Once daily long‐acting beta2‐agonists and long‐acting muscarinic antagonists in a combined inhaler versus placebo for chronic obstructive pulmonary disease
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effects of single‐inhaler LABA/LAMA combinations versus placebo on clinically meaningful outcomes in patients with stable COPD.
Background
Description of the condition
Chronic obstructive pulmonary disease (COPD) is a progressive condition resulting from the complex interplay between environmental exposures (e.g. cigarette smoke) and genetic factors. The disease is characterised by a chronic limitation of airflow, which is not fully reversible, and intermittent exacerbations during which symptoms increase in severity. Symptoms include shortness of breath, increased sputum production and cough. The condition is diagnosed objectively by spirometric evaluation, with a post bronchodilator forced expiratory volume in one second/forced vital capacity (FEV1/FVC) < 0.70 confirming the presence of airflow limitation. COPD severity is graded by the extent of airflow limitation according to International guideline criteria (GOLD 2017).
COPD is the fourth most common cause of death worldwide (WHO 2015), and has an estimated prevalence of 6.4%; the burden on worldwide healthcare services is significant (CDC 2016; GOLD 2017).
Current treatment strategies are multi‐modal and aim to reduce morbidity and morality and increase patients' quality of life by slowing disease progression and preventing exacerbations. Interventions include cessation of smoking and pulmonary rehabilitation, vaccination against influenza and pneumonia, and the use of inhaled corticosteroids (ICS) and bronchodilators (GOLD 2017). Supplemental oxygen is a life‐prolonging option in hypoxaemic patients. Although treatment is not curative, patients may occasionally be candidates for lung transplantation (GOLD 2017).
Description of the intervention
Long‐acting beta2‐agonists (LABA) and long‐acting anticholinergics (LAMA) are commonly used in patients with COPD as recommended by COPD guidelines (GOLD 2017; Wedzicha 2017). Each bronchodilator can be taken individually or in combination using either two separate inhalers or a single inhaler in a fixed‐dose combination (denoted herein by LABA/LAMA). Evidence suggests that combination of a LABA and tiotropium in individual inhalers offers benefits over the use of either component alone, in terms of lung function and quality of life (Farne 2015). The need for single‐inhaler fixed‐dose combinations arose for several reasons including the underwhelming efficacy of salmeterol and tiotropium administered via separate devices (Aaron 2007) and potential advantages in terms of convenience and adherence (Bangalore 2007). This review will synthesise the evidence for the safety and efficacy of once‐daily LABA/LAMA fixed‐dose combinations versus placebo in patients with COPD.
How the intervention might work
The co‐administration of LABA/LAMA in COPD has beneficial effects on lung function, dyspnoea scores, health‐related quality of life, and possibly in preventing acute exacerbations of COPD (AECOPD) (Calzetta 2016; Wedzicha 2014). Bronchodilation is thought to form the foundation of these benefits, but a reduction in hyperinflation, modulation of mucous production and clearance, and potentially anti‐inflammatory effects are theorized to contribute as well (Beeh 2016). In terms of bronchodilation, use of LABA and LAMA together is more effective compared to either agent alone (Singh 2014; van Noord 2005), but the nature of this interaction is not entirely clear, with in‐vitro and clinical studies suggesting that there is a synergistic rather than additive effect (Cazzola 2015). The mechanism of increased bronchodilation has mainly been attributed to the activation of presynaptic beta2‐receptors, which attenuates the release of junctional acetylcholine (Calzetta 2015). In addition, airway smooth muscle relaxation achieved by a LABA (via increased cyclic adenosine monophosphate) is amplified by the blockade of acetylcholine by inhibition of M3 muscarinic receptors (Cazzola 2010), and there is evidence to suggest that M2 receptors interact with adenyl cyclase as well (Beeh 2016).
Why it is important to do this review
Multiple fixed‐dose LABA/LAMA combination inhalers are currently available, and approved for COPD. The introduction of these inhalers follow guideline‐based recommendations to optimise inhaled bronchodilator use (Quaseem 2011; Vestbo 2013). Recent meta‐analyses have clarified the utility of LABA/LAMA combination inhalers compared to their mono‐components in COPD, particularly with respect to trough FEV1, transitional dyspnoea index (TDI), St. George’s Respiratory Questionnaire (SGRQ) and safety (Calzetta 2016; Calzetta 2017). They found statistically and clinically significant improvements in trough FEV1 for all fixed‐dose combinations (FDC). Though there were statistically significant improvements in TDI and SGRQ, these fell below previously established MCIDs, and thus the clinical meaning of this benefit is unclear. Side‐effects, including cardiac events, were no greater in those taking LABA/LAMA. There were no significant differences between different FDCs for the outcomes examined (Calzetta 2016; Calzetta 2017). Individual clinical trials have demonstrated a reduction in AECOPD with LABA/LAMA versus monocomponents and versus placebo (Bateman 2015; Wedzicha 2017). Unfortunately, the benefits of LABA/LAMA on rescue inhaler use and AECOPD were not included in the meta‐analyses, and thus remain to be clarified. Furthermore, new research on LABA/LAMA using a co‐suspension delivery method has recently been published (Martinez 2017).
Objectives
To assess the effects of single‐inhaler LABA/LAMA combinations versus placebo on clinically meaningful outcomes in patients with stable COPD.
Methods
Criteria for considering studies for this review
Types of studies
We will include parallel‐group randomised controlled trials (RCTs). We will include studies reported as full‐text, those published as abstract only, and unpublished data. We will exclude very short‐term (i.e. ≤ three weeks in duration) trials.
Types of participants
We will include adults (≥ 40 years old) with a diagnosis of stable COPD. We will record study authors' definition of stable COPD. We will not exclude participants with co‐morbidities.
Types of interventions
We will include trials comparing LABA/LAMA in a single inhaler (i.e. fixed dose combination) versus placebo.
We will include studies that allowed participants to continue using their ICS during the trial as long as the ICS is not part of the randomised treatment; if ICS was administered in combination with LABA prior to the trial, participants should be transitioned to the equivalent ICS monotherapy prior to study start. The effect of continued ICS use will be examined by subgroup analysis (see Subgroup analysis and investigation of heterogeneity).
Types of outcome measures
Primary outcomes
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All‐cause mortality.
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Serious Adverse Events (SAE) of any cause.
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Acute Exacerbations of COPD (AECOPD).
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Respiratory Health‐related Quality of Life (HRQoL), as measured by the
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Chronic Respiratory Questionnaire (CRQ)
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St. George’s Respiratory Questionnaire (SGRQ).
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Comments about primary outcomes
Serious adverse events
SAEs can include death, life‐threatening adverse reaction, hospitalisation or increased length of hospital stay, disability, and birth defects. As such, SAEs capture both benefits and harms, and represent an important indicator of net health effects of drug therapy. We will record each study's definition of an SAE when it varies from our definition.
Respiratory health‐related quality of life
CRQ and SGRQ are widely‐used, reliable and valid measures of patient‐reported health status in COPD (Guyatt 1987; Jones 1992). SGRQ scores three domains of health status (symptoms, patient activity and disease impact), and reports scores ranging from zero (best) to 100 (worst). It has a Minimally Important Difference (MID) of approximately four (Schunemann 2003). That is, a clinically meaningful change in health status is equal to a change of about four points on SGRQ. CRQ scores four domains (shortness of breath, fatigue, emotional function, and mastery), reports scores ranging from one (worst) to seven (best), and has an MID of 0.5 (Schunemann 2005). While CRQ and SGRQ provide very similar information and are highly correlated, SGRQ is less responsive; it was shown to underestimate treatment effect when compared to CRQ in identical populations (Puhan 2006). Thus, pooling SGRQ data with CRQ data may spuriously suggest heterogeneity of treatment effect. Therefore, SGRQ and CRQ will be considered as separate outcomes; this approach agrees with the recommendations of Puhan et al, who suggest that mean differences for SGRQ and CRQ should be reported separately.
Acute exacerbations of COPD
We are including AECOPD as a main outcome because exacerbations are consistently linked to mortality, morbidity and costly hospitalisations. Since a consensus definition and standard reporting criteria do not exist for AECOPD (Cazzola 2008), we will meta‐analyse AECOPD data only when study authors use one of the following definitions:increase in symptoms precipitating the use of antibiotics;increase in symptoms precipitating the use of systemic steroids;increase in symptoms precipitating emergency room visit or hospitalisation. The MID for AECOPD outcomes is not established: Calverley 2005 estimated an MID of 20% to 25% using "back‐of‐the‐envelope" calculations, while Chapman 2013 used an expert consensus process to estimate an MID of 11%.
Secondary outcomes
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Trough (pre‐dose) Forced Expiratory Volume in One Second (FEV1).
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Peak (post‐dose) FEV1.
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Six minute walking test (6MWT).
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Adverse effects.
Comments about secondary outcomes
Forced expiratory volume
FEV1 is the volume of air forcibly exhaled one second after maximum inhalation. FEV1 is often used for staging COPD (GOLD 2017): FEV1 is 20% lower than normal for patients with mild COPD, 70% lower than normal for patients with very severe COPD. FEV1 is also used to assess treatment effect, but an MID for FEV1 has not been quantitatively established (expert opinion proposes an MID of 100 mL to 140 mLl) (Cazzola 2008). Moreover, FEV1 is an intermediate endpoint, representing airflow as a surrogate for clinically important outcomes. Surrogate outcomes are not patient‐centred. Nevertheless, we will include trough FEV1 because one meta‐analysis points to a modest correlation between increased trough FEV1 and improved SGRQ (Westwood 2011).
Six minute walking test
In the ECLIPSE study (a non‐intervention cohort study of treated COPD patients), one‐year change in 6MWT predicted death in the subsequent 12 months. The mean between‐group change between survivors and non‐survivors was 30 m (95% CI 26 to 34). Using these results, Polkey 2013 proposed an MID of about 30 m.
Advese effects
We will report adverse effects with a focus on severe effects reported in studies of LABA or LAMA (i.e. adverse cardiac events). Specifically, we will report on the following pre‐specified events: any arrhythmia, acute coronary syndrome, cardiac mortality, hospitalisation due to cardiac event, and sudden deaths. Admittedly, the scope of our review of adverse effects will be narrow. A broader scope may be possible in a review dedicated to safety data.
Search methods for identification of studies
Electronic searches
We will identify studies from the Cochrane Airways Trials Register, which is maintained by the Information Specialist for the Group. The Cochrane Airways Trials Register contains studies identified from several sources:
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monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL), through the Cochrane Register of Studies Online (crso.cochrane.org);
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weekly searches of MEDLINE Ovid SP 1946 to date;
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weekly searches of Embase Ovid SP 1974 to date;
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Monthly searches of PsycINFO Ovid SP 1967 to date;
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Monthly searches of CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature) 1937 to date;
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Monthly searches of AMED EBSCO (Allied and Complementary Medicine);
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handsearches of the proceedings of major respiratory conferences.
Studies contained in the Trials Register are identified through search strategies based on the scope of Cochrane Airways. Details of these strategies, as well as a list of handsearched conference proceedings are in Appendix 1. See Appendix 2 for search terms used to identify studies for this review.
We will search the following trials registries:
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US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov)
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World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch)
We will search the Cochrane Airways Trials Register and additional sources from inception to present, with no restriction on language of publication.
Searching other resources
We will check reference lists of all primary studies and review articles for additional references. We will search relevant manufacturers' web sites for trial information.
We will search for errata or retractions from included studies published in full‐text on PubMed (www.ncbi.nlm.nih.gov/pubmed) and report the date this was done within the review.
Data collection and analysis
Selection of studies
Two review authors (DE and UM) will independently screen titles and abstracts for inclusion of all the potential studies we identify as a result of the search and code them as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'. We will retrieve the full‐text study reports or publication and two review authors (DE and UM) will independently screen the full‐text and identify studies for inclusion, and identify and record reasons for exclusion of the ineligible studies. We will resolve any disagreement through discussion or, if required, we will consult a third person (TH). We will identify and exclude duplicates and collate multiple reports of the same study so that each study rather than each report is the unit of interest in the review. We will record the selection process in sufficient detail to complete a PRISMA flow diagram and 'Characteristics of excluded studies' table.
Data extraction and management
We will use a data collection form for study characteristics and outcome data which has been piloted on at least one study in the review. One review author (DE) will extract study characteristics from included studies. We will extract the following study characteristics.
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Methods: study design, total duration of study, details of any 'run in' period, number of study centres and location, study setting, withdrawals, and date of study.
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Participants: N, mean age, age range, gender, severity of condition, diagnostic criteria, baseline lung function, smoking history, inclusion criteria, and exclusion criteria.
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Interventions: intervention, comparison, concomitant medications, and excluded medications.
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Outcomes: primary and secondary outcomes specified and collected, and time points reported.
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Notes: funding for trial, and notable conflicts of interest of trial authors.
Two review authors (DE, UM or TH) will independently extract outcome data from each included study. We will note in the 'Characteristics of included studies' table if outcome data were not reported in a usable way. We will resolve disagreements by consensus or by involving a third person (UM or TH). One review author (DE) will transfer data into the Review Manager file. We will double‐check that data have been entered correctly by comparing the data presented in the systematic review with the study reports. A second review author (UM) will spot‐check study characteristics for accuracy against the trial report.
Trials may report continuous outcomes as change scores (i.e. change from baseline) or final values. As per the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), we will present mean differences in change scores in one subgroup, mean differences in final values in another, and pool both subgroups for an overall analysis.
Where multiple time points are reported for dichotomous outcomes, we will choose the time point that maximises length of follow‐up for the randomised treatment period. Where multiple time points are reported for continuous outcomes, we will pool results for three time‐points: six, twelve and 24 months.
Assessment of risk of bias in included studies
Two review authors (DE, KP or FE) will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreements by discussion or by involving another author (UM). We will assess the risk of bias according to the following domains.
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Random sequence generation.
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Allocation concealment.
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Blinding of participants and personnel.
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Blinding of outcome assessment.
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Incomplete outcome data.
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Selective outcome reporting.
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Other bias.
We will grade each potential source of bias as high, low or unclear and provide a quote from the study report together with a justification for our judgment in the 'Risk of bias' table. We will summarise the risk of bias judgements across different studies for each of the domains listed. We will consider blinding separately for different key outcomes where necessary (e.g. for unblinded outcome assessment, risk of bias for all‐cause mortality may be very different than for a patient reported pain scale). Where information on risk of bias relates to unpublished data or correspondence with a trialist, we will note this in the 'Risk of bias' table.
When considering treatment effects, we will take into account the risk of bias for the studies that contribute to that outcome.
Assessment of bias in conducting the systematic review
We will conduct the review according to this published protocol and report any deviations from it in the 'Differences between protocol and review' section of the systematic review.
Measures of treatment effect
We will analyse dichotomous data as odds ratios and continuous data as mean difference or standardised mean difference. We will enter data presented as a scale with a consistent direction of effect.
We will undertake meta‐analyses only where this is meaningful, i.e. if the treatments, participants and the underlying clinical question are similar enough for pooling to make sense.
We will narratively describe skewed data reported as medians and interquartile ranges.
Where multiple trial arms are reported in a single trial, we will include only the relevant arms. If two comparisons (e.g. drug A versus placebo and drug B versus placebo) are combined in the same meta‐analysis, we will halve the control group to avoid double‐counting.
Unit of analysis issues
We will analyse dichotomous data using participants as the unit of analysis (rather than events) to avoid counting the same participant more than once.
Dealing with missing data
We will contact investigators or study sponsors in order to obtain missing numerical outcome data where possible (e.g. when a study is identified as abstract only). That is, if study authors do not report true intention‐to‐treat (ITT) data, we will attempt an available case analysis by including data for all participants for whom outcome data were collected (whether the participants completed or did not complete the trial). Please note that a case analysis is not a true ITT analysis, nor a per‐protocol analysis.
Where we cannot obtain missing data from study authors, we will:
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compare our available case analysis with an imputed, true ITT analysis (see Sensitivity Analyses);
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use an average standard deviation (SD) borrowed from other studies included in our meta‐analysis if the SD for a mean difference is unavailable (or incalculable);
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use final values instead of the change‐from‐baseline values if the standard deviation for a change score is missing.
Where the missing data are thought to introduce serious bias, we will explore the impact of including such studies in the overall assessment of results by a sensitivity analysis.
Assessment of heterogeneity
We will use the I² statistic to measure heterogeneity among the trials in each analysis. If we identify substantial heterogeneity we will report it and explore possible causes by prespecified subgroup analysis.
Assessment of reporting biases
If we are able to pool more than 10 trials, we will create and examine a funnel plot to explore possible small study and publication biases.
Data synthesis
We will use a fixed‐effect model and perform a sensitivity analysis with random model. Where study authors report exacerbation rate, we will meta‐analyse rate data when study authors account for duration of follow‐up and inter‐patient variability (Aaron 2008). The rate ratio will be our primary summary statistic. Where possible, we will also report AECOPD as the percentage of participants experiencing at least one exacerbation. This way, we can present AECOPD as a dichotomous outcome, and report a patient‐based number needed to treat (NNT). When possible, we will also report SGRQ and CRQ as dichotomous outcomes (i.e. patients who reached the MID vs patients who did not).
Summary of findings table
We will create a 'Summary of findings' table using the seven primary and secondary outcomes identified above; for health‐related quality of life, CRQ will be reported in the summary of findings table. We will use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of a body of evidence as it relates to the studies which contribute data to the meta‐analyses for the prespecified outcomes. We will use methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) using GRADEpro software. We will justify all decisions to down‐grade or up‐grade the quality of studies using footnotes and we will make comments to aid reader's understanding of the review where necessary.
Subgroup analysis and investigation of heterogeneity
We plan to carry out the following subgroup analyses:
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participants with ICS use during the trial versus participants without ICS use during the trial;
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different LAMA/LABA combinations;
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length of follow‐up (less than six months versus six months or longer);
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baseline COPD severity.
We will use our primary outcomes in subgroup analyses.
We will use the formal test for subgroup interactions in Review Manager.
Sensitivity analysis
We plan to carry out the following sensitivity analyses:
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a comparison of available case analysis to true ITT analyses, where the ITT analyses are imputed with best‐case and worse‐case outcome data;
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a comparison of results from fixed‐effect models with results from random‐effects models;
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a comparison based on our risk of bias assessments.
