0
Original Research: Asthma |

What Is the Role of Tiotropium in Asthma?Tiotropium for Asthma: A Systematic Review With Meta-analysis FREE TO VIEW

Gustavo J. Rodrigo, MD; José A. Castro-Rodríguez, MD, PhD
Author and Funding Information

From the Departamento de Emergencia (Dr Rodrigo), Hospital Central de las Fuerzas Armadas, Montevideo, Uruguay; and Departments of Pediatrics and Family Medicine (Dr Castro-Rodríguez), School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.

CORRESPONDENCE TO: Gustavo J. Rodrigo, MD, Departamento de Emergencia, Hospital Central de las Fuerzas Armadas. Av. 8 de Octubre 3020, Montevideo 11300, Uruguay; e-mail: gustavo.javier.rodrigo@gmail.com


FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;147(2):388-396. doi:10.1378/chest.14-1698
Text Size: A A A
Published online

BACKGROUND:  The role of tiotropium for the treatment of asthma has not yet been clearly defined. The aim of this systematic review was to assess the efficacy and safety of tiotropium in patients with asthma.

METHODS:  Randomized placebo-controlled trials were included. Primary outcomes were peak and trough FEV1 and morning and evening peak expiratory flow (PEF).

RESULTS:  Thirteen studies (4,966 patients) were included. Three different therapeutic protocols were identified. Tiotropium as an add-on to inhaled corticosteroids (ICSs) showed statistically and clinically significant increases in PEF (22-24 L/min) and FEV1 (140-150 mL). Additionally, tiotropium decreased the rate of exacerbations (number needed to treat for benefit [NNTB], 36) and improved asthma control. The use of tiotropium in patients poorly controlled despite the use of medium to high doses of ICS was not inferior to salmeterol. Finally, the use of tiotropium as an add-on to ICS/salmeterol combination increased pulmonary function to a clinically significant magnitude, reduced asthma exacerbations (relative risk, 0.70; 95% CI, 0.53-0.94; P < .02; I2 = 0%; NNTB, 17), and improved asthma control compared with ICS/salmeterol. Tiotropium was well tolerated, and no potential safety signals were observed.

CONCLUSIONS:  Tiotropium resulted noninferiorly to salmeterol and superiorly to placebo in patients with moderate to severe asthma who were not adequately controlled by ICS or ICS/salmeterol. Major benefits were concentrated in the increase in lung function and in the case of patients with severe asthma, in the reduction of exacerbations.

Figures in this Article

Since the early 1970s, there has been a renewed interest in the use of anticholinergics, given the need to develop alternatives to therapy with β2-agonist agents. In acute severe asthma, the addition of ipratropium bromide to β2-agonists has been shown to reduce hospital admissions and improve respiratory function more than β2-agonists alone,1,2 whereas in chronic asthma, use of short-acting anticholinergic agents resulted in less bronchodilation than have β2-agonists.3

A group of studies evaluated the potential benefits and safety of the use of tiotropium bromide (the first long-acting anticholinergic agent) for the treatment of symptomatic asthma.46 The evidence from these and other studies were partially analyzed by two published reviews. The first was a systematic review without meta-analysis that included five randomized controlled trials (RCTs),7 and the second8 was a systematic review with a meta-analysis based on six RCTs. Both reviews concluded that tiotropium may play a beneficial role in the treatment of inadequately controlled asthma, compared with placebo, without an increase in adverse events (AEs). However, based on the small number of studies and the low accuracy of their conclusions, we conducted a new systematic review to clarify the role of tiotropium in the treatment of patients with asthma. The objective was to assess the efficacy and safety of tiotropium in symptomatic patients with asthma with various levels of severity and therapeutic protocols.

Search and Selection Criteria

This study was registered with the International Prospective Register of Systematic Reviews (PROSPERO) (http://www.crd.york.ac.uk/PROSPERO) as CRD42014009840. We adopted PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines to perform this review.9 We identified published studies from Medline, Embase, CINAHL, Scopus, and CENTRAL (Cochrane Central Register of Controlled Trials) (September 2014) databases and ClinicalTrials.gov using the following search terms: “tiotropium OR Ba 679 BR OR Spiriva AND asthma.” Additionally, we performed a search of relevant files from the drug manufacturer’s database. The search was without language restriction and included unpublished studies. Trials published solely in abstract form were excluded because the methods and results could not be fully analyzed.

To be included, studies had to meet all the following criteria: (1) adults and adolescents aged > 12 years with symptomatic stable asthma of any severity and receiving inhaled corticosteroids (ICSs) or an ICS plus long-acting β2-agonist (LABA); (2) RCT (parallel group or crossover) of ≥ 4 weeks duration; (3) comparison of inhaled tiotropium (5 μg once daily [OD] through a Respimat inhaler [Boehringer Ingelheim GmbH], 18 μg through a HandiHaler [Boehringer Ingelheim GmbH], or any device) with any treatment; and (4) report of at least one of the following outcomes: pulmonary function in terms of peak or trough FEV1 and morning or evening peak expiratory flow (PEF) rate as primary outcomes and rescue medication use (puffs/d), asthma symptom-free days per week, quality of life (Mini-Asthma Quality of Life Questionnaire [AQLQ] total score),10 asthma control (Asthma Control Questionnaire 7 [ACQ-7] total score),11 ACQ-7 responder rate determined by the percentage of patients with an improvement (decrease) in the ACQ-7 total score of at least 0.5 points, asthma exacerbations (number of patients with one or more episodes that required the use of systemic corticosteroids), withdrawals (total and due to AEs), and safety (AEs and serious adverse events [SAEs]) as secondary outcomes. For both the AQLQ and the ACQ-7, the minimal clinically important difference (MCID) is 0.5 units.10,11 An SAE was defined as any untoward medical occurrence that sometimes results in death, is life threatening, requires inpatient hospitalization, or results in persistent or significant disability or incapacity.12

Data Extraction and Assessment of Risk of Bias

We independently analyzed titles, abstracts, and citations and from the full text, independently assessed all studies for inclusion based on the criteria for population intervention, study design, and outcomes. After obtaining full reports about potentially relevant trials, we assessed eligibility. We both were independently involved in all stages of study selection, data extraction, and risk-of-bias assessment. The latter was assessed according to recommendations outlined in the Cochrane handbook13 for the following items: (1) adequacy of sequence generation, (2) allocation concealment, (3) blinding of participants and investigators, (4) blinding of outcome assessment, (5) incomplete outcome data, (6) selective outcome reporting, and (7) other bias. Disagreements were discussed and resolved by consensus.

Data Analysis

Analysis was by intention to treat and included all participants to minimize bias. Outcomes were pooled using mean differences (inverse variance method) or Mantel-Haenszel risk ratios. The precision of the estimates was quantified by 95% CI. When effect estimates were significantly different between groups, the number needed to treat for benefit (NNTB) or for harm was obtained. Heterogeneity was measured by the I2 test14 (≤ 25%, absent; 26%-39%, unimportant; 40%-60%, moderate; 60%-100%, substantial). A fixed-effects model was used when there was no evidence of significant heterogeneity in the analysis; if significant heterogeneity was found, a random-effects model was used.15 As an a priori subgroup analysis, we explored the influence of asthma severity. Subgroups were compared using the residual χ2 test from the Peto ORs.16 Potential publication bias was analyzed quantitatively by means of Egger regression using a significance level of P < .1.17 Otherwise, P < .05 (two-tailed test) was considered significant. The meta-analysis was performed with Review Manager version 5.3.3 software (The Nordic Cochrane Centre, The Cochrane Collaboration).

The process of study selection is outlined in Figure 1. Thirteen RCTs including 4,966 patients met the entry criteria.4,6,1828 One study included data from two replicate trials.20 Two replicated trials were presented separately in two different studies.26,27 Four studies included two different comparisons.6,18,26,27 Characteristics of the trials are shown in Table 1. The selected studies were grouped into three treatment protocols: (1) tiotropium OD as add-on to ICS in patients with mild to moderate asthma,6,18,2128 (2) tiotropium OD added to ICS vs bid LABA plus ICS in patients with moderate asthma,6,18,26,27 and (3) tiotropium OD as add-on to LABA plus ICS vs LABA plus ICS in patients with severe asthma.4,19,20 Severity was determined according GINA (Global Initiative for Asthma) criteria.29 The main inclusion criteria of the studies were reversible airways obstruction (improvement in FEV1 of at least 12% and 200 mL) and a history of asthma diagnosed before age 40. Patients were nonsmokers or former smokers in the year before enrollment. Six trials were unpublished.21,22,2528 The duration of studies ranged between 4 and 52 weeks. Only one study was not sponsored by a pharmaceutical company.6 Most of the studies used the Respimat device to administer 5 μg tiotropium OD.1828 The HandiHaler device (18 μg tiotropium OD) was used in only one study,6 and a pressurized metered-dose inhaler in another (18 μg tiotropium OD).4 All but one of the studies showed a low risk of bias in the six items of the Cochrane instrument; the one study4 had an unclear sequence generation, and concealment was judged to have a high risk of bias.

Figure Jump LinkFigure 1 –  Flowchart for the identification of studies used. RCT = randomized controlled trial.Grahic Jump Location
Table Graphic Jump Location
TABLE 1 ]  Characteristics of Included Studies

Data are presented as No. (% female sex) or mean (range) unless otherwise indicated. AUC = area under the curve; BI = Boehringer Ingelheim; CO = crossover; ICS = inhaled corticosteroid; DB = double blind; N/A = data not available; OD = once daily; PC = placebo controlled; PEF = peak expiratory flow; PG = parallel group; R = randomized; SAL = salmeterol; TIO = tiotropium.

Tiotropium as Add-on to ICS

Ten trials compared tiotropium as add-on to ICS with ICS alone in symptomatic patients with asthma. Of these, seven included patients with moderate asthma receiving a medium dose of ICS,6,2224,2628 one included patients with mild asthma receiving a low dose of ICS,25 and two included patients with moderate asthma treated with a medium to high dose of ICS.18,21 The data analysis indicated that tiotropium OD as add-on to ICS was associated with significant improvements in morning and evening PEF (mean change from baseline, 22-24 L/min, P < .00001) compared with ICS monotherapy (Fig 2). The results were statistically homogeneous, and there was no evidence of systematic bias (P = .74 and P = .73). In the same way, tiotropium improved peak FEV1 (mean change from baseline, 150 mL; P < .00001) and trough FEV1 (mean change from baseline, 140 mL; P < .00001) compared with ICS alone. Both comparisons were statistically homogeneous (Table 2). Additionally, tiotropium significantly improved AQLQ and ACQ-7 total scores from baseline (0.07 [P < .03] and −0.14 units [P < .00001], respectively), although these improvements and their CIs did not achieve the MCID. However, tiotropium showed a greater likelihood of achieving an MCID in ACQ-7 (66.3% vs 60.2%), with an NNTB of 16. Furthermore, tiotropium produced a significant decrease in the number of patients with at least one episode of asthma exacerbation compared with ICS monotherapy (10.5% vs 13.3%), with an NNTB of 36. Finally, there were no significant differences in asthma symptom-free days, total withdrawals, withdrawals due to AEs, AEs (34.6% vs 34.6%), and SAEs (1.9% vs 2.1%).

Figure Jump LinkFigure 2 –  A and B, Pooled mean difference for morning (A) and evening (B) peak expiratory flow at the end of treatment (change from baseline) with 95% CIs of eligible studies comparing ICS plus tiotropium vs ICS (patients with mild to moderate asthma). df = degrees of freedom; ICS = inhaled corticosteroid; IV = inverse variance.Grahic Jump Location
Table Graphic Jump Location
TABLE 2 ]  Tiotropium as Add-on to ICS on Asthma Outcomes (Mild to Moderate Asthma)

ACQ-7 = Asthma Control Questionnaire 7; AE = adverse event; AQLQ = Asthma Quality of Life Questionnaire; MD = mean difference; NNTB = number needed to treat for benefit; RR = relative risk; SAE = serious adverse event. See Table 1 legend for expansion of other abbreviation.

Tiotropium Plus ICS vs LABA Plus ICS

Four studies compared tiotropium OD added to ICS vs bid LABA plus ICS. All included patients with moderate asthma. Three used a medium dose of ICS6,26,27 and one a medium to high dose.18 Tiotropium significantly improved morning PEF more than LABA (Fig 3A), although the magnitude of the increase was small (6.6 L/min). On the other hand, there was no significant difference in evening PEF between groups (Fig 3B). In the same way, there was no significant differences in peak and trough FEV1. On the contrary, patients receiving LABA experienced a significant reduction in the use of rescue medication (−0.2 puffs/d) and an improved AQLQ total score (0.12 units) (Table 3) but without reaching the MCID. There were no significant differences in asthma symptom-free days; ACQ-7 total score and responder rate; number of patients with at least one asthma exacerbation; and withdrawals, AEs (67.6% vs 72.8%), and SAEs (1.9% vs 2.5%).

Figure Jump LinkFigure 3 –  A and B, Pooled mean difference for morning (A) and evening (B) peak expiratory flow at the end of treatment (change from baseline) with 95% CIs of eligible studies comparing ICS plus tiotropium vs ICS plus LABA. LABA = long-acting β2-agonist. See Figure 2 legend for expansion of other abbreviations.Grahic Jump Location
Table Graphic Jump Location
TABLE 3 ]  Tiotropium Plus ICS vs LABA Plus ICS on Asthma Outcomes (Moderate Asthma)

LABA = long-acting β2-agonist. See Table 1 and 2 legends for expansion of other abbreviations.

Tiotropium as Add-on to LABA Plus ICS

Three studies4,19,20 compared a triple therapy (tiotropium OD added to bid LABA plus ICS) vs a combination of bid LABA plus high doses of ICS in symptomatic patients with severe asthma. One study20 comprised two replicate trials. Tiotropium as add-on to LABA plus ICS was associated with significant improvements in morning and evening PEF (16 [P < .0004] and 20 L/min [P < .00001], respectively) (Fig 4). The heterogeneity among studies was moderate, and there was no evidence of systematic bias (P = .15 and P = .68). In the same way, triple therapy increased peak and trough FEV1 significantly by a magnitude of 120 and 80 mL, respectively, compared with LABA plus ICS (Table 4). Although the combination of tiotropium, LABA, and ICS resulted in significant increases in AQLQ and ACQ-7 total scores, they did not reach the MCDI. However, tiotropium showed a greater likelihood of achieving an MCID in ACQ-7 score (58.1% vs 45.1%), with an NNTB of 8. Finally, triple therapy showed a significant reduction in the number of patients who experienced at least one asthma exacerbation (18.2% vs 24.0%), with an NNTB of 17. There were no significant differences between groups in the remainder of outcomes.

Figure Jump LinkFigure 4 –  A and B, Pooled mean difference for morning (A) and evening (B) peak expiratory flow at the end of treatment (change from baseline) with 95% CIs of eligible studies comparing ICS plus LABA plus TIO vs ICS plus LABA. TIO = tiotropium. See Figure 2 and 3 legends for expansion of other abbreviations.Grahic Jump Location
Table Graphic Jump Location
TABLE 4 ]  Tiotropium as Add-on to ICS Plus LABA vs ICS Plus LABA on Asthma Outcomes (Severe Asthma)

See Table 1-3 legends for expansion of abbreviations.

a 

20(1), 2(2)0 = trials 1 and 2 from Kerstjens et al.20

The role of tiotropium as a treatment for asthma has only recently been a subject of clinical investigation. Two systematic reviews7,8 placed the tiotropium as add-on treatment in patients with inadequately controlled asthma despite a moderate to high dose of ICS. However, this conclusion arises from an incomplete analysis of the available data. Thus, we conducted a new systematic review to clarify the role of tiotropium for the treatment of patients with asthma of varying levels of severity. To our knowledge, this systematic review contains the largest amount of information currently available (13 studies with 14 RCTs in almost 5,000 patients with asthma) regarding the use of tiotropium in adolescents and adults with mild to severe symptomatic, stable asthma.

The present analysis identified three different therapeutic protocols. In the first protocol, we found that for the treatment of patients with mild to moderate asthma, tiotropium as an add-on to ICS provided statistically and clinically significant improvements in lung function compared with ICS monotherapy. Of note, all increases achieved the MCID (PEF, 20 L/min; FEV1, 100 mL).30 These effects were paralleled by significant improvements in other outcomes, such as asthma control and health status, although these improvements did not achieve their respective MCIDs. Even so, patients receiving tiotropium had a slightly higher probability of experiencing an increase of ≥ 0.5 points in ACQ-7 score, with an NNTB of 16. Additionally, tiotropium significantly reduced exacerbations and episodes of worsening asthma (NNTB, 36). Finally, tiotropium was well tolerated, and no potential safety signals were observed.

The assessment of the second protocol suggests that tiotropium OD in symptomatic patients with moderate asthma despite the use of medium to high doses of ICS is not inferior to bid LABA. Except for small differences in morning PEF, rescue medication use, and health status, overall, the evidence suggests that tiotropium may be an alternative to the use of bid LABA. The incidence of AEs and SAEs was similar in both groups.

Finally, the third protocol involved patients with poorly controlled severe asthma despite treatment with high doses of ICS and bid LABA. In this case, the addition of tiotropium to the ICS plus LABA combination increased pulmonary function ​​close to or reaching the MCID. Furthermore, adding tiotropium reduced asthma exacerbations by 30% (NNTB, 17). In the same way, tiotropium improved ACQ-7 and AQLQ scores and other secondary outcomes, although these improvements did not reach their respective MCIDs. Nevertheless, patients receiving tiotropium had a higher probability of achieving a decrease of ≥ 0.5 points in ACQ-7 score, with an NNTB of 8.

This review was performed according to scientific guidelines.9 Several relevant databases were searched for published and unpublished articles in any language. Risk of bias was formally assessed. The composition of the sample was large and included the full spectrum of asthma severity. The studies were homogeneous and showed a high methodologic quality. Overall, the effect sizes were consistent, and only a few comparisons showed evidence of a substantial heterogeneity. However, several potential limitations should be considered. The use of data from unpublished studies allows the analysis of the latest information but should be considered as not peer reviewed. In some cases, it was difficult to evaluate the clinical significance of changes. MCIDs were derived on the basis of differences vs placebo or changes from baseline rather than differences between two active treatments,31,32 and the improvement in various end points occurred in patients taking high doses of medication (sustained-release theophylline, leukotriene modifiers, oral corticosteroids, and even omalizumab). Additionally, almost 40% of the studies included had too short a duration of treatment (< 12 weeks) to allow a complete assessment of efficacy and safety.

In conclusion, this systematic review suggests that tiotropium is noninferior to salmeterol and superior to placebo in patients with moderate to severe asthma who are not adequately controlled by low to moderate ICS or high doses of ICS plus LABA. Major benefits are concentrated in lung function and, in patients with severe asthma, an increase in control and a decrease in exacerbations. Thus, tiotropium might be an alternative to LABA in patients with mild to moderate asthma whose symptoms are not well controlled by ICS alone or as an add-on therapy in patients with severe asthma not controlled with available medications, including ICS plus LABA. Although the results of this review show no increase in AEs associated with the use of tiotropium Respimat, potential undesirable effects (cardiovascular and others) must be taken into consideration given several warnings made in the literature.3335 Finally, these findings apply mainly to the use of 5 μg tiotropium OD delivered through the Respimat device.

Author contributions: G. J. R. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. G. J. R. contributed to the study concept and design, data acquisition, data analysis and interpretation, drafting of the manuscript, critical revision of the manuscript for important intellectual content, and final approval of the manuscript and J. A. C.-R. contributed to the study concept and design, data interpretation, critical revision of the manuscript for important intellectual content, and final approval of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Rodrigo has participated as a lecturer, speaker, and advisor in scientific meetings and courses under the sponsorship of Air Products & Chemicals, Inc; Almirall, SA; AstraZeneca; Boehringer Ingelheim GmbH; Esteve; GlaxoSmithKline plc; Merck Sharp & Dohme Corp; and Novartis AG. Dr Castro-Rodríguez has participated as a lecturer and speaker in scientific meetings and courses under the sponsorship of Merck Sharp & Dohme Corp, GlaxoSmithKline plc, and Grünenthal and as member of the advisory board for GlaxoSmithKline plc.

ACQ-7

Asthma Control Questionnaire 7

AE

adverse event

AQLQ

Asthma Quality of Life Questionnaire

ICS

inhaled corticosteroid

LABA

long-acting β2-agonist

MCID

minimal clinically important difference

NNTB

number needed to treat for benefit

OD

once daily

PEF

peak expiratory flow

RCT

randomized controlled trial

SAE

serious adverse event

Rodrigo GJ, Rodrigo C. First-line therapy for adult patients with acute asthma receiving a multiple-dose protocol of ipratropium bromide plus albuterol in the emergency department. Am J Respir Crit Care Med. 2000;161(6):1862-1868. [CrossRef] [PubMed]
 
Rodrigo GJ, Castro-Rodriguez JA. Anticholinergics in the treatment of children and adults with acute asthma: a systematic review with meta-analysis. Thorax. 2005;60(9):740-746. [CrossRef] [PubMed]
 
Westby M, Benson M, Gibson P. Anticholinergic agents for chronic asthma in adults. Cochrane Database Syst Rev. 2004;;(3):CD003269.
 
Fardon T, Haggart K, Lee DKC, Lipworth BJ. A proof of concept study to evaluate stepping down the dose of fluticasone in combination with salmeterol and tiotropium in severe persistent asthma. Respir Med. 2007;101(6):1218-1228. [CrossRef] [PubMed]
 
Magnussen H, Bugnas B, van Noord J, Schmidt P, Gerken F, Kesten S. Improvements with tiotropium in COPD patients with concomitant asthma. Respir Med. 2008;102(1):50-56. [CrossRef] [PubMed]
 
Peters SP, Kunselman SJ, Icitovic N, et al; National Heart, Lung, and Blood Institute Asthma Clinical Research Network. Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med. 2010;363(18):1715-1726. [CrossRef] [PubMed]
 
Befekadu E, Onofrei C, Colice GL. Tiotropium in asthma: a systematic review. J Asthma Allergy. 2014;7:11-21. [PubMed]
 
Tian JW, Chen JW, Chen R, Chen X. Tiotropium versus placebo for inadequately controlled asthma: a meta-analysis. Respir Care. 2014;59(5):654-666. [CrossRef] [PubMed]
 
Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med. 2009;151(4):W-65-W-94. [CrossRef]
 
Juniper EF, Guyatt GH, Cox FM, Ferrie PJ, King DR. Development and validation of the Mini Asthma Quality of Life Questionnaire. Eur Respir J. 1999;14(1):32-38. [CrossRef] [PubMed]
 
Juniper EF, Svensson K, Mörk AC, Ståhl E. Measurement properties and interpretation of three shortened versions of the asthma control questionnaire. Respir Med. 2005;99(5):553-558. [CrossRef] [PubMed]
 
Safety Guidelines. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use website. http://www.ich.org/products/guidelines/safety/article/safety-guidelines.html. Accessed May 10, 2014.
 
Higgins JPT, Altman DG, Gøtzsche PC, et al; Cochrane Bias Methods Group; Cochrane Statistical Methods Group. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. [CrossRef] [PubMed]
 
Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557-560. [CrossRef] [PubMed]
 
Borenstein M, Hedges LV, Higgins JPT, Rothstein HR. Introduction to Meta-analysis. Chichester, West Sussex, England: John Wiley and Sons; 2009.
 
Deeks JJ, Altman DG, Bradburn MJ. Statistical methods for examining heterogeneity, combining results from several studies in meta-analysis.. In:Egger M, Smith GD, Altman DG., eds. Systematic Reviews in Health Care: Meta-analysis in Context. London, England: BMJ Publishing Group; 2001:285-312.
 
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629-634. [CrossRef] [PubMed]
 
Bateman ED, Kornmann O, Schmidt P, Pivovarova A, Engel M, Fabbri LM. Tiotropium is noninferior to salmeterol in maintaining improved lung function in B16-Arg/Arg patients with asthma. J Allergy Clin Immunol. 2011;128(2):315-322. [CrossRef] [PubMed]
 
Kerstjens HAM, Disse B, Schröder-Babo W, et al. Tiotropium improves lung function in patients with severe uncontrolled asthma: a randomized controlled trial. J Allergy Clin Immunol. 2011;128(2):308-314. [CrossRef] [PubMed]
 
Kerstjens HA, Engel M, Dahl R, et al. Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med. 2012;367(13):1198-1207. [CrossRef] [PubMed]
 
Clinical trials. BI Trial No.: 205.464. Boehringer Ingelheim website. http://trials.boehringer-ingelheim.com/content/dam/internet/opu/clinicaltrial/com_EN/results/205/205.464_U13-2279-01.pdf. Accessed on May 10, 2014.
 
Clinical trials. BI Trial No.: 205.420. Boehringer Ingelheim website. http://trials.boehringer-ingelheim.com/content/dam/internet/opu/clinicaltrial/com_EN/results/205/205.420_U12-2227-01-DS.pdf. Accessed on May 10, 2014.
 
Vogelberg C, Engel M, Moroni-Zentgraf P, et al. Tiotropium in asthmatic adolescents symptomatic despite inhaled corticosteroids: A randomised dose-ranging study. Respir Med. 2014;108(9):1268-1276. [CrossRef] [PubMed]
 
Beeh KM, Moroni-Zentgraf P, Ablinger O, et al. Tiotropium Respimat in asthma: a double-blind, randomised, dose-ranging study in adult patients with moderate asthma. Respir Res. 2014;15:61. [CrossRef] [PubMed]
 
Clinical trials. BI Trial No.: 205.442. Boehringer Ingelheim website. http://trials.boehringer-ingelheim.com/content/dam/internet/opu/clinicaltrial/com_EN/results/205/205.442_U13-1003-01.pdf. Accessed on May 10, 2014.
 
Clinical trials. BI Trial No.: 205.418. Boehringer Ingelheim website. http://trials.boehringer-ingelheim.com/content/dam/internet/opu/clinicaltrial/com_EN/results/205/205.418_c02036039-03.pdf. Accessed on May 10, 2014.
 
Clinical trials. BI Trial No.: 205.419. Boehringer Ingelheim website. http://trials.boehringer-ingelheim.com/content/dam/internet/opu/clinicaltrial/com_EN/results/205/205.419_c02036086-05.pdf. Accessed on May 10, 2014.
 
Clinical trials. BI Trial No.: 205.444. Boehringer Ingelheim website. http://trials.boehringer-ingelheim.com/content/dam/internet/opu/clinicaltrial/com_EN/results/205/205.444_c01846621-02.pdf. Accessed on September 8, 2014.
 
GINA report, global strategy for the asthma management and prevention. Global Initiative for Asthma website. http://www.ginasthma.org/local/uploads/files/GINA_Report_2014_Jun11.pdf. Accessed July 10, 2014.
 
Reddel HK, Taylor DR, Bateman ED, et al; American Thoracic Society/European Respiratory Society Task Force on Asthma Control and Exacerbations. An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care Med. 2009;180(1):59-99. [CrossRef] [PubMed]
 
Donohue JF. Minimal clinically important differences in COPD lung function. COPD. 2005;2(1):111-124. [CrossRef] [PubMed]
 
Jones PW, Beeh KM, Chapman KR, Decramer M, Mahler DA, Wedzicha JA. Minimal clinically important differences in pharmacological trials. Am J Respir Crit Care Med. 2014;189(3):250-255. [CrossRef] [PubMed]
 
Bel EH. Tiotropium for asthma—promise and caution. N Engl J Med. 2012;367(13):1257-1259. [CrossRef] [PubMed]
 
Loke YK, Singh S, Furberg CD. Tiotropium and the risk of death in COPD. N Engl J Med. 2014;370(5):480-481. [CrossRef] [PubMed]
 
Verhamme KMC, van Blijderveen N, Sturkenboom MCJM. Tiotropium and the risk of death in COPD. N Engl J Med. 2014;370(5):481-482. [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Flowchart for the identification of studies used. RCT = randomized controlled trial.Grahic Jump Location
Figure Jump LinkFigure 2 –  A and B, Pooled mean difference for morning (A) and evening (B) peak expiratory flow at the end of treatment (change from baseline) with 95% CIs of eligible studies comparing ICS plus tiotropium vs ICS (patients with mild to moderate asthma). df = degrees of freedom; ICS = inhaled corticosteroid; IV = inverse variance.Grahic Jump Location
Figure Jump LinkFigure 3 –  A and B, Pooled mean difference for morning (A) and evening (B) peak expiratory flow at the end of treatment (change from baseline) with 95% CIs of eligible studies comparing ICS plus tiotropium vs ICS plus LABA. LABA = long-acting β2-agonist. See Figure 2 legend for expansion of other abbreviations.Grahic Jump Location
Figure Jump LinkFigure 4 –  A and B, Pooled mean difference for morning (A) and evening (B) peak expiratory flow at the end of treatment (change from baseline) with 95% CIs of eligible studies comparing ICS plus LABA plus TIO vs ICS plus LABA. TIO = tiotropium. See Figure 2 and 3 legends for expansion of other abbreviations.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Characteristics of Included Studies

Data are presented as No. (% female sex) or mean (range) unless otherwise indicated. AUC = area under the curve; BI = Boehringer Ingelheim; CO = crossover; ICS = inhaled corticosteroid; DB = double blind; N/A = data not available; OD = once daily; PC = placebo controlled; PEF = peak expiratory flow; PG = parallel group; R = randomized; SAL = salmeterol; TIO = tiotropium.

Table Graphic Jump Location
TABLE 2 ]  Tiotropium as Add-on to ICS on Asthma Outcomes (Mild to Moderate Asthma)

ACQ-7 = Asthma Control Questionnaire 7; AE = adverse event; AQLQ = Asthma Quality of Life Questionnaire; MD = mean difference; NNTB = number needed to treat for benefit; RR = relative risk; SAE = serious adverse event. See Table 1 legend for expansion of other abbreviation.

Table Graphic Jump Location
TABLE 3 ]  Tiotropium Plus ICS vs LABA Plus ICS on Asthma Outcomes (Moderate Asthma)

LABA = long-acting β2-agonist. See Table 1 and 2 legends for expansion of other abbreviations.

Table Graphic Jump Location
TABLE 4 ]  Tiotropium as Add-on to ICS Plus LABA vs ICS Plus LABA on Asthma Outcomes (Severe Asthma)

See Table 1-3 legends for expansion of abbreviations.

a 

20(1), 2(2)0 = trials 1 and 2 from Kerstjens et al.20

References

Rodrigo GJ, Rodrigo C. First-line therapy for adult patients with acute asthma receiving a multiple-dose protocol of ipratropium bromide plus albuterol in the emergency department. Am J Respir Crit Care Med. 2000;161(6):1862-1868. [CrossRef] [PubMed]
 
Rodrigo GJ, Castro-Rodriguez JA. Anticholinergics in the treatment of children and adults with acute asthma: a systematic review with meta-analysis. Thorax. 2005;60(9):740-746. [CrossRef] [PubMed]
 
Westby M, Benson M, Gibson P. Anticholinergic agents for chronic asthma in adults. Cochrane Database Syst Rev. 2004;;(3):CD003269.
 
Fardon T, Haggart K, Lee DKC, Lipworth BJ. A proof of concept study to evaluate stepping down the dose of fluticasone in combination with salmeterol and tiotropium in severe persistent asthma. Respir Med. 2007;101(6):1218-1228. [CrossRef] [PubMed]
 
Magnussen H, Bugnas B, van Noord J, Schmidt P, Gerken F, Kesten S. Improvements with tiotropium in COPD patients with concomitant asthma. Respir Med. 2008;102(1):50-56. [CrossRef] [PubMed]
 
Peters SP, Kunselman SJ, Icitovic N, et al; National Heart, Lung, and Blood Institute Asthma Clinical Research Network. Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med. 2010;363(18):1715-1726. [CrossRef] [PubMed]
 
Befekadu E, Onofrei C, Colice GL. Tiotropium in asthma: a systematic review. J Asthma Allergy. 2014;7:11-21. [PubMed]
 
Tian JW, Chen JW, Chen R, Chen X. Tiotropium versus placebo for inadequately controlled asthma: a meta-analysis. Respir Care. 2014;59(5):654-666. [CrossRef] [PubMed]
 
Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med. 2009;151(4):W-65-W-94. [CrossRef]
 
Juniper EF, Guyatt GH, Cox FM, Ferrie PJ, King DR. Development and validation of the Mini Asthma Quality of Life Questionnaire. Eur Respir J. 1999;14(1):32-38. [CrossRef] [PubMed]
 
Juniper EF, Svensson K, Mörk AC, Ståhl E. Measurement properties and interpretation of three shortened versions of the asthma control questionnaire. Respir Med. 2005;99(5):553-558. [CrossRef] [PubMed]
 
Safety Guidelines. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use website. http://www.ich.org/products/guidelines/safety/article/safety-guidelines.html. Accessed May 10, 2014.
 
Higgins JPT, Altman DG, Gøtzsche PC, et al; Cochrane Bias Methods Group; Cochrane Statistical Methods Group. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. [CrossRef] [PubMed]
 
Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557-560. [CrossRef] [PubMed]
 
Borenstein M, Hedges LV, Higgins JPT, Rothstein HR. Introduction to Meta-analysis. Chichester, West Sussex, England: John Wiley and Sons; 2009.
 
Deeks JJ, Altman DG, Bradburn MJ. Statistical methods for examining heterogeneity, combining results from several studies in meta-analysis.. In:Egger M, Smith GD, Altman DG., eds. Systematic Reviews in Health Care: Meta-analysis in Context. London, England: BMJ Publishing Group; 2001:285-312.
 
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629-634. [CrossRef] [PubMed]
 
Bateman ED, Kornmann O, Schmidt P, Pivovarova A, Engel M, Fabbri LM. Tiotropium is noninferior to salmeterol in maintaining improved lung function in B16-Arg/Arg patients with asthma. J Allergy Clin Immunol. 2011;128(2):315-322. [CrossRef] [PubMed]
 
Kerstjens HAM, Disse B, Schröder-Babo W, et al. Tiotropium improves lung function in patients with severe uncontrolled asthma: a randomized controlled trial. J Allergy Clin Immunol. 2011;128(2):308-314. [CrossRef] [PubMed]
 
Kerstjens HA, Engel M, Dahl R, et al. Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med. 2012;367(13):1198-1207. [CrossRef] [PubMed]
 
Clinical trials. BI Trial No.: 205.464. Boehringer Ingelheim website. http://trials.boehringer-ingelheim.com/content/dam/internet/opu/clinicaltrial/com_EN/results/205/205.464_U13-2279-01.pdf. Accessed on May 10, 2014.
 
Clinical trials. BI Trial No.: 205.420. Boehringer Ingelheim website. http://trials.boehringer-ingelheim.com/content/dam/internet/opu/clinicaltrial/com_EN/results/205/205.420_U12-2227-01-DS.pdf. Accessed on May 10, 2014.
 
Vogelberg C, Engel M, Moroni-Zentgraf P, et al. Tiotropium in asthmatic adolescents symptomatic despite inhaled corticosteroids: A randomised dose-ranging study. Respir Med. 2014;108(9):1268-1276. [CrossRef] [PubMed]
 
Beeh KM, Moroni-Zentgraf P, Ablinger O, et al. Tiotropium Respimat in asthma: a double-blind, randomised, dose-ranging study in adult patients with moderate asthma. Respir Res. 2014;15:61. [CrossRef] [PubMed]
 
Clinical trials. BI Trial No.: 205.442. Boehringer Ingelheim website. http://trials.boehringer-ingelheim.com/content/dam/internet/opu/clinicaltrial/com_EN/results/205/205.442_U13-1003-01.pdf. Accessed on May 10, 2014.
 
Clinical trials. BI Trial No.: 205.418. Boehringer Ingelheim website. http://trials.boehringer-ingelheim.com/content/dam/internet/opu/clinicaltrial/com_EN/results/205/205.418_c02036039-03.pdf. Accessed on May 10, 2014.
 
Clinical trials. BI Trial No.: 205.419. Boehringer Ingelheim website. http://trials.boehringer-ingelheim.com/content/dam/internet/opu/clinicaltrial/com_EN/results/205/205.419_c02036086-05.pdf. Accessed on May 10, 2014.
 
Clinical trials. BI Trial No.: 205.444. Boehringer Ingelheim website. http://trials.boehringer-ingelheim.com/content/dam/internet/opu/clinicaltrial/com_EN/results/205/205.444_c01846621-02.pdf. Accessed on September 8, 2014.
 
GINA report, global strategy for the asthma management and prevention. Global Initiative for Asthma website. http://www.ginasthma.org/local/uploads/files/GINA_Report_2014_Jun11.pdf. Accessed July 10, 2014.
 
Reddel HK, Taylor DR, Bateman ED, et al; American Thoracic Society/European Respiratory Society Task Force on Asthma Control and Exacerbations. An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care Med. 2009;180(1):59-99. [CrossRef] [PubMed]
 
Donohue JF. Minimal clinically important differences in COPD lung function. COPD. 2005;2(1):111-124. [CrossRef] [PubMed]
 
Jones PW, Beeh KM, Chapman KR, Decramer M, Mahler DA, Wedzicha JA. Minimal clinically important differences in pharmacological trials. Am J Respir Crit Care Med. 2014;189(3):250-255. [CrossRef] [PubMed]
 
Bel EH. Tiotropium for asthma—promise and caution. N Engl J Med. 2012;367(13):1257-1259. [CrossRef] [PubMed]
 
Loke YK, Singh S, Furberg CD. Tiotropium and the risk of death in COPD. N Engl J Med. 2014;370(5):480-481. [CrossRef] [PubMed]
 
Verhamme KMC, van Blijderveen N, Sturkenboom MCJM. Tiotropium and the risk of death in COPD. N Engl J Med. 2014;370(5):481-482. [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543