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Meta-Analysis
. 2016 Jun 6;2016(6):CD008532.
doi: 10.1002/14651858.CD008532.pub3.

Combination inhaled steroid and long-acting beta₂-agonist in addition to tiotropium versus tiotropium or combination alone for chronic obstructive pulmonary disease

Maria Ximena Rojas-Reyes  1 , Olga M García Morales, Rodolfo J Dennis, Charlotta Karner
Affiliations
Meta-Analysis

Combination inhaled steroid and long-acting beta₂-agonist in addition to tiotropium versus tiotropium or combination alone for chronic obstructive pulmonary disease

Maria Ximena Rojas-Reyes et al. Cochrane Database Syst Rev. .

Abstract

Background: The long-acting bronchodilator tiotropium and single-inhaler combination therapy of inhaled corticosteroids and long-acting beta2-agonists (ICS/LABA) are commonly used for maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). Combining these treatments, which have different mechanisms of action, may be more effective than administering the individual components.

Objectives: To assess relative effects of the following treatments on markers of exacerbations, symptoms, quality of life and lung function in patients with COPD.• Tiotropium plus LABA/ICS versus tiotropium.• Tiotropium plus LABA/ICS versus LABA/ICS.

Search methods: We searched the Cochrane Airways Group Specialised Register of Trials (April 2015), ClinicalTrials.gov (www.ClinicalTrials.gov), the World Health Organization (WHO) trials portal and reference lists of relevant articles.

Selection criteria: We included parallel, randomised controlled trials (RCTs) lasting three months or longer conducted to compare ICS and LABA combination therapy in addition to inhaled tiotropium versus tiotropium alone or combination therapy alone.

Data collection and analysis: We independently assessed trials for inclusion, then extracted data on trial quality and outcome results. We contacted study authors to ask for additional information. We collected trial information on adverse effects.

Main results: Tiotropium plus LABA/ICS versus tiotropiumWe included six studies (1902 participants) with low risk of bias that compared tiotropium in addition to inhaled corticosteroid and long-acting beta2-agonist combination therapy versus tiotropium alone. Investigators found no statistically significant differences in mortality between treatments (odds ratio (OR) 1.80, 95% confidence interval (CI) 0.55 to 5.91; two studies; 961 participants), a reduction in all-cause hospitalisations with the use of combined therapy (tiotropium + LABA/ICS) (OR 0.61, 95% CI 0.40 to 0.92; two studies; 961 participants; number needed to treat for an additional beneficial outcome (NNTB) 19.7, 95% CI 10.75 to 123.41). The effect on exacerbations was heterogeneous among trials and was not meta-analysed. Health-related quality of life measured by St. George's Respiratory Questionnaire (SGRQ) showed a statistically significant improvement in total scores with use of tiotropium + LABA/ICS compared with tiotropium alone (mean difference (MD) -3.46, 95% CI -5.05 to -1.87; four studies; 1446 participants). Lung function was significantly different in the combined therapy (tiotropium + LABA/ICS) group, although average benefit with this therapy was small. None of the included studies included exercise tolerance as an outcome.A pooled estimate of these studies did not show a statistically significant difference in adverse events (OR 1.16, 95% CI 0.92 to 1.47; four studies; 1363 participants), serious adverse events (OR 0.86, 95% CI 0.57 to 1.30; four studies; 1758 participants) and pneumonia (Peto OR 1.62, 95% CI 0.54 to 4.82; four studies; 1758 participants). Tiotropium plus LABA/ICS versus LABA/ICSOne of the six studies (60 participants) also compared combined therapy (tiotropium + LABA/ICS) versus LABA/ICS therapy alone. This study was affected by lack of power; therefore results did not allow us to draw conclusions for this comparison.

Authors' conclusions: In this update, we found new moderate-quality evidence that combined tiotropium + LABA/ICS therapy compared with tiotropium plus placebo decreases hospital admission. Low-quality evidence suggests an improvement in disease-specific quality of life with combined therapy. However, evidence is insufficient to support the benefit of tiotropium + LABA/ICS for mortality and exacerbations (moderate- and low-quality evidence, respectively). Of note, not all participants enrolled in the included studies would be candidates for triple therapy according to current international guidance.Compared with the use of tiotropium plus placebo, tiotropium + LABA/ICS-based therapy does not increase undesirable effects such as adverse events or serious non-fatal adverse events.

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Conflict of interest statement

Dr. OM Garcia has received financial support to attend scientific meetings from pharmaceutical companies which manufacture tiotropium preparations. The remaining three authors were not aware of any conflict of interest that should be declared covering the past three years.

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 + LABA/ICS combination versus tiotropium + placebo, outcome: 1.2 Hospital admission (all causes).
4
4
Forest plot of comparison: 1 Tiotropium + LABA/ICS combination versus tiotropium + placebo, outcome: 1.4 Quality of life up to 6 months (SGRQ).
5
5
Forest plot of comparison: 1 Tiotropium + LABA/ICS combination versus tiotropium + placebo, outcome: 1.7 Serious adverse events all reported (non‐fatal).
6
6
Forest plot of comparison: 1 Tiotropium + LABA/ICS combination versus tiotropium + placebo, outcome: 1.4 FEV1 pre‐dose.
1.1
1.1. Analysis
Comparison 1 Tiotropium + LABA/ICS combination versus tiotropium + placebo, Outcome 1 Mortality (all‐cause).
1.2
1.2. Analysis
Comparison 1 Tiotropium + LABA/ICS combination versus tiotropium + placebo, Outcome 2 Hospital admission (all causes).
1.3
1.3. Analysis
Comparison 1 Tiotropium + LABA/ICS combination versus tiotropium + placebo, Outcome 3 Exacerbation.
1.4
1.4. Analysis
Comparison 1 Tiotropium + LABA/ICS combination versus tiotropium + placebo, Outcome 4 Quality of life up to 6 months (SGRQ).
1.5
1.5. Analysis
Comparison 1 Tiotropium + LABA/ICS combination versus tiotropium + placebo, Outcome 5 Sensitivity analysis ‐ QoL up to 6 months (SGRQ).
1.6
1.6. Analysis
Comparison 1 Tiotropium + LABA/ICS combination versus tiotropium + placebo, Outcome 6 FEV1 pre‐dose.
1.7
1.7. Analysis
Comparison 1 Tiotropium + LABA/ICS combination versus tiotropium + placebo, Outcome 7 Serious adverse events all reported (non‐fatal).
1.8
1.8. Analysis
Comparison 1 Tiotropium + LABA/ICS combination versus tiotropium + placebo, Outcome 8 Pneumonia.
1.9
1.9. Analysis
Comparison 1 Tiotropium + LABA/ICS combination versus tiotropium + placebo, Outcome 9 Sensitivity analysis ‐ SAE all reported (non‐fatal).
1.10
1.10. Analysis
Comparison 1 Tiotropium + LABA/ICS combination versus tiotropium + placebo, Outcome 10 Adverse event.
2.1
2.1. Analysis
Comparison 2 Tiotropium + LABA/ICS combination vs LABA/ICS combination + placebo, Outcome 1 FEV1 GIV.
2.2
2.2. Analysis
Comparison 2 Tiotropium + LABA/ICS combination vs LABA/ICS combination + placebo, Outcome 2 Adverse event.
2.3
2.3. Analysis
Comparison 2 Tiotropium + LABA/ICS combination vs LABA/ICS combination + placebo, Outcome 3 FEV1.
See this image and copyright information in PMC

Update of

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