Both β₂-agonists and corticosteroids are needed for optimal asthma control, as soon as asthma is persistent moderate since these two classes target different and complementary aspects of the inflammatory process in asthma. Furthermore, as shown before, they interact in a beneficial way, since corticosteroids prevent the loss of function of β₂-agonists associated with chronic use, whereas β₂-agonists improve the local anti-inflammatory actions of corticosteroids. Therefore, their combination in a single inhaler (LABACS) is supported by a strong scientific rationale and it is now widely proved to be remarkably effective. First investigations with this regard have been performed starting from mid 1990s and, on the basis of the obtained positive results, the approach to asthma therapy changed. The most relevant studies are briefly described below.

FACET study:
Effect of inhaled formoterol and budesonide on exacerbations of asthma
Pauwels, R.A. et al. N Engl J Med 1997; 337: 1405-1411 (18)

In this study, asthmatic patients, characterised at baseline by a FEV₁ of at least 50% of the predicted value, were randomised to one of the following treatments, administered on a twice daily regimen for 12 months: budesonide 100 μg plus placebo, budesonide 100 μg plus formoterol 12 μg, budesonide 400 μg plus placebo and budesonide 400 μg plus formoterol 12 μg. The study revealed that the addition of formoterol to budesonide allowed to achieve a greater reduction of the exacerbation rate than with corresponding doses of budesonide alone; furthermore, as shown in the scheme of Figure 13, greater improvements in lung function (FEV₁ data are reported for every group as mean percentages of predicted values) were obtained with the lower dose of ICS plus formoterol compared to higher doses of budesonide alone.

Figure 13: Forced expiratory volume in one second (FEV₁) during the study.

This was a very important piece of evidence since it demonstrated that adding a long-acting inhaled β₂-agonist to an ICS provides better control of the symptoms of asthma and lung function than increasing 2-fold the dose of the ICS alone.

COMBAT trial:
Improved asthma control with budesonide/formoterol in a single inhaler, compared with budesonide alone.
Zetterström, O. et al. Eur Respir J 2001; 18: 262–268 (19)

This study was performed in asthmatic patients not responding to steroids (FEV₁ 73.8% predicted), who were randomised for 12 weeks to receive budesonide/formoterol (Symbicort^®) 160/4.5 μg two inhalations b.i.d., or corresponding treatment with budesonide, or budesonide plus formoterol via separate inhalers. This study demonstrated for the first time that budesonide/formoterol administered via a single inhaler is more effective than budesonide alone in patients whose asthma was not previously fully controlled by inhaled glucocorticosteroid treatment. At the end of the study period, single inhaler combination treatment was also shown to be as effective and well tolerated as treatment with budesonide plus formoterol, administered via separate inhalers. Interestingly, during the first 30 days of treatment, single inhaler therapy tended to show more rapid improvement in lung function and symptom scores compared with separate inhaler therapy. The improvement in lung function, reduction in symptom scores and reduction in rescue-medication usage attained in this 12-week study after administration of budesonide/formoterol via a single inhaler were similar to those achieved over a 1-year period in the FACET study with separate inhalers.

COMET study:
Budesonide and formoterol in a single inhaler improves asthma control compared with increasing the dose of corticosteroid in adults with mild-to-moderate asthma
Umesh, G. et al. Chest 2003; 123: 1480-1487 (20)

This 12-week trial aimed at evaluating the efficacy and safety of low-dose fixed budesonide/formoterol combination (Symbicort^®), 80 μg/4.5 μg b.i.d., in a single inhaler compared with an increased dose of budesonide, 200 μg b.i.d., in adult patients with mild-to-moderate asthma not fully controlled on low doses of inhaled corticosteroid alone.

The results of the study showed that single-inhaler therapy with budesonide and formoterol provided greater improvements in asthma control than increasing the maintenance dose of inhaled corticosteroid.

These clinical evidence confirm the scientific rationale supporting LABA/ICS combination use in asthma.