Bronchoprotective tolerance with indacaterol is not modified by concomitant tiotropium in persistent asthma

Summary Background Tiotropium is a long acting muscarinic antagonist (LAMA), licensed as triple therapy with inhaled corticosteroid and long‐acting beta‐agonist (ICS/LABA). There may be a synergistic benefit between LAMA and LABA as a consequence of receptor cross‐talk, which in turn could modify beta‐2 receptor downregulation and associated tolerance induced by LABA. Objective We hypothesize this mechanism may result in a reduction of airway hyperresponsiveness (AHR) when using triple therapy. Methods We evaluated 14 non‐smoking asthmatics using an open‐label, randomized crossover design. ICS with Indacaterol and Tiotropium (IND/TIO) vs ICS with Indacaterol (IND) over 4 weeks with challenge performed after first and last doses at trough. Results We found no significant difference in mannitol sensitivity, expressed as the provocative dose of mannitol required to reach a 15% drop in FEV1, or mannitol reactivity, expressed as the response dose ratio (RDR: max % fall in FEV1/cumulative dose), when comparing ICS/IND/TIO to ICS/IND. Geometric mean fold differences for RDR comparing single and chronic dosing were 3.26‐fold (95% CI 1.46‐7.29) and 2.51‐fold (95% CI 1.32‐4.79) for IND and IND/TIO, respectively. Furthermore, salbutamol recovery post‐challenge was significantly blunted after chronic compared to single dosing with either ICS/IND (P