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Long-acting ß-agonist controversy

The problem

Bandolier is usually on the look out for controversy, and examples of where the principles of evidence are misused. Where both circumstances come together, then it is likely that we have a good learning example. Such an occurrence is with conflicting views about what systematic reviews and meta-analyses say about the safety of long acting ß-agonist inhalers taken with inhaled corticosteroids for asthma.

The problem

The problem is neatly outlined by some folk from the Canadian Asthma Guidelines Group [1]. They point out that a meta-analysis published in 2006 [2] has been prominent in questioning the safety of long-acting ß-agonists in asthma. The meta-analysis suggested an increase in severe exacerbations requiring hospital admission, and life-threatening exacerbations requiring intubation and ventilation, with risks of both about doubled.

The problem was that in a large proportion of the studies in this meta-analysis, patients were not required to take inhaled corticosteroids. Yet current guidance endorses long-acting ß-agonists as add-on therapy to inhaled corticosteroids.

The results of this meta-analysis differ from two others, both Cochrane reviews [3,4]. In one, the control for long-acting ß-agonists in addition to inhaled corticosteroid was placebo [3]. In the other, long-acting ß-agonists in addition to inhaled corticosteroid was compared with a higher dose of inhaled corticosteroid [4].

The results of all three meta-analyses for hospital admissions for exacerbations of asthma are shown in Table 1. As well as having different controls for long-acting ß-agonists in addition to inhaled corticosteroid, the total number of events was low in each case, and the event rates generally below 2%.

Table 1: Summary of evidence on hospital admissions for asthma from three systematic reviews and meta-analyses that used different standards for inhaled corticosteroids with long-acting ß-agonists

Long-acting ß-agonists
Inhaled corticosteroids
Events per 1000
Events per 1000
Odds ratio
Salpeter et al, 2006 [1]
inconsistent use
2.6 (1.6 to 4.3)
Ni Chroinin et al, 2005 [2]
Same dose both groups
0.8 (0.5 to 1.4)
Greenstone et al, 2005 [3]
Higher dose in controls
0.7 (0.3 to 1.5)


With rare but serious adverse events the major difficulty is one of numbers. We often have only small numbers of events. When this is compounded by different comparators, and especially by comparators that are outside usual treatment guidelines, interpretation becomes especially difficult. A third complication here is that of ethnicity. A large randomised trial designed to look at rare adverse events with long-acting ß-agonists (not necessarily as add-on therapy to inhaled corticosteroids) was originally designed to enrol 60,000 patients, but was discontinued early because of an unexpected deaths in African-American patients [5]. The major effect was in African-Americans not using inhaled corticosteroids.

Increased use of long-acting ß-agonists has occurred at the same time as asthma hospital admissions and mortality have been falling. When patients with asthma are not well controlled with low dose inhaled corticosteroids the options are higher doses of steroids (which has its own drawbacks like cataract and fracture), or long-acting ß-agonists in addition to inhaled corticosteroid.

Benefit and possible harm have to be balanced, something not easily compressed into a headline because the issues are complex [6]. In this case, the lesson seems to be to keep taking the guidance.


  1. P Ernst et al. Safety and effectiveness of long acting inhaled ß-agonist bronchodilators when taken with inhaled corticosteroids. Annals of Internal Medicine 2006 145:692-694.
  2. SR Salpeter et al. Meta-analysis: effect of long-acting ß-agonists on severe asthma exacerbations and asthma-related deaths. Annals of Internal Medicine 2006 144:904-912.
  3. M Ni Chroinin et al. Long-acting beta2-agonists versus placebo in addition to inhaled corticosteroids in children and adults with chronic asthma. Cochrane database of Systematic Reviews 2005:CD005535.
  4. IR Greenstone et al. Combination of long-acting beta2-agonists and inhaled steroids versus higher dose of inhaled steroids in children and adults with persistent asthma. Cochrane database of Systematic Reviews 2005:CD005533.
  5. HS Nelson et al. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006 129:15-26.
  6. HS Nelson. Long-acting ß-agonists in adult asthma: evidence that these drugs are safe. Primary Care Respiratory Journal 2006 15:271-277.

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