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Ducharme FM, Ni Chroinin M, Greenstone I, Lasserson TJ. Addition of long-acting beta2-agonists to inhaled steroids versus higher dose inhaled steroids in adults and children with persistent asthma. Cochrane Database of Systematic Reviews 2010, Issue 4.

Efficacy Endpoints

Asthma attack prevention

Harm Endpoints

Increased asthma attacks, death

Narrative

Long-acting beta-agonists (LABAs) are designed to keep smooth muscle in the airways constantly relaxed, and they are the novel ingredient in the combination inhalers Advair® and Symbicort®. Unfortunately, these LABA medicines are proven to increase severe asthma attacks and asthma-related deaths and thus fell out of favor, most markedly after the 'SMART trial' published in 2006.1 Despite this, it is still felt by some that if the LABAs could be combined with steroids this might reduce any danger by providing steroid protection. This could theoretically allow the two medicines to work side-by-side to improve asthma control safely. While no one has suggested this as a first line therapy (inhaled steroids are first line), it has been suggested as a therapy when a first attempt to use inhaled steroids is inadequate.

This review examined 48 trials including over 33,000 subjects in an attempt to determine if there is a benefit to the combination LABA/steroid inhalers over simply increasing the dose of inhaled steroids. The combination medicine successfully reduced the chances of mild to moderate asthma attacks for about 1 in every 73 people using them. This effect depended heavily upon the severity of the asthma attack. For study subjects with a nearly 20% (1 in 5) chance of an asthma attack requiring pills in the next three months the benefit was 1 in every 45 people. But if the chance was only 1% then only 1 in every 673 people benefited. Thus the more severe the asthma, the more likely the benefit.

The combination therapy reduced general daily symptoms of asthma as well, but by very little. Quality of life was the same, and the symptom reductions were not clinically important.

However, large reviews suggest that there is a danger with using the combination of LABA and inhaled steroids for asthma maintenance. 2,3 These reviews vary in their findings only slightly, and suggest that approximately for 1 out of 140 people taking the combined therapy in trials the LABA/steroids combination caused a severe asthma attack. For 1 in every 1400 the combination seems to have caused an asthma-related death.

Caveats

While most asthma patients use their inhaler medications for months and years, the benefits of the combination inhaler were tested in predominantly 12-week trials, thus there may be less or more benefit when their use is extended.

The symptom reductions in these trials that were found with combination therapy were very small. Typically the therapy led to 0.5 pumps/day fewer uses of the rescue (beta-agonist) inhaler, and about 10% more 'symptom-free days' during the 12-week study periods. Despite these findings there was no 'Quality of Life' advantage. However, these advantages may be greater if the asthma is more severe. This may be a consideration for patients with severe relapsing asthma that leads to multiple hospital admissions. On the other hand, these patients may also be at highest risk for a fatal or severe attack, which would make LABA medicines potentially dangerous. This difficult balance will have to be struck by physicians and patients in concert based on symptoms, risk thresholds, and patient values.

Of the 48 trials represented in this review, 44 were sponsored by the pharmaceutical maker of the combination therapy. A long history of misrepresentation of data and occasionally fraudulent reporting of data suggests that industry sponsored results are often more optimistic than subsequent data produced by researchers and parties that do not have a financial stake in the results.

We have chosen to designate this therapy RED (no benefits) rather then BLACK (harms>benefits) because of the small benefit and the possibility of a trade-off of harms and benefits that may be worthwhile based on individual circumstances. In addition, while asthma-related deaths increase, all-cause mortality was unchanged in the reviewed studies, making the overall harm impact less definitive in terms of fatalities.

Author

David Newman, MD

Published/Updated

May 16, 2011