Dr. Anna A.P.H. Vaessen-Verberne at Amphia Hospital in Breda and colleagues conducted a non-inferiority trial with 158 children (ages 6 to 16) who were still symptomatic on fluticasone propionate 100 mcg bid. They randomized the children to two protocols: one that combined 50 mcg of salmeterol with each 100-mcg dose of fluticasone (a combination marketed in the U.S. as Advair), and another that doubled the steroid dose.
“We wanted to do this research because for children it is not well established whether to increase the dose of ICS or to add a LABA,” Dr. Vaessen-Verberne told Reuters Health by e-mail. “Although we always recommend the lowest dose of ICS for children, side effects still are possible.” On the other hand, the long-acting beta agonists have serious risks as well.
In the 26-week trial, 78 children added salmeterol and 80 took the doubled steroid dose. In both arms, children could take 200 mcg salbutamol for rescue therapy.
In a July 9th online article in the American Journal of Respiratory and Critical Care Medicine, the research team reports that on intention-to-treat analysis, over the last 10 weeks of the trial, the mean adjusted difference in symptom-free days between the two groups was 0.4% (p = 0.93); the difference on per-protocol analysis was 2.6% (p = 0.63).
The fluticasone-only and the salmeterol/fluticasone groups also had similar numbers of exacerbations (9 and 13, respectively) and percentage of days when rescue salbutamol was used (20% and 22%, respectively). Two patients in the combination therapy group had severe exacerbations.
Likewise, measurements of forced expiratory volume in one second, forced vital capacity, maximal expiratory flow at 50% of vital flow capacity, and peak expiratory flow rate did not differ between groups after the first week. (Nor did any of these parameters change from baseline.)
LABAs, such as salmeterol and formoterol, are controversial, particularly in children. Studies indicate that LABA monotherapy increases mortality, though the risk is lower when LABAs are combined with ICS. The U.S. Food and Drug Administration advises that LABAs not be used alone in children. (See Reuters Health reports of Jan 6 and June 2, 2010).
The FDA also advises that once asthma control is achieved and maintained, step down therapy to wean patients from the LABA should begin if possible.
“Further research should focus on which type of patient will benefit more from increasing ICS and which patients will do better on addition of a LABA,” Dr. Vaessen-Verberne said.
Dr. David Rosenstreich, chief of the division of allergy and immunology at Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, told Reuters Health there are “small differences between the two approaches, which vary from patient to patient.”
Dr. Rosenstreich, who was not involved in the research, said, “Personally, I use a lot of the salmeterol/fluticasone combination, because of the concern about long-term effects of ICS – growth retardation, and down the road, there’s a potential for cataracts and glaucoma, especially in children. It seems safer to use a little bit of two drugs than a lot of one drug.”
But “either of the two solutions is preferable to” an exacerbation requiring oral steroids and possibly hospitalization, he said.
The study was funded by GlaxoSmithKline Pharma Europe, maker of Advair (fluticasone and salmeterol oral inhalation).
Am J Resp Crit Care Med 2010.