What are the risks and recommendations for using long-acting beta agonists (LABAs) as monotherapy in asthma?

From the Guidelines

Long-acting beta agonists (LABAs) should never be used as monotherapy for asthma due to significant safety concerns, including increased risk of asthma-related deaths, hospitalizations, and severe exacerbations, as highlighted in the guidelines from the Journal of Allergy and Clinical Immunology 1. The use of LABAs as monotherapy has been associated with an increased risk for severe asthma exacerbations, and they carry black box warnings from regulatory agencies. LABAs work by relaxing airway smooth muscles but do not address the underlying inflammation of asthma, which can mask worsening inflammation while providing symptom relief, potentially delaying appropriate treatment. The proper approach is to always use LABAs in combination with an inhaled corticosteroid (ICS), such as in products like Advair (fluticasone/salmeterol), Symbicort (budesonide/formoterol), or Dulera (mometasone/formoterol), as recommended in the guidelines 1. These combination inhalers ensure patients receive anti-inflammatory therapy alongside bronchodilation. For patients requiring bronchodilation without anti-inflammatory effects, short-acting beta agonists (SABAs) like albuterol should be used for rescue therapy, while long-acting muscarinic antagonists (LAMAs) like tiotropium may be considered as add-on therapy in severe asthma cases, but not as monotherapy either, as discussed in the Mayo Clinic Proceedings 1. Key points to consider include:

• LABAs should only be used in combination with ICS therapy
• The Food and Drug Administration has issued a black-box warning against the use of LABAs as monotherapy for long-term control of asthma
• Anti-IgE therapy with omalizumab may be considered for patients aged 12 years or older with IgE-mediated allergic asthma who have inadequate control with ICSs and LABAs.

From the FDA Drug Label

The use of LABA as monotherapy (without ICS) for asthma is associated with an increased risk of asthma-related death [see Salmeterol Multicenter Asthma Research Trial (SMART)] Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients. Glaucoma and cataracts may occur with long-term use of inhaled corticosteroids. Be alert to eosinophilic conditions, hypokalemia, and hyperglycemia.

The use of long-acting beta agonists (LABAs) as monotherapy in asthma has been associated with an increased risk for:

• Severe asthma exacerbations
• Asthma-related death
• Asthma-related hospitalization
• Cataracts
• Hypokalemia
• Hyperglycemia It is not recommended to use LABAs as monotherapy for asthma due to the increased risk of serious asthma-related events. Instead, LABAs should be used in fixed-dose combination with an inhaled corticosteroid (ICS) to minimize the risk of adverse effects 2.

From the Research

Risks Associated with Long-Acting Beta Agonists (LABAs) as Monotherapy in Asthma

• The use of LABAs as monotherapy in asthma has been associated with an increased risk of asthma-related events, including deaths 3.
• LABAs alone may increase the risk of asthma exacerbations, hospitalizations, and life-threatening episodes 4.
• A systematic review found that LABA monotherapy reduced exacerbations requiring corticosteroids but showed a significant increase in asthma-related deaths (Relative Risk=3.83; 95% CI, 1.21-12.14) 4.
• Subgroup analysis suggests that children, patients receiving salmeterol, and a duration of treatment >12 weeks are associated with a higher risk of serious adverse effects 4.

Recommendations for Using LABAs in Asthma

• Current asthma guidelines recommend the use of LABAs in combination with inhaled corticosteroids (ICSs) for long-term control and prevention of symptoms in persistent asthma 5.
• The combination of LABA/ICS reduces exacerbations (RR=0.73; 95% CI, 0.67-0.79) and hospitalizations (RR=0.58,95% CI, 0.45-0.74) compared to ICS alone 4.
• LABA/ICS combination therapy is associated with a lower risk of asthma-related hospitalizations and/or ER visits than ICSs alone (odds ratio: 0.82; 95% confidence interval: 0.72-0.94) 5.
• The use of LABA alone is not recommended for asthma therapy, and LABAs should only be used in combination with ICSs 6, 3, 4.

Specific Considerations

• Children and patients receiving salmeterol may be at a higher risk of serious adverse effects, including asthma-related deaths 4.
• The concomitant use of ICSs has a protective effect against the increased risk of serious adverse effects associated with LABA monotherapy 4.
• The addition of LABA to ICSs significantly reduces the risk of exacerbations compared to a similar ICS dose, with a number needed to treat of 18 7.