Long Acting Beta Agonists in Children with Asthma
Is the use of long acting beta agonists safe in young children with asthma?
By Omer Kalayci, MD (Hacettepe University School of Medicine, Ankara, Turkey
Following the initial concerns regarding the use of long acting beta agonists (LABA), it is now widely accepted that the use LABAs is safe as long as it is administered together with inhaled corticosteroids (ICS) in patients older than 6 years of age. In fact, recently published GINA document (1) states that for children 6-11 years the preferred controller is medium dose ICS or low dose ICS-LABA which has similar benefits.
However, the use of LABAs in children younger than six years of age has been a matter of controversy with respect to both efficacy and safety. Two studies have highlighted on this controversial issue.
Stempel et al (2) randomly assigned, in a 1:1 ratio, children 4 to 11 years of age who required daily asthma medications and had a history of asthma exacerbations in the previous year to receive fluticasone propionate plus salmeterol or fluticasone alone for 26 weeks. The primary safety end point was the first serious asthma-related event (death, endotracheal intubation, or hospitalization), as assessed in a time-to-event analysis. Among the 6208 patients, 27 patients in the fluticasone-salmeterol group and 21 in the fluticasone-alone group had a serious asthma-related event (all were hospitalizations); the hazard ratio with fluticasone-salmeterol versus fluticasone alone was 1.28 (95% confidence interval [CI], 0.73 to 2.27), which showed the noninferiority of fluticasone-salmeterol (P=0.006). A total of 265 patients (8.5%) in the fluticasone-salmeterol group and 309 (10.0%) in the fluticasone-alone group had a severe asthma exacerbation (hazard ratio, 0.86; 95% CI, 0.73 to 1.01). The authors of the study have concluded that salmeterol in a fixed-dose combination with fluticasone was associated with the risk of a serious asthma-related event that was similar to the risk with fluticasone alone.
A more recent study has investigated the safety and efficacy of ICS-LABA in children younger than 4 years of age (3). In a randomized, double-blind trial three hundred children aged 8 months – 4 years were randomized in a 1:1 ratio to receive fluticasone/salmeterol combination or fluticasone propionate alone in an 8 week double blind period followed by 16 weeks of open label combination treatment. Mean change from baseline in total asthma symptom scores was -3.97 for fluticasone/salmeterol and -3.01 with fluticasone. The between-group difference was not statistically significant (P = 0.21; 95% confidence interval: -2.47, 0.54) suggesting that the efficacy of the two medications was not different in this age group.
In the double blind period the incidence of adverse events was virtually identical between the fluticasone/salmeterol (74%) and fluticasone (73%) groups and was not associated with age (young than 2 or 2 years and above) or number of inhalations (2 or 4 /day). Incidence of drug‐related adverse events (fluticasone, 1 child, stomatitis) and adverse events (fluticasone/salmeterol, <1%; fluticasone, 3%) was very low; no adverse events were considered by the investigators to be drug‐related. Overall, there was no difference in the severity and frequency of adverse events between the two groups throughout the whole study.
In summary, fluticasone/salmeterol did not show superior efficacy to fluticasone in children younger than four years of age. At the same time, however, no clinically significant differences in safety were noted between the two groups, either.
In this era of personalized medicine, determinants of the best response to each treatment remains to be a challenge.
- Stempel DA, Szefler SJ, Pedersen S, Zeiger RS, Yeakey AM, Lee LA, et al. Safety of adding salmeterol to fluticasone propionate in children with asthma. N Engl J Med. 2016;375:840-9.
- Yoshihara S, Tsubaki T, Ikeda M, Lenney W, Tomiak R, Hattori T, Hashimoto K,Soutome T, Kato S. The efficacy and safety of fluticasone/salmeterol compared to fluticasone in children younger than four years of age. Pediatr Allergy Immunol.2019;30:195-203