To wheeze or not to wheeze?


According to the World Health Organization, an estimated 235 million people worldwide suffer from asthma and it is the most common chronic disease among children (WHO 2014). Asthma is a non-communicable condition that affects the airways, often leading to wheezing, coughing and problems breathing. Beta-2-agonists are commonly prescribed to relax the airways and relieve symptoms of asthma. Short-acting beta-2-agonists (SABAs), such as salbutamol, are typically recommended as first line treatment to open the airways. Children with regular symptoms of asthma include an inhaled corticosteroid (ICS) as add-on to the SABA, aimed at preventing long-term damage due to inflammation in their lungs. Increasing severity or exacerbations can be addressed with the addition of a regular long-acting beta-2-agonist (LABA), such as formoterol or salmeterol, to ICS therapy.

A Cochrane overview (Cates 2012) examined the safety of regular formoterol or salmeterol, alone (monotherapy) or as combination therapy with an ICS, in children with asthma. Six reviews and two additional recent trials were included in the overview, for a total of 21 trials on 7474 children aged 4 to 17 years. The assessment of safety was done through direct (randomized evidence from trials) and indirect (testing for differences between pooled results of different trials) comparisons of formoterol and salmeterol:

  • Formoterol vs. placebo
  • Salmeterol vs. placebo
  • Formoterol + ICS vs. ICS
  • Salmeterol + ICS vs. ICS
  • Formoterol vs. salmeterol
  • Formoterol + ICS vs. salmeterol + ICS

The results…

  • Serious adverse events: The included reviews defined serious adverse event as any untoward medical occurrence that at any dose: a) results in death; b) is life threatening; c) requires inpatient hospitalization or prolongation of existing hospitalization; d) results in persistent or significant disability/incapacity; or e) is a congenital anomaly/birth defect. All therapies were associated with an increased odds of children having a serious adverse event (SAE), but this was only statistically significant for formoterol monotherapy. Similarly, there was an increase in the odds of children having asthma-related SAEs with both formoterol and salmeterol monotherapy. One child died of a sub-arachnoid hemorrhage while on formoterol monotherapy.
  • Monotherapy vs. combination therapy: No significant difference was found between monotherapy (LABA vs. placebo) and combination therapy (LABA + ICS vs. ICS); however, the ICS control arm had fewer SAEs than the placebo control arm, indicating key differences between the trials.
  • Formoterol vs. salmeterol: No significant difference was found in comparative safety.

Strengths and Limitations:

  • Overall quality of the included reviews was high
  • There are no trials randomizing children to monotherapy versus combination therapy, so the interpretation of the safety interaction with ICS is based on indirect comparisons
  • Adverse event reporting may not capture the whole picture (e.g. AEs related to medications vs. asthma, poor reporting in journals)
  • Children younger than 4 years old were not included in any of the studies

Take-home message:

Trial data in adolescents and adults with asthma have shown an increase in the risk of death from regular salmeterol monotherapy. The Food and Drug Administration (FDA) found significant increased risk of serious asthma events for children on LABA monotherapy and made recommendations to restrict LABAs to combination ICS/LABA therapy only.

Dr. Chris Cates, coordinating editor of the Cochrane Airways Group and first author of the overview, states:

“All we can say is that combination therapy looks safer than using formoterol or salmeterol on their own but may still carry a small additional risk of a serious adverse event. Children on combination therapy should still be carefully monitored and seek help promptly if their asthma gets worse.”

Source: Wikimedia Commons

Source: Wikimedia Commons


Cates, C. J., Stovold, E., Wieland, S., Oleszczuk, M., Thomson, D., & Becker, L. (2012). The Cochrane Library and safety of regular long‐acting beta2‐agonists in children with asthma: an overview of reviews. Evidence‐Based Child Health: A Cochrane Review Journal, 7(6), 1798-1806.]

Overview of the safety of regular formoterol or salmeterol in children with asthma. (2012). Cochrane Podcast.

World Health Organization 2014.

One thought on “To wheeze or not to wheeze?

  1. Thank you for that initiative.
    I strongly suspect that LABA is dangerous because it masks an unaddressed inflammatory state if taken alone (a aberration in itself) or a suboptimal antiinflammatory treatment if taken in combination with an ICS.
    Thank you for your attention,
    Nathanael Goldman

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