Introduction

Experience with long-acting beta agonists (LABAs, or ‘symptom controllers’) over the last 10 years indicates that these drugs are potent and effective bronchodilators, capable of improving asthma control in those with moderate to severe disease. They are optimally used in combination with inhaled corticosteroids (ICS), these two classes thereby providing a dual anti-inflammatory and bronchodilator action.

Combination therapy with these agents is most appropriate in patients with moderate to severe asthma who remain symptomatic on ICS therapy, requiring frequent symptom relief with short-acting beta agonists.

The rationale and evidence for combination therapy 

ICS have a vital role in gaining and maintaining control in mild, moderate and severe asthma. Their use is based primarily on the understanding that cellular mechanisms cause inflammatory mediator release, airway injury and remodelling, leading to poorer lung function and unstable disease. LABAs are potent bronchodilator drugs that are not suitable for use as monotherapy in asthma. Their use in combination with ICS has led to the rethinking of some important issues in asthma management. 

Does the addition of a symptom controlling agent lead to any ‘masking’ of underlying airway inflammation?¹ 

This may seem possible, given that any worsening of disease would not necessarily be perceived by patients taking symptom-controlling LABAs. However, current evidence does not support this. In one study, symptomatic asthmatics taking ICS were given either more ICS or a LABA to gain effective symptom control. Bronchial biopsies were examined at the start of the study and after 3 months. Those taking a LABA had better symptom control and showed no evidence of masking of underlying airway inflammation.² 

Is there any evidence of an anti-inflammatory effect of LABAs in addition to ICS? 

Some studies have found that although LABAs alone do not act as anti-inflammatory agents³, they may enhance the anti-inflammatory effect of ICS. In studies examining airway inflammation in people with asthma who remain symptomatic on ICS, the addition of a LABA resulted in less airway inflammation.⁴ Eosinophils are sensitive indicators of corticosteroid activity and are readily suppressed by ICS. Studies on sputum⁵ and peripheral blood⁶ have indicated that LABAs in combination with ICS may exert an anti-eosinophilic effect. Recent evidence supports this view, showing that ICS have enhanced activity at glucocorticoid receptors after exposure to LABAs.⁷ 

Recent studies have also found a plateau effect with ICS. There is minimal clinical benefit of increasing doses above 250-500mcg/day of fluticasone propionate (FP). This has been observed with other ICS.⁸ This finding is a clear indication for the addition of a LABA to achieve better asthma control in symptomatic patients taking higher doses of ICS. 

When these findings are taken together, evidence indicates that there is likely to be an interaction between the two drugs, manifesting as reduced airway inflammation with prolonged and enhanced bronchodilation, reflected in better clinical outcomes. 

In studies of the combination given in a single versus two devices, statistically significant, but no clinically important differences have been shown in favour of one versus two devices.⁹ The reasons for these apparent small benefits may relate to the simultaneous delivery of ICS and LABAs.