In the JournalsPerspective

Symbicort yields lower risk for asthma exacerbations than budesonide

Symbicort and budesonide monotherapy showed a comparable risk profile for serious asthma-related events in adolescents and adults with moderate-to-severe asthma, while the combination therapy yielded a lower risk for exacerbations, according to recently published data.

“Current guidelines for the management of asthma suggest that inhaled glucocorticoids should be used as initial controller therapy, with a [long-acting beta-agonist (LABA)] then added if symptoms remain uncontrolled or increase in severity,” Stephen P. Peters, MD, PhD, acting section chief of pulmonary, critical care, allergy and immunologic medicine at Wake Forest Baptist Health, and colleagues wrote. “Although LABAs have been an available treatment option for asthma since 1990, questions remain regarding the safety of this drug class.”

To assess the risk for asthma-related adverse events associated with Symbicort (budesonide/formoterol, AstraZeneca), Peters and colleagues conducted a multicenter, double blind, 26-week study of asthma-affected patients aged 12 years and older. Patients were randomly assigned budesonide/formoterol (n = 5,846) or budesonide monotherapy (n = 5,847).

Forty patients who received budesonide experienced serious asthma-related events vs. 43 patients in the budesonide/formoterol group (HR = 1.07; 95% CI, 0.7-1.65). Two asthma-related deaths occurred in the budesonide/formoterol group, including one patient who had undergone an asthma-related intubation. Overall, 9.2% of budesonide/formoterol patients reported 637 exacerbations, while 10.8% of patients in the budesonide monotherapy group reported 762 exacerbations (HR = 0.84; 95% CI, 0.74-0.94).

“Although the current study was designed primarily to assess safety, the evaluation of prespecified efficacy measures was included to further assess the benefit:risk profile of the treatment groups,” the researchers wrote. “The risk of asthma exacerbation, the primary efficacy variable, was 16.5% lower with budesonide/formoterol than with budesonide alone; this significantly lower risk was observed despite the high percentage of patients reporting asthma control at baseline.” – by Kate Sherrer

Disclosure: The study was funded by AstraZeneca. Peters reports nonfinancial support from AstraZeneca during the conduct of this study, along with personal fees from Array Biopharma, Integrity CE, Aerocrine, Boehringer Ingelheim, Experts in Asthma, Gilead Sciences, GlaxoSmithKline, Merck, Ono Pharmaceuticals, Pfizer, PPD Development, Quintiles, Sunovion, Saatchi & Saatchi, Targacept, Teva, Theron, and Sanofi - Regeneron, and personal fees and other support from AstraZeneca and Novartis outside the submitted work. Please see the full study for a list of all other authors’ relevant financial disclosures.

Symbicort and budesonide monotherapy showed a comparable risk profile for serious asthma-related events in adolescents and adults with moderate-to-severe asthma, while the combination therapy yielded a lower risk for exacerbations, according to recently published data.

“Current guidelines for the management of asthma suggest that inhaled glucocorticoids should be used as initial controller therapy, with a [long-acting beta-agonist (LABA)] then added if symptoms remain uncontrolled or increase in severity,” Stephen P. Peters, MD, PhD, acting section chief of pulmonary, critical care, allergy and immunologic medicine at Wake Forest Baptist Health, and colleagues wrote. “Although LABAs have been an available treatment option for asthma since 1990, questions remain regarding the safety of this drug class.”

To assess the risk for asthma-related adverse events associated with Symbicort (budesonide/formoterol, AstraZeneca), Peters and colleagues conducted a multicenter, double blind, 26-week study of asthma-affected patients aged 12 years and older. Patients were randomly assigned budesonide/formoterol (n = 5,846) or budesonide monotherapy (n = 5,847).

Forty patients who received budesonide experienced serious asthma-related events vs. 43 patients in the budesonide/formoterol group (HR = 1.07; 95% CI, 0.7-1.65). Two asthma-related deaths occurred in the budesonide/formoterol group, including one patient who had undergone an asthma-related intubation. Overall, 9.2% of budesonide/formoterol patients reported 637 exacerbations, while 10.8% of patients in the budesonide monotherapy group reported 762 exacerbations (HR = 0.84; 95% CI, 0.74-0.94).

“Although the current study was designed primarily to assess safety, the evaluation of prespecified efficacy measures was included to further assess the benefit:risk profile of the treatment groups,” the researchers wrote. “The risk of asthma exacerbation, the primary efficacy variable, was 16.5% lower with budesonide/formoterol than with budesonide alone; this significantly lower risk was observed despite the high percentage of patients reporting asthma control at baseline.” – by Kate Sherrer

Disclosure: The study was funded by AstraZeneca. Peters reports nonfinancial support from AstraZeneca during the conduct of this study, along with personal fees from Array Biopharma, Integrity CE, Aerocrine, Boehringer Ingelheim, Experts in Asthma, Gilead Sciences, GlaxoSmithKline, Merck, Ono Pharmaceuticals, Pfizer, PPD Development, Quintiles, Sunovion, Saatchi & Saatchi, Targacept, Teva, Theron, and Sanofi - Regeneron, and personal fees and other support from AstraZeneca and Novartis outside the submitted work. Please see the full study for a list of all other authors’ relevant financial disclosures.

    Perspective
    Jay M. Portnoy

    Jay M. Portnoy

    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.

    • Jay M. Portnoy, MD
    • Division director, allergy/asthma/immunology The Children’s Mercy Hospital Professor of pediatrics University of Missouri-Kansas City School of Medicine ACAAI past president

    Disclosures: Portnoy reports no relevant financial disclosures.

    Perspective
    Chitra Dinakar

    Chitra Dinakar

    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.

    • Chitra Dinakar, MD
    • Pediatric allergy and immunology The Children’s Mercy Hospital Professor of pediatrics University of Missouri-Kansas City School of Medicine

    Disclosures: Dinakar reports no relevant financial disclosures.