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Study flow diagram.
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Figure 1

Study flow diagram.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Forest plot of comparison: 1 LABA plus tiotropium versus tiotropium, outcome: 1.1 Change in quality of life.
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Figure 3

Forest plot of comparison: 1 LABA plus tiotropium versus tiotropium, outcome: 1.1 Change in quality of life.

Forest plot of comparison: 1 LABA plus tiotropium versus tiotropium, outcome: 1.2 Hospital admission (all cause).
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Figure 4

Forest plot of comparison: 1 LABA plus tiotropium versus tiotropium, outcome: 1.2 Hospital admission (all cause).

Forest plot of comparison: 1 LABA plus tiotropium versus tiotropium, outcome: 1.3 Hospital admission (exacerbation).
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Figure 5

Forest plot of comparison: 1 LABA plus tiotropium versus tiotropium, outcome: 1.3 Hospital admission (exacerbation).

Forest plot of comparison: 1 LABA plus tiotropium versus tiotropium, outcome: 1.4 Mortality (all cause).
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Figure 6

Forest plot of comparison: 1 LABA plus tiotropium versus tiotropium, outcome: 1.4 Mortality (all cause).

Comparison 1 LABA plus tiotropium versus tiotropium, Outcome 1 Change in quality of life.
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Analysis 1.1

Comparison 1 LABA plus tiotropium versus tiotropium, Outcome 1 Change in quality of life.

Comparison 1 LABA plus tiotropium versus tiotropium, Outcome 2 Hospital admission (all cause).
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Analysis 1.2

Comparison 1 LABA plus tiotropium versus tiotropium, Outcome 2 Hospital admission (all cause).

Comparison 1 LABA plus tiotropium versus tiotropium, Outcome 3 Hospital admission (exacerbation).
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Analysis 1.3

Comparison 1 LABA plus tiotropium versus tiotropium, Outcome 3 Hospital admission (exacerbation).

Comparison 1 LABA plus tiotropium versus tiotropium, Outcome 4 Mortality (all cause).
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Analysis 1.4

Comparison 1 LABA plus tiotropium versus tiotropium, Outcome 4 Mortality (all cause).

Comparison 1 LABA plus tiotropium versus tiotropium, Outcome 5 Exacerbation.
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Analysis 1.5

Comparison 1 LABA plus tiotropium versus tiotropium, Outcome 5 Exacerbation.

Comparison 1 LABA plus tiotropium versus tiotropium, Outcome 6 Trough FEV1.
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Analysis 1.6

Comparison 1 LABA plus tiotropium versus tiotropium, Outcome 6 Trough FEV1.

Comparison 1 LABA plus tiotropium versus tiotropium, Outcome 7 Symptom score.
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Analysis 1.7

Comparison 1 LABA plus tiotropium versus tiotropium, Outcome 7 Symptom score.

Comparison 1 LABA plus tiotropium versus tiotropium, Outcome 8 Serious adverse event (non‐fatal).
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Analysis 1.8

Comparison 1 LABA plus tiotropium versus tiotropium, Outcome 8 Serious adverse event (non‐fatal).

Comparison 1 LABA plus tiotropium versus tiotropium, Outcome 9 Withdrawal.
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Analysis 1.9

Comparison 1 LABA plus tiotropium versus tiotropium, Outcome 9 Withdrawal.

Summary of findings for the main comparison. LABA plus tiotropium versus tiotropium for chronic obstructive pulmonary disease

LABA plus tiotropium versus tiotropium for chronic obstructive pulmonary disease

Patient or population: chronic obstructive pulmonary disease
Settings:
Intervention: LABA plus tiotropium versus tiotropium

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Tiotropium

LABA plus tiotropium

Change in quality of life
St George's Respiratory Questionaire (SGRQ). Scale from: 0 to 100.
Follow‐up: 6 to 12 months

The mean change in quality of life in the control group was
‐4.5 units1

The mean change in quality of life in the intervention group was

‐6.3 units1

(‐7.43 to ‐4.79)

MD ‐1.61
(‐2.93 to ‐0.29)

732
(2 studies)

⊕⊕⊕⊝
moderate2

The mean treatment effect was statistically significant but it was smaller than what is regarded as a clinically important difference.

Exacerbations leading to hospital admission
Number of patients experiencing one or more events
Follow‐up: 6 to 12 months

88 per 1000

93 per 1000
(57 to 148)

OR 1.07
(0.63 to 1.81)

732
(2 studies)

⊕⊕⊝⊝
low2,3

Hospital admission (all cause)
Number of patients experiencing one or more events
Follow‐up: 6 to 12 months

119 per 1000

120 per 1000
(79 to 179)

OR 1.01
(0.63 to 1.61)

732
(2 studies)

⊕⊕⊝⊝
low2,3

Mortality (all cause)
Number of patients
Follow‐up: 3 to 12 months

4 per 1000

6 per 1000
(2 to 16)

OR 1.56
(0.56 to 4.33)

3263
(5 studies)

⊕⊕⊝⊝
low4

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 The control group risk is based on Aaron 2007.

2 One study was a year long with high and unbalanced dropouts.
3 Wide confidence interval and few participants and events.
4 There were two trials with no deaths and few deaths in the remaining three trials, leading to a wide confidence interval. Mortality was largely unknown in those who discontinued treatment.

Figures and Tables -
Summary of findings for the main comparison. LABA plus tiotropium versus tiotropium for chronic obstructive pulmonary disease
Comparison 1. LABA plus tiotropium versus tiotropium

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Change in quality of life Show forest plot

2

732

Mean Difference (Fixed, 95% CI)

‐1.61 [‐2.93, ‐0.29]

1.1 Salmeterol

1

304

Mean Difference (Fixed, 95% CI)

‐1.8 [‐3.32, ‐0.28]

1.2 Formoterol

1

428

Mean Difference (Fixed, 95% CI)

‐1.0 [‐3.70, 1.70]

2 Hospital admission (all cause) Show forest plot

2

732

Odds Ratio (M‐H, Fixed, 95% CI)

1.01 [0.63, 1.61]

2.1 Salmeterol

1

304

Odds Ratio (M‐H, Fixed, 95% CI)

1.03 [0.61, 1.76]

2.2 Formoterol

1

428

Odds Ratio (M‐H, Fixed, 95% CI)

0.95 [0.36, 2.50]

3 Hospital admission (exacerbation) Show forest plot

2

732

Odds Ratio (M‐H, Fixed, 95% CI)

1.07 [0.63, 1.81]

3.1 Salmeterol

1

304

Odds Ratio (M‐H, Fixed, 95% CI)

1.16 [0.66, 2.06]

3.2 Formoterol

1

428

Odds Ratio (M‐H, Fixed, 95% CI)

0.64 [0.15, 2.69]

4 Mortality (all cause) Show forest plot

5

3263

Peto Odds Ratio (Peto, Fixed, 95% CI)

1.56 [0.56, 4.33]

4.1 Salmeterol

1

304

Peto Odds Ratio (Peto, Fixed, 95% CI)

1.59 [0.45, 5.62]

4.2 Formoterol

2

683

Peto Odds Ratio (Peto, Fixed, 95% CI)

0.0 [0.0, 0.0]

4.3 Indacaterol

2

2276

Peto Odds Ratio (Peto, Fixed, 95% CI)

1.48 [0.26, 8.57]

5 Exacerbation Show forest plot

3

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

5.1 Salmeterol

1

Odds Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

5.2 Formoterol

2

Odds Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

6 Trough FEV1 Show forest plot

5

3263

Mean Difference (Fixed, 95% CI)

0.07 [0.05, 0.09]

6.1 Salmeterol

1

304

Mean Difference (Fixed, 95% CI)

0.03 [‐0.07, 0.13]

6.2 Formoterol

2

683

Mean Difference (Fixed, 95% CI)

0.06 [0.02, 0.11]

6.3 Indacaterol

2

2276

Mean Difference (Fixed, 95% CI)

0.07 [0.05, 0.10]

7 Symptom score Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

7.1 Formoterol

1

Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

8 Serious adverse event (non‐fatal) Show forest plot

5

3263

Odds Ratio (M‐H, Fixed, 95% CI)

1.09 [0.76, 1.55]

8.1 Salmeterol

1

304

Odds Ratio (M‐H, Fixed, 95% CI)

0.95 [0.37, 2.40]

8.2 Formoterol

2

683

Odds Ratio (M‐H, Fixed, 95% CI)

1.07 [0.54, 2.13]

8.3 Indacaterol

2

2276

Odds Ratio (M‐H, Fixed, 95% CI)

1.14 [0.72, 1.81]

9 Withdrawal Show forest plot

5

3263

Odds Ratio (M‐H, Random, 95% CI)

1.00 [0.74, 1.37]

9.1 Salmeterol

1

304

Odds Ratio (M‐H, Random, 95% CI)

0.84 [0.54, 1.33]

9.2 Formoterol

2

683

Odds Ratio (M‐H, Random, 95% CI)

1.46 [0.52, 4.09]

9.3 Indacaterol

2

2276

Odds Ratio (M‐H, Random, 95% CI)

0.93 [0.65, 1.34]

Figures and Tables -
Comparison 1. LABA plus tiotropium versus tiotropium