Safe use of long-acting β-agonists: what have we learnt?

Long-acting β-agonists (LABAs) added to inhaled corticosteroids (ICS) reduce symptoms, improve lung function and enhance overall asthma control. However, several studies have indicated an increased risk of asthma mortality and asthma-related serious adverse events and the FDA recently mandated restrictions to the use of LABAs in asthma.

This review highlights the clinical studies on which safety analyses pertaining to salmeterol and formoterol have been based and then focuses on recent meta-analyses of safety outcomes with and without consideration of concomitant ICS.

The phenomenon of masking of inflammation by LABA if ICS dose is insufficient underscores the potential for confounding in determining real safety risks. Under-treatment with ICS and differential dosing of ICS in many trials are major factors driving the LABA safety concern. The FDA meta-analysis, when stratified for mandatory ICS use, found no significant increase in the composite outcome of asthma mortality, intubations and hospitalizations. Add-on therapy with LABA is effective and safe if the dose of ICS is adequate to treat airway inflammation. LABA and ICS given in a single device will negate the possibility of LABA monotherapy which is contraindicated. The FDA has recommended that LABAs be withdrawn when control is achieved with combination therapy but recent evidence suggests this may result in loss of symptom control.