For people with COPD, is it better to take a combination of tiotropium and long-acting beta2-agonists than either inhaler alone?

What is COPD?

Chronic obstructive pulmonary disease (COPD) is a lung disease that includes the conditions chronic bronchitis and emphysema. The symptoms include breathlessness and a chronic cough. COPD is an irreversible disease that is usually brought on by airway irritants, such as smoking or inhaled dust.

What are tiotropium and long-acting beta2-agonists?

Tiotropium and long-acting beta2-agonists (LABAs) are two types of inhaled medicines that help widen the airways (bronchodilators) for up to 12 to 24 hours. These bronchodilators are commonly used to manage persistent symptoms of COPD. They can be used in combination or on their own.

Why is the question important?

These bronchodilators work in different ways and therefore might be more beneficial if used together. The purpose of this review was to determine the benefits and risks of using a combination of both types of bronchodilator compared to the individual bronchodilators.

How did we answer the question?

Two people looked for published and unpublished research in several databases and websites to find relevant studies comparing tiotropium plus LABA with either (tiotropium or a LABA) on its own in adults with COPD. We analysed the results available up to July 2015 in this systematic review.

What did we find?

We found 10 studies involving 10,894 participants comparing the long-term effectiveness and side effects of combining tiotropium with a LABA. The combination of tiotropium plus LABA resulted, on average, in a slightly better quality of life and lung function for the participants compared to using only either tiotropium or a LABA alone, but did not show a difference in hospital admissions or death. The combination treatment also reduced the risk of episodes of acutely worse symptoms ('exacerbations'), compared to a LABA alone but not tiotropium. There were not enough data to determine the risks and benefits of the different types of LABA.

Authors' conclusions: 

The results from this review indicated a small mean improvement in health-related quality of life and FEV1 for participants on a combination of tiotropium and LABA compared to either agent alone, and this translated into a small increase in the number of responders on combination treatment. In addition, adding tiotropium to LABA reduced exacerbations, although adding LABA to tiotropium did not. Hospital admission and mortality were not altered by adding LABA to tiotropium, although there may not be enough data. While it is possible that this is affected by higher attrition in the tiotropium group, one would expect that participants withdrawn from the study would have had less favourable outcomes; this means that the expected direction of attrition bias would be to reduce the estimated benefit of the combination treatment. The results were largely from studies of olodaterol and there was insufficient information to assess whether the other LABAs were equivalent to olodaterol or each other.

Read the full abstract...
Background: 

Long-acting bronchodilators, comprising long-acting beta2-agonists (LABA) and long-acting anti-muscarinic agents (LAMA, principally tiotropium), are commonly used for managing persistent symptoms of chronic obstructive pulmonary disease (COPD). Combining these treatments, which have different mechanisms of action, may be more effective than the individual components. However, the benefits and risks of combining tiotropium and LABAs for the treatment of COPD are unclear.

Objectives: 

To compare the relative effects on markers of quality of life, exacerbations, symptoms, lung function and serious adverse events in people with COPD randomised to LABA plus tiotropium versus tiotropium alone; or LABA plus tiotropium versus LABA alone.

Search strategy: 

We searched the Cochrane Airways Group Specialised Register of trials and ClinicalTrials.gov up to July 2015.

Selection criteria: 

We included parallel-group, randomised controlled trials of three months or longer comparing treatment with tiotropium in addition to LABA against tiotropium or LABA alone for people with COPD.

Data collection and analysis: 

Two review authors independently assessed trials for inclusion and then extracted data on trial quality and the outcome results. We contacted study authors for additional information. We collected information on adverse effects from the trials.

Main results: 

This review included 10 trials on 10,894 participants, mostly recruiting participants with moderate or severe COPD. All of the trials compared tiotropium in addition to LABA to tiotropium alone, and four trials additionally compared LAMA plus LABA with LABA alone. Four studies used the LABA olodaterol, three used indacaterol, two used formoterol, and one used salmeterol.

Compared to tiotropium alone, treatment with tiotropium plus LABA resulted in a slightly larger improvement in mean health-related quality of life (St George's Respiratory Questionnaire (SGRQ) (mean difference (MD) -1.34, 95% confidence interval (CI) -1.87 to -0.80; 6709 participants; 5 studies). The MD was smaller than the four units that is considered clinically important, but a responder analysis indicated that 7% more participants receiving tiotropium plus LABA had a noticeable benefit (greater than four units) from treatment in comparison to tiotropium alone. In the control arm in one study, which was tiotropium alone, the SGRQ improved by falling 4.5 units from baseline and with tiotropium plus LABA the improvement was a fall of a further 1.3 units (on average). Most of the data came from studies using olodaterol. High withdrawal rates in the trials increased the uncertainty in this result, and the GRADE assessment for this outcome was therefore moderate. There were no significant differences in the other primary outcomes (hospital admission or mortality).

The secondary outcome of pre-bronchodilator forced expiratory volume in one second (FEV1) showed a small mean increase with the addition of LABA over the control arm (MD 0.06, 95% CI 0.05 to 0.07; 9573 participants; 10 studies), which showed a change from baseline ranging from 0.03 L to 0.13 L with tiotropium alone. None of the other secondary outcomes (exacerbations, symptom scores, serious adverse events, and withdrawals) showed any statistically significant differences between the groups. There was moderate heterogeneity for both exacerbations and withdrawals.

This review included data on four LABAs: two administered twice daily (salmeterol, formoterol) and two once daily (indacaterol, olodaterol). The results were largely from studies of olodaterol and there was insufficient information to assess whether the other LABAs were equivalent to olodaterol or each other.

Comparing LABA plus tiotropium treatment with LABA alone, there was a small but significant improvement in SGRQ (MD -1.25, 95% CI -2.14 to -0.37; 3378 participants; 4 studies). The data came mostly from studies using olodaterol and, although the difference was smaller than four units, this still represented an increase of 10 people with a clinically important improvement for 100 treated. There was also an improvement in FEV1 (MD 0.07, 95% CI 0.06 to 0.09; 3513 participants; 4 studies), and in addition an improvement in exacerbation rates (odds ratio (OR) 0.80, 95% CI 0.69 to 0.93; 3514 participants; 3 studies).

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