A proof of concept study to evaluate stepping down the dose of fluticasone in combination with salmeterol and tiotropium in severe persistent asthma

Abstract

We conducted a double blind, randomised, placebo-controlled, crossover study evaluating the effects of halving inhaled steroid dosage plus salmeterol, or salmeterol and tiotropium. Eighteen life-long non-smoking severe asthmatics [mean FEV(1) 1.49 l (51%)] were run-in for 4 weeks on HFA-fluticasone propionate 1000 microg daily, and were subsequently randomised to 4 weeks of either (a) HFA-fluticasone propionate 500 microg BD/salmeterol 100 microg BD/HFA-tiotropium bromide18 microg od; or (b) fluticasone propionate 500 microg BD/salmeterol 100 microg BD matched placebo. Measurements of spirometry and body plethysmography were made. Adding salmeterol to half the dose of fluticasone led to a mean improvement (95% CI) vs. baseline in morning PEF of 41.5 (14.0-69.0)l/min [p<0.05]; and RAW of 0.98 (0.14-1.8)cm H(2)O/l/s [p<0.05]. Adding salmeterol/tiotropium produced similar improvements in PEF and RAW, but also improved FEV(1) by 0.17 (0.01-0.32)l [p<0.05]; FVC 0.24 (0.05-0.43)l [p<0.05] and reduced exhaled NO by 2.86 (0.12-5.6)ppb [p<0.05]. RV and TLC were not altered by either treatment; there were no significant changes in symptoms or quality of life compared with baseline. Addition of salmeterol/tiotropium to half the dose of fluticasone afforded small, but significant improvements in pulmonary function. These effects were not associated with commensurate changes in subjective symptoms or quality of life.

Tiotropium bromide is effective for severe asthma with noneosinophilic phenotype

“…Tiotropium bromide, a recently developed anticholinergic, is a long-acting bronchodilator with a well-established effectiveness for treating chronic obstructive pulmonary disease [2]. Although some subgroups of asthmatics seem to respond better to anticholinergics, the pathophysiological features of these responders have yet to be established [3,4]. Previous studies that aimed to identify asthma subgroups which respond better to anticholinergics have suggested the following clinical features: patients with nocturnal symptoms, chronic asthma showing concurrent fixed airway obstruction, intrinsic asthma with longer duration of disease and nonatopic asthma [1,5].…”

Current opinion: Pharmacological approaches in asthma and COPD

“…Recent research has indicated that the addition of salmeterol and tiotropium in association with halving the dose of fl uticasone propionate in severe asthmatics leads to small improvements in effort-dependent and -independent pulmonary function outcomes, but not in quality-of-life scores [46]. The magnitude of improvements in pulmonary function provided by salmeterol and tiotropium were not predicted by the acute reversibility to salbutamol and ipratropium.…”

Pharmacology and Therapeutics of Bronchodilators

“…Moreover, adding tiotropium bromide once daily as maintenance treatment in addition to at least high-dose ICSs combined with LABAs offers significant potential to improve airway patency in patients with severe persistent asthma who are still symptomatic and obstructed on maximal therapy (Kerstjens et al, 2011). Furthermore, the addition of salmeterol/tiotropium bromide facilitates the step down of ICS in severe patients (Fardon et al, 2007).…”