Pairing LABAs and Inhaled Glucocorticoids: Safety Data Are Finally In

William T. Basco, Jr., MD, MS


October 23, 2018

The Safety of Combination Asthma Therapy

Before removing the black box warning about combining a long-acting beta agonist (LABA) with an inhaled glucocorticoid in the management of asthma, the US Food and Drug Administration (FDA) mandated further safety data. Each of the four companies marketing a LABA for asthma was required to perform a prospective, randomized controlled trial comparing the safety of combination therapy (LABA plus inhaled glucocorticoid) with inhaled glucocorticoid alone in adolescents and adults with asthma.[1]

The four manufacturers conducted separate trials but coordinated trial methods to enable an independent oversight committee to conduct a meta-analysis of the combined data. More than 36,000 adolescents (aged 12-17 years) and adults with persistent asthma were enrolled into 26-week, multicenter, randomized, double-blind, noninferiority trials. Each trial had two treatment groups: One received inhaled glucocorticoid therapy alone and the other received an inhaled glucocorticoid plus a LABA. The primary outcome of interest was a composite of asthma-related endotracheal intubation or death. A secondary outcome of serious asthma-related events included intubation, hospitalization, or death.

In the meta-analysis conducted by Busse and colleagues,[1] there were three asthma-related intubations and two asthma-related deaths among a total of 36,010 patients. Both of the patients who died had received combination therapy. Given that hospitalizations were more frequent, the composite outcome of serious asthma-related event was more revealing. It was almost identical between the two groups (0.60% in the inhaled glucocorticoid group and 0.66% in the combined therapy group; relative risk, 1.09; 95% confidence interval, 0.83-1.43). Rates of asthma exacerbation were higher in the group receiving inhaled glucocorticoid alone (11.7% vs 9.8% in the combination therapy group).

Subgroups of patients who were deemed to be at higher risk for asthma-related events and exacerbations were analyzed separately. However, the analysis detected no significant increase in the relative risk for asthma-related events among adolescents aged 12-17, black patients, Asian patients, or obese patients compared with the entire group. Moreover, combination therapy did not appear to have differential effects on the higher-risk subgroups.

The investigators concluded that combination therapy with a LABA and glucocorticoid did not result in higher risk for serious asthma-related events, and patients receiving combination therapy had a lower frequency of asthma exacerbations.


These data were a long time coming, and as the study authors point out, are in support of the recent FDA decision to remove the black box warning for combining a LABA with an inhaled glucocorticoid in the management of asthma. And although it wasn't a primary goal, the individual studies as well as the combined analysis show that combination therapy can be more effective in controlling asthma exacerbations than inhaled steroids alone. Practitioners still need to remember to appropriately counsel patients on the proper use of controllers so that they don't try to use combination or other controller preparations to excess during exacerbations and instead use the appropriate rescue inhaler.


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