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Long-acting beta-agonists increase severe asthma events

Clinical Question:
Do long-acting beta-agonists, in combination with a corticosteroid, increase the risk of intubation or death in patients with asthma?

Bottom Line:
The long-acting beta-agonists (LABA) salmeterol and formoterol increase the likelihood of a patient requiring intubation or dying as a result of an acute asthma event, even when combined with a corticosteroid (such as in the products Advair and Symbicort). The actual risk is an increase of 3 to 16 deaths or intubations per 10,000 treated patients. (LOE = 1a)

Salpeter SR, Wall AJ, Buckley NS. Long-acting beta-agonists with and without inhaled corticosteroids and catastrophic asthma events. Am J Med 2010; 123(4) :322-328.  [PMID:20176343]

Study Design:
Meta-analysis (randomized controlled trials)

Self-funded or unfunded

Various (meta-analysis)

Research showing an increase in asthma-related hospitalizations, intubations, and deaths with the use of salmeterol and formoterol resulted in the United States Food and Drug Administration's requirement that these products be labeled for use only as a last resort. This meta-analysis assessed the adverse effects when either drug was studied with inhaled corticosteroids in patients with asthma. The authors searched relevant databases, including the Cochrane databases, and obtained research data from the manufacturer of salmeterol. They included data from randomized studies comparing treatment with (1) LABA with variable steroid use versus placebo, or (2) LABA plus inhaled corticosteroid versus corticosteroid alone. The authors excluded studies without at least 1 incidence of intubation or death. Two researchers independently extracted the data. There was no heterogeneity in the data. They did not report on publication bias but their use of unpublished data directly from the company archives minimizes this risk. In 5 studies enrolling a total of 29,335 patients, half of whom were also receiving inhaled steroid (90% enrolled in a single study of salmeterol), the rate of the combined outcome of intubation or death was almost twice as high in the treated patients (odds ratio {OR] = 1.83; 95% CI, 1.14 - 2.95). In 7 studies of 7263 patients randomized to receive steroid alone or a LABA/steroid combination, the rate of intubation or death was 3.65 times higher (OR = 1.39 - 9.55) in the combination group. The absolute rates of intubations or death are less frightening: Overall, an additional 16 deaths or intubations per 10,000 patients treated for an average of 5 months in the included trials, dropping to 3 per 10,000 if all studies are included. These authors did not report the effect of the combination on quality of life or hospitalization rate.


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