Which long-acting inhalers are the most effective and safest for people with advanced chronic obstructive pulmonary disease (COPD)?

What is COPD and why does a doctor prescribe an inhaler?

Chronic obstructive lung disease (COPD) is usually caused by smoking or other airway irritants. COPD damages the lungs and causes airways to narrow which makes it difficult to breathe.

There are two types of inhalers for COPD: rescue and maintenance. A rescue inhaler is short- and fast-acting, and used as needed for quick relief of symptoms, whereas a maintenance inhaler is long-acting and used on a daily basis to relieve daily symptoms and reduce flare-ups. The long-acting inhalers are usually reserved for more advanced COPD.

Does it matter which long-acting inhaler is used in people with advanced COPD?

Commonly used maintenance inhalers are grouped into four different groups: long-acting beta2-agonists (LABAs); long-acting muscarinic antagonists (LAMAs); LABA/inhaled corticosteroid (ICS) combinations; and LABA/LAMA combinations. Combination inhalers are usually reserved for individuals whose single-maintenance inhaler, such as LAMA or LABA fails. There are not many head-to-head comparisons to determine which treatment group or individual inhaler is better compared to the others. Preventing severe flare-ups and hospital admissions is especially important to people with COPD, healthcare providers, policy makers and society.

How did we answer the question?

We collected and analysed data from 99 studies, including a total of 101,311 participants with advanced COPD, using a special method called network meta-analysis, which enabled us to simultaneously compare the four inhaler groups and 28 individual inhalers (4 LABAs, 5 LAMAs, 9 LABA/ICS combinations, and 10 LABA/LAMA combinations).

What did we find?

The LABA/LAMA combination was the best treatment, followed by LAMA, in preventing flare-ups although there was some uncertainty in the results. Combination inhalers (LABA/LAMA and LABA/ICS), are more effective for controlling symptoms than single-agent therapies (LAMA and LABA), in general. The LABA/LAMA combination was better than LABA/ICS combination, especially in people with a prior episode of flare-ups. The LABA/ICS combination had a higher incidence of severe pneumonia compared to the others. We did not find a difference in benefits and harms, including side effects, among individual inhalers within the same treatment groups.

Conclusion

The LABA/LAMA combination is likely the best treatment in preventing COPD flare-ups. LAMA-containing inhalers appear to have an advantage over those without LAMA for preventing flare-ups. Combination inhalers (LABA/LAMA and LABA/ICS), appear more effective for controlling symptoms than single-agent therapies (LAMA and LABA). Inhaled steroids carry an increased risk of pneumonia.

Authors' conclusions: 

The LABA/LAMA combination was the highest ranked treatment group to reduce COPD exacerbations although there was some uncertainty in the results. LAMA containing inhalers may have an advantage over those without a LAMA for preventing COPD exacerbations based on the rank statistics. Combination therapies appear more effective than monotherapies for improving symptom and quality-of-life scores. ICS-containing inhalers are associated with an increased risk of pneumonia.

Our most comprehensive review including intraclass/group comparisons, free combination therapies, 99 studies, and 20 outcomes for each high- and low-risk population summarises the current literature and could help with updating existing COPD guidelines.

Read the full abstract...
Background: 

Long-acting bronchodilators such as long-acting β-agonist (LABA), long-acting muscarinic antagonist (LAMA), and LABA/inhaled corticosteroid (ICS) combinations have been used in people with moderate to severe chronic obstructive pulmonary disease (COPD) to control symptoms such as dyspnoea and cough, and prevent exacerbations. A number of LABA/LAMA combinations are now available for clinical use in COPD. However, it is not clear which group of above mentioned inhalers is most effective or if any specific formulation works better than the others within the same group or class.

Objectives: 

To compare the efficacy and safety of available formulations from four different groups of inhalers (i.e. LABA/LAMA combination, LABA/ICS combination, LAMA and LABA) in people with moderate to severe COPD. The review will update previous systematic reviews on dual combination inhalers and long-acting bronchodilators to answer the questions described above using the strength of a network meta-analysis (NMA).

Search strategy: 

We identified studies from the Cochrane Airways Specialised Register, which contains several databases. We also conducted a search of ClinicalTrials.gov and manufacturers’ websites. The most recent searches were conducted on 6 April 2018.

Selection criteria: 

We included randomised controlled trials (RCTs) that recruited people aged 35 years or older with a diagnosis of COPD and a baseline forced expiratory volume in one second (FEV1) of less than 80% of predicted. We included studies of at least 12 weeks' duration including at least two active comparators from one of the four inhaler groups.

Data collection and analysis: 

We conducted NMAs using a Bayesian Markov chain Monte Carlo method. We considered a study as high risk if recruited participants had at least one COPD exacerbation within the 12 months before study entry and as low risk otherwise. Primary outcomes were COPD exacerbations (moderate to severe and severe), and secondary outcomes included symptom and quality-of-life scores, safety outcomes, and lung function. We collected data only for active comparators and did not consider placebo was not considered. We assumed a class/group effect when a fixed-class model fitted well. Otherwise we used a random-class model to assess intraclass/group differences. We supplemented the NMAs with pairwise meta-analyses.

Main results: 

We included a total of 101,311 participants from 99 studies (26 studies with 32,265 participants in the high-risk population and 73 studies with 69,046 participants in the low-risk population) in our systematic review. The median duration of studies was 52 weeks in the high-risk population and 26 weeks in the low-risk population (range 12 to 156 for both populations). We considered the quality of included studies generally to be good.

The NMAs suggested that the LABA/LAMA combination was the highest ranked treatment group to reduce COPD exacerbations followed by LAMA in the both populations.

There is evidence that the LABA/LAMA combination decreases moderate to severe exacerbations compared to LABA/ICS combination, LAMA, and LABA in the high-risk population (network hazard ratios (HRs) 0.86 (95% credible interval (CrI) 0.76 to 0.99), 0.87 (95% CrI 0.78 to 0.99), and 0.70 (95% CrI 0.61 to 0.8) respectively), and that LAMA decreases moderate to severe exacerbations compared to LABA in the high- and low-risk populations (network HR 0.80 (95% CrI 0.71 to 0.88) and 0.87 (95% CrI 0.78 to 0.97), respectively). There is evidence that the LABA/LAMA combination reduces severe exacerbations compared to LABA/ICS combination and LABA in the high-risk population (network HR 0.78 (95% CrI 0.64 to 0.93) and 0.64 (95% CrI 0.51 to 0.81), respectively).

There was a general trend towards a greater improvement in symptom and quality-of-life scores with the combination therapies compared to monotherapies, and the combination therapies were generally ranked higher than monotherapies.

The LABA/ICS combination was the lowest ranked in pneumonia serious adverse events (SAEs) in both populations. There is evidence that the LABA/ICS combination increases the odds of pneumonia compared to LAMA/LABA combination, LAMA and LABA (network ORs: 1.69 (95% CrI 1.20 to 2.44), 1.78 (95% CrI 1.33 to 2.39), and 1.50 (95% CrI 1.17 to 1.92) in the high-risk population and network or pairwise OR: 2.33 (95% CI 1.03 to 5.26), 2.02 (95% CrI 1.16 to 3.72), and 1.93 (95% CrI 1.29 to 3.22) in the low-risk population respectively). There were significant overlaps in the rank statistics in the other safety outcomes including mortality, total, COPD, and cardiac SAEs, and dropouts due to adverse events.

None of the differences in lung function met a minimal clinically important difference criterion except for LABA/LAMA combination versus LABA in the high-risk population (network mean difference 0.13 L (95% CrI 0.10 to 0.15). The results of pairwise meta-analyses generally agreed with those of the NMAs. There is no evidence to suggest intraclass/group differences except for lung function at 12 months in the high-risk population.

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