Objectives: We wished to evaluate the effects of once-daily combination therapy on surrogate inflammatory markers.
Methods: Fifteen patients with atopic persistent asthma were evaluated (mean age, 32.4 years; FEV(1), 75.2% predicted) in a randomized, double-blind, double-dummy, placebo-controlled crossover study with a 1-week placebo washout period, comparing the following once-daily nighttime treatments: (1) formoterol (FM), 12 microg, for 2 weeks and FM, 24 microg, for 2 weeks; or (2) budesonide (BUD), 400 microg, for 2 weeks and BUD, 800 microg, for 2 weeks; or (3) FM, 12 microg, plus BUD, 400 microg, for 2 weeks and FM, 24 microg, plus BUD, 800 microg, for 2 weeks. Adenosine monophosphate (AMP) bronchial challenge, exhaled nitric oxide (NO), and serum eosinophilic cationic protein (ECP) were evaluated at 12 h postdosing after administration of each placebo and after 2 and 4 weeks of each treatment.
Results: The results of AMP challenge (provocative concentration causing a 20% fall in FEV(1)) at 4 weeks showed significant (p<0.05) improvements after patients had received all active treatments compared to placebo (20 mg/mL), with FM plus BUD, 261 mg/mL, being superior (p<0.05) to FM alone, 82 mg/mL, but not to BUD, 201 mg/mL. NO and ECP showed significant (p<0.05) reductions compared to placebo with FM plus BUD or BUD alone but not with FM alone. Combination therapy was associated with optimal patient preference (rank order, FM plus BUD > FM > BUD; p<0.0005), highest domiciliary peak expiratory flow, and lowest rescue inhaler usage. All three treatments produced equivalent improvements in spirometry.
Conclusions: Patients preferred once-daily combination therapy, but this had no greater effect on inflammatory markers than therapy with BUD alone. FM alone had no anti-inflammatory activity but exhibited bronchoprotection. This emphasizes the importance of first optimizing anti-inflammatory control with inhaled corticosteroids before considering adding a regular long-acting beta(2)-agonist.