Safety of long-acting β-agonists: urgent need to clear the air remains

The introduction of long-acting β-agonist (LABA) drugs in the 1990s was considered a major advance in bronchodilator therapy with evidence that their use led to improved lung function and quality of life 1, 2. There were also potential safety advantages due to the twice daily, fixed dose usage, which reduced the risk of overuse of β-agonist therapy in the situation of severe exacerbations. The subsequent introduction of the combination of LABA/inhaled corticosteroid (ICS) products had the added potential value of ensuring that the patient received concomitant ICS therapy while improving compliance with ICS therapy 3, 4. However, concerns about the possible risks associated with LABA therapy were raised soon after their introduction into clinical practice, with the evidence that regular LABA use had the potential to reduce bronchodilator sensitivity to β-agonists 5, 6 and induce tolerance to their bronchoprotective effects 7, which may not be restored by concurrent use of ICS 8. It also became apparent that patients using LABAs may be at risk of severe exacerbations if the symptom control achieved with LABA use led to a discontinuation of ICS therapy 9. There were also concerns about a potential risk of mortality from the Salmeterol Nationwide Surveillance Study 10. In this UK-based study of >25,000 subjects, there was a nonsignificant three-fold increased risk of asthma death in subjects treated with salmeterol compared with regular salbutamol; however, there was no increase in hospital admissions or life-threatening events. This led to the USA-based Salmeterol Multicenter Asthma Research Trial (SMART), a placebo-controlled study of the safety of salmeterol in adults with unstable asthma 11. The trial was stopped after an interim analysis of 26,000 subjects because it showed a statistically significant, four-fold increase in asthma mortality with salmeterol. Unfortunately, due to low …