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Meta-Analysis
. 2005 Apr 18;2005(2):CD002876.
doi: 10.1002/14651858.CD002876.pub2.

Inhaled tiotropium for stable chronic obstructive pulmonary disease

R G Barr  1 , J Bourbeau, C A Camargo, F S F Ram
Affiliations
Meta-Analysis

Inhaled tiotropium for stable chronic obstructive pulmonary disease

R G Barr et al. Cochrane Database Syst Rev. .

Abstract

Background: Tiotropium is a new anticholinergic therapy for chronic obstructive pulmonary disease (COPD) that differs from ipratropium by its functional relative selectivity for muscarinic receptor subtypes and which allows once-per-day dosing.

Objectives: To determine the efficacy of tiotropium on clinical endpoints such exacerbations and hospitalisations, symptom scales and pulmonary function compared to placebo and other bronchodilators used for stable COPD.

Search strategy: Randomised controlled trials (RCTs) were identified from the Cochrane Airways Review Group Specialised Register, a compilation of systematic searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and CINAHL, and hand searching of 20 respiratory journals. Bibliographies from included studies and reviews were searched. The date of the last search was October 2004.

Selection criteria: Randomised clinical trials comparing tiotropium with placebo, ipratropium bromide, or long-acting ss2-agonists for greater than, or equal to, one month's duration.

Data collection and analysis: Two reviewers independently extracted data. Missing data were obtained from authors or the manufacturer of tiotropium. The data were analysed using the Cochrane Review Manager RevMan 4.2. Studies were pooled to yield weighted mean differences (WMD) or odds ratios (OR) and reported using 95% confidence intervals (CI).

Main results: From 69 identified references, nine RCTs (6,584 patients) met inclusion criteria. Tiotropium reduced the odds of a COPD exacerbation (OR 0.74; 95% CI 0.66 to 0.83) and related hospitalisations (OR 0.64; 95% CI 0.51 to 0.82) compared to placebo or ipratropium. When applied to an annual baseline risk of 45% for exacerbations and 10% for hospitalisation, the number of patients needed to treat with tiotropium for one year were 14 (95% CI 11 to 22) to prevent one exacerbation and 30 (95% CI 22 to 61) to prevent one hospitalisation compared to placebo and ipratropium. Reductions in these endpoints compared to long-acting ss2-agonists were not statistically significant. Similar patterns were evident for quality-of-life and symptom scales. Increases in FEV1 and FVC from baseline were significantly larger with tiotropium than with placebo, ipratropium and long-acting ss2-agonists over 6 to 12 months. The decline in trough FEV1 from steady state was 30 ml (95% CI 7 to 53 ml) less with tiotropium than with placebo or ipratropium over one year; no data on decline in FEV1 from steady state were available for long-acting ss2-agonists. Dry mouth was increased by tiotropium.

Authors' conclusions: Tiotropium reduced COPD exacerbations and related hospitalisations compared to placebo and ipratropium. It also improved health-related quality-of-life and symptom scores among patients with moderate and severe disease, and may have slowed decline in FEV1. Additional long-term studies are required to evaluate its effect on mortality and change in FEV1 to clarify its role in comparison to, or in combination with, long-acting ss2-agonists and to assess its effectiveness in mild and very severe COPD.

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Conflict of interest statement

Dr Bourbeau has received unrestricted educational grants for research from Boehringer‐Ingelheim and GlaxoSmithKline. Dr Camargo has received financial support from government agencies, private foundations, professional organizations, and manufacturers of pharmaceuticals and medical devices including Boehringer‐Ingelheim and GlaxoSmithKline.

Figures

1
1
Forest plot of comparison: 1 Health outcomes, outcome: 1.1 Exacerbations.
2
2
Patients suffering COPD exacerbation when given Tiotropium for one year in comparison to placebo or Ipratropium
3
3
Forest plot of comparison: 1 Health outcomes, outcome: 1.3 Hospitalisations for COPD.
4
4
Patients with hospitalisation over one year on Tiotropium compared to placebo or Ipratropium
5
5
Forest plot of comparison: 1 Health outcomes, outcome: 1.6 All‐cause mortality ‐‐ summary estimate.
6
6
Funnel plot of included studies for COPD exacerbations
1.1
1.1. Analysis
Comparison 1 Health outcomes, Outcome 1 Exacerbations.
1.2
1.2. Analysis
Comparison 1 Health outcomes, Outcome 2 Exacerbations ‐‐ summary estimate.
1.3
1.3. Analysis
Comparison 1 Health outcomes, Outcome 3 Hospitalisations for COPD.
1.4
1.4. Analysis
Comparison 1 Health outcomes, Outcome 4 Hospitalisations for COPD ‐‐ summary estimate.
1.5
1.5. Analysis
Comparison 1 Health outcomes, Outcome 5 All‐cause mortality.
1.6
1.6. Analysis
Comparison 1 Health outcomes, Outcome 6 All‐cause mortality ‐‐ summary estimate.
2.1
2.1. Analysis
Comparison 2 Quality of life and symptom scales, Outcome 1 Mean change in SGRQ.
2.2
2.2. Analysis
Comparison 2 Quality of life and symptom scales, Outcome 2 Mean change in SGRQ ‐‐ summary estimate.
2.3
2.3. Analysis
Comparison 2 Quality of life and symptom scales, Outcome 3 Clinically significant change in SGRQ.
2.5
2.5. Analysis
Comparison 2 Quality of life and symptom scales, Outcome 5 Clinically significant change in TDI focal score.
3.1
3.1. Analysis
Comparison 3 Spirometry, Outcome 1 Change in trough FEV1 from baseline.
3.2
3.2. Analysis
Comparison 3 Spirometry, Outcome 2 Change in mean FEV1 from baseline.
3.3
3.3. Analysis
Comparison 3 Spirometry, Outcome 3 Change in peak FEV1 from baseline.
3.4
3.4. Analysis
Comparison 3 Spirometry, Outcome 4 Change in trough FVC from baseline.
3.5
3.5. Analysis
Comparison 3 Spirometry, Outcome 5 Change in mean FVC from baseline.
3.6
3.6. Analysis
Comparison 3 Spirometry, Outcome 6 Change in peak FVC from baseline.
3.7
3.7. Analysis
Comparison 3 Spirometry, Outcome 7 Change in morning PEFR from baseline.
3.8
3.8. Analysis
Comparison 3 Spirometry, Outcome 8 Change in evening PEFR from baseline.
3.9
3.9. Analysis
Comparison 3 Spirometry, Outcome 9 Change in trough FEV1 from day 8, with summary estimate.
3.10
3.10. Analysis
Comparison 3 Spirometry, Outcome 10 Change in mean FEV1 from day 8, with summary estimate.
3.11
3.11. Analysis
Comparison 3 Spirometry, Outcome 11 Change in peak FEV1 from day 8, with summary estimate.
3.12
3.12. Analysis
Comparison 3 Spirometry, Outcome 12 Change in trough FVC from day 8.
3.13
3.13. Analysis
Comparison 3 Spirometry, Outcome 13 Change in mean FVC from day 8, with summary estimate.
3.14
3.14. Analysis
Comparison 3 Spirometry, Outcome 14 Change in peak FVC from day 8, with summary estimate.
7.1
7.1. Analysis
Comparison 7 Adverse events, Outcome 1 Dry mouth.
See this image and copyright information in PMC

Comment in

References

References to studies included in this review

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Tashkin 2003 {published data only}
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References to studies awaiting assessment

205.215 {unpublished data only}
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205.234 {unpublished data only}
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205.244 {unpublished data only}
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205.247 {unpublished data only}
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Briggs 2005 {published data only}
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Casaburi 2005 {published data only}
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Covelli 2005 {published data only}
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Criner 2006 {published data only}
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EVEREST {published data only}
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Hsu 2006 {published data only}
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Incorvaia 2007 {published data only}
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Langley 2004 {published data only}
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Lindsay 2005 {published data only}
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Maltais 2005 {published data only}
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MISTRAL {published data only}
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Moita 2008 {published data only}
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Powrie 2006 {published data only}
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SAFE {unpublished data only}
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SPRUCE {published data only}
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TIPHON {published data only}
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UPLIFT {published data only}
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    1. Celli B, Tashkin D, Decramer M, Burkhart D, Cassino C, Kesten S. Acute bronchodilator responsiveness in a global respiratory trial (UPLIFT) following maximal inhaled bronchodilators. European RespiratorY Journal 2005;26(Suppl 49):716s.
    1. Decramer M, Celli B, Tashkin DP, Burkhart D, Kesten S, Cassino C. Regional differences in the treatment of patients with moderate COPD enrolled in a global clinical trial. European Respiratory Journal 2006;28(Suppl 50):526s.
    1. Decramer M, Celli B, Tashkin DP, Pauwels RA, Burkhart D, Cassino C, et al. Clinical trial design considerations in assessing long‐term functional impacts of tiotropium in COPD: the UPLIFT trial. Journal of Chronic Obstructive Pulmonary Disease 2004;1(2):303‐12. - PubMed
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van Noord 2005 {published data only}
    1. Noord JA, Aumann J, Janssens E, Mueller A, Cornelissen PJG. A comparison of the 24 hour bronchodilator effect of tiotropium QD [T10] salmeterol BID [SALM] or their combination in COPD. American Thoracic Society 2005 International Conference; May 20‐25; San Diego, California 2005:B93 Poster: 311.
    1. Noord JA, Aumann J‐L, Janssens E, Smeets JJ, Verhaert J, Disse B, et al. Comparison of tiotropium once daily, formoterol twice daily and both combined once daily in patients with COPD. European Respiratory Journal 2005;26(2):214‐22. - PubMed
    1. Noord JA, Smeets JJ, Otte A, Bindels H, Mueller A, Cornellissen PJG. The effect of tiotropium, salmeterol and it's combination on dynamic hyperinflation in COPD. American Thoracic Society 2005 International Conference; May 20‐25; San Diego, California. 2005:B93 Poster: 310.
Verkindre 2006 {published data only}
    1. Verkindre C, Bart F, Aguilaniu B, Fortin F, Guerin J‐C, 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 {unpublished data only}
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