DENVER – When you prescribe a long-acting beta-agonist for a child with asthma, you may want to consider adding an inhaled corticosteroid as well, according to a meta-analysis conducted by Food and Drug Administration investigators.
"Overall, there was an increased risk of asthma-related hospitalizations, intubation, or death to asthmatics of all ages using long-acting beta-agonists [LABAs]," Dr. Ann W. McMahon said at the annual meeting of the Pediatric Academic Societies.
Dr. McMahon and her colleagues also found an age effect as well, with asthmatics aged 4-11 years at greater risk, compared with older patients. "Children are at increased risk, primarily of hospitalization, from asthma with LABA use compared to the overall population."
The elevated overall and age-related risks are no longer statistically significant, however, when patients are prescribed an inhaled corticosteroid (ICS) along with a LABA as part of a study protocol, Dr. McMahon said.
"Although further study is indicated, simultaneous use of inhaled corticosteroids and LABAs may mitigate this risk in children," said Dr. McMahon, deputy director of the division of pharmacovigilance, office of surveillance and epidemiology, FDA.
In a previous meta-analysis, LABA use was associated with a higher overall risk for adverse outcomes, a risk difference estimate of 2.80 for an asthma composite index of asthma-related hospitalizations, intubations, and deaths. In a 2008 meta-analysis that included 60,954 patients of all ages from 110 trials, Mark Levenson, Ph.D., one of Dr. McMahon’s FDA colleagues, found the highest risk associated with LABA therapy was among those aged 4-11 years, who had a risk difference estimate of 14.83/1,000 participants.
Dr. McMahon presented a secondary analysis of the 2008 meta-analysis in which she and her associates assessed a subset of patients assigned an ICS as part of their study regimen. Using a forest plot analysis, they compared 7,862 patients also treated with a LABA versus 7,330 who did not receive a LABA.
"What we see here is no overall risk for this subset of patients and no particular age trend either," Dr. McMahon said. The overall risk difference was 0.2/1,000 patients.
"I just want to caution that this is a smaller group of patients. So whether we can conclude this is definitive, I would say probably not," Dr. McMahon said. "But it is very intriguing that this subgroup that took assigned inhaled corticosteroids really did not have an age effect or an overall increased risk."
In contrast, when all users and nonusers of inhaled corticosteroids were combined, overall risk associated with LABA use was 6.3 additional adverse events per 1,000 patients.
Another analysis of the data looked at all patients who took some concomitant ICS therapy (those intentionally prescribed an ICS and those noted to be taking an ICS at baseline). This analysis "looks very similar, with a slight increased risk overall" of 6.1 events per 1,000 patients, Dr. McMahon said.
Age again made a difference, with a point estimate risk of 19.8/1,000 participants for those aged 4-11 years, a statistically significant higher risk compared with that of patients aged 12-17 years, 18-64 years, and 65 years and older.
"Children are at increased risk primarily of [asthma-related] hospitalization," Dr. McMahon said. Data on intubations and deaths were insufficient to calculate these outcomes among children, she added.
Dr. McMahon’s findings concur with those of other published studies. For example the Salmeterol Multicenter Asthma Research Trial (SMART) and the Serevent Nationwide Surveillance (SNS) study in the United Kingdom "both gave similar results to the extent that there was a three- to fourfold increase in risk of serious asthma outcomes such as asthma-related death and intubation" associated with LABA use (Chest 2006;129:15-26; BMJ 1993;306:1034-7). However, these trials did not include children younger than 12 years and did not include enough adolescents for investigators to be able to analyze those data separately, she added.
Three of the LABAs approved for asthma treatment in the United States are combined LABA/ICS inhalers: Advair (salmeterol, fluticasone); Dulera (formoterol, mometasone); and Symbicort (formoterol, budesonide). Other approved LABA products that do not contain an ICS are Brovana (arformoterol), Foradil (formoterol), and Serevent (salmeterol).
Dr. McMahon said she had no relevant financial disclosures.