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Original Research: COPD |

Paradoxical Trough Effects of Triple Therapy With Budesonide/Formoterol and Tiotropium Bromide on Pulmonary Function Outcomes in COPD

Peter A. Williamson, MBChB; Philip M. Short, MBChB; Karine L. Clearie, MBChB; Sriram Vaidyanathan, MBChB; Thomas C. Fardon, MD; Laura J. Howaniec, BSc(Hons); Brian J. Lipworth, MD
Author and Funding Information

From the Asthma and Allergy Research Group, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland.

Correspondence to: Brian J. Lipworth, MD, Asthma and Allergy Research Group, University of Dundee, Ninewells Hospital & Medical School, Dundee DD1 9SY, Scotland; e-mail: brianlipworth@googlemail.com


Funding/Support: This study was performed using department funds of the Asthma and Allergy Research Group.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).


© 2010 American College of Chest Physicians


Chest. 2010;138(3):595-604. doi:10.1378/chest.10-0247
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Background:  Lowest receptor occupancy for a drug occurs at trough prior to the next dose. Previous studies have focused on the effects of triple therapy at peak dose intervals using forced expiratory maneuvers. Impulse oscillometry (IOS) and body plethysmography (PLETH) are more sensitive than spirometry to assess inhaled therapies in COPD.

Methods:  Nineteen patients with COPD (FEV1/FVC ratio < 0.7; FEV1 < 60%) completed a double-blind randomized crossover trial of tiotropium 18 μg/d or placebo for 2 weeks each, with a 1-week washout. Prior to this procedure, there was a nonrandomized 4 week run-in of budesonide/formoterol 200/6 2 puffs bid, which continued throughout the study. Spirometry, IOS, and PLETH were performed both before pre- and post-budesonide/formoterol run-in and at trough following the first and last dose of tiotropium (ie, 24 h posttiotropium and 12 h post-budesonide/formoterol).

Results:  Mean ± SEM for age and FEV1 were 65 ± 2 years and 42 ± 2%, respectively. Following initial budesonide/formoterol, there were no significant changes in spirometry; however, all measures of IOS and PLETH deteriorated (P < .01 for all outcomes). Compared with placebo, tiotropium was additive to budesonide/formoterol after single and chronic dosing measured by FEV1 (P < .001 and P = .014, respectively) and forced expiratory flow, midexpiratory phase (P = .001; P= .026), whereas specific airway resistance, reactance, resonant frequency, and area under the reactance curve showed additive benefits at a single dose only.

Conclusions:  Budesonide/formoterol caused an unexpected worsening of IOS and PLETH outcomes compared with a washed-out baseline in the nonplacebo-controlled run-in. This finding was not observed with spirometry. Subsequent addition of tiotropium improved lung function with all techniques after a single dose and for spirometry after chronic dosing. These paradoxical findings may reflect β2-adrenoceptor downregulation and muscarinic 3 receptor cross talk. Placebo-controlled studies are required to explore this result.

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