FCAAIA Notes: A little bad press can go a long way and can be hard to overcome even with a lot of good press. The long-acting beta agonists (long-acting cousins of albuterol, LABAs) are available with low dose inhaled in serval combination inhalers. LABAs were vilified about 10 years ago when a study showed they placed patients at risk of serious and even sometimes fatal asthma flares. However, that study (SMART study) looked at patients using salmeterol alone, without any inhaled steroids. In addition, patients requiring LABAs have more severe asthma to start with.

These two papers show that LABAs are extraordinarily safe when prescribed correctly. They should not be prescribed to patients with asthma without a concomitant inhaled steroid. The best way to do so is with one of the combo inhalers.  If your asthma is not well controlled on inhaled steroids and higher doses of inhaled steroids do not provide better control, you should consider starting a LABA.  It is safer than poorly controlled asthma.

Serious Asthma Events with Budesonide plus Formoterol vs. Budesonide Alone

(Source: Sept. 8, 2016. Adapted from N Engl J Med 2016; 375:850-860)

BACKGROUND: Concerns remain about the safety of adding long-acting β2-agonists to inhaled glucocorticoids for the treatment of asthma. In a postmarketing safety study mandated by the Food and Drug Administration, we evaluated whether the addition of formoterol to budesonide maintenance therapy increased the risk of serious asthma-related events in patients with asthma.

METHODS: In this multicenter, double-blind, 26-week study, we randomly assigned patients, 12 years of age or older, who had persistent asthma, were receiving daily asthma medication, and had had one to four asthma exacerbations in the previous year to receive budesonide–formoterol or budesonide alone. Patients with a history of life-threatening asthma were excluded. The primary end point was the first serious asthma-related event (a composite of adjudicated death, intubation, and hospitalization), as assessed in a time-to-event analysis. The noninferiority of budesonide–formoterol to budesonide was defined as an upper limit of the 95% confidence interval for the risk of the primary safety end point of less than 2.0. The primary efficacy end point was the first asthma exacerbation, as assessed in a time-to-event analysis.

RESULTS: A total of 11,693 patients underwent randomization, of whom 5846 were assigned to receive budesonide–formoterol and 5847 to receive budesonide. A serious asthma-related event occurred in 43 patients who were receiving budesonide–formoterol and in 40 patients who were receiving budesonide (hazard ratio, 1.07; 95% confidence interval [CI], 0.70 to 1.65]); budesonide–formoterol was shown to be noninferior to budesonide alone. There were two asthma-related deaths, both in the budesonide–formoterol group; one of these patients had undergone an asthma-related intubation. The risk of an asthma exacerbation was 16.5% lower with budesonide–formoterol than with budesonide (hazard ratio, 0.84; 95% CI, 0.74 to 0.94; P=0.002).

CONCLUSIONS: Among adolescents and adults with predominantly moderate-to-severe asthma, treatment with budesonide–formoterol was associated with a lower risk of asthma exacerbations than budesonide and a similar risk of serious asthma-related events.

Are Long-Acting Beta-Agonists Safe to Add to Treatment Regimens for Asthma in Children?

(Source: Sept. 8, 2016)

Janine is a 9-year-old girl who you’ve been seeing in your clinic for years. She struggles with asthma despite treatment with low-dose inhaled glucocorticoids. You wonder if any other medications can be added to her treatment regimen, and peruse the literature on long-acting beta-agonists (LABAs). The literature is mixed – it seems clear that LABAs, when used alone, have been associated with increased risk of asthma-related deaths. However, more recent studies have reported that LABAs may be safer when combined with low-dose inhaled glucocorticoids. Indeed, in the recent AUSTRI study, there was no increased risk of serious asthma-related events in adults and adolescents with moderate asthma who received LABA with glucocorticoids, compared with those receiving glucocorticoids alone. However, this study did not include patients of Janine’s age, and thus, the safety of combining LABAs with glucocorticoids in children remains unclear.

In this week’s issue of NEJM, Stempel et al. address this issue in the VESTRI trial— a randomized, double-blind, international 26-week trial involving 6208 asthmatic children (aged 4-11 years). The children were randomized to receive either the glucocorticoid fluticasone propionate with the LABA salmeterol or fluticasone-alone. For the primary endpoint of asthma-related events, fluticasone-salmeterol combination therapy was noninferior to fluticasone-alone, with similar risk of asthma-related events in the two groups. Additionally, the fluticasone-salmeterol combination therapy group had a nonsignificant 14% reduction in severe asthma exacerbations compared to the fluticasone-alone group.

In an accompanying editorial,, Bush and Frey applaud this trial for its large sample size and low number of adverse events. However, they caution against immediately starting patients like Janine on combination glucocorticoid-LABA therapy, especially as a first-line treatment. Most asthmatic children, they argue, can still be well controlled on inhaled glucocorticoid therapy, and checking with the family about action plans, adequacy of medication delivery technique, and other steps to control asthma should be taken before adding LABAs to the treatment plan.

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