In people with asthma are single inhalers that contain both formoterol and budesonide better than current best practice?


Background to the review
‘Single inhaler therapy’ means that a single inhaler containing two drugs is used. One of these drugs acts quickly and is called the "reliever". The other works much more slowly and is called the "preventer". The reliever is a beta-agonist bronchodilator, which help to open the airways and help people breathe more easily. The preventer is a steroid that controls the underlying inflammation in the lungs, which is caused by the asthma. People on 'single inhaler therapy' (SiT) have one inhaler for use every day to control their underlying inflammation and also for symptom relief. The idea behind SiT is that when people take their inhalers to reduce their shortness of breath or wheezing they will also be getting an increased dose of the steroid preventer.

We wanted to discover whether using the SiT was better or worse than alternatives, such as receiving two separate inhalers for regular treatment and relief of symptoms.

What did we do?
We reviewed the clinical trials that looked at SiT against inhaled steroids and reliever medication given as two separate inhalers (sometimes called current best practice).

What did we find out?
We found 13 trials on 13,152 adults and one trial also included 224 children, up to February 2013. The trials were all sponsored by the manufacturer of the single inhaler.

When compared with current best practice or higher doses of inhaled steroid, we found that SiT probably reduces the number of flare-ups that will need treatment with an oral steroid in adults but we are uncertain whether the number of adults admitted to hospital would be reduced. When compared with high doses of inhaled steroids, we found that fewer people experienced a flare-up that needed treatment with an oral steroid.

The results for death (1 per 1000 people given either treatment), or life threatening problems (just under 50 per 1000 people given either treatment), were too imprecise to enable us to rule out either treatment being more harmful than the other. More adults left the trial early because they experienced adverse effects in the group taking single inhalers. There was only one small trial in children, so we are unable to make any firm conclusions in children.

The studies were generally well-designed, although in the studies which compared SiT against current best practice people knew which treatment they were getting, and this could have affected the reliability of the results. The studies comparing SiT against inhaled steroids were designed differently and were more reliable. Overall, we think that more evidence from future trials might change the strength of the conclusions for the question of whether SiT is better than current best practice. We believe that there is good quality evidence that SiT is more effective than high dose inhaled steroids, although the studies recruited people who were likely to respond.

Authors' conclusions: 

Single inhaler therapy has now been demonstrated to reduce exacerbations requiring oral corticosteroids against current best practice strategies and against a fixed higher dose of inhaled steroids. The strength of evidence that SiT reduces hospitalisation against these same treatments is weak. There were more discontinuations due to adverse events on SiT compared to current best practice, but no significant differences in serious adverse events. Our confidence in these conclusions is limited by the open-label design of the trials, and by the unknown adherence to treatment in the current best practice arms of the trials.

Single inhaler therapy can reduce the risk of asthma exacerbations needing oral corticosteroids in comparison with fixed dose maintenance ICS and separate relief medication. The reduced odds of exacerbations with SiT compared with higher dose ICS should be viewed in the context of the possible impact of LABA withdrawal during study run-in. This may have made the study populations more likely to respond to SiT.

Single inhaler therapy is not currently licensed for children under 18 years of age in the United Kingdom and there is currently very little research evidence for this approach in children or adolescents.

Read the full abstract...
Background: 

Traditionally inhaled treatment for asthma has used separate preventer and reliever therapies. The combination of formoterol and budesonide in one inhaler has made possible a single inhaler for both prevention and relief of symptoms (single inhaler therapy or SiT).

Objectives: 

To assess the efficacy and safety of budesonide and formoterol in a single inhaler for maintenance and reliever therapy in asthma compared with maintenance with inhaled corticosteroids (ICS) (alone or as part of current best practice) and any reliever therapy.

Search strategy: 

We searched the Cochrane Airways Group trials register in February 2013.

Selection criteria: 

Parallel, randomised controlled trials of 12 weeks or longer in adults and children with chronic asthma. Studies had to assess the combination of formoterol and budesonide as SiT, against a control group that received inhaled steroids and a separate reliever inhaler.

Data collection and analysis: 

We used standard methodological procedures expected by Cochrane.

Main results: 

We included 13 trials involving 13,152 adults and one of the trials also involved 224 children (which have been separately reported). All studies were sponsored by the manufacturer of the SiT inhaler. We considered the nine studies assessing SiT against best practice to be at a low risk of selection bias, but a high risk of detection bias as they were unblinded.

In adults whose asthma was not well-controlled on ICS, the reduction in hospital admission with SiT did not reach statistical significance (Peto odds ratio (OR) 0.81; 95% confidence interval (CI) 0.45 to 1.44, eight trials, N = 8841, low quality evidence due to risk of detection bias in open studies and imprecision). The rates of hospital admission were low; for every 1000 people treated with current best practice six would experience a hospital admission over six months compared with between three and eight treated with SiT. The odds of experiencing exacerbations needing treatment with oral steroids were lower with SiT compared with control (OR 0.83; 95% CI 0.70 to 0.98, eight trials, N = 8841, moderate quality evidence due to risk of detection bias). For every 100 adults treated with current best practice over six months, seven required a course of oral steroids, whilst for SiT there would be six (95% CI 5 to 7). The small reduction in time to first severe exacerbation needing medical intervention was not statistically significant (hazard ratio (HR) 0.94; 95% CI 0.85 to 1.04, five trials, N = 7355). Most trials demonstrated a reduction in the mean total daily dose of ICS with SiT (mean reduction was based on self-reported data from patient diaries and ranged from 107 to 385 µg/day). Withdrawals due to adverse events were more common in people treated with SiT in comparison to current best practice (OR 2.85; 95% CI 1.89 to 4.30, moderate quality evidence due to risk of detection bias).

Three studies including 4209 adults compared SiT with higher dose budesonide maintenance and terbutaline for symptom relief. The studies were considered as low risk of bias. The run-in for these studies involved withdrawal of LABA, and patients were recruited who were symptomatic during run-in. The reduction in the odds of hospitalisation with SiT compared with higher dose ICS did not reach statistical significance (Peto OR; 0.56; 95% CI 0.28 to 1.09, moderate quality evidence due to imprecision). Fewer patients on SiT needed a course of oral corticosteroids (OR 0.54; 95% CI 0.45 to 0.64, high quality evidence). For every 100 adults treated with ICS over 11 months, 18 required a course of oral steroids, whilst for SiT there would be 11 (95% CI 9 to 12). Withdrawals due to adverse events were less common in people treated with SiT in comparison to higher dose budesonide maintenance (OR 0.57; 95% CI 0.35 to 0.93, high quality evidence).

One study included children (N = 224), in which SiT was compared with higher dose budesonide. There was a significant reduction in participants who needed an increase in their inhaled steroids with SiT, but there were only two hospitalisations for asthma and no separate data on courses of oral corticosteroids. Less inhaled and oral corticosteroids were used in the SiT group and the annual height gain was also 1 cm greater in the SiT group, (95% CI 0.3 cm to 1.7 cm).

The results for fatal serious adverse events were too rare to rule out either treatment being harmful. There was no significant difference found in non-fatal serious adverse events for any of the comparisons.

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