Effects of fluticasone plus salmeterol versus twice the dose of fluticasone in asthmatic patients

Objective: Current guidelines advocate adding a long acting beta(2)-agonist (LABA) to an inhaled corticosteroid as an alternative to increasing the dose of the latter. Since it is unclear how this translates into effects on surrogate inflammatory markers, we evaluated the anti-inflammatory activity of fluticasone plus salmeterol in combination versus twice the dose of fluticasone alone. Methods: Fifteen mild-to-moderate asthmatics (mean FEV1 80% predicted) uncontrolled on inhaled corticosteroids (mean dose 470 mug) were randomised in a single-blind crossover fashion to receive 2 weeks each of fluticasone 250 mug plus salmeterol 50 mug in combination (FP+SM), I puff b.i.d., and fluticasone 500 mug (FP), I puff b.i.d. Prior to each randomised treatment, there was a 2-week run-in and washout period during which patients used their usual inhaled corticosteroid therapy. Measurements were made before and after randomised treatment periods. The primary outcome was airway hyper-responsiveness to adenosine monophosphate (AMP PC20), while secondary endpoints were exhaled tidal nitric oxide (NO), forced expiratory volume in I second (FEV1) and forced mid-expiratory flow (FEF25-75). Results: For AMP PC20, FP alone but not FP + SM conferred a significant (P<0.05) improvement amounting to 3.27 (95% Cl 1.46-7.32) and 1.44 (95% CI 0.64 3.23) geometric mean fold shifts, respectively, from baseline. while the difference between treatments was significantly (P<0.05) greater with FP alone: a 2.26-fold (95% CI 1.01-5.07) difference. Both FP alone and FP+SM conferred significant (P<0.05) falls in NO from baseline: 2.33 (95% CI 1.71-3.19) and 1.49 (95% CI 1.09-2.03) geometric mean fold changes, respectively, while between treatments the reduction was significantly (P<0.05) greater with FP alone: a 1.57-fold (95% Cl 1.15-2.14) difference. Neither treatment significantly improved FEV1 or FEF25-75. Conclusion: Double the dose of FP alone relative to FP + SM conferred superior effects on surrogate inflammatory markers but not on lung function. Longterm studies are required to evaluate whether these improvements on surrogate inflammatory markers translate into commensurate reductions in airway remodelling and exacerbations.