Research ArticleOriginal Research

Tiotropium Versus Placebo for Inadequately Controlled Asthma: A Meta-Analysis

Jing-wei Tian, Jin-wu Chen, Rui Chen and Xin Chen
Respiratory Care May 2014, 59 (5) 654-666; DOI: https://doi.org/10.4187/respcare.02703

Abstract

OBJECTIVE: This meta-analysis was performed to evaluate the efficacy and safety of the addition of tiotropium to standard treatment regimens for inadequately controlled asthma.

METHODS: A systematic search was made of PubMed, EMBASE, MEDLINE, and CENTRAL databases, and ClinicalTrials.gov, and a hand search of leading respiratory journals. Randomized, double-blind clinical trials on the treatment of inadequately controlled asthma for ≥ 4 weeks with the addition of tiotropium, compared with placebo, were reviewed. Studies were pooled to odds ratio (OR) and weighted mean differences (WMDs), with 95% CI.

RESULTS: Six trials met the inclusion criteria. The addition of tiotropium, compared with placebo, significantly improved all spirometric indices, including morning and evening peak expiratory flow (WMD 20.59 L/min, 95% CI 15.36–25.81 L/min, P < .001; and WMD 24.95 L/min, 95% CI 19.22–30.69 L/min, P < .001, respectively), trough and peak FEV1 (WMD 0.13 L, 95% CI 0.09–0.18 L, P < .001; and WMD 0.10 L, 95% CI 0.06–0.14 L, P < .001, respectively), the area under the curve of the first 3 h of FEV1 (WMD 0.13 L, 95% CI 0.08–0.18 L, P < .001), trough and peak FVC (WMD 0.1 L, 95% CI 0.05–0.15 L, P < .001; and WMD 0.08 L, 95% CI 0.04–0.13 L, P < .001, respectively), the area under the curve of the first 3 h of FVC (WMD 0.11 L, 95% CI 0.06–0.15 L, P < .001). The mean change in the 7-point Asthma Control Questionnaire score (WMD −0.12, 95% CI −0.21 to −0.03, P = .01) was markedly lower in tiotropium group, but not clinically important. There were no significant differences in Asthma Quality of Life Questionnaire score (WMD 0.09, 95% CI −0.01 to 0.20, P = .09), night awakenings (WMD 0.00, 95% CI −0.05 to 0.05, P = .99) or rescue medication use (WMD −0.18, 95% CI −0.36 to 0.00, P = .06). No significant increase was noticed in adverse events in the tiotropium group (OR 0.80, 95% CI 0.62–1.03, P = .08).

CONCLUSIONS: The addition of tiotropium to standard treatment regimens has significantly improved lung function without increasing adverse events in patients with inadequately controlled asthma. Long-term trials are required to assess the effects of the addition of tiotropium on asthma exacerbations and mortality.

Introduction

Asthma is a chronic respiratory disease characterized by reversible airway obstruction that is secondary to airway inflammation and excessive smooth muscle contraction.1 A great proportion of patients with asthma experience recurring symptoms and exacerbations, even after the administration of high doses of inhaled corticosteroids combined with a long-acting β2 agonists. The Global Initiative for Asthma guidelines recommend the addition of another medication, such as antileukotrienes, theophyllines, anti-IgE, and immunosuppressants (eg, systemic corticosteroids or cyclosporine), to achieve optimal asthma control.2 Nevertheless, many patients do not achieve symptom control with current options. Furthermore, there are also concerns about the safety of regular use of high-dose long-acting β2 agonists and inhaled corticosteroids in patients with asthma. Adding a second bronchodilator with a different mechanism of action into the treatment of inadequately controlled asthma might be a new available way to address the problem.

The parasympathetic nervous system is an important neural pathway that controls airway smooth muscle by muscarinic receptors. Stimulation of the parasympathetic nerve can result in bronchoconstriction, bronchial vasodilatation, and mucus secretion. Moreover, recent investigations revealed that the non-neuronal cholinergic system was widely expressed in epithelial cells, eosinophils, submucosal glands, smooth muscle cells, and a variety of immune cells including lymphocytes, macrophages, and mast cells in the airway, suggesting that non-neuronal cholinergic signals played an important role in the pathophysiology of asthma.3 Therefore, it seems favorable to add an anticholinergic agent to block cholinergic signals in the treatment of asthma. Previous studies found no long-term benefits of short-acting anticholinergic agents in patients with persistent asthma.4,5 Tiotropium bromide is an anticholinergic agent with long-lasting action that is characterized by a slow dissociation from acetylcholine M1 and M3 receptors.6,7 Current COPD treatment guidelines recommend tiotropium as the first-choice long-acting bronchodilator for maintenance therapy in patients with moderate or severe COPD because of its effectiveness, safety, and convenient once-daily dosing.8 However, little has been known about its efficacy in patients with asthma. In animal models of allergic asthma it was shown that tiotropium inhibited airway inflammation and reduced airway remodeling.9,10 Recently, beneficial effects of tiotropium maintenance dosing in patients with asthma have been reported in clinical study. Peters et al11 demonstrated that the addition of tiotropium improved symptoms and lung function in patients with mild-to-moderate asthma that had been poorly controlled with only low-dose inhaled corticosteroids, and its effects were found not to be inferior to those of salmeterol. In addition, Bateman et al12 reported that tiotropium was not inferior to salmeterol in maintaining improved lung function in B16-Arg/Arg patients with asthma and that the addition of tiotropium to treatment with a high-dose inhaled corticosteroid plus a long-acting β2 agonist improved lung function in patients with poorly controlled severe asthma.16

The aim of the present meta-analysis was to evaluate the efficacy and safety of tiotropium versus placebo in asthmatic patients whose symptoms were inadequately controlled with standard treatment regimens (ie, inhaled corticosteroids with or without long-acting β2 agonists).

QUICK LOOK

Current knowledge

Asthma is a common obstructive airway disease typically managed with inhaled bronchodilators and corticosteroids. The benefits of combining two long-acting bronchodilators with different modes of action have been reported in patients with COPD.

What this paper contributes to our knowledge

This meta-analysis suggests that the addition of tiotropium to the treatment of inadequately controlled asthma, compared with placebo, may improve lung function without an increase in adverse events.

Methods

Data Sources

We searched PubMed, EMBASE, MEDLINE, and CENTRAL databases and ClinicalTrials.gov for trials published from January 1980 to December 2012 using the following search terms: “tiotropium OR Ba 679 BR OR Spiriva AND asthma.” These searches were supplemented by hand searching of leading respiratory journals and conference abstracts. All publications and abstracts in the English language were considered. Moreover, a further search in April 2013 did not identify additional trials that fulfilled our search criteria.

Study Selection

The inclusion criteria of trials were as follows: (1) double-blind randomized controlled trials (RCTs) on tiotropium compared with placebo; (2) duration of at least 4 weeks; (3) ≥ 12 y of age; (4) patients with symptomatic asthma even after treatment with an inhaled corticosteroid or an inhaled corticosteroid plus long-acting β2 agonist; (5) a history of asthma without other lung diseases; and (6) a modified Jadad score of ≥ 4 points.

Quality Assessment

The methodological quality of each study was assessed by the Modified Jadad Scale (7 points),13 which scores trials according to randomization, concealment of allocation, double blinding, withdrawals, and dropouts. Studies with a score of ≥ 4 points were included.

Data Extraction

Data extraction was based on reported statistics (means, SD, and SE) for the intention-to-treat population. Two authors (J-wT and J-wC) independently extracted data from the selected studies. If disagreement arose, all the authors conferred until a consensus was reached. Authors of a publication were contacted if only its abstract was available or data were missing. Primary outcomes were changes from baseline in morning and evening peak expiratory flow (PEF). Secondary outcomes included changes from baseline in peak and trough FEV1, peak and trough FVC, the areas under the curve of the first 3 h of FEV1 and FVC, nighttime awakenings, rescue bronchodilator use, 7-point Asthma Control Questionnaire (ACQ-7) score, Asthma Quality of Life Questionnaire (AQLQ) score, and adverse events. The ACQ is a questionnaire consisting of a 7-point scale ranging from 0 (no impairment) to 6 (maximum impairment), with a minimal clinically important difference of 0.5 units.

Statistical Analysis

RevMan (Review Manager, version 5.2, The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) was used to analyze all collected data. Fixed-effects odds ratios (OR) for dichotomous outcomes and the weighted mean difference (WMD) for continuous outcomes, with corresponding 95% CIs, were calculated for individual trials. Trials were pooled using a fixed-effects OR or WMD as appropriate. Heterogeneity was tested with a P value < .1, which is considered statistically significant. The inconsistency (I2) test was also calculated to efficiently test heterogeneity, with values of 25%, 50%, and 75% considered to represent low, moderate, and high heterogeneity, respectively. The differences between patients receiving tiotropium and those receiving placebo were pooled using a fixed-effects model when there was no evidence of significant heterogeneity in the analysis; if significant heterogeneity was found a random-effects model was used.14 Publication bias was examined using funnel plots.15

Results

Search Results

The progress of searching and selecting trials is presented in Figure 1. Of the 42 English-language articles that were screened, we excluded 37 that were either not relevant or had incomplete data. To reduce heterogeneity across different trials, we selected only those comparing tiotropium (5 μg once a day, with Respimat inhaler) with placebo at both baseline and at the end of the treatment period. Five articles involving 1,648 participants, including 6 RCTs (3 parallel RCTs and 3 crossover RCTs) that met our inclusion criteria were selected for the present meta-analysis. Characteristics of the trials we included are shown in Table 1 and Table 2. All data adopted in the present study had been published openly either on a web site (http://ClinicalTrials.gov) or in journals.

Fig. 1.
Fig. 1.

Flow chart for identification of relevant studies. RCT = randomized controlled trials, ACQ = Asthma Control Questionnaire, AQLQ = Asthma Quality of Life Questionnaire, PEF = peak expiratory flow.

View this table:
Table 1.

Characteristics of Participants of Included Studies

View this table:
Table 2.

Studies Included in the Present Analysis

Primary Outcome

Change in Morning and Evening PEF.

The 6 trials included took morning and evening PEF values as end points. The results of each study showed significant improvements in morning and evening PEF in subjects treated with tiotropium. The overall analysis showed statistically significant improvements in morning PEF (WMD 20.25 L/min, 95% CI 15.36–25.81 L/min, P < .001) and in evening PEF (WMD 24.95 L/min, 95% CI 19.22–30.69 L/min, P < .001) in the tiotropium group (Fig. 2).

Fig. 2.
Fig. 2.

Effects of tiotropium versus placebo on peak expiratory flow (PEF). A. Change in morning PEF. B. Change in evening PEF.

Secondary Outcomes

Change in FEV1.

Five trials reported peak and trough FEV1, and 4 trials reported the area under the curve of the first 3 h of FEV1. The results of each study showed significantly greater improvements in peak and trough FEV1 in subjects treated with tiotropium than in those treated with placebo. The pooled analysis (1,260 participants) showed statistically significant improvements in peak FEV1 (WMD 0.13 L, 95% CI 0.09–0.18 L, P < .001) and in trough FEV1 (WMD 0.10 L, 95% CI 0.06–0.14 L, P < .001) in the tiotropium group. Three trials showed obvious improvements in the area under the curve of the first 3 h of FEV1 in the tiotropium group, although one study showed no significant differences between the two groups. The pooled analysis showed a statistically significant improvement in the area under the curve of the first 3 h of FEV1 (WMD 0.13 L, 95% CI 0.08–0.18 L, P < .001) in the tiotropium group. Nevertheless, improvement in FEV1 was not nearly the minimum clinically important difference of 230 mL in asthma20 (Fig. 3).

Fig. 3.
Fig. 3.

Effects of tiotropium versus placebo on FEV1. A. Change in peak FEV1. B. Change in trough FEV1. C. Change in area under the curve of the first 3 h of FEV1.

Change in FVC.

Five included trials reported the FVC. Although no obvious improvements in peak FVC, trough FVC, and area under the curve of the first 3 h of FVC were observed in any single study, the cumulative analysis showed a statistically significant improvement, respectively, in peak FVC (WMD 0.10 L, 95% CI 0.06–0.14 L, P < .001), trough FVC (WMD 0.08 L, 95% CI 0.04–0.13 L, P < .001), and area under the curve of the first 3 h of FVC (WMD 0.11 L, 95% CI 0.06–0.15 L, P < .001) in tiotropium group (Fig. 4).

Fig. 4.
Fig. 4.

Effects of tiotropium versus placebo on FVC. A. Change in peak FVC. B. Change in trough FVC. C. Change in area under the curve of the first 3 h of FVC.

Asthma Control.

Of the trials included, 3 reported score of the ACQ-7. The score was statistically lower with tiotropium than with placebo (WMD −0.12, 95% CI −0.21 to −0.03, P = .01). However, the improvement in ACQ-7 score did not achieve the minimum clinically important difference of 0.5 units in asthma.

Night Awakenings.

Three trials showed data for the mean number of night awakenings during the last week of treatment. The cumulative analysis showed no statistical differences between patients receiving tiotropium and those receiving placebo (WMD 0.00, 95% CI −0.05 to 0.05; I2 = 0%, P = .99) (Fig. 5).

Fig. 5.
Fig. 5.

Effects of tiotropium versus placebo on night awakenings.

Rescue Medication Use.

The mean number of puffs of rescue medication during the whole day in the last week of treatment was reported in 5 trials. Although the pooled analysis showed a dropping trend in patients receiving tiotropium compared with those receiving placebo (WMD −0.18, 95% CI −0.36 to 0.00; I2 = 0%, P = .06), the difference was not statistically significant (Fig. 6).

Fig. 6.
Fig. 6.

Effects of tiotropium versus placebo on rescue medication use.

Quality of Life.

Three trials reported the AQLQ score. Although the cumulative analysis showed a little decrease in patients receiving tiotropium compared with those receiving placebo (WMD 0.09, 95% CI −0.01 to 0.20; I2 = 0%, P = .09), no significant difference between the two groups was observed.

Adverse Events.

The incidence of adverse events was evaluated in 6 studies. The overall cumulative incidence of adverse events was 44% in the tiotropium group and 47.4% in the placebo group. All the adverse events reported in at least 2 trials are shown in Table 3. The overall analysis showed no statistically significant increase in the total number of adverse events in the tiotropium group (OR 0.80, 95% CI 0.62–1.03, P = .08). Among adverse events, asthma exacerbations (OR 0.69, 95% CI 0.54–0.89, P = .004) and PEF rate decline decreased (OR 0.70, 95% CI 0.52–0.96, P = .02) markedly in tiotropium group. There was no statistical significant difference in serious adverse events between the two groups (OR 1.15, 95% CI 0.74–1.79, P = .54) (Fig. 7).

View this table:
Table 3.

Adverse Events With Tiotropium Compared With Placebo

Fig. 7.
Fig. 7.

Effects of tiotropium versus placebo on adverse events. A. Total adverse events. B. Serious adverse events.

Discussion

Asthma is a common airway obstructive diseases, and bronchodilators are very important to the management of asthma symptoms.21 The added benefits of combining two long-acting bronchodilators with different modes of action have been observed in patients with COPD.22 Tiotropium will be approved by the FDA for the treatment of asthma in the next few months. However, guidelines do not specifically recommend the addition of an inhaled long-acting anticholinergic drug to the current treatment of asthma.23 This meta-analysis incorporates 6 RCTs and includes data from 1,648 patients with inadequately controlled asthma. To our knowledge this is the first meta-analysis to date of the efficacy and safety of tiotropium versus placebo regarding clinically relevant outcomes in patients with inadequately controlled asthma who are receiving treatment with inhaled corticosteroids or inhaled corticosteroids plus long-acting β2 agonists. The efficacy of tiotropium is evaluated by its impact on lung function and other clinical outcomes, including asthma control, quality of life, night awakenings, and rescue medication use.

This meta-analysis clearly shows the beneficial effects of the addition of tiotropium on lung function in inadequately controlled asthma patients who are receiving treatment with inhaled corticosteroids or inhaled corticosteroids plus long-acting β2 agonists. When compared with placebo, patients treated with tiotropium showed statistically significant improvements from baseline in all spirometric indices, including trough and peak FEV1, area under the curve of the first 3 h of FEV1, trough and peak FVC, area under the curve of the first 3 h of FVC, and morning and evening PEF. Although the improvement in FEV1 was not nearly the minimum clinically important difference of 230 mL in asthma,20 it should be noted that the increases were in patients who were receiving inhaled corticosteroids or inhaled corticosteroids plus long-acting β2 agonists. There were no significant differences between tiotropium and placebo groups in AQLQ score, night awakenings, or use of rescue medication. Although a statistically significant difference was reported for ACQ-7 score, it was not clinically important. This suggests that despite the good effects of tiotropium on lung function no significant effect on other clinical parameters was demonstrated. Only 2 studies by Kerstjens et al16 reported data about exacerbations. Because the data currently available on exacerbations are insufficient for a meta-analysis, further investigation into the effects of tiotropium on exacerbations are required. Kerstjens et al16 reported that the addition of tiotropium prolonged the time to the first severe exacerbation (282 vs 226 d) with an overall reduction of 21% in the risk of a severe exacerbation (hazard ratio 0.79, P = .03). The results are inconsistent with a previous study. Peters et al11 found that the addition of tiotropium had no significant effect on asthma exacerbations although a trend was observed toward a better effect of tiotropium compared with a higher dose of inhaled corticosteroid. The difference may be attributed to the treatment course in the study by Peters et al,11 which was too short to examine the rate of asthma exacerbations. Moreover, the study by Peters et al11 compared tiotropium with salmeterol and a higher dose of inhaled corticosteroid while that by Kerstjens et al16 compared tiotropium with placebo in patients with poorly controlled asthma. Hospitalization and severe asthma exacerbations will affect the quality of life in subjects with asthma. Although Kerstjens et al16 found a significantly longer time to the first exacerbation, our results showed no significant differences between the tiotropium and placebo groups in AQLQ score. The AQLQ was developed to measure patients' functional experiences over a 2-week period, and it asks patients to recall their experiences during the previous days. Therefore, it is not suitable for capturing the rapidly changing experiences that occur during an acute asthma exacerbation.30 Furthermore, although the difference was not statistically significant, it was noticeable that there were trends toward the improvement of AQLQ score (P = .09) and a reduction in the number of instances of rescue medication use (P = .06) among patients treated with tiotropium. It indicated that the increase in sample size might get a positive result.

It was surprising for us to find a decreasing although statistically insignificant trend in this meta-analysis in the total number of adverse events among patients treated with tiotropium. Among all adverse events, there was an obvious decrease in asthma exacerbations and PEF rate decline in the tiotropium group, which might account for the decreasing trend in total number of adverse events among patients treated with tiotropium. In addition, no significant increase in serious adverse events was observed. Dry mouth, urinary retention, and cardiovascular events are the most concerning adverse side effects of anticholinergic agents. This analysis showed that these adverse events, which were of mild-to-moderate severity according to statements in the relevant articles, were reported in a very small portion of the patients included in the study. It should be noted that the low incidence of cardiovascular events might have resulted from the exclusion of patients with serious cardiovascular diseases in the trials included for this meta-analysis. Excess cardiovascular events might have been anticipated in such patients.

We are very interested in the studies on tiotropium that used a powder inhaler in the treatment of asthma, because Handihaler is the only device now available in China for administering tiotropium. We found 6 RCTs on tiotropium that used the powder inhaler in an asthma population. Of the 6 RCTs, one evaluated the addition of tiotropium to an inhaled glucocorticoid, compared with a doubling of the inhaled glucocorticoid or the addition of salmeterol.11 The results showed that tiotropium improved symptoms and lung function in patients with inadequately controlled asthma when added to an inhaled glucocorticoid. Its effects appeared to be equivalent to those with the addition of salmeterol. To reduce heterogeneity of different trials, we selected only the data comparing tiotropium with placebo. Another RCT was designed to determine the spirometric effects of tiotropium in COPD patients with concomitant asthma.24 The results showed that the patients with COPD and concomitant asthma achieved spirometric improvements with tiotropium treatment along with symptomatic benefits as seen by a reduced need for rescue medication. To reduce the heterogeneity of different trials, we also selected only data from asthma patients without other lung diseases. An RCT by Fardon et al25 compared tiotropium with placebo, but the data it provided were not suitable for our meta-analysis. Three RCTs investigated the protection of tiotropium administered with a powder inhaler device versus that of placebo or other anticholinergic drugs against methacholine-induced bronchoconstriction in patients with asthma,26–28 but they were not relevant to this meta-analysis. Hence, we excluded the 6 RCTs on tiotropium that used a powder inhaler before ultimate analysis.

The main strength of our study was the inclusion of a large pool of patients with inadequately controlled asthma, allowing us to perform robust analysis of clinically relevant outcomes following the addition of tiotropium versus placebo to standard treatment strategy. The trials included in this analysis were of good quality and used almost identical designs with regard to inclusion and exclusion criteria. And the clinical characteristics of study populations were quite homogeneous. However, the results should be interpreted with caution because they might have been influenced by other factors. First, there were differences in trial duration. The duration of treatment in most trials here was too short to allow adequate evaluation of the long-term efficacy and safety of tiotropium. Although a meta-analysis showed a 46% relative risk increase of death in COPD trials that used the 5 μg tiotropium Respimat inhaler,29 it has not been elucidated whether the increase in death among asthma patients was brought about by the use of the Respimat inhaler. Further long-term studies are anticipated to answer this question. Second, the patients with inadequately controlled asthma included in this meta-analysis were ≥ 12 y old, free from other pulmonary diseases, and in non-smoking status. Therefore, it is inappropriate to generalize the results of this meta-analysis to all asthma patients. Third, the trials included in this analysis had different criteria for the use of comedications. In the current trials, tiotropium is a medicine to be added to standard treatment regimens rather than a first-choice medicine.

The clinical homogeneity of the trials resulted in statistical homogeneity for all outcome measures across the trials. Selection bias was avoided using a systematic search strategy, and we specified the inclusion and exclusion criteria. Furthermore, two reviewers independently evaluated the selected studies, and a third reviewer was consulted to reach consensus if necessary. Double counting of patients from overlapping publications was avoided. Funnel plots for the primary end point showed no clear evidence of publication bias. Selective reporting of secondary end points and non-intention-to-treat reports in published manuscripts may have biased the results. We minimized this bias by obtaining supplemental data for the included studies.

Conclusions

This meta-analysis indicates that the addition of tiotropium to the treatment of inadequately controlled asthma, compared with placebo, may improve lung function and not increase the number of adverse events. Because of the limitations of this meta-analysis, we suggest that further work should be required to compare the addition of tiotropium with that of placebo. Larger, longer, multicenter, double-blind, parallel RCTs are expected to validate the efficacy and safety of the addition of tiotropium to standard treatment regimens for inadequately controlled asthma.

Acknowledgments

We thank Guang-qiao Zeng MD, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China, for his assistance in medical writing and statistical advice.

Footnotes

  • Correspondence: Rui Chen PhD, Department of Respiratory Diseases, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Road, Guangzhou 510120, China. E-mail: gzchenrui{at}163.com.

  • The authors have disclosed no conflicts of interest.

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