Once daily long-acting beta2-agonists and long-acting muscarinic antagonists in a combined inhaler versus placebo for COPD

We wanted to know whether once-daily treatment with a fixed-dose combination of a long-acting beta2 agonist (LABA) plus a long-acting muscarinic antagonist (LAMA) delivered via a single inhaler is better than treatment with a dummy inhaler (placebo) for people with chronic obstructive pulmonary disease (COPD).

Background to the review

COPD is a disease of the lungs and is the fourth most common cause of death worldwide. People with COPD experience symptoms of cough, breathlessness and a build up of mucus, which become worse over time. Current treatments for COPD aim to manage these symptoms and improve the quality of life of people with the disease.

A combination of a LABA plus a LAMA taken once-daily in a single inhaler (LABA/LAMA) has been shown to be more effective than taking each separately in individual inhalers. Several different combinations of inhaled LABA and LAMA are available (e.g. indacaterol/glycopyrronium, olodaterol/tiotropium, formoterol/aclidinium, and vilanterol/umeclidinium) and are used for the treatment of COPD. By gathering information from clinical trials that compare once-daily LABA/LAMA with placebo in a dummy inhaler we will provide information to help future research decide which combination is best for treating people with COPD.

What did we find?

Twenty-two studies (including 8641 people with COPD) compared once-daily LABA/LAMA in a single inhaler with a dummy inhaler. People were allowed to continue to use their inhaled corticosteroids (ICS) during the studies; approximately a third to a half of people were using their ICS at the beginning of each study. The evidence presented in this review is current up to December 2018. The majority of people who took part in the studies had mild-to-moderate COPD and the average age of people in each study ranged from 59 to 65 years. Six studies evaluated the once-daily combination of indacaterol/glycopyrronium, seven studies evaluated tiotropium/olodaterol, eight studies evaluated umeclidinium/vilanterol and one study evaluated aclidinium/formoterol.

People who took once-daily LABA/LAMA using a single inhaler showed a greater improvement in quality of life than those taking placebo in a dummy inhaler; lung function was also improved in people taking once-daily LABA/LAMA. People taking umeclidinium/vilanterol had fewer flare-ups (exacerbations). There was no significant difference between groups (LABA/LAMA versus placebo) in the number of people who died, or in the number of people who experienced serious adverse events or any adverse event. The results were similar for the different LABA/LAMA combinations and doses that we evaluated.

The included studies were generally well designed and well reported. People in the studies and those performing the research did not know which treatment people were receiving, which ensures a fair evaluation of the treatments.

In three of the studies, people who were taking once-daily LABA/LAMA had more severe COPD at the start of the study than people taking dummy inhalers; this could have reduced the treatment effect seen with LABA/LAMA in these studies so we can be confident that our findings do not overestimate the effect seen with once-daily LABA/LAMA. One of the outcomes of interest (how far a person is able to walk in six minutes) was not reported by any of the included studies. Overall, we can be confident in the conclusions of this review.

Authors' conclusions: 

Compared with placebo, once-daily LABA/LAMA (either IND/GLY, UMEC/VI or TIO/OLO) via a combination inhaler is associated with a clinically significant improvement in lung function and health-related quality of life in patients with mild-to-moderate COPD; UMEC/VI appears to reduce the rate of exacerbations in this population. These conclusions are supported by moderate or high certainty evidence based on studies with an observation period of up to one year.

Read the full abstract...
Background: 

Chronic obstructive pulmonary disease (COPD) is a respiratory condition causing accumulation of mucus in the airways, cough, and breathlessness; the disease is progressive and is the fourth most common cause of death worldwide. Current treatment strategies for COPD are multi-modal and aim to reduce morbidity and mortality and increase patients' quality of life by slowing disease progression and preventing exacerbations. Fixed-dose combinations (FDCs) of a long-acting beta2-agonist (LABA) plus a long-acting muscarinic antagonist (LAMA) delivered via a single inhaler are approved by regulatory authorities in the USA, Europe, and Japan for the treatment of COPD. Several LABA/LAMA FDCs are available and recent meta-analyses have clarified their utility versus their mono-components in COPD. Evaluation of the efficacy and safety of once-daily LABA/LAMA FDCs versus placebo will facilitate the comparison of different FDCs in future network meta-analyses.

Objectives: 

We assessed the evidence for once-daily LABA/LAMA combinations (delivered in a single inhaler) versus placebo on clinically meaningful outcomes in patients with stable COPD.

Search strategy: 

We identified trials from Cochrane Airways' Specialised Register (CASR) and also conducted a search of the US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch). We searched CASR and trial registries from their inception to 3 December 2018; we imposed no restriction on language of publication.

Selection criteria: 

We included parallel-group and cross-over randomised controlled trials (RCTs) comparing once-daily LABA/LAMA FDC versus placebo. We included studies reported as full-text, those published as abstract only, and unpublished data. We excluded very short-term trials with a duration of less than 3 weeks. We included adults (≥ 40 years old) with a diagnosis of stable COPD. We included studies that allowed participants to continue using their ICS during the trial as long as the ICS was not part of the randomised treatment.

Data collection and analysis: 

Two review authors independently screened the search results to determine included studies, extracted data on prespecified outcomes of interest, and assessed the risk of bias of included studies; we resolved disagreements by discussion with a third review author. Where possible, we used a random-effects model to meta-analyse extracted data. We rated all outcomes using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) system and presented results in 'Summary of findings’ tables.

Main results: 

We identified and included 22 RCTs randomly assigning 8641 people with COPD to either once-daily LABA/LAMA FDC (6252 participants) or placebo (3819 participants); nine studies had a cross-over design. Studies had a duration of between three and 52 weeks (median 12 weeks). The mean age of participants across the included studies ranged from 59 to 65 years and in 21 of 22 studies, participants had GOLD stage II or III COPD. Concomitant inhaled corticosteroid (ICS) use was permitted in all of the included studies (where stated); across the included studies, between 28% to 58% of participants were using ICS at baseline. Six studies evaluated the once-daily combination of IND/GLY (110/50 μg), seven studies evaluated TIO/OLO (2.5/5 or 5/5 μg), eight studies evaluated UMEC/VI (62.5/5, 125/25 or 500/25 μg) and one study evaluated ACD/FOR (200/6, 200/12 or 200/18 μg); all LABA/LAMA combinations were compared with placebo.

The risk of bias was generally considered to be low or unknown (insufficient detail provided), with only one study per domain considered to have a high risk of bias except for the domain 'other bias' which was determined to be at high risk of bias in four studies (in three studies, disease severity was greater at baseline in participants receiving LABA/LAMA compared with participants receiving placebo, which would be expected to shift the treatment effect in favour of placebo).

Compared to the placebo, the pooled results for the primary outcomes for the once-daily LABA/LAMA arm were as follows: all-cause mortality, OR 1.88 (95% CI 0.81 to 4.36, low-certainty evidence); all-cause serious adverse events (SAEs), OR 1.06 (95% CI 0.88 to 1.28, high-certainty evidence); acute exacerbations of COPD (AECOPD), OR 0.53 (95% CI 0.36 to 0.78, moderate-certainty evidence); adjusted St George's Respiratory Questionnaire (SGRQ) score, MD -4.08 (95% CI -4.80 to -3.36, high-certainty evidence); proportion of SGRQ responders, OR 1.75 (95% CI 1.54 to 1.99). Compared with placebo, the pooled results for the secondary outcomes for the once-daily LABA/LAMA arm were as follows: adjusted trough forced expiratory volume in one second (FEV1), MD 0.20 L (95% CI 0.19 to 0.21, moderate-certainty evidence); adjusted peak FEV1, MD 0.31 L (95% CI 0.29 to 0.32, moderate-certainty evidence); and all-cause AEs, OR 0.95 (95% CI 0.86 to 1.04; high-certainty evidence). No studies reported data for the 6-minute walk test. The results were generally consistent across subgroups for different LABA/LAMA combinations and doses.

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