Long‐acting muscarinic antagonists (LAMA) added to inhaled corticosteroids (ICS) versus the same dose of ICS for adults with asthma
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the efficacy and safety of a long‐acting muscarinic antagonist (LAMA) added to any dose of an inhaled corticosteroid (ICS) compared with the same dose of ICS alone for adults whose asthma is not well controlled.
Background
Description of the condition
Asthma is a "heterogeneous disease, usually characterized by chronic airway inflammation. It is defined by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness, and cough that vary over time and in intensity, together with variable expiratory airflow limitation" (GINA 2014b). Common triggers include allergens, pollutants and viral infections, although endogenous factors have also been identified. The World Health Organization (WHO) recognises the global burden of asthma and estimates a worldwide prevalence of 300 million people of all ages, with 250,000 people dying each year (WHO 2007). Asthma prevalence is greater in urbanised communities, and with the world's urbanised population projected to grow from 45% to 59% by 2025, the number of people diagnosed with asthma is predicted to increase by 100 million over this time (Global Burden of Asthma Report 2004). Epidemiological data suggest that prevalence is greatest in the developed world, with prevalence amongst adults at 8.2% in the USA (CDC 2014) and at 9% to 10% in the UK (DOH 2012). Asthma presents a heavy financial burden on health services in the UK and worldwide (Global Asthma Report 2011), with the National Health Service (NHS) spending a billion pounds per year on treatment of patients with asthma (Asthma UK 2014). This considerable expense represents direct medical costs, such as provision of medicines and frequent general practitioner (GP) consultations, outpatient services and hospital admissions due to poorly controlled disease (Barnes 1996). However the economic cost of asthma is worsened by indirect costs to the patient resulting from time off work or school due to sickness and loss of earnings due to morbidity and early mortality (Global Burden of Asthma Report 2004).
Asthma can present with varying degrees of severity; in the most severe cases, it can cause daily chronic symptoms and frequent exacerbations (defined as acute worsening of asthma symptoms). Overarching principles of treatment focus on controlling daily symptoms and preventing exacerbations.
Bronchodilating agents and corticosteroids delivered via inhaler devices are the mainstay in asthma management. Short‐acting bronchodilating agents such as salbutamol are used on a "when required" basis as reliever therapy, and inhaled corticosteroids (ICSs) are used regularly as maintenance therapy. Other agents employed in asthma management include inhaled long‐acting bronchodilating beta2‐agonists (LABAs) and leukotriene‐receptor antagonists (taken as tablets). Treatment is introduced and increased through a stepwise approach, depending on the severity and frequency of symptoms (BTS/SIGN 2012; GINA 2014a).
Description of the intervention
Asthma treatment is commenced at the level most likely to achieve control of the patient's symptoms; treatment is stepped up to maintain this control and is stepped down when the patient's condition is stable and well maintained (BTS/SIGN 2012; GINA 2014a). Step 1 involves the sole use of a short‐acting bronchodilating agent on a when‐required basis; patients who remain inadequately controlled are increased to step 2 with the introduction of an inhaled corticosteroid (ICS) for regular use as maintenance therapy. Regular daily therapy with an ICS is known to improve lung function and symptom control while reducing airway inflammation and the use of reliever therapy compared with intermittent use of an ICS by patients with asthma (Chauhan 2013). However, if regular use of an ICS at a low to medium dose does not maintain control of the patient's symptoms—that is, the patient suffers from recurrent exacerbations or nocturnal awakening, or frequently uses reliever therapy to relieve symptoms of breathlessness, chest tightness and wheeze—a step‐up in treatment to step 3 is required. At step 3 in the management guidelines, the addition of a long‐acting beta2‐agonist (LABA) is recommended for adults, as this was found to be superior to alternative treatments (Chauhan 2014: Ducharme 2010). Alternative therapies for people whose asthma is not well controlled on low to medium doses of ICS and for whom a LABA has not worked include introducing a daily leukotriene receptor antagonist tablet or increasing the ICS dose (BTS/SIGN 2012; GINA 2014a).
Long‐acting muscarinic antagonists (LAMAs) are not currently recommended for the treatment of asthma in evidence‐based guidelines; only one LAMA preparation (Spiriva Respimat 2.5 mcg) has had its licence extended for use in people with asthma, and only for patients already taking combination LABA and ICS who have had at least one severe exacerbation in the previous year (eMC 2014a). However, several other LAMA preparations are used frequently for the treatment of chronic obstructive pulmonary disease (COPD). COPD, like asthma, is characterised in part by airway obstruction, and patients benefit from the bronchodilating effects of LAMAs, which reduce airflow limitation and improve symptoms (NICE 2010). Previous studies have demonstrated that the LAMA tiotropium significantly reduced the frequency of exacerbations and hospital admissions related to COPD, and improved lung function and quality of life in patients with COPD (Karner 2014).
How the intervention might work
LAMAs act by inhibiting the effects of acetylcholine at muscarinic receptors (M). When administered via inhalation, they competitively antagonise M3‐receptors, preventing acetylcholine‐mediated constriction of bronchial smooth muscle. This permits dilation of the airways. Their slow dissociation from local M3‐receptors and prolonged half‐lives mean that such agents are administered only once or twice daily (EMC 2013a; EMC 2013b; EMC 2014b).
COPD and asthma share similar symptoms, namely, shortness of breath, chronic cough and wheeze (BTS/SIGN 2012; NICE 2010). The regulation of airway smooth muscle tone by M‐receptors is enhanced and contributes to airflow obstruction in both COPD and asthma (Gosens 2006). Therefore, a reduction in M‐receptor–mediated airway constriction would be beneficial in relieving these common symptoms of COPD and asthma.
Previous studies and national guidelines for COPD have reported that LAMAs and LABAs have comparable efficacy in treating patients with moderate COPD (NICE 2010). LABA is also a bronchodilator and is the favoured treatment for introduction at step 3 or 4 of asthma management, where it is administered concomitantly with an ICS to improve control of symptoms (GINA 2014a). Although a LAMA mediates bronchial smooth muscle relaxation in a different manner from that of a LABA, its bronchodilatory effect may be beneficial for patients who require a step‐up in their asthma management when ICS alone is insufficient.
Why it is important to do this review
Although several evidence‐based therapies and non‐pharmacological strategies are available to improve control of symptoms and to prevent exacerbations of asthma, mortality due to asthma remains a risk for patients. Asthma UK reported 1167 deaths due to asthma in 2011, while "75% of hospital admissions for asthma are avoidable and as many as 90% of the deaths from asthma are preventable" (Asthma UK 2014). This highlights the fact that current management of asthma remains sub‐optimal and indicates that development of new management strategies and treatments would be beneficial.
As a result of the common features of COPD and asthma—such as up‐regulation of M‐receptor–mediated airway tone and subsequent symptoms of breathlessness, cough and wheeze—known benefits of inhaled LAMAs in COPD may also be beneficial for patients with asthma, particularly those with severe asthma whose condition remains inadequately controlled by current recommended step 3 therapy.
Previous trials have demonstrated the potentially beneficial effects of the LAMA tiotropium on lung function in patients with asthma (Peters 2010; Vogelberg 2014). However, a definitive conclusion on the benefit of LAMAs in asthma and where in the current step‐wise management strategy they would be most beneficial is lacking. Therefore a systematic review of all available randomised controlled trials on the addition of a LAMA to an ICS would be beneficial in revealing any benefit to be derived by the use of LAMAs in asthma that remains uncontrolled by an ICS alone.
Three associated reviews will assess:
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LAMA add‐on compared with LABA add‐on;
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LAMA add‐on compared with increasing ICS dose; and
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LAMA add‐on as triple therapy with LABA + ICS compared with LABA + ICS alone.
Objectives
To assess the efficacy and safety of a long‐acting muscarinic antagonist (LAMA) added to any dose of an inhaled corticosteroid (ICS) compared with the same dose of ICS alone for adults whose asthma is not well controlled.
Methods
Criteria for considering studies for this review
Types of studies
We will include parallel or cross‐over randomised controlled trials (RCTs) of at least 12 weeks' duration reported as full text, those published as abstract only and those with unpublished data.
We will not exclude studies on the basis of blinding.
Types of participants
We will include adults (aged 18 or older) whose asthma is not well controlled by ICS alone. We will exclude trials that include participants with other chronic respiratory co‐morbidities (e.g. COPD, bronchiectasis).
If studies include adults and adolescents or children younger than age 12 and data are not reported separately, we will include them if the mean age in both groups is over 18 years.
Types of interventions
We will include trials comparing a LAMA added to any dose of ICS therapy versus continued use of ICS at the same dose. We will include studies that permit the use of short‐acting medications (e.g. salbutamol, terbutaline, ipratropium) as reliever therapy. We will exclude trials in which a long‐acting beta2‐agonist was given as part of the randomly assigned treatment and those in which most participants continued their LABA alongside the randomly assigned treatment. Studies involving the addition of any of the following LAMA preparations will be included.
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Tiotropium (Spiriva Handihaler or Respimat).
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Aclidinium bromide (Eklira Genuair).
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Glycopyrronium bromide (Seebri Breezhaler).
Types of outcome measures
Primary outcomes
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Exacerbations requiring oral corticosteroids.
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Quality of life (measured on a validated asthma scale, e.g. Asthma Quality of Life Questionnaire).
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All‐cause serious adverse events.
Secondary outcomes
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Exacerbations requiring hospitalisation.
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Lung function (in particular, trough forced expiratory volume in one second (FEV1)).
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Asthma control (as measured on a validated scale, e.g. Asthma Control Questionnaire or Asthma Control Test).
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Any adverse events.
Reporting in the trial of one or more of the outcomes listed here is not an inclusion criterion for the review.
If exacerbations are reported as a composite of more than one definition (e.g. study participants with one or more exacerbations requiring hospitalisation or an emergency department (ED) visit), we will analyse these separately.
Search methods for identification of studies
Electronic searches
We will identify trials from the Cochrane Airways Group Specialised Register (CAGR), which is maintained by the Trials Search Co‐ordinator for the Group. This 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 meeting abstracts (please see Appendix 1 for further details). We will search all records in the CAGR using the search strategy provided in Appendix 2.
We will also conduct a search of ClinicalTrials.gov (www.ClinicalTrials.gov) and the World Health Organization (WHO) trials portal (www.who.int/ictrp/en/). We will search all databases from their inception to the present, and we will impose no restriction on language of publication.
Searching other resources
We will check the reference lists of all primary studies and review articles to look for additional references. We will search relevant manufacturers' websites 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 will report within the review the date this was done.
Data collection and analysis
Selection of studies
Two review authors (DA and KK) will independently screen titles and abstracts for inclusion of all potential studies identified as a result of the search and will code them as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve.' We will retrieve the full‐text study reports/publications; two review authors (DA and KK) will independently screen the full text reports to identify studies for inclusion and will identify and record reasons for exclusion of ineligible studies. We will resolve disagreements through discussion or, if required, will consult a third person. We will identify and exclude duplicates and will 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 (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) flow diagram and a 'Characteristics of excluded studies' table.
Data extraction and management
We will use a data collection form to record study characteristics and outcome data that has been piloted on at least one study in the review. One review author (KK) will extract the following study characteristics from included studies.
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Methods: study design, total duration of study, details of any 'run‐in' period, number of study centres and locations, study settings, withdrawals and dates 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: interventions, comparisons, 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 (DA and KK) will independently extract outcome data from included studies. 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 discussion. One review author (KK) will transfer data into the Review Manager (Review Manager 2014 (RevMan)) file. We will double‐check that data have been entered correctly by comparing data presented in the systematic review with those provided in the study reports. A second review author (DA) will spot‐check study characteristics for accuracy against the trial report.
Assessment of risk of bias in included studies
Two review authors (DA and KK) 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 disagreements by discussion and will assess 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 will provide a quote from the study report together with a justification for our judgement in the 'Risk of bias' table. We will summarise risk of bias judgements across different studies for each of the domains listed. We will consider blinding separately for different key outcomes when 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). When information on risk of bias is related to unpublished data or correspondence with a trial author, we will note this in the 'Risk of bias' table.
In cases where the method of random sequence generation or allocation concealment is not adequately described, but the study was funded by a manufacturer with whom methods have previously been confirmed, we will assume that the same methods were applied. When other uncertainties are due to insufficient reporting, we will contact the study author or sponsor to ask for additional information.
When considering treatment effects, we will take into account the risk of bias for studies that contributed to that outcome.
Assessment of bias in conducting the systematic review
We will conduct the review according to this published protocol and will report 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 differences or standardised mean differences. We will enter data presented as a scale with a consistent direction of effect. We will narratively describe skewed data reported as medians and interquartile ranges. We will analyse data from cross‐over trials using generic inverse variance (GIV) and using only results derived from paired analyses. When both raw data and adjusted analyses (e.g. accounting for baseline differences) are presented, we will use the latter.
We will undertake meta‐analyses only when this is meaningful (i.e. when treatments, participants and the underlying clinical question are similar enough for pooling to make sense).
When multiple trial arms are reported in a single trial, we will include only the relevant arms. When two comparisons (e.g. drug A vs placebo and drug B vs placebo) are combined in the same meta‐analysis, we will halve the control group to avoid double counting.
When change from baseline and endpoint scores are available for continuous data, we will use change from baseline unless most studies report endpoint scores. If a study reports outcomes at multiple time points, we will use the end‐of‐study measurement.
When both an analysis using only participants who completed the trial and an analysis that imputes data for participants who were randomly assigned but did not provide endpoint data (e.g. last observation carried forward) are available, we will use the latter.
For dichotomous outcomes, we will assume equivalence of treatments if the odds ratio estimate and its 95% confidence interval are between the predefined arbitrary limits of 0.9 and 1.1.
Unit of analysis issues
For dichotomous outcomes, we will use participants rather than events as the unit of analysis (i.e. number of adults admitted to hospital rather than number of admissions per adult).
Dealing with missing data
We will contact investigators or study sponsors to verify key study characteristics and to obtain missing numerical outcome data when possible (e.g. when a study is identified as an abstract only). When this is not possible, and when missing data are thought to introduce serious bias, we will explore the impact of including such studies in the overall assessment of results by performing 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 (e.g. I2 > 30%), we will report this and will explore possible causes through 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 random‐effects model for all analyses, as we expect variation in effects due to differences in study populations and methods. We will perform sensitivity analyses using fixed‐effect models.
'Summary of findings' table
We will create a 'Summary of findings' table for all primary and secondary outcomes listed in the protocol. We will use the five GRADE (Grades of Recommendation, Assessment, Development and Evaluation) 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 that contributed data to the meta‐analyses for prespecified outcomes. We will use methods and recommendations as described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) using GRADEpro software (Brozek 2008). We will justify all decisions to downgrade or upgrade the quality of studies by using footnotes and by making comments to aid the reader's understanding of the review when necessary.
Subgroup analysis and investigation of heterogeneity
We plan to carry out the following subgroup analyses for the primary outcomes.
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Duration of therapy (≤ 6 months, > 6 months).
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Corticosteroid dose (according to GINA 2014 defined as low, medium and high cutoffs).
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Dose and type of LAMA (e.g. tiotropium HandiHaler 18 mcg, tiotropium Respimat 5 mcg).
We will use the formal test for subgroup interactions provided in Review Manager 2014 (RevMan).
Sensitivity analysis
We plan to carry out sensitivity analyses on the primary outcomes while excluding the following studies.
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Unpublished data.
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Studies at high risk of bias for blinding (participants and personnel).
