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Meta-Analysis
. 2014 Jul 21;2014(7):CD009285.
doi: 10.1002/14651858.CD009285.pub3.

Tiotropium versus placebo for chronic obstructive pulmonary disease

Charlotta Karner  1 , Jimmy Chong, Phillippa Poole
Affiliations
Meta-Analysis

Tiotropium versus placebo for chronic obstructive pulmonary disease

Charlotta Karner et al. Cochrane Database Syst Rev. .

Abstract

Background: Tiotropium is an anticholinergic agent which has gained widespread acceptance as a once daily maintenance therapy for symptoms and exacerbations of stable chronic obstructive pulmonary disease (COPD). In the past few years there have been several systematic reviews of the efficacy of tiotropium, however, several new trials have compared tiotropium treatment with placebo, including those of a soft mist inhaler, making an update necessary.

Objectives: To evaluate data from randomised controlled trials (RCTs) comparing the efficacy of tiotropium and placebo in patients with COPD, upon clinically important endpoints.

Search methods: We searched the Cochrane Airways Group's Specialised Register of Trials (CAGR) and ClinicalTrials.gov up to February 2012.

Selection criteria: We included parallel group RCTs of three months or longer comparing treatment with tiotropium against placebo for patients with COPD.

Data collection and analysis: Two review authors independently assessed studies for inclusion and then extracted data on study quality and the outcome results. We contacted study authors and trial sponsors for additional information, and collected information on adverse effects from all trials. We analysed the data using Cochrane Review Manager 5, RevMan 5.2.

Main results: This review included 22 studies of good methodological quality that had enrolled 23,309 participants with COPD. The studies used similar designs, however, the duration varied from three months to four years. In 19 of the studies, 18 mcg tiotropium once daily via the Handihaler dry powder inhaler was evaluated, and in three studies, 5 or 10 mcg tiotropium once daily via the Respimat soft mist inhaler was evaluated. Compared to placebo, tiotropium treatment significantly improved the mean quality of life (mean difference (MD) -2.89; 95% confidence interval (CI) -3.35 to -2.44), increased the number of participants with a clinically significant improvement (odds ratio (OR) 1.52; 95% CI 1.38 to 1.68), and reduced the number of participants with a clinically significant deterioration (OR 0.65; 95% CI 0.59 to 0.72) in quality of life (measured by the St George's Respiratory Questionnaire (SGRQ)). Tiotropium treatment significantly reduced the number of participants suffering from exacerbations (OR 0.78; 95% CI 0.70 to 0.87). This corresponds to a need to treat 16 patients (95% CI 10 to 36) with tiotropium for a year in order to avoid one additional patient suffering exacerbations, based on the average placebo event rate of 44% from one-year studies. Tiotropium treatment led to fewer hospitalisations due to exacerbations (OR 0.85; 95% CI 0.72 to 1.00), but there was no statistically significant difference in all-cause hospitalisations (OR 1.00; 95% CI 0.88 to 1.13) or non-fatal serious adverse events (OR 1.03; 95% CI 0.97 to 1.10). Additionally, there was no statistically significant difference in all-cause mortality between the tiotropium and placebo groups (Peto OR 0.98; 95% CI 0.86 to 1.11). However, subgroup analysis found a significant difference between the studies using a dry powder inhaler and those with a soft mist inhaler (test for subgroup differences: P = 0.01). With the dry powder inhaler there were fewer deaths in the tiotropium group (Peto OR 0.92; 95% CI 0.80 to 1.05) than in the placebo group (yearly rate 2.8%), but with the soft mist inhaler there were significantly more deaths in the tiotropium group (Peto OR 1.47; 95% CI 1.04 to 2.08) than in the placebo group (yearly rate 1.8%). It is noted that the rates of patients discontinuing study treatment were uneven, with significantly fewer participants withdrawing from tiotropium treatment than from placebo treatment (OR 0.66; 95% CI 0.59 to 0.73). Participants on tiotropium had improved lung function at the end of the study compared with those on placebo (trough forced expiratory volume in one second (FEV1) MD 118.92 mL; 95% CI 113.07 to 124.77).

Authors' conclusions: This review shows that tiotropium treatment was associated with a significant improvement in patients' quality of life and it reduced the risk of exacerbations, with a number needed to treat to benefit (NNTB) of 16 to prevent one exacerbation. Tiotropium also reduced exacerbations leading to hospitalisation but no significant difference was found for hospitalisation of any cause or mortality. Thus, tiotropium appears to be a reasonable choice for the management of patients with stable COPD, as proposed in guidelines. The trials included in this review showed a difference in the risk of mortality when compared with placebo depending on the type of tiotropium delivery device used. However, these results have not been confirmed in a recent trial when 2.5 mcg or 5 mcg of tiotropium via Respimat was used in a direct comparison to the 18 mcg Handihaler.

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Conflict of interest statement

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.
3
3
Forest plot of comparison: 1 Tiotropium versus placebo, outcome: 1.1 Quality of life (SGRQ total score).
4
4
Forest plot of comparison: 1 Tiotropium versus placebo, outcome: 1.9 Patients with ≥ 1 exacerbation.
5
5
In the placebo group 44 people out of 100 had one or more exacerbations over one year, compared to 38 (95% CI 34 to 41) out of 100 for the tiotropium group.
6
6
Funnel plot of comparison: 1 Tiotropium versus placebo, outcome: 1.9 Patients with ≥ 1 exacerbation.
7
7
Forest plot of comparison: 1 Tiotropium versus placebo, outcome: 1.21 Subgroup analysis: mortality by inhaler device.
1.1
1.1. Analysis
Comparison 1 Tiotropium versus placebo, Outcome 1 Quality of life (SGRQ total score).
1.2
1.2. Analysis
Comparison 1 Tiotropium versus placebo, Outcome 2 Patients with ≥ 4 units improvement in quality of life (SGRQ).
1.3
1.3. Analysis
Comparison 1 Tiotropium versus placebo, Outcome 3 Patients with ≥ 4 units worsening in quality of life (SGRQ).
1.4
1.4. Analysis
Comparison 1 Tiotropium versus placebo, Outcome 4 Subgroup analysis: Quality of life ICS/ no ICS (SGRQ).
1.5
1.5. Analysis
Comparison 1 Tiotropium versus placebo, Outcome 5 Subgroup analysis: Quality of life LABA/ no LABA (SGRQ).
1.6
1.6. Analysis
Comparison 1 Tiotropium versus placebo, Outcome 6 Subgroup analysis: Quality of life (SGRQ) by disease severity.
1.7
1.7. Analysis
Comparison 1 Tiotropium versus placebo, Outcome 7 Quality of life (EQ‐5D total score).
1.8
1.8. Analysis
Comparison 1 Tiotropium versus placebo, Outcome 8 Quality of life (CRQ total score).
1.9
1.9. Analysis
Comparison 1 Tiotropium versus placebo, Outcome 9 Patients with ≥ 1 exacerbation.
1.10
1.10. Analysis
Comparison 1 Tiotropium versus placebo, Outcome 10 Subgroup analysis: patients with ≥ 1 exacerbation by study duration.
1.11
1.11. Analysis
Comparison 1 Tiotropium versus placebo, Outcome 11 Subgroup analysis: patients with ≥ 1 exacerbations ICS/ no ICS by concomitant medication.
1.12
1.12. Analysis
Comparison 1 Tiotropium versus placebo, Outcome 12 Subgroup analysis: patients with ≥ 1 exacerbation by inhaler device.
1.13
1.13. Analysis
Comparison 1 Tiotropium versus placebo, Outcome 13 Subgroup analysis: patients with ≥ 1 exacerbation by disease severity.
1.14
1.14. Analysis
Comparison 1 Tiotropium versus placebo, Outcome 14 Patients with ≥ 1 exacerbation requiring hospitalisation.
1.15
1.15. Analysis
Comparison 1 Tiotropium versus placebo, Outcome 15 Patients with ≥ 1 hospitalisation (all‐cause).
1.16
1.16. Analysis
Comparison 1 Tiotropium versus placebo, Outcome 16 Subgroup analysis: patients with ≥ 1 exacerbation requiring hospitalisation by study duration.
1.17
1.17. Analysis
Comparison 1 Tiotropium versus placebo, Outcome 17 Subgroup analysis: patients with ≥ 1 exacerbation requiring hospitalisation by inhaler device.
1.18
1.18. Analysis
Comparison 1 Tiotropium versus placebo, Outcome 18 Subgroup analysis: patients with ≥ 1 exacerbation requiring hospitalisation by disease severity.
1.19
1.19. Analysis
Comparison 1 Tiotropium versus placebo, Outcome 19 Mortality.
1.20
1.20. Analysis
Comparison 1 Tiotropium versus placebo, Outcome 20 Subgroup analysis: mortality by study duration.
1.21
1.21. Analysis
Comparison 1 Tiotropium versus placebo, Outcome 21 Subgroup analysis: mortality by inhaler device.
1.22
1.22. Analysis
Comparison 1 Tiotropium versus placebo, Outcome 22 Subgroup analysis: mortality LABA/ no LABAby concomitant medication.
1.23
1.23. Analysis
Comparison 1 Tiotropium versus placebo, Outcome 23 Subgroup analysis: mortality ICS/LABA/ no ICS/LABA by concomitant medication.
1.24
1.24. Analysis
Comparison 1 Tiotropium versus placebo, Outcome 24 Subgroup analysis: mortality ICS/ no ICS by concomitant medication.
1.25
1.25. Analysis
Comparison 1 Tiotropium versus placebo, Outcome 25 Subgroup analysis: mortality by disease severity.
1.26
1.26. Analysis
Comparison 1 Tiotropium versus placebo, Outcome 26 Trough FEV1.
1.27
1.27. Analysis
Comparison 1 Tiotropium versus placebo, Outcome 27 Patients with ≥ 1 serious adverse event (non‐fatal).
1.28
1.28. Analysis
Comparison 1 Tiotropium versus placebo, Outcome 28 Withdrawals.
1.29
1.29. Analysis
Comparison 1 Tiotropium versus placebo, Outcome 29 Sensitivity analysis of SGRQ responders imputing 0% for missing participants.
1.30
1.30. Analysis
Comparison 1 Tiotropium versus placebo, Outcome 30 Sensitivity analysis of SGRQ responders imputing 20% for missing participants.
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Update of

References

References to studies included in this review

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    1. Tonnel AB. Effect of a 9‐month treatment of SPIRIVA® on health related quality of life in patients with chronic obstructive pulmonary disease. Validation of a new HRQoL questionnaire appropriate to common daily practice. (TIPHON Study). www.trials.boehringer‐ingelheim.com. [trial number: 205.256]
    1. Tonnel AB, Bravo ML, Brun M. Clinically significant improvements of health status of COPD patients after 9 months treatment with tiotropium bromide: the TIPHON study [Abstract]. American Thoracic Society International Conference; May 20‐25; San Diego. 2005:[B93] [Poster: 302].
    1. Tonnel AB, Perez T, Grosbois JM, Bravo ML, Brun M. Improvement in HRQoL of COPD patients after 9 months treatment with tiotropium bromide: use of a new scale for daily medical practice [Abstract]. European Respiratory Society 15th Annual Congress; 2005 September 17 ‐ 21; Copenhagen. 2005.
    1. Tonnel AB, Perez T, Grosbois JM, Verkindre C, Bravo ML, Brun M. Effect of tiotropium on health‐related quality of life as a primary efficacy endpoint in COPD. International Journal of COPD 2008;3(2):301‐10. [CTG: NCT00274053] - PMC - PubMed
Trooster 2011 {published and unpublished data}
    1. Carron K. A 24 week, randomized, double‐blind, placebo‐controlled, multicenter study to evaluate the efficacy and safety of 18 mcg of tiotropium inhalation capsules administered by handihaler® once‐daily plus prn albuterol (salbutamol) vs. placebo plusprn albuterol (salbutamol) in chronic obstructive pulmonary disease subjects naive to maintenance therapy. www.trials.boehringer‐ingelheim.com. [trial number: 205.365]
    1. Sciurba FC, Siafakas N, Troosters T, Klioze SS, Sutradhar S, Weisman I, et al. The efficacy and safety of tiotropium Handihaler, 18 µg, once daily plus PRN salbutamol versus placebo plus prn salbutamol in COPD subjects naive to maintenance therapy [Abstract]. American Thoracic Society 2011 International Conference; 2011 May 13‐18; Denver. 2011; Vol. 183:A1589.
    1. Troosters T, Weisman I, Dobbels F, Giardino N, Valluri SR. Assessing the impact of tiotropium on lung function and physical activity in GOLD Stage II COPD patients who are naive to maintenance respiratory therapy: a study protocol. The Open Respiratory Medicine Journal 2011;5:1‐9. [CTG: NCT00523991] - PMC - PubMed
Verkinde 2006 {published and unpublished data}
    1. Huchon G. Effect of a 12‐week treatment with inhaled tiotropium (18 mcg once daily) on lung function and static lung volumes in stable, moderate to severe COPD patients. Correlation to dyspnoea scales: a double‐blind, placebo‐controlled, randomized, parallel group study. www.trials.boehringer‐ingelheim.com. [trial number: 205.215]
    1. Huchon G, Verkindre C, Bart F, Aguilaniu B, Guerin JC, Lemerre C, et al. Improvements with tiotropium on endurance measure by the shuttle walking test (SWT) and on health related quality of life (HRQoL) in COPD patients. European Respiratory Society Congress; 2002 September 14‐18; Stockholm. 2002.
    1. Verkindre C, Bart F, Aguilaniu B, Fortin F, Guerin JC, Merre C, et al. The effect of tiotropium on hyperinflation and exercise capacity in chronic obstructive pulmonary disease. Respiration 2006;73(4):420‐7. - PubMed
Voshaar 2008 {published and unpublished data}
    1. Boehringer Ingelheim. A randomised, double‐blind, double‐dummy, placebo‐ and active‐controlled, parallel group efficacy and safety comparison of 12‐week treatment of two doses [5 mcg (2 actuations of 2.5 mcg) and 10 mcg (2 actuations of 5 mcg)] of tiotropium inhalation solution delivered by the Respimat inhaler, placebo and ipratropium bromide inhalation aerosol (MDI) in patients with chronic obstructive pulmonary disease (COPD). www.trials.boehringer‐ingelheim.com. [trial number: 205.251]
    1. Boehringer Ingelheim. A randomized, double‐blind, double‐dummy, placebo‐ and active‐controlled, parallel group efficacy and safety comparison of 12‐week treatment of two doses (5 Mcg and 10 Mcg) of tiotropium inhalation solution delivered by the Respimat inhaler, placebo and ipratropium bromide inhalation aerosol (MDI) in patients with chronic obstructive pulmonary disease (COPD). www.clinicaltrials.gov 2002; Vol. Sept 2004 End Date. [trial number: 205.252]
    1. Voshaar T, Lapidus R, Maleki‐Yazdi R, Timmer W, Rubin E, Lowe L, et al. A randomised study of tiotropium Respimat soft mist inhaler versus ipratropium PMDI in chronic obstructive pulmonary disease [Abstract]. Thorax 2006;61(Suppl 2):ii40 [S112]. - PubMed
    1. Voshaar T, Lapidus R, Maleki‐Yazdi R, Timmer W, Rubin E, Lowe L, et al. A randomized study of tiotropium Respimat Soft Mist inhaler vs. ipratropium pMDI in COPD. Respiratory Medicine 2008;102(1):32‐41. [CTG: NCT00239473; CTG: NCT00240435] - PubMed

References to studies excluded from this review

Ambrosino 2008 {published data only}
    1. Ambrosino N, Foglio K, Balzano G, Paggiaro PL, Lessi P, Kesten S, et al. Tiotropium and exercise training in COPD patients: effects on dyspnea and exercise tolerance. International Journal of Chronic Obstructive Pulmonary Disease 2008;3(4):771‐80. - PMC - PubMed
Baloira 2005 {published data only}
    1. Baloira A, Vilarino C. Effects of tiotropium bromide in exercise tolerance in patients with chronic obstructive pulmonary disease [Abstract]. European Respiratory Society Congress; 2005 September 17‐21; Copenhagen. 2005; Vol. 26, issue Suppl 49:Abstract No. 1929.
Bedard 2011 {published data only}
    1. Bedard ME, Brouillard C, Pepin V, Milot J, Lacasse Y, Leblanc P, et al. Tiotropium improves walking endurance in chronic obstructive pulmonary disease patients. American Journal of Respiratory and Critical Care Medicine. 2011; Vol. 183:A1590.
Calverley 2000 {published data only}
    1. Calverley PMA, Towse LJ, Lee A. The timing of dose and pattern of bronchodilatation of tiotropium (TIO) in stable COPD. European Respiratory Journal 2000;16(Suppl 31):56s.
Casaburi 2005 {published data only}
    1. Casaburi R, Kukafka D, Cooper CB, Kesten S. Improvement in exercise endurance with the combination of tiotropium and rehabilitative exercise training in COPD patients [Abstract]. American Thoracic Society 100th International Conference; 2004 May 21‐26; Orlando. 2004:D14.
    1. Casaburi R, Kukafka D, Cooper CB, Witek TJ Jr, Kesten S. Improvement in exercise tolerance with the combination of tiotropium and pulmonary rehabilitation in patients with COPD. Chest 2005;127(3):809‐17. - PubMed
    1. Cooper CB, Kukafka D, Casburi R, Kesten S. Tiotropium augments improvements in dyspnea and health‐related quality of life following pulmonary rehabilitation in COPD patients [Abstract]. American Thoracic Society 100th International Conference; 2004 May 21‐26; Orlando. 2004:C22 Poster 507.
    1. Kesten S, Casaburi R, Kukafka D, Cooper CB. Improvement in self‐reported exercise participation with the combination of tiotropium and rehabilitative exercise training in COPD patients. International Journal of COPD 2008;3(1):127‐36. - PMC - PubMed
Celli 2002 {published data only}
    1. Celli BR, Zuwallack RL, Wang S, Kesten S. Improvements in inspiratory capacity with tiotropium in patients with COPD [Abstract]. European Respiratory Society Annual Congress 2002. 2002:abstract nr: P3079.
da Fonseca 2010 {published data only}
    1. Fonseca Reis LF, Ventura TG, Jayme S, Bispo P, Cantanhede LA. A role of tiotropium in patients with severe COPD subject to a supervised program of exercises [Abstract]. European Respiratory Society Annual Congress; 2010 September 18‐22; Barcelona, Spain. 2010:[P4872].
de Guia 2004 {published data only}
    1. Guia T, Punzal P, Canizares L, Sy‐Naval S, Salonga R, Tan D, et al. Evaluation of the response of Filipino COPD patients to Tiotropium (EVEREST STUDY) [Abstract]. American Thoracic Society 100th International Conference; 2004 May 21‐26; Orlando. 2004:C47 Poster F78.
Diba 2009 {published data only}
    1. Diba C, Salome CM, Berend N, Harris B, Bailey D, King GG. Effect of bronchodilator on ventilation heterogeneity in COPD [Abstract]. Respirology 2009;14(Suppl 1):A19.
Diba 2011 {published data only}
    1. Diba C, King GG, Berend N, Salome CM. Improved respiratory system conductance following bronchodilator predicts reduced exertional dyspnoea. Respiratory Medicine 2011; Vol. 105, issue 9:1345‐51. - PubMed
Friedman 1998 {published data only}
    1. Friedman M, Auerbach D, Campbell S, Dunn L, Illowite J, Littner M, et al. Tiotropium in patients with COPD. American Journal of Respiratory and Critical Care Medicine 1998;157(3 Suppl):A804.
Fuhr 2010 {published data only}
    1. Fuhr R, Magnussen H, Ribera A, Kirsten AM, Falques M, Caracta C, et al. Efficacy and safety of twice‐daily aclidinium bromide 400 µg compared with placebo and tiotropium 18 µg qd in moderate to severe COPD patients [Abstract]. Chest 2010;138(4):465A. - PubMed
    1. Fuhr R, Magnussen H, Ribera Llovera A, Kirsten A, Falques M, Caracta C, et al. Efficacy and safety of twice‐daily aclidinium bromide compared with tiotropium and placebo in patients with moderate to severe COPD [Abstract]. European Respiratory Society Annual Congress; 2010 September 18‐22; Barcelona, Spain. 2010:[P1236].
Gelb 2011 {published data only}
    1. Gelb AF, Fraser C, Zamel N. Lack of protective effect of tiotropium vs induced dynamic hyperinflation in moderate COPD. Respiratory Medicine 2011;105:755‐60. - PubMed
Gurzhiy 2007 {published data only}
    1. Gurzhiy O, Pertseva T, Lykholat O. Evaluation of mucociliary clearance 's (MCC) condition in patients with COPD influence of tiotropium bromide (TB) on MCC [Abstract]. European Respiratory Journal 2007;30(Suppl 51):73s [P582].
Halpin 2006 {published data only}
    1. Halpin DMG, Menjoge S, Viel K. Tiotropium reduces the risk of COPD exacerbation irrespective of its characterization by the treatment intervention [Abstract]. European Respiratory Journal 2006;28(Suppl 50):764s [4397].
Hasani 2001 {published data only}
    1. Hasani A, Agnew J, Dilworth J, Begent L, Mier A, Sarno M, et al. Effect of tiotropium on distribution pattern of aerosol particles deposited in the lung [abstract]. American Journal of Respiratory and Critical Care Medicine 2001;163(5 Suppl):A277.
    1. Hasani A, Agnew JE, Dilworth JP, Creer D, Mier A, Sarno M, et al. Effect of tiotropium on lung ventilatory distribution in COPD patients. American Journal of Respiratory and Critical Care Medicine 2001;163(5 Suppl):A282.
Hasani 2001b {published data only}
    1. Hasani A, Toms N, Creer DD, Agnew JE, Dilworth JP, Sarno M, et al. Effect of inhaled tiotropium on tracheobronchial clearance in patients with COPD. European Respiratory Journal 2001;18(Suppl 33):245s.
Hirata 2003 {published data only}
    1. Hirata K, Nishimura M, Ichinose M, Nishimura K, Nagai A, Yoshida M, et al. Tiotropium once daily improves health status in Japanese patients with COPD [Abstract]. American Thoracic Society 99th International Conference; 2003 May 16‐21; Seattle. 2003:A035 Poster D79.
    1. Ichinose M, Nishimura M, Hirata K, Nagai A, Yoshida M, Fukuchi Y. Tiotropium once daily improves spirometry over 24 hours in Japanese patient with COPD [Abstract]. American Thoracic Society Meeting; 2003 May 16‐21; Seattle. 2003:A035 Poster D80.
Kerstjens 2004 {published data only}
    1. Kerstjens HAM, Bantje TA, Luursema PB, Damste HEJS, Jong JW, Lee A, et al. Tiotropium maintainence therapy and the additive effects of a single dose of ipratropium bromide or fenoterol in patient with COPD [Abstract]. American Thoracic Society 100th International Conference 2004 May 21‐26 Orlando. 2004:C22 Poster 514.
Langley 2002 {published data only}
    1. Langley S, Towse L, Kesten S, Claverley PM. Heart rate and rhythm analysis from holter monitoring in COPD patients receiving tiotropium. American Journal of Respiratory and Critical Care Medicine 2002;165(Suppl 8):A592.
McNicholas 2001 {published data only}
    1. McNicholas WT, Calverley PMA, Edwards C, Lee A. Effects of anticholinergic therapy (tiotropium) on REM‐related desaturation (SaO2) and sleep quality in patients with COPD. American Journal of Respiratory and Critical Care Medicine 2001;163(5 Suppl):A280.
Meshcheriakova 2007 {published data only}
    1. Meshcheriakova N, Belevskiy A, Cherniak A. The role of tiotropium bromide in physical training for patients with COPD [Abstract]. European Respiratory Journal 2007;30(Suppl 51):516s [E3091].
O'Donnell 2002 {published data only}
    1. Magnussen H, O'Donnell DE, Casaburi R, Keston S, Gerken F, Flüge T. Spiriva® (tiotropium) reduces lung hyper inflation in COPD. American Journal of Respiratory and Critical Care Medicine 2002;165(Suppl 8):A227.
    1. O'Donnell D, He Z, Lam M, Webb K, Flüge T, Hamilton A. Reproducibility of measurements of inspiratory capacity dyspnea intensity and exercise endurance in multicentre trials in COPD [Abstract]. European Respiratory Journal 2004;24(Suppl 48):323s.
    1. O'Donnell DE, Magnussen H, Aguilaniu B, Gerken F, Hamilton A, Flüge T. Spiriva (tiotropium) improves exercise tolerance in COPD [Abstract]. First National COPD Conference; 2003 November 14‐15; Arlington, Virginia. 2003:Abstract no: 1192.
    1. O'Donnell DE, Magnussen H, Aguilaniu B, Gerken F, Hamilton A, Flüge T. Spiriva® (Tiotropium) improves exercise tolerance in COPD. American Journal of Respiratory and Critical Care Medicine 2002;165(Suppl 8):A227.
    1. O'Donnell DE, Magnussen H, Aguilaniu B, Make B, Flüge T, Hamilton A. Spiriva® (Tiotropium) reduces exertional dyspnea in COPD. American Journal of Respiratory and Critical Care Medicine 2002;165(Suppl 8):A265.
O'Donnell 2004a {published data only}
    1. O'Donnell D, Maltais F, Sciurba F, Kesten S, Hamilton A. SPIRIVA® (Tiotropium) improves symptom‐limited exercise tolerance in COPD patients [Abstract]. American Thoracic Society 100th International Conference; 2004 May 21‐26; Orlando. 2004:D23 Poster 207.
    1. O'Donnell D, Marciniuk D, Hernandez P, Richter K, Kesten S, Hamilton A. Spiriva® (Tiotropium) reduces lung hyperinflation at rest and during exercise in COPD patients [Abstract]. American Thoracic Society 100th International Conference; 2004 May 21‐26 2004; Orlando. 2004:D23 Poster 210.
    1. O'Donnell DE, Johnson B, Richter K, Kesten S, Hamilton A. Inspiratory capacity (IC) and dyspnea during recovery from symptom‐limited exercise in COPD patients treated with tiotropium [Abstract]. European Respiratory Journal 2004;24(Suppl 48):214s.
O'Donnell 2005 {published data only}
    1. O'Donnell D, Hamilton A, Kesten S. Influence of the exercise‐limiting symptom on the relationship between lung hyperinflation and endurance time in COPD patients treated with tiotropium [Abstract]. American Thoracic Society 2005 International Conference; 2005 May 20‐25; San Diego, California. 2005:[B23] [Poster: 502].
O'Donnell 2005a {published data only}
    1. O'Donnell D, Webb KA. The effect of tiotropium on ventilatory mechanics during exercise in COPD [Abstract]. American Thoracic Society 2005 International Conference; 2005 May 20‐25; San Diego, California. 2005:[B65] [Poster: A51].
Olson 2009 {published data only}
    1. Olson T, Baldi J, Afessa B, Scanlon P, Hulsebus M, Miller A, et al. Cardiac consequences of obstruction during exercise: benefits of bronchodilation [Abstract]. American Thoracic Society International Conference; 2009 May 15‐20; San Diego. 2009:A4571 [Poster #J84].
Reisner 2011 {published data only}
    1. Orevillo C, St. Rose E, Strom S, Fischer T, Golden M, Thomas M, et al. Glycopyrrolate MDI demonstrates comparable efficacy and safety to tiotropium DPI in a randomized, double‐blind, placebo‐controlled phase 2b study in patients with COPD [Abstract]. European Respiratory Society Annual Congress;2011 September 24‐28; Amsterdam, The Netherlands 2011;38(55):724s [P3975].
    1. Reisner C, Fogarty C, Spangenthal S, Dunn L, Kerwin EM, Quinn D, et al. Novel combination of glycopyrrolate and formoterol MDI (GFF‐MDI) provides superior bronchodilation compared to its components administered alone, tiotropium DPI, and formoterol DPI in a randomized, double‐blind, placebo‐controlled phase 2b study in patients with COPD [Abstract]. American Journal of Respiratory and Critical Care Medicine. 2011; Vol. 183:A6435.
    1. Reisner C, St. Rose E, Strom S, Fischer T, Golden M, Thomas M, et al. Fixed combination of glycopyrrolate and formoterol MDI (GFF‐MDI) demonstrates superior inspiratory capacity (IC) compared to tiotropium DPI (Tio) following 7 days dosing, in a randomized, double‐blind, placebo‐controlled phase 2b study in patients with COPD [Abstract]. European Respiratory Society Annual Congress; 2011 September 24‐28; Amsterdam, The Netherlands 2011;38(55):150s [P879].
Rossi 2008 {published data only}
    1. Rossi S, Gladly C, Baril J, Perrault H, Bourbeau J. COPD patients who respond to tiotropium with dyspnea relief: A proof of efficacy? [Abstract]. American Thoracic Society International Conference 2008 May 16‐21; Toronto. 2008:A648[#F15].
Schilling 2000 {published data only}
    1. Schilling JC, Witek TJ, Feifel U, Souhrada JF, Disse B. Safety and tolerability of supra‐therapeutic doses of inhaled tiotropium (TIO). European Respiratory Journal 2000;16(Suppl 31):361s.
Schurmann 2004 {published data only}
    1. Schurmann W, Schmidtmann S, Moroni P, Massey D, Qidan M. Patients prefer Respimat® Soft Mist TM inhaler to HFA‐MDI [Abstract]. Primary Care Respiratory Journal 2004;13(2):118 ABS044.
Sposato 2005 {published data only}
    1. Sposato B, Salvatore M, Giovanna MM, Alberto R, Elena C, Aldo G, et al. Formoterol or tiotropium bromide do not influence nocturnal hypoxemia in stable COPD [Abstract]. European Respiratory Journal 2005;26(Suppl 49):Abstract No. 1959.
ten Hacken 2007 {published data only}
    1. Hacken NH, Haart H, Grevink R, Thompson S, Roemer W, Postma DS. Bronchodilation improves endurance but not muscular efficiency in COPD [Abstract]. American Thoracic Society International Conference; 2007 May 18‐23; San Francisco, California, USA. 2007:Poster #M72.
van Noord 2006 {published data only}
    1. Noord JA, Cornelissen G, Aumann JL, Platz J, Mueller A, Fogarty C. Efficacy in COPD patients of tiotropium administered via the Respimat soft mist inhaler (SMI) compared to handihaler (HH) [Abstract]. European Respiratory Journal 2006;28(Suppl 50):431s [P2516]. - PubMed
Vincken 2001 {published data only}
    1. Vincken WG, Vermiere P, Menjoge SS, Keston S, Cornelissen PJG. Maintenance of bronchodilation following tiotropium in patients with mild, moderate and severe COPD in one year clinical trials. European Respiratory Journal 2001;18(Supp 33):331s.

References to studies awaiting assessment

Gu 2007 {published data only}
    1. Gu W, Sun LH, Tan Y. Effects of tiotropium on the exercise endurance of patients with COPD. Journal Southeast University (Med. Sci. Edi.) 2007;26:332–5.
Min 2006 {published data only}
    1. Min R, Huang M, Yin KS, Fu WZ, Yu WZ. Clinical trial on tiotropium for COPD. Jiangsu Medical Journal 2006;32:1078–9.
NCT00528996 {published data only}
    1. Boehringer Ingelheim. Tiotropium (SPIRIVA®) RESPIMAT®: Evaluation of fatal events – February 2010. www.trials.boehringer‐ingelheim.com (accessed 12 July 2010). [CTG: NCT00528996; trial number: 1205.14]
Xia 2007 {published data only}
    1. Xia QP, Chen JR, Tao YJ. The curative effect of tiotropium bromide in treating stable COPD. Journal of Clinical Pulmonary Medicine 2007;12:1327–8.
Yin 2010 {published data only}
    1. Yin KS, Zhang DP, Shi Y, Sun LH, Min R, Xiao YL, et al. A randomized, double‐blind, placebo‐control study of once‐daily inhaled tiotropium in chronic obstructive pulmonary disease. Zhonghua Jie He He Hu Xi Za Zhi 2010;33(7):519‐23. - PubMed

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