Effects of tiotropium on lung function in severe asthmatics with or without emphysematous changes

doi:10.1016/j.pupt.2012.09.007

Pulmonary Pharmacology & Therapeutics

Volume 26, Issue 2, April 2013, Pages 159-166

https://doi.org/10.1016/j.pupt.2012.09.007 Get rights and content

Abstract

The effects of tiotropium, an inhaled long-acting anti-cholinergic agent, on lung function were investigated in obstructed severe asthmatics with and without emphysematous changes despite maximal recommended treatments with high-dose of inhaled glucocorticoids and inhaled long-acting β₂-agonists.

We conducted a double-blind, placebo-controlled study of an inhaled single-dose of tiotropium in 18 asthmatics with emphysema and 18 without emphysema in a crossover manner. The primary efficacy outcome was the relative change in forced expiratory volume in 1 s (FEV₁) from baseline to 60 min, and the secondary outcome was a relative change in FEV₁ from baseline to 12 h. Subsequently, the patients were treated with tiotropium inhaled once daily for 12 weeks in an open label manner, and lung function and symptoms were evaluated.

At baseline, patients with or without emphysema had a mean FEV₁ of 55.9% before tiotropium and 56.8% before placebo, or 77.4% before tiotropium and 77.6% before placebo of the predicted value and were taking a mean dose of inhaled glucocorticoids of 1444 or 1422 μg/day. Among patients with emphysema, the increase from baseline FEV₁ was 12.6 percentage points higher at 60 min after tiotropium than after placebo. Among patients without emphysema, the increase from baseline FEV₁ was 5.4 percentage points higher at 60 min after tiotropium than after placebo.

Tiotropium resulted in improved lung function and symptoms in asthmatics with and without emphysema. These findings suggest that tiotropium will provide a new strategy for the treatment of bronchial asthma and of overlapping asthma and COPD.

Introduction

Bronchial asthma is emerging as a heterogeneous disease, and there is significant variability in response to treatment [1], [2]. Despite treatment with an inhaled corticosteroid (ICS) plus a long-acting β₂-agonist (LABA), many patients have uncontrolled asthma that requires more intensive therapies.

Previous studies have shown that anti-cholinergic agents provide equal to or greater bronchodilatation than β₂-adrenoreceptor agonists in chronic obstructive pulmonary disease (COPD), while short-acting anti-cholinergic agents result in less bronchodilation than β₂-agonists in asthmatic patients [3]. Tiotropium bromide is an anti-cholinergic agent with long-lasting action which is led by a slow-dissociation rate of this antagonist from acetylcholine M₁ and M₃ receptors [4], [5]. There is accumulating evidence showing effects of tiotropium on COPD in both symptoms and lung function, which suggests a very important role in controlling COPD [6]. On the other hand, studies reporting the clinical efficacy of tiotropium on asthmatics have been limited.

Recently, it was demonstrated that the addition of tiotropium improved symptoms and lung function in patients with mild-to-moderate asthma uncontrolled with only low-dose ICS, and its effects were found to be noninferior to those of salmeterol [7]. Furthermore, tiotropium was reported to be noninferior to salmeterol in maintaining improved lung function in B16-Arg/Arg patients with asthma [8], and the addition of tiotropium to high-dose ICS plus LABA improved lung function in patients with uncontrolled severe asthma [9]. Therefore, in addition to the effects on COPD, long-acting anti-cholinergic agents are also considered to be useful to control asthma.

Asthma and COPD occur commonly, and, in clinical practice, there are patients who have the clinical features of both diseases. Such disease state is recently getting recognized as an “overlap syndrome” between bronchial asthma and COPD. It is possible that asthmatic patients with COPD may respond favorably to anti-cholinergic agents. However, patient with overlap syndrome were typically excluded from most of clinical trials. Here, we studied the effect of a single-dose of tiotropium on lung function in obstructed severe asthmatics with and without emphysematous changes despite maximal recommended treatments with high-dose of ICSs and inhaled LABAs, in a randomized double-blind placebo-controlled crossover design. Subsequently, the effects of open-labeled uncontrolled treatment with once-daily treatment with tiotropium for 12 weeks were evaluated.

Section snippets

Study subjects

The study was conducted in the outpatient clinic of the Department of Pulmonary Medicine of Kyushu University Hospital and National Fukuoka-Higashi Medical Center. Patients with severe asthma, who did not suffer from other disorders, for example, liver, kidney, or metabolic diseases, were recruited. The diagnosis of asthma was based on a history consistent with asthma, diffuse expiratory wheezes heard on auscultation of the chest, eosinophils over 3% of total cells in sputum, and the

Results

Thirty-six participants of the present study, 18 asthmatics with emphysema and 18 asthmatics without emphysema, underwent randomization, and all completed the first double-blind, randomized, single-dose, crossover trial. In a subsequent open-label tiotropium study, 3 subjects out of each of 18 in both groups, a total of 6, did not complete the study; 4 of them were not approved for enrollment, and 2 quit because of severe dry mouth as an adverse effect of tiotropium. The mean (±SE) ages were

Discussion

The present study demonstrated an additional effect of tiotropium with ICS plus LABA in asthmatic patients, not only in those without emphysema but also in those with emphysema. To our knowledge, this is the first study to report the effect of tiotropium on asthmatics with emphysema. Significant improvements in lung function were observed when tiotropium was added to treatment with high-dose ICS plus LABA in severe asthmatics, supporting the results of a previous study [9]; only FEV₁ and PEFR

Acknowledgements

This work was partially supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS), a Grant-in-Aid for Challenging Exploratory Research from JSPS, and a Grant-in-Aid for Scientific Research on Innovative Areas from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan, and by the National Institute of Biomedical Innovation, Japan.

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Using a therapeutic strategy that is free from traditional diagnostic labels and based on the identification of “treatable traits” (TTs), which are influential in clinical presentations in each patient, might overcome the difficulties in identifying and validating asthma phenotypes and endotypes. Growing evidence is documenting the importance of using the triple therapy with ICS, LABA, and LAMAs in a single inhaler (SITT) in cases of asthma not controlled by ICS/LABA and in the prevention of exacerbations. The identification of TTs may overcome the possibility of using SITT without considering the specific needs of the patient. In effect, it allows a treatment strategy that is closer to the precision strategy now widely advocated for the management of patients with asthma. There are different TTs in asthma that may benefit from treatment with SITT, regardless of guideline recommendations. The airflow limitation and small airway dysfunction are key TTs that are present in different phenotypes/endotypes, do not depend on the degree of T2 inflammation, and respond better than other treatments to SITT. We suggest that the 5T (Triple Therapy Targeting Treatable Traits) approach should be applied to the full spectrum of asthma, not just severe asthma, and, consequently, SITT should begin earlier than currently recommended.
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Overlap of asthma and chronic obstructive lung disease (ACO) in patients with obstructive lung disease is growing in recognition, though there is no consistent agreement on the diagnostic criteria for the disease process. Patients with ACO have distinct clinical characteristics and trajectories, which are representative of a heterogenous, multifactorial, and incompletely understood inflammatory pathophysiology. Current treatment strategies are focused on titration of inhaled therapies such as long-acting bronchodilators, with increasing interest in the use of targeted biologic therapies aimed at the underlying inflammatory mechanisms. Future directions for research will focus on elucidating the varied inflammatory signatures leading to ACO, the development of consistent diagnostic criteria and biomarkers of disease, and improving the clinical management with an eye toward targeted therapies.
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Respiratory physicians in 16 Japanese hospitals answered a questionnaire on treatment for patients with asthma between December 2014 and February 2015. Medical records were reviewed for 1756 patients with asthma.
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However, it is not well known which phenotype(s) of asthma will receive more benefit from treatment with LAMA [19]. We previously reported that a single dose of inhaled tiotropium improved lung function in asthmatics both with and without emphysematous changes [20]. In this study, we found that the improvement of lung function was greater in asthmatics with emphysematous changes.
The effects of tiotropium, an inhaled long-acting muscarinic antagonist, on lung function were investigated in current smokers and nonsmokers with asthma treated with inhaled corticosteroids (ICSs) and other asthma controllers: inhaled long-acting β₂ agonists, leukotriene receptor antagonists, and/or theophylline.
We conducted a double-blind, placebo-controlled study of an inhaled single dose of tiotropium in 9 asthmatics currently smoking and 9 asthmatics who have never smoked in a crossover manner. Lung function was measured before and 1, 3, and 24 h after inhalation of 18 μg of tiotropium or a placebo. The primary outcome was a change in forced expiratory volume in 1 s (FEV₁) from the baseline, and the secondary outcomes were changes in peak expiratory flow rate (PEFR), ${\dot{V}}_{50}$ , and ${\dot{V}}_{25}$ .
At baseline, asthmatics with and without a smoking history had a mean FEV₁ of 2590 ml and 2220 ml and were taking a mean dose of ICSs of 1208 and 1000 μg/day, respectively. The increase from the baseline FEV₁ was 169 ml and 105 ml higher at 3 h after tiotropium than after the placebo in current smokers and nonsmokers, respectively.
PEFR, ${\dot{V}}_{50}$ , and ${\dot{V}}_{25}$ were also significantly increased after tiotropium as compared with the placebo in both study groups. Changes in FEV₁ and PEFR tended to be greater in asthmatics currently smoking than in subjects who have never smoked, although there were no statistical differences at any time points.
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A total of 167 patients were recruited; among them, 123 patients completed the study. At baseline, no significant difference (P > 0.05) was observed in any of the outcome measures. Significant within-group improvement in FEV₁ was observed in all the groups. At day 90, between-group difference revealed that improvement in FEV₁ was significantly (P < 0.05) high for budesonide plus formoterol followed by budesonide plus doxofylline, budesonide plus montelukast, and, lastly, budesonide plus tiotropium. Similarly, within-group comparison revealed a significant (P < 0.05) reduction in rescue medication use in all the groups. The intensity in decrease was more in budesonide plus formoterol group followed by budesonide plus doxofylline, budesonide plus montelukast, and budesonide plus tiotropium groups.
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Effects of tiotropium on lung function in severe asthmatics with or without emphysematous changes

Abstract

Introduction

Section snippets

Study subjects

Results

Discussion

Acknowledgements

J Allergy Clin Immunol

Eur J Pharmacol

Life Sci

J Allergy Clin Immunol

J Allergy Clin Immunol

Respir Med

Am J Med

Chest

Respir Med

Chest

Can guideline-defined asthma control be achieved? The gaining optimal asthma control study

Am J Respir Crit Care Med