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Serious asthma-related events comparable for Advair, fluticasone
Serious asthma-related events associated with the administration of Advair Diskus did not spike in children requiring daily asthma therapy compared with those assigned fluticasone propionate monotherapy, according to data from the VESTRI safety trial.
“A 2008 meta-analysis conducted by the FDA showed a higher risk of asthma-related events among patients receiving [long-acting beta-agonists (LABAs)] than among patients not receiving these medications,” David A. Stempel, MD, of respiratory clinical development at GlaxoSmithKline, and colleagues wrote. “In a subsequent meta-analysis, a higher risk of serious asthma-related events was observed with salmeterol than with non-LABA agents among patients who received no inhaled glucocorticoids and among those who received inhaled glucocorticoids as background maintenance medication or in an inhaler that was separate from the one with salmeterol.”
In response to an FDA request, GlaxoSmithKline researchers addressed questions raised on an increased risk for hospitalizations in children who used combined glucocorticoid-LABA therapies. Stempel and colleagues conducted an international, double blind, active-comparator, 26-week trial (VESTRI) to examine whether Advair Diskus (fluticasone/salmeterol, GlaxoSmithKline) was noninferior to fluticasone monotherapy regarding the risk for asthma-related events in children aged 4 to 11 years. The patients had histories of asthma exacerbations 1 year previously and consistently used asthma medication 4 weeks before study enrollment. Patients were randomly assigned fluticasone/salmeterol (n = 3,107) or fluticasone (n = 3,101) for the study period.
The researchers calculated that the cohort would provide the trial with “90% power to show the noninferiority of fluticasone/salmeterol vs. fluticasone” if 43 patients had a composite serious asthma-related event. Among the cohort, 27 patients in the fluticasone/salmeterol arm and 21 patients who received fluticasone monotherapy were hospitalized for serious asthma-related events (HR = 1.28; 95% CI, 0.73-2.27). The researchers wrote that 8.5% of patients in the fluticasone/salmeterol group experienced severe asthma exacerbations, compared with 10% in the fluticasone monotherapy group (HR = 0.86; 95% CI, 0.73-1.01).
“Asthma-related deaths are uncommon in children, and no association with LABAs has been reported previously,” the researchers wrote. “No deaths or asthma-related intubations occurred in our trial. The hospitalization rate in our trial was approximately 1.5 hospitalizations per 100 patient-years with each treatment, which is consistent with the incidence observed by the U.S. National Surveillance of Asthma among children 5 to 14 years of age.” – by Kate Sherrer
Disclosure: The study was funded by GlaxoSmithKline. Stempel reports being an employee of and holding stock in GlaxoSmithKline. Please see the full study for a list of all other authors’ relevant financial disclosures.
Perspective
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The strengths of these trials are the well-thought out study design, large numbers of children enrolled (more than 3,000 participants in each group for the fluticasone-salmeterol study by Stempel and colleagues; and more than 5,800 participants in each group for the budesonide-formoterol group in the study by Peters and colleagues), and reassuringly low numbers of adverse events.
While these were not designed to be efficacy studies, they do add to the body of evidence regarding the potential benefits (such as the BADGER study published by Lemanske and colleagues in 2010) vs. the low likelihood of risks associated with the use of a fixed-dose combination of LABA with an inhaled glucocorticoid, for the subgroup of children with asthma uncontrolled on low-dose inhaled steroid therapy.
However, it is to be emphasized that there is no evidence to support the use of a combined inhaled glucocorticoid and LABA inhaler as first-line preventive therapy in children. Also, monotherapy with a LABA in a child should not be prescribed in the United States, consistent with the requirement by the FDA in 2010.
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The studies by Peters and Stempel were performed in response to concerns about the potential for serious events in patients with asthma who are treated with long-acting beta agonists (LABAs). The concern stems from the SMART study, published over a decade ago, in which a small increase in deaths was observed in African-Americans who were treated with LABAs, in particular, salmeterol. The result was that a black box warning was included in the package insert for inhalers with LABAs. Pharmaceutical companies that produce inhalers with such agents were urged to perform clinical trials to determine whether this risk is real and, if so, what its magnitude is. These studies were the result.
The study by Peters included budesonide-formoterol, while the study by Stempel included fluticasone-salmeterol. Both were compared with their respective single-agent steroid in pediatric patients with asthma who were randomly assigned one or the other treatment. Both studies used a noninferiority model in which it is possible to say, with a given certainty, that there is no difference between the two groups. For these studies, the risk for serious events was no different between the two treatments with at least a 95% certainty, meaning that if there is a difference, there is a 95% likelihood that it would have been detected.
It should be noted that these were not efficacy studies. The combination products may very well be more effective for controlling asthma that their single-agent analogues. What could be concluded is that it is highly unlikely that these two LABAs are associated with an increased risk for severe, potentially life-threatening events. The results should be reassuring to pediatricians who prescribe combination inhalers to children with asthma.