Long-acting β-agonists: use in chronic obstructive pulmonary disease

Overall benefits of long-acting β-agonists (LABAs) in the treatment of chronic obstructive pulmonary disease (COPD) continue to outweigh any risks.

From:
Medicines and Healthcare products Regulatory Agency
Published
11 December 2014
Therapeutic area:
Respiratory disease and allergy

Article date: July 2009

The overall benefits of long-acting β-agonists (LABAs), both as monotherapy and in combination with inhaled corticosteroids (ICS), in the treatment of chronic obstructive pulmonary disease (COPD) continue to outweigh any risks. However, healthcare professionals are reminded that ICS should not be used alone in COPD. A key issue remains the increased risk of pneumonia associated with the use of ICS in COPD

Chronic obstructive pulmonary disease

COPD is a slowly progressive, mainly irreversible disease characterised by airflow limitation. It is one of the few diseases associated with an increasing mortality rate, and by 2020 is predicted to be the third most common cause of death.

NICE (National Institute for Health and Clinical Excellence) and GOLD (Global initiative for chronic Obstructive Lung Disease) guidelines recommend the addition of a LABA to short-acting β2 agonists when moderate COPD is diagnosed (ie, FEV1 between 80% and 50% of predicted), and the addition of ICS in severe disease (ie, FEV1 ≤50% and repeated exacerbations).

However, recent prescribing data suggest that most patients who are prescribed a LABA receive it in conjunction with an ICS, which may suggest that ICS are being introduced earlier than guidelines recommend. The two LABAs currently licensed for treatment of COPD are salmeterol and formoterol (eformoterol). Both are licensed in COPD either as monotherapy or in conjunction with an ICS (fluticasone propionate and budesonide, respectively).

MHRA review of LABA use in COPD

We have recently completed a comprehensive review of the use of LABAs, both as monotherapy and in combination with ICS, in COPD. The review assessed the published literature (for some key examples, see refs [footnote 1] [footnote 2] [footnote 3] [footnote 4] [footnote 5] [footnote 6] [footnote 7] [footnote 8] [footnote 9] [footnote 10]) and unpublished trials investigating the efficacy or safety (or both) of LABA or LABA plus ICS against a range of clinical endpoints. The review concluded that:

  • a LABA/ICS combination had greater efficacy than either LABA or ICS monotherapy in every study
  • however, the extent of the additional benefit provided by the LABA/ICS combination versus LABA alone was variable and was not always clinically significant. A convincing additional benefit of combination therapy was however seen in the reduction in the rate of exacerbations
    *a significant additional benefit of the LABA/ICS combination has not been proven for milder disease and ICS should not be introduced earlier than guidelines suggest
  • iIn terms of efficacy, no clear dose-response relation was shown for either LABAs or ICS; to date, no treatment has been shown to influence the accelerated decline in lung function that is characteristic of COPD, highlighting the limited treatment options for this patient population

Side effects

A range of side effects have been reported after LABA or LABA/ICS therapy. However their incidence should be considered in the context of the patients, many of whom have systemic inflammation and several co-existing conditions (including cardiovascular disease). Despite this, it is now clear that treatment with an ICS in COPD—either alone or in combination with a LABA—significantly increases the risk of pneumonia (although in clinical trials there was no associated increase in the rate of mortality due to pneumonia).

In the TORCH3 study the probability of pneumonia was 19.6% in the salmeterol/fluticasone group and 18.3% with fluticasone alone versus 12.3% in placebo. No increase in pneumonia risk was observed with salmeterol alone (13.3%). Although β2-agonists have the potential to cause cardiac side effects, no strong signal for an increased risk was identified in the review, even when LABAs were prescribed with a potassium-depleting diuretic. However, the patient population is restricted in clinical trials and the risk may therefore be different in clinical practice.

Advice for healthcare professionals:

  • the overall balance of benefits and risks for LABAs in the treatment of COPD remains positive when used in line with current GOLD and NICE guidelines
  • in all trials combination therapy was better than monotherapy; however the benefit is limited and ICS should be introduced only when COPD progresses to severe disease, in line with current guidelines
  • ICS should not be used alone in COPD
  • akey issue is the increased risk of pneumonia with ICS treatment in COPD. This risk is not apparent with LABAs alone

Article citation: Drug Safety Update July 2009, vol 2 issue 12: 7.

  1. Albers R, et al. Eur Respir J 2002; 19: 936–43. ↩

  2. Appleton S, et al. Cochrane Database Syst Rev 2006; 3: 1–84. ↩

  3. Calverley PM, et al. New Engl J Med 2007; 356: 775–89. ↩

  4. Calverley PM, et al. Lancet 2003; 361: 449–56. ↩

  5. Calverley PM, et al. Eur Respir J 2003; 22: 912–19. ↩

  6. Campbell M, et al. Resp Med 2005; 99: 1511–20. ↩

  7. Nannini LJ, et al. Cochrane Database Syst Rev 2008; 4: 1–108. ↩

  8. Szafranski W, et al. Eur Respir J 2003; 21: 74–81. ↩

  9. Wadbo M, et al. Eur Respir J 2002; 20: 1138–46. ↩

  10. Wedzicha JA, et al. Am J Crit Care Med 2008; 177: 19–26. ↩

Published 11 December 2014
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