Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS) for stable chronic obstructive pulmonary disease

Abstract

Background

Long‐acting beta‐agonists (LABAs), long‐acting muscarinic antagonists (LAMAs), and inhaled corticosteroids (ICSs) are inhaled medications used to manage chronic obstructive pulmonary disease (COPD). When two classes of medications are required, a LAMA plus an ICS (LABA+ICS) were previously recommended within a single inhaler as the first‐line treatment for managing stable COPD in people in high‐risk categories. However, updated international guidance recommends a LAMA plus a LABA (LAMA+LABA). This systematic review is an update of a Cochrane Review first published in 2017.

Objectives

To compare the benefits and harms of LAMA+LABA versus LABA+ICS for treatment of people with stable COPD.

Search methods

We performed an electronic search of the Cochrane Airways Group Specialised Register, ClinicalTrials.gov, and the World Health Organization Clinical Trials Search Portal, followed by handsearches. Two review authors screened the selected articles. The most recent search was run on 10 September 2022.

Selection criteria

We included parallel or cross‐over randomised controlled trials of at least one month's duration, comparing LAMA+LABA and LABA+ICS for stable COPD. We included studies conducted in an outpatient setting and irrespective of blinding.

Data collection and analysis

Two review authors independently extracted data and evaluated risk of bias. We resolved any discrepancies through discussion. We analysed dichotomous data as odds ratios (ORs), and continuous data as mean differences (MDs), with 95% confidence intervals (CIs) using Review Manager 5. Primary outcomes were: participants with one or more exacerbations of COPD; serious adverse events; quality of life, as measured by the St. George's Respiratory Questionnaire (SGRQ) total score change from baseline; and trough forced expiratory volume in one second (FEV₁). We used the GRADE framework to rate our certainty of the evidence in each meta‐analysis as high, moderate, low or very low. 

Main results

This review updates the first version of the review, published in 2017, and increases the number of included studies from 11 to 19 (22,354 participants). The median number of participants per study was 700. In each study, between 54% and 91% (median 70%) of participants were males. Study participants had an average age of 64 years and percentage predicted FEV₁ of 51.5% (medians of study means). Included studies had a generally low risk of selection, performance, detection, attrition, and reporting biases. All but two studies were sponsored by pharmaceutical companies, which had varying levels of involvement in study design, conduct, and data analysis.

Primary outcomes

The odds of having an exacerbation were similar for LAMA+LABA compared with LABA+ICS (OR 0.91, 95% CI 0.78 to 1.06; I² = 61%; 13 studies, 20,960 participants; moderate‐certainty evidence). The odds of having a serious adverse event were also similar (OR 1.02, 95% CI 0.91 to 1.15; I² = 20%; 18 studies, 23,183 participants; high‐certainty evidence). Participants receiving LAMA+LABA had a similar improvement in quality of life, as measured by the SGRQ, to those receiving LABA+ICS (MD ‐0.57, 95% CI ‐1.36 to 0.21; I² = 78%; 9 studies, 14,437 participants; moderate‐certainty evidence) but showed a greater improvement in trough FEV₁ (MD 0.07, 95% CI 0.05 to 0.08; I² = 73%; 12 studies, 14,681 participants; moderate‐certainty evidence). 

Secondary outcomes

LAMA+LABA decreased the odds of pneumonia compared with LABA+ICS from 5% to 3% (OR 0.61, 95% CI 0.52 to 0.72; I² = 0%; 14 studies, 21,829 participants; high‐certainty evidence) but increased the odds of all‐cause death from 1% to 1.4% (OR 1.35, 95% CI 1.05 to 1.75; I² = 0%; 15 studies, 21,510 participants; moderate‐certainty evidence). The odds of achieving a minimal clinically important difference of four or more points on the SGRQ were similar between LAMA+LABA and LABA+ICS (OR 1.06, 95% CI 0.90 to 1.25; I² = 77%; 4 studies, 13,614 participants; moderate‐certainty evidence).

Authors' conclusions

Combination LAMA+LABA therapy probably holds similar benefits to LABA+ICS for exacerbations and quality of life, as measured by the St George's Respiratory Questionnaire, for people with moderate to severe COPD, but offers a larger improvement in FEV₁ and a slightly lower risk of pneumonia. There is little to no difference between LAMA+LABA and LAMA+ICS in the odds of having a serious adverse event. Whilst all‐cause death may be lower with LABA+ICS, there was a very small number of events in the analysis, translating to a low absolute risk. Findings are based on moderate‐ to high‐certainty evidence from heterogeneous trials with an observation period of less than one year. This review should be updated again in a few years.

Plain language summary

Which combination of inhaled medications are safe and effective for chronic obstructive pulmonary disease (COPD)?

Key messages

• Using an inhaler containing a long‐acting muscarinic antagonist plus a long‐acting beta‐agonist (LAMA+LABA) for chronic obstructive pulmonary disease (COPD) probably improves respiratory function and reduces the risk of pneumonia compared to LABA plus an inhaled corticosteroid (LABA+ICS).

• LAMA+LABA and LABA+ICS probably work as well as each other in reducing COPD exacerbations and improving quality of life.

• The risk of death was slightly higher in people taking LAMA+LABA.

What is chronic obstructive pulmonary disease, and how is it treated?

Chronic obstructive pulmonary disease (COPD) is a long‐term lung condition characterised by cough, sputum production (fluids from the lungs, i.e. phlegm), and difficulty breathing. 

COPD is treated with medications called 'bronchodilators' that make breathing easier by relaxing the muscles in the lungs and widening the airways. Two key types of bronchodilator medicines are long‐acting muscarinic antagonists (LAMAs) and long‐acting beta‐agonists (LABAs). Healthcare guidelines now recommend that people with stable, high‐risk COPD use inhalers containing either a combined LAMA+LABA medicine or a combined LABA plus inhaled corticosteroid (LABA+ICS) medicine. Corticosteroids are anti‐inflammatory medicines.

What did we want to find out?

We examined the findings of trials that randomised people to receive either LAMA+LABA or LABA+ICS to see how they compare.

What did we do?

We searched for trials that explored the benefits and harms of LAMA+LABA and LABA+ICS for the treatment of people with COPD. We summarised these results and rated our confidence in the evidence.

What did we find?

We included 19 studies involving 22,354 participants. The studies lasted from 6 to 52 weeks. The studies included more men than women (approximately 70% of participants were men), and the people in the studies were about 64 years old. Most studies included people with moderate to severe COPD. Pharmaceutical companies were involved in most of the studies, which might affect how much we can trust the results.

Compared to LABA+ICS, LAMA+LABA led to an improvement in lung function, reduced pneumonia from 5% to 3% but increased the risk of death from 1% to 1.4%. LAMA+LABA probably made little to no difference to COPD exacerbations (flare‐ups) compared to LABA+ICS. People in each of the treatment groups reported similar quality of life scores and were about as likely to experience serious side effects, which were rare. 

What are the limitations of the evidence?

Our confidence in the evidence was moderate to high because the included studies were well‐designed and had a sufficient number of participants with mainly moderate to severe COPD.

How up to date is this evidence?

This review is up to date to 10 September 2022. The results from future or ongoing trials evaluating newly developed medicines are awaited. This review should be updated again in a few years.

Summary of findings

Summary of findings 1. Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS) for stable chronic obstructive pulmonary disease (COPD).

LAMA plus LABA versus LABA plus ICS for stable COPD
Population: people with stable COPD Setting: outpatient. Studies were conducted in > 50 countries including low‐, medium‐, and high‐income countries from all continents Intervention: LAMA+LABA Comparison: LABA+ICS
Outcomes	Anticipated absolute effects* (95% CI)		Relative effects (95% CI)	Number of participants (studies)	Certainty of the evidence (GRADE)	Comments
	LABA+ICS	LAMA+LABA
Exacerbations (number of people experiencing ≥ 1 exacerbations) Follow‐up: 6 to 52 weeks	291 per 1000	272 per 1000 (243 to 303)	OR 0.91 (0.78 to 1.06)	20,960 (13 RCTs)	⊕⊕⊕⊝ Moderatea‐e	Low OR means favourable outcome
Serious adverse events (number of people experiencing ≥ 1 SAEs) Follow‐up: 6 to 52 weeks	148 per 1000	150 per 1000 (136 to 166)	OR 1.02 (0.91 to 1.15)	23,183 (18 RCTs)	⊕⊕⊕⊕ Highb,c,d,e	Low OR means favourable outcome. Herth 2020 was discarded as no events were reported in either arm.
Quality of life as measured by SGRQ total score change from baseline (MD) Follow‐up: 12 to 52 weeks Scale 0 to 100	‐	‐	MD ‐0.57 (1.36 lower to 0.21 higher)	14,437 (9 RCTs)	⊕⊕⊕⊝ Moderatea‐e	Low MD means favourable outcome
Trough FEV1 change from baseline Follow‐up: 6 to 52 weeks	‐	‐	MD 0.07 L (0.05 to 0.08)	14,681 (12 RCTs)	⊕⊕⊕⊝ Moderatea,b,d,e	High MD means favourable outcome
Pneumonia Follow‐up: 12 to 52 weeks	45 per 1000	28 per 1000 (24 to 33)	OR 0.61 (0.52 to 0.72)	21,829 (14 RCTs)	⊕⊕⊕⊕ Highb,d,e	Low OR means favourable outcome
All‐cause death Follow‐up: 6 to 52 weeks	10 per 1000	14 per 1000 (11 to 18)	OR 1.35 (1.05 to 1.75)	21,510 (15 RCTs)	⊕⊕⊕⊝ Moderateb,d,e,f	Low OR means favourable outcome
SGRQ total score change from baseline (≥ 4 points, MCID) Follow‐up: 26 to 52 weeks	373 per 1000	387 per 1000 (349 to 427)	OR 1.06 (0.90 to 1.25)	13,614 (4 RCTs)	⊕⊕⊕⊝ Moderatea‐e	High OR means favourable outcome
*The absolute risk (and its 95% CI) of LAMA+LABA group is based on the assumed risk in the LABA+ICS group and the OR of the intervention (and its 95% CI). CI: confidence interval; COPD: chronic obstructive pulmonary disease; FEV1: forced expiratory volume in one second; ICS: inhaled corticosteroid; LABA: long‐acting beta‐agonist; LAMA: long‐acting muscarinic antagonist; MCID: minimal clinically important difference; MD: mean difference; OR: odds ratio; RCT: randomised controlled trial; SGRQ: St. George's Respiratory Questionnaire.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of effect but may be substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

^aThere was a considerable heterogeneity, I² > 50%.
^bStudies varied in their inclusion criteria around recent history of exacerbation, baseline percentage predicted FEV₁ and exclusion of asthma. No indirectness downgrades, but impacts interpretation and applicability of results (see Discussion).
^cConfidence interval includes benefit of either treatment but lies within predefined threshold for clinical importance (0.7 to 1.5 for OR outcomes; 4‐point MCID for SGRQ) ‐ no downgrade for imprecision
^dNo downgrades for publication bias. Funnel plots examined for primary outcomes (exacerbations, serious adverse events, SGRQ, FEV₁) do not show obvious asymmetry (see Figure 3; Figure 3; Figure 4; Figure 6). Nearly all studies included in pneumonia and all‐cause death analyses. Only 4 studies included in SGRQ 4+ change analysis but not specified in most studies. 
^eNo downgrades for risk of bias. Across outcomes, all or almost all studies were at high risk of 'other' bias due to conflicts of interest, and studies contributing between 18.5% and 35.9% of the analysis weight were rated high risk of bias in at least one other domain. We did not prespecify a threshold or specific domains for downgrading, but considered it insufficient to downgrade if studies contributing more than half the analysis weight were at low or unclear risk of bias in all but the 'other' domain.
^fThere was imprecision due to a low number of events.

Background

Description of the condition

Chronic obstructive pulmonary disease (COPD) is characterised by bronchial obstruction, systemic inflammation, and comorbidities. It is the third leading cause of death worldwide, with more than 3.23 million people dying due to COPD each year (WHO 2019). In addition to active tobacco smoking, indoor biomass smoke, outdoor air pollution, and occupational exposure also play a role in the development of COPD. The most common symptoms of COPD – shortness of breath on exertion and cough – are present for a prolonged period and typically worsen over time (GOLD 2023).

Since the late 1960s, the definition of COPD has repeatedly been modified. Early definitions of COPD included chronic bronchitis, which is clinically characterised by chronic cough, and emphysema, which is pathologically defined by damaged sacs or alveoli in the lungs (Burrows 1966). In 2001, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) released its first report, Global Strategy for the Diagnosis, Management, and Prevention of COPD (Pauwels 2001), which supported the definition of COPD, indicating that the disorder is recognised primarily by chronic obstruction of lung airflow (Pauwels 2001).

If COPD is properly diagnosed and managed, symptoms can be ameliorated. Smoking cessation, smoke‐free cooking, vaccination, and an active lifestyle are the first steps in COPD management, and daily pharmacological treatment is required for most people with symptomatic stable COPD (GOLD 2023).

Description of the intervention

While asymptomatic individuals with mild airflow limitations can be treated with on‐demand short‐acting bronchodilators, key medications for symptomatic COPD management consist of three classes of inhaled medication: long‐acting beta‐agonists (LABAs), long‐acting muscarinic antagonists (LAMAs), and inhaled corticosteroids (ICSs) (GOLD 2023). If the disease cannot be adequately controlled with LAMA or LABA monotherapy, administration of two or more medications from different classes may prove beneficial. When two classes of medication are required, a LAMA plus a LABA (LAMA+LABA) or a LABA plus an ICS (LABA+ICS) are often selected because these combinations can be administered via a single medication device (Frampton 2014; Malerba 2014; Nannini 2013; Schachter 2013), which is most beneficial for improving patient adherence (Horita 2015a).

How the intervention might work

Currently, there are no medications that can cure COPD. Thus, the practical goal of COPD treatment is to control the symptoms, reduce the frequency of exacerbations, and improve exercise tolerance and quality of life. COPD treatment usually consists of smoking cessation, vaccination, inhaled bronchodilators, ICSs, oral medication, long‐term oxygen therapy, and pulmonary rehabilitation (GOLD 2023). According to the GOLD approach, people are classified into three categories depending on the degree of symptoms and the risk of exacerbations (GOLD 2023). Medications belonging to a specific class are recommended based on the following criteria:

• Category A (low symptoms plus few exacerbations): bronchodilator (short‐ or long‐acting); consider switching to another depending on response;

• Category B (high symptoms plus few exacerbations): LAMA+LABA;

• Category E (high symptoms plus many exacerbations): LAMA+LABA; LAMA+LABA+ICS is considered if blood eosinophil count is high.

Long‐acting muscarinic antagonists

LAMAs dilate the airway by selectively blocking acetylcholine M₃ receptors and inhibiting bronchoconstriction (Alagha 2014). Since the early 2000s, LAMAs, especially tiotropium, have been regarded as the first‐choice medication for treating COPD. LAMAs confer anti‐inflammatory effects and, more importantly, anti‐airway remodelling effects (Tashkin 2004).

Long‐acting beta‐agonists

LABAs widen the airway by relaxing the airway muscles. Studies have suggested that LABAs may also provide anti‐inflammatory and protective effects against bronchoconstrictive substances. Regular use of a short‐acting beta‐agonist that works quickly and lasts for four to six hours is not currently recommended for people with asthma or COPD. A LABA that lasts for approximately 12 to 24 hours is considered a maintenance medication (Anderson 2014; Tashkin 2004).

Inhaled corticosteroids

ICSs reduce airway inflammation. Although ICSs are indicated for bronchial asthma, in which eosinophils play a key role, they are not as effective when neutrophils are observed in the airways of people with COPD (Barnes 2010; Hanania 2008; Suissa 2009). The previous GOLD report recommended that ICSs be prescribed in combination with LABA for people with COPD with severe airflow limitation or with a high risk of exacerbations (GOLD 2016). Studies have suggested that LABA+ICS may be highly effective for people with a high sputum/blood eosinophil count (Pascoe 2015).

Why it is important to do this review

The previous GOLD report recommended the first‐line use of ICSs only for people with severe to very severe airflow limitation and two or more exacerbations per year, with one or more hospitalisations for exacerbations (GOLD 2016). That report suggested that ICSs reduce the risk of exacerbations (GOLD 2016). Nonetheless, prescription rates for ICSs and combined LABA+ICS agents are high (Drivenes 2014; White 2013). This is probably because many randomised controlled trials (RCTs) have supported the hypothesis that the salmeterol (LABA) plus fluticasone propionate (ICS) combination – the oldest combination treatment – can improve quality of life, especially for people with dyspnoea, and can also decrease acute exacerbations of COPD and reduce yearly declines in pulmonary function (GOLD 2016). Blood and sputum eosinophil counts can serve as predictive biomarkers for differentiating between people with COPD who will derive the greatest benefit from ICS administration and people who will not benefit from an ICS (Pascoe 2015). The GOLD 2023 report now recommends LAMA+LABA+ICS only for people with category E COPD who have a high eosinophil count, and recommends that ICSs should not be over‐prescribed in COPD cases.

Understanding which type of combination treatment (LAMA+LABA or LABA+ICS) is most beneficial for people with COPD, regardless of eosinophil count, is important, and this systematic review contributes to answering this question.

Objectives

To compare the benefits and harms of LAMA+LABA versus LABA+ICS for treatment of people with stable COPD.

Methods

Criteria for considering studies for this review

Types of studies

We planned to include individually‐randomised and cluster‐randomised controlled trials and cross‐over trials, but not quasi‐RCTs. We included studies reported as full text, those published as abstract only, and unpublished data. When we could not obtain sufficient data from published articles, we contacted authors and sponsors, and accessed trial registration websites. We included open‐label, single‐blinded, and double‐blinded studies. The minimum accepted trial duration was one month.

Types of participants

We included adults with a diagnosis of COPD according to GOLD guidelines (GOLD 2023). We did not set specific exclusion criteria involving comorbidities. We planned to exclude original studies focusing on asthma‐COPD overlap syndrome (ACOS).

Types of interventions

We included trials comparing LAMA+LABA versus LABA+ICS. We permitted treatments administered via a single combined device or via two separate devices. We excluded trials of short‐acting bronchodilators (e.g. ipratropium). We included co‐interventions when they were not part of the randomly assigned treatment.

Types of outcome measures

Primary outcomes

• Exacerbations (participants with one or more)

• Serious adverse events (participants with one or more)

• Quality of life, as measured by the St. George's Respiratory Questionnaire (SGRQ) total score change from baseline

• Trough forced expiratory volume in one second (FEV₁) change from baseline

Secondary outcomes

• Pneumonia (participants with one or more occurrences); assessed based on chest x‐ray

• All‐cause death

• SGRQ total score change from baseline (4 points or greater)

• Hospitalisations for COPD exacerbations (participants with one or more occurrences)

Search methods for identification of studies

Electronic searches

We identified trials from the Cochrane Airways Group Specialised Register (CAGR), which is maintained by the Information Specialist for the Group. The Register contains trial reports identified through systematic searches of bibliographic databases, including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Allied and Complementary Medicine Database (AMED), and PsycINFO, and through handsearching of respiratory journals and conference abstracts (see Appendix 1 for details). We searched all records in the CAGR from the date it was last searched for the previous version of this review (2 February 2016) to 10 September 2022, using the search strategy provided in Appendix 2.

We conducted a search of ClinicalTrials.gov (www.ClinicalTrials.gov) and the World Health Organization (WHO) Clinical Trials Search Portal (www.who.int/ictrp/en/), from the date they were last searched (4 June 2016) to 10 September 2022 (Appendix 3; Appendix 4).

We searched all databases from their inception, and we imposed no restrictions on language of publication.

Searching other resources

We checked reference lists of all primary studies and review articles for additional references, and we searched relevant manufacturers' websites for trial information. We searched for errata or retractions from included studies published as full text on PubMed (www.ncbi.nlm.nih.gov/pubmed). Handsearches were done up to 1 November 2021.

Data collection and analysis

Selection of studies

We used Cochrane’s Screen4Me workflow to help assess the search results. Screen4Me comprises three components: (1) known assessments – a service that matches records in the search results to records that have already been screened in Cochrane Crowd and labelled as an RCT or 'Not an RCT'; (2) the RCT classifier – a machine learning model that distinguishes RCTs from non‐RCTs; and (3) if appropriate, Cochrane Crowd – Cochrane’s citizen science platform where the Crowd helps to identify and describe health evidence. For more information about Screen4Me and the evaluations that have been done, please visit the Screen4Me webpage on the Cochrane Information Specialists' portal: community.cochrane.org/organizational-info/resources/resources-groups/information-specialists-portal.

Two review authors (NF and NH) independently screened the titles and abstracts of all studies identified by the search for possible inclusion, and coded studies as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'. We retrieved the full‐text publications. Two review authors (NF and NH) independently screened the full texts to identify studies for inclusion and recorded reasons for exclusion of ineligible studies. We resolved disagreements through discussion, or, when required, we consulted a third review author (TK). We identified and excluded duplicates and collated multiple reports of the same study, so that each study, rather than each report, was the unit of interest in the review. We recorded the selection process in sufficient detail to complete a PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) flow diagram and a Characteristics of excluded studies table (Moher 2009).

Data extraction and management

We used a data collection form that had been piloted on at least one study in the review to document study characteristics and outcome data. Two review authors (NF and NH) extracted the following study characteristics from the included studies.

• Methods: study design, duration of study follow‐up and 'run‐in' period, number of study centres and countries, and study start date.

• Participants: number, mean and standard deviation (SD) age, gender, mean and SD of baseline FEV₁ key inclusion criteria, number of participants randomised and completed, and follow‐up duration.

• Interventions: intervention, comparison, and dosage of the intervention.

• Outcomes: primary outcomes specified and collected and time points reported.

• Notes: funding for trial and notable conflicts of interest (COI) of trial authors, trial registration, and other information if necessary.

Two review authors (NF and NH) independently extracted outcome data from the included studies. We noted in the Characteristics of included studies table if outcome data were not reported in a useable way. We resolved disagreements by consensus or by consultation with a third review author (TK). One review author (NF) transferred data into Review Manager 5 (Review Manager 2014). We double‐checked that data were entered correctly by comparing data presented in the systematic review versus data provided in study reports. A second review author (NH) spot‐checked study characteristics for accuracy against the trial report.

Assessment of risk of bias in included studies

Two review authors (NF and NH) independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We resolved disagreements by discussion or by consultation with another review author (EO). We assessed risk of bias according to the following domains:

• random sequence generation;

• allocation concealment;

• blinding of participants and personnel;

• blinding of outcome assessment;

• incomplete outcome data;

• selective outcome reporting;

• other bias.

We graded each potential source of bias as high, low, or unclear and provided an explanation from the study report together with a justification for our judgement in the risk of bias table. We summarised risk of bias judgements across studies for each of the domains listed. We classified outcomes as subjective and objective to consider different risks of performance and selection bias for different blinding methods. All‐cause death is the only outcome of interest to this review that may be considered truly objective and the SGRQ is the only subjective, self‐reported measure. The other outcomes (exacerbations, serious adverse events, FEV₁ and pneumonia) might be considered semi‐objective: they involve a degree of patient reporting, behaviour, or clinician judgement that could introduce bias (intentionally or otherwise) if the randomised treatment had been inadvertently detected through side effects or other means. For example, this could happen in the grading of an adverse event as serious or non‐serious, effort given when measuring FEV₁, or the interpretation of a chest X‐ray to determine pneumonia. When we requested information on risk of bias related to unpublished data or corresponded with a trialist, we noted this in the risk of bias table.

When considering treatment effects, we took into account risk of bias for studies that contributed to that outcome.

Assessment of bias in conducting the systematic review

We conducted the review according to the previously published protocol (Horita 2016).

Measures of treatment effect

We analysed dichotomous data as odds ratios (ORs), and continuous data as MDs with 95% confidence intervals (CIs). We entered data presented as a scale with a consistent direction of effect (i.e. data in the LAMA+LABA arm minus data in the LABA+ICS arm). Although there is no universal rule to interpret the magnitude of the therapeutic effect from ORs, we believe that an OR greater than 1.5 and an OR of less than 0.7 mean that there is a considerable chance that the outcome is clinically important.

We undertook meta‐analyses only when this was meaningful (i.e. if treatments, participants, and the underlying clinical question were similar enough for pooling to make sense).

We had planned to describe skewed data using medians and interquartile ranges; however, we found no report describing skewed data.

According to the original protocol, when multiple trial arms were reported in a single trial, we included only the relevant arms.

Unit of analysis issues

We analysed the number of participants, not the number of events, as the unit of analysis for dichotomous data (i.e. participants with one or more events). For continuous data, we used MDs.

Dealing with missing data

We tried to contact investigators, study sponsors, and registration websites to verify key study characteristics and to obtain missing numerical outcome data when possible (e.g. when a study was only reported in an abstract format). When this was not possible, and when missing data were thought to introduce serious bias, we explored the impact of including such studies in the overall assessment of results by conducting a sensitivity analysis.

Assessment of heterogeneity

We used the I² statistic to measure heterogeneity amongst the trials in each analysis: 0% to 40%: might not be important; 30% to 60%: might represent moderate heterogeneity; 50% to 90%: might represent substantial heterogeneity; 75% to 100%: might show considerable heterogeneity (Higgins 2011). When we identified considerable heterogeneity, we reported this and explored possible causes by performing a prespecified subgroup analysis. 

Assessment of reporting biases

We created and examined a funnel plot to explore possible small‐study and publication biases for the primary outcomes.

Data synthesis

We used a random‐effects model and performed a sensitivity analysis by using a fixed‐effect model (see Sensitivity analysis).

Subgroup analysis and investigation of heterogeneity

We planned the following subgroup analyses for all primary and secondary outcomes:

• LAMA+LABA: 'combined indacaterol + glycopyrronium bromide (IND/GLY)' versus 'combined umeclidinium + vilanterol (UMEC/VI)' versus 'other LAMA/LABA inhalers'.

• COPD severity: 'including only mild or moderate (or both) (% predicted FEV₁ 50% or greater)' versus 'including severe and/or very severe (% predicted FEV₁ less than 50%)' versus 'including both categories.'

We were unable to perform the COPD severity subgroup analysis because separate data for participants with different severities were not reported. 

We used the I² test to detect heterogeneity, as discussed in Higgins 2003. We used the formal test for subgroup differences provided in Review Manager 5 (Review Manager 2014).

Sensitivity analysis

We conducted sensitivity analyses using a fixed‐effect model for the primary outcomes and reported any important differences compared with results using the random‐effects model.

Summary of findings and assessment of the certainty of the evidence

We created a summary of findings table to present the following outcomes:

• exacerbations (participants with one or more);

• serious adverse events (participants with one or more);

• quality of life, as measured by the St. George's Respiratory Questionnaire (SGRQ) total score change from baseline;

• trough FEV₁ change from baseline;

• pneumonia (participants with one or more occurrences);

• all‐cause death;

• SGRQ total score change from baseline (4 points or greater).

We used the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the certainty of a body of evidence (very low, low, moderate, and high certainty of evidence) as it related to studies that contributed data to meta‐analyses for prespecified outcomes (Guyatt 2008). We used the methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), with GRADEpro software (GRADEpro). We justified all decisions to downgrade or upgrade the certainty of the evidence by using footnotes, and we provided comments to aid readers' understanding of the review when necessary.

We did not prespecify specific domains or percentages for downgrading due to risk of bias, but considered it reasonable to downgrade if studies contributing more than half the analysis weight were at high risk of bias in the 'other bias' domain and at least one other domain. For inconsistency, we downgraded if I² was greater than 50%. For imprecision, we based downgrade decisions on prespecified thresholds (clinical importance 0.7 to 1.5 for outcomes as odds ratios) or established minimal clinically important differences (MCIDs) (4 points for SGRQ).

Results

Description of studies

See Included studies (Table 2), Excluded studies, and Ongoing studies.

1. Summary of characteristics of included studies.

Study	LAMA+LABA	LABA+ICS	Key inclusion criteria	Follow‐up duration (weeks)	Mean/median age (years)	Number randomised
Beeh 2016	Tiotropium/olodaterol (2.5/5 μg) or tiotropium/olodaterol (5/5 μg)	Salmeterol/fluticasone (50/250 μg) twice daily or salmeterol/fluticasone (50/500 μg) twice daily	%pred FEV1 30% to 80% Ex(‐)	6 × 4 time periods (cross‐over)	64	229
Donohue 2015a	Umeclidinium/vilanterol (62.5/25 μg)	Salmeterol/fluticasone (50/250 μg) twice daily	%pred FEV1 30% to 70%, mMRC ≥ 2, Ex(‐)	12	63	707
Donohue 2015b	Umeclidinium/vilanterol (62.5/25 μg)	Salmeterol/fluticasone (50/250 μg) twice daily	%pred FEV1 30% to 70%, mMRC ≥ 2, Ex(‐)	12	64	700
Ferguson 2018	Glycopyrronium/formoterol fumarate (18/9.6 μg)	Formoterol/budesonide/ fumarate (160/4.8 μg)  twice daily	CAT ≥ 10, %pred FEV1 25% to 80%, not required to have exacerbation	24	65	943
Frith 2018	Glycopyrronium/indacaterol (50/110 μg)	Salmeterol/fluticasone (50/500 μg) twice daily	CAT ≥ 10, %pred FEV1 30% to 80%, Ex(+)	12	65	502
Herth 2020	Tiotropium/olodaterol (5/5 μg)	Salmeterol/fluticasone  (50/500 μg)	%pred FEV1 < 70%, Ex(‐)	6	62	76
Hoshino 2015	Tiotropium/indacaterol (18/150 μg)	Salmeterol/fluticasone (50/250 μg) twice daily	%pred FEV1 30% to 80%, Ex(‐)	16	71	46
Lipson 2018	Umeclidinium/vilanterol (62.5/25 μg)	Vilanterol/fluticasone furoate (25/100 μg)	CAT ≥ 10, %pred FEV1 < 80%, Ex(+)	52	65	6204
Magnussen 2012	Tiotropium/salmeterol (18/50 μg) twice daily	Salmeterol/fluticasone (50/500 μg) twice daily	%pred FEV1 ≤ 65%, Ex(‐)	8 x 2 time periods (cross‐over)	61	344
Mostafa 2021	Tiotropium (18 μg) once daily/formoterol (9 μg) twice daily	Formoterol/budesonide (160/4.5 μg) twice daily	%pred FEV1 30% to 80%, Ex(‐)	12	64	40
NCT03240575	Tiotropium (5μg)/olodaterol (5μg) once daily	Salmeterol/fluticasone (50μg/250μg) twice daily	%pred FEV1 30% to 80%, Ex(‐)	12	64	302
Rabe 2008	Tiotropium/formoterol (18/24 μg) twice daily	Salmeterol/fluticasone (50/500 μg) twice daily	%pred FEV1 ≤ 65%, Ex(‐)	6	62	605
Rabe 2020	Glycopyrronium/formoterol (9/4.8 µg)  twice daily.	Formoterol/budesonide (4.8/160 µg) twice daily.	%pred FEV1 25‐65%, CAT ≥ 10, Ex(+)	52	65	4294
Singh 2015	Umeclidinium/vilanterol (62.5/25 μg)	Salmeterol/fluticasone (50/500 μg) twice daily	%pred FEV1 30% to 70%, mMRC ≥ 2, Ex(‐)	12	62	717
Vogelmeier 2013	Indacaterol/glycopyrronium bromide (110/50 μg)	Salmeterol/fluticasone (50/500 μg) twice daily	%pred FEV1 30% to 80%, Ex(‐)	26	63	523
Vogelmeier 2016	Aclidinium/formoterol (400/12 μg) twice daily	Salmeterol/fluticasone (50/500 μg) twice daily	%pred FEV1 < 80%, CAT ≥ 10, Ex(‐)	24	63	933
Vogelmeier 2017	Glycopyrronium/Indacaterol (50/110 μg)	any	%pred FEV1 50% ‐80%, mMRC ≥ 1, Ex(+)	12	65	1083
Wedzicha 2016	Indacaterol/glycopyrronium bromide (110/50 μg)	Salmeterol/fluticasone (50/500 μg) twice daily	%pred FEV1 25% to 60%, mMRC ≥ 2, Ex(+)	52	65	3362
Zhong 2015	Indacaterol/glycopyrronium bromide (110/50 μg)	Salmeterol/fluticasone (50/500 μg) twice daily	%pred FEV1 30% to 80%, mMRC ≥ 2, Ex(‐)	26	65	744

%pred FEV₁: % predicted forced expiratory volume in one second; CAT: chronic obstructive pulmonary disease assessment test; Ex(‐): without recent exacerbation; Ex(+): with recent exacerbation; LABA: long‐acting beta‐agonist; LAMA: long‐acting muscarinic antagonist; mMRC: modified Medical Research Council dyspnoea scale

Results of the search

We identified a total of 2685 records from update searches of electronic databases conducted on 1 November 2021 and 10 September 2022, including ClinicalTrials.gov and the WHO Clinical Trials Search Portal. We found an additional 20 records through manual searches. After removing 1248 duplicate records, there were 1458 records eligible for screening. The Screen4Me workflow removed 376 records, and we excluded 1046 records after viewing titles and abstracts alone. We excluded a further 21 after viewing full texts, which comprised 17 new excluded studies and four records identified as duplicates of records that had already been included. The remaining 15 records met the inclusion criteria for the review, corresponding to eight new included studies and one ongoing study.

Thus, we have included a total of 19 studies in the quantitative synthesis in the review (11 studies in the previous version of the review plus eight new included studies; see Figure 1).

1.

PRISMA study flow diagram

Included studies

The 19 studies included 22,354 participants. Seventeen studies used a parallel‐group design and two used a cross‐over design (Magnussen 2012; Vogelmeier 2017), with an 84‐day washout period between treatments. All studies delivered treatment in a double‐blind manner, except two open‐label studies (Hoshino 2015; Vogelmeier 2017).

The number of participants included in each study ranged from 40 to 6204, with a median of 700 participants per study. Thirteen studies included participants with moderate to severe COPD without recent exacerbation. Four trials that included only participants with a recent exacerbation accounted for 65% of the total participants. In each study, between 54% and 91% (median 70%) of participants were males. The mean age of the participants in each study ranged from 61 to 71 years (median 64 years). The percent predicted (%pred) FEV₁ in each study ranged from 43% to 64%, with a median of 51.5%.

Treatment

Treatment duration ranged from six to 52 weeks. Of the LABA+ICS treatments used in these studies, 14 studies used combined salmeterol/fluticasone propionate (Beeh 2016; Donohue 2015a; Donohue 2015b; Frith 2018; Herth 2020; Hoshino 2015; Magnussen 2012; NCT03240575; Rabe 2008; Singh 2015; Vogelmeier 2013; Vogelmeier 2016; Wedzicha 2016; Zhong 2015), three studies used combined formoterol/budesonide (Ferguson 2018; Mostafa 2021; Rabe 2020), and one study used combined vilanterol/fluticasone furoate (Lipson 2018). One study permitted any type or dose of LABA+ICS (Vogelmeier 2017). Of the administered LAMA+LABA treatments, five studies used glycopyrronium/indacaterol (Frith 2018; Vogelmeier 2013; Vogelmeier 2017; Wedzicha 2016; Zhong 2015), four studies used umeclidinium/vilanterol (Donohue 2015a; Donohue 2015b; Lipson 2018; Singh 2015), two studies used tiotropium/formoterol (Rabe 2008; Mostafa 2021), three studies used tiotropium/olodaterol (Beeh 2016; Herth 2020; NCT03240575), two studies used glycopyrronium/formoterol (Ferguson 2018; Rabe 2020), one study used tiotropium/indacaterol (Hoshino 2015), one study used tiotropium/salmeterol (Magnussen 2012), and one study used aclidinium/formoterol (Vogelmeier 2016).

Outcomes

The reporting of outcomes across studies, organised by the type of LAMA+LABA combination investigated, is shown in Table 3. Thirteen studies reported exacerbations in a way that could be brought together in a meta‐analysis, 17 reported serious adverse events, 13 studies reported FEV₁, 14 reported pneumonia, and 14 reported all‐cause death. Quality of life, as measured by the St. George's Respiratory Questionnaire (SGRQ), was less consistently reported, with nine studies reporting mean total scores and only four reporting the number of participants with a 4‐point or higher improvement on the scale. None of the included studies measured hospitalisations for COPD exacerbations. 

2. ORBIT matrix of outcome reporting across included studies.

	Objective or semi‐objective outcomes (investigator‐assessed)					Subjective outcomes (patient‐reported)
	Exacerbations	SAEs	Trough FEV1	Pneumonia	All‐cause death	SGRQ (mean)	SGRQ ≥ 4 unit benefit
Indacaterol/glycopyrronium studies
Frith 2018	X	X	X	X	X
Vogelmeier 2013	X	X	X	X	X	X	X
Vogelmeier 2017	X	X	X	X	X
Wedzicha 2016	X	X	X	X	X	X	X
Zhong 2015	X	X		X	X
Umeclidinium/vilanterol studies
Donohue 2015a	X	X	X	X	X	X
Donohue 2015b	X	X	X	X	X	X
Lipson 2018	X	X	X	X	X	X	X
Singh 2015	X	X	X	X	X	X
Other LAMA/LABA inhaler studies
Beeh 2016		X	X	X	X
Ferguson 2018		X	X	X	X	X
Herth 2020			X
Hoshino 2015						X
Magnussen 2012	X	X
Mostafa 2021		X			X
NCT03240575		X	X	X	X
Rabe 2008	X	X
Rabe 2020	X	X		X	X	X	X
Vogelmeier 2016	X	X		X

Outcomes shown are those included in the summary of findings table. Outcomes are classed as objective or subjective for the purposes of risk of bias assessment to consider differences in performance and detection bias.

FEV₁: forced expiratory volume in one second; ORBIT: outcome reporting bias in trials; SAEs: serious adverse events; SGRQ: St George’s Respiratory Questionnaire

Excluded studies

We excluded 24 studies after viewing full texts (see Characteristics of excluded studies and Figure 1), of which 17 were new excluded studies in this update. Overall, 11 were not relevant because they did not compare LAMA+LABA versus LABA+ICS (Bruhn 2003; Calverley 2007; Knobil 2004a; Knobil 2004b; NCT00120978; Sciurba 2004; NCT03504527; NCT04320342; NCT04923347; NCT05097014; Papi 2018), three studies were not eligible because they were systematic reviews (Aziz 2018; Oba 2016; Pavord 2016), four studies were not eligible because they did not report an RCT (Anzueto 2017; Mahler 2016; NCT03376295; NCT04138758), two studies were not eligible because they reported cost‐effectiveness analyses (Price 2014; Skoupa 2018), two studies were letters or commentaries (Michael 2016; Singh 2019), one study was not eligible because it reported only patients with eosinophilic inflammation (UMIN000024905), and one study was not eligible because the data were only analysed for asthma‐COPD overlap (EUCTR2015‐002046‐31‐ES).

Ongoing studies

We found one ongoing study awaiting results (EUCTR2016‐004473‐41‐GB). The study, which started in 2016, is a trial comparing tiotropium/olodaterol with vilanterol/fluticasone furoate, sponsored by Mundipharma Research Limited (see Characteristics of ongoing studies). The primary end point is change from baseline in eosinophil count and one of the secondary end points is change from baseline in pre‐dose FEV₁.

Risk of bias in included studies

Included studies had generally low risk of bias for random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, and selective outcome reporting. The potential for performance and detection bias for different types of outcome (e.g. subjective, objective) is discussed under the Blinding heading. See Figure 2.

2.

Risk of bias summary: included studies had generally low risk of bias for random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, and selective outcome reporting.

Allocation

Nine studies reported methods of random sequence generation that suggested a low risk of bias (Donohue 2015a; Donohue 2015b; Frith 2018; Magnussen 2012; NCT03240575; Singh 2015; Vogelmeier 2013; Wedzicha 2016; Zhong 2015). Ten studies had an unclear risk of bias in this domain because no details were reported (Beeh 2016; Ferguson 2018; Herth 2020; Hoshino 2015; Lipson 2018; Mostafa 2021; Rabe 2008; Rabe 2020 Vogelmeier 2016; Vogelmeier 2017). We rated 10 studies at low risk of bias relating to allocation concealment (Donohue 2015a; Donohue 2015b; Frith 2018; Magnussen 2012; Mostafa 2021; NCT03240575; Singh 2015; Vogelmeier 2013; Wedzicha 2016; Zhong 2015), two at high risk (Ferguson 2018; Herth 2020), and seven as unclear risk of bias because detailed methods were not provided (Beeh 2016; Hoshino 2015; Lipson 2018; Rabe 2008; Rabe 2020; Vogelmeier 2016; Vogelmeier 2017).

Blinding

We considered the impact of performance and detection bias on subjective and objective outcomes depending on the blinding methods used within studies. The reporting of objective, semi‐objective, and subjective outcomes across studies is shown in Table 3. Though bias is still possible in double‐blind studies for subjective and semi‐objective outcomes where blinding is broken unintentionally, there was no evidence that this had happened. Therefore, we rated all 17 double‐blind studies as low risk of performance and detection bias (Beeh 2016; Donohue 2015a; Donohue 2015b; Frith 2018; Ferguson 2018; Herth 2020; Lipson 2018; Magnussen 2012; Mostafa 2021; NCT03240575; Rabe 2008; Rabe 2020; Singh 2015; Vogelmeier 2013; Vogelmeier 2016; Wedzicha 2016;Zhong 2015). 

Two studies adopted neither double‐ nor single‐blinding methods and we rated these high risk of bias for both blinding domains, because there is a risk of bias for all outcomes except all‐cause death (Hoshino 2015; Vogelmeier 2017).

Incomplete outcome data

Our prespecified criteria for high attrition bias was a dropout rate of more than 20% of randomised participants. Two trials had a dropout rate of more than 20% (Mostafa 2021; Rabe 2020), and we therefore rated them high risk of bias. We considered all other studies to be at low risk of attrition bias. 

Selective reporting

Our criteria for rating a study as having a risk of selective reporting bias was if it was a non‐registered trial or if it considerably deviated from the registered protocol concerning outcome reporting. Two trials had a high risk of selective reporting bias due to non‐registration (Hoshino 2015; Mostafa 2021).

Other potential sources of bias

Seventeen out of 19 trials were sponsored by pharmaceutical companies (Beeh 2016; Donohue 2015a; Donohue 2015b; Frith 2018; Ferguson 2018; Herth 2020; Lipson 2018; Magnussen 2012; NCT03240575; Rabe 2008; Rabe 2020; Singh 2015; Vogelmeier 2013; Vogelmeier 2016; Vogelmeier 2017; Wedzicha 2016; Zhong 2015). Although pharmaceutical company sponsorship does not automatically signify a high risk of bias, scrutiny of disclosure statements revealed that all 17 studies had authors that were employed by the company, held shares, and/or received grants or fees for the work. In all cases, these authors were involved explicitly in the design of the study, its conduct (including data analysis), or interpretation and write up, which warranted high risk of bias judgements. 

We found no other sources of bias apart from conflicts of interest. 

Effects of interventions

See: Table 1

See Table 1.

Primary outcomes

Exacerbations (participants with one or more event)

Thirteen studies with 20,960 participants evaluated exacerbations over six to 52 weeks of observation. Participants randomised to LAMA+LABA had similar odds of experiencing one or more exacerbations to those randomised to LABA+ICS (OR 0.91, 95% CI 0.78 to 1.06; P = 0.22, I² = 56%;  moderate‐certainty evidence; Analysis 1.1). Our confidence in the result was reduced from high to moderate due to considerable heterogeneity.

1.1. Analysis.

Comparison 1: Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS), Outcome 1: Exacerbations

The test for subgroup differences indicated a difference between LAMA+LABA subgroups, with the largest benefit of LAMA+LABA versus LABA+ICS seen in the glycopyrronium/indacaterol studies (OR 0.72, 95% CI 0.63 to 0.83; P = 0.02, I² = 0%) and the pooled effect for the umeclidinium/vilanterol subgroup laying in the opposite direction (OR 1.20, 95% CI 1.03 to 1.40; P < 0.001, I² = 0%; test for subgroup differences P < 0.001). However, results are observational and should be interpreted with caution. The overall pooled result was similar to the random‐effects analysis when a fixed‐effect model was tested (OR 0.94, 95% CI 0.87 to 1.01; P = 0.08, I² = 56%; Analysis 1.8).

1.8. Analysis.

Comparison 1: Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS), Outcome 8: Exacerbations (fixed‐effect sensitivity)

Serious adverse events (participants with one or more event)

Eighteen studies with 23,183 participants evaluated serious adverse events over six to 52 weeks of observation. We discarded data from one study because no serious adverse events were reported in either arm (Herth 2020). Participants randomised to LAMA+LABA had similar odds of having a serious adverse event as those randomised to LABA+ICS (OR 1.02, 95% CI 0.91 to 1.15; I² = 20%; high‐certainty evidence; Analysis 1.2; test for subgroup differences P = 0.25). We did not downgrade the evidence in any of the GRADE domains and therefore have high confidence in the result.

1.2. Analysis.

Comparison 1: Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS), Outcome 2: Serious adverse events

Results were similar to the random‐effects analysis when a fixed‐effect model was tested (OR 1.03, 95% CI 0.95 to 1.12; I² = 20%; Analysis 1.9). 

1.9. Analysis.

Comparison 1: Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS), Outcome 9: Serious adverse events (fixed‐effect sensitivity)

Quality of life, as measured by the St. George's Respiratory Questionnaire (SGRQ) total score change from baseline

Nine studies with 14,437 participants assessed mean change in SGRQ scores over 12 to 52 weeks of observation. The benefit of LAMA+LABA versus LAMA+ICS was neither statistically nor clinically important (MD ‐0.57, 95% CI ‐1.36 to 0.21; I² = 78%; moderate‐certainty evidence; Analysis 1.3; test for subgroup differences P < 0.004). Our confidence in the result was reduced from high to moderate due to considerable heterogeneity. 

1.3. Analysis.

Comparison 1: Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS), Outcome 3: Quality of life as measured by the St George's Respiratory Questionnaire (SGRQ) total score change from baseline

The test for subgroup differences indicated a difference between LAMA+LABA subgroups, with the largest benefit of LAMA+LABA versus LABA+ICS seen in the indacaterol/glycopyrronium studies (MD ‐1.29, 95% CI ‐2.08 to ‐0.50; P = 0.001, I² = 0%). The sensitivity analysis using a fixed‐effect model brought the point estimate from lying in favour of LAMA+LABA to zero (i.e. no effect) (MD 0.00, 95% CI ‐0.02 to 0.02; I² = 78%; Analysis 1.10). 

1.10. Analysis.

Comparison 1: Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS), Outcome 10: SGRQ mean change (fixed‐effect sensitivity)

Trough FEV₁ mean change

In total, 12 studies with 14,681 participants reported change in trough FEV₁ over six to 52 weeks. Compared to LABA+ICS, there was a significant increase in the trough FEV₁ change from baseline with LAMA+LABA (MD 0.07 L, 95% CI 0.05 to 0.08; I² = 73%; moderate‐certainty evidence; Analysis 1.4). This difference was less than the minimal clinically important difference (Donohue 2005). Our confidence in the result was reduced from high to moderate due to considerable heterogeneity.

1.4. Analysis.

Comparison 1: Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS), Outcome 4: Trough FEV₁ mean change (litres)

In the LAMA+LABA subgroup analysis, each subgroup was consistently associated with an increase in trough FEV₁ change from baseline (test for subgroup differences P = 0.93). Results from the sensitivity analysis using a fixed‐effect model were in line with the main random‐effects analysis (MD 0.06, 95% CI 0.05 to 0.07; I² = 73%; Analysis 1.11).

1.11. Analysis.

Comparison 1: Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS), Outcome 11: Trough FEV₁ mean change (fixed‐effect sensitivity)

Secondary outcomes

Pneumonia (participants with one or more event)

Fourteen studies with 21,829 participants evaluated pneumonia over 12 to 52 weeks of observation. Compared to LABA+ICS, there was a large reduction in the number of participants experiencing one or more episodes of pneumonia with LAMA+LABA (OR 0.61, 95% CI 0.52 to 0.72; I² = 0%; high‐certainty evidence; Analysis 1.5; test for subgroup differences P = 0.90). We did not downgrade the evidence in any of the GRADE domains and therefore have high confidence in the result. Although it would be possible to calculate an absolute risk reduction, we decided not to do so, as the absolute effect size is highly dependent on the study duration.

1.5. Analysis.

Comparison 1: Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS), Outcome 5: Pneumonia

All‐cause death

Fifteen studies with 21,510 participants evaluated all‐cause death at six to 52 weeks of observation. There was an increased risk of all‐cause death with LAMA+LABA compared with LABA+ICS (OR 1.35, 95% CI 1.05 to 1.75; I² = 0%; moderate‐certainty evidence; Analysis 1.6). Our confidence in the result was reduced from high to moderate due to imprecision in the effect.

1.6. Analysis.

Comparison 1: Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS), Outcome 6: All‐cause death

Point estimates and confidence intervals varied across subgroups containing studies of different LAMA+LABA combinations, but the test for subgroup differences indicated the differences were not statistically significant (test for subgroup differences P = 0.51).

SGRQ improvement of 4 points or greater

Four studies with 13,614 participants evaluated the SGRQ total score change from baseline (≥ 4 points) at 26 to 52 weeks of observation. There was little to no significant change in the SGRQ total score (4 points or greater) between LAMA+LABA and LABA+ICS (OR 1.06, 95% CI 0.90 to 1.25; I² = 77%; moderate‐certainty evidence; Analysis 1.7; test for subgroup differences P = 0.002). Our confidence in the result was reduced from high to moderate due to considerable heterogeneity.

1.7. Analysis.

Comparison 1: Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS), Outcome 7: SGRQ improvement ≥ 4 points

Hospitalisations for COPD exacerbations

None of the included studies reported this outcome.  

Discussion

Summary of main results

We conducted a systematic review and meta‐analysis to compare the efficacy and safety of LAMA+LABA and LABA+ICS therapy in people with stable COPD. The review includes 19 studies with 22,354 participants, including 11 studies from the previous version of the review. Most studies were parallel, double‐blind RCTs. We noted selection, attrition, and selective reporting bias in a small number of studies and there is a risk of bias from involvement of authors employed by the pharmaceutical sponsors in 17 of the 19 studies. 

Compared to LABA+ICS, the review found there to be a greater improvement in FEV₁ in the LAMA+LABA group (moderate‐certainty evidence), lower odds of pneumonia (high‐certainty evidence), and increased mortality (moderate‐certainty evidence). This update did not find a difference in exacerbations between LAMA+LABA and LABA+ICS (moderate‐certainty evidence), which was reported in the previous review (Horita 2017). The odds of having a serious adverse event are likely to be similar for LAMA+LABA and LABA+ICS (high‐certainty evidence), as were quality of life scores as measured by the St George's Respiratory Questionnaire (moderate‐certainty evidence). 

Overall completeness and applicability of evidence

Most of the studies included in this analysis recruited people with moderate to severe COPD, according to the GOLD reports. Therefore, attention should be paid when applying our results to people with mild and very severe COPD.

Despite the apparent benefits of LAMA+LABA over LABA+ICS for trough FEV₁ and reduced risk of pneumonia, the findings suggest little difference for exacerbations, serious adverse events, and quality of life as measured by the SGRQ. Although exacerbations and pneumonia should share risk factors, a paradox can occur in COPD treated with ICS where the risk of exacerbations and mortality reduces despite an increased risk of pneumonia. The apparent conflicting results of this review may partially relate to this relationship, and should also be interpreted with caution due to the limited follow‐up and number of observed events. It should also be noted that studies recruited outpatient populations and cases of pneumonia may have been mild. Variation in study results also reduced our confidence in some of these findings, and in some cases, such as the exacerbations analysis where Lipson 2018 reported a significant benefit in favour of LABA+ICS, outlier studies impacted on the overall findings.

There was also variation across the included studies in their exclusion of people with a history of asthma, and the reporting of blood eosinophil counts that may be indicative of ACOS was patchy. Given that ICSs are effective in preventing exacerbations in asthma (Reddel 2021), results may have been skewed in favour of the LABA+ICS group because people with ACOS or a high blood eosinophil sensitivity to ICS may have fared better than those receiving LAMA+LABA.

Studies further varied in their inclusion criteria around recent history of exacerbation, which is a known risk factor for COPD mortality (Esteban 2018). The variation may have impacted on analyses where studies that enroled participants with a history of exacerbations carried a large proportion of the weight within an analysis (e.g. Rabe 2020 in the all‐cause death analysis). Moreover, the % predicted FEV₁ of participants in Rabe 2020 was as low as 25% to 65%, suggesting that participants' condition in this trial was poorer than those in other RCTs. 

Limitations of the evidence include the lack of long‐term follow‐up data and the possibility that discontinuation of therapy may have contributed to early events such as withdrawal and death. For example, in Wedzicha 2016, all participants were treated with tiotropium during a one‐month run‐in period. Exacerbations in the LAMA+LABA groups might have occurred because participants who had been using ICSs prior to the trial had to discontinue them. As such, in studies where a recent exacerbation was not permitted, removal of these participants may have led to a biased population. In Lipson 2018, the participants who had been receiving ICSs before enroling in the trial were partly randomised to the LAMA+LABA group. These participants were actually stepping down in their treatment; this could lead to COPD exacerbations (Suissa 2018). 

Certainty of the evidence

GRADE ratings of certainty in the evidence along with reasons for downgrading, or choosing not to downgrade, are summarised in Table 1. We downgraded most outcomes once to moderate certainty, meaning the true effect is likely to be close to the estimate of effect but may be substantially different. The pooled effects for serious adverse events and pneumonia were both rated high certainty, meaning the true effect lies close to that of the estimate of effect. The most common reason for downgrading was considerable heterogeneity (exacerbations, SGRQ mean change, FEV₁ mean change and SGRQ improvement of 4 or more points), which may reflect the clinical heterogeneity between studies, discussed above. Only the all‐cause death analysis was downgraded due to imprecision, because there was a very small number of events in the analysis, leading to wide confidence intervals. The confidence intervals around the pooled result for several other outcomes include a potential benefit in either direction (exacerbations, serious adverse events, SGRQ mean change, SGRQ improvement of 4 or more points), but they lay within the threshold for clinical importance that was predefined in the protocol for this review, so we chose not to downgrade (0.7 to 1.5 for OR outcomes; 4‐point MCID for SGRQ).

We did not downgrade any outcomes due to indirectness of the contributing studies to the review question. However, variation in study inclusion criteria around recent history of exacerbation, baseline percentage predicted FEV₁, and exclusion of asthma are noteworthy, and affect how the pooled results can be interpreted and applied to different subpopulations of people with COPD. Similarly, we did not downgrade any outcomes for suspected publication bias, and there was no obvious asymmetry on funnel plots for the primary outcomes.

The potential impact of risk of bias across analyses is difficult to quantify, and we did not prespecify a threshold for downgrading the evidence due to risk of bias in certain domains or in studies contributing a certain percentage of the analysis weight. Amongst the 19 included studies, only two with a few participants did not have any commercial sponsorship (Hoshino 2015; Mostafa 2021). In the remaining 17 studies, study authors involved in key aspects of the study were employed by, held shares for, or received fees from the sponsoring manufacturer (Table 4). Otherwise, the included studies were mostly well‐designed and conducted, with adequate sample sizes. Therefore, across outcomes, all or almost all studies are at high risk of 'other' bias due to conflicts of interest, and studies contributing between 18.5% and 35.9% of the analysis weight are rated high risk of bias in at least one other domain. We set a post hoc rule for downgrading, and considered it insufficient to downgrade if studies contributing more than half the analysis weight were at low or unclear risk of bias in all but the 'other' domain, meaning no outcomes were downgraded for this reason. There is a need for large, well‐conducted trials funded by national funding bodies to overcome the bias inherent in evidence funded by pharmaceutical companies.

3. Sponsor list for chronic obstructive pulmonary disease studies.

Sponsor	Record count	% of 1723
GlaxoSmithKline	134	7.78
Novartis	128	7.43
AstraZeneca	122	7.08
Boehringer Ingelheim	113	6.56
Pfizer	84	4.88
Nycomed	49	2.84
GSK	45	2.61
Chiesi	41	2.38
Almirall	36	2.09
Merck	30	1.74

Web of Science Core Collection, advanced search for "TI=(COPD) AND TS=(inhal*)" without any restriction hit 1723 reports as of 13 June 2016. "Results analysis" > "Source Titles" output the table above.

Potential biases in the review process

Although we tried to extract data on exacerbations of any severity, some trials counted only moderate to severe exacerbations. In addition, some outcomes, such as exacerbation and adverse effects, were dependent on the threshold determined by the researchers of the original articles. Confidence intervals for the two cross‐over studies might be conservative in our analysis (Magnussen 2012; Vogelmeier 2017), due to the way we included the data in the analysis to avoid overestimating precision.

Agreements and disagreements with other studies or reviews

The previous version of this review, which included 11 studies with 9839 participants (Horita 2017), concluded there was no difference between the LAMA+LABA and LABA+ICS groups for all‐cause death (OR 1.01, 95% CI 0.61 to 1.67), whereas this update found a probable benefit of LABA+ICS over LAMA+LABA. As discussed above, this may be partially explained by differences in the presence and reporting of ACOS within the newer studies that carry a large proportion of the analysis weight. 

A recent network meta‐analysis which included a LAMA+LABA versus LABA+ICS comparison looked at many of the same outcomes to this review in studies of low‐ and high‐risk COPD populations (Oba 2018). The review included many of the same studies (nine studies), and many others for comparisons not of interest to this review, but excluded those with a cross‐over design and those shorter than 12 weeks. Oba and colleagues also presented data separately for high‐ and low‐risk populations and looked at FEV₁ and the SGRQ at three, six, and 12 months. Results for the high‐risk population are largely in line with this review: the finding relating to exacerbations was similar to ours (OR 0.89, 95% CI 0.78 to 1.04) and quality of life, as measured by the SGRQ (MD ‐1.47, 95% CI ‐3.74 to 0.45). It is noteworthy that there was no significant difference in all‐cause mortality (OR 1.15, 95% CI 0.70 to 1.95). A similarly large effect was seen for pneumonia (OR 0.61, 95% CI 0.34 to 1.01) and trough FEV₁ (MD 0.05, 95% CI 0.03 to 0.07) in favour of LAMA+LABA, and effects were generally smaller or inconclusive in the low‐risk population studies (Oba 2018). A further review of incident pneumonia and mortality in people with COPD showed no difference between ICS and non‐ICS arms in pneumonia‐related mortality despite a significantly increased risk of pneumonia (Festic 2015). 

Authors' conclusions

Implications for practice.

Combined long‐acting muscarinic antagonist (LAMA) and long‐acting beta‐agonist (LABA) inhalers probably hold similar benefits to LABA plus inhaled corticosteroid (ICS) inhalers for exacerbations and quality of life (as measured by the St George's Respiratory Questionnaire) for people with moderate to severe chronic obstructive pulmonary disease (COPD), but offer a larger improvement in forced expiratory volume in one second (FEV₁)and a lower risk of pneumonia. Clinicians need to consider pneumonia as an underlying cause when people with COPD using LABA plus ICS (LABA+ICS) inhalers have exacerbations. All‐cause death may be lower with LABA+ICS. However, there was a very small number of events in the analysis, which means absolute risk was low. Findings are based on moderate‐ to high‐certainty evidence from heterogeneous trials with an observation period of less than one year. 

The choice between LAMA+LABA and LABA+ICS may need to take account of the individual's condition, including blood eosinophil count, history of pneumonia, and recent exacerbations. This review should be updated again in a few years.

Implications for research.

Further research is indicated to clarify the relative positions of LABA+ICS and LAMA+LABA in the COPD treatment guidelines. Trials should exclude people with asthma and should rapidly switch participants from any prior treatment to trial treatment to reduce the number of people who withdraw from the study. Longer‐term follow‐up data would be beneficial, especially to identify any impact on serious adverse events or mortality. Results from future or ongoing trials evaluating newly developed bronchodilators are awaited. Meta‐analyses that access the data for each combined medication separately are also anticipated.

Feedback

Interpretation of SGRQ data and missing data, 20 March 2017

Summary

My colleagues and I thank Dr. Horita and colleagues for their efforts on their Cochrane Review (1). With the recent publication of the FLAME trial (2) that compared the utility of indacaterol‐glycopyrronium versus salmeterol‐fluticasone for chronic obstructive pulmonary disease (COPD) and its potential to change our current standard of care, we appreciate their work in evaluating the results of this trial and putting this evidence into perspective.

As we reviewed the manuscripts presented in the article, we focused on the applicability of the evidence. The authors reported that for the treatment of COPD, combination LAMA+LABA was associated with more frequent St. George’s Respiratory Questionnaire (SGRQ) total score improvement exceeding the minimal clinically important difference (4 points or greater).(1) Respectively, after critically appraising the data presented, we have reservations about the conclusions made regarding the impact of LABA+LAMA on the SGRQ. Please refer to our additional letter regarding the outcomes of rate of exacerbations and serious adverse events.

In this review, the outcome of SGRQ total score improvement (≥4 points) was based on two trials with the FLAME trial driving the results (Analysis 1.7).(1) We are concerned that the data set used for this outcome from FLAME is incomplete. Rather than using the modified intention to treat (mITT) population (N=3354) or even the per protocol population (N=3084), it appears that only patients who completed 52 weeks of treatment were included (N=2760).(2) It is possible that the exclusion of these 594 patients may have skewed the results of this analysis. Furthermore, it is unclear where the data used for this outcome came from, as neither the FLAME publication nor the supplemental appendices identify the SGRQ results for this population of patients who completed 52 weeks of treatment. This information is also not available through clinicaltrials.gov. In Figure 6 of this review, the outcome of mean difference in SGRQ from baseline was also driven by this same population.(1) Therefore, this begs the question of whether it is fair to base conclusions regarding the effects of LABA+LAMA versus LABA+ICS on SGRQ on the results of only two trials especially given that the larger trial’s data set does not appear to be complete.

In summary, with greater transparency and citation of the original data used for analyses, we believe that our conclusions potentially could align more closely with those identified by the Cochrane review authors. At present, perhaps the conclusions regarding the impact of these interventions on SGRQ could incorporate a greater sense of uncertainty and/or acknowledgement of the limitations of the available evidence. Overall, aside from the clarification of the data reported in the Cochrane review, we agree with the authors that a call for more research is warranted to ascertain the relative position of LAMA+LABA and LABA+ICS for COPD treatment and disaggregated data for participants in different COPD severity groups.

We hope that you will consider our constructive feedback and look forward to hearing from you soon.

References:

1. Horita N, Goto A, Shibata Y, Ota E, Nakashima K, Nagai K, Kaneko T. Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS) for stable chronic obstructive pulmonary disease (COPD). Cochrane Database Syst Rev. 2017 Feb 10;2:CD012066.

2. Wedzicha JA, Banerji D, Chapman KR, Vestbo J, Roche N, Ayers RT, Thach C, Fogel R, Patalano F, Vogelmeier CF, FLAME Investigators. Indacaterol‐Glycopyrronium versus Salmterol‐Fluticasone for COPD. N Engl J Med. 2016 Jun 9;374(23):2222‐34.

Reply

Cochrane Airways awaits a final response from the author team.

Contributors

Stephanie Garland, BSc. Pharm, Pharmacy Resident
Andrea Wan, BSc. Pharm, Pharmacy Resident
Anna Yee, BSc. Pharm, Pharmacy Resident
Grant Gill, BSc. Pharm, Pharmacy Resident
Aaron Tejani, BSc. Pharm, PharmD

Exacerbations and missing data, 13 April 2017

Summary

With the recent publication of the FLAME trial (1) and its potential to change clinical practice, we would like to thank Dr. Horita and colleagues for their efforts in evaluating the results of this trial and putting this evidence into perspective in their Cochrane Review (2). The authors reported that for the treatment of COPD, combination LAMA+LABA was associated with fewer exacerbations, and a non‐significant decrease in serious adverse events (SAE) (2). Respectively, we have reservations in making similar claims and would like to address our chief concerns below.

First, we would like to focus on the reported reduction in the rate of COPD exacerbations and the implications based on the data set analysed. As illustrated in Figure 3, the FLAME trial was a primary driver of this finding, and the only trial to show a statistically significant reduction in the number of exacerbations.(2) When examining the FLAME data set, we were concerned that the data used to make this conclusion was incomplete. Of the 598 patients who did not complete 52 weeks of treatment, only 192 patients were continually followed with respect to exacerbations and adverse events (1). Thus, 406 patients were unaccounted for in both groups combined that may have experienced an exacerbation and unbalanced the intervention and control groups. Without delineating how these patients may have skewed the results, we are less confident that the results observed were the true effect. Moreover, of the 1680 patients randomised to indacaterol‐glycopyrronium and 1682 patients randomised to salmeterol‐fluticasone, 152 and 126 patients were unaccounted for in each group respectively in the per protocol analysis (1). Interestingly, the data from the per protocol analysis was used to quantify the primary outcomes in the FLAME trial, which complicates whether the observed effects are reliable. Additionally, when comparing the results of FLAME to those reported in this review, we found a discrepancy in exacerbation reporting. In Figure 3, 1290/1675 and 1377/1679 exacerbation events were reported in the LAMA+LABA and LABA+ICS groups respectively (2). However, it is unclear where this data originated from, as neither the FLAME publication, the supplemental appendices, nor the data from clinicaltrials.gov provided these exact results. Regarding the generalisability of the outcome data, patients in the FLAME trial experienced an average of 3.59 or 4.09 exacerbations during the 52 weeks of indacaterol‐glycopyrronium and salmeterol‐fluticasone treatment respectively, and these rates were primarily driven the total number of mild exacerbations recorded (1). Thus, it would be difficult to meaningfully apply this data to patients with chronic COPD who experience moderate to severe exacerbations. Given the potentially incomplete data from FLAME, the discrepancy in the data used, and the limited applicability of the primary outcome results, it is difficult to draw a definitive conclusion about the effects of LAMA+LABA compared to LABA+ICS on reducing the rate of COPD exacerbations at this time.

Second, despite the reduction in COPD exacerbations and the risk of pneumonia in patients randomised to the LAMA+LABA group, these differences failed to translate into statistically significant reductions in SAE and adverse events (AE), and produced no change in all cause mortality between the two treatment modalities. These discordant findings raise further questions about the validity of the data being meta‐analyzed. Predictably, we have identified the FLAME trial as a contributor to these potentially skewed results due to its ambiguous reporting of outcome data that does not outline the proportion of SAE, AE, or mortality following early discontinuation of study drugs and early withdrawal. As mentioned above, 406 patients were unaccounted for and without information on whether these patients may have experienced additional SAE or AE, it is difficult to interpret and make conclusions about the true effect.

In summary, with greater transparency and citation of the original data used for analyses, and acknowledgement of the limitations in the demographics of the studied patient population and reporting of primary outcomes, we believe that our conclusions could potentially more closely align with those identified by the Cochrane review authors. Acutely, perhaps the conclusions originally stated could incorporate a greater sense of uncertainty, and/or caveats to the generalizations provided. To close, we agree with the authors that a call for more research to ascertain the relative position of LAMA+LABA and LABA+ICS for COPD treatment and disaggregated data for participants in different COPD severity groups is warranted.

We hope that you will consider our constructive feedback and look forward to hearing from you soon.

The authors of this letter have no known conflicts of interest to declare.

References:

1. Wedzicha JA, Banerji D, Chapman KR, Vestbo J, Roche N, Ayers RT, Thach C, Fogel R, Patalano F, Vogelmeier CF, FLAME Investigators. Indacaterol‐Glycopyrronium versus Salmterol‐Fluticasone for COPD. N Engl J Med. 2016 Jun 9;374(23):2222‐34.

2. Horita N, Goto A, Shibata Y, Ota E, Nakashima K, Nagai K, Kaneko T. Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS) for stable chronic obstructive pulmonary disease (COPD). Cochrane Database Syst Rev. 2017 Feb 10;2:CD012066.

Reply

Cochrane Airways awaits a final response from the author team.

Contributors

Andrea Wan, BSc. Pharm, Pharmacy Resident
Anna Yee, BSc. Pharm, Pharmacy Resident
Grant Gill, BSc. Pharm, Pharmacy Resident
Stephanie Garland, BSc. Pharm, Pharmacy Resident
Aaron Tejani, BSc. Pharm, PharmD

Questioning the pooling of exacerbation data, 18 December 2017

Summary

I read with great interest the systematic review on Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS) for stable chronic obstructive pulmonary disease (COPD) (1). The review is illustrated with a forest plot of the association of combined therapy with COPD exacerbation. This figure shows that indacaterol/glycopyrronium is the only combination able to prevent exacerbations.

The first step when a reader goes through a systematic review is to assess its credibility. In the case of this forest plot, this credibility is questioned when we inspect the rate of events. The indacaterol/glycopyrronium trials had a 66.4% of events in the control group, meanwhile it was 2.4% in the umeclidinium/vilanterol trials and 11.1% in the other inhalers. Although there is no statistically significant heterogeneity according to Cochrane Q test or I², it is questionable to construct a forest plot in the presence of significant clinical heterogeneity (e.g. trials with exacerbation rates ranging between 2.4 to 66.4%).

The FLAME trial (2) was the only one designed to assess COPD exacerbations. This trial included patients with recent exacerbations and followed them for 52 weeks. In contrast, the other trials included patients without recent COPD exacerbations and followed them for only 6 to 12 weeks. It is nearly impossible to draw conclusions about the role of LAMA/LABA in the prevention of COPD exacerbation with these last trial designs. Neither the population, nor the follow‐up period were adequate to assess the prevention of COPD exacerbation. The importance of the follow‐up length could be illustrated in figure 2 of the own FLAME trial (2), where there were no differences in the rate of severe exacerbations until week 32.

We can be fairly confident about indacaterol/glycopyrronium preventing COPD exacerbations for patients with frequent exacerbations, but we do not have either enough evidence about the role of the others LABA/LAMA combinations to prevent COPD exacerbations, or the role of indacaterol/glycopyrronium in patients without frequent exacerbations.

In my opinion, the forest plot in question is misleading due its combination of apples and oranges.

Luis Corral‐Gudino

References

1. Horita N, Goto A, Shibata Y, Ota E, Nakashima K, Nagai K, Kaneko T. Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS) for stable chronic obstructive pulmonary disease (COPD). Cochrane Database Syst Rev. 2017 Feb 10;2:CD012066.

2. Wedzicha JA, Banerji D, Chapman KR, Vestbo J, Roche N, Ayers RT, Thach C, Fogel R, Patalano F, Vogelmeier CF. Indacaterol–glycopyrronium versus salmeterol–fluticasone for COPD. N Engl J Med. 2016 Jun 9;2016(374):2222‐34.

Reply

We appreciate Dr. Corral‐Gudino's comments concerning the exacerbation forest plot in our review [1].

As correctly mentioned, the subgroup analysis of the exacerbation forest plot shows non‐negligible discrepancy. This planned subgroup analysis is impressive. While indacaterol/glycopyrronium clearly decreased the risk of exacerbation, medications in the other two subgroups did not. I² for subgroup difference is as high as 69.7% with significant P value of 0.04. We agree with Dr. Corral‐Gudino that only indacaterol/glycopyrronium seemed to prevent exacerbations, which we discussed in the ‘Overall Completeness and Applicability of Evidence’ section of our review [1]. Given some limitations, the GRADE quality of evidence related to the outcome of exacerbations was downgraded to 'low.'[1]

Dr. Corral‐Gudino rightly commented that the study designs of included studies varied greatly. Thus, the between‐study heterogeneity should be assessed. It is reasonable to evaluate the heterogeneity using Cochrane Q test (P value = 0.29) and I² statics (17%), which dispelled considerable inconsistency (Figure 1) [1].

The frequencies of exacerbation were indeed different between studies. Absolute risk reduction and number needed to treatment are meaningless if event frequencies are largely different among studies. However, odds ratios are known to be robust even when exacerbation frequencies vary greatly. For example, the incidence of exacerbations in Vogelmeier's, Wedzicha's and Zhong's studies were (44+62)/(258+264)=20%, (1290+1377)/(1675/1679)=80%, and (75+97)/(372/369)=23%, respectively. Yet the corresponding odds ratios were 0.67, 0.73, and 0.71 [1]. Compared to patients who were treated by control medication, those treated by indacaterol/glycopyrronium had a 30% lower chance of exacerbation regardless of absolute risk. As long as odds ratios are calculated, inconsistent frequencies between studies is not a considerable problem.

While Wedzicha's trial included patients with recent exacerbation, Vogeleier's and Zhong's trials included patients without recent exacerbation. Dr. Corral‐Gudino insists we do not have enough evidence about the role of indacaterol/glycopyrronium in patients without frequent exacerbations. However, our analysis clearly shows that the medication constantly decreased the risk of exacerbation in the three trials, with an odds ratio of approximately 0.7 without heterogeneity (I²=0%, P for heterogeneity = 0.92) regardless of recent exacerbations.

As Dr. Corral‐Gudino pointed out, observed exacerbations in each study were not sufficient in all studies, except Wedzicha's, due to small sample size, inclusion of patients without recent exacerbation, and short follow‐up periods. This is exactly why meta‐analysis is needed. A meta‐analysis can integrate many studies that do not have statistical power.

Reference

1. Horita N, Goto A, Shibata Y, Ota E, Nakashima K, Nagai K, Kaneko T. Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS) for stable chronic obstructive pulmonary disease (COPD). Cochrane Database Syst Rev. 2017 Feb 10;2:CD012066.

Contributors

Feedback submitter

Luis Corral‐Gudino PhD MD, Internal Medicine Department. Hospital El Bierzo, Ponferrada Leon.

Do you have any affiliation with or involvement in any organisation with a financial interest in the subject matter of your comment?

I do not have any affiliation with or involvement in any organisation with a financial interest in the subject matter of my comment

Authors

Nobuyuki Horita, Atsushi Goto, Yuji Shibata, Erika Ota, Kentaro Nakashima, Kenjiro Nagai, Takeshi Kaneko

What's new

Date	Event	Description
5 June 2023	New search has been performed	New search run September 10, 2022.
5 June 2023	New citation required and conclusions have changed	New studies identified; review redrafted; conclusions changed.

History

Protocol first published: Issue 2, 2016
Review first published: Issue 2, 2017

Date	Event	Description
17 January 2018	Amended	Feedback added.
14 June 2017	Feedback has been incorporated	Two pieces of feedback added to the review. Cochrane Airways awaits a full response from the author team.

Appendices

Appendix 1. Sources and search methods for the Cochrane Airways Group Specialised Register (CAGR)

Electronic searches: core databases

Database	Frequency of search
MEDLINE (Ovid)	Weekly
Embase (Ovid)	Weekly
CENTRAL	Monthly
PsycINFO (Ovid)	Monthly
CINAHL (EBSCO)	Monthly
AMED (EBSCO)	Monthly

Handsearches: core respiratory conference abstracts

Conference	Years searched
American Academy of Allergy, Asthma and Immunology (AAAAI)	2001 onwards
American Thoracic Society (ATS)	2001 onwards
Asia Pacific Society of Respirology (APSR)	2004 onwards
British Thoracic Society Winter Meeting (BTS)	2000 onwards
Chest Meeting	2003 onwards
European Respiratory Society (ERS)	1992, 1994, 2000 onwards
International Primary Care Respiratory Group Congress (IPCRG)	2002 onwards
Thoracic Society of Australia and New Zealand (TSANZ)	1999 onwards

Condition search

1. Lung Diseases, Obstructive/

2. exp Pulmonary Disease, Chronic Obstructive/

3. emphysema$.mp.

4. (chronic$ adj3 bronchiti$).mp.

5. (obstruct$ adj3 (pulmonary or lung$ or airway$ or airflow$ or bronch$ or respirat$)).mp.

6. COPD.mp.

7. COAD.mp.

8. COBD.mp.

9. AECB.mp.

10. or/1‐9

Filter to identify randomised controlled trials

1. exp "clinical trial [publication type]"/

2. (randomised or randomised).ab,ti.

3. placebo.ab,ti.

4. dt.fs.

5. randomly.ab,ti.

6. trial.ab,ti.

7. groups.ab,ti.

8. or/1‐7

9. Animals/

10. Humans/

11. 9 not (9 and 10)

12. 8 not 11

The MEDLINE strategy and RCT filter are adapted to identify trials in other electronic databases

Appendix 2. Search strategy to identify relevant trials from the Cochrane Airways Group Specialised Register (CAGR)

#1 MeSH DESCRIPTOR Pulmonary Disease, Chronic Obstructive Explode All

#2 MeSH DESCRIPTOR Bronchitis, Chronic

#3 (obstruct*) near3 (pulmonary or lung* or airway* or airflow* or bronch* or respirat*)

#4 COPD:MISC1

#5 (COPD OR COAD OR COBD OR AECOPD):TI,AB,KW

#6 #1 OR #2 OR #3 OR #4 OR #5

#7 MeSH DESCRIPTOR Muscarinic Antagonists

#8 muscarinic* NEXT antagonist*

#9 LAMA:ti,ab

#10 tiotropium*

#11 Spiriva

#12 glycopyrronium*

#13 NVA237

#14 Seebri

#15 umeclidinium*

#16 GSK573719

#17 Incruse

#18 aclidinium*

#19 LAS34273

#20 Turdorza

#21 Eklira

#22 #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21

#23 MeSH DESCRIPTOR Adrenergic beta‐2 Receptor Agonists

#24 long* NEAR beta* NEAR agonist*

#25 salmeterol*

#26 *formoterol*

#27 indacaterol*

#28 QAB149

#29 vilanterol*

#30 GW642444

#31 olodaterol*

#32 "BI 1744 CL"

#33 #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or #31 or #32

#34 MeSH DESCRIPTOR Adrenal Cortex Hormones Explode All

#35 inhal* NEAR (corticosteroid* or steroid* or glucocorticoid*)

#36 fluticasone*

#37 budesonide*

#38 beclomethasone*

#39 ciclesonide*

#40 flunisolide*

#41 mometasone*

#42 triamcinolone*

#43 #34 or #35 or #36 or #37 or #38 or #39 or #40 or #41 or #42

#44 #6 AND #22 AND #33 AND #43

#45 Ultibro

#46 QVA149

#47 Stiolto

#48 Anoro

#49 #45 or #46 or #47 or #48

#50 Symbicort

#51 Viani

#52 Seretide

#53 Advair

#54 Atmadisc

#55 Adoair

#56 Foster or Fostair

#57 Inuvair

#58 Dulera

#59 Flutiform

#60 Breo

#61 #50 or #51 or #52 or #53 or #54 or #55 or #56 or #57 or #58 or #59 or #60

#62 #49 AND #61

#63 #49 AND #43

#64 #61 AND #22

#65 (#62 or #63 or #64) AND #6

#66 #44 or #65

[Note: in search line #4, MISC1 denotes the field in the record where the reference has been coded for condition, in this case, COPD]

Appendix 3. Search strategy to identify relevant trials from the ClinicalTrials.gov

Search term: (COPD OR chronic obstructive lung disease) AND (glycopyrrolate OR umeclidinium OR tiotropium OR aclidinium OR olodaterol OR QVA149) AND (indacaterol OR formoterol OR vilanterol OR salmeterol OR QVA149) AND (fluticasone OR budesonide)
Study type: Intervention

Appendix 4. Search strategy to identify relevant trials from the World Health Organization search portal

Title search: (COPD OR chronic obstructive lung disease) AND (glycopyrrolate OR umeclidinium OR tiotropium OR aclidinium OR olodaterol OR QVA149) AND (indacaterol OR formoterol OR vilanterol OR salmeterol OR QVA149) AND (fluticasone OR budesonide)

Data and analyses

Comparison 1. Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Exacerbations	13	20960	Odds Ratio (M‐H, Random, 95% CI)	0.91 [0.78, 1.06]
1.1.1 Indacaterol/glycopyrronium	5	6200	Odds Ratio (M‐H, Random, 95% CI)	0.72 [0.63, 0.83]
1.1.2 Umeclidinium/vilanterol	4	8323	Odds Ratio (M‐H, Random, 95% CI)	1.20 [1.03, 1.40]
1.1.3 Other LAMA/LABA inhalers	4	6437	Odds Ratio (M‐H, Random, 95% CI)	0.97 [0.87, 1.08]
1.2 Serious adverse events	18	23158	Odds Ratio (M‐H, Random, 95% CI)	1.02 [0.91, 1.15]
1.2.1 Indacaterol/glycopyrronium	5	6204	Odds Ratio (M‐H, Random, 95% CI)	0.88 [0.76, 1.03]
1.2.2 Umeclidinium/vilanterol	4	8323	Odds Ratio (M‐H, Random, 95% CI)	1.07 [0.73, 1.55]
1.2.3 Other LAMA/LABA inhalers	9	8631	Odds Ratio (M‐H, Random, 95% CI)	1.04 [0.92, 1.19]
1.3 Quality of life as measured by the St George's Respiratory Questionnaire (SGRQ) total score change from baseline	9	14437	Mean Difference (IV, Random, 95% CI)	‐0.57 [‐1.36, 0.21]
1.3.1 Indacaterol/glycopyrronium	2	3693	Mean Difference (IV, Random, 95% CI)	‐1.29 [‐2.08, ‐0.50]
1.3.2 Umeclidinium/vilanterol	4	6615	Mean Difference (IV, Random, 95% CI)	‐0.00 [‐0.02, 0.02]
1.3.3 Other LAMA/LABA inhalers	3	4129	Mean Difference (IV, Random, 95% CI)	‐1.14 [‐4.06, 1.78]
1.4 Trough FEV1 mean change (litres)	12	14681	Mean Difference (IV, Random, 95% CI)	0.07 [0.05, 0.08]
1.4.1 Indacaterol/glycopyrronium	4	5843	Mean Difference (IV, Random, 95% CI)	0.07 [0.05, 0.09]
1.4.2 Umeclidinium/vilanterol	4	6669	Mean Difference (IV, Random, 95% CI)	0.08 [0.04, 0.11]
1.4.3 Other LAMA/LABA inhalers	4	2169	Mean Difference (IV, Random, 95% CI)	0.07 [0.02, 0.11]
1.5 Pneumonia	14	21829	Odds Ratio (M‐H, Random, 95% CI)	0.61 [0.52, 0.72]
1.5.1 Indacaterol/glycopyrronium	5	6204	Odds Ratio (M‐H, Random, 95% CI)	0.61 [0.44, 0.85]
1.5.2 Umeclidinium/vilanterol	4	8323	Odds Ratio (M‐H, Random, 95% CI)	0.63 [0.50, 0.80]
1.5.3 Other LAMA/LABA inhalers	5	7302	Odds Ratio (M‐H, Random, 95% CI)	0.58 [0.43, 0.78]
1.6 All‐cause death	15	21510	Odds Ratio (M‐H, Random, 95% CI)	1.35 [1.05, 1.75]
1.6.1 Indacaterol/glycopyrronium	5	6204	Odds Ratio (M‐H, Random, 95% CI)	1.02 [0.59, 1.76]
1.6.2 Umeclidinium/vilanterol	4	8324	Odds Ratio (M‐H, Random, 95% CI)	1.51 [1.00, 2.26]
1.6.3 Other LAMA/LABA inhalers	6	6982	Odds Ratio (M‐H, Random, 95% CI)	1.43 [0.94, 2.17]
1.7 SGRQ improvement ≥ 4 points	4	13614	Odds Ratio (M‐H, Random, 95% CI)	1.06 [0.90, 1.25]
1.7.1 Indacaterol/glycopyrronium	2	3192	Odds Ratio (M‐H, Random, 95% CI)	1.25 [1.09, 1.44]
1.7.2 Umeclidinium/vilanterol	1	6204	Odds Ratio (M‐H, Random, 95% CI)	1.00 [0.89, 1.12]
1.7.3 Other LAMA/LABA inhalers	1	4218	Odds Ratio (M‐H, Random, 95% CI)	0.89 [0.79, 1.01]
1.8 Exacerbations (fixed‐effect sensitivity)	13	20960	Odds Ratio (M‐H, Fixed, 95% CI)	0.94 [0.87, 1.01]
1.8.1 Indacaterol/glycopyrronium	5	6200	Odds Ratio (M‐H, Fixed, 95% CI)	0.72 [0.63, 0.83]
1.8.2 Umeclidinium/vilanterol	4	8323	Odds Ratio (M‐H, Fixed, 95% CI)	1.20 [1.03, 1.40]
1.8.3 Other LAMA/LABA inhalers	4	6437	Odds Ratio (M‐H, Fixed, 95% CI)	0.97 [0.87, 1.08]
1.9 Serious adverse events (fixed‐effect sensitivity)	18	23158	Odds Ratio (M‐H, Fixed, 95% CI)	1.03 [0.95, 1.12]
1.9.1 Indacaterol/glycopyrronium	5	6204	Odds Ratio (M‐H, Fixed, 95% CI)	0.88 [0.75, 1.03]
1.9.2 Umeclidinium/vilanterol	4	8323	Odds Ratio (M‐H, Fixed, 95% CI)	1.13 [0.99, 1.27]
1.9.3 Other LAMA/LABA inhalers	9	8631	Odds Ratio (M‐H, Fixed, 95% CI)	1.05 [0.92, 1.20]
1.10 SGRQ mean change (fixed‐effect sensitivity)	9	14437	Mean Difference (IV, Fixed, 95% CI)	‐0.00 [‐0.02, 0.02]
1.10.1 Indacaterol/glycopyrronium	2	3693	Mean Difference (IV, Fixed, 95% CI)	‐1.29 [‐2.08, ‐0.50]
1.10.2 Umeclidinium/vilanterol	4	6615	Mean Difference (IV, Fixed, 95% CI)	‐0.00 [‐0.02, 0.02]
1.10.3 Other LAMA/LABA inhalers	3	4129	Mean Difference (IV, Fixed, 95% CI)	‐0.23 [‐1.01, 0.54]
1.11 Trough FEV1 mean change (fixed‐effect sensitivity)	12	14681	Mean Difference (IV, Fixed, 95% CI)	0.06 [0.05, 0.07]
1.11.1 Indacaterol/glycopyrronium	4	5843	Mean Difference (IV, Fixed, 95% CI)	0.07 [0.05, 0.08]
1.11.2 Umeclidinium/vilanterol	4	6669	Mean Difference (IV, Fixed, 95% CI)	0.06 [0.05, 0.07]
1.11.3 Other LAMA/LABA inhalers	4	2169	Mean Difference (IV, Fixed, 95% CI)	0.06 [0.04, 0.07]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Beeh 2016.

Study characteristics
Methods	Design: randomised, double‐blind, cross‐over, double‐dummy, placebo‐controlled 4‐period 4‐arm trial Countries: 8 countries (mainly EU countries) Site: 29 centres Study duration: 6 weeks × 4 time periods Study start: October 2013 Run‐in period: unclear
Participants	Key inclusion criteria: %pred FEV1 30% to 80%, without recent exacerbation Numbers of randomised and consequent‐treatment completed cases: 229 and 202 Age: 63.6 (SD 7.6) years Male/female: 148/81 %pred FEV1: unclear
Interventions	LAMA/LABA: tiotropium/olodaterol (2.5/5 μg) or tiotropium/olodaterol (5/5 μg) LABA/ICS: salmeterol/fluticasone (50/250 μg) twice daily or salmeterol/fluticasone (50/500 μg) twice daily
Outcomes	Primary outcome: change from baseline FEV1 AUC (0‐12 h) after 6 weeks of treatment Tiotropium/olodaterol (2.5/5 μg): 0.295 (SE 0.014) Tiotropium/olodaterol (5/5 μg): 0.317 (SE 0.014) Salmeterol/fluticasone (50/250 μg): 0.192 (SE 0.015) Salmeterol/fluticasone (50/500 μg): 0.188 (SE 0.014)
Notes	Registration: NCT01969721 COI: sponsored by Boehringer Ingelheim
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study described as randomised but no details provided about methods of sequence generation
Allocation concealment (selection bias)	Unclear risk	Methods of allocation concealment not described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study was double‐blinded. Some participants and/or personnel may have inadvertently detected the randomised treatment (e.g. through side effects), but there was no evidence to suggest this was the case or that it introduced bias in the subjective or semi‐objective outcome results.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Study was double‐blinded. Detection bias was not suspected.
Incomplete outcome data (attrition bias) All outcomes	Low risk	202/229 participants completed the study. Considerable attrition bias was not suspected because attrition was < 20%. Attrition was 6.9% with T+O 2.5/5 > T+O 5/5 > F+S 250/50 > F+S 500/50, 17.4% with T+O 5/5 > F+S 500/50 > T+O 2.5/5 > F+S 250/50, 10.0% with F+S 250/50 > T+O 2.5/5 > F+S 500/50 > T+O 5/5, and 11.5% with F+S 500/50 > F+S 250/50 > T+O 5/5 > T+O 2.5/5 Note: this was a four‐arm cross‐over study. Each arm used four consecutive treatments. For example, participants in the first arm were treated by T+O 2.5/5, then treated by T+O 5/5, then treated by F+S 250/50, then F+S 500/50.
Selective reporting (reporting bias)	Low risk	Study was registered and the prespecified outcomes were appropriately described
Other bias	High risk	Study funding statement indicates that one or more authors were employees of the pharmaceutical sponsor (Boehringer Ingelheim) and were involved in the design, conduct and data analysis of the study.

Donohue 2015a.

Study characteristics
Methods	Design: randomised, double‐blind, parallel‐group, double‐dummy, placebo‐controlled trial Countries: 7 countries (USA and European countries) Site: 63 centres Study duration: 12 weeks Study start: March 2013 Run‐in period: 7 to 14 days
Participants	Key inclusion criteria: %pred FEV1 30% to 70%, mMRC ≥ 2, no recent exacerbation Numbers of randomised and completed cases: 707 and 634 Age: 62.8 (SD 9.0) years Male/female: 497/213 %pred FEV1: 49.4% (SD 10.9)
Interventions	LAMA/LABA: umeclidinium/vilanterol (62.5/25 μg) LABA/ICS: salmeterol/fluticasone (50/250 μg) twice daily
Outcomes	Primary endpoint: change from baseline in 24‐h weighted‐mean serial FEV1 on day 84 Umeclidinium/vilanterol (62.5/25 μg): 0.165 (SE 0.0130) Salmeterol/fluticasone (50/250 μg) twice daily: 0.091 (SE 0.0131)
Notes	Registration: NCT01817764, GSK‐DB2114930 COI: sponsored by GlaxoSmithKline
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Central randomisation schedule was generated using a validated computer system (RanAll, GSK)
Allocation concealment (selection bias)	Low risk	Centralised randomisation prevented foreknowledge of intervention assignments by both researchers and participants
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study was double‐blinded. Some participants and/or personnel may have inadvertently detected the randomised treatment (e.g. through side effects), but there was no evidence to suggest this was the case or that it introduced bias in the subjective or semi‐objective outcome results.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Study was double‐blinded. Detection bias was not suspected.
Incomplete outcome data (attrition bias) All outcomes	Low risk	634/707 participants completed the study. Considerable attrition bias was not suspected because attrition was < 20%. Attrition was 9.6% in umeclidinium/vilanterol arm and 10.8% in salmeterol/fluticasone arms.
Selective reporting (reporting bias)	Low risk	Study was registered and the prespecified outcomes were appropriately described.
Other bias	High risk	Study funding statement indicates that all but one of the study authors were employees of and held stock in the pharmaceutical sponsor (GlaxoSmithKline) and were involved in the design, conduct and data analysis of the study.

Donohue 2015b.

Study characteristics
Methods	Design: randomised, double‐blind, parallel‐group, double‐dummy, placebo‐controlled trial Countries: 7 countries (USA, European countries, and Russia) Site: 71 centres Study duration: 12 weeks Study start: June 2013 Run‐in period: 7 to 14 days
Participants	Key inclusion criteria: %pred FEV1 30% to 70%, mMRC ≥ 2, no recent exacerbation Numbers of randomised and completed cases: 700 and 638 Age: 63.6 (SD 8.9) years Male/female: 528/169 %pred FEV1: 49.5% (SD 10.9)
Interventions	LAMA/LABA: umeclidinium/vilanterol (62.5/25 μg) LABA/ICS: salmeterol/fluticasone (50/250 μg) twice daily
Outcomes	Primary endpoint: change from baseline in 24‐h weighted‐mean serial FEV1 on treatment day 84 Umeclidinium/vilanterol (62.5/25 μg): 0.213 (SE 0.0137) Salmeterol/fluticasone (50/250 μg) twice daily: 0.112 (SE 0.0139)
Notes	Registration: NCT01879410, GSK‐DB2114951 COI: sponsored by GlaxoSmithKline
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Central randomisation schedule was generated using a validated computer system (RanAll, GSK)
Allocation concealment (selection bias)	Low risk	Centralised randomisation prevented foreknowledge of intervention assignments by both researchers and participants.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study was double‐blinded. Some participants and/or personnel may have inadvertently detected the randomised treatment (e.g. through side effects), but there was no evidence to suggest this was the case or that it introduced bias in the subjective or semi‐objective outcome results.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Study was double‐blinded. Detection bias was not suspected.
Incomplete outcome data (attrition bias) All outcomes	Low risk	638/700 participants completed the study. Considerable attrition bias was not suspected because attrition was < 20%. Attrition was 6.9% in umeclidinium/vilanterol arm and 10.9% in salmeterol/fluticasone arm.
Selective reporting (reporting bias)	Low risk	Study was registered and the prespecified outcomes were appropriately described.
Other bias	High risk	Study funding statement indicates that all but one of the study authors were employees of and held stock in the pharmaceutical sponsor (GlaxoSmithKline) and were involved in the design, conduct and data analysis of the study.

Ferguson 2018.

Study characteristics
Methods	Design: randomised, double‐blind, parallel‐group, double‐dummy, placebo‐controlled trial Countries: 4 countries (Canada, China, Japan, USA) Site: 215 centres Study duration: 24 weeks Study start: August 2015 Run‐in period: unclear
Participants	Key inclusion criteria: CAT ≥ 10, %pred FEV1 25% to 80%, not required to have exacerbation Numbers of randomised and consequent‐treatment completed cases: 943 and 790 Age: 65.1 (SD 7.4) years Male/female: 654/285 %pred FEV1: unclear
Interventions	LAMA/LABA: glycopyrronium/formoterol fumarate (18/9.6 μg) once daily LABA/ICS: formoterol fumarate/budesonide (4.8/160 μg) twice daily
Outcomes	Primary outcome: change from baseline in morning pre‐dose FEV1 over 24 weeks LAMA/LABA: glycopyrronium/formoterol fumarate (18/9.6 μg): 125 mL (SD 6.6) LABA/ICS: formoterol fumarate/budesonide (9.6/320 μg): 601 mL (SD 9.2)
Notes	Registration: NCT02497001 COI: sponsored by AstraZeneca Notes: two of the references identified as relating to Ferguson 2018 (JPRN‐JapicCTI‐184080 and NCT03262012) are registry records for a 28‐week extension in the subset of participants recruited from Japanese centres (22% of total). We did not include extension data within the review because this would have caused double counting within the analysis.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study described as randomised but no details provided about methods of sequence generation
Allocation concealment (selection bias)	High risk	Methods of allocation concealment not described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study was double‐blinded. Some participants and/or personnel may have inadvertently detected the randomised treatment (e.g. through side effects), but there was no evidence to suggest this was the case or that it introduced bias in the subjective or semi‐objective outcome results.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Study was double‐blinded. Detection bias was not suspected.
Incomplete outcome data (attrition bias) All outcomes	Low risk	790/943 participants completed the study. Considerable attrition bias was not suspected because attrition was < 20%. Attrition was 16.5% in glycopyrronium + formoterol fumarate arm and 15.9% in budesonide + formoterol fumarate arm.
Selective reporting (reporting bias)	Low risk	Study was registered and the prespecified outcomes were appropriately described.
Other bias	High risk	Seven study authors who were involved in design, data management and interpretation were employees of AstraZeneca or its subsidiaries.

Frith 2018.

Study characteristics
Methods	Design: randomised, double‐blind, double‐dummy, active control, parallel group study Countries: 11 countries (mainly EU countries) Site: 60 centres Study duration: 12 weeks Study start: October 2015 Run‐in period: unclear
Participants	Key inclusion criteria: CAT ≥ 10, %pred FEV1 30% to 80%, moderate to severe COPD and up to one exacerbation in the previous year Numbers of randomised and consequent‐treatment completed cases: 502 and 473 Age: 65.1 (SD 8.8) years Male/female: 444/54 %pred FEV1: 51.5 (SD 12.7)
Interventions	LAMA/LABA: glycopyrronium/indacaterol (50/110 μg) once daily  LABA/ICS: salmeterol/fluticasone (50/500 μg) twice daily
Outcomes	Primary outcome: pre‐dose trough FEV1 at week 12 Mean difference: 0.045 L (95% CI 0.005 to 0.084) (P = 0.028)
Notes	Registration: NCT02516592 COI: sponsored by Novartis Pharmaceuticals
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	All eligible participants were randomised via interactive response technology.
Allocation concealment (selection bias)	Low risk	All eligible participants were randomised via interactive response technology.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study was double‐blinded. Some participants and/or personnel may have inadvertently detected the randomised treatment (e.g. through side effects), but there was no evidence to suggest this was the case or that it introduced bias in the subjective or semi‐objective outcome results.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Study was double‐blinded. Detection bias was not suspected.
Incomplete outcome data (attrition bias) All outcomes	Low risk	473/502 participants completed the study. Considerable attrition bias was not suspected because attrition was < 20%. Attrition was 6.4% in glycopyrronium/indacaterol arm and 5.2% in salmeterol/fluticasone arm.
Selective reporting (reporting bias)	Low risk	Study was registered and the prespecified outcomes were appropriately described.
Other bias	High risk	Most or all authors received fees from the sponsor, Novartis Pharmaceuticals, during the conduct of the study.

Herth 2020.

Study characteristics
Methods	Design: randomised, double‐blind, cross‐over, double‐dummy trial Country: Germany Site: 10 centres Study duration: 6 weeks Study start: unclear Run‐in period: unclear
Participants	Key inclusion criteria: %pred FEV1 < 70%, without recent exacerbation Numbers of randomised and consequent‐treatment completed cases: 76 and 67 Age: 61.9 (SD 7.1) years Male/female: 45/31 %pred FEV1: 52.9 (SD12.1)
Interventions	LAMA/LABA: tiotropium/olodaterol (5/5 μg) once daily LABA/ICS: salmeterol/fluticasone propionate (50/500 μg) twice daily
Outcomes	Primary outcome: change from baseline in left ventricular end‐diastolic volume index after 6 weeks of treatment Mean difference: ‐0.537 mL/m2 (95% CI ‐2.779 to 1.705) (P = 0.6331)
Notes	Registration: NCT03055988 COI: sponsored by Boehringer Ingelheim
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study described as randomised but no details provided about methods of sequence generation
Allocation concealment (selection bias)	High risk	Methods of allocation concealment not described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study was double‐blinded. Some participants and/or personnel may have inadvertently detected the randomised treatment (e.g. through side effects), but there was no evidence to suggest this was the case or that it introduced bias in the subjective or semi‐objective outcome results.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Study was double‐blinded. Detection bias was not suspected.
Incomplete outcome data (attrition bias) All outcomes	Low risk	67/76 participants completed the study. Considerable attrition bias was not suspected because attrition was < 20%.
Selective reporting (reporting bias)	Low risk	Study was registered and the prespecified outcomes were appropriately described.
Other bias	High risk	Study funding statement indicates that one or more authors were employees of the pharmaceutical sponsor (Boehringer Ingelheim) and were involved in the design, conduct, and data analysis of the study.

Hoshino 2015.

Study characteristics
Methods	Design: randomised, parallel‐group, open‐label trial Countries: 1 country (Japan) Site: 1 centre Study duration: 16 weeks Study start: unclear Run‐in period: 21 days
Participants	Key inclusion criteria: %pred FEV1 30% to 80%, without recent exacerbation Numbers of randomised and completed cases: 46 and 43 Age: LAMA/LABA, 72 years (SD 7); LABA/ICS, 69 years (SD 6) Male/female: 36/7 %pred FEV1: LAMA/LABA, 61.9% (SD 16.3%); LABA/ICS, 60.8% (SD 16.4%)
Interventions	LAMA/LABA: tiotropium/indacaterol (18/150 μg) LABA/ICS: salmeterol/fluticasone (50/250 μg) twice daily
Outcomes	Primary outcomes: effects on airway dimensions
Notes	Registration: none COI: none
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study described as randomised but no details provided about methods of sequence generation
Allocation concealment (selection bias)	Unclear risk	Methods of allocation concealment not described
Blinding of participants and personnel (performance bias) All outcomes	High risk	Study had an open‐label design. Knowledge of the randomised treatment could have affected participant or personnel behaviour that biased the results for subjective and semi‐objective outcomes.
Blinding of outcome assessment (detection bias) All outcomes	High risk	Study had an open‐label design. Knowledge of the randomised treatment could have affected outcome assessor judgement for the subjective and semi‐objective outcomes.
Incomplete outcome data (attrition bias) All outcomes	Low risk	43/46 participants completed the study. Considerable attrition bias was not suspected because attrition was < 20%. Attrition was 8.3% in tiotropium/indacaterol arm and 4.5% in salmeterol/fluticasone arm.
Selective reporting (reporting bias)	High risk	We could not rule out reporting bias because this trial was not registered.
Other bias	Low risk	We found no risk of other bias.

Lipson 2018.

Study characteristics
Methods	Design: randomised, double‐blind, parallel‐group trial Countries: 37 countries (mainly EU countries) Site: 29 centres Study duration: 52 weeks Study start: June 2014 Run‐in period: unclear
Participants	Key inclusion criteria: CAT ≥ 10, %pred FEV1 that was less than 50% and at least one moderate or severe exacerbation in the previous year.  %pred FEV1 50% to 80% and at least two moderate exacerbations or one severe exacerbation in the previous year. Numbers of randomised and consequent‐treatment completed cases: 6204 and 5373 Age: 65.3 (SD 8.3) years Male/female: 4104/2100 %pred FEV1: 45.5 (SD 14.7)
Interventions	LAMA/LABA: umeclidinium/vilanterol (62.5/25 μg) once daily LABA/ICS: vilanterol/fluticasone furoate (25/100 μg) once daily
Outcomes	Primary outcome: annual rate of moderate or severe exacerbations during treatment Umeclidinium/vilanterol: 1.21 Vilanterol/fluticasone furoate: 1.07
Notes	Registration: NCT02164513 COI: sponsored by GlaxoSmith Kline
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study described as randomised but no details provided about methods of sequence generation.
Allocation concealment (selection bias)	Unclear risk	Methods of allocation concealment not described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study was double‐blinded. Some participants and/or personnel may have inadvertently detected the randomised treatment (e.g. through side effects), but there was no evidence to suggest this was the case or that it introduced bias in the subjective or semi‐objective outcome results.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Study was double‐blinded. Detection bias was not suspected.
Incomplete outcome data (attrition bias) All outcomes	Low risk	5373/6204 participants completed the study. Considerable attrition bias was not suspected because attrition was < 20%. Attrition was 87.0% in umeclidinium/vilanterol  arm and 85.7% in vilanterol/fluticasone furoate arm.
Selective reporting (reporting bias)	Low risk	Study was registered and the prespecified outcomes were appropriately described.
Other bias	High risk	Authors declared a variety of conflicts of interest associated with the sponsor, GlaxoSmithKline, and employees were involved in the design and conduct of the study.

Magnussen 2012.

Study characteristics
Methods	Design: randomised, double‐blind, cross‐over, double‐dummy, placebo‐controlled trial Countries: 7 countries Site: 40 centres Study duration: 8 weeks Study start: September 2007 Run‐in period: 15 days
Participants	Key inclusion criteria: %pred FEV1 ≤ 65%, without recent exacerbation Numbers of randomised and completed cases: 344 and 300 Age: 61.0 years (SD 7.6) Male/female: 247/97 %pred FEV1: 47% (SD 12%)
Interventions	LAMA/LABA: tiotropium/salmeterol (18/50 μg) twice daily LABA/ICS: salmeterol/fluticasone (50/500 μg) twice daily
Outcomes	Co‐primary endpoint 1: post‐dose thoracic gas volume (functional residual capacity) (after 8 weeks) Mean difference ‐0.087 (SE 0.044). Co‐primary endpoint 2: endurance time (after 8 weeks) Mean difference 3.0 (95% CI ‐9.5 to 27.5)
Notes	Registration: NCT00530842 COI: sponsored by Boehringer Ingelheim and Pfizer
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Centralised randomisations of 4 blocks stratified according to sites.
Allocation concealment (selection bias)	Low risk	Centralised randomisations of 4 blocks stratified according to sites.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study was double‐blinded. Some participants and/or personnel may have inadvertently detected the randomised treatment (e.g. through side effects), but there was no evidence to suggest this was the case or that it introduced bias in the subjective or semi‐objective outcome results.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Study was double‐blinded. Detection bias was not suspected.
Incomplete outcome data (attrition bias) All outcomes	Low risk	300/344 participants completed the study. Considerable attrition bias was not suspected because attrition was < 20%. Attrition was 13.4% in tiotropium/salmeterol > salmeterol/fluticasone arm and 12.2% in salmeterol/fluticasone > tiotropium/salmeterol arm.
Selective reporting (reporting bias)	Low risk	Study was registered and the prespecified outcomes were appropriately described. We found no risk of reporting bias.
Other bias	High risk	Contributing authors included those employed by the sponsors, Boehringer Ingelheim and Pfizer, and those who received grants, honoraria, and consultancy fees from the study sponsors.

Mostafa 2021.

Study characteristics
Methods	Design: randomised, double‐blind, prospective parallel study Countries: 1 country (Egypt) Site: 1 centre Study duration: 12 weeks Study start: November 2016 Run‐in period: unclear
Participants	Key inclusion criteria: %pred FEV1 30% to 80%, without recent exacerbation Numbers of randomised and consequent‐treatment completed cases: 40 and 30 Age: 64.2 (SD 9.2) years Male/female: 21/9 %pred FEV1: 60.9 (SD 15.1)
Interventions	LAMA/LABA: tiotropium (18 μg) once daily + formoterol (9 μg) twice daily LABA/ICS: formoterol/budesonide (160/4.5 μg) twice daily
Outcomes	Primary outcome: changes that occurred in FEV1 as a percent of predicted after 12‐week treatment Tiotropium/formoterol: 77.61 (SD 21.34) mL Formoterol/budesonide: 73.83 (SD 15.97) mL
Notes	Registration: NCT04520230
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study described as randomised but no details provided about methods of sequence generation
Allocation concealment (selection bias)	Low risk	The independent researcher kept the original random allocation sequences in an inaccessible place.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study was double‐blinded. Some participants and/or personnel may have inadvertently detected the randomised treatment (e.g. through side effects), but there was no evidence to suggest this was the case or that it introduced bias in the subjective or semi‐objective outcome results.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Study was double‐blinded. Detection bias was not suspected.
Incomplete outcome data (attrition bias) All outcomes	High risk	30/40 participants completed the study. Considerable attrition bias was suspected because attrition was > 20%.
Selective reporting (reporting bias)	High risk	There was no protocol.
Other bias	Low risk	No conflicts of interest or other sources of bias identified

NCT03240575.

Study characteristics
Methods	Design: randomised, double‐blind, parallel‐group, double‐dummy trial Countries: 1 country (USA) Site: 45 centres Study duration: 12 weeks Study start: August 2017 Run‐in period: 4 weeks during which LABAs, LAMAs and ICSs were withdrawn prior to randomisation
Participants	Key inclusion criteria: outpatients of either sex; aged ≥ 40 years with a diagnosis of COPD; smoking history > 10 pack years; post‐bronchodilator 30% ≤ FEV1 predicted < 80%; postbronchodilator FEV1/FVC < 70%. Numbers of randomised and completed cases: 302 randomised; 291 in treated set (all who received at least one dose); 275 completed Age: LAMA/LABA 63.95 years (SD 8.32); LABA/ICS 64.74 years (SD 7.33) Male/female: LAMA/LABA 74/72; LABA/ICS 83/62 (54.0% male) %pred FEV1: not reported
Interventions	LAMA/LABA: tiotropium/olodaterol (5 μg/5 μg) once daily LABA/ICS: fluticasone Propionate/salmeterol (250 μg/50 μg) twice daily
Outcomes	Primary endpoint: FEV1 area under the curve from 0 to 24 hours (not relevant to review). Reports trough FEV1 change from baseline to 12 weeks, all‐cause mortality and serious adverse events (included pneumonia)
Notes	Registration: NCT03240575; ENERGITO2 trial COI: sponsored by Boehringer Ingelheim
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Boehringer Ingelheim will generate the randomization scheme using validated randomization software, and prepare and code the medication in a blinded fashion"
Allocation concealment (selection bias)	Low risk	"An interactive response technology (IRT) system will be used for randomisation to treatment in this trial and for allocation of medication to patients throughout the treatment period."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"Patients, investigators and everyone involved in analyzing or with an interest in this double‐blind study will remain blinded with regard to the randomized treatment assignments until after database lock." "Boehringer Ingelheim will...prepare and code the medication in a blinded fashion"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Patients, investigators and everyone involved in analyzing or with an interest in this double‐blind study will remain blinded with regard to the randomized treatment assignments until after database lock." "Boehringer Ingelheim will...prepare and code the medication in a blinded fashion"
Incomplete outcome data (attrition bias) All outcomes	Low risk	302 enrolled; 291 in treated set (at least one dose), 146 in the LAMA/LABA group and 145 in the LABA/ICS group. 2 participants in the LAMA/LABA group did not complete the study (1.4%) compared with 14 in the LABA/ICS group (9.7%), primarily due to participant withdrawal (n = 11). Analyses were conducted on the full analysis set, i.e. everyone who had baseline and at least one post‐baseline measurement for at least one efficacy parameter. The mixed‐effects repeated measurement (MMRM) model defined the participants who contributed to the model.  The numbers and reasons for participant dropout varies between groups but is low and an appropriate method for imputing data for missing measurements was used and is unlikely to introduce bias.
Selective reporting (reporting bias)	Low risk	Outcomes in line with statistical analysis plan and protocol available on clinicaltrials.gov
Other bias	High risk	The trial sponsor was responsible for coordinating the trial, directing clinical trial personnel in conduct and reporting, training, monitoring, data management and statistical evaluation.

Rabe 2008.

Study characteristics
Methods	Design: randomised, double‐blind, parallel‐group, double‐dummy, placebo‐controlled trial Countries: 8 countries, mainly EU Site: multicentre Study duration: 6 weeks Study start: November 2003 Run‐in period: 2 to 4 weeks
Participants	Key inclusion criteria: %pred FEV1 ≤ 65% without recent exacerbation Numbers of randomised and completed cases: 605 and unclear Age: 62 years (SD 9) Male/female: 414/191 %pred FEV1: 55% (SD 13%)
Interventions	LAMA/LABA: tiotropium/formoterol (18 μg/24 μg) twice daily LABA/ICS: salmeterol/fluticasone propionate (50 μg/500 μg) twice daily
Outcomes	Co‐primary endpoint 1: FEV1 AUC (0 to 12 h) after 6 weeks of treatment Mean difference 78 mL (95% CI 34 to 122) higher in tiotropium/formoterol arm Co‐primary endpoint 2: peak FEV1 measured after 6 weeks of treatment Mean difference 103 mL (95% CI 55 to 150) higher in tiotropium/formoterol arm
Notes	Registration: NCT00239421 COI: sponsored by Boehringer and Pfizer
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study described as randomised but no details provided about methods of sequence generation
Allocation concealment (selection bias)	Unclear risk	Methods of allocation concealment not described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study was double‐blinded. Some participants and/or personnel may have inadvertently detected the randomised treatment (e.g. through side effects), but there was no evidence to suggest this was the case or that it introduced bias in the subjective or semi‐objective outcome results.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Study was double‐blinded. Detection bias was not suspected.
Incomplete outcome data (attrition bias) All outcomes	Low risk	592/605 participants completed the study. Considerable attrition bias was not suspected because attrition was < 20%. Attrition was 2.3% in tiotropium/formoterol arms and 2.0% in salmeterol/fluticasone propionate arms.
Selective reporting (reporting bias)	Low risk	Study was registered and the prespecified outcomes were appropriately described. We found no risk of reporting bias.
Other bias	High risk	Contributing authors included those employed by the sponsors, Boehringer Ingelheim and Pfizer, and those who received grants, honoraria or consultancy fees from the study sponsors.

Rabe 2020.

Study characteristics
Methods	Design: randomised, double‐blind, parallel‐group trial Countries: 26 countries Study duration: 52 weeks Study start: June 2015  Run‐in period: unclear
Participants	Key inclusion criteria: %pred FEV1 25% to 65%, CAT ≥ 10, at least one moderate or severe exacerbation in the year (%pred FEV1 < 50%), at least two moderate or at least one severe exacerbation in the year (%pred FEV1 ≥ 50%) Numbers of randomised and completed cases: 4294 and 3225 Age: 64.7 years (SD 7.6) Male/female: 2523/1728 %pred FEV1: 43.4 (SD 10.3)
Interventions	LAMA/LABA: glycopyrronium/formoterol (9/4.8 µg) twice daily LABA/ICS: formoterol/budesonide (4.8/160 µg) twice daily
Outcomes	Primary outcome: annual rate of moderate or severe COPD exacerbation Glycopyrronium/formoterol (9/4.8 µg): 1.42 Formoterol/budesonide (4.8/160 µg): 1.24
Notes	Registration: NCT02465567 COI: sponsored by AstraZeneca
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study described as randomised but no details provided about methods of sequence generation.
Allocation concealment (selection bias)	Unclear risk	Methods of allocation concealment not described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study was double‐blinded. Some participants and/or personnel may have inadvertently detected the randomised treatment (e.g. through side effects), but there was no evidence to suggest this was the case or that it introduced bias in the subjective or semi‐objective outcome results.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Study was double‐blinded. Detection bias was not suspected.
Incomplete outcome data (attrition bias) All outcomes	High risk	3225/4294 participants completed the study. Considerable attrition bias was suspected because attrition was > 20%. Attrition was 26.2% in glycopyrronium/formoterol arm and 23.6% in formoterol/budesonide arm.
Selective reporting (reporting bias)	Low risk	Study was registered and the prespecified outcomes were appropriately described.
Other bias	High risk	Conflict of interest statements available on the New England Journal of Medicine website indicate most contributing authors were either employees of the sponsor, AstraZeneca, or received fees from the company outside the submitted work.

Singh 2015.

Study characteristics
Methods	Design: randomised, double‐blind, parallel‐group, double‐dummy, placebo‐controlled trial Countries: 8 countries (mainly EU) Site: 79 centres Study duration: 12 weeks Study start: April 2013 Run‐in period: 7 to 14 days
Participants	Key inclusion criteria: %pred FEV1 30% to 70%, mMRC ≥ 2, without recent exacerbation Numbers of randomised and completed cases: 717 and 674 Age: 61.6 years (SD 8.0) Male/female: 515/201 %pred FEV1: 50.6% (SD 10.7%)
Interventions	LAMA/LABA: umeclidinium/vilanterol (62.5/25 μg) LABA/ICS: salmeterol/fluticasone (50/500 μg) twice daily
Outcomes	Primary outcome: change from baseline in 0 to 24 h weighted mean serial FEV1 at day 84 Mean difference 0.080 L (95% CI 0.046 to 0.113) (P < 0.001)
Notes	Registration: NCT01822899, GSK‐DB2116134 COI: sponsored by GlaxoSmithKline
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Validated computer system (RandAll) was used to generate central randomisation
Allocation concealment (selection bias)	Low risk	Validated computer system (RandAll) was used to generate central randomisation
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study was double‐blinded. Some participants and/or personnel may have inadvertently detected the randomised treatment (e.g. through side effects), but there was no evidence to suggest this was the case or that it introduced bias in the subjective or semi‐objective outcome results.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Study was double‐blinded. Detection bias was not suspected.
Incomplete outcome data (attrition bias) All outcomes	Low risk	674/717 participants completed the study. Considerable attrition bias was not suspected because attrition was < 20%. Attrition was 6.7% in umeclidinium/vilanterol arm and 5.0% in salmeterol/fluticasone arm.
Selective reporting (reporting bias)	Low risk	Study was registered and the prespecified outcomes were appropriately described. We found no risk of reporting bias.
Other bias	High risk	All but one author were employees and shareholders of the sponsor, GlaxoSmithKline, and the lead author received grants and personal payments from GSK.

Vogelmeier 2013.

Study characteristics
Methods	Design: randomised, double‐blind, parallel‐group, double‐dummy, placebo‐controlled trial Countries: 10 countries (mainly EU) Site: 92 centres Study duration: 26 weeks Study start: March 2011 Run‐in period: 14 days
Participants	Key inclusion criteria: post‐bronchodilator 30% ≤ FEV1 predicted < 80%, without recent exacerbation Numbers of randomised and completed cases: 523 and 432 Age: LAMA/LABA, 63.2 years (SD 8.2); LABA/ICS, 63.4 years (SD 7.7) Male/female: LAMA/LABA, 181/77; LABA/ICS, 189/75 %pred FEV1: LAMA/LABA, 60.5% (SD 10.5%); LABA/ICS, 60.0% (SD 10.7%)
Interventions	LAMA/LABA: indacaterol/glycopyrronium (110/50 μg) LABA/ICS: salmeterol/fluticasone (50/500 μg) twice daily
Outcomes	Primary outcome: FEV1 AUC (0 to 12 h) LAMA/LABA: 1.69 (SE 0.027) LABA/ICS: 1.56 (SE 0.026)
Notes	Registration: NCT01315249 COI: sponsored by Novartis Study name: ILLUMINATE
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Investigators used an automated, interactive response technology to assign randomisation numbers to participants.
Allocation concealment (selection bias)	Low risk	Investigators used an automated, interactive response technology to assign randomisation numbers to participants.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study was double‐blinded. Some participants and/or personnel may have inadvertently detected the randomised treatment (e.g. through side effects), but there was no evidence to suggest this was the case or that it introduced bias in the subjective or semi‐objective outcome results.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Study was double‐blinded. Detection bias was not suspected.
Incomplete outcome data (attrition bias) All outcomes	Low risk	432/523 participants completed the study. Considerable attrition bias was not suspected because attrition was < 20%. Attrition was 17.0% in indacaterol/glycopyrronium arm and 17.0% in salmeterol/fluticasone arms.
Selective reporting (reporting bias)	Low risk	Study was registered and the prespecified outcomes were appropriately described.
Other bias	High risk	Five of the seven listed authors are employees of the sponsor, Novartis.

Vogelmeier 2016.

Study characteristics
Methods	Design: randomised, double‐blind, parallel‐group, double‐dummy, placebo‐controlled trial Countries: 14 countries (mainly EU) Site: 126 centres Study duration: 24 weeks Study start: September 2013 Run‐in period: unclear
Participants	Key inclusion criteria: %pred FEV1 < 80%, CAT ≥ 10, without recent exacerbation Numbers of randomised and completed cases: 933 and 788 Age: 63.4 years (SD 7.8) Male/female: 607/326
Interventions	LAMA/LABA: aclidinium/formoterol (400/12 μg) twice daily LABA/ICS: salmeterol/fluticasone (50/500 μg) twice daily
Outcomes	Primary outcome: peak FEV1 at week 24 LAMA/LABA: 1.655 (SE 0.011) LABA/ICS: 1.562 (SE 0.011)
Notes	Registration: NCT01908140, EudraCT 2013‐000116‐14 COI: sponsored by AstraZeneca
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study described as randomised but no details provided about methods of sequence generation
Allocation concealment (selection bias)	Unclear risk	Methods of allocation concealment not described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study was double‐blinded. Some participants and/or personnel may have inadvertently detected the randomised treatment (e.g. through side effects), but there was no evidence to suggest this was the case or that it introduced bias in the subjective or semi‐objective outcome results.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Study was double‐blinded. Detection bias was not suspected.
Incomplete outcome data (attrition bias) All outcomes	Low risk	788/933 participants completed the study. Considerable attrition bias was not suspected because attrition was < 20%. Attrition was 14.1% in aclidinium/formoterol arm and 17.0% in salmeterol/fluticasone arm.
Selective reporting (reporting bias)	Low risk	Study was registered and the prespecified outcomes were appropriately described. We found no risk of reporting bias.
Other bias	High risk	Author disclosure statements could not be viewed on the publisher's website, but affiliations show that three authors involved in the design, conduct, or interpretation of the study were employed by the sponsors, Almirall or AstraZeneca. Writing support was provided by an AstraZeneca‐funded company.

Vogelmeier 2017.

Study characteristics
Methods	Design: randomised, open‐label, pragmatic study Countries: 23 countries (mainly Europe) Sites: 560 Study duration: 12 weeks Study start: June 2014  Run‐in period: April 2016
Participants	Key inclusion criteria: %pred FEV1 50% to 80%, mMRC ≥ 1, without ≥ 2 exacerbation in the previous 12 months Numbers of randomised and completed cases: 1083 and 899 Age: 64.6 years (SD 8.85) Male/female: 692/388 %pred FEV1: 63.6% (SD 8.40%)
Interventions	LAMA/LABA: glycopyrronium/indacaterol (50/110 μg) LABA/ICS: any
Outcomes	Primary endpoints: trough FEV1 Mean difference: 71 mL (95% CI 36 to 107) higher in glycopyrronium/indacaterol arm
Notes	COI: sponsored by Novartis Pharmaceuticals Study name: CRYSTAL
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study described as randomised but no details provided about methods of sequence generation
Allocation concealment (selection bias)	Unclear risk	Methods of allocation concealment not described
Blinding of participants and personnel (performance bias) All outcomes	High risk	Study was open‐label. Knowledge of the randomised treatment could have affected participant or personnel behaviour that biased the results for subjective and semi‐objective outcomes.
Blinding of outcome assessment (detection bias) All outcomes	High risk	Study was open‐label. Knowledge of the randomised treatment could have affected outcome assessor judgement for the subjective and semi‐objective outcomes.
Incomplete outcome data (attrition bias) All outcomes	Low risk	899/1083 participants completed the study. Considerable attrition bias was not suspected because attrition was < 20%. Attrition was 18.3% in glycopyrronium/indacaterol arm and 13.0% in LABA/ICS arm.
Selective reporting (reporting bias)	Low risk	Study was registered and the prespecified outcomes were appropriately described. We found no risk of reporting bias.
Other bias	High risk	Most authors were either employed by the sponsor, Novartis Pharmaceuticals, held shares, or received fees for the design and conduct of the study (but not for development of the manuscript).

Wedzicha 2016.

Study characteristics
Methods	Design: randomised, double‐blind, parallel‐group, double‐dummy, placebo‐controlled trial Countries: 43 countries Site: 496 centres Study duration: 52 weeks Study start: July 2013 Run‐in period: 4 weeks
Participants	Key inclusion criteria: %pred FEV1 25% to 60%, mMRC ≥ 2, with recent exacerbation Numbers of randomised and completed cases: 3362 and 2760 Age: 64.6 years (SD 7.8) Male/female: 2557/805 %pred FEV1: 44.1% (SD 9.5%)
Interventions	LAMA/LABA: indacaterol/glycopyrronium (110/50 μg) LABA/ICS: salmeterol/fluticasone (50/500 μg) twice daily
Outcomes	Primary outcome: rate of COPD exacerbations per year LAMA/LABA: 3.59 (95% CI 3.28 to 3.94) LABA/ICS: 4.03 (95% CI 3.68 to 4.41)
Notes	Registration: NCT01782326 COI: sponsored by Novartis Study name: FLAME
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomised via interactive response technology to 1 of the treatment arms.
Allocation concealment (selection bias)	Low risk	Participants were randomised via interactive response technology to 1 of the treatment arms.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study was double‐blinded. Some participants and/or personnel may have inadvertently detected the randomised treatment (e.g. through side effects), but there was no evidence to suggest this was the case or that it introduced bias in the subjective or semi‐objective outcome results.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Study was double‐blinded. Detection bias was not suspected.
Incomplete outcome data (attrition bias) All outcomes	Low risk	2760/3362 participants completed the study. Considerable attrition bias was not suspected because attrition was < 20%. Attrition was 16.6% in indacaterol/glycopyrronium arm and 19.0% in salmeterol/fluticasone arm.
Selective reporting (reporting bias)	Low risk	Study was registered and the prespecified outcomes were appropriately described.
Other bias	High risk	Author disclosure statements available on the New England Journal of Medicine website indicate that several authors involved in design, conduct, and interpretation were employees and shareholders of the sponsor, Novartis, and others received personal fees or grants from the sponsor.

Zhong 2015.

Study characteristics
Methods	Design: randomised, double‐blind, parallel‐group, double‐dummy, placebo‐controlled trial Countries: 4 countries (recruited mainly in China) Site: 56 centres Study duration: 26 weeks Study start: November 2012 Run‐in period: 14 days
Participants	Key inclusion criteria: post‐bronchodilator 30% ≤ FEV1 predicted < 80%, mMRC ≥ 2, without recent exacerbation Numbers of randomised and completed cases: 744 and 676 Age: LAMA/LABA 64.8 years (SD 7.8); LABA/ICS 65.3 years (SD 7.9) Male/female: 672/69 %pred FEV1: LAMA/LABA 51.6% (SD 12.8%), LABA/ICS 52.0% (SD 12.9%)
Interventions	LAMA/LABA: indacaterol/glycopyrronium (110/50 μg) LABA/ICS: salmeterol/fluticasone (50/500 μg) twice daily
Outcomes	Primary outcome: trough FEV1 following 26 weeks of treatment to demonstrate the non‐inferiority of indacaterol/glycopyrronium to salmeterol/fluticasone LAMA/LABA: 1.248 L (SE 0.0173) LABA/ICS: 1.176 L (SE 0.0172)
Notes	Registration: NCT01709903 COI: sponsored by Novartis Study name: LANTERN
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomised via interactive response technology to 1 of the treatment arms.
Allocation concealment (selection bias)	Low risk	Participants were randomised via interactive response technology to 1 of the treatment arms.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study was double‐blinded. Some participants and/or personnel may have inadvertently detected the randomised treatment (e.g. through side effects), but there was no evidence to suggest this was the case or that it introduced bias in the subjective or semi‐objective outcome results.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Study was double‐blinded. Detection bias was not suspected.
Incomplete outcome data (attrition bias) All outcomes	Low risk	676/744 participants completed the study. Considerable attrition bias was not suspected because attrition was < 20%. Attrition was 7.8% in indacaterol/glycopyrronium arm and 10.4% in salmeterol/fluticasone arm.
Selective reporting (reporting bias)	Low risk	Study was registered and the prespecified outcomes were appropriately described.
Other bias	High risk	Five of the nine listed authors, who were involved in the design, conduct, and interpretation of the study, were employees of the sponsor, Novartis.

%pred FEV₁: % predicted forced expiratory volume in one second; AUC: area under the curve; CAT: chronic obstructive pulmonary disease assessment test; CI: confidence interval; COI: conflicts of interest; COPD: chronic obstructive pulmonary disease; FEV₁: forced expiratory volume in one second; FVC: forced vital capacity; h: hour; ICS: inhaled corticosteroid; LABA: long‐acting beta‐agonist; LAMA: long‐acting muscarinic antagonist; mMRC: modified Medical Research Council dyspnoea scale; SD: standard deviation; SE: standard error

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Anzueto 2017	Not an RCT
Aziz 2018	Systematic review
Bruhn 2003	Not comparing LAMA+LABA versus LABA+ICS
Calverley 2007	Not comparing LAMA+LABA versus LABA+ICS
EUCTR2015‐002046‐31‐ES	Results only reported for those with asthma‐COPD overlap syndrome
Knobil 2004a	Not comparing LAMA+LABA versus LABA+ICS
Knobil 2004b	Not comparing LAMA+LABA versus LABA+ICS
Mahler 2016	Not an RCT
Michael 2016	Commentary on included study (Wedzicha 2016)
NCT00120978	Not comparing LAMA+LABA versus LABA+ICS
NCT03376295	Not an RCT ‐ observational study
NCT03504527	Not comparing LAMA+LABA versus LABA+ICS
NCT04138758	Not an RCT ‐ retrospective study
NCT04320342	Not comparing LAMA+LABA versus LABA+ICS
NCT04923347	Not comparing LAMA+LABA versus LABA+ICS
NCT05097014	Not comparing LAMA+LABA versus LABA+ICS
Oba 2016	Systematic review
Papi 2018	Not comparing LAMA+LABA versus LABA+ICS
Pavord 2016	Systematic review
Price 2014	Cost‐effectiveness analysis using previously published data
Sciurba 2004	Not comparing LAMA+LABA versus LABA+ICS
Singh 2019	Letter
Skoupa 2018	Cost‐effectiveness analysis
UMIN000024905	Only participants with eosinophilic inflammation

COPD: chronic obstructive pulmonary disease; ICS: inhaled corticosteroids; LABA: long‐acting beta‐agonist; LAMA: long‐acting muscarinic antagonist; RCT: randomised controlled trial

Characteristics of ongoing studies [ordered by study ID]

EUCTR2016‐004473‐41‐GB.

Study name	INCOGNITO
Methods	Design: randomised, open‐label, parallel group trial Countries: United Kingdom Study duration: 6 months
Participants	Key inclusion criteria: %pred FEV1 < 80%, without recent exacerbation
Interventions	LAMA/LABA: tiotropium/olodaterol (5/5 μg) once daily LABA/ICS: vilanterol/fluticasone furoate (22/92 μg) once daily
Outcomes	Primary end point: bacterial load of total respiratory pathogens determined by quantitative polymerase chain reaction
Starting date	Study start: March 2017
Contact information	Chalmers 01382 383642
Notes	Registration: EUCTR2016‐004473‐41‐GB COI: sponsored by Boehringer Ingelheim

%pred FEV₁: % predicted forced expiratory volume in one second; CAT: chronic obstructive pulmonary disease assessment test; COI: conflicts of interest; COPD: chronic obstructive pulmonary disease; FEV₁: forced expiratory volume in one second; ICS: inhaled corticosteroid; LABA: long‐acting beta‐agonist; LAMA: long‐acting muscarinic antagonist

Differences between protocol and review

The original protocol prespecified that we would assess risk of bias separately for different outcomes where necessary, but did not specify how this would be accomplished. Therefore, we expanded the methods in this version by introducing a system to classify outcomes as subjective and objective to consider different risks of performance and selection bias for different blinding methods. All‐cause death is the only outcome of interest to this review that may be considered truly objective and the SGRQ is the only subjective, self‐reported measure. The other outcomes might be considered semi‐objective (exacerbations, serious adverse events, FEV₁, and pneumonia) because they involve a degree of patient reporting, behaviour, or clinician judgement that could introduce bias.

We did not prespecify specific domains or percentages for GRADE assessments of risk of bias, but considered it reasonable to downgrade if studies contributing more than half the analysis weight were at high risk of bias in the 'other bias' domain and at least one other. For inconsistency, we downgraded if I² was greater than 50%, and for imprecision, we based downgrade decisions on prespecified thresholds (clinical importance 0.7 to 1.5 for outcomes as odds ratios) or established MCIDs (4 points for SGRQ).

Contributions of authors

NF contributed to the conception of the work, data acquisition, data analysis, interpretation, drafting, and critical revision.

NH contributed to the conception of the work, data acquisition, data analysis, interpretation, and critical revision.

AK and AG performed interpretation and critical revision.

TK contributed to the conception of the work, interpretation, and critical revision.

EO contributed to data analysis, interpretation, and critical revision.

KK performed critical revision.

All review authors provided final approval and took accountability.

Contributions of editorial team

Sally Spencer (Co‐ordinating Editor) edited the review; advised on methodology, interpretation and content; approved the review prior to publication.

Ian Yang (Contact Editor): edited the review; advised on methodology, interpretation and content.

Emma Dennett (Deputy Co‐ordinating Editor): checked the data entry; advised on methodology, interpretation and content; edited the review.

Cathryn Broderick (Editor): undertook the MECIR check for the Airways Group.

Emma Jackson (Managing Editor): co‐ordinated the editorial process; conducted peer review; edited the review and reference sections of the review. 

Elizabeth Stovold (Information Specialist): designed the search strategy; ran the searches. 

Vittoria Lutje (Freelance Information Specialist): ran the updated search.

Sources of support

Internal sources

• N/A, Other

  The authors declare that no internal funding was received for this systematic review.

External sources

• Cochrane Airways, UK

  This project was supported by the National Institute for Health Research (NIHR), via Cochrane Infrastructure funding to the Cochrane Airways Group.

Declarations of interest

NF: none known.
NH: personally received a lecture fee from AstraZeneca.
AK: none known.
AG: none known.
TK: acted as an independent contractor, with monies paid to institution, for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline and Novartis. TK also received grants with monies paid to host institution from Boehringer Ingelheim and Novartis.
EO: none known.
KK: worked as a freelance editor with Cochrane Airways at the time of writing but was not involved in the editorial process for this review.

New search for studies and content updated (conclusions changed)