P239 Effects of tiotropium on asthma exacerbations are not explained by airway hyperresponsiveness, exhaled breath nitric oxide or airway geometry

Background Long acting muscarinic antagonists (LAMA) such as tiotropium (TIO) reduce asthma exacerbations in patients receiving inhaled corticosteroids and long-acting beta-agonists (ICS/LABA). However the mechanism for this protective action of LAMA remains unclear. Objectives To evaluate the response to indacaterol (IND) either alone in combination with tiotropium (IND/TIO) in addition to ICS on airway hyperresponsiveness (AHR), FeNO and impulse oscillometry (IOS). Methods n = 14 ICS treated asthmatic patients (Mean age 46 years, FEV1 86% predicted, R5 160% predicted, ICS 693ug/day),were randomised in cross-over fashion to receive either IND 150ug alone (ICS/LABA) or in combination with TIO 18ug once daily (ICS/LABA/LAMA) for 4 weeks with 2 week run-in and washout periods. Mannitol sensitivity (PD15) and reactivity (RDR), airway resistance (R5,R5-R20), reactance (AXE) and FeNO were measured at 24 hours after the first and last doses. Results There were significant improvements in mannitol PD15 and RDR with IND or IND/TIO vs baseline after single but not chronic dosing (Figure) . There was also a significant difference in RDR between single and chronic dosing for both treatments. R5,R5-R20 and AXE were significantly improved with both treatments compared to baseline after single and chronic dosing . There were no significant differences between treatments after chronic dosing for either mannitol or IOS . In contrast FeNO was unchanged with either treatment compared to baseline. Conclusions There were significant improvements in mannitol sensitivity and reactivity with either IND or IND/TIO after single but not chronic dosing, while FeNO remained unchanged . Airway resistance and reactance were significantly decreased to the same degree with both treatments after chronic dosing . This in turn suggests that the mechanism by which LAMA reduces exacerbations is unlikely to be related to AHR, FeNO or airway geometry.