Dec 162012
Just How "Dangerous" Are Long-Acting Beta-Agonists, Really?

Gustavo Rodriguez and Jose Castro-Rodriguez reviewed 20 systematic reviews and databases reporting on the incidence of adverse events with long-acting beta-agonist (LABA) therapy for asthma, for the April 2012 Thorax.

They conclude the following:

  • LABAs as monotherapy significantly increase the risk for adverse effects and bad outcomes from asthma. Authors estimate a number-needed-to-kill using LABA monotherapy of about 1,200 people with asthma.
  • LABAs when used with inhaled corticosteroids are helpful. Multiple reviews/meta-analyses suggest that long-acting beta-agonists + inhaled corticosteroids reduce asthma hospitalizations compared to inhaled corticosteroids alone. (One review by Salpeter et al concludes the opposite, and they try to discredit it.)

Most of all, they emphasize the weakness of the primary data in terms of statistical strength, simply because asthma-related deaths and intubations are so rare. For example:

  • In the FDA's meta-analysis (which did not include all available data), 44 deaths and intubations occurred in 30,100 LABA-exposed patients total. 43 of those deaths occurred in patients participating in studies in which inhaled corticosteroid use was not mandatory.
  • In the 7,862 patients in the FDA's meta-analysis who were obligated to take ICS (usually because a combination product was being tested), there was only one death.

The FDA issued its black-box warning for LABAs (including those in combination products like Advair and Symbicort) not just because of the perceived risk, but because the FDA also did not see unequivocal clinical benefit from LABAs (unlike these authors). Since so many generally healthy people take asthma inhalers, they demanded a high benefit-to-risk ratio, and felt LABAs did not clearly meet that standard. The FDA has demanded that Pharma conduct 5 large trials to test LABA/ICS safety; these authors are skeptical that those will settle the issue either, since event rates are so low and achieving the power to conclude anything will be exceedingly difficult.

Both authors report receiving "consulting fees" from multiple producers of asthma inhalers.

Rodrigo GJ, Castro-Rodriguez JA. Safety of long-acting β agonists for the treatment of asthma: clearing the air. Thorax 2012;67:342-349. Black Box Warning for long-acting beta-agonists (LABA) for asthma.

FDA's explanation for the decision to make the warning, in the New England Journal of Medicine.

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Long-acting beta agonist safety for asthma (Review)