Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2015 Jun 2;2015(6):CD011438.
doi: 10.1002/14651858.CD011438.pub2.

Long-acting muscarinic antagonists (LAMA) added to inhaled corticosteroids (ICS) versus addition of long-acting beta2-agonists (LABA) for adults with asthma

Kayleigh M Kew  1 , David J W Evans, Debbie E Allison, Anne C Boyter
Affiliations
Meta-Analysis

Long-acting muscarinic antagonists (LAMA) added to inhaled corticosteroids (ICS) versus addition of long-acting beta2-agonists (LABA) for adults with asthma

Kayleigh M Kew et al. Cochrane Database Syst Rev. .

Abstract

Background: Poorly controlled asthma and preventable exacerbations place a significant strain on healthcare, often requiring additional medications, hospital stays or treatment in the emergency department.Long-acting beta2-agonists (LABA) are the preferred add-on treatment for adults with asthma whose symptoms are not well controlled on inhaled corticosteroids (ICS), but have important safety concerns in asthma. Long-acting muscarinic antagonists (LAMA) have confirmed efficacy in chronic obstructive pulmonary disease and are now being considered as an alternative add-on therapy for people with uncontrolled asthma.

Objectives: To assess the efficacy and safety of adding a LAMA to ICS compared with adding a LABA for adults whose asthma is not well controlled on ICS alone.

Search methods: We searched the Cochrane Airways Group's Specialised Register (CAGR) from inception to April 2015, and imposed no restriction on language of publication. We searched additional resources to pick up unpublished studies, including ClinicalTrials.gov, World Health Organization trials portal, reference lists of primary studies and existing reviews, and manufacturers' trial registries. The most recent search was conducted in April 2015.

Selection criteria: We searched for parallel and cross-over RCTs in which adults whose asthma was not well controlled with ICS alone were randomised to receive LAMA add-on or LABA add-on for at least 12 weeks.

Data collection and analysis: Two review authors independently screened the electronic and additional searches and extracted data from study reports. We used Covidence for duplicate screening, extraction of study characteristics and numerical data, and risk of bias ratings.The pre-specified primary outcomes were exacerbations requiring oral corticosteroids (OCS), quality of life and serious adverse events.

Main results: We included eight studies meeting the inclusion criteria, but four double-blind, double-dummy studies of around 2000 people dominated the analyses. These four trials were between 14 and 24 weeks long, all comparing tiotropium (usually Respimat) with salmeterol on top of medium doses of ICS.Studies reporting exacerbations requiring OCS showed no difference between the two add-ons, but our confidence in the effect was low due to inconsistency between studies and because the confidence intervals (CI) included significant benefit of either treatment (odds ratio (OR) 1.05, 95% CI 0.50 to 2.18; 1753 participants; 3 studies); three more people per 1000 might have an exacerbation on LAMA, but the CIs ranged from 29 fewer to 61 more. Imprecision was also an issue for serious adverse events and exacerbations requiring hospital admission, rated low (serious adverse events) and very low quality (exacerbations requiring hospital admission), because there were so few events in the analyses.People taking LAMA scored slightly worse on two scales measuring quality of life (Asthma Quality of Life Questionnaire; AQLQ) and asthma control (Asthma Control Questionnaire; ACQ); the evidence was rated high quality but the effects were small and unlikely to be clinically significant (AQLQ: mean difference (MD) -0.12, 95% CI -0.18 to -0.05; 1745 participants; 1745; 4 studies; ACQ: MD 0.06, 95% CI 0.00 to 0.13; 1483 participants; 3 studies).There was some evidence to support small benefits of LAMA over LABA on lung function, including on our pre-specified preferred measure trough forced expiratory volume in one second (FEV1) (MD 0.05 L, 95% CI 0.01 to 0.09; 1745 participants, 4 studies). However, the effects on other measures varied, and it is not clear whether the magnitude of the differences were clinically significant.More people had adverse events on LAMA but the difference with LABA was not statistically significant.

Authors' conclusions: Direct evidence of LAMA versus LABA as add-on therapy is currently limited to studies of less than six months comparing tiotropium (Respimat) to salmeterol, and we do not know how they compare in terms of exacerbations and serious adverse events. There was moderate quality evidence that LAMAs show small benefits over LABA on some measures of lung function, and high quality evidence that LABAs are slightly better for quality of life, but the differences were all small. Given the much larger evidence base for LABA versus placebo for people whose asthma is not well controlled on ICS, the current evidence is not strong enough to say that LAMA can be substituted for LABA as add-on therapy.The results of this review, alongside pending results from related reviews assessing the use of LAMA in other clinical scenarios, will help to define the role of these drugs in asthma and it is important that they be updated as results from ongoing and planned trials emerge.

PubMed Disclaimer

Conflict of interest statement

Kayleigh Kew: none known.

David Evans: none known.

Debbie Allison: none known.

Anne Boyter: none known.

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1 Long‐acting muscarinic antagonists (LAMA) add‐on versus long‐acting beta2‐agonists (LABA) add‐on, Outcome 1 Exacerbations (oral corticosteroid).
1.2
1.2. Analysis
Comparison 1 Long‐acting muscarinic antagonists (LAMA) add‐on versus long‐acting beta2‐agonists (LABA) add‐on, Outcome 2 Asthma Quality of Life Questionnaire (AQLQ) total.
1.3
1.3. Analysis
Comparison 1 Long‐acting muscarinic antagonists (LAMA) add‐on versus long‐acting beta2‐agonists (LABA) add‐on, Outcome 3 Serious adverse events (all).
1.4
1.4. Analysis
Comparison 1 Long‐acting muscarinic antagonists (LAMA) add‐on versus long‐acting beta2‐agonists (LABA) add‐on, Outcome 4 Exacerbations (hospital).
1.5
1.5. Analysis
Comparison 1 Long‐acting muscarinic antagonists (LAMA) add‐on versus long‐acting beta2‐agonists (LABA) add‐on, Outcome 5 Trough forced expiratory volume in 1 second (FEV1) (L).
1.6
1.6. Analysis
Comparison 1 Long‐acting muscarinic antagonists (LAMA) add‐on versus long‐acting beta2‐agonists (LABA) add‐on, Outcome 6 Peak FEV1 (L).
1.7
1.7. Analysis
Comparison 1 Long‐acting muscarinic antagonists (LAMA) add‐on versus long‐acting beta2‐agonists (LABA) add‐on, Outcome 7 Trough peak expiratory flow (PEF) (L/min).
1.8
1.8. Analysis
Comparison 1 Long‐acting muscarinic antagonists (LAMA) add‐on versus long‐acting beta2‐agonists (LABA) add‐on, Outcome 8 Trough forced vital capacity (FVC) (L).
1.9
1.9. Analysis
Comparison 1 Long‐acting muscarinic antagonists (LAMA) add‐on versus long‐acting beta2‐agonists (LABA) add‐on, Outcome 9 Peak FVC (L).
1.10
1.10. Analysis
Comparison 1 Long‐acting muscarinic antagonists (LAMA) add‐on versus long‐acting beta2‐agonists (LABA) add‐on, Outcome 10 Asthma Control Questionnaire (ACQ) total.
1.11
1.11. Analysis
Comparison 1 Long‐acting muscarinic antagonists (LAMA) add‐on versus long‐acting beta2‐agonists (LABA) add‐on, Outcome 11 ACQ response.
1.12
1.12. Analysis
Comparison 1 Long‐acting muscarinic antagonists (LAMA) add‐on versus long‐acting beta2‐agonists (LABA) add‐on, Outcome 12 Adverse events AEs (all).
1.13
1.13. Analysis
Comparison 1 Long‐acting muscarinic antagonists (LAMA) add‐on versus long‐acting beta2‐agonists (LABA) add‐on, Outcome 13 AEs classified as asthma.
2.1
2.1. Analysis
Comparison 2 Long‐acting muscarinic antagonists (LAMA) dose subgroups, Outcome 1 Exacerbations (oral corticosteroid).
2.2
2.2. Analysis
Comparison 2 Long‐acting muscarinic antagonists (LAMA) dose subgroups, Outcome 2 Asthma Quality of Life Questionnaire (AQLQ) total.
2.3
2.3. Analysis
Comparison 2 Long‐acting muscarinic antagonists (LAMA) dose subgroups, Outcome 3 Serious adverse events (SAEs) (all).
3.1
3.1. Analysis
Comparison 3 Long‐acting muscarinic antagonists (LAMA) dose head‐to‐head, Outcome 1 Exacerbations (oral corticosteroid).
3.2
3.2. Analysis
Comparison 3 Long‐acting muscarinic antagonists (LAMA) dose head‐to‐head, Outcome 2 Asthma Quality of Life Questionnaire (AQLQ) total.
3.3
3.3. Analysis
Comparison 3 Long‐acting muscarinic antagonists (LAMA) dose head‐to‐head, Outcome 3 Serious adverse events (SAEs) (all).
4.1
4.1. Analysis
Comparison 4 Sensitivity analysis excluding the cross‐over trial, Outcome 1 Exacerbations (oral corticosteroid).
4.2
4.2. Analysis
Comparison 4 Sensitivity analysis excluding the cross‐over trial, Outcome 2 Asthma Quality of Life Questionnaire (AQLQ) total.
4.3
4.3. Analysis
Comparison 4 Sensitivity analysis excluding the cross‐over trial, Outcome 3 Serious adverse events (SAEs) (all).
See this image and copyright information in PMC

Update of

References

References to studies included in this review

NCT00350207 {published data only}
    1. 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. Journal of Allergy and Clinical Immunology 2011;128(2):315‐22. - PubMed
    1. NCT00350207. A 16‐week randomised, placebo‐controlled, double‐blind, double‐dummy, parallel‐group study comparing the efficacy and safety of tiotropium inhalation solution delivered by the Respimat Inhaler (2 actuations of 2.5 mcg once daily) with that of salmeterol from the hydrofluoroalkane metered dose inhaler (2 actuations of 25 mcg twice daily) in moderate persistent asthma patients with the B16‐Arg/Arg genotype. clinicaltrials.gov/show/NCT00350207 (accessed 18 December 2014).
NCT00565266 {published and unpublished data}
    1. Lane M. Tiotropium bromide in asthma patients: an alternative to inhaled long‐acting beta‐agonists?. Journal of the Royal College of Physicians of Edinburgh 2010;40(4):321‐2. - PubMed
    1. NCT00565266. Asthma Clinical Research Network (ACRN) Trial ‐ Tiotropium bromide as an alternative to increased inhaled corticosteroid in patients inadequately controlled on a lower dose of inhaled corticosteroid (TALC). clinicaltrials.gov/show/NCT00565266 (accessed 14 January 2015).
    1. Peters SP, Bleecker ER, Kunselman SJ, Icitovic N, Moore WC, Pascual R, et al. Predictors of response to tiotropium versus salmeterol in asthmatic adults. Journal of Allergy and Clinical Immunology 2013;132(5):1068‐74. - PMC - PubMed
    1. Peters SP, Kunselman SJ, Icitovic N, Moore WC, Pascual R, Ameredes BT, et al. Tiotropium bromide step‐up therapy for adults with uncontrolled asthma. New England Journal of Medicine 2010;363(18):1715‐26. - PMC - PubMed
NCT00706446 {published data only}
    1. NCT00706446. Genotype stratified treatment with anticholinergic vs. beta‐agonist (long acting) and exacerbations (GABLE). clinicaltrials.gov/show/NCT00706446 (accessed 18 December 2014).
NCT01172808 {published data only}
    1. NCT01172808. A phase III randomised, double‐blind, placebo‐controlled, parallel‐group trial to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® Inhaler (2.5 and 5 µg once daily) compared with placebo and salmeterol HFA MDI (50 µg twice daily) over 24 Weeks in moderate persistent asthma. clinicaltrials.gov/show/NCT01172808 (accessed 18 December 2014).
NCT01172821 {published data only}
    1. Casale T, Bleecker E, Meltzer E, Pizzichini E, Schmidt O, Bateman E, et al. Phase III trials to investigate tiotropium as add‐on therapy to inhaled corticosteroids for patients with symptomatic asthma: trial design and planned statistical analyses. Allergy 2013;68:377.
    1. Casale TB, Bateman ED, Dahl R, Pizzichini E, Vandewalker ML, Virchow JC, et al. Tiotropium Respimat (R) add‐on therapy reduces airflow obstruction in patients with symptomatic moderate asthma, independent of T(H)2 inflammatory status. Journal of Allergy and Clinical Immunology 2014;133(2):Ab5.
    1. NCT01172821. A phase III randomised, double‐blind, placebo‐controlled, parallel‐group trial to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® Inhaler (2.5 and 5 µg once daily) compared with placebo and salmeterol HFA MDI (50 µg twice daily) over 24 Weeks in moderate persistent asthma. clinicaltrials.gov/show/NCT01172821 (accessed 18 December 2014).
NCT01290874 {published data only}
    1. NCT01290874. Blacks and exacerbations on LABA vs. tiotropium (BELT). clinicaltrials.gov/show/NCT01290874 (accessed 18 December 2014).
Rajanandh 2014 {published data only}
    1. Rajanandh MG, Nageswari AD, Ilango K. Pulmonary function assessment in mild to moderate persistent asthma patients receiving montelukast, doxofylline, and tiotropium with budesonide: a randomized controlled study. Clinical Therapeutics 2014;36(4):526‐33. - PubMed
Rajanandh 2015 {published data only}
    1. Ilango K. A clinical trial to study the effects of few anti asthmatic drug combinations on asthma patients. apps.who.int/trialsearch/Trial2.aspx?TrialID=CTRI/2012/08/002915 (accessed 8 January 2015).
    1. Rajanandh MG, Nageswari AD, Ilango K. Assessment of montelukast, doxofylline, and tiotropium with budesonide for the treatment of asthma: which is the best among the second‐line treatment? A randomized trial. Clinical Therapeutics 2015;37(2):41826. - PubMed
    1. Rajanandh MG, Nageswari AD, Ilango K. Assessment of various second‐line medications in addition to inhaled corticosteroid in asthma patients: a randomized trial. Clinical and Experimental Pharmacology and Physiology 2014;41(7):509‐13. - PubMed

References to studies excluded from this review

CTRI/2008/091/000306 {published data only}
    1. Chest Research Foundation. A clinical trial comparing bronchodilator effects of two drugs, tiotropium bromide and formoterol fumarate each over 24 hours in subjects with asthma. apps.who.int/trialsearch/Trial2.aspx?TrialID=CTRI/2008/091/000306 (accessed 8 January 2015).
EUCTR2006‐003385‐34‐NL {published data only}
    1. Boehringer Ingelheim Pharma GmbH, Co. KG. The effect of tiotropium‐bromide on deep inspiration‐induced bronchodilation and airway responsiveness in asthma ‐ tiotropium‐bromide and lung mechanics. apps.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2006‐003385‐34‐NL (accessed 8 January 2015).
JPRN‐UMIN000003618 {published data only}
    1. Saitama Medical University. Randomized clinical study with tiotropium and formoterol/budesonide in COPD with asthma. apps.who.int/trialsearch/Trial2.aspx?TrialID=JPRN‐UMIN000003618 (accessed 8 January 2015).
JPRN‐UMIN000005459 {published data only}
    1. EACC (Ehime Asthma COPD Conference). Add‐on therapy for COPD receiving inhaled bronchodilators. apps.who.int/trialsearch/Trial2.aspx?TrialID=JPRN‐UMIN000005459 (accessed 8 January 2015).
JPRN‐UMIN000010352 {published data only}
    1. Fukuoka National Hospital. Study for effects of tiotropium on smokers and non‐smokers with bronchial asthma. apps.who.int/trialsearch/Trial2.aspx?TrialID=JPRN‐UMIN000010352 (accessed 8 January 2015).
Kerstjens 2012 {published data only}
    1. Corren J, Frew A, Engel M, Schmidt H, Moroni‐Zentgraf P, Kerstjens HAM. Tiotropium as add‐on therapy to ICS+LABA in patients with symptomatic severe asthma: spirometric assessment over 24 hours [Abstract]. American College of Chest Physicians 2013;144(4):91A.
    1. Kerstjens HAM, Engel M, Dahl R, Paggiaro P, Beck E, Vandewalker M, et al. Tiotropium in asthma poorly controlled with standard combination therapy. New England Journal of Medicine 2012;367(13):1198‐207. - PubMed
    1. Vandewalker ML, Engel M, Schmidt H, Siebold W, Moroni‐Zentgraf P, Kerstjens H, et al. Efficacy of tiotropium in patients with asthma in relation to allergic status [Abstract]. Journal of Allergy and Clinical Immunology 2013;131:AB1.
NCT00546234 {published data only}
    1. NCT00546234. Assessing treatment options for smokers with asthma. www.clinicaltrials.gov/ct2/show/NCT00546234 (accessed 8 January 2015).
NCT00557180 {published data only}
    1. National Jewish Health. Examining the link between obesity, inflammation, and response to asthma medications. clinicaltrials.gov/show/NCT00557180 (accessed 8 January 2015).
NCT00557700 {published data only}
    1. NCT00557700. Study to investigate the effect of inhaled tiotropium bromide on neurokinin‐A induced bronchoconstriction in patients with mild‐to‐moderate asthma. www.clinicaltrials.gov/ct2/show/NCT00557700 (accessed 8 January 2015).
NCT00772538 {published data only}
    1. NCT00772538. A phase III randomised, double‐blind, placebo‐controlled, parallel‐group trial to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® inhaler (5 mcg/day) over 48 weeks as add‐on controller therapy on top of usual care in patients with severe persistent asthma. www.clinicaltrials.gov/ct2/show/NCT00772538 (accessed 8 January 2015).
NCT00776984 {published data only}
    1. NCT00776984. A phase III randomised, double‐blind, placebo‐controlled, parallel‐group trial to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® inhaler (5 mcg/day) over 48 weeks as add‐on controller therapy on top of usual care in patients with severe persistent asthma. www.clinicaltrials.gov/ct2/show/NCT00776984 (accessed 8 January 2015).
NCT01316380 {published data only}
    1. NCT01316380. A phase III, randomised, double‐blind, placebo‐controlled, parallel‐group trial to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® inhaler (2.5 ug and 5 ug once daily) compared to placebo over 12 weeks in mild persistent asthma. www.clinicaltrials.gov/show/NCT01316380 (accessed 15 January 2015).
    1. Paggiaro P, Engel M, Tudoric N, Forstner B, Radeczky E, Zubek V, et al. Phase III trial of tiotropium as add‐on therapy to low‐dose inhaled corticosteroids for patients with symptomatic mild persistent asthma: Design and planned analyses [Abstract]. European Respiratory Journal 2013;42 (Suppl 57):877s.
    1. Paggiaro P, Halpin DMG, Buhl R, Engel M, Zubek V, Blahova Z, et al. Tiotropium Respimat add‐on to inhaled corticosteroids improves lung function in patients with symptomatic mild asthma: results from a phase III trial. Journal of Allergy and Clinical Immunology 2014;133(2):AB4.
NCT01340209 {published data only}
    1. NCT01340209. A phase III randomised, double‐blind, placebo‐controlled, parallel‐group trial to evaluate safety and efficacy of tiotropium inhalation solution delivered via Respimat inhaler (2.5 and 5 µg once daily) compared with placebo over 52 weeks in patients with moderate to severe persistent asthma. www.clinicaltrials.gov/show/NCT01340209 (accessed 15 January 2015).
NCT01573624 {published data only}
    1. NCT01573624. Evaluate the safety, efficacy and dose response of GSK573719 in combination with fluticasone furoate in subjects with asthma (ILA115938). clinicaltrials.gov/show/NCT01573624 (accessed 18 December 2014).
NCT01641692 {published data only}
    1. NCT01641692. A multi‐national, randomized, double‐blind, placebo‐controlled, 3‐period crossover study with GSK 573719 as monotherapy in adult subjects with asthma. www.clinicaltrials.gov/ct2/show/NCT01641692 (accessed 8 January 2015).
NCT01696214 {published data only}
    1. NCT01696214. SAPS: Smoking Asthmatics Pilot Study. clinicaltrials.gov/show/NCT01696214 (accessed 18 December 2014).
NCT02066298 {published data only}
    1. NCT02066298. Steroids in eosinophil negative asthma. www.clinicaltrials.gov/ct2/show/NCT02066298 (accessed 8 January 2015).
NCT02127697 {published data only}
    1. NCT02127697. A randomized, double‐blind, parallel group, 52‐week study evaluating the efficacy, safety and tolerability of NVA237 in patients with poorly controlled asthma. www.clinicaltrials.gov/ct2/show/NCT02127697 (accessed 8 January 2015).
Vogelberg 2014 {published data only}
    1. Vogelberg C, Engel M, Moroni‐Zentgraf P, Leonaviciute‐Klimantaviciene M, Sigmund R, Downie J, et al. Once‐daily tiotropium in adolescents with symptomatic asthma despite inhaled corticosteroid treatment: a dose‐ranging study [Abstract]. Clinical and Translational Allergy 2014;4((Suppl 1)):2.

References to studies awaiting assessment

MezzoTinA {published data only}
    1. Casale TB, Dahl R, Virchow JC, Engel M, Moroni‐Zentgraf P, Luehmann R, et al. Tiotropium respimat add‐on therapy reduces exacerbation risk in patients with symptomatic moderate to severe asthma, independent of t helper 2 status. A. Morikawa, Gunma University, Gunma, Japan: American Thoracic Society, 2015; Vol. 191:A4193 MISC1 ‐ AST.
    1. DE Doherty, M Castro, P Moroni‐Zentgraf, M Engel, R Luehmann, R Buhl. Tiotropium respimat add‐on therapy improves lung function, as measured by peak expiratory flow, in adult patients across severities of symptomatic asthma. A. Morikawa, Gunma University, Gunma, Japan: American Thoracic Society, 2015; Vol. 191:A4258.
    1. Dahl R, Bateman ED, Casale T, Pizzichini E, Vandewalker M, Virchow JC, et al. Once‐daily tiotropium Respimat as add‐on to at least medium‐ to high‐dose ICS, with or without LABA, improves lung function in patients with symptomatic asthma, independent of allergic status. 33rd congress of the european academy of allergy and clinical immunology. 2014:515.
    1. Dahl R, Casale T, Bleecker E, Pizzichini E, Engel M, Moroni‐Zentgraf P, et al. Efficacy of tiotropium Respimat in adults with moderate asthma, by baseline LTRA use. European Respiratory Journal 2015;46.
    1. Dahl R, Casale T, Pizzichini E, Vandewalker M, Virchow JC, Engel M, et al. Once‐daily tiotropium Respimat as add‐on to at least medium‐to high‐dose ICS, with or without LABA, improves lung function in patients with symptomatic asthma, independent of allergic status. Thorax 2014;69:A177‐A178.
Wechsler 2015 {published data only}
    1. NCT01290874. Blacks and exacerbations on LABA vs. tiotropium (BELT). Http://clinicaltrials.gov/show/nct01290874 2014.
    1. Wechsler ME, Yawn BP, Fuhlbrigge AL, Pace WD, Pencina MJ, Doros G, et al. Anticholinergic vs long‐acting β2‐agonist in combination with inhaled corticosteroids in Black adults with asthma: The BELT randomized clinical trial. JAMA 2015;314(16):1720‐1730. - PubMed
Zhang 2018 {published data only}
    1. Zhang L, Huang G, Jin L. Therapeutic effects of a long‐acting cholinergic receptor blocker, tiotropium bromide, on asthma. Medical Science Monitor 2018;24:944‐50. - PMC - PubMed

Additional references

Adams 2008a
    1. Adams NP, Bestall JB, Malouf R, Lasserson TJ, Jones PW. Beclomethasone versus placebo for chronic asthma. Cochrane Database of Systematic Reviews 2008, Issue 4. [DOI: 10.1002/14651858.CD002738.pub2] - DOI - PMC - PubMed
Adams 2008b
    1. Adams NP, Bestall JC, Lasserson TJ, Jones P, Cates CJ. Fluticasone versus placebo for chronic asthma in adults and children. Cochrane Database of Systematic Reviews 2008, Issue 4. [DOI: 10.1002/14651858.CD003135.pub4] - DOI
Allison 2014
    1. Allison DE, Kew KM, Boyter AC. Long‐acting muscarinic antagonists (LAMA) added to inhaled corticosteroids (ICS) versus the same dose of ICS for adults with asthma. Cochrane Database of Systematic Reviews 2014, Issue 11. [DOI: 10.1002/14651858.CD011397] - DOI - PMC - PubMed
Anderson 2005
    1. Anderson HR. Prevalence of asthma. BMJ 2005;330:1037. - PMC - PubMed
Bateman 2004
    1. Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJ, Pauwels RA, et al. Can guideline‐defined asthma control be achieved? The gaining optimal asthma control study. American Journal of Respiratory and Critical Care Medicine 2004;170(8):836‐44. - PubMed
Befekadu 2014
    1. Befekadu E, Onofrei C, Colice GL. Tiotropium in asthma: a systematic review. Journal of Asthma and Allergy 2014;7:11‐21. - PMC - PubMed
BNF
    1. Joint Formulary Committee. British National Formulary. www.medicinescomplete.com (accessed 29 August 2014).
Brozek 2008 [Computer program]
    1. Brozek J, Oxman A, Schünemann H. GRADEPro Version 3.2 for Windows. McMasters, Canada, 2008.
BTS/SIGN 2014
    1. British Thoracic Society/Scottish Intercollegiate Guidelines Network. BTS/SIGN British guideline on the management of asthma, October 2014. www.brit‐thoracic.org.uk/guidelines‐and‐quality‐standards/asthma‐guideline/ (accessed 16 February 2015).
Cates 2013
    1. Cates CJ, Karner C. Combination formoterol and budesonide as maintenance and reliever therapy versus current best practice (including inhaled steroid maintenance), for chronic asthma in adults and children. Cochrane Database of Systematic Reviews 2013, Issue 4. [DOI: 10.1002/14651858.CD007313.pub3] - DOI - PMC - PubMed
Cates 2014
    1. Cates CJ, Wieland LS, Oleszczuk M, Kew KM. Safety of regular formoterol or salmeterol in adults with asthma: an overview of Cochrane reviews. Cochrane Database of Systematic Reviews 2014, Issue 2. [DOI: 10.1002/14651858.CD010314.pub2] - DOI - PMC - PubMed
Chauhan 2014
    1. Chauhan BF, Ducharme FM. Addition to inhaled corticosteroids of long‐acting beta2‐agonists versus anti‐leukotrienes for chronic asthma. Cochrane Database of Systematic Reviews 2014, Issue 1. [DOI: 10.1002/14651858.CD003137.pub5] - DOI - PMC - PubMed
Chong 2012
    1. Chong J, Karner C, Poole P. Tiotropium versus long‐acting beta‐agonists for stable chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2012, Issue 9. [DOI: 10.1002/14651858.CD009157.pub2] - DOI - PMC - PubMed
Covidence [Computer program]
    1. The Alfred Hospital, Monash University, National ICT Australia and the University of London. Covidence. Version 1. Melbourne: Alfred Health, 2013.
Ducharme 2008
    1. Ducharme FM, Ni Chroinin M, Greenstone I, Lasserson TJ. Addition of long‐acting beta2‐agonists to inhaled corticosteroids versus same dose inhaled corticosteroids for chronic asthma in adults and children. Cochrane Database of Systematic Reviews 2008, Issue 5. [DOI: 10.1002/14651858.CD005535.pub2] - DOI - PMC - PubMed
Ducharme 2010
    1. Ducharme FM, Ni Choinin M, Greenstone I, Lasserson TJ. Addition of long‐acting beta2‐agonists to inhaled steroids versus higher dose inhaled steroids in adults and children with persistent asthma. Cochrane Database of Systematic Reviews 2010, Issue 4. [DOI: 10.1002/14651858.CD005533.pub2] - DOI - PMC - PubMed
Elbourne 2002
    1. Elbourne DR, Altman DG, Higgins JPT, Curtin F, Worthington H, Vale A. Meta‐analyses involving cross‐over trials: methodological issues. International Journal of Epidemiology 2002;31:140‐9. - PubMed
eMC 2014
    1. Electronic Medicines Compendium. License extension 19th September 2014: Spiriva Respimat 2.5 micrograms solution for inhalation. www.medicines.org.uk/emc/history/20134 (accessed 24 October 2014).
Ernst 2006
    1. Ernst P, McIvor A, Ducharme FM, Boulet LP, Fitzgerald M, Chapman KR, et al. Safety and effectiveness of long‐acting inhaled beta‐agonist bronchodilators when taken with inhaled corticosteroids. Annals of Internal Medicine 2006;146(9):692‐4. - PubMed
FDA 2010
    1. United States Food, Drug Administration. FDA Drug Safety Communication: New safety requirements for long‐acting inhaled asthma medications called long‐acting beta‐agonists (LABAs). www.fda.gov/drugs/drugsafety/ (accessed 29 August 2014).
GINA 2014
    1. Global Initiative for Asthma. From the Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA) 2014. www.ginasthma.org/ (accessed 29 August 2014).
Global Asthma Report 2011
    1. International Union Against Tuberculosis and Lung Disease. The Global Asthma Report 2011. theunion.org/what‐we‐do/publications/technical/global‐asthma‐report (accessed 1 September 2014).
Gosens 2006
    1. Gosens R, Zaagsma J, Meurs H, Halayko AJ. Muscarinic receptor signaling in the pathophysiology of asthma and COPD. Respiratory Research 2006;7(1):73. - PMC - PubMed
Higgins 2011
    1. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.
Karner 2014
    1. Karner C, Chong J, Poole P. Tiotropium versus placebo for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2014, Issue 7. [DOI: 10.1002/14651858.CD009285.pub3] - DOI - PMC - PubMed
Kew 2013
    1. Kew KM, Karner C, Mindus SM, Ferrara G. Combination formoterol and budesonide as maintenance and reliever therapy versus combination inhaler maintenance for chronic asthma in adults and children. Cochrane Database of Systematic Reviews 2013, Issue 12. [DOI: 10.1002/14651858.CD009019.pub2] - DOI - PMC - PubMed
Kew 2014
    1. Kew KM, Allison DE, Evans DJW, Boyter AC. Long‐acting muscarinic antagonists (LAMA) added to inhaled corticosteroids (ICS) versus higher dose ICS for adults with asthma. Cochrane Database of Systematic Reviews 2014, Issue 12. [DOI: 10.1002/14651858.CD011437] - DOI - PMC - PubMed
Kew 2015a
    1. Kew KM, Dahri K. Long‐acting muscarinic antagonists (LAMA) added to combination long‐acting beta2‐agonists and inhaled corticosteroids (LABA/ICS) versus LABA/ICS for adults with asthma. Cochrane Database of Systematic Reviews 2015, Issue 5. [DOI: 10.1002/14651858.CD011721] - DOI - PMC - PubMed
Lipworth 2014
    1. Lipworth BJ. Emerging role of long acting muscarinic antagonists for asthma. British Journal of Clinical Pharmacology 2014;77(1):55‐62. - PMC - PubMed
MECIR 2013
    1. MECIR. Methodological Expectations for the conduct of Cochrane Intervention Reviews. editorial‐unit.cochrane.org/mecir (accessed 3 February 2015).
MHRA 2010
    1. Medicines and Healthcare Products Regulatory Agency (MHRA). Drug safety update: tiotropium. www.gov.uk/drug‐safety‐update/tiotropium (accessed 21 April 2015).
MHRA 2014
    1. Medicines and Healthcare Products Regulatory Agency. Asthma long‐acting ß2 agonists: use and safety. www.gov.uk/government/publications/asthma‐long‐acting‐ss2‐agonists‐use‐a... (accessed 16 February 2015).
Moulton 2011
    1. Moulton BC, Fryer AD. Muscarinic receptor antagonists, from folklore to pharmacology; finding drugs that actually work in asthma and COPD. British Journal of Clinical Pharmacology 2011;163(1):44‐52. - PMC - PubMed
Nelson 2006
    1. Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM, SMART Study Group. The salmeterol multicenter asthma research trial. Chest 2006;129:15‐26. - PubMed
Ni 2014
    1. Ni H, Soe Z, Moe S. Aclidinium bromide for stable chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2014, Issue 9. [DOI: 10.1002/14651858.CD010509.pub2] - DOI - PMC - PubMed
NICE 2013
    1. National Institute for Health and Care Excellence. NICE advice [KTT5] high‐dose inhaled corticosteroids in asthma. www.nice.org.uk/Advice/ktt5 (accessed 1 September 2014).
NRAD 2014
    1. Royal College of Physicians. Why asthma still kills: the national review of asthma deaths. www.rcplondon.ac.uk/sites/default/files/why‐asthma‐still‐kills‐full‐repo... (accessed 1 September 2014).
Rashid 2014
    1. Rashid Q, Klein R. Tiotropium in the treatment of patients with asthma. Southern Medical Journal 2014;107(5):330‐7. - PubMed
RevMan 2014 [Computer program]
    1. The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
Rodrigo 2015
    1. Rodrigo GJ, Castro‐Rodríguez JA. What is the role of tiotropium in asthma? A systematic review with meta‐analysis. Chest 2015;147(2):388‐96. - PubMed
Salpeter 2006
    1. Salpeter SR, Buckley NS, Ormiston TM, Salpeter EE. Meta‐analysis: effect of long‐acting beta‐agonists on severe asthma exacerbations and asthma related deaths. Annals of Internal Medicine 2006;144:904‐12. - PubMed
Tee 2009
    1. Tee A, Koh MS, Gibson PG, Lasserson TJ, Wilson A, Irving LB. Long‐acting beta2‐agonists versus theophylline for maintenance treatment of asthma. Cochrane Database of Systematic Reviews 2009, Issue 3. [DOI: 10.1002/14651858.CD001281.pub2] - DOI - PMC - PubMed
Tian 2014
    1. Tian JW, Chen JW, Chen R, Chen X. Tiotropium versus placebo for inadequately controlled asthma: a meta‐analysis. Respiratory Care 2014;59(5):654‐66. - PubMed
Verhamme 2013
    1. Verhamme KM, Afonso A, Romio S, Stricker BC, Brusselle GG, Sturkenboom MC. Use of tiotropium Respimat Soft Mist Inhaler versus HandiHaler and mortality in patients with COPD. European Respiratory Journal 2013;42(3):606‐15. - PubMed
Wise 2013
    1. Wise RA, Anzueto A, Cotton D, Dahl R, Devins T, Disse B, et al. Tiotropium Respimat Inhaler and the risk of death in COPD. New England Journal of Medicine 2013;369:1491‐501. - PubMed

References to other published versions of this review

Kew 2015
    1. Kew KM, Allison DE, Evans DJW, Boyter AC. Long‐acting muscarinic antagonists (LAMA) added to inhaled corticosteroids (ICS) versus addition of long‐acting beta2‐agonists (LABA) for adults with asthma. Cochrane Database of Systematic Reviews 2015, Issue 1. [DOI: 10.1002/14651858.CD011438] - DOI - PMC - PubMed

Publication types

MeSH terms