Assessment of the safety of long-acting β<inf>2</inf> -agonists in routine asthma care: The ASTRO-LAB protocol

BACKGROUND The safety of long-acting β<inf>2</inf>-agonists (LABAs) remains controversial in asthma, particularly in children, which led regulators to contraindicate LABAs as a single agent in asthma treatment. Current evidence regarding the safety of LABAs in combination with inhaled corticosteroids (ICs), based on meta-analyses of randomised clinical trials (RCTs), is less consistent. Recently updated meta-analyses for formoterol and salmeterol failed to reassure on safety. Despite the absence of evidence of serious risk with LABAs associated with ICs, the precision of results was low owing to infrequent outcomes. Furthermore, RCTs include highly selected populations, and they are not properly designed to assess infrequent and/or long-term adverse events in actual conditions of drug use. Evidence is also limited in the observational context. A recent systematic review assessing the risk of LABAs associated with ICs, compared with ICs alone, did not indicate any increased risk for emergency visits or hospital admissions. However, no reliable conclusions could be drawn neither in children, nor on potential differences between LABAs associated with ICs, in fixed-dose combinations, and in two separate canisters, due to the lack of published data for these specific issues. This review also highlighted the scarcity of prospective studies and the lack of data on drug adherence. Most of the observational studies were based on claims databases, providing only a partial assessment of drug exposure. There is an evidence gap, as detailed and valid exposure data are needed. For instance, irregular use of ICs in persistent asthma is a well-known source of exacerbations. Thus, there is a need to explore potential risks associated with LABAs in real life, with more extensive assessments of patterns of use, including ICs concomitant therapy, asthma control and exacerbations over time. AIMS The ASTRO-LAB project aims to provide new evidence about the safety of LABAs in children and adults in routine clinical care. Its main objective is to investigate with prospective data whether asthma patients receiving LABAs are at a higher risk of severe asthma exacerbations (SAEx), taking into account baseline differences in severity. Potential variations of respective drug exposures to LABAs and ICs over time, using complementary data sources will also be investigated. In addition, it will be verified whether differential adherence to LABAs and to ICs is a possible mechanism of increased risk of SAEx and other asthma outcomes in patients using these drugs in two separate canisters. A key question that ASTRO-LAB aims to explore is whether the potential LABAassociated risk can be explained by suboptimal adherence to ICs. METHODS ASTRO-LAB is a 24-month prospective observational study in asthma, conducted in France and in the United Kingdom (UK).