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

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

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

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

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

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

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

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

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

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

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

Authors' conclusions: 

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

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

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

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

Read the full abstract...
Background: 

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

Objectives: 

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

Search strategy: 

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

Selection criteria: 

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

Data collection and analysis: 

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

Main results: 

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

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

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

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

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