Long-acting beta2-agonists in asthma: not so SMART?

Asthma is a worldwide chronic disorder that is characterised by airway inflammation and hyper-responsiveness, which results in intermittent airflow obstruction and subsequent perception of symptoms and exacerbations. Inhaled corticosteroids are a fundamental component in the prevention of the short- and long-term complications associated with inadequately controlled asthma. However, many individuals experience persistent symptoms and exacerbations despite receiving low-to-medium doses of an inhaled corticosteroid (400-800 microg/day of beclometasone or equivalent). In these symptomatic asthmatic patients, guidelines advocate the initiation of a long-acting beta2-adrenoceptor agonist (LABA) as additional second-line controller therapy. The recent SMART (Salmeterol Multi-centre Asthma Research Trial) study was designed to compare the effects of add-on salmeterol 42 microg (ex-actuator) twice daily with placebo over 28 weeks in a randomised, double-blind, parallel-group fashion, with the intention to enrol 60,000 asthmatic patients. However, the study was halted prematurely because preliminary data revealed an increased mortality associated with regular use of salmeterol. Moreover, concerning rates of respiratory-related deaths, asthma-related deaths and life-threatening events were observed among African Americans, who constituted up to 18% of the study population. This in turn prompted the US FDA to announce important safety information regarding inhalers containing LABAs and advise that new labelling be produced outlining the "small but significant risk in asthma-related deaths" associated with their regular use. This evidence-based review discusses the data from SMART and highlights potentially important drawbacks with regular use of LABAs in persistent asthma.