adding long-acting inhaled beta2 agonists to inhaled corticosteroids versus adding leukotriene antagonists to inhaled corticosteroids 4 0 0 −1 0 Moderate Directness point deducted for inclusion of adolescents
4 (3993) Hospital admission Adding long-acting inhaled beta2 agonists to inhaled corticosteroids versus adding leukotriene antagonists to inhaled corticosteroids 4 0 0 −1 0 Moderate Directness point deducted for inclusion of adolescents
3 (2893) Quality of life Adding long-acting inhaled beta2 agonists to inhaled corticosteroids versus adding leukotriene antagonists to inhaled corticosteroids 4 0 0 −1 0 Moderate Directness point deducted for inclusion of adolescents
At least 30 (at least 9342) Symptom severity (excluding lung function) Adding long-acting inhaled beta2 agonists to inhaled corticosteroids versus increased inhaled corticosteroid dose 4 0 0 −1 0 Moderate Directness point deducted for inclusion of adolescents
At least 30 (at least 9342) Lung function Adding long-acting inhaled beta2 agonists to inhaled corticosteroids versus increased inhaled corticosteroid dose 4 0 0 −1 0 Moderate Directness point deducted for inclusion of adolescents
1 (155) Lung function Adding theophylline to inhaled corticosteroids versus adding placebo to inhaled corticosteroids or versus inhaled corticosteroids alone 4 −2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
1 (64) Lung function Adding theophylline to inhaled corticosteroids versus adding long-acting beta2 agonists to inhaled corticosteroids 4 −1 0 0 0 Moderate Quality point deducted for sparse data
1 (64) Lung function Adding theophylline to inhaled corticosteroids versus adding leukotriene antagonists to inhaled corticosteroids 4 −2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
1 (66) Symptom severity (excluding lung function) Adding theophylline to inhaled corticosteroids versus increased inhaled corticosteroid dose 4 −2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
2 (221) Lung function Adding theophylline to inhaled corticosteroids versus increased inhaled corticosteroid dose 4 −1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
3 (988) Symptom severity (excluding lung function) Adding leukotriene antagonists to inhaled corticosteroids versus adding placebo to inhaled corticosteroids 4 0 0 −1 0 Moderate Directness point deducted for inclusion of children
1 (889) Symptom severity (excluding lung function) Adding leukotriene antagonists to inhaled corticosteroids versus increasing inhaled corticosteroid dose 4 0 0 −1 0 Moderate Directness point deducted for inclusion of adolescents
1 (889) Lung function Adding leukotriene antagonists to inhaled corticosteroids versus increasing inhaled corticosteroid dose 4 0 0 −1 0 Moderate Directness point deducted for inclusion of adolescents
1 (889) Quality of life Adding leukotriene antagonists to inhaled corticosteroids versus increasing inhaled corticosteroid dose 4 0 0 −1 0 Moderate Quality point deducted for incomplete reporting of results
at least 7 (2466) Symptom severity (excluding lung function) Adding anti-IgE treatment versus adding placebo to inhaled corticosteroids plus long-acting beta2 agonists plus either leukotriene antagonists, theophylline, or oral corticosteroids, alone or in any combination 4 0 0 –1 0 Moderate Directness point deducted for inclusion of adolescents.
at least 5 (at least 1966) Lung function Adding anti-IgE treatment versus adding placebo to inhaled corticosteroids plus long-acting beta2 agonists plus either leukotriene antagonists, theophylline, or oral corticosteroids, alone or in any combination 4 0 0 –1 0 Moderate Directness point deducted for inclusion of adolescents
3 (1405) Hospital admission Adding anti-IgE treatment versus adding placebo to inhaled corticosteroids plus long-acting beta2 agonists plus either leukotriene antagonists, theophylline, or oral corticosteroids, alone or in any combination 4 0 0 –1 0 Low Directness point deducted for inclusion of adolescents
5 (2131) Quality of life Adding anti-IgE treatment versus adding placebo to inhaled corticosteroids plus long-acting beta2 agonists plus either leukotriene antagonists, theophylline, or oral corticosteroids, alone or in any combination 4 –1 0 –1 0 Low Quality point deducted for incomplete recording of results. Directness point deducted for inclusion of adolescents
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We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.

Glossary

Diurnal variation

A characteristic of people with asthma is increased variation in peak flow rates and forced expiratory volume in 1 second during the day. The diurnal variation is sometimes expressed as the difference between maximum and minimum values expressed as a fraction of the maximum value.

Forced expiratory volume in 1 second (FEV1)

The volume breathed out in the first second of forceful blowing into a spirometer, measured in litres.

High-quality evidence

Further research is very unlikely to change our confidence in the estimate of effect.

Low-quality evidence

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.

Moderate-quality evidence

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Peak expiratory flow rate (PEFR)

The maximum rate that gas is expired from the lungs when blowing into a peak flow meter or a spirometer. It is measured at an instant, but the units are expressed as litres per minute.

Asthma and other wheezing disorders in children

Asthma in adults (acute)

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Contributor Information

Dr Rodolfo J Dennis, Head, Departments of Medicine and Research, Fundacion Cardioinfantil Instituto de Cardiologia, Bogota, Colombia.

Dr Ivan Solarte, Respiratory Medicine Unit, Hospital San Ignacio, Bogota, Colombia.

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BMJ Clin Evid. 2011 Jul 13;2011:1512.

Short-acting inhaled beta2 agonists as needed for symptom relief versus regular short-acting beta2 agonists in adults with mild or moderate asthma

Summary

Taking short-acting beta 2 agonists as needed is as likely to relieve symptoms and improve lung function as a regular dosing schedule in adults with chronic asthma.

Benefits and harms

Short-acting inhaled beta2 agonists as needed for symptom relief versus regular short-acting beta2 agonists:

We found one systematic review (search date 2002, 41 RCTs in adults, 3 RCTs in children [18 parallel group RCTs and 26 crossover RCTs]) comparing regular versus as-needed beta2 agonists in adults or children with a diagnosis of asthma for at least 6 months. Results from crossover RCTs and parallel-group RCTs were analysed separately. Four of the included RCTs did not allow the use of co-interventions. We also found three RCTs assessing deterioration in airway hyper-responsiveness after stopping the medication, allergen-induced bronchoconstriction, and tremor.

Symptom severity (excluding lung function)

Compared with regular-use short-acting inhaled beta2 agonists As-needed and regular use of short-acting inhaled beta2 agonists seem equally effective at reducing exacerbations and at improving daytime and night-time symptoms, but we don't know whether they are as effective at reducing the use of rescue medication in people with asthma for at least 6 months (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity (excluding lung function)

Systematic review		 2922 adults with a diagnosis of asthma for at least 6 months
10 RCTs in this analysis		 People with >1 major exacerbation
with regular beta2 agonists
with as-needed beta2 agonists
OR 0.86
95% CI 0.71 to 1.04
Results were similar in the crossover RCTs 		Not significant

Systematic review		 1492 adults with a diagnosis of asthma for at least 6 months
7 RCTs in this analysis		 Daytime symptom score
with regular beta2 agonists
with as-needed beta2 agonists
WMD –0.02
95% CI –0.12 to +0.09
Results were similar in the crossover RCTs 		Not significant

Systematic review		 1137 adults with a diagnosis of asthma for at least 6 months
5 RCTs in this analysis		 Night-time symptom score
with regular beta2 agonists
with as-needed beta2 agonists
WMD –0.11
95% CI –0.23 to +0.02
Results were similar in the crossover RCTs 		Not significant
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No data from the following reference on this outcome.

Lung function

Compared with regular-use short-acting inhaled beta2 agonists As-needed and regular use of short-acting inhaled beta2 agonists seem equally effective at improving morning peak expiratory flow rate (PEFR), and may be as effective at improving forced expiratory volume in 1 second (FEV1) in people with asthma for at least 6 months (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function

Systematic review		 2576 adults or children with a diagnosis of asthma for at least 6 months
11 RCTs in this analysis		 Morning PEFR
with regular beta2 agonists
with as-needed beta2 agonists
WMD –2.7 L/minute
95% CI –10.4 L/minute to +5.0 L/minute
Results were similar in the crossover RCTs 		Not significant

Systematic review		 1483 adults and children with a diagnosis of asthma for at least 6 months
9 RCTs in this analysis		 FEV1
with regular beta2 agonists
with as-needed beta2 agonists
WMD –0.08 L
95% CI –0.15 L to –0.01 L 		Effect size not calculated as-needed beta2 agonists

Systematic review		 1522 adults with a diagnosis of asthma for at least 6 months
16 RCTs in this analysis		 FEV1
with regular beta2 agonists
with as-needed beta2 agonists
WMD –0.09 L
95% CI –0.22 L to +0.44 L 		Not significant
Open in a new tab

No data from the following reference on this outcome.

Hospital admission

No data from the following reference on this outcome.

Quality of life

Compared with regular-use short-acting inhaled beta2 agonists As-needed and regular use of short-acting inhaled beta2 agonists seem equally effective at improving quality of life in people with asthma for at least 6 months (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Quality of life

Systematic review		 225 adults with a diagnosis of asthma for at least 6 months
Data from 1 RCT		 Quality-of-life scores
with regular beta2 agonists
with as-needed beta2 agonists
WMD +0.01
95% CI –0.24 to +0.26 		Not significant
Open in a new tab

No data from the following reference on this outcome.

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

Systematic review		 752 adults with a diagnosis of asthma for at least 6 months
4 RCTs in this analysis		 Incidence of pharmacologically predictable adverse effects
with regular beta2 agonists
with as-needed beta2 agonists
OR 1.03
95% CI 0.72 to 1.49 		Not significant

Systematic review		 1165 adults with a diagnosis of asthma for at least 6 months
5 RCTs in this analysis		 Headache
with regular beta2 agonists
with as-needed beta2 agonists
OR 1.02
95% CI 0.63 to 1.65 		Not significant

Systematic review		 518 adults with a diagnosis of asthma for at least 6 months
2 RCTs in this analysis		 Palpitations/tachycardia
with regular beta2 agonists
with as-needed beta2 agonists
OR 1.52
95% CI 0.42 to 5.46 		Not significant

Systematic review		 1514 adults with a diagnosis of asthma for at least 6 months
3 RCTs in this analysis		 Tremor
with regular beta2 agonists
with as-needed beta2 agonists
OR 13.47
95% CI 3.17 to 57.24 		Large effect size as-needed beta2 agonists

Systematic review		 Number of people in this analysis not reported Worsening of airways function
with stopping regular treatment with beta2 agonists
with as-needed beta2 agonists
Absolute results not reported

RCT		 Number of people in this analysis not reported Adverse effects
with regular use of inhaled beta2 agonists
with as-needed beta2 agonists
Absolute results not reported

RCT		 Number of people in this analysis not reported Adverse effects
with regular use of inhaled beta2 agonists
with as-needed beta2 agonists
Absolute results not reported

RCT		 Number of people in this analysis not reported Adverse effects
with regular beta2 agonists
with as-needed beta2 agonists
Absolute results not reported
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Further information on studies

None.

Comment

Non-experimental studies found an association between increased asthma mortality and over use of short-acting inhaled beta2 agonists. However, the results of these non-randomised studies should be interpreted with caution because of the risk of confounding by factors other than treatment. See also harms of adding long-acting inhaled beta2 agonists to inhaled corticosteroids.

Clinical guide:

There is strong evidence that short-acting beta2 agonists should be used for symptom relief only, and moderate evidence favouring as-needed rather than regular use. Nevertheless, an increase in the need for this medication should alert both patient and physician that asthma is not under control. A review assessing the adverse effects of long-acting and short-acting beta2 agonists is described in adding long-acting inhaled beta2 agonists to inhaled corticosteroids.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Jul 13;2011:1512.

Leukotriene antagonists in people with mild-to-moderate persistent asthma not taking inhaled corticosteroids

Summary

Leukotriene antagonists are more effective than placebo at reducing symptoms in people with chronic asthma, but may be less effective than inhaled corticosteroids.

CAUTION: Leukotriene antagonists have been associated with a possible increased risk of neuropsychiatric events.

Benefits and harms

Leukotriene antagonists versus placebo:

We found no systematic review. We found 4 RCTs comparing leukotriene antagonists versus placebo.

Symptom severity (excluding lung function)

Compared with placebo Leukotriene antagonists (zafirlukast or montelukast) seem more effective at reducing daytime and night-time asthma symptoms and at reducing beta2 agonist use in people with asthma (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity (excluding lung function)

RCT		 762 people, aged 12 years or older, with a history of asthma Daytime symptoms (mean 7-day cumulative daytime symptom score measured on a scale from 0 [no symptoms] to 3 [severe symptoms])
8.05 with zafirlukast for 13 weeks
9.45 with placebo for 13 weeks
P <0.01 		Effect size not calculated zafirlukast

RCT		 762 people, aged 12 years or older, with a history of asthma Night-time wakenings
2.05/week with zafirlukast for 13 weeks
2.52/week with placebo for 13 weeks
P <0.05 		Effect size not calculated zafirlukast

RCT		 762 people, aged 12 years or older, with a history of asthma Beta2 agonist use
3.1 puffs/day with zafirlukast for 13 weeks
3.9 puffs/day with placebo for 13 weeks
P <0.01 		Effect size not calculated zafirlukast

RCT		 146 people, aged >12 years, with mild-to-moderate asthma Mean number of symptom-free days per month
6.3 days with zafirlukast 20 mg for 13 weeks
3.7 days with placebo for 13 weeks
Adjusted mean difference 3.1 days
P = 0.03 		Effect size not calculated zafirlukast

RCT		 146 people, aged >12 years, with mild-to-moderate asthma Mean number of days per month with no beta2 agonist use
7.8 days with zafirlukast 20 mg for 13 weeks
6.0 days with placebo for 13 weeks
Adjusted mean difference 4.8 days
P = 0.001 		Effect size not calculated zafirlukast

RCT		 146 people, aged >12 years, with mild-to-moderate asthma Mean number of days per month with no episodes of asthma
6.8 days with zafirlukast 20 mg for 13 weeks
5.1 days with placebo for 13 weeks
Adjusted mean difference 4.0 days
P = 0.003 		Effect size not calculated zafirlukast

RCT		 146 people, aged >12 years, with mild-to-moderate asthma Mean number of limitation-free days
25.8 days with zafirlukast 20 mg for 13 weeks
24.9 days with placebo for 13 weeks
Adjusted mean difference 2.2 days
P = 0.10 		Not significant

RCT		 146 people, aged >12 years, with mild-to-moderate asthma Mean number of days with no sleep disturbance
22.3 days with zafirlukast 20 mg for 13 weeks
23.1 days with placebo for 13 weeks
Adjusted mean difference 1.2 days
P >0.2 		Not significant

RCT		 454 people, aged >12 years, with asthma Mean daytime asthma score (not further defined) 13 weeks
1.40 with zafirlukast for 13 weeks
1.55 with placebo for 13 weeks
Treatment difference: –0.14
P <0.001 		Effect size not calculated zafirlukast

RCT		 454 people, aged >12 years, with asthma Mean number of night-time wakenings per week 13 weeks
2.07 with zafirlukast for 13 weeks
2.69 with placebo for 13 weeks
Treatment difference: –0.63
P <0.001 		Effect size not calculated zafirlukast

RCT		 454 people, aged >12 years, with asthma Beta2 agonist use 13 weeks
3.60 puffs/day with zafirlukast for 13 weeks
4.25 puffs/day with placebo for 13 weeks
Treatment difference: –0.64 puffs/day
P <0.001 		Effect size not calculated zafirlukast

RCT		 215 people, aged 12 to 60 years, with mild-to-moderate asthma Daytime symptoms (measured on a scale of 0 = no symptoms to 5 = symptoms so severe that they affect work and normal activity) 12 weeks
0.67 with zafirlukast 20 mg twice daily for 12 weeks
1.05 with placebo twice daily 12 weeks
P value not reported

RCT		 215 people, aged 12 to 60 years, with mild-to-moderate asthma Night-time symptoms (measured on a scale of 0 = no symptoms to 5 = symptoms so severe the participant did not sleep) 12 weeks
0.45 with zafirlukast 20 mg twice daily for 12 weeks
0.82 with placebo twice daily for 12 weeks
P value not reported

RCT		 215 people, aged 12 to 60 years, with mild-to-moderate asthma Use of rescue medication 12 weeks
4.73 rotacaps of salbutamol 200 micrograms with zafirlukast 20 mg twice daily for 12 weeks
19.81 rotacaps of salbutamol 200 micrograms with placebo twice daily for 12 weeks
P >0.05 		Not significant
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Lung function

Compared with placebo Leukotriene antagonists (zafirlukast or montelukast) seem more effective at improving morning FEV1 and PEFR in people with asthma (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function

RCT		 762 people, aged 12 years or older, with a history of asthma Morning FEV1
7% with zafirlukast for 13 weeks
3% with placebo for 13 weeks
P <0.01 		Effect size not calculated zafirlukast

RCT		 454 people, aged >12 years, with asthma Morning PEFR 13 weeks
387.5 L/minute with zafirlukast for 13 weeks
374.4 L/minute with placebo for 13 weeks
Treatment difference: 13.1 L/minute
P <0.001 		Effect size not calculated zafirlukast

RCT		 454 people, aged >12 years, with asthma Evening PEFR 13 weeks
416.1 L/minute with zafirlukast for 13 weeks
404.6 L/minute with placebo for 13 weeks
Treatment difference: 11.5 L/minute
P <0.001 		Effect size not calculated zafirlukast

RCT		 454 people, aged >12 years, with asthma FEV1 13 weeks
2.64 L with zafirlukast for 13 weeks
2.60 L with placebo for 13 weeks
Treatment difference: 0.05
P = 0.33 		Not significant

RCT		 454 people, aged >12 years, with asthma FEV1 % predicted 13 weeks
66.8% with zafirlukast for 13 weeks
66.4% with placebo for 13 weeks
Treatment difference: 1.3
P = 0.305 		Not significant

RCT		 215 people, aged 12 to 60 years, with mild-to-moderate asthma FEV1 12 weeks
1.86 L with zafirlukast 20 mg twice daily for 12 weeks
1.71 L with placebo twice daily for 12 weeks
P <0.05 		Effect size not calculated zafirlukast

RCT		 215 people, aged 12 to 60 years, with mild-to-moderate asthma FVC 12 weeks
2.39 L with zafirlukast 20 mg twice daily for 12 weeks
2.20 L with placebo twice daily for 12 weeks
P >0.05 		Not significant

RCT		 215 people, aged 12 to 60 years, with mild-to-moderate asthma PEFR 12 weeks
387.71 L/minute with zafirlukast 20 mg twice daily for 12 weeks
354.89 L/minute with placebo twice daily for 12 weeks
P >0.05 		Not significant

RCT		 215 people, aged 12 to 60 years, with mild-to-moderate asthma FEV1 % predicted 12 weeks
70.38% with zafirlukast 20 mg twice daily for 12 weeks
63.50% with placebo twice daily for 12 weeks
P >0.05 		Not significant
Open in a new tab

No data from the following reference on this outcome.

Hospital admission

No data from the following reference on this outcome.

Quality of life

Compared with placebo Leukotriene antagonists (zafirlukast) seem to improve quality of life in people with asthma (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Quality of life

RCT		 454 people, aged >12 years, with asthma Quality of life (as measured by the asthma quality-of-life questionnaire: scores range from 1 = maximal impairment to 7 = no impairment) 13 weeks
5.08 with zafirlukast for 13 weeks
4.82 with placebo for 13 weeks
Treatment difference: 0.26
P = 0.004 		Effect size not calculated zafirlukast
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No data from the following reference on this outcome.

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

RCT		 762 people, aged 12 years or older, with a history of asthma Adverse effects
350/514 (68%) with zafirlukast for 13 weeks
160/248 (65%) with placebo for 13 weeks
Significance not assessed

RCT		 454 people, aged >12 years, with asthma Adverse effects
125/231 (54%) with zafirlukast for 13 weeks
132/223 (59%) with placebo for 13 weeks
Significance not assessed

RCT		 215 people, aged 12 to 60 years, with mild-to-moderate asthma Adverse effects
22/116 (19%) with zafirlukast 20 mg twice daily for 12 weeks
13/99 (13%) with placebo twice daily for 12 weeks
P >0.05 		Not significant
Open in a new tab

No data from the following reference on this outcome.

Leukotriene antagonists versus low-dose inhaled corticosteroids:

We found one systematic review (search date 2003) and two subsequent RCTs.

Symptom severity (excluding lung function)

Compared with low-dose inhaled corticosteroids Leukotriene antagonists seem less effective at increasing symptom-free days, reducing the risk of asthma exacerbations (need for systemic corticosteroids), or reducing the need for rescue medication in people with asthma (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity (excluding lung function)

Systematic review		 4965 people with FEV1 >50% predicted
18 RCTs in this analysis		 Proportion of people with exacerbations requiring systemic corticosteroids
254/2529 (10%) with leukotriene antagonists (montelukast, pranlukast, zafirlukast) for 4 to 37 weeks
128/2436 (5%) with low- or moderate-dose inhaled corticosteroids (beclometasone [beclomethasone], fluticasone) for 4 to 37 weeks
RR 1.65
95% CI 1.36 to 2.00 		Small effect size inhaled corticosteroids

RCT
3-armed trial 		225 adults, 199 completed the study, mean age 33 years, baseline FEV1 88% predicted Number of symptom-free days 1 year
3.1 with zafirlukast 20 mg twice daily
4.0 with low-dose inhaled budesonide 200 micrograms twice daily
2.9 with placebo
P = 0.03 for the difference among groups
The RCT may have been under-powered to detect clinically important differences between groups
Open in a new tab

No data from the following reference on this outcome.

Lung function

Compared with low-dose inhaled corticosteroids Leukotriene antagonists seem less effective at improving FEV1 in people with asthma (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function

RCT
4-armed trial 		51 non-smokers, mean age 26 years, baseline FEV1 94% to 99% predicted across treatment groups, taking a short-acting beta2 agonist as needed % predicted FEV1 for baseline to after treatment 12 weeks
from 94.8% to 96.3% with montelukast 10 mg daily
from 99.9% to 100.4% with low-dose budesonide 400 micrograms twice daily
from 99.2% to 98.9% with budesonide 800 micrograms twice daily
Reported as not significant
P value not reported
The RCT may have been underpowered to detect clinically important differences between groups 		Not significant

RCT
3-armed trial 		225 adults, 199 completed the study, mean age 33 years, baseline FEV1 88% predicted Pre-bronchodilator FEV1 1 year
1.1% with zafirlukast 20 mg twice daily
4% with low-dose inhaled budesonide 200 micrograms twice daily
0.7% with placebo
P = 0.005 for the difference among groups
The RCT may have been underpowered to detect clinically important differences between groups 		Not significant
Open in a new tab

No data from the following reference on this outcome.

Hospital admission

Compared with low-dose inhaled corticosteroids Leukotriene antagonists and low-dose inhaled corticosteroids seem equally effective at reducing hospital admissions in people with asthma (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Hospital admission

Systematic review		 3189 people with FEV1 >50% predicted in this analysis not reported
13 RCTs in this analysis		 Hospital admission rates for acute exacerbations
10/1641 (0.6%) with leukotriene antagonists (montelukast, pranlukast, zafirlukast) for 4 to 37 weeks
5/1548 (0.3%) with low- or moderate-dose inhaled corticosteroids (beclometasone [beclomethasone], fluticasone) for 4 to 37 weeks
RR 1.62
95% CI 0.64 to 4.15 		Not significant
Open in a new tab

No data from the following reference on this outcome.

Quality of life

No data from the following reference on this outcome.

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

Systematic review		 Number of people with FEV1 >50% predicted in this analysis not reported Withdrawals for any cause
with leukotriene antagonists (montelukast, pranlukast, zafirlukast) for 4 to 37 weeks
with low- or moderate-dose inhaled corticosteroids (beclometasone [beclomethasone], fluticasone) for 4 to 37 weeks
Reported as significant 		Effect size not calculated inhaled corticosteroids

Systematic review		 6277 people with FEV1 >50% predicted
16 RCTs in this analysis		 Withdrawals caused by adverse effects
96/3257 (2.9%) with leukotriene antagonists (montelukast, pranlukast, zafirlukast) for 4 to 37 weeks
77/3020 (2.5%) with low- or moderate-dose inhaled corticosteroids (beclometasone [beclomethasone], fluticasone) for 4 to 37 weeks
RR 1.15
95% CI 0.86 to 1.54 		Not significant

RCT
4-armed trial 		51 non-smokers, mean age 26 years, baseline FEV1 94% to 99% predicted across treatment groups, taking a short-acting beta2 agonist as needed Adverse effects
with montelukast
with budesonide
Absolute results not reported

RCT
3-armed trial 		225 adults, 199 completed the study, mean age 33 years, baseline FEV1 88% predicted Adverse effects
with montelukast
with budesonide
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Leukotriene antagonists versus low-dose inhaled corticosteroids plus long-acting beta2 agonists:

We found no systematic review but found two RCTs.

Symptom severity (excluding lung function)

Compared with low-dose inhaled corticosteroids plus long-acting beta2 agonists Leukotriene antagonists seem less effective at reducing the risk of exacerbations, decreasing symptoms, or increasing symptom-free days in people with asthma (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity (excluding lung function)

RCT		 423 adults with symptomatic asthma taking short-acting beta2 agonists Increase in symptom-free days from baseline 12 weeks
22% with montelukast 20 mg once daily
49% with low-dose fluticasone 100 micrograms plus salmeterol 50 micrograms twice daily
WMD 27%
95% CI 20% to 35% 		Effect size not calculated fluticasone plus salmeterol

RCT		 423 adults with symptomatic asthma taking short-acting beta2 agonists Exacerbations 12 weeks
11 with montelukast 20 mg once daily
0 with low-dose fluticasone 100 micrograms plus salmeterol 50 micrograms twice daily
P <0.001 		Effect size not calculated fluticasone plus salmeterol

RCT		 432 people, aged 15 years or older, with persistent asthma, symptomatic on short-acting beta2 agonists Increase in symptom-free days 12 weeks
27% with oral montelukast alone 10 mg once daily
40% with low-dose fluticasone 100 micrograms twice-daily plus salmeterol 50 micrograms twice daily
P <0.02 		Effect size not calculated fluticasone plus salmeterol
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Lung function

Compared with inhaled corticosteroids plus long-acting beta2 agonists Leukotriene antagonists seem less effective at improving lung function in people with asthma (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function

RCT		 432 people, aged 15 years or older, with persistent asthma, symptomatic on short-acting beta2 agonists Increase in FEV1 12 weeks
13% with oral montelukast alone 10 mg once daily
27% with low-dose fluticasone 100 micrograms twice daily plus salmeterol 50 micrograms twice daily
P <0.001 		Effect size not calculated fluticasone plus salmeterol
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No data from the following reference on this outcome.

Hospital admission

No data from the following reference on this outcome.

Quality of life

No data from the following reference on this outcome.

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

RCT		 423 adults with symptomatic asthma taking short-acting beta2 agonists Adverse effects
62% with montelukast 20 mg once daily
61% with low-dose fluticasone 100 micrograms plus salmeterol 50 micrograms twice daily
Significance not reported

RCT		 432 people, aged 15 years or older, with persistent asthma, symptomatic on short-acting beta2 agonists Adverse effects
with oral montelukast alone 10 mg once daily
with low-dose fluticasone 100 micrograms twice daily plus salmeterol 50 micrograms twice daily
Absolute results not reported
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Further information on studies

None.

Comment

One systematic review (search date 2000) identified 22 cases of the Churg–Strauss syndrome associated with leukotriene antagonists, but the total number of people exposed was not reported.

Harms alerts:

The FDA has issued a drug safety alert on the possible increased risk of neuropsychiatric events (mood and behavioural changes) associated with leukotriene inhibitors (montelukast, zafirlukast, and zileuton).

Clinical guide:

Compared with placebo, there is reasonable evidence that leukotriene antagonists as first-line controller therapy in adults with asthma are beneficial, but there is less evidence of benefit when compared with inhaled corticosteroids, or with inhaled corticosteroids plus long-acting beta2 agonists. Unless contraindicated, most people who have uncontrolled asthma should be given inhaled corticosteroids.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Jul 13;2011:1512.

Low-dose inhaled corticosteroids in people with mild, chronic asthma

Summary

Low-dose inhaled corticosteroids improve symptoms and lung function in chronic asthma compared with placebo or regular inhaled beta 2 agonists.

Benefits and harms

Low-dose inhaled corticosteroids versus placebo:

We found one systematic review (search date 1999; 43 RCTs [29 parallel studies, 14 crossover studies]; 2801 adults, adolescents, and children with asthma who had not been treated with oral corticosteroids) and 7 subsequent RCTs (reported in 9 papers; 6 RCTs in 1210 adults and adolescents, 1 RCT in 7241 people aged 5–66 years) comparing budesonide versus placebo. We found one systematic review (search date 2008, 86 RCTs, 16,160 adults and children) comparing fluticasone versus placebo for 4 weeks to 2 years in people with chronic asthma. We found one systematic review (search date 2003, 60 RCTs, 6542 adults and children with asthma) comparing beclometasone (beclomethasone) versus placebo for 4 weeks to 6 months. We also found 9 additional RCTs (>3000 adults and adolescents with persistent asthma) assessing low doses of triamcinolone, flunisolide, mometasone, and one subsequent RCT assessing ciclesonide. We also found three systematic reviews that specifically assessed adverse effects of inhaled corticosteroids. The first review (search date 2001, 2 RCTs, 892 people) examined the effects of inhaled corticosteroids on fracture rate. The second review (search date 1998, 27 RCTs) assessed overall adverse effects of inhaled corticosteroids.The third review (search date 2005, 31 RCTs) assessed the impact of inhaled corticosteroids on cortisol suppression.

Symptom severity (excluding lung function)

Compared with placebo Low-dose inhaled corticosteroids seem more effective at improving symptoms and reducing exacerbations and the need for short-acting bronchodilators in people with mild, moderate, or severe asthma (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity (excluding lung function)

Systematic review		 480 adolescents and adults with non-oral, corticosteroid-treated asthma
5 RCTs in this analysis		 Change in use of inhaled beta2 agonists
with budesonide 400–1000 micrograms once daily for 1 week to >6 months
with placebo once daily for 1 week to >6 months
WMD –0.4 puffs/day
95% CI –0.8 puffs/day to –0.06 puffs/day 		Effect size not calculated budesonide

RCT
3-armed trial 		698 people, aged >12 years, with mild asthma not taking corticosteroids
Subgroup analysis		 Risk of exacerbation
with budesonide 100 micrograms twice daily
with placebo twice daily
RR 0.40
95% CI 0.27 to 0.59 		Moderate effect size budesonide

RCT
3-armed trial 		698 people, aged >12 years, with mild asthma not taking corticosteroids
Subgroup analysis		 Exacerbations/person/year
0.29 with budesonide 100 micrograms twice daily
0.34 with budesonide 100 micrograms plus formoterol 4.5 micrograms twice daily
P = 0.50 		Not significant

RCT
5-armed trial 		1272 people, aged >12 years, with mild asthma taking low-dose inhaled corticosteroids
Subgroup analysis		 Exacerbations/person/year
0.92 with budesonide 100 micrograms twice daily for 1 year
0.56 with budesonide 100 micrograms plus formoterol 4.5 micrograms twice daily for 1 year
0.96 with budesonide 200 micrograms twice daily for 1 year
0.36 with budesonide 200 micrograms plus formoterol 4.5 micrograms twice daily for 1 year
Budesonide 100 micrograms twice daily plus formoterol v budesonide 200 micrograms twice daily alone: P = 0.0001 		Effect size not calculated

Systematic review		 1043 adults with mild, moderate, or severe asthma
7 RCTs in this analysis		 Use of inhaled beta2 agonists
with fluticasone 100 micrograms or less once daily
with placebo once daily
Absolute results not reported
WMD –1.36 puffs/day
95% CI –1.66 puffs/day to –1.06 puffs/day 		Effect size not calculated fluticasone

Systematic review		 508 adults
Data from 1 RCT		 Change in need for beta2 agonists
with beclometasone (beclomethasone) 400 micrograms or less once daily
with placebo once daily
WMD –2.32 puffs/day
95% CI –2.55 puffs/day to –2.09 puffs/day 		Effect size not calculated beclometasone

RCT
4-armed trial 		708 people, aged 12 years and older, with mild-to-moderate persistent asthma not using an inhaled corticosteroid Mean change in salbutamol (albuterol) use (puffs/day) 16 weeks
+1.69 with ciclesonide 80 micrograms twice daily
–1.38 with ciclesonide 160 micrograms once daily
–1.57 with ciclesonide 80 micrograms twice daily for 4 weeks /160 micrograms once daily for 12 weeks
–0.97 with placebo
P = 0.01 for ciclesonide at any dose v placebo 		Effect size not calculated ciclesonide

RCT
4-armed trial 		708 people, aged 12 years and older, with mild-to-moderate persistent asthma not using an inhaled corticosteroid Mean change in night-time awakenings (per night) 16 weeks
–0.37 with ciclesonide 80 micrograms twice daily
–0.22 with placebo
P = 0.004 		Effect size not calculated ciclesonide 80 micrograms twice-daily

RCT
4-armed trial 		708 people, aged 12 years and older, with mild-to-moderate persistent asthma not using an inhaled corticosteroid Mean change in night-time awakenings (per night) 16 weeks
–0.29 with ciclesonide 160 micrograms once daily
–0.22 with placebo
P = 0.175 		Not significant

RCT
4-armed trial 		708 people, aged 12 years and older, with mild-to-moderate persistent asthma not using an inhaled corticosteroid Mean change in night-time awakenings (per night) 16 weeks
–0.30 with ciclesonide 80 micrograms twice daily for 4 weeks/160 micrograms once daily for 12 weeks
–0.22 with placebo
P = 1.04 		Not significant
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No data from the following reference on this outcome.

Lung function

Compared with placebo Low-dose inhaled corticosteroids seem more effective at improving lung function (FEV1 and PEFR) in people with mild, moderate, or severe asthma (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function

Systematic review		 103 adults with non-oral, corticosteroid-treated asthma
4 RCTs in this analysis		 FEV1
with budesonide 400–1000 micrograms once daily for 1 week to >6 months
with placebo once daily for 1 week to >6 months
WMD +0.07 L
95% CI –0.25 L to +0.40 L 		Not significant

Systematic review		 94 children with non-oral, corticosteroid-treated asthma
3 RCTs in this analysis		 Morning PEFR
with budesonide 400–1000 micrograms once daily for 1 week to >6 months
with placebo once daily for 1 week to >6 months
Absolute results not reported
WMD –31 L/minute
95% CI –67 L/minute to +5.0 L/minute 		Not significant

RCT
3-armed trial 		273 adults, aged 19 to 70 years, with mild-to-moderate asthma and poorly controlled with bronchodilator treatment PEFR
with budesonide Turbohaler 200 micrograms twice daily for 12 weeks
with placebo twice daily for 12 weeks
Absolute results not reported
Difference from placebo: 43.63 L/minute
P <0.001 		Effect size not calculated budesonide

RCT
3-armed trial 		273 adults, aged 19 to 70 years, with mild-to-moderate asthma, poorly controlled with bronchodilator treatment PEFR
with budesonide Turbohaler 400 micrograms twice daily for 12 weeks
with placebo twice daily for 12 weeks
Difference from placebo: 40.10 L/minute
P <0.001 		Effect size not calculated budesonide

RCT
3-armed trial 		273 adults, aged 19 to 70 years, with mild-to-moderate asthma, poorly controlled with bronchodilator treatment PEFR
with budesonide Turbohaler 200 micrograms twice daily for 12 weeks
with placebo twice daily for 12 weeks
Difference from placebo: 0.44 L
P <0.001 		Effect size not calculated budesonide

RCT
3-armed trial 		273 adults, aged 19 to 70 years, with mild-to-moderate asthma, poorly controlled with bronchodilator treatment PEFR
with budesonide Turbohaler 400 micrograms twice daily for 12 weeks
with placebo twice daily for 12 weeks
Difference from placebo: 0.50 L
P <0.001 		Effect size not calculated budesonide

RCT
3-armed trial 		309 adults, aged 18 to 70 years, with FEV1 >15% after 2 to 4 puffs of salbutamol (albuterol); included people taking (about 40%) and not taking (about 60%) inhaled corticosteroids FEV1 change from baseline
+0.12 L with budesonide Turbohaler 200 micrograms once daily for 6 weeks
+0.13 L with budesonide Turbohaler 400 micrograms once daily for 6 weeks
–0.03 L with placebo once daily for 6 weeks
P <0.01 for budesonide at either dose v placebo 		Effect size not calculated budesonide at either dose

RCT
4-armed trial 		267 adults with mild-to-moderate, non-steroid-dependent asthma PEFR change from baseline
0.14 L with budesonide Turbohaler 100 micrograms twice daily for 6 weeks
0.23 L with budesonide Turbohaler 200 micrograms twice daily for 6 weeks
0.28 L with budesonide Turbohaler 400 micrograms twice daily for 6 weeks
0.15 L with placebo twice daily for 6 weeks
Reported as not significant
P value not reported 		Not significant

RCT		 177 adults, aged 18 to 70 years, with non-steroid-dependent asthma FEV1 change from baseline
0.31 L with budesonide Turbohaler 400 micrograms once daily for 12 weeks
0.17 L with placebo
P = 0.007 		Effect size not calculated budesonide

RCT
3-armed trial 		698 people, aged >12 years, with mild asthma not taking corticosteroids
Subgroup analysis		 Change in FEV1 as % predicted
4.04% with budesonide 100 micrograms twice daily
5.87% with budesonide 100 micrograms plus formoterol 4.5 micrograms twice daily
P = 0.0001 		Effect size not calculated budesonide plus formoterol

Systematic review		 1352 adults with mild, moderate, or severe asthma
8 RCTs in this analysis		 FEV1
with fluticasone 100 micrograms or less once daily
with placebo once daily
Absolute results not reported
WMD 0.26 L
95% CI 0.21 L to 0.31 L
Significant improvements were also reported for fluticasone 200 micrograms once daily and 500 micrograms once daily, compared with placebo 		Effect size not calculated fluticasone

Systematic review		 1352 adults with mild, moderate, or severe asthma
8 RCTs in this analysis		 Morning PEFR
with fluticasone 100 micrograms or less once daily
with placebo once daily
WMD 22 L/minute
95% CI 18 L/minute to 26 L/minute
Significant improvements were also reported for fluticasone 200 micrograms once daily and 500 micrograms once daily, compared with placebo 		Effect size not calculated fluticasone

Systematic review		 256 adults
Data from 1 RCT		 FEV1
with beclometasone (beclomethasone) 400 micrograms or less once daily
with placebo once daily
WMD 0.40 L
95% CI 0.26 L to 0.54 L 		Effect size not calculated beclometasone

Systematic review		 764 adults
2 RCTs in this analysis		 Morning PEFR
with beclometasone (beclomethasone) 400 micrograms or less once daily
with placebo once daily
WMD 35.09 L/minute
95% CI 26.29 L/minute to 43.88 L/minute 		Effect size not calculated beclometasone

Systematic review		 1677 people
5 RCTs in this analysis		 Change in FEV1
with ciclesonide 100 micrograms/day or less
with placebo
0.08 L
95% CI 0.05 L to 0.11 L
Significant improvements were also reported for ciclesonide 200 micrograms/day and 400 micrograms/day, compared with placebo 		Effect size not calculated ciclesonide

Systematic review		 1677 people
5 RCTs in this analysis		 Change in a.m. PEFR
with ciclesonide 100 micrograms/day or less
with placebo
14 L/minute
95% CI 10 L/minute to 18 L/minute
Significant improvements were also reported for ciclesonide 200 micrograms/day and 400 micrograms/day, compared with placebo 		Effect size not calculated ciclesonide

Systematic review		 1677 people
5 RCTs in this analysis		 Change in p.m. PEFR
with ciclesonide 100 micrograms/day or less
with placebo
12 L/minute
95% CI 8 L/minute to 16 L/minute
Significant improvements were also reported for ciclesonide 200 micrograms/day and 400 micrograms/day, compared with placebo 		Effect size not calculated ciclesonide

RCT		 121 adults with mild-to-moderate asthma who were poorly controlled with beta2 agonists; about 50% were using an inhaled corticosteroid FEV1
2.6 L at baseline to 3.1 L at follow-up with triamcinolone acetonide 400 micrograms twice daily for 6 weeks
2.7 L at baseline to 2.8 L at follow-up with placebo twice daily for 6 weeks
P = 0.0001 		Effect size not calculated triamcinolone acetonide

RCT		 101 adults, aged 18 years or older, with mild-to-moderate asthma poorly controlled with beta2 agonist treatment Change in FEV1 from baseline
+17% with triamcinolone acetonide 400 micrograms twice daily for 6 weeks
–0.3% with placebo twice daily for 6 weeks
P = 0.0007 		Effect size not calculated triamcinolone acetonide

RCT
3-armed trial 		514 adults, aged 18 years or older, with FEV1 50% to 90% predicted Change in FEV1 from baseline
15.9% to 42.5% depending on dose and propellant (see other comment) with triamcinolone acetonide for 8 weeks
6.8% with placebo for 8 weeks
P <0.05 		Effect size not calculated triamcinolone acetonide

RCT
7-armed trial 		669 people, aged 12 years or older, with mild-to-moderate asthma taking inhaled corticosteroids Percentage increase in FEV1
12.2% with flunisolide with an HFA propellant 170 micrograms twice daily for 12 weeks
14.7% with flunisolide with an HFA propellant 340 micrograms twice daily for 12 weeks
5.4% with placebo twice daily for 12 weeks
P <0.01 for flunisolide at either dose v placebo 		Effect size not calculated flunisolide at either dose

RCT
7-armed trial 		669 people, aged 12 years or older, with mild-to-moderate asthma taking inhaled corticosteroids Percentage increase in FEV1
About 7% with flunisolide with a CFC propellant 250 micrograms twice daily for 12 weeks
About 10% with flunisolide with a CFC propellant 500 micrograms twice daily for 12 weeks
About 14.6% with flunisolide with a CFC propellant 1000 micrograms twice daily for 12 weeks
Absolute results reported graphically
Significance not assessed

RCT
4-armed trial 		227 people, aged 13 to 70 years, with moderate asthma, maintained on inhaled corticosteroids Change in FEV1
+0.12 L with mometasone furoate 100 micrograms delivered using dry powder inhaler twice daily for 12 weeks
+0.25 L with mometasone furoate 200 micrograms delivered using dry powder inhaler twice daily for 12 weeks
–0.11 L with placebo twice daily for 12 weeks
P <0.01

RCT
4-armed trial 		227 people, aged 13 to 70 years, with moderate asthma, maintained on inhaled corticosteroids Change in FEV1
+0.11 L with beclometasone (beclomethasone) dipropionate 168 micrograms twice daily for 12 weeks
–0.21 L with placebo twice daily for 12 weeks
P <0.01 		Effect size not calculated beclometasone

RCT
4-armed trial 		227 people, aged 13 to 70 years, with moderate asthma, maintained on inhaled corticosteroids Change in FEV1
7.4% with mometasone furoate 100 micrograms delivered using dry powder inhaler twice-daily for 12 weeks
14.0% with mometasone furoate 200 micrograms delivered using dry powder inhaler twice-daily for 12 weeks
6.5% with beclometasone (beclomethasone) dipropionate 168 micrograms twice daily for 12 weeks
Reported as not significant
P value not reported 		Not significant

RCT
3-armed trial 		262 adults, aged 18 to 82 years, with moderate persistent asthma previously using twice-daily inhaled corticosteroids Percentage change in FEV1
+8.9% with mometasone furoate 440 micrograms once daily by dry powder inhaler for 8 weeks
–3.9% with placebo for 8 weeks
P <0.01 		Effect size not calculated mometasone furoate

RCT
3-armed trial 		262 adults, aged 18 to 82 years, with moderate persistent asthma previously using twice-daily inhaled corticosteroids Percentage change in FEV1
8.9% with mometasone furoate 440 micrograms once daily by dry powder inhaler for 8 weeks
2.1% with budesonide 400 micrograms once daily for 8 weeks
P <0.01 		Effect size not calculated mometasone furoate

RCT		 196 adults and adolescents with mild-to-moderate persistent asthma, previously using only short-acting beta2 agonists Percentage change in FEV1
17% with mometasone furoate 200 micrograms once daily by dry powder inhaler for 12 weeks
6% with placebo for 12 weeks
P <0.01 		Effect size not calculated mometasone furoate

RCT		 708 people, aged 12 years and older, with mild-to-moderate persistent asthma not using an inhaled corticosteroid Mean change in FEV1 16 weeks
0.30 L with ciclesonide 80 micrograms twice daily
0.18 L with ciclesonide 160 micrograms once daily
0.19 L with ciclesonide 80 micrograms twice daily for 4 weeks/160 micrograms once daily for 12 weeks
0.07 L with placebo
Ciclesonide 80 micrograms: 95% CI 0.24 to 0.36
Ciclesonide 160 micrograms: 95% CI 0.12 to 0.24
Ciclesonide 80 micrograms/160 micrograms: 95% CI 0.12 to 0.25
Placebo: 95% CI 0.01 to 0.13
P <0.01 for ciclesonide at any dose v placebo 		Effect size not calculated ciclesonide at any dose

RCT		 708 people, aged 12 years and older, with mild-to-moderate persistent asthma not using an inhaled corticosteroid Mean change in PEFR a.m. 16 weeks
39.5 L/minute with ciclesonide 80 micrograms twice daily
26.7 L/minute with ciclesonide 160 micrograms once daily
34.1 L/minute with ciclesonide 80 micrograms twice daily for 4 weeks/160 micrograms once daily for 12 weeks
3.3 L/minute with placebo
ciclesonide 80 micrograms: 95% CI 30.0 to 49.0
ciclesonide 160 micrograms: 95% CI 0.17.3 to 36.0
ciclesonide 80 micrograms/160 micrograms: 95% CI 24.6 to 43.5
placebo: 95% CI –5.91 to +12.6
P <0.01 for ciclesonide at any dose v placebo 		Effect size not calculated ciclesonide at any dose
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No data from the following reference on this outcome.

Hospital admission

Compared with placebo Low-dose inhaled corticosteroids seem more effective at improving asthma-related events requiring admission or emergency treatment in people with mild, moderate, or severe asthma (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Hospital admission

RCT		 7241 children and adults, aged 5 to 66 years, with mild asthma and no previous corticosteroids Severe asthma-related event defined as needing admission or emergency treatment or death because of asthma about 2.4 years
with budesonide 400 micrograms once daily for adults and 200 micrograms once daily for children aged <11 years for about 2.4 years
with placebo for about 2.4 years
HR 0.56
95% CI 0.45 to 0.71 		Small effect size budesonide
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No data from the following reference on this outcome.

Quality of life

Compared with placebo Low-dose inhaled corticosteroids are more effective at improving quality of life in people with mild, moderate, or severe asthma (high-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Quality of life

RCT		 177 adults, aged 18 to 70 years, with non-steroid-dependent asthma Asthma Quality of Life Questionnaire scores 12 weeks
with budesonide Turbohaler 400 micrograms once daily for 12 weeks
with placebo
P <0.001 		Effect size not calculated budesonide

RCT		 184 adults, aged 18 to 70 years, having previous inhaled corticosteroid therapy for 16 weeks or longer at a constant dose before study entry Health-related QOL (mean change over time in Juniper's AQLQ, measured on a 7-point scale) week 4 and week 12
+0.29 with budesonide 400 micrograms once daily for 12 weeks
–0.29 with placebo for 12 weeks
P <0.001 		Effect size not calculated budesonide

Systematic review		 343 adults with asthma
2 RCTs in this analysis		 Health-related AQLQ (mean change over time in Juniper's AQLQ, measured on a 7-point scale) 12 weeks
with fluticasone 200 micrograms
with placebo
Absolute results not reported
Mean difference 0.65
95% CI 0.41 to 0.88 		Effect size not calculated fluticasone
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No data from the following reference on this outcome.

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

Systematic review		 Number of adults in this analysis not reported Adverse effects
with ciclesonide 100 micrograms/day or less
with placebo

RCT		 121 adults with mild-to-moderate asthma who were poorly controlled with beta2 agonists; about 50% were using an inhaled corticosteroid Adverse effects
with triamcinolone acetonide 400 micrograms twice daily for 6 weeks
with placebo twice daily for 6 weeks

RCT
3-armed trial 		514 adults, aged 18 years or older, with FEV1 50% to 90% predicted Adverse effects
with triamcinolone acetonide for 8 weeks
with placebo for 8 weeks

RCT
7-armed trial 		669 people, aged 12 years or older, with mild-to-moderate asthma taking inhaled corticosteroids Adverse effects
with flunisolide with a CFC or HFC propellant at 250 micrograms, 500 micrograms, or 1000 micrograms twice daily for 12 weeks (6 arms)
with placebo twice daily for 12 weeks

RCT
3-armed trial 		262 adults, aged 18 to 82 years, with moderate persistent asthma previously using twice daily inhaled corticosteroids Adverse effects
with mometasone furoate 440 micrograms once daily by dry powder inhaler for 8 weeks
with budesonide 400 micrograms once daily for 8 weeks

Systematic review		 892 people
2 RCTs in this analysis		 Proportion of people who had vertebral fractures
6/484 (1.2%) with conventional doses of inhaled corticosteroid
3/409 (0.7%) with placebo
OR 1.87
95% CI 0.50 to 7.03 		Not significant

Systematic review		 Number of people in this analysis not reported
27 RCTs in this analysis		 Adverse effects
with inhaled corticosteroids

RCT		 708 people, aged 12 years or older, with mild-to-moderate persistent asthma not using an inhaled corticosteroid Adverse effects 16 weeks
56% with ciclesonide 80 micrograms twice daily
53% with ciclesonide 160 micrograms once daily
58% with ciclesonide 80 micrograms twice daily/160 micrograms once daily
57% with placebo
Significance not assessed

Systematic review		 31 studies (24 RCTs), 216 estimates of cortisol suppression Cortisol suppression (% of baseline value)
18% with low inhaled corticosteroid use
27% with medium inhaled corticosteroid use
36% with high inhaled corticosteroid use
Significance not assessed
Oral candidiasis

Systematic review		 139 adolescents and adults with non-oral, corticosteroid-treated asthma Proportion of people who developed oral candidiasis
1/73 (1%) with budesonide 400–1000 micrograms once daily for 1 week to >6 months
0/66 (0%) with placebo once daily for 1 week to >6 months
RR 3.00
95% CI 0.13 to 68.57
The analysis is likely to have been underpowered to detect a clinically important difference between groups 		Not significant

Systematic review		 645 adults with mild, moderate, or severe asthma
4 RCTs in this analysis		 Oral candidiasis
with fluticasone 100 micrograms or less once daily
with placebo once daily
OR 4.84
95% CI 1.39 to 16.88 		Moderate effect size placebo

Systematic review		 2087 adults with mild, moderate, or severe asthma
10 RCTs in this analysis		 Oral candidiasis
with fluticasone 200 micrograms or less once daily
with placebo once daily
OR 4.09
95% CI 2.28 to 7.35 		Moderate effect size placebo

Systematic review		 1254 adults with mild, moderate, or severe asthma
7 RCTs in this analysis		 Oral candidiasis
with fluticasone 500 micrograms or less once daily
with placebo once daily
OR 5.17
95% CI 2.50 to 10.67 		Large effect size placebo

Systematic review		 392 adults and children
4 RCTs in this analysis		 Oral candidiasis
6/194 (3%) with beclometasone (beclomethasone) 400 micrograms or less to 1000 micrograms once daily
5/198 (3%) with placebo once daily
RR 1.71
95% CI 0.41 to 3.33 		Not significant

RCT		 196 adults and adolescents with mild-to-moderate persistent asthma, previously using only short-acting beta2 agonists Mild oral candidiasis
5% with mometasone furoate 200 micrograms once daily by dry powder inhaler for 12 weeks
1% with placebo for 12 weeks
Absolute numbers not reported
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No data from the following reference on this outcome.

Low-dose inhaled corticosteroids versus leukotriene antagonists:

See leukotriene antagonists in people with mild-to-moderate persistent asthma not taking inhaled corticosteroids.

Low-dose inhaled corticosteroids versus inhaled corticosteroids plus long-acting inhaled beta2 agonists:

See adding long-acting inhaled beta2 agonists to inhaled corticosteroids.

Low-dose inhaled corticosteroids versus inhaled corticosteroids plus theophylline:

See adding theophylline to inhaled corticosteroids.

Low-dose inhaled corticosteroids versus inhaled corticosteroids plus leukotriene antagonists:

See adding leukotriene antagonists to inhaled corticosteroids.

Further information on studies

None.

Comment

Clinical guide:

There is strong evidence that low-dose inhaled corticosteroids are as effective and safe as first controller therapy in people with persistent mild-to-moderate asthma. Two RCTs have found that inhaled corticosteroids delivered using chlorofluorocarbon-free propellants, such as hydrofluoroalkane, are effective at low doses for people with mild, persistent asthma, but dose equivalence varies with each delivery system. The dose of inhaled corticosteroid may need to be adjusted if a chlorofluorocarbon-free propellant is used. Even low doses of inhaled corticosteroids may be associated with decreases in cortisol levels; doses of inhaled corticosteroids used in clinical practice should be the minimum necessary to achieve and maintain asthma control.

Substantive changes

Low-dose inhaled corticosteroids in people with chronic asthma New evidence added. Categorisation unchanged (Beneficial).

BMJ Clin Evid. 2011 Jul 13;2011:1512.

Adding long-acting inhaled beta2 agonists to inhaled corticosteroids in people with mild-to-moderate chronic asthma that is poorly controlled by inhaled corticosteroids alone

Summary

Adding long-acting beta 2 agonists to inhaled corticosteroids decreases the number of exacerbations and improves symptoms, lung function, and quality of life in people with mild-to-moderate chronic asthma that is partly or poorly controlled with corticosteroids

CAUTION: Long-acting beta 2 agonists have been associated with increased asthma-related mortality, possibly by making asthma episodes more severe, and should always be used with inhaled corticosteroids.

Benefits and harms

Adding long-acting inhaled beta2 agonists to inhaled corticosteroids versus adding placebo to inhaled corticosteroids or versus inhaled corticosteroids alone:

We found one systematic review (search date 2008, 77 RCTs, 21,248 people, of whom 16,623 were adults), comparing adding long-acting beta2 agonists to inhaled corticosteroids versus adding placebo to inhaled corticosteroids or versus inhaled corticosteroids alone for 4 to 54 weeks. The review included RCTs of both adults and children. We found one systematic review (search date 2008, 57 RCTs, 48 in adults, 34,747 adults and children with asthma) that assessed the adverse effects associated with long-acting beta2 agonists in combination with inhaled corticosteroids compared with those associated with inhaled corticosteroids alone. We found one further systematic review (search date 2009, 26 RCTs, 62,815 people) specifically assessing the health risks associated with the long-acting beta2 agonist salmeterol compared with placebo when salmeterol was given alone. In many of the included trials, participants were taking concomitant inhaled corticosteroids so data are generalisable to combination treatment. We also found one systematic review (search date 2003, 22 RCTs, 353 people, mean trial duration 3 weeks) assessing respiratory tolerance (effects of beta2 agonist use on respiratory function and beta2 receptor function) in people taking short- or long-acting beta2 agonists alone, most not taking concomitant corticosteroids. These effects may also occur in people taking combination treatment so we report this review below.

Symptom severity (excluding lung function)

Compared with inhaled corticosteroids Adding long-acting inhaled beta2 agonists to inhaled corticosteroids seems more effective at reducing the risk of exacerbations (defined as reducing the need for systemic corticosteroids) and decreasing symptom-free and rescue-free days in people with poorly controlled asthma (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity (excluding lung function)

Systematic review		 6808 adults
30 RCTs in this analysis		 Risk of exacerbations (defined as the need for systemic corticosteroids)
423/1816 (23%) with adding long-acting beta2 agonists to inhaled corticosteroids
518/1809 (29%) with inhaled corticosteroids alone
RR 0.77
95% CI 0.68 to 0.87 		Small effect size adding long-acting beta2 agonists to inhaled corticosteroids

Systematic review		 2169 adults and adolescents
6 RCTs in this analysis		 Percentage of symptom-free days
with adding long-acting beta2 agonists to inhaled corticosteroids
with inhaled corticosteroids alone
WMD 7.31
95% CI 0.50 to 14.12 		Effect size not calculated adding long-acting beta2 agonists to inhaled corticosteroids

Systematic review		 409 adults and adolescents
Data from 1 RCT		 Rescue-free days
with adding long-acting beta2 agonists to inhaled corticosteroids
with inhaled corticosteroids alone
Mean difference 6.30
95% CI 1.2 to 11.40 		Effect size not calculated adding long-acting beta2 agonists to inhaled corticosteroids
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Lung function

Compared with inhaled corticosteroids Adding long-acting inhaled beta2 agonists to inhaled corticosteroids seems more effective at improving lung function (FEV1 and PEFR) at 4 to 54 weeks in people with poorly controlled asthma (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function

Systematic review		 4008 adults
14 RCTs in this analysis		 Change in FEV1
with adding long-acting beta2 agonists to inhaled corticosteroids
with inhaled corticosteroids alone
WMD 0.34
95% CI 0.26 to 0.42 		Effect size not calculated adding long-acting beta2 agonists to inhaled corticosteroids

Systematic review		 14,365 adults and adolescents
53 RCTs in this analysis		 Mean change in morning PEFR from baseline
37.4 L/minute with adding long-acting beta2 agonist formoterol 9 micrograms twice daily to the inhaled corticosteroid budesonide 320 micrograms twice daily for 12 weeks
4.5 L/minute with budesonide alone for 12 weeks
Mean difference 19.64 L/minute
95% CI 17.08 L/minute to 22.20 L/minute 		Effect size not calculated adding long-acting beta2 agonist to inhaled corticosteroid

Systematic review		 1787 people
8 RCTs in this analysis		 Morning PEFR at end point
38 L/minute with adding long-acting beta2 agonist salmeterol 50 micrograms to the inhaled corticosteroid fluticasone 250 micrograms twice daily via an inhaler for 12 months (95 people)
21 L/minute with fluticasone 250 micrograms alone twice daily via an inhaler for 12 months (95 people)
Mean difference 26.21 L/minute
95% CI 13.31 L/minute to 39.10 L/minute 		Effect size not calculated adding long-acting beta2 agonist to inhaled corticosteroid
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Hospital admission

No data from the following reference on this outcome.

Quality of life

No data from the following reference on this outcome.

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

Systematic review		 16,213 people
57 RCTs in this analysis		 Serious adverse events including respiratory
with long-acting beta2 agonist plus inhaled corticosteroids
with inhaled corticosteroids alone
RR 1.06
95% CI 0.87 to 1.30 		Effect size not calculated Not significant

Systematic review		 9505 people
38 RCTs in this analysis		 Withdrawal owing to poor asthma control or exacerbation
with long-acting beta2 agonists plus inhaled corticosteroids
with inhaled corticosteroids alone
RR 0.50
95% CI 0.41 to 0.61 		Small effect size long-acting beta2 agonists plus inhaled corticosteroids

Systematic review		 14,038 adults
52 RCTs in this analysis		 Withdrawal owing to adverse effects
with long-acting beta2 agonists plus inhaled corticosteroids
with inhaled corticosteroids alone
OR 1.04
95% CI 0.86 to 1.26 		Small effect size placebo

Systematic review		 353 people
22 RCTs in this analysis		 Peak FEV1 response to future beta2 agonist administration
with regular short- or long-acting beta2 agonists for longer than a week
with placebo
Absolute results not reported
WMD –17.8%
95% CI –27.2% to –8.5% 		Effect size not calculated placebo

Systematic review		 353 people
22 RCTs in this analysis		 FEV1 dose response to future beta2 agonist administration
with regular short- or long-acting beta2 agonists for longer than a week
with placebo
Absolute results not reported
WMD –34.8%
95% CI –45.7% to –24.0% 		Effect size not calculated placebo

Systematic review		 353 people
22 RCTs in this analysis		 Response to bronchoconstriction (as measured by 20% reduction in FEV1 [PC20])
with regular short- or long-acting beta2 agonists for longer than a week
with placebo
Absolute results not reported
WMD –26%
95% CI –37% to –11% 		Effect size not calculated placebo

Systematic review		 353 people
22 RCTs in this analysis		 Leukocyte receptor density
with regular short- or long-acting beta2 agonists for longer than a week
with placebo
WMD –18.3%
95% CI –31.6% to –5.1% 		Effect size not calculated placebo

Systematic review		 353 people
22 RCTs in this analysis		 Beta2 receptor binding affinity
with regular short- or long-acting beta2 agonists for longer than a week
with placebo
WMD –23.1%
95% CI –34.4% to –6.8% 		Effect size not calculated placebo
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Adding long-acting inhaled beta2 agonists to inhaled corticosteroids versus leukotriene antagonists alone:

See leukotriene antagonists.

Adding long-acting inhaled beta2 agonists to inhaled corticosteroids versus adding leukotriene antagonists to inhaled corticosteroids:

We found one systematic review (search date 2006, 11 RCTs, 6030 adults and adolescents who remained symptomatic despite being given inhaled corticosteroids [400–565 micrograms of beclometasone (beclomethasone) equivalent]) comparing adding the long-acting beta2 agonists (salmeterol or formoterol) versus adding the leukotriene antagonists (montelukast or zafirlukast) to inhaled corticosteroids over 4 to 48 weeks.

Symptom severity (excluding lung function)

Compared with adding leukotriene antagonists to inhaled corticosteroids Adding long-acting inhaled beta2 agonists to inhaled corticosteroids seems more effective at 4 to 48 weeks at decreasing the need for systemic corticosteroids, increasing the number of symptom-free days, and reducing the need for rescue medications in people with persistent and poorly controlled asthma (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity (excluding lung function)

Systematic review		 5571 adults and adolescents who remained symptomatic, despite being given inhaled corticosteroids (400–565 micrograms of beclometasone [beclomethasone] equivalent)
6 RCTs in this analysis		 Proportion of people with exacerbations (defined as the need for systemic corticosteroids)
251/2777 (9%) with adding long-acting beta2 agonists (salmeterol or formoterol) to inhaled corticosteroids over 4 to 48 weeks
305/2794 (11%) with adding leukotriene antagonists (montelukast or zafirlukast) to inhaled corticosteroids over 4 to 48 weeks
RR 0.83
95% CI 0.71 to 0.97
P = 0.02 		Small effect size adding long-acting beta2 agonists to inhaled corticosteroids

Systematic review		 2612 adults and adolescents who remained symptomatic, despite being given inhaled corticosteroids (400–565 micrograms of beclometasone [beclomethasone] equivalent)
5 RCTs in this analysis		 Rescue-free days: % change from baseline
with adding long-acting beta2 agonists (salmeterol or formoterol) to inhaled corticosteroids over 4 to 48 weeks
with adding leukotriene antagonists (montelukast or zafirlukast) to inhaled corticosteroids over 4 to 48 weeks
WMD 9.18%
95% CI 5.39% to 12.98%
P <0.00001 		Effect size not calculated adding long-acting beta2 agonists to inhaled corticosteroids

Systematic review		 2626 adults and adolescents who remained symptomatic, despite being given inhaled corticosteroids (400–565 micrograms of beclometasone [beclomethasone] equivalent)
5 RCTs in this analysis		 Symptom-free days: % change from baseline
with adding long-acting beta2 agonists (salmeterol or formoterol) to inhaled corticosteroids over 4 to 48 weeks
with adding leukotriene antagonists (montelukast or zafirlukast) to inhaled corticosteroids over 4 to 48 weeks
WMD 6.75%
95% CI 3.11% to 10.39%
P = 0.0003 		Effect size not calculated adding long-acting beta2 agonists to inhaled corticosteroids

Systematic review		 4055 adults and adolescents who remained symptomatic, despite being given inhaled corticosteroids (400–565 micrograms of beclometasone [beclomethasone] equivalent)
7 RCTs in this analysis		 Need for rescue medications
with adding long-acting beta2 agonists (salmeterol or formoterol) to inhaled corticosteroids over 4 to 48 weeks
with adding leukotriene antagonists (montelukast or zafirlukast) to inhaled corticosteroids over 4 to 48 weeks
WMD –0.49 puffs/day
95% CI –0.75 puffs/day to –0.24 puffs/day
P = 0.0001 		Effect size not calculated adding long-acting beta2 agonists to inhaled corticosteroids
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Lung function

Compared with adding leukotriene antagonists to inhaled corticosteroids Adding long-acting inhaled beta2 agonists to inhaled corticosteroids seems more effective at improving lung function (FEV1 and PEFR) in people with persistent and poorly controlled asthma (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function

Systematic review		 5669 adults and adolescents who remained symptomatic, despite being given inhaled corticosteroids (400–565 micrograms of beclometasone [beclomethasone] equivalent)
10 RCTs in this analysis		 Morning PEFR
with adding long-acting beta2 agonists (salmeterol or formoterol) to inhaled corticosteroids over 4 to 48 weeks
with adding leukotriene antagonists (montelukast or zafirlukast) to inhaled corticosteroids over 4 to 48 weeks
WMD 15.66 L/minute
95% CI 13.21 L/minute to 18.11 L/minute
P <0.00001 		Effect size not calculated adding long-acting beta2 agonists to inhaled corticosteroids

Systematic review		 3958 adults and adolescents who remained symptomatic, despite being given inhaled corticosteroids (400–565 micrograms of beclometasone [beclomethasone] equivalent)
9 RCTs in this analysis		 Evening PEFR
with adding long-acting beta2 agonists (salmeterol or formoterol) to inhaled corticosteroids over 4 to 48 weeks
with adding leukotriene antagonists (montelukast or zafirlukast) to inhaled corticosteroids over 4 to 48 weeks
WMD 12.09 L/minute
95% CI 9.26 L/minute to 14.29 L/minute
P <0.00001 		Effect size not calculated adding long-acting beta2 agonists to inhaled corticosteroids

Systematic review		 4485 adults and adolescents who remained symptomatic, despite being given inhaled corticosteroids (400–565 micrograms of beclometasone [beclomethasone] equivalent)
8 RCTs in this analysis		 FEV1
with adding long-acting beta2 agonists (salmeterol or formoterol) to inhaled corticosteroids over 4 to 48 weeks
with adding leukotriene antagonists (montelukast or zafirlukast) to inhaled corticosteroids over 4 to 48 weeks
WMD 0.08 L
95% CI 0.06 L to 0.10 L
P <0.00001 		Effect size not calculated adding long-acting beta2 agonists to inhaled corticosteroids
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Hospital admission

Compared with adding leukotriene antagonists to inhaled corticosteroids Adding long-acting inhaled beta2 agonists to inhaled corticosteroids seems equally effective at reducing hospital admissions in people with poorly controlled asthma (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Hospital admission

Systematic review		 3993 adults and adolescents who remained symptomatic, despite being given inhaled corticosteroids (400–565 micrograms of beclometasone [beclomethasone] equivalent)
4 RCTs in this analysis		 People with 1 or more exacerbations requiring hospital admission
13/1984 (0.7%) with adding long-acting beta2 agonists (salmeterol or formoterol) to inhaled corticosteroids over 4 to 48 weeks
10/2009 (0.5%) with adding leukotriene antagonists (montelukast or zafirlukast) to inhaled corticosteroids over 4 to 48 weeks
RR 1.31
95% CI 0.58 to 2.98
P = 0.5 		Not significant
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Quality of life

Compared with adding leukotriene antagonists to inhaled corticosteroids Adding long-acting inhaled beta2 agonists to inhaled corticosteroids seems more effective at improving quality of life scores in people with symptomatic asthma (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Quality of life

Systematic review		 2893 adults and adolescents who remained symptomatic, despite being given inhaled corticosteroids (400–565 micrograms of beclometasone [beclomethasone] equivalent)
3 RCTs in this analysis		 Global Asthma Quality of Life scores: change from baseline
with adding long-acting beta2 agonists (salmeterol or formoterol) to inhaled corticosteroids over 4 to 48 weeks
with adding leukotriene antagonists (montelukast or zafirlukast) to inhaled corticosteroids over 4 to 48 weeks
WMD 0.11
95% CI 0.05 to 0.17
P = 0.0006 		Effect size not calculated adding long-acting beta2 agonists to inhaled corticosteroids
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Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

Systematic review		 6225 adults and adolescents who remained symptomatic, despite being given inhaled corticosteroids (400–565 micrograms of beclometasone [beclomethasone] equivalent)
10 RCTs in this analysis		 Number of withdrawals because of adverse effects
117/3102 (4%) with adding long-acting beta2 agonists (salmeterol or formoterol) to inhaled corticosteroids over 4 to 48 weeks
115/3123 (4%) with adding leukotriene antagonists (montelukast or zafirlukast) to inhaled corticosteroids over 4 to 48 weeks
RR 1.02
95% CI 0.80 to 1.32
P = 0.9 		Not significant

Systematic review		 5911 adults and adolescents who remained symptomatic, despite being given inhaled corticosteroids (400–565 micrograms of beclometasone [beclomethasone] equivalent)
8 RCTs in this analysis		 Overall adverse events
1862/2945 (63%) with adding long-acting beta2 agonists (salmeterol or formoterol) to inhaled corticosteroids over 4 to 48 weeks
1822/2966 (61%) with adding leukotriene antagonists (montelukast or zafirlukast) to inhaled corticosteroids over 4 to 48 weeks
RR 1.03
95% CI 0.99 to 1.07
P = 0.1 		Not significant
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Adding long-acting inhaled beta2 agonists to inhaled corticosteroids versus adding theophylline to inhaled corticosteroids:

See adding theophylline to inhaled corticosteroids.

Adding long-acting inhaled beta2 agonists to inhaled corticosteroids versus increased inhaled corticosteroid dose:

We found two systematic reviews comparing the effects of adding long-acting beta2 agonists to inhaled corticosteroids versus increasing the dose of inhaled corticosteroids. The more recent systematic review (search date 2008, 47 RCTs, 40 in adults, 6 in children, 2 in adults and children; 15,155 people, 14,000 adults) performed a subgroup analysis of adults for one outcome only. All the RCTs in the first systematic review (search date 1999, 9 RCTs, 3685 people) were included in the more recent systematic review, but the first review included adults and adolescents only.

Symptom severity (excluding lung function)

Compared with increased inhaled corticosteroid dose Adding long-acting inhaled beta2 agonists to inhaled corticosteroids seems more effective at decreasing the number of exacerbations requiring systemic corticosteroids, improving symptoms, increasing symptom-free days, and reducing the need for rescue medications at 3 to 6 months in people with poorly controlled asthma (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity (excluding lung function)

Systematic review		 4140 adults with persistent asthma
13 RCTs in this analysis		 Number of people with exacerbations requiring systemic corticosteroids
295/2085 (14%) with adding long-acting beta2 agonists to inhaled corticosteroids for 1 month to 1 year
334/2055 (16%) with increased inhaled corticosteroid dose (at least double the usual dose) for 1 month to 1 year
RR 0.88
95% CI 0.76 to 1.01
P = 0.07 		Not significant

Systematic review		 9509 people (9342 adults) with persistent asthma
30 RCTs in this analysis		 Percentage of symptom-free days
with adding long-acting beta2 agonists to inhaled corticosteroids for 1 month to 1 year
with increased inhaled corticosteroid dose (at least double the usual dose) for 1 month to 1 year
WMD 11.9%
95% CI 7.37% to 16.44%
P <0.0001 		Effect size not calculated adding long-acting beta2 agonists to inhaled corticosteroids

Systematic review		 9509 people (9342 adults) with persistent asthma
30 RCTs in this analysis		 Daytime use of rescue beta2 agonists
with adding long-acting beta2 agonists to inhaled corticosteroids for 1 month to 1 year
with increased inhaled corticosteroid dose (at least double the usual dose) for 1 month to 1 year
WMD –0.99 puffs/day
95% CI –1.41 puffs/day to –0.58 puffs/day
P <0.0001 		Effect size not calculated adding long-acting beta2 agonists to inhaled corticosteroids

Systematic review		 3685 people with symptomatic asthma on their current dose of inhaled corticosteroids
9 RCTs in this analysis		 Days without symptoms 6 months
with adding regular doses of long-acting beta2 agonists (salmeterol or formoterol) to inhaled corticosteroids for 3 to 6 months
with increased inhaled corticosteroid dose (at least double the usual dose) for 3 to 6 months
WMD 15 days
95% CI 12 days to 18 days
P <0.001 		Effect size not calculated adding long-acting beta2 agonists to inhaled corticosteroids

Systematic review		 3685 people with symptomatic asthma on their current dose of inhaled corticosteroids
9 RCTs in this analysis		 Nights without symptoms 6 months
with adding regular doses of long-acting beta2 agonists (salmeterol or formoterol) to inhaled corticosteroids for 3 to 6 months
with increased inhaled corticosteroid dose (at least double the usual dose) for 3 to 6 months
WMD 5 nights
95% CI 3 nights to 7 nights
P <0.001 		Effect size not calculated adding long-acting beta2 agonists to inhaled corticosteroids

Systematic review		 3685 people with symptomatic asthma on their current dose of inhaled corticosteroids
9 RCTs in this analysis		 Mean percentage of days without need for rescue medication 3 months
with adding regular doses of long-acting beta2 agonists (salmeterol or formoterol) to inhaled corticosteroids for 3 to 6 months
with increased inhaled corticosteroid dose (at least double the usual dose) for 3 to 6 months
WMD 17%
95% CI 14% to 20%
P <0.001 		Effect size not calculated adding long-acting beta2 agonists to inhaled corticosteroids

Systematic review		 3685 people with symptomatic asthma on their current dose of inhaled corticosteroids
9 RCTs in this analysis		 Mean percentage of nights without need for rescue medication 3 months
with adding regular doses of long-acting beta2 agonists (salmeterol or formoterol) to inhaled corticosteroids for 3 to 6 months
with increased inhaled corticosteroid dose (at least double the usual dose) for 3 to 6 months
WMD 9%
95% CI 7% to 11%
P <0.001 		Effect size not calculated adding long-acting beta2 agonists to inhaled corticosteroids

Systematic review		 3685 people with symptomatic asthma on their current dose of inhaled corticosteroids
9 RCTs in this analysis		 Mean percentage of days without need for rescue medication 6 months
with adding regular doses of long-acting beta2 agonists (salmeterol or formoterol) to inhaled corticosteroids for 3 to 6 months
with increased inhaled corticosteroid dose (at least double the usual dose) for 3 to 6 months
WMD 20%
95% CI 17% to 23%
P <0.001 		Effect size not calculated adding long-acting beta2 agonists to inhaled corticosteroids

Systematic review		 3685 people with symptomatic asthma on their current dose of inhaled corticosteroids
9 RCTs in this analysis		 Mean percentage of nights without need for rescue medication 6 months
with adding regular doses of long-acting beta2 agonists (salmeterol or formoterol) to inhaled corticosteroids for 3 to 6 months
with increased inhaled corticosteroid dose (at least double the usual dose) for 3 to 6 months
WMD 8%
95% CI 6% to 11%
P <0.001 		Effect size not calculated adding long-acting beta2 agonists to inhaled corticosteroids

Systematic review		 3685 people with symptomatic asthma on their current dose of inhaled corticosteroids
9 RCTs in this analysis		 Exacerbations
with adding regular doses of long-acting beta2 agonists (salmeterol or formoterol) to inhaled corticosteroids for 3 to 6 months
with increased inhaled corticosteroid dose (at least double the usual dose) for 3 to 6 months
Absolute results reported graphically
P = 0.02 		Effect size not calculated adding long-acting beta2 agonists to inhaled corticosteroids
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Lung function

Compared with increased inhaled corticosteroid dose Adding long-acting inhaled beta2 agonists to inhaled corticosteroids seems more effective at improving lung function (FEV1 and PEFR) in people with poorly controlled asthma (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function

Systematic review		 9509 people (9342 adults) with persistent asthma
30 RCTs in this analysis		 FEV1
with adding long-acting beta2 agonists to inhaled corticosteroids for 1 month to 1 year
with increased inhaled corticosteroid dose (at least double the usual dose) for 1 month to 1 year
WMD 0.10 L
95% CI 0.07 L to 0.12 L
P <0.0001 		Effect size not calculated adding long-acting beta2 agonists to inhaled corticosteroids

Systematic review		 3685 people with symptomatic asthma on their current dose of inhaled corticosteroids
9 RCTs in this analysis		 Morning PEFR 3 months
with adding regular doses of long-acting beta2 agonists (salmeterol or formoterol) to inhaled corticosteroids for 3 to 6 months
with increased inhaled corticosteroid dose (at least double the usual dose) for 3 to 6 months
WMD 22 L/minute
95% CI 15 L/minute to 30 L/minute
P <0.001 		Effect size not calculated adding long-acting beta2 agonists to inhaled corticosteroids

Systematic review		 3685 people with symptomatic asthma on their current dose of inhaled corticosteroids
9 RCTs in this analysis		 Morning PEFR 6 months
with adding regular doses of long-acting beta2 agonists (salmeterol or formoterol) to inhaled corticosteroids for 3 to 6 months
with increased inhaled corticosteroid dose (at least double the usual dose) for 3 to 6 months
WMD 28 L/minute
95% CI 19 L/minute to 36 L/minute
P <0.001 		Effect size not calculated adding long-acting beta2 agonists to inhaled corticosteroids
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Hospital admission

No data from the following reference on this outcome.

Quality of life

No data from the following reference on this outcome.

Adverse effects

No data from the following reference on this outcome.

Further information on studies

The systematic review (search date 2008, 34,747 people with asthma; 9 RCTs included children and adolescents, 33 RCTs were of <12 weeks duration, 24 RCTs >12 weeks) found no significant difference in the incidence of asthma-related mortality between long-acting beta2 agonists in combination with corticosteroids and corticosteroids alone, although mortality was higher in people taking combination treatment (0.02% with beta2 agonists plus corticosteroids v 0% with corticosteroids alone; RR 2.96, 95% CI 1.21 to 12.14; P = 0.23; absolute numbers not reported).

The systematic review (search date 2008, 29,128 people) found no significant difference in all-cause mortality between salmeterol alone and placebo (44/15271 [0.3%] with salmeterol v 33/14983 [0.2%] with placebo; OR 1.33, 95% CI 0.85 to 2.08). However, the review was likely to have been underpowered to detect a clinically meaningful difference between groups in this outcome. The review found a significantly greater risk of asthma-related mortality in people taking salmeterol alone than in those taking placebo (13/13176 [0.09%] with salmeterol v 3/13179 [0.02%] with placebo; OR 3.49, 95% CI 1.31 to 9.31).

Comment

We found another RCT (475 people with persistent asthma) comparing adding long-acting inhaled beta2 agonists to inhaled corticosteroids versus inhaled corticosteroids alone. We have not reported this paper above as it did not meet Clinical Evidence reporting criteria of a maximum of 20% loss to follow-up of participants. The study consisted of a 2-week screening period on low-dose inhaled corticosteroids; a 4-week open-label fluticasone propionate 250 microgram twice-daily run-in period; followed by a 52-week double-blind period of fluticasone propionate/salmeterol 100/50 micrograms (239 participants) or fluticasone propionate 100 micrograms (236 participants); and, finally, 4 weeks' fluticasone propionate 250 microgram twice daily run-out period. It found no significant difference in asthma exacerbation rates between groups. Fluticasone propionate plus salmeterol significantly improved lung function measures and night-time awakenings compared with fluticasone propionate alone. Both fluticasone propionate plus salmeterol and fluticasone propionate alone were well-tolerated and showed similar safety profiles over the year of treatment.

Harms alerts:

The FDA has issued a safety alert requesting that product labels of long-acting beta2 agonists be updated to state that, although they decrease the frequency of asthma episodes, long-acting beta2 agonists may make asthma episodes more severe when they occur and may increase mortality when those episodes occur.

The FDA has issued a drug safety alert on the possible increased risk of neuropsychiatric events (mood and behavioural changes) associated with leukotriene inhibitors (montelukast, zafirlukast, and zileuton).

Clinical guide:

There is reasonable evidence that adding long-acting beta2 agonists to inhaled corticosteroids in adults with poorly controlled asthma is more effective than using inhaled corticosteroids alone, increasing the dose of inhaled corticosteroids, or adding leukotriene antagonists to inhaled corticosteroids. Most people taking inhaled corticosteroids who have partly controlled or uncontrolled asthma should be given long-acting beta2 agonists in addition to their inhaled corticosteroids, unless there are contraindications. Long-acting beta2 agonists have been associated with increased asthma-related mortality and should always be used with inhaled corticosteroids in fixed combinations.

Substantive changes

Adding long-acting inhaled beta2 agonists to inhaled corticosteroids in people with mild-to-moderate chronic asthma that is partly or poorly controlled by inhaled corticosteroids alone New evidence added. Categorisation unchanged (Beneficial).

BMJ Clin Evid. 2011 Jul 13;2011:1512.

Adding theophylline to inhaled corticosteroids in people with mild-to-moderate chronic asthma poorly controlled by inhaled corticosteroids alone

Summary

Adding theophylline to inhaled corticosteroids may improve lung function in people with mild or moderate chronic asthma that is poorly controlled with inhaled corticosteroids alone, but we don't know if they are of benefit compared with adding long-acting beta 2 agonists, adding leukotriene antagonists, or increasing corticosteroid dose.

Benefits and harms

Adding theophylline to inhaled corticosteroids versus adding placebo to inhaled corticosteroids or versus inhaled corticosteroids alone:

We found one RCT (155 people with persistent asthma that was poorly controlled with inhaled corticosteroids) comparing three treatments: continuing low-dose inhaled corticosteroids 200 micrograms twice daily plus placebo, continuing low-dose inhaled corticosteroids 200 micrograms twice daily plus slow-release theophylline 200 mg twice daily, and high-dose inhaled corticosteroids 500 micrograms twice daily.

Symptom severity (excluding lung function)

No data from the following reference on this outcome.

Lung function

Compared with adding placebo to inhaled corticosteroids Adding theophylline to low-dose corticosteroids may be more effective at improving morning and evening PEFR at 6 months in people with mild-to-moderate persistent asthma that is poorly controlled with inhaled corticosteroids (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function

RCT
3-armed trial 		155 people with persistent asthma that was poorly controlled with inhaled corticosteroids Mean change in morning PEFR 6 months
21.8 L/minute with continuing low-dose inhaled corticosteroids 200 micrograms twice daily plus slow-release theophylline 200 mg twice daily
4.4 L/minute with continuing low-dose inhaled corticosteroids 200 micrograms twice daily plus placebo
P value not reported

RCT
3-armed trial 		155 people with persistent asthma that was poorly controlled with inhaled corticosteroids Mean change in evening PEFR 6 months
22.5 L/minute with continuing low-dose inhaled corticosteroids 200 micrograms twice daily plus slow-release theophylline 200 mg twice daily
1.9 L/minute with continuing low-dose inhaled corticosteroids 200 micrograms twice daily plus placebo
P value not reported
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Hospital admission

No data from the following reference on this outcome.

Quality of life

No data from the following reference on this outcome.

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

RCT
3-armed trial 		155 people with persistent asthma that was poorly controlled with inhaled corticosteroids Adverse effects
with continuing low-dose inhaled corticosteroids 200 micrograms twice daily plus slow-release theophylline 200 mg twice daily
with continuing low-dose inhaled corticosteroids 200 micrograms twice daily plus placebo
with high-dose inhaled corticosteroids 500 micrograms twice daily
P >0.05 for all between-group comparisons 		Not significant
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Adding theophylline to inhaled corticosteroids versus adding long-acting beta2 agonists to inhaled corticosteroids:

We found one RCT (64 people with moderate persistent asthma poorly controlled using the inhaled corticosteroid budesonide with doses >800 micrograms/day) comparing the addition of theophylline, the leukotriene antagonist zafirlukast, or the long-acting beta2 agonist inhaled formoterol to budesonide.

Lung function

Compared with adding long-acting beta2 agonists to inhaled corticosteroids Adding theophylline to inhaled corticosteroids seems equally effective at improving lung function (FEV1 ) in people with moderate and persistent asthma that is poorly controlled (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function

RCT
3-armed trial 		64 people with moderate persistent asthma poorly controlled using the inhaled corticosteroid budesonide with doses >800 micrograms/day Mean improvement in % predicted FEV1 3 months
21% with adding theophylline to budesonide
23% with adding inhaled formoterol to budesonide
P >0.05 		Not significant
Open in a new tab

Hospital admission

No data from the following reference on this outcome.

Quality of life

No data from the following reference on this outcome.

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

RCT
3-armed trial 		64 people with moderate persistent asthma poorly controlled using the inhaled corticosteroid budesonide with doses >800 micrograms/day Adverse effects
20% with adding theophylline to budesonide
20% with adding inhaled formoterol to budesonide
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Adding theophylline to inhaled corticosteroids versus adding leukotriene antagonists to inhaled corticosteroids:

We found one RCT (64 people with moderate persistent asthma poorly controlled using the inhaled corticosteroid budesonide with doses >800 micrograms/day) comparing the addition of theophylline, the leukotriene antagonist zafirlukast, or the long-acting beta2 agonist inhaled formoterol to budesonide.

Lung function

Compared with adding leukotriene antagonists to inhaled corticosteroids We don't know whether adding theophylline to inhaled corticosteroids is more effective than adding the leukotriene antagonist zafirlukast to inhaled corticosteroids at improving lung function (FEV1) at 3 months in people with moderate persistent asthma that is not well controlled (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function

RCT
3-armed trial 		64 people with moderate persistent asthma poorly controlled using the inhaled corticosteroid budesonide with doses >800 micrograms/day Mean improvement in % predicted FEV1 3 months
21.4% with adding theophylline to budesonide
20.7% with adding zafirlukast to budesonide
P value not reported 		Not significant
Open in a new tab

Hospital admission

No data from the following reference on this outcome.

Quality of life

No data from the following reference on this outcome.

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

RCT
3-armed trial 		64 people with moderate persistent asthma poorly controlled using the inhaled corticosteroid budesonide with doses >800 micrograms/day Adverse effects
31% with adding theophylline to budesonide
20% with adding zafirlukast to budesonide
P value not reported
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Adding theophylline to inhaled corticosteroids versus increased inhaled corticosteroid dose:

We found two RCTs.

Symptom severity (excluding lung function)

Compared with increased dose of inhaled corticosteroids We don't know whether adding theophylline to low-dose inhaled corticosteroids is more effective at improving severity of daytime and night-time symptoms at 12 weeks in people with persistent asthma (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity (excluding lung function)

RCT		 66 people with persistent asthma not controlled by inhaled corticosteroids Severity of daytime symptoms 12 weeks
with adding theophylline 250 mg or 375 mg (depending on body weight) to budesonide 400 micrograms twice daily for 3 months
with high-dose budesonide (800 micrograms) plus placebo twice daily for 3 months
Absolute results reported graphically
P = 0.57
The study may have lacked power to detect clinically important differences 		Not significant

RCT		 66 people with persistent asthma not controlled by inhaled corticosteroids Severity of night-time symptoms 12 weeks
with adding theophylline 250 mg or 375 mg (depending on body weight) to budesonide 400 micrograms twice daily for 3 months
with high-dose budesonide (800 micrograms) plus placebo twice daily for 3 months
Absolute results reported graphically
P = 0.59
The study may have lacked power to detect clinically important differences 		Not significant
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No data from the following reference on this outcome.

Lung function

Compared with increasing the dose of inhaled corticosteroids Adding theophylline to inhaled corticosteroids seems no more effective at improving lung function (morning and evening PEFR) at 12 weeks in people with persistent asthma (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function

RCT
3-armed trial 		155 people with persistent asthma that was poorly controlled with inhaled corticosteroids Mean change in morning PEFR
21.8 L/minute with continuing low-dose inhaled corticosteroids 200 micrograms twice daily plus slow-release theophylline 200 mg twice daily
19.5 L/minute with high-dose inhaled corticosteroids 500 micrograms twice daily
Reported as not significant
P value not reported
The study may have lacked power to detect clinically important differences 		Not significant

RCT
3-armed trial 		155 people with persistent asthma that was poorly controlled with inhaled corticosteroids Mean change in evening PEFR
22.5 L/minute with continuing low-dose inhaled corticosteroids 200 micrograms twice daily plus slow-release theophylline 200 mg twice daily
8.3 L/minute with high-dose inhaled corticosteroids 500 micrograms twice daily
P value not reported
The study may have lacked power to detect clinically important differences 		Not significant

RCT		 66 people with persistent asthma not controlled by inhaled corticosteroids FEV1 12 weeks
with adding theophylline 250 mg or 375 mg (depending on body weight) to budesonide 400 micrograms twice daily for 3 months
with high-dose budesonide (800 micrograms) plus placebo twice daily for 3 months
Absolute results reported graphically
P = 0.03
The improvement in FEV1 was probably not clinically important; the study may have lacked power to detect clinically important differences 		Effect size not calculated adding theophylline

RCT		 66 people with persistent asthma not controlled by inhaled corticosteroids PEFR 12 weeks
with adding theophylline 250 mg or 375 mg (depending on body weight) to budesonide 400 micrograms twice daily for 3 months
with high-dose budesonide (800 micrograms) plus placebo twice daily for 3 months
Absolute results reported graphically
P = 0.16
The study may have lacked power to detect clinically important differences 		Not significant
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Hospital admission

No data from the following reference on this outcome.

Quality of life

No data from the following reference on this outcome.

Adverse effects

No data from the following reference on this outcome.

Further information on studies

Adding theophylline to inhaled corticosteroids versus adding leukotriene antagonists to inhaled corticosteroids: The RCT comparing the addition of theophylline, zafirlukast, or inhaled formoterol to budesonide found no significant difference between adding theophylline or adding zafirlukast in decreasing daily PEFR variability, daytime or night-time asthma symptoms, or in the mean number of rescue inhalations after 3 months. The RCT did not present results for asthma exacerbations.

Comment

Harms alerts:

The FDA has issued a drug safety alert on the possible increased risk of neuropsychiatric events (mood and behavioural changes) associated with leukotriene inhibitors (montelukast, zafirlukast, and zileuton).

We also found two systematic reviews comparing theophylline versus long-acting beta2 agonists. These reviews included RCTs of people in whom inhaled corticosteroid use was not required, poorly standardised, or not optimally titrated before study randomisation. We therefore excluded these reviews. We identified one study comparing oral theophylline versus inhaled formoterol, and this will be considered for inclusion once translated.

Clinical guide:

There is no clear evidence that using theophylline as add-on therapy in adults with poorly controlled asthma on inhaled corticosteroids is beneficial compared with increasing the dose of inhaled corticosteroids, or with adding long-acting beta2 agonists or leukotriene antagonists. Unless there are contraindications, most adults who have uncontrolled asthma on inhaled corticosteroids should initially be given long-acting beta2 agonists, leukotriene antagonists, or else the dose of inhaled corticosteroid should be increased. However, costs or locally available resources might be taken into consideration.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Jul 13;2011:1512.

Adding leukotriene antagonists to inhaled corticosteroids in people with mild-to-moderate chronic asthma

Summary

Adding leukotriene antagonists to inhaled corticosteroids is of benefit in people with chronic asthma.

CAUTION: Leukotriene antagonists have been associated with a possible increased risk of neuropsychiatric events.

Benefits and harms

Adding leukotriene antagonists to inhaled corticosteroids versus adding placebo to inhaled corticosteroids:

We found one systematic review (search date 2003, 11 RCTs in adults, 2 RCTs in children with symptomatic asthma on their current dose of inhaled corticosteroids, 2492 people) and one subsequent RCT comparing adding leukotriene antagonists to inhaled corticosteroids versus adding placebo to inhaled corticosteroids.

Symptom severity (excluding lung function)

Compared with adding placebo to inhaled corticosteroids Adding leukotriene antagonists to inhaled corticosteroids seems no more effective at 4 to 16 weeks at reducing asthma exacerbations in people with mild-to-moderate persistent asthma (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity (excluding lung function)

Systematic review		 988 adults or children with symptomatic asthma on their current dose of inhaled corticosteroids
3 RCTs in this analysis		 Proportion of people with exacerbations requiring systemic corticosteroids 4 to 16 weeks
22/493 (4%) with adding leukotriene antagonists at a licensed dose (montelukast 5 mg/day or 10 mg/day, pranlukast 450 mg/day, or zafirlukast 80 mg/day) to inhaled corticosteroids
35/495 (7%) with adding placebo to inhaled corticosteroids
RR 0.64
95% CI 0.38 to 1.07 		Not significant
Open in a new tab

No data from the following reference on this outcome.

Hospital admission

No data from the following reference on this outcome.

Quality of life

No data from the following reference on this outcome.

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

Systematic review		 816 adults or children with symptomatic asthma on their current dose of inhaled corticosteroids
3 RCTs in this analysis		 Liver enzyme elevation
14/410 (3%) with adding leukotriene antagonists at a higher than licenced dose to inhaled corticosteroids
2/406 (1%) with adding placebo to inhaled corticosteroids
RR 4.97
95% CI 1.45 to 17.00 		Moderate effect size adding placebo

Systematic review		 816 adults or children with symptomatic asthma on their current dose of inhaled corticosteroids
3 RCTs in this analysis		 Oral moniliasis
4/410 (1%) with adding leukotriene antagonists at a higher than licenced dose to inhaled corticosteroids
15/406 (4%) with adding placebo to inhaled corticosteroids
RR 0.29
95% CI 0.10 to 0.81 		Moderate effect size adding leukotriene antagonists

Systematic review		 Number of adults or children with symptomatic asthma on their current dose of inhaled corticosteroids in this analysis not reported Adverse effects
with adding leukotriene antagonists at a higher than licenced dose to inhaled corticosteroids
with adding placebo to inhaled corticosteroids
Reported as not significant
P value not reported 		Not significant
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Adding leukotriene antagonists to inhaled corticosteroids versus adding long-acting beta2 agonists to inhaled corticosteroids:

See adding long-acting inhaled beta2 agonists to inhaled corticosteroids.

Adding leukotriene antagonists to inhaled corticosteroids versus adding theophylline to inhaled corticosteroids:

See adding theophylline to inhaled corticosteroids.

Adding leukotriene antagonists to inhaled corticosteroids versus increasing inhaled corticosteroid dose:

We found one RCT (889 non-smokers, aged 15–75 years, poorly controlled with the inhaled corticosteroid budesonide 800 micrograms/day, baseline FEV1 69% predicted) comparing adding the leukotriene antagonist montelukast 10 mg daily to budesonide versus doubling the dose of budesonide to 1600 micrograms daily for 12 weeks.

Symptom severity (excluding lung function)

Compared with increasing inhaled corticosteroid dose Adding leukotriene antagonists to inhaled corticosteroids seems no more effective at decreasing daytime symptoms, nocturnal waking, and days with asthma exacerbations in people with mild-to-moderate persistent asthma (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity (excluding lung function)

RCT		 889 non-smokers, aged 15 to 75 years, poorly controlled with the inhaled corticosteroid budesonide 800 micrograms/day, baseline FEV1 69% predicted Change in daytime symptom score, on a scale from 0 (least severe) to 24 (most severe)
–0.34 with adding leukotriene antagonist montelukast 10 mg daily to budesonide for 12 weeks
–0.35 with doubling the dose of budesonide to 1600 micrograms daily for 12 weeks
P = 0.91 		Not significant

RCT		 889 non-smokers, aged 15 to 75 years, poorly controlled with the inhaled corticosteroid budesonide 800 micrograms/day, baseline FEV1 69% predicted Change in number of nights with nocturnal waking
12% to 2% with adding leukotriene antagonist montelukast 10 mg daily to budesonide for 12 weeks
14% to 4% with doubling the dose of budesonide to 1600 micrograms daily for 12 weeks
P = 0.35 		Not significant

RCT		 889 non-smokers, aged 15 to 75 years, poorly controlled with the inhaled corticosteroid budesonide 800 micrograms/day, baseline FEV1 69% predicted Median days with exacerbations
6.7% with adding leukotriene antagonist montelukast 10 mg daily to budesonide for 12 weeks
6.3% with doubling the dose of budesonide to 1600 micrograms daily for 12 weeks
P = 0.78 		Not significant
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Lung function

Compared with increasing inhaled corticosteroid dose Adding leukotriene antagonists to inhaled corticosteroids seems no more effective at improving PEFR in people with mild-to-moderate persistent asthma (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function

RCT		 889 non-smokers, aged 15 to 75 years, poorly controlled with the inhaled corticosteroid budesonide 800 micrograms/day, baseline FEV1 69% predicted Mean increase PEFR
33.5 L/minute with adding leukotriene antagonist montelukast 10 mg daily to budesonide for 12 weeks
30.1 L/minute with doubling the dose of budesonide to 1600 micrograms daily for 12 weeks
Difference +3.4 L/minute
95% CI –12.9 L/minute to +4.8 L/minute 		Not significant
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Hospital admission

No data from the following reference on this outcome.

Quality of life

Compared with increasing inhaled corticosteroid dose Adding leukotriene antagonists to inhaled corticosteroids seems no more effective at improving quality of life in people with mild-to-moderate persistent asthma (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Quality of life

RCT		 889 non-smokers, aged 15 to 75 years, poorly controlled with the inhaled corticosteroid budesonide 800 micrograms/day, baseline FEV1 69% predicted Absolute risk for increase in quality of life by 0.5 points or greater
about 43% with adding leukotriene antagonist montelukast 10 mg daily to budesonide for 12 weeks
about 40% with doubling the dose of budesonide to 1600 micrograms daily for 12 weeks
Reported as not significant
P value not reported 		Not significant
Open in a new tab

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

RCT		 889 non-smokers, aged 15 to 75 years, poorly controlled with the inhaled corticosteroid budesonide 800 micrograms/day, baseline FEV1 69% predicted Adverse effects 12 weeks
with adding leukotriene antagonist montelukast 10 mg daily to budesonide for 12 weeks
with doubling the dose of budesonide to 1600 micrograms daily for 12 weeks
Not significant 		Not significant
Open in a new tab

Further information on studies

None.

Comment

Harms alerts:

The FDA has issued a drug safety alert on the possible increased risk of neuropsychiatric events (mood and behavioural changes) associated with leukotriene inhibitors (montelukast, zafirlukast, and zileuton).

Clinical guide:

There is no clear evidence that adding long-acting leukotriene antagonists to inhaled corticosteroids in adults with poorly controlled asthma is beneficial compared with increasing the dose of inhaled corticosteroids, or with the addition of long-acting beta2 agonists, or placebo. Unless there are contraindications, most adults who have uncontrolled asthma despite using inhaled corticosteroids should initially be offered long-acting beta2 agonists, or the dose of inhaled corticosteroid should be increased.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Jul 13;2011:1512.

Adding anti-IgE treatment to inhaled corticosteroids plus long-acting beta2 agonists plus either leukotriene antagonists, theophylline, or oral corticosteroids, alone or in any combination, in people with severe, chronic asthma

Summary

Anti-IgE treatment (omalizumab) as an adjunct to treatment with inhaled and oral corticosteroids improves symptom severity, decreases exacerbation frequency, decreases the use of inhaled corticosteroid therapy, and may decrease hospital admission rates in people with chronic moderate to severe asthma.

Benefits and harms

Adding anti-IgE treatment versus adding placebo to inhaled corticosteroids plus long-acting beta2 agonists plus either leukotriene antagonists, theophylline, or oral corticosteroids, alone or in any combination:

We found one systematic review (search date 2006; 14 parallel RCTs; 3143 adults, adolescents, and children with mild-to-severe allergic asthma). Seven trials in the review compared the anti-IgE monoclonal antibody omalizumab as an adjunct to treatment with inhaled and oral corticosteroids versus treatment with corticosteroids alone. We found one subsequent RCT from Japan comparing anti-IgE monoclonal antibody omalizumab as an adjunct to treatment with inhaled and oral corticosteroids and other treatments. We also found one additional RCT from Brazil that specifically assessed the safety of the anti-IgE monoclonal antibody omalizumab in people with asthma at risk of geohelminth infection.

Symptom severity (excluding lung function)

Compared with on-going asthma therapy including inhaled and oral corticosteroids The anti-IgE monoclonal antibody omalizumab seems more effective at improving symptoms and reducing exacerbations and the need for short-acting bronchodilators in people with moderate or severe asthma, both as an adjunctive or corticosteroid-sparing strategy (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity (excluding lung function)

Systematic review		 1317 people
3 RCTs in this analysis		 Change in symptoms score 12 to 28 weeks (stable corticosteroid phase)
with anti-IgE monoclonal antibody given subcutaneously as add-on to corticosteroid therapy
with placebo as add-on to corticosteroid therapy
Absolute results not reported
Mean difference –0.46
95% CI –0.63 to –0.29 		Effect size not calculated anti-IgE

Systematic review		 2151 people
6 RCTs in this analysis		 Number of people with at least one exacerbation 12 to 28 weeks (stable corticosteroid phase)
with anti-IgE monoclonal antibody given subcutaneously as add-on to corticosteroid therapy
with placebo as add-on to corticosteroid therapy
Absolute results not reported
OR 0.55
95% CI 0.45 to 0.69 		Small effect size anti-IgE

Systematic review		 1726 people
5 RCTs in this analysis		 Number of people with at least one exacerbation 12 to 16 weeks (corticosteroid tapering phase)
with anti-IgE monoclonal antibody given subcutaneously as add-on to corticosteroid therapy
with placebo as add on to corticosteroid therapy
Absolute results not reported
OR 0.50
95% CI 0.39 to 0.63 		Small effect size anti-IgE

Systematic review		 1799 people
5 RCTs in this analysis		 Change in rescue medication (puffs/day) 12 to 28 weeks (stable corticosteroid phase)
with anti-IgE monoclonal antibody given subcutaneously as add-on to corticosteroid therapy
with placebo as add-on to corticosteroid therapy
Absolute results not reported
Mean difference –0.68
95% CI –0.99 to –0.36 		Effect size not calculated anti-IgE

Systematic review		 1373 people
4 RCTs in this analysis		 Change in rescue medication (puffs/day) 12 to 16 weeks (corticosteroid tapering phase)
with anti-IgE monoclonal antibody given subcutaneously as add-on to corticosteroid therapy
with placebo as add-on to corticosteroid therapy
Absolute results not reported
WMD –0.74
95% CI –1.05 to –0.43 		Effect size not calculated anti-IgE

RCT		 315 people, aged 20 to 75 years, with uncontrolled asthma Proportion of people with an exacerbation 16 weeks
6/151 (4%) with anti-IgE monoclonal antibody given subcutaneously as add-on to on-going asthma therapy
18/164 (11%) with placebo given as on-going asthma therapy
P = 0.019 		Moderate effect size anti-IgE
Need for rescue medication of oral or inhaled corticosteroid use

Systematic review		 1634 people
4 RCTs in this analysis		 Complete inhaled corticosteroid withdrawal 12 to 16 weeks (steroid tapering phase)
with omalizumab
with placebo
Absolute results not reported
OR 2.50
95% CI 2.00 to 3.13 		Moderate effect size adding anti IgE treatment

Systematic review		 1634 people
4 RCTs in this analysis		 Greater than 50% inhaled corticosteroid reduction 12 to 16 weeks (steroid tapering phase)
with omalizumab
with placebo
Absolute results not reported
OR 2.50
95% CI 2.02 to 3.10 		Moderate effect size adding anti IgE treatment

Systematic review		 95 people
Data from 1 RCT		 Complete oral corticosteroid withdrawal 12 to 16 weeks (steroid tapering phase)
with omalizumab
with placebo
Absolute results not reported
OR 1.18
95% CI 0.53 to 2.63 		Not significant

Systematic review		 95 people
Data from 1 RCT		 Median reduction daily oral corticosteroid dose 12 to 16 weeks (steroid tapering phase)
69% with omalizumab
75% with placebo
Absolute results not reported
P = 0.675 		Not significant
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No data from the following reference on this outcome.

Lung function

Compared with on-going asthma therapy including inhaled and oral corticosteroids Addition of the anti-IgE monoclonal antibody omalizumab does not seem to improve lung function (FEV1 and PEFR) in people with moderate or severe asthma (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function

Systematic review		 1651 people
4 RCTs in this analysis		 Peak expiratory flow rate (a.m.) 12 to 28 weeks (stable corticosteroid phase)
with anti-IgE monoclonal antibody given subcutaneously as add-on to corticosteroid therapy
with placebo as add-on to corticosteroid therapy
Absolute results not reported
Mean difference +3.56
95% CI –5.05 to +12.18 		Not significant

Systematic review		 1071 people
2 RCTs in this analysis		 FEV1 12 to 28 weeks (stable corticosteroid phase)
with anti-IgE monoclonal antibody given subcutaneously as add-on to corticosteroid therapy
with placebo as add-on to corticosteroid therapy
Absolute results not reported
Mean difference +68.31 mL
95% CI –23.45 mL to +160 mL 		Not significant

RCT		 315 people, 20 to 75 years of age, with uncontrolled asthma Peak expiratory flow rate (a.m.), change from baseline 16 weeks
15.45 L/minute with anti-IgE monoclonal antibody given subcutaneously as add-on to on-going asthma therapy.
2.25 L/minute with on-going asthma therapy
Mean difference 13.19 L/minute
95% CI 5.93 L/minute to 20.46 L/minute
P <0.001 		Effect size not calculated anti-IgE

RCT		 315 people, aged 20 to 75 years, with uncontrolled asthma Change from baseline in FEV1 16 weeks
Increased by 39 mL compared with baseline with anti-IgE monoclonal antibody given subcutaneously as add-on to on-going asthma therapy
Decreased by –24 mL compared with baseline with on-going asthma therapy
Mean difference 63 mL
P = 0.03 		Effect size not calculated anti-IgE
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Hospital admission

Compared with on-going asthma therapy including inhaled and oral corticosteroids Addition of the anti-IgE monoclonal antibody omalizumab may reduce asthma exacerbations requiring hospital admission in people with moderate or severe asthma (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Hospital admission

Systematic review		 1405 people
3 RCTs in this analysis		 Exacerbations requiring hospital admission 12 to 16 weeks (corticosteroid tapering phase)
with anti-IgE monoclonal antibody given subcutaneously as add-on to on-going corticosteroid therapy
with on-going corticosteroid therapy
Absolute results not reported
OR 0.11
95% CI 0.03 to 0.48 		Moderate effect size Anti-IgE
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No data from the following reference on this outcome.

Quality of life

Compared with on-going asthma therapy including inhaled and oral corticosteroids Addition of the anti-IgE monoclonal antibody omalizumab may be more effective at improving asthma-related quality of life (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Quality of life

Systematic review		 2131 people
5 RCTs in this analysis		 AQLQ scores 12 to 28 weeks (stable corticosteroid phase)
with anti-IgE monoclonal antibody given subcutaneously as add-on to on-going corticosteroid therapy
with on-going corticosteroid therapy
Absolute results not reported
Mean difference 0.32
95% CI 0.22 to 0.43 		Moderate effect size Anti-IgE
Open in a new tab

No data from the following reference on this outcome.

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

Systematic review		 1531 people
4 RCTs in this analysis		 Proportion of people who developed urticaria
with anti-IgE monoclonal antibody given subcutaneously
with placebo injection
Absolute results not reported
OR 0.93
95% CI 0.38 to 2.30 		Not significant

Systematic review		 1679 people
4 RCTs in this analysis		 Proportion of people who developed injection site reactions
with anti-IgE monoclonal antibody given subcutaneously
with placebo injection
Absolute results not reported
OR 2.00
95% CI 1.37 to 2.92 		Small effect size placebo

Systematic review		 1652 people
4 RCTs in this analysis		 Proportion of withdrawals owing to adverse events
with anti-IgE monoclonal antibody given subcutaneously
with placebo injection
Absolute results not reported
OR 0.53
95% CI 0.21 to 1.32 		Not significant

RCT		 315 people, 20 to 75 years of age, uncontrolled asthma Proportion of people who developed injection site reactions 16 weeks
36/151 (24%) with anti-IgE monoclonal antibody given subcutaneously
17/164 (10%) with placebo injection

RCT		 137 people, 2 to 30 years of age at risk of geohelminth infection Proportion of people with at least 1 episode of intestinal geohelminth infection 52 weeks
34/68 (50%) with anti-IgE monoclonal antibody given subcutaneously
28/69 (41%) with placebo injection
OR 2.2 (adjusted by study visit, baseline infection, sex, and age)
95% CI 0.94 to 5.15
P value (one sided) = 0.035
P <0.025 excessive risk of developing infection 		Small effect size placebo
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Further information on studies

Most trials in this review examined the effect on adults and adolescents aged >12 years. Severity of asthma varied within and between studies. Most trials recruited patients with moderate to severe allergic asthma based on BTS criteria. All trials required positivity of skin tests to common aero-allergens and threshold ranges of IgE levels. This review analysed the effects of adding anti-IgE monoclonal antibody treatment to participants' on-going asthma therapy and on the need participants had for oral or inhaled corticosteroids. They found that adding anti-IgE monoclonal antibody treatment to on-going asthma therapy increased the rates of complete inhaled corticosteroid withdrawal after 12 to 16 weeks, and led to an increase in the number of participants who reduced their inhaled corticosteroid intake by >50%. There was no significant difference between treatment groups for complete oral corticosteroid withdrawal or for median reduction in daily oral corticosteroid use.

In this trial, "on-going asthma therapy" was defined as treatment with beclometasone (beclomethasone) dipropionate chlorofluorocarbon (CFC), containing a metered-dose inhaler of at least 800 micrograms daily (or equivalent) and one or more of the following additional controller medications: long-acting beta2 agonist, sustained-release theophylline, leukotriene receptor antagonist, and oral corticosteroid.

Comment

Clinical guide:

Anti-IgE treatment (omalizumab) as an adjunct to treatment with inhaled and oral corticosteroids is effective at improving symptoms and decreasing exacerbations, as well as decreasing or withdrawing inhaled corticosteroid therapy. In severe asthmatic patients on oral corticosteroids, it may not be able to decrease their use. Additionally, it is not clear if it is more clinically beneficial or cost effective when compared with other available treatment options identified in current treatment guidelines, such as inhaled corticosteroids plus long-acting beta2 agonists plus either leukotriene antagonists or theophylline, alone or in combination.

Controlled trials and an unpublished observational study show an infrequent but numerical increase in arterial thrombotic events associated with the use of omalizumab. While this finding is not currently statistically significant, prescribers are advised to be vigilant for possible thrombotic adverse reactions (http://www.mhra.gov.uk/home/groups/dsu/documents/publication/con108718.pdf).

Substantive changes

Adding anti-IgE treatment to inhaled corticosteroids plus long-acting beta2 agonists plus either leukotriene antagonists, theophylline, or oral corticosteroids, alone or in any combination, in people with severe, chronic asthma New option added. Categorised as Likely to be beneficial.

Articles from BMJ Clinical Evidence are provided here courtesy of BMJ Publishing Group

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