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Meta-Analysis
. 2016 Jan 21;2016(1):CD011721.
doi: 10.1002/14651858.CD011721.pub2.

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

Kayleigh M Kew  1 , Karen Dahri
Affiliations
Meta-Analysis

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

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

Abstract

Background: Maintenance treatment with long-acting beta2-agonists and inhaled corticosteroids (LABA/ICS) can relieve asthma symptoms and reduce the frequency of exacerbations, but there are limited treatment options for people who do not gain control on combination LABA/ICS. Long-acting muscarinic antagonists (LAMA) are a class of inhaled drug which have been effective for people with chronic obstructive pulmonary disease and are now becoming available for people with asthma to take alongside their LABA/ICS inhaler.

Objectives: To assess the effects of adding a long-acting muscarinic antagonist (LAMA) to combination long-acting beta2-agonists (LABA) and inhaled corticosteroids (ICS) in adults whose asthma is not well controlled by LABA/ICS.

Search methods: We identified trials from the Cochrane Airways Review Group Specialised Register (CAGR) up to January 2016. We also searched ClinicalTrials.gov, the WHO trials portal, and reference lists of other reviews, and we contacted trial authors for additional information.

Selection criteria: We included parallel randomised controlled trials (RCTs) of at least 12 weeks' duration. Studies met the inclusion criteria if they compared LAMA as an add-on to LABA/ICS versus LABA/ICS alone for adults with asthma. We included studies reported as full text, those published as abstract only, and unpublished data. Primary outcomes were exacerbations requiring oral corticosteroids (OCS), validated measures of asthma control, and serious adverse events (including mortality).

Data collection and analysis: Two review authors screened searches and independently extracted details on risk of bias and numerical data. We analysed dichotomous data as odds ratios (ORs) and continuous data as mean differences (MD) using a random-effects model. We rated all outcomes using GRADE.

Main results: We found four double-blind, double-dummy trials comparing LAMA to placebo, including 1197 people with asthma taking combination LABA/ICS. One of the trials was designed to study glycopyrronium bromide but was withdrawn prior to enrolment, and the other three all studied tiotropium bromide (mostly 5 µg once daily via Respimat) over 48 to 52 weeks. People in the trials had a mean forced expiratory volume in one second (FEV1) of 55% of their predicted value, indicating severe asthma.People randomised to take tiotropium add-on had fewer exacerbations requiring oral corticosteroids than those continuing to take LABA/ICS alone, but the confidence intervals did not rule out no difference (OR 0.76, 95% CI 0.57 to 1.02; moderate quality evidence). Over 48 weeks, 328 out of 1000 people taking their usual LABA/ICS would have to take oral corticosteroids for an exacerbation compared with 271 if they took tiotropium as well (95% CI 218 to 333 per 1000). Analyses comparing the number of exacerbations per patient in each group (rate ratio) and the time until first exacerbation (hazard ratio) were in keeping with the main result. Quality of life, as measured by the Asthma Quality of Life Questionnaire (AQLQ) was no better for those taking tiotropium add-on than for those taking LABA/ICS alone when considered in light of the 0.5 minimal clinically important difference on the scale (MD 0.09, 95% CI - 0.03 to 0.20), and evidence for whether tiotropium increased or decreased serious adverse events in this population was inconsistent (OR 0.60, 95% CI 0.24 to 1.47; I(2) = 76%).Within the secondary outcomes, exacerbations requiring hospital admission were too rare to tell whether tiotropium was beneficial over LABA/ICS alone. There was high quality evidence showing benefits to lung function (trough FEV1 and forced vital capacity (FVC)) and potentially small benefits to asthma control. People taking tiotropium add-on were less likely to experience non-serious adverse events.

Authors' conclusions: Tiotropium add-on may have additional benefits over LABA/ICS alone in reducing the need for rescue oral steroids in people with severe asthma. The effect was imprecise, and there was no evidence for other LAMA preparations. Possible benefits on quality of life were negligible, and evidence for the effect on serious adverse events was inconsistent. There are likely to be small added benefits for tiotropium Respimat 5 µg daily on lung function and asthma control over LABA/ICS alone and fewer non-serious adverse events. The benefit of tiotropium add-on on the frequency of hospital admission is still unknown, despite year-long trials.Ongoing and future trials should clearly describe participants' background medications to help clinicians judge how the findings relate to stepwise care. If studies test LAMAs other than tiotropium Respimat for asthma, they should be at least six months long and use accepted and validated outcomes to allow comparisons of the safety and effectiveness between different preparations.

PubMed Disclaimer

Conflict of interest statement

Kayleigh M. Kew: none known.

Karen Dahri: 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 LAMA + LABA/ICS vs LABA/ICS, Outcome 1 Exacerbations requiring oral corticosteroids (patients with at least one).
1.2
1.2. Analysis
Comparison 1 LAMA + LABA/ICS vs LABA/ICS, Outcome 2 Exacerbations requiring oral corticosteroids (number per patient).
1.3
1.3. Analysis
Comparison 1 LAMA + LABA/ICS vs LABA/ICS, Outcome 3 Time to first exacerbation requiring oral corticosteroids.
1.4
1.4. Analysis
Comparison 1 LAMA + LABA/ICS vs LABA/ICS, Outcome 4 Quality of life (AQLQ).
1.5
1.5. Analysis
Comparison 1 LAMA + LABA/ICS vs LABA/ICS, Outcome 5 Serious adverse events.
1.6
1.6. Analysis
Comparison 1 LAMA + LABA/ICS vs LABA/ICS, Outcome 6 Exacerbations requiring hospital admission.
1.7
1.7. Analysis
Comparison 1 LAMA + LABA/ICS vs LABA/ICS, Outcome 7 Lung function (change in trough FEV1 L).
1.8
1.8. Analysis
Comparison 1 LAMA + LABA/ICS vs LABA/ICS, Outcome 8 Lung function (change in trough FVC).
1.9
1.9. Analysis
Comparison 1 LAMA + LABA/ICS vs LABA/ICS, Outcome 9 Asthma control (ACQ).
1.10
1.10. Analysis
Comparison 1 LAMA + LABA/ICS vs LABA/ICS, Outcome 10 Asthma control (ACQ responder).
1.11
1.11. Analysis
Comparison 1 LAMA + LABA/ICS vs LABA/ICS, Outcome 11 Any adverse events.
1.12
1.12. Analysis
Comparison 1 LAMA + LABA/ICS vs LABA/ICS, Outcome 12 Quality of life (AQLQ) by timeframe.
See this image and copyright information in PMC

Update of

References

References to studies included in this review

Kerstjens 2012a {published and unpublished data}
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    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. American Thoracic Society International Conference; 2015 May 15‐20; Denver. 2015:A4193.
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Kerstjens 2012b {published and unpublished data}
    1. 2008‐001414‐25. 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 μg/day) over 48 weeks as add‐on controller therapy on top of usual care in patients with severe persistent asthma. https://www.clinicaltrialsregister.eu/ctr‐search/trial/2008‐001414‐25/re... (accessed 23 June 2015).
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NCT02127697 {published and unpublished data}
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Ohta 2014 {published and unpublished data}
    1. Ichinose M, Ohta K, Tohda Y, Engel M, Moroni‐Zentgraf P, Kunimitsu S, et al. Once‐daily tiotropium respimat is well tolerated and efficacious over 52 weeks in Japanese patients with symptomatic asthma receiving inhaled corticosteroids (ICS) + long‐acting B2‐agonist (LABA): A randomized, double‐blind, placebo‐controlled study. Respirology 2014;19(Suppl 3):65.
    1. NCT01340209. Evaluation of tiotropium 2.5 and 5 µg once daily delivered via the Respimat inhaler compared to placebo in patients with moderate to severe persistent asthma. https://clinicaltrials.gov/ct2/show/NCT01340209 (accessed 22 June 2015).
    1. Ohta K, Ichinose M, Tohda Y, Engel M, Moroni‐Zentgraf P, Kunimitsu S, et al. Long‐term once‐daily tiotropium Respimat is well tolerated and maintains efficacy over 52 weeks in patients with symptomatic asthma in Japan: A randomised, placebo‐controlled study. PLOS ONE 2015;10(4):e0124109. - PMC - PubMed
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References to studies excluded from this review

2009‐018006‐21 {unpublished data only}
    1. 2009‐018006‐21. A phase II, randomised, double‐ blind, placebo controlled, cross‐over efficacy and safety comparison of tiotropium 5 μg administered once daily (in the evening) and tiotropium 2.5 μg administered twice daily delivered by the Respimat® inhaler for four weeks versus placebo in patients with moderate persistent asthma. https://www.clinicaltrialsregister.eu/ctr‐search/trial/2009‐018006‐21/re... (accessed 23 June 2015).
2010‐018471‐26 {unpublished data only}
    1. 2010‐018471‐26. A phase II randomised, double‐blind, placebo controlled, cross‐over efficacy and safety comparison of three doses of tiotropium inhalation solution delivered via Respimat® inhaler (1.25, 2.5 and 5.0 μg once daily) versus placebo in patients with moderate persistent asthma. https://www.clinicaltrialsregister.eu/ctr‐search/trial/2010‐018471‐26/re... (accessed 23 June 2015).
Bateman 2011 {published data only}
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Beeh 2013 {published data only}
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    1. Beeh KM, Moroni‐Zentgraf P, Ablinger O, Hollaenderova Z, Unseld A, Engel M, et al. Tiotropium Respimat in asthma: a double‐blind, randomised, dose‐ranging study in adult patients with moderate asthma. Respiratory Research 2014;15:61. - PMC - PubMed
Dusser 2014 {published data only}
    1. Dusser D, Buhl R, Castro M, Kerstjens H, Paggiaro P, Engel M, et al. Once‐daily tiotropium respimat add‐on to at least ICS in adult patients with symptomatic asthma: Pooled safety analysis. European Respiratory Journal 2014;44(Suppl 58):P905.
Fardon 2007 {published data only}
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FitzGerald 2014 {published data only}
    1. FitzGerald J M, Kerstjens H, Paggiaro P, Ohta K, Ichinose M, Moroni‐Zentgraf P, et al. Once‐daily tiotropium respimat add‐on to ICS+/‐LABA improves control across asthma severities. European Respiratory Journal 2014;44(Suppl 58):1894.
Haggart 2004 {published data only}
    1. Haggart K, Fardon TC, Lee DKC, Lipworth BJ. Stepping down inhaled steroids in severe asthma with long acting bronchodilators: utilising effort dependent and independent measures of pulmonary function [Abstract]. British Thoracic Society Winter Meeting; 2004 Dec 1‐3; London, United Kingdom. 2004; Vol. 59:ii72.
Haughney 2014 {published data only}
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Jiang 2006 {published data only}
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    1. Kerstjens HA, Casale TB, Bleecker ER, Meltzer EO, Pizzichini E, Schmidt O, et al. Tiotropium or salmeterol as add‐on therapy to inhaled corticosteroids for patients with moderate symptomatic asthma: two replicate, double‐blind, placebo‐controlled, parallel‐group, active‐comparator, randomised trials. The Lancet Respiratory Medicine 2015;3(5):367‐76. - PubMed
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Lee 2014 {published data only}
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Lommatzsch 2014 {published data only}
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Murphy 2014 {published data only}
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NCT01573624 {published data only}
    1. NCT01573624. A multi‐center, randomized, double‐blind, dose‐ranging study to evaluate GSK573719 in combination with fluticasone furoate, fluticasone furoate alone, and an active control of fluticasone furoate/vilanterol combination in subjects with asthma. http://clinicaltrials.gov/show/NCT01573624 (accessed 22 June 2015).
NCT02039011 {published data only}
    1. NCT02039011. Proof of concept study to evaluate single and chronic dosing effects of ultra‐long acting bronchodilator therapy on mannitol challenge in asthmatic patients taking inhaled corticosteroids ‐ MAN02 Ultra‐long Acting Bronchodilator Therapy in Asthmatics. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2013‐001953‐28‐GB (accessed 23 June 2015).
Paggiaro 2013 {published data only}
    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 [P4133].
Peters 2010 {published data only}
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Price 2014 {published data only}
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Rajanandh 2014 {published data only}
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Rajanandh 2015 {published data only}
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Rodrigo 2015 {published data only}
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Salvi 2009 {published data only}
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Timmer 2014 {published data only}
    1. Timmer W, Moroni‐Zentgraf P, Cornelissen P, Unseld A, Pizzichini E, Buhl R. Once‐daily tiotropium Respimat 5 mug is an efficacious 24‐h bronchodilator in adults with symptomatic asthma. Respiratory Medicine 2015;109(3):329‐38. - PubMed
Vandewalker 2015 {published data only}
    1. Vandewalker M, Harper III T, Moroni‐Zentgraf P, Engel M, Luhmann R, Bernstein JA. Once‐daily tiotropium Respimat add‐on therapy improves lung function in adolescent patients with moderate symptomatic asthma, independent of t helper 2 inflammatory status. Annals of Allergy, Asthma & Immunology 2015;115(5 Suppl 1):A54‐5.
Vogelberg 2014 {published data only}
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Yoshida 2013 {published data only}
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References to ongoing studies

NCT01696214 {published data only}
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References to other published versions of this review

Kew 2015
    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

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