Abstract
Background
Long-acting bronchodilators comprising long-acting beta2-agonists and the anticholinergic agent tiotropium are commonly used for managing persistent symptoms of chronic obstructive pulmonary disease. Combining these treatments, which have different mechanisms of action, may be more effective than the individual components. However, the benefits and risks of combining tiotropium and long-acting beta2-agonists for the treatment of chronic obstructive pulmonary (COPD) disease are unclear.
Objectives
To assess the relative effects of treatment with tiotropium in addition to long-acting beta2-agonist compared to tiotropium or long-acting beta2-agonist alone in patients with chronic obstructive pulmonary disease.
Search methods
We searched the Cochrane Airways Group Specialised Register of trials and clinicaltrials.gov up to January 2012.
Selection criteria
We included parallel group, randomised controlled trials of three months or longer comparing treatment with tiotropium in addition to long-acting beta2-agonist against tiotropium or long-acting beta2-agonist alone for patients with chronic obstructive pulmonary disease.
Data collection and analysis
Two review authors independently assessed trials for inclusion and then extracted data on trial quality and the outcome results. We contacted study authors for additional information. We collected information on adverse effects from the trials.
Main results
Five trials were included in this review, mostly recruiting participants with moderate or severe chronic obstructive pulmonary disease. All of them compared tiotropium in addition to long-acting beta2-agonist to tiotropium alone, but only one trial additionally compared a combination of the two types of bronchodilator with long-acting beta2-agonist (formoterol) alone. Two studies used the long-acting beta2-agonist indacaterol, two used formoterol and one used salmeterol.
Compared to tiotropium alone (3263 patients), treatment with tiotropium plus long-acting beta2-agonist resulted in a slightly larger improvement in the mean health-related quality of life (St George’s Respiratory Questionnaire (SGRQ) MD −1.61; 95% CI −2.93 to −0.29). In the control arm, tiotropium alone, the SGRQ improved by falling 4.5 units from baseline and with both treatments the improvement was a fall of 6.1 units from baseline (on average). High withdrawal rates in the trials increased the uncertainty in this result, and the GRADE assessment for this outcome was therefore moderate. There were no significant differences in the other primary outcomes (hospital admission or mortality).
The secondary outcome of pre-bronchodilator FEV1 showed a small mean increase with the addition of long-acting beta2-agonist (MD 0.07 L; 95% CI 0.05 to 0.09) over the control arm, which showed a change from baseline ranging from 0.03 L to 0.13 L on tiotropium alone. None of the other secondary outcomes (exacerbations, symptom scores, serious adverse events, and withdrawals) showed any statistically significant differences between the groups. There were wide confidence intervals around these outcomes and moderate heterogeneity for both exacerbations and withdrawals.
The results from the one trial comparing the combination of tiotropium and long-acting beta2-agonist to long-acting beta2-agonist alone (417 participants) were insufficient to draw firm conclusions for this comparison.
Authors’ conclusions
The results from this review indicate a small mean improvement in health-related quality of life for patients on a combination of tiotropium and long-acting beta2-agonist compared to tiotropium alone, but it is not clear how clinically important this mean difference may be. Hospital admission and mortality have not been shown to be altered by adding long-acting beta2-agonists to tiotropium as there were not enough data to determine the relative efficacy and safety of tiotropium plus long-acting beta2-agonist compared to long-acting beta2-agonist alone. There were insufficient data to make comparisons between the different long-acting beta2-agonists when used in addition to tiotropium.
Medical Subject Headings (MeSH): Adrenergic beta-2 Receptor Agonists [*therapeutic use]; Albuterol [analogs & derivatives; therapeutic use]; Bronchodilator Agents [*therapeutic use]; Ethanolamines [therapeutic use]; Indans [therapeutic use]; Pulmonary Disease, Chronic Obstructive [*drug therapy]; Quality of Life; Quinolones [therapeutic use]; Scopolamine Derivatives [*therapeutic use]
MeSH check words: Aged, Humans, Middle Aged
BACKGROUND
Description of the condition
Chronic Obstructive Pulmonary Disease (COPD) is a respiratory disease characterised by chronic and progressive breathlessness, cough, sputum production, and airflow obstruction, which leads to restricted activity and poor quality of life (GOLD). The World Health Organization (WHO) has estimated that COPD is the fourth or fifth most common single cause of death worldwide and the treatment and management costs present a significant burden to public health. In the UK the annual cost of COPD to the National Health Service (NHS) is estimated to be £1.3 million per 100,000 people (NICE 2011). Furthermore, because of the slow onset and the under-recognition of the disease, it is heavily underdiagnosed (GOLD). COPD comprises a combination of bronchitis and emphysema and involves chronic inflammation and structural changes in the lung. Cigarette smoking is the most important risk factor, however air pollution and occupational dust and chemicals are also recognised risk factors. COPD is a progressive disease leading to decreased lung function over time, even with the best available care. There is currently no cure for COPD, though it is both a preventable and treatable disease. As yet, apart from smoking cessation and non-pharmacological treatments such as long term oxygen therapy in hypoxic patients, no intervention has been shown to reduce mortality (GOLD). Management of the disease is multi-faceted and includes interventions for smoking cessation (van der Meer 2001), pharmacological treatments (GOLD), education (Effing 2007), and pulmonary rehabilitation (Lacasse 2006). Pharmacological therapy is aimed at relieving symptoms, improving exercise tolerance and quality of life, slowing decline and even improving lung function, or preventing and treating exacerbations. COPD exacerbations impair patients’ quality of life (GOLD). Furthermore, a large part of the economic burden of COPD is attributed to the cost of managing exacerbations, particularly those resulting in use of acute care services or hospitalisations (Hutchinson 2010). In the UK, one in eight emergency admissions to hospital is for COPD, which makes it the second largest cause of emergency admissions and one of the most costly conditions treated by the NHS (NICE 2011). Appropriate pharmacological management of the disease is therefore important to try to reduce and prevent exacerbations.
Description of the intervention
COPD pharmacological management tends to begin with one treatment and additional therapies are introduced, as necessary, to control symptoms (GOLD). The first step is often a short-acting bronchodilator for control of breathlessness when needed, either a short-acting beta2-agonist or the short-acting anticholinergic agent ipratropium. For persistent or worsening breathlessness associated with lung function decline, long-acting bronchodilators may be introduced (GOLD). Long-acting bronchodilators include long-acting beta2-agonists (LABA), such as salmeterol or formoterol; new ultra long-acting beta2-agonist, such as indacaterol; and the long-acting anticholinergic agent tiotropium. Regular treatment with the long acting tiotropium has been shown to be more effective and safer than treatment with short-acting ipratropium (Cheyne 2013). For symptomatic patients with severe or very severe COPD (FEV1 < 50% predicted) and repeated exacerbations, GOLD recommends the addition of inhaled corticosteroids (ICS) to bronchodilator treatment.
How the intervention might work
Tiotropium
Tiotropium is an anticholinergic agent which blocks the action of the neurotransmitter acetylcholine. It has an antagonistic effect on muscarinic acetylcholine receptors. Tiotropium has similar affinity for the five different subtypes of muscarinic receptors (M1 to M5), however airway smooth muscle expresses only the M2 and M3 subtypes (Proskocil 2005). Activation of the M3 receptor stimulates a number of intracellular signalling cascades leading to changes in intracellular Ca2+ homeostasis and contraction. Tiotropium dissociates slowly from M3 receptors giving a bronchodilator effect lasting over 24 hours, but dissociates rapidly from M2 receptors, which appear to be feedback inhibitory receptors (Barr 2005).
Tiotropium has gained widespread acceptance as a once daily maintenance therapy in stable COPD (Barr 2005; GOLD) for its effects on symptoms and exacerbations. In an early Cochrane review (Barr 2005) tiotropium was shown to reduce the primary endpoint of participants with COPD exacerbations compared to placebo (odds ratio (OR) 0.75; 95% CI 0.66 to 0.85). Within the same review, tiotropium was also associated with a significant benefit over placebo in breathlessness, quality of life, and a reduction in participants with exacerbations that required hospitalisation. Similar effects on symptoms and exacerbations were confirmed in a more recent, large randomised controlled trial of almost 6000 patients who were followed for over four years (Tashkin 2008). There was, however, no significant effect of tiotropium on lung function decline in this longer study. Anticholinergic side effects that may occur with tiotropium include dry mouth, constipation and tachycardia (Tashkin 2008). There has been concern expressed about cardiovascular adverse events on tiotropium (Singh 2009), but this was not shown in meta-analysis including the recent UPLIFT study (Celli 2010).
Long-acting beta2-agonists
Inhaled beta2-agonists activate beta2-receptors in the smooth muscle of the airway leading to a cascade of reactions that result in bronchodilation. Beta2-agonists may also act through other mechanisms such as respiratory muscle function or mucociliary clearance because patients have shown improvements in symptoms whilst showing no improvement in lung function tests. Beta2-agonists are particularly useful bronchodilators because they reverse bronchoconstriction regardless of the initial cause. The commonly used long-acting beta2-agonists salmeterol and formoterol and the ultra long-acting beta2-agonist indacaterol all have a higher selectivity for beta2-receptors than beta1-receptors (Moen 2010; Wallukat 2002). Beta2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the heart, although 10% to 50% of the total beta-receptors in the heart are comprised of beta2-receptors. The presence of beta2-receptors in the heart raises the possibility that even highly selective beta2-agonists may have cardiac effects. The duration of action for salmeterol and formoterol is approximately 12 hours, and they are therefore usually taken twice daily. Indacaterol has a duration of action of 24 hours and can, therefore, be taken once daily. The mechanism for activating beta2-receptors differs between these long-acting beta2-agonists. Formoterol is taken up into a membrane depot from where it gradually leaks out to interact with the receptor, whilst salmeterol binds near the receptor, allowing it to remain at the receptor site continually binding and releasing (Johnson 1998). Indacaterol has a higher affinity to lipid domains within the membrane than salmeterol, which may potentially explain its prolonged duration of action (Beier 2011). Independent of long-acting beta2-agonist (LABA) type, stimulation of the beta2-receptors leads to changes in intracellular Ca2+ homeostasis and bronchodilation (Tanaka 2005). As with tiotropium, LABAs are used as ‘symptom controllers’ in stable COPD. A prior Cochrane review found that salmeterol improves lung function compared to placebo (Appleton 2006). A more recent, large (3045 patients), long-term (three-year) randomised control trial also compared salmeterol to placebo (TORCH) (Calverley 2007). In this trial salmeterol use was associated with an increase in lung function and a significant reduction in the annual rate of moderate or severe exacerbations compared with placebo (rate ratio 0.85, P < 0.001). A systematic review, which included the TORCH study and another 13 trials looking at salmeterol or formoterol (6453 participants), showed that treatment with a LABA reduced the rate of exacerbations and improved lung function and quality of life compared to placebo, but had no significant effect on mortality (Rodrigo 2008). There have also been a few studies on indacaterol showing improvements in lung function, quality of life and exacerbations compared to placebo (Moen 2010). Possible side effects of LABAs include cardiac effects such as arrhythmia and palpitations, and muscle tremors, head ache, cough, and dry mouth (Beeh 2009; Berger 2008).
Why it is important to do this review
Both tiotropium and long-acting beta2-agonists are recommended for treatment of stable COPD (GOLD). However, patients whose COPD is not adequately managed by either LABA or tiotropium treatment alone could potentially benefit from treatment with a combination of the two. It has been suggested that combination therapies directed at both adrenergic and muscarinic receptors could provide greater, and potentially additive, bronchodilation compared with a beta2-agonist or a muscarinic antagonist alone (Proskocil 2005). A number of trials have been published looking at the effect of adding tiotropium to LABA for treatment of COPD, and the clinical evidence to date suggests there may be benefits in combining the treatments without increasing side effects (Cazzola 2010). This review is necessary to specify and quantify the potential benefits from the combination treatment with LABA and tiotropium compared to the individual components alone.
This review will form part of a suite of reviews on the various combinations of tiotropium, long-acting beta2-agonists and inhaled corticosteroids for the treatment of COPD. These reviews will ultimately be summarised in an overview. The first two of these reviews compared a combination of inhaled corticosteroids and long-acting beta2-agonists with tiotropium (Welsh 2010) and triple therapy (inhaled corticosteroids, long-acting beta2-agonist and tiotropium) with either tiotropium alone or inhaled corticosteroid (ICS) and LABA combination therapy (Karner 2011). Further reviews are in preparation comparing alternate permutations of these three drugs.
OBJECTIVES
To compare the relative effects on markers of quality of life, exacerbations, symptoms, lung function and serious adverse events in patients with chronic obstructive pulmonary disease randomised to the following therapies:
long-acting beta2-agonists and tiotropium versus long-acting beta2-agonists alone; or
long-acting beta2-agonists and tiotropium versus tiotropium alone.
METHODS
Criteria for considering studies for this review
Types of studies
We included only randomised trials (RCTs) with a parallel group design of at least 12 weeks duration. We did not exclude studies on the basis of blinding.
Types of participants
We included populations with a diagnosis of chronic obstructive pulmonary disease. We only included studies where an external set of criteria had been used to screen participants for this condition (for example the Global initiative for chronic Obstructive Lung Disease (GOLD), American Thoracic Society (ATS), British Thoracic Society (BTS), Thoracic Society of Australia and New Zealand (TSANZ)).
Types of interventions
We included participants who were randomised to receive inhaled long-acting beta2-agonist in addition to tiotropium bromide compared to those on either inhaled tiotropium bromide alone or inhaled long-acting beta2-agonist alone. We allowed any formulation of long-acting beta2-agonists and tiotropium bromide. Participants were allowed inhaled steroids and other co-medications provided they were not part of the randomised treatment.
Types of outcome measures
Primary outcomes
Quality of life (measured with a validated scale for COPD, e.g. St George’s Respiratory Questionnaire, Chronic Respiratory Disease Questionnaire)
Hospital admissions; all cause and due to exacerbations
Mortality; all-cause
Disease specific mortality, if independently adjudicated
Secondary outcomes
Exacerbations; requiring short burst oral corticosteroids or antibiotics, or both
Forced expiratory volume in one second (FEV1)
Symptoms
All-cause non-fatal serious adverse events
Disease specific serious adverse events, if independently adjudicated
Withdrawals
Search methods for identification of studies
Electronic searches
We identified trials from the Cochrane Airways Group Specialised Register of trials (CAGR), which is derived from systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED, and PsycINFO, and handsearching of respiratory journals and meeting abstracts (please see Appendix 1 for further details). All records in the CAGR coded as ‘COPD’ were searched in January 2012 using the following terms:
(tiotropium or spiriva) AND (*formoterol or salmeterol or bambuterol or indacaterol or clenbuterol or Serevent or Foradil or Oxis or (beta* and agonist*))
Clinicaltrials.gov was also searched in September 2011. The search terms are in Appendix 2. All databases were searched from their inception to the present and there was no restriction on language of publication.
Searching other resources
We searched the following manufacturer web sites in September 2011: Boehringer Ingelheim (Spiriva, Spiriva Respimat); Pfizer (Spiriva); Novartis (indacaterol, formoterol); GlaxoSmithKline (salmeterol); AstraZeneca (formoterol). We reviewed reference lists of all primary studies and review articles for additional references.
Data collection and analysis
Selection of studies
Two review authors screened the titles and abstracts of citations retrieved through literature searches and obtained those deemed to be potentially relevant. We assigned each reference to a study identifier and independently assessed them against the inclusion criteria of this review.
Data extraction and management
We extracted information from each study for the following characteristics.
Design (design, total study duration and run-in, number of study centres and location, withdrawals, date of study).
Participants (N, mean age, age range, gender, COPD severity, diagnostic criteria, baseline lung function, smoking history, inclusion criteria, exclusion criteria).
Interventions (run-in, intervention treatment and inhaler type, control treatment and inhaler type).
Outcomes (primary and secondary outcomes specified and collected, time points reported).
Two authors extracted data from the studies into data collection forms. We discussed and resolved any discrepancies in the data, or consulted a third party where necessary. We transferred data from the data collection forms into Review Manager 5.
Assessment of risk of bias in included studies
We assessed the risk of bias according to recommendations outlined in the Cochrane Handbook for Systematic reviews of Interventions (Higgins 2008) for the following items.
Allocation sequence generation.
Concealment of allocation.
Blinding of participants and investigators.
Incomplete outcome data.
Selective outcome reporting.
We noted other sources of bias. We graded each potential source of bias as low, high or unclear risk of bias.
Measures of treatment effect
Dichotomous data
We analysed dichotomous data variables (such as mortality and withdrawals) using odds ratios (OR). If count data were not available as the number of participants experiencing an event, we analysed the data as continuous, time-to-event or rate ratios, depending on how they were reported. This includes the outcomes: hospital admissions, exacerbations, and serious adverse events.
Continuous data
We analysed continuous outcome data (such as FEV1 and quality of life) as fixed-effect model mean differences (MD) when the same scale was used, and standardised mean differences when different scales were employed in different studies. Mean difference based on the change from baseline was preferred over mean difference based on absolute values.
If data were not available for the same time point in all studies, we used the closest time points. Alternatively, end of study was used as a time of analysis for all studies. We used intention-to-treat (ITT) analysis on outcomes from all randomised participants, where possible, for primary analyses.
Unit of analysis issues
We analysed 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 contacted investigators or study sponsors in order to verify key study characteristics and obtain missing numerical outcome data, where possible. We also considered the impact of the unknown status of participants who withdrew from the trials as part of the sensitivity analysis.
Assessment of heterogeneity
We assessed the amount of statistical variation between the study results with the I2 statistic measurement.
Assessment of reporting biases
We minimised reporting bias from non-publication of studies or selective outcome reporting by using a broad search strategy, contacting study authors directly and checking references of included studies. If we had found sufficient numbers of trials, we planned to visually inspect funnel plots.
Data synthesis
We combined dichotomous data using Mantel-Haenzsel odds ratios with 95% confidence intervals, with a fixed-effect model. Where events were rare, we employed the Peto odds ratio (OR) (since this does not require a continuity correction for zero cells). Where treatment effects were reported as a mean difference with 95% confidence interval or exact P value, we calculated the standard error, entered it with the mean difference (MD) and combined the results using a fixed effect Generic Inverse Variance (GIV) model in Review Manager 5.
Rate ratios and hazard ratios were combined using a fixed-effect GIV model.
Numbers needed to treat would have been calculated from the pooled odds ratio and its confidence interval (CI), and applied to appropriate levels of baseline risk.
We presented the findings of our primary outcomes in a summary of findings table using GradePro software and recommendations in the Handbook for Systematic Reviews of Interventions (Higgins 2008).
Subgroup analysis and investigation of heterogeneity
Studies were subgrouped, where possible, according to:
type of long-acting beta-agonist;
severity of disease at baseline; and
tiotropium formulation.
Sensitivity analysis
We assessed the sensitivity of our primary outcomes to degree of bias by comparing the overall results with those exclusively from trials assessed as being at low risk of bias. We also compared the results from the fixed-effect models with results from random-effects models.
RESULTS
Description of studies
Results of the search
The database search identified 172 references in September 2011 and an additional five references in January 2012. Of these we identified 27 as potentially relevant, which we obtained in full text for further assessment. Fifteen of these were eligible and belonged to five studies (Aaron 2007; Mahler 2010a; Mahler 2010b; Tashkin 2009; Vogelmeier 2008) (see Characteristics of included studies). Searching the manufacturers’ web sites we found study reports for three of the included studies (Mahler 2010a; Mahler 2010b; Vogelmeier 2008). Searching clinicaltrials.gov in September 2011 did not generate any additional eligible trials. For the study flow diagram see Figure 1.
Figure 1.
Study flow diagram.
Included studies
Study design
The longest study was Aaron 2007 with a duration of one year, then Vogelmeier 2008 with 24 weeks and Mahler 2010a, Mahler 2010b and Tashkin 2009 with 12 weeks of treatment. They were all multi-centre studies. The Aaron 2007 study was conducted at 27 Canadian medical centres, Tashkin 2009 in 35 centres across the United States, and three studies were conducted in a large number of study centre in several different countries (Mahler 2010a; Mahler 2010b; Vogelmeier 2008).
Sample size
There were 3473 participants randomised to the relevant treatment arms in the included studies: LABA + tiotropium (1621), tiotropium (1642), and LABA (210).
Participants
The mean age of participants varied from 63 to 68 years. The gender distribution varied from 54% to 79% males. All studies included participants with moderate to severe COPD, although Aaron 2007 and Vogelmeier 2008 also included patients with very severe COPD (FEV1 less than 30% predicted) according to GOLD guideline definitions of COPD. The mean baseline lung function varied between 38% and 52% predicted across the studies.
Interventions
All included studies used 18 μg of tiotropium (Handihaler), one inhalation daily. In Aaron 2007 the LABA used was salmeterol 25 μg/puff, two puffs twice daily using a pressurized metered-dose inhaler and a spacer device. Both Mahler 2010a and Mahler 2010b used indacaterol single-dose dry powder inhaler (SDDPI) at 150 μg once daily. Tashkin 2009 and Vogelmeier 2008 both used formoterol. In Tashkin 2009 the dose used was 12 μg twice daily (Foradil Aerolizer) and in Vogelmeier 2008 the concentration was 10 μg twice daily (multi-dose dry powder inhaler).
Permitted co-treatment
In all five studies participants were allowed to use inhaled salbutamol, when necessary, to relieve symptoms. Mahler 2010a, Mahler 2010b, Tashkin 2009 and Vogelmeier 2008 permitted continued use of regimens of inhaled corticosteroid that were stable prior to entry throughout the study. In Aaron 2007 respiratory medications such as oxygen, antileukotrienes, and methylxanthines were continued in all patient groups.
Outcomes
The primary outcome for Aaron 2007 was the proportion of patients suffering one or more COPD exacerbations. The primary outcome for Vogelmeier 2008 was FEV1 measured two hours post-dose at the end of the study. In Tashkin 2009 the primary outcome was also post-dose FEV1, but the normalised area under the curve for FEV1 measured from zero to four hours post-morning dose at the last visit.
Funding
The Aaron 2007 study was funded by the Canadian Institutes of Health Research and the Ontario Thoracic Society. The Tashkin 2009 study was funded by Schering-Plough (markets formoterol) and Mahler 2010a, Mahler 2010b and Vogelmeier 2008 by Novartis (markets formoterol and indacaterol).
Excluded studies
Eleven studies failed to meet the eligibility criteria for the review (see Characteristics of excluded studies). Seven of these compared tiotropium alone with a long-acting beta2-agonist but had no treatment arm with a combination of the two (Bateman 2001; Brusasco 2003; Di Marco 2003; Fujimoto 2007; Gross 2003; Meyer 2008; ten Hacken 2007). Six studies were of crossover design (Gross 2003; Jones 2010; Meyer 2008; ten Hacken 2007; van Noord 2003; van Noord 2005) and seven had a treatment period shorter than 12 weeks (Fujimoto 2007; Gross 2003; Meyer 2008; New 2009; ten Hacken 2007; van Noord 2003; van Noord 2005).
Risk of bias in included studies
An assessment of the risk of bias is presented in the Characteristics of included studies table, and an overview of the findings is shown in (Figure 2).
Figure 2.
Risk of bias summary: review authors’ judgements about each risk of bias item for each included study.
Allocation
All three studies reported adequate sequence generation, through a computer generated system, and allocation concealment. Information from Vogelmeier 2008 was kindly supplied on request. In Aaron 2007 and Vogelmeier 2008 randomisation data were kept strictly confidential until the time of unbinding, and was not accessible by anyone involved in the study before or after randomisation. In Tashkin 2009 the randomisation code was labelled on the medication kit.
Blinding
The blinding in Aaron 2007 was adequate. In Aaron 2007 both research staff and patients were blinded to the treatment assignment until the end of the study. The different inhalers were identical and they were enclosed in tamper-proof blinding devices. Clinical data for suspected exacerbations were reviewed by a blinded committee and the statistician who performed the analysis was initially blinded to patient group assignments. The Vogelmeier 2008 study was partially blinded with tiotropium being administered open-label, but double-blind for the long-acting beta2-agonist treatment. The risk of performance bias was therefore high for the comparison LABA + tiotropium versus LABA, and low for LABA + tiotropium versus tiotropium. The risk of detection bias was also low as outcome assessors and data analysts were blinded to patient group assignments. Information from Vogelmeier 2008 was kindly supplied on request. Tashkin 2009 did not fully describe in the study report who was blinded.
Incomplete outcome data
Aaron 2007 suffered from high withdrawal rates in the different study groups (74 patients (47%) withdrew from the tiotropium + placebo group and 64 patients (43%) on LABA + tiotropium). For most patients, data were recorded throughout the one-year trial period regardless of whether patients discontinued treatment with study medications. The rates of patients who stopped therapy and did not complete the trial were 30 patients (19%) on tiotropium + placebo and 20 patients (14%) on LABA + tiotropium. Mortality data were obtained for all participants with the exception of two out of 148 participants (1.4%) on LABA + tiotropium and four out of 156 participants (2.6%) on tiotropium + placebo, who withdrew and declined further study. In Tashkin 2009 the number of withdrawals was also uneven but was relatively low (LABA + tiotropium (14.5%), and tiotropium + placebo (6.1%)). In the other three studies the number of withdrawals in the different groups were relatively low and even (Mahler 2010a: LABA + tiotropium (6.8%) and tiotropium + placebo (6.2%); Mahler 2010b: LABA + tiotropium (5.1%) and tiotropium + placebo (6.5%); Vogelmeier 2008: LABA + tiotropium (12%), LABA (12%) and tiotropium + placebo (13%)).
Selective reporting
All the included studies adequately reported outcome data for the primary and secondary outcomes that they had pre-specified in the study records, but we did not compare reported outcomes to the trial protocols.
Effects of interventions
See: Summary of findings for the main comparison LABA plus tiotropium versus tiotropium for chronic obstructive pulmonary disease
LABA plus tiotropium versus tiotropium
We planned to analyse the data using subgroups for disease severity, type of long-acting beta2-agonist, and tiotropium formulation. We subgrouped the data in the forest plots according to type of long-acting beta2-agonist. However, these need to be interpreted with caution because of the small number of trials and the many significant differences between them, including length of study.
Primary outcome: quality of life
Two studies (729 participants) looked at changes in quality of life using the St George’s Respiratory Questionnaire (SGRQ); Aaron 2007 added salmeterol to tiotropium and Vogelmeier 2008 added formoterol to tiotropium. A decrease in SGRQ score denotes an improvement in quality of life and a difference of at least four units is regarded as clinically significant (SGRQ-C manual 2008). Aaron 2007 showed an improvement in quality of life in the control arm, tiotropium alone, of −4.5 units after one year. The pooled result of the treatment difference between LABA + tiotropium and tiotropium alone showed that the combination treatment led to −6.1 unit improvement in quality of life. This difference was significantly larger (statistically) than with tiotropium alone (MD −1.61; 95% CI −2.93 to −0.29), see Figure 3. The confidence interval of this mean difference excludes the minimal clinically important difference of four units but there is additional uncertainty in relation to the quality of life in those patients who withdrew from the study.
Figure 3.
Forest plot of comparison: 1 LABA plus tiotropium versus tiotropium, outcome: 1.1 Change in quality of life.
Primary outcome: hospital admissions
Aaron 2007 and Vogelmeier 2008 (729 participants) also reported the number of patients who were admitted to hospital for any cause and due to exacerbations. Data for Aaron 2007 and Vogelmeier 2008 were kindly supplied on request. The number of hospitalised patients were similar and there was no statistically significant difference between the treatment groups for hospitalisations for any cause (OR 1.01; 95% CI 0.63 to 1.61) or due to exacerbation (OR 1.07; 95% CI 0.63 to 1.81). There was a wide confidence interval for the result as the total number of participants with an event was low, and there was additional uncertainty arising from the potential additional admissions that were not known in the patients who withdrew. See Figure 4 and Figure 5 respectively.
Figure 4.
Forest plot of comparison: 1 LABA plus tiotropium versus tiotropium, outcome: 1.2 Hospital admission (all cause).
Figure 5.
Forest plot of comparison: 1 LABA plus tiotropium versus tiotropium, outcome: 1.3 Hospital admission (exacerbation).
Primary outcome: mortality (all causes)
All five studies (3263 participants) reported mortality for formoterol, salmeterol and indacaterol, however, there were no deaths during the study periods in Tashkin 2009 and Vogelmeier 2008. In the remaining three studies there was no statistically significant difference between the treatment groups as the number of events was low, leading to wide confidence intervals for the difference between the groups (Peto OR 1.56; 95% CI 0.56 to 4.33), see Figure 6. Moreover, there were considerably more participants who discontinued treatment than the numbers who died, adding further uncertainty to the true impact on mortality.
Figure 6.
Forest plot of comparison: 1 LABA plus tiotropium versus tiotropium, outcome: 1.4 Mortality (all cause).
Secondary outcome: exacerbations
Three studies (987 participants), on formoterol and salmeterol, reported the number of patients suffering one or more exacerbation during the study period (Aaron 2007; Tashkin 2009; Vogelmeier 2008). Aaron 2007 defined exacerbations as a sustained worsening of the patient’s respiratory condition, from the stable state and beyond normal day-to-day variations, necessitating a change in regular medication in a patient with underlying COPD. Vogelmeier 2008 reported the number of patients suffering COPD exacerbations who required additional therapy, defined as COPD-related adverse events (AEs) requiring additional therapy, where COPD-related AEs were defined as AEs coding to the preferred terms: COPD, COPD exacerbated, cough, any term containing ‘dyspnoea’, lower respiratory tract infection, chronic bronchitis, bronchospasm, bronchial obstruction and respiratory failure; and additional therapy was any COPD therapy reported as being used to treat a COPD exacerbation, other than rescue bronchodilator. In Tashkin 2009 the definition of exacerbation was not described, but it was stated that most patients who needed treatment for their exacerbations received antibiotics alone or a course of antibiotics and systemic steroids. The baseline risk also varied greatly between the studies. In the one-year study (Aaron 2007) 62.8% of patients on tiotropium alone experienced one or more exacerbations, whereas in Tashkin 2009 and Vogelmeier 2008 the number was 10.7% and 10.4%, respectively. There was also substantial heterogeneity between the studies (I2 = 55%) and the exacerbation status of the patients who withdrew from each study was unknown. In Tashkin 2009 there were more patients experiencing exacerbations in the LABA + tiotropium group (OR 1.70; 95% CI 0.82 to 3.52); Vogelmeier 2008 showed the opposite result (OR 0.58; 95% CI 0.28 to 1.17); and in Aaron 2007 there was almost no difference between the groups (OR 1.09; 95% CI 0.68 to 1.75). In a sensitivity analysis Aaron 2007 reported a similar result when assuming that all patients who were lost to follow up had an exacerbation (OR 0.87; 95% CI 0.52 to 1.45). We did not pool the results for this outcome due to the clinical heterogeneity between the studies.
Secondary outcome: lung function (pre-dose FEV1)
All five studies (3263 participants) looked at lung function. Four of the studies looked at different measures of post-bronchodilator FEV1 as their primary outcome, but all five also reported pre-bronchodilator FEV1 values. The improvement in pre-bronchodilator FEV1 at the end of the study showed a statistically signifi-cant increase in the LABA + tiotropium group compared to the tiotropium group (MD 0.07 L; 95% CI 0.05 to 0.09). The improvement in FEV1 in the control arm, tiotropium alone, after six months of treatment was 0.13 L in Vogelmeier 2008 and 0.03 L after one year in Aaron 2007. Data for both Aaron 2007 and Vogelmeier 2008 were kindly supplied on request.
Secondary outcome: symptom score
Both Tashkin 2009 and Vogelmeier 2008 looked at changes in symptom scores. However, we were not able to obtain standard deviations for the data from Tashkin 2009. Vogelmeier 2008 used a total daily symptom score which was the sum of the scores for breathlessness, cough, wheeze, amount and colour of sputum. Each were scored on a scale from zero to three where zero was equal to no symptoms. Vogelmeier 2008 kindly supplied data on request which showed a large uncertainty and no statistically significant difference between the treatment groups in total symptom score (MD 0.21; 95% CI −0.30 to 0.72).
Secondary outcome: serious adverse events (non-fatal)
All five studies (3263 participants) reported the number of patients suffering from serious, but non-fatal, adverse events during the study period, for which there was no statistically significant difference (OR 1.09; 95% CI 0.76 to 1.55). However, the confidence interval was wide. Data for Vogelmeier 2008 were kindly supplied on request. It appears that Tashkin 2009 and Vogelmeier 2008 included COPD primary outcome data in the serious adverse events but Aaron 2007 did not.
Secondary outcome: withdrawal
All five studies (3263 participants) reported the number of withdrawals from study medication in each treatment group. Most of the studies had relatively even withdrawal rates and there was no statistically significant difference between the treatment groups (OR 1.00; 95% CI 0.74 to 1.37). The exception was Tashkin 2009 (LABA + tiotropium 12%, tiotropium alone 6%), which introduced moderate heterogeneity in the pooled result (I2 = 38%).
LABA plus tiotropium versus LABA
Vogelmeier 2008 was the only eligible study identified that compared LABA + tiotropium versus LABA (417 patients). The study was not blinded for this comparison for any of the outcomes as tiotropium was administered open-label. The LABA used in Vogelmeier 2008 was formoterol. The study reported the following results for outcomes of interest for this review.
Primary outcomes
For the primary outcomes there were no significant differences between the treatments for quality of life (SGRQ, MD 0.00; 95% CI −2.70 to 2.70) and the number of patients admitted to hospital for any cause (OR 1.02; 95% CI 0.37 to 2.76) (data kindly supplied by Vogelmeier 2008). There were, however, fewer patients admitted to hospital for an exacerbation in the formoterol + tiotropium group (3 people out of 207) compared to the formoterol group (9 people out of 221), but the number of events was low and the confidence intervals were wide (OR 0.35; 95% CI 0.09 to 1.30). There were no deaths reported in either of the treatment groups.
Secondary outcomes
For all of the secondary outcomes, there were wide confidence intervals and no statistically significant difference between formoterol + tiotropium and formoterol alone: number of patients suffering exacerbations (OR 0.76; 95% CI 0.36 to 1.61), lung function (pre-dose FEV1 at the end of study, MD 0.00 L; 95% CI −0.10 to 0.10), total symptom score (MD 0.09; 95% CI −0.46 to 0.64) (data kindly supplied by Vogelmeier 2008), number of patients suffering serious non-fatal adverse events (OR 1.07; 95% CI 0.44 to 2.63) (data kindly supplied by Vogelmeier 2008), and withdrawals (OR 1.02; 95% CI 0.56 to 1.84).
DISCUSSION
Summary of main results
This systematic review set out to investigate the long-term (three months or longer) effects of tiotropium in combination with LABA compared to either LABA alone or tiotropium alone, for the treatment of COPD. Five randomised, parallel group, placebo-controlled trials with 3473 participants were identified. All five studied the effects of tiotropium in combination with LABA compared to tiotropium alone, whereas only one of these studies (Vogelmeier 2008, 417 participants) also looked at tiotropium in combination with LABA compared to LABA alone.
LABA plus tiotropium versus tiotropium
This review found that compared to tiotropium alone, treatment with tiotropium plus long-acting beta2-agonist resulted in a slightly larger improvement in the mean health-related quality of life (SGRQ, MD −1.61; 95% CI −2.93 to −0.29). This represented a change from baseline of −6.1 units with both treatments compared to tiotropium alone, which improved by −4.5 units from baseline. This mean improvement was small in relation to the threshold of four units for a clinically significant difference. No significant differences were found in the other primary outcomes (hospital admissions and mortality). Pre-bronchodilator FEV1 also showed a statistically significant improvement with LABA + tiotropium compared to tiotropium alone. None of the other secondary outcomes (exacerbations, symptom scores, serious adverse events, and withdrawals) showed any statistically significant difference between the groups. There were, however, wide confidence intervals regarding the results for all outcomes and moderate heterogeneity for both exacerbations and withdrawals.
LABA plus tiotropium versus LABA
The study looking at the effect of formoterol + tiotropium versus formoterol (Vogelmeier 2008, 417 participants) showed very wide confidence intervals and no statistically significant difference between the treatment groups for any of the relevant outcomes reported: health-related quality of life, hospitalisations (all-cause and due to exacerbations), mortality (there were no deaths during the study period in either group), exacerbations, FEV1, symptom scores, serious adverse events or withdrawals. The fact that only one study, with a relatively small total number of participants, was included in this review makes the result for outcomes with few events or small differences less reliable.
Overall completeness and applicability of evidence
The lack of clear differences in effect between the treatment groups for many of the outcomes may be due to the relatively short treatment duration, with four out of five studies being shorter than one year. This led to few events, wide confidence intervals and low power to detect any differences. For continuous outcomes such as lung function, quality of life and symptom scores, studies with a duration of less than six months may not provide enough time to reach a steady state, which may also influence the result in a conservative way.
The results from this review indicate a small improvement in the mean health-related quality of life and lung function for patients on a combination of LABA and tiotropium compared to tiotropium alone. The mean improvement for both outcomes was statistically significant but relatively small in relation to the minimum clinically important difference for each outcome. However, there may still be a significant number of patients who have a clinically relevant improvement compared to the number with a clinically relevant deterioration. This kind of responder analysis may be a useful additional way of measuring health-related quality of life.
Quality of the evidence
We encountered heterogeneity in the outcomes COPD exacerbations and the number of patients withdrawing from the studies. This could be from one or more of several sources, such as the differences in definition of exacerbation and the length of the studies. The smallest study (Tashkin 2009, 255 participants) had more uneven withdrawal rates compared with the other studies.
Agreements and disagreements with other studies or reviews
In addition to the long-term (three months or longer duration) studies presented in this review there have been several studies looking at acute and short-term (up to six weeks) effects of tiotropium + LABA compared to tiotropium or LABA alone (Cazzola 2010). One short-term, parallel group study also looked at health-related quality of life using the SGRQ (Tashkin 2008a). After six weeks treatment they found no difference between tiotropium + LABA compared to tiotropium alone. However, at least for LABA it may take up to six months of treatment to reach a steady state and to see the full effect on quality of life (Calverley 2007).
Cost effectiveness
The cost effectiveness of tiotropium + LABA treatment compared to both tiotropium alone and triple therapy consisting of ICS and LABA combination inhaler + tiotropium has been assessed for the Aaron 2007 study (Najafzadeh 2008). The setting for this one-year study was within the Canadian healthcare system and the cost effectiveness evaluation was based on 2006 prices. In this study, treatment with tiotropium + LABA resulted in both higher costs and a higher rate of exacerbations than treatment with tiotropium alone. However, when focusing on patients with severe COPD tiotropium + LABA resulted in equal exacerbation rates and slightly lower costs compared to tiotropium alone, although there was considerable uncertainty around this result. Therefore, based on Aaron 2007, tiotropium on its own is the most cost effective treatment compared to tiotropium + LABA when looking at the incremental cost for exacerbations avoided and per additional quality adjusted life year. However, for a chronic illness like COPD a cost effectiveness study of one year is unlikely to capture all relevant costs and benefits.
AUTHORS’ CONCLUSIONS
Implications for practice
The results from this review indicate a small mean improvement in health-related quality of life for patients on a combination of tiotropium and long-acting beta2-agonist compared to tiotropium alone, but it is not clear how clinically important this mean difference may be. Hospital admission and mortality have not been shown to be altered by adding long-acting beta2-agonists to tiotropium. There were not enough data to determine the relative efficacy and safety of tiotropium plus long-acting beta2-agonist compared to long-acting beta2-agonist alone. There were insufficient data to make comparisons between the different long-acting beta2-agonists when used in addition to tiotropium.
Implications for research
Additional long-term (12 months or longer) larger studies are needed to clarify the risks and benefits of tiotropium + LABA treatment compared to the individual drugs. If the number of participants is large enough this will enable analysis to assess the suitability of this combination of therapies for patients with different severities of COPD. For quality of life measurements in future studies, it may be beneficial to use both mean changes with 95% confidence intervals and responders analysis. However, the responders analysis would preferably include both the number of people who have a clinically meaningful improvement as well as the number of people who have a clinically meaningful worsening. Presenting just one side of the data distribution, as in the percentage of patients with a clinically meaningful improvement, is becoming more common but is of limited value.
PLAIN LANGUAGE SUMMARY.
Is it better to take a combination of tiotropium and long-acting beta2-agonists than either inhaler alone for the treatment of COPD?
Chronic obstructive pulmonary disease (COPD) is a lung disease which includes the conditions chronic bronchitis and emphysema. The symptoms include breathlessness and a chronic cough. COPD is an irreversible disease that is usually brought on by airway irritants, such as smoking or inhaled dust.
Long-acting beta2-agonists and tiotropium are two types of inhaled medications that help widen the airways (bronchodilators) for up to 12 to 24 hours. These bronchodilators are commonly used to manage persistent symptoms of COPD. They can be used in combination or on their own. These bronchodilators work in different ways and therefore might be more beneficial if used together. The purpose of this review was to determine the benefits and risks of using a combination of both types of bronchodilator compared to the individual bronchodilators.
We found five studies involving 3263 patients comparing the long-term efficacy and side effects of combining tiotropium with a long-acting beta2-agonist. The combination of tiotropium plus long-acting beta2-agonist resulted, on average, in a slightly better quality of life and lung function for the patients compared to using only tiotropium, but did not show a difference in hospital admissions or mortality. There were not enough data to determine the risks and benefits of tiotropium plus long-acting beta2-agonist treatment compared to long-acting beta2-agonist alone.
ACKNOWLEDGEMENTS
We are grateful to Elizabeth Stovold for help in designing the search strategy, Elora Baishnab for going through the search and extracting data for relevant studies, and Steven Edwards for his feedback on incorporation of an economic perspective in the review.
CRG Funding Acknowledgement: The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Airways Group.
Disclaimer: The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health.
SOURCES OF SUPPORT
Internal sources
St George’s University of London, UK.
External sources
NIHR, UK.
Programme grant funding
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON
LABA plus tiotropium versus tiotropium for chronic obstructive pulmonary disease
Patient or population: chronic obstructive pulmonary disease
Settings:
Intervention: LABA plus tiotropium versus tiotropium
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | No of Participants (studies) | Quality of the evidence (GRADE) | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Tiotropium | LABA plus tiotropium | |||||
|
Change in quality of life St George’s Respiratory Questionaire (SGRQ). Scale from: 0 to 100. Follow-up: 6 to 12 months |
The mean change in quality of life in the control group was −4.5 units1 |
The mean change in quality of life in the intervention group was −6.3 units1 (−7.43 to −4.79) |
MD −1.61 (−2.93 to −0.29) |
732 (2 studies) |
⊕⊕⊕○ moderate2 |
The mean treatment effect was statistically significant but it was smaller than what is regarded as a clinically important difference |
|
Exacerbations leading to hospital admission Number of patients experiencing one or more events Follow-up: 6 to 12 months |
88 per 1000 |
93 per 1000 (57 to 148) |
OR 1.07 (0.63 to 1.81) |
732 (2 studies) |
⊕⊕○○ low2,3 |
|
|
Hospital admission (all cause) Number of patients experiencing one or more events Follow-up: 6 to 12 months |
119 per 1000 |
120 per 1000 (79 to 179) |
OR 1.01 (0.63 to 1.61) |
732 (2 studies) |
⊕⊕○○ low2,3 |
|
|
Mortality (all cause) Number of patients Follow-up: 3 to 12 months |
4 per 1000 |
6 per 1000 (2 to 16) |
OR 1.56 (0.56 to 4.33) |
3263 (5 studies) |
⊕⊕○○ low4 |
|
The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
The control group risk is based on Aaron 2007.
One study was a year long with high and unbalanced dropouts.
Wide confidence interval and few participants and events.
There were two trials with no deaths and few deaths in the remaining three trials, leading to a wide confidence interval. Mortality was largely unknown in those WHO discontinued treatment.
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
| Methods | Design: A randomised, double-blind, placebo-controlled, parallel group trial from October 2003 to January 2006. The trial included 27 Canadian medical centres; 20 centres were academic hospital-based pulmonary clinics, 5 were community-based pulmonary clinics, and 2 were community-based primary care clinics | |
| Participants |
Population: 304 adults, with a clinical history of moderate or severe COPD as defined by ATS and GOLD guidelines, were randomised to tiotropium + salmeterol (148) and tiotropium (156) Baseline Characteristics: Mean age 68 years. COPD severity moderate to severe with mean FEV1 predicted of 38%. 57% men. Inclusion Criteria: At least 1 exacerbation of COPD that required treatment with systemic steroids or antibiotics within the 12 months before randomisation; age older than 35 years; a history of 10 pack-years or more of cigarette smoking; documented chronic airflow obstruction, with an FEV1/FVC ratio less than 0.70 and a post-bronchodilator FEV1 less than 65% of the predicted value. Exclusion Criteria: History of physician-diagnosed asthma before 40 years of age; history of physician-diagnosed chronic congestive heart failure with known persistent severe left ventricular dysfunction; those receiving oral prednisone; those with a known hypersensitivity or intolerance to tiotropium, salmeterol, or fluticasone-salmeterol; history of severe glaucoma or severe urinary tract obstruction, previous lung transplantation or lung volume reduction surgery, or diffuse bilateral bronchiectasis; and those WHO were pregnant or were breastfeeding |
|
| Interventions |
1. Tiotropium + salmeterol: tiotropium 18 μg once daily using a Handihaler plus salmeterol 25 μg/puff, 2 puffs twice daily using a pressurized metered-dose inhaler using a spacer device 2. Tiotropium + placebo: tiotropium, 18 μg once daily, plus placebo inhaler, 2 puffs twice daily |
|
| Outcomes |
Primary: Proportion of patients with one or more exacerbation of COPD Secondary: Mean number of COPD exacerbations per patient-year; the total number of exacerbations that resulted in urgent visits to a health care provider or emergency department; the number of hospitalizations for COPD; the total number of hospitalizations for all causes; changes in health-related quality of life, dyspnoea, lung function |
|
| Notes | Co-medication: All study patients were provided with inhaled albuterol and were instructed to use it when necessary to relieve symptoms. At baseline, tiotropium + placebo group 52% on combined inhalers (ICS+LABA), 25% on ICS inhaler; tiotropium + salmeterol group 44% on combined inhalers (ICS+LABA) and 35% on ICS inhalers. Any treatment with inhaled corticosteroids, long-acting 2-agonists, and anticholinergics that the patient may have been using before entry was discontinued on entry into the study. Therapy with other respiratory medications, such as oxygen, antileukotrienes, and methylxanthines, was continued in all patient groups | |
| Risk of bias | ||
| Bias | Authors’ judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Randomisation was done through central allocation of a randomisation schedule that was prepared from a computer-generated random listing of the 3 treatment allocations, blocked in variable blocks of 9 or 12 and stratified by site |
| Allocation concealment (selection bias) | Unclear risk | Neither research staff nor patients were aware of the treatment assignment before or after randomisation |
| Blinding of participants and personnel (LABA+TIO versus TIO) (performance bias) | Low risk | Neither research staff nor patients were aware of the treatment assignment before or after randomisation. The metered-dose inhalers containing placebo, salmeterol, and fluticasone-salmeterol were identical in taste and appearance, and they were enclosed in identical tamper-proof blinding devices. The medication canisters within the blinding devices were stripped of any identifying labelling |
| Blinding of outcome assessment (detection bias) Exacerbations |
Low risk | The assembled data from the visit for the suspected exacerbation were presented to a blinded adjudication committee for review, and the committee confirmed whether the encounter met the study definition of COPD exacerbation |
| Incomplete outcome data (attrition bias) All outcomes |
Unclear risk | The number of people WHO stopped drug therapy was high in both groups. 74 patients (47%) withdrew from the tiotropium + placebo group and 64 patients (43%) on LABA + tiotropium group. However, the number of people WHO did not complete the trial was lower (30 patients (19%) on tiotropium + placebo and 20 patients (14%) on LABA + tiotropium). The incomplete data were however addressed by sensitivity analyses of the data comprising alternative assumptions for patients WHO prematurely withdrew from treatment |
| Selective reporting (reporting bias) | Low risk | Results for all listed primary and secondary outcomes were reported |
| Methods | Design: Amulti-centre, multi-national, randomised, double-blind, parallel-group study from March 2009 to March 2010. The trial included 186 study centres in 14 countries: Argentina (10), Australia (6), Colombia (5), Denmark (5), Germany (25), Greece (4), Guatemala (5), Mexico (5), Peru (6), Philippines (2), South Africa (6), Spain (13), Turkey (13), and USA (81) | |
| Participants |
Population: 1134 patients with a clinical history of moderate or severe COPD as defined by GOLD guidelines, were randomised to tiotropium + indacaterol (570) and tiotropium (564) Baseline Characteristics: Mean age 64 years, 67% male, mean FEV1 1.3 L, mean FEV1 predicted 49%, 47 pack-years smoking history. Inclusion Criteria: Men and women aged ≥40 years with moderate-to-severe COPD, with a smoking history ≥10 pack-years and post-bronchodilator FEV1 ≤ 65% and ≥ 30% predicted and FEV1/FVC < 70%. Exclusion Criteria: Patients WHO have received systematic corticosteroids and/or antibiotics and/or was hospitalised for a COPD exacerbation in the 6 weeks prior to screening or during the run-in period or had a respiratory tract infection within 6 weeks prior to screening. Patients with concomitant pulmonary disease, a history of asthma, diabetes Type I or uncontrolled diabetes Type II, lung cancer or a history of lung cancer, a history of certain cardiovascular comorbid conditions |
|
| Interventions |
1. Indacaterol 150 μg through single-dose dry powder inhaler (SDDPI), once daily + tiotropium 18 μg through SDDPI Handihaler, once daily 2. Placebo to indacaterol + tiotropium 18 μg through SDDPI Handihaler, once daily |
|
| Outcomes |
Primary: Standardised area under the curve (AUC) FEV1 between 5min and 8h post-dose after 12 weeks of treatment. Secondary: Trough FEV1 on day 1 and after 12 weeks treatment, FEV1 AUC (5min-8h) day 1, FEV1 AUC (5min-4h) on day 1 and after 12 weeks of treatment, resting inspiratory capacity (IC), use of albuterol as rescue medication, safety (adverse events and serious adverse events) |
|
| Notes | Co-medication: Albuterol was available for rescue use. Patients (53%) receiving inhaled corticosteroids (ICS) at baseline continued treatment (or the ICS component alone if taken as a fixed combination with a bronchodilator) at equivalent dose and regimen throughout the study | |
| Risk of bias | ||
| Bias | Authors’ judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | A patient randomisation list was produced by the IVRS provider using a validated system that automates the random assignment of patient numbers to randomisation numbers |
| Allocation concealment (selection bias) | Low risk | The randomisation numbers were linked to the different treatment arms, which in turn were linked to medication numbers. A separate medication randomisation list was produced by or under the responsibility of Novartis Drug Supply Management using a validated system that automates the random assignment of medication numbers to medication packs containing each of the study drugs |
| Blinding of participants and personnel (LABA+TIO versus TIO) (performance bias) | Low risk | Patients, investigator staff, persons performing the assessments, data analysts and the Novartis trial team were all blinded |
| Blinding of outcome assessment (detection bias) Exacerbations |
Low risk | Persons performing the assessments were blinded. |
| Incomplete outcome data (attrition bias) All outcomes |
Low risk | The withdrawal rates were low and even (tiotropium + indacaterol 6.8%, tiotropium 6.2%) |
| Selective reporting (reporting bias) | Low risk | Results for all listed primary and secondary outcomes were reported |
| Methods | Design: Amulti-centre, multi-national, randomised, double-blind, parallel-group study from April 2009 to February 2010. The trial included 182 study centres in 11 countries: Argentina (9), Canada (16), Colombia (3), Czech Republic (9), Hungary (4), India (9), Netherlands (6), Philippines (3), Slovakia (10), Spain (11), and USA (102) | |
| Participants |
Population: 1142 patients with a clinical history of moderate or severe COPD as defined by GOLD guidelines, were randomised to tiotropium + indacaterol (572) and tiotropium (570) Baseline Characteristics: Mean age 63 years, 65% male, mean FEV1 1.3 L, mean FEV1 predicted 49%, 46 pack-years smoking history. Inclusion Criteria: Men and women aged ≥40 years with moderate-to-severe COPD, with a smoking history ≥10 pack-years and post-bronchodilator FEV1 ≤ 65% and ≥ 30% predicted and FEV1/FVC < 70%. Exclusion Criteria: Patients WHO have received systematic corticosteroids and/or antibiotics and/or was hospitalised for a COPD exacerbation in the 6 weeks prior to screening or during the run-in period or had a respiratory tract infection within 6 weeks prior to screening. Patients with concomitant pulmonary disease, a history of asthma, diabetes Type I or uncontrolled diabetes Type II, lung cancer or a history of lung cancer, a history of certain cardiovascular comorbid conditions |
|
| Interventions |
1. Indacaterol 150 μg through single-dose dry powder inhaler (SDDPI), once daily + tiotropium 18 μg through SDDPI Handihaler, once daily 2. Placebo to indacaterol + tiotropium 18 μg through SDDPI Handihaler, once daily |
|
| Outcomes |
Primary: Standardised area under the curve (AUC) FEV1 between 5min and 8h post-dose after 12 weeks of treatment. Secondary: Trough FEV1 on day 1 and after 12 weeks treatment, FEV1 AUC (5min-8h) day 1, FEV1 AUC (5min-4h) on day 1 and after 12 weeks of treatment, resting inspiratory capacity (IC), use of albuterol as rescue medication, safety (adverse events and serious adverse events) |
|
| Notes | Co-medication: Albuterol was available for rescue use. Patients (53%) receiving inhaled corticosteroids (ICS) at baseline continued treatment (or the ICS component alone if taken as a fixed combination with a bronchodilator) at equivalent dose and regimen throughout the study | |
| Risk of bias | ||
| Bias | Authors’ judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | A patient randomisation list was produced by the IVRS provider using a validated system that automates the random assignment of patient numbers to randomisation numbers |
| Allocation concealment (selection bias) | Low risk | The randomisation numbers were linked to the different treatment arms, which in turn were linked to medication numbers. A separate medication randomisation list was produced by or under the responsibility of Novartis Drug Supply Management using a validated system that automates the random assignment of medication numbers to medication packs containing each of the study drugs |
| Blinding of participants and personnel (LABA+TIO versus TIO) (performance bias) | Low risk | Patients, investigator staff, persons performing the assessments, data analysts and the Novartis trial team were all blinded |
| Blinding of outcome assessment (detection bias) Exacerbations |
Low risk | Persons performing the assessments were blinded. |
| Incomplete outcome data (attrition bias) All outcomes |
Low risk | The withdrawal rates were low and even (tiotropium + indacaterol 5.1%, tiotropium 6.5%) |
| Selective reporting (reporting bias) | Low risk | Results for all listed primary and secondary outcomes were reported |
| Methods | Design: A randomised, double-blind, active-control, parallel group trial. The trial included 35 centres across the United States, of which the majority were primary care centres | |
| Participants |
Population: 255 adults with a clinical history of COPD were randomised to tiotropium + formoterol (124) and tiotropium (131) Baseline Characteristics: Mean age 64 years. COPD severity mild to severe. 67% men. Inclusion Criteria: Male and non-pregnant female patients aged >40 years WHO had a clinical history of COPD were enrolled in this study. Each patient had a post-bronchodilator FEV1 < 70% and >30% predicted normal or >0.75 L, whichever was less, at run-in, and a FEV1 to FVC ratio (FEV1/FVC) of < 0.70 at screening and run-in. Daytime and/or nighttime symptoms of COPD, including dyspnoea, must have been present on ≥4 of the 7 days before the baseline visit Exclusion Criteria: A current or previous history of asthma or other significant medical condition that may have interfered with study treatment as assessed by the investigator, smoking cessation within the previous 3 months, ventilator support for respiratory failure within the previous year, the use of oxygen (≥2 L/min or for >2 h/d), initiation of pulmonary rehabilitation within the previous 3 months, the requirement for nasal continuous positive airway pressure or bilevel positive airway pressure, clinically significant lung disease other than COPD (i.e., bronchiectasis, sarcoidosis, pulmonary fibrosis, tuberculosis), sleep apnoea, chronic narrow-angle glaucoma, symptomatic prostatic hyperplasia or bladder neck obstruction, and the need for chronic or prophylactic antibiotic therapy |
|
| Interventions |
1. Formoterol (Foradil Aerolizer) 12 μg twice daily and tiotropium (Handihaler) 18 μg once-daily in the morning delivered via 2 separate inhalers 2. Formoterol-matched placebo twice-daily and tiotropium 18 μg once-daily delivered via 2 separate inhalers |
|
| Outcomes |
Primary: The normalized area under the curve (AUC) for FEV1 measured 0 to 4 hours post-morning dose (FEV1 AUC 0-4 h) at the last visit. Secondary: Changes from baseline in trough (average of values obtained 10 and 30 min pre-dose) FEV1 and FVC, weekly morning and evening peak expiratory flow (PEF), symptom severity scores, transition dyspnoea index (TDI), and health related quality of life (St. George’s Respiratory Questionnaire, SGRQ) scores, number and severity of exacerbations, the global therapeutic response, discontinuations because of worsening COPD, and percentages of patients achieving targeted improvements in the SGRQ and TDI scores, use of rescue albuterol, nocturnal awakenings requiring rescue albuterol, changes in study or concomitant medications, and adverse events |
|
| Notes |
Co-medication: Continued use of prior stable inhaled corticosteroid (27%) regimens and systemic corticosteroids for the treatment of exacerbations was permitted throughout the study. All patients were provided with albuterol for use as rescue medication Run-in: Following screening, prohibited medications (i.e., beta-agonists, beta-blockers, cromolyn sodium, ipratropium bromide, leukotriene antagonists, cytotoxic agent, and theophylline) were withdrawn. Patients previously using TIO or FORM discontinued the drugs at least 4 weeks or 48 hours before screening, respectively. Patients completed a 2-week run-in period using placebo and as-needed rescue albuterol |
|
| Risk of bias | ||
| Bias | Authors’ judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Patients were randomised sequentially as they qualified for the study according to a pre-generated computer code labelled on the medication kit |
| Allocation concealment (selection bias) | Unclear risk | A pre-generated computer code was labelled on the medication kit |
| Blinding of participants and personnel (LABA+TIO versus TIO) (performance bias) | Unclear risk | Not described |
| Blinding of outcome assessment (detection bias) Exacerbations |
Unclear risk | Not described |
| Incomplete outcome data (attrition bias) All outcomes |
Unclear risk | The number of withdrawals in the different groups was relatively low but uneven (LABA + tiotropium (14.5%), and tiotropium + placebo (6.1%)) |
| Selective reporting (reporting bias) | Low risk | Results for all listed primary and secondary outcomes were reported |
| Methods |
Design: A randomised, partly-blind , partly placebo-controlled, parallel group trial from October 2004 to November 2005. The trial included 86 centres in Germany (30), Italy (19), Netherlands (9), Russian federation (9), Poland (7), Czech Republic (4), Spain (4) and Hungary (4) |
|
| Participants |
Population: 638 adults, with a clinical history of moderate to very severe COPD as defined by GOLD guidelines, were randomised to tiotropium + formoterol (207), formoterol (210), and tiotropium (221) Baseline Characteristics: Mean age 63 years. COPD severity moderate to very severe with mean FEV1 predicted of 52%. 78% men. Inclusion Criteria: Males and females with stable COPD aged ≥40 years at COPD onset and with a smoking history of ≥10 pack-years, forced expiratory volume in 1 second (FEV1) < 70% of patient’s predicted normal value (and ≥1.00 L), and FEV1/forced vital capacity (FVC) < 70%. They were to be symptomatic on at least 4 of 7 days prior to randomisation (symptom score >0 on diary card) Exclusion Criteria: Patients WHO had a respiratory tract infection or had been hospitalised for an acute exacerbation of COPD within the month prior to screening. Patients with a clinically significant condition such as ischaemic heart disease that might compromise patient safety or compliance were also excluded |
|
| Interventions |
1. Formoterol 10 μg twice daily via multi-dose dry powder inhaler (MDDPI) 2. Tiotropium 18 μg once daily via the HandiHaler + formoterol 10 μg via MDDPI |
|
| Outcomes |
Primary: FEV1 measured 2 hours post-dose after 24 weeks of treatment. Secondary: FEV1 and FVC at other time points during the study (5 min, 2 and 3 hours post-dose following the first dose of treatment, and after 12 and 24 weeks of treatment); COPD exacerbations; symptom scores, rescue medication use and PEF; quality of life, and 6-minute walking distance |
|
| Notes |
Co-medication: Salbutamol pMDI (2 × 100 μg/puff) was permitted as rescue medication. Patients were asked not to use salbutamol in the 8 hours before a study visit. Patients (40 to 44%) could receive inhaled corticosteroids (ICS) at a stable daily dose (any patients receiving fixed combinations of ICS and beta2-agonists were switched to receive the same dose of ICS and on demand salbutamol) Run-in: A screening period of up to 4 weeks included 2 weeks for washout of disallowed medications and 2 weeks for eligibility assessment and baseline evaluations |
|
| Risk of bias | ||
| Bias | Authors’ judgement | Support for judgement |
| Random sequence generation (selection bias) | Low riks | A randomisation list was produced using a validated system that automates the random assignment of treatment groups to randomisation numbers in the specified ratio. The randomisation scheme was reviewed by a Biostatistics Quality Assurance Group and locked by them after approval |
| Allocation concealment (selection bias) | Low risk | Randomisation data were kept strictly confidential until the time of unbinding, and was not accessible by anyone else involved in the study |
| Blinding of participants and personnel (LABA+TIO versus TIO) (performance bias) | Low risk | The study was partially blinded. The study was double-blind for treatment comparison tiotropium + formoterol vs. tiotropium + placebo(MDDPI only), but not for other comparisons as tiotropium was administered open-label. Randomisation was not stratified. Certihaler active and placebo devices were identical in packaging, labelling, schedule of administration and appearance |
| Blinding of participants and personnel (LABA+TIO versus LABA) (performance bias) | High risk | The study was partially blinded. The study was double-blind for treatment comparison tiotropium + formoterol vs. tiotropium + placebo (MDDPI only), but not for other comparisons as tiotropium was administered open-label. Randomisation was not stratified. Certihaler active and placebo devices were identical in packaging, labelling, schedule of administration and appearance |
| Blinding of outcome assessment (detection bias) Exacerbations |
Low risk | Persons performing the assessments, and data analysts were blinded to the identity of the treatment from the time of randomisation until database lock |
| Incomplete outcome data (attrition bias) All outcomes |
Low risk | The number of withdrawals in the different groups were relatively low and even (LABA + tiotropium (12.1%), formoterol (11.9%) and tiotropium + placebo (13.1%)) |
| Selective reporting (reporting bias) | Low risk | Results for all listed primary and secondary outcomes were reported |
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Bateman 2001 | No tiotropium plus long-acting beta2-agonists combination treatment |
| Brusasco 2003 | No tiotropium plus long-acting beta2-agonists combination treatment |
| Di Marco 2003 | No tiotropium plus long-acting beta2-agonists combination treatment |
| Fujimoto 2007 | 8 weeks of treatment and no tiotropium plus long-acting beta2-agonists combination treatment |
| Gross 2003 | 4 weeks of treatment, no tiotropium plus long-acting beta2-agonists combination treatment, and crossover design |
| Jones 2010 | crossover design |
| Meyer 2008 | 2 weeks of treatment, no tiotropium plus long-acting beta2-agonists combination treatment, and crossover design |
| New 2009 | 6 weeks of treatment |
| ten Hacken 2007 | 6 weeks of treatment, no tiotropium plus long-acting beta2-agonists combination treatment, and crossover design |
| van Noord 2003 | 6 weeks of treatment and crossover design |
| van Noord 2005 | 6 weeks of treatment and crossover design |
DATA AND ANALYSES
Comparison 1.
LABA plus tiotropium versus tiotropium
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Change in quality of life | 2 | 732 | Mean Difference (Fixed, 95% CI) | −1.61 [−2.93, −0.29] |
| 1.1 Salmeterol | 1 | 304 | Mean Difference (Fixed, 95% CI) | −1.8 [−3.32, −0.28] |
| 1.2 Formoterol | 1 | 428 | Mean Difference (Fixed, 95% CI) | −1.0 [−3.70, 1.70] |
| 2 Hospital admission (all cause) | 2 | 732 | Odds Ratio (M-H, Fixed, 95% CI) | 1.01 [0.63, 1.61] |
| 2.1 Salmeterol | 1 | 304 | Odds Ratio (M-H, Fixed, 95% CI) | 1.03 [0.61, 1.76] |
| 2.2 Formoterol | 1 | 428 | Odds Ratio (M-H, Fixed, 95% CI) | 0.95 [0.36, 2.50] |
| 3 Hospital admission (exacerbation) | 2 | 732 | Odds Ratio (M-H, Fixed, 95% CI) | 1.07 [0.63, 1.81] |
| 3.1 Salmeterol | 1 | 304 | Odds Ratio (M-H, Fixed, 95% CI) | 1.16 [0.66, 2.06] |
| 3.2 Formoterol | 1 | 428 | Odds Ratio (M-H, Fixed, 95% CI) | 0.64 [0.15, 2.69] |
| 4 Mortality (all cause) | 5 | 3263 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.56 [0.56, 4.33] |
| 4.1 Salmeterol | 1 | 304 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.59 [0.45, 5.62] |
| 4.2 Formoterol | 2 | 683 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 4.3 Indacaterol | 2 | 2276 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.48 [0.26, 8.57] |
| 5 Exacerbation | 3 | Odds Ratio (M-H, Random, 95% CI) | Totals not selected | |
| 5.1 Salmeterol | 1 | Odds Ratio (M-H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 5.2 Formoterol | 2 | Odds Ratio (M-H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6 Trough FEV1 | 5 | 3263 | Mean Difference (Fixed, 95% CI) | 0.07 [0.05, 0.09] |
| 6.1 Salmeterol | 1 | 304 | Mean Difference (Fixed, 95% CI) | 0.03 [−0.07, 0.13] |
| 6.2 Formoterol | 2 | 683 | Mean Difference (Fixed, 95% CI) | 0.06 [0.02, 0.11] |
| 6.3 Indacaterol | 2 | 2276 | Mean Difference (Fixed, 95% CI) | 0.07 [0.05, 0.10] |
| 7 Symptom score | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 7.1 Formoterol | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 8 Serious adverse event (non-fatal) | 5 | 3263 | Odds Ratio (M-H, Fixed, 95% CI) | 1.09 [0.76, 1.55] |
| 8.1 Salmeterol | 1 | 304 | Odds Ratio (M-H, Fixed, 95% CI) | 0.95 [0.37, 2.40] |
| 8.2 Formoterol | 2 | 683 | Odds Ratio (M-H, Fixed, 95% CI) | 1.07 [0.54, 2.13] |
| 8.3 Indacaterol | 2 | 2276 | Odds Ratio (M-H, Fixed, 95% CI) | 1.14 [0.72, 1.81] |
| 9 Withdrawal | 5 | 3263 | Odds Ratio (M-H, Random, 95% CI) | 1.00 [0.74, 1.37] |
| 9.1 Salmeterol | 1 | 304 | Odds Ratio (M-H, Random, 95% CI) | 0.84 [0.54, 1.33] |
| 9.2 Formoterol | 2 | 683 | Odds Ratio (M-H, Random, 95% CI) | 1.46 [0.52, 4.09] |
| 9.3 Indacaterol | 2 | 2276 | Odds Ratio (M-H, Random, 95% CI) | 0.93 [0.65, 1.34] |
Analysis 1.1. Comparison 1 LABA plus tiotropium versus tiotropium, Outcome 1 Change in quality of life
Review: Long-acting beta2-agonist in addition to tiotropium versus either tiotropium or long-acting beta2-agonist alone for chronic obstructive pulmonary disease
Comparison: 1 LABA plus tiotropium versus tiotropium
Outcome: 1 Change in quality of life
 |
Analysis 1.2. Comparison 1 LABA plus tiotropium versus tiotropium, Outcome 2 Hospital admission (all cause)
Review: Long-acting beta2-agonist in addition to tiotropium versus either tiotropium or long-acting beta2-agonist alone for chronic obstructive pulmonary disease
Comparison: 1 LABA plus tiotropium versus tiotropium
Outcome: 2 Hospital admission (all cause)
 |
Analysis 1.3. Comparison 1 LABA plus tiotropium versus tiotropium, Outcome 3 Hospital admission (exacerbation)
Review: Long-acting beta2-agonist in addition to tiotropium versus either tiotropium or long-acting beta2-agonist alone for chronic obstructive pulmonary disease
Comparison: 1 LABA plus tiotropium versus tiotropium
Outcome: 3 Hospital admission (exacerbation)
 |
Analysis 1.4. Comparison 1 LABA plus tiotropium versus tiotropium, Outcome 4 Mortality (all cause)
Review: Long-acting beta2-agonist in addition to tiotropium versus either tiotropium or long-acting beta2-agonist alone for chronic obstructive pulmonary disease
Comparison: 1 LABA plus tiotropium versus tiotropium
Outcome: 4 Mortality (all cause)
 |
Analysis 1.5. Comparison 1 LABA plus tiotropium versus tiotropium, Outcome 5 Exacerbation
Review: Long-acting beta2-agonist in addition to tiotropium versus either tiotropium or long-acting beta2-agonist alone for chronic obstructive pulmonary disease
Comparison: 1 LABA plus tiotropium versus tiotropium
Outcome: 5 Exacerbation
 |
Analysis 1.6. Comparison 1 LABA plus tiotropium versus tiotropium, Outcome 6 Trough FEV1
Review: Long-acting beta2-agonist in addition to tiotropium versus either tiotropium or long-acting beta2-agonist alone for chronic obstructive pulmonary disease
Comparison: 1 LABA plus tiotropium versus tiotropium
Outcome: 6 Trough FEV1
 |
Analysis 1.7. Comparison 1 LABA plus tiotropium versus tiotropium, Outcome 7 Symptom score
Review: Long-acting beta2-agonist in addition to tiotropium versus either tiotropium or long-acting beta2-agonist alone for chronic obstructive pulmonary disease
Comparison: 1 LABA plus tiotropium versus tiotropium
Outcome: 7 Symptom score
 |
Analysis 1.8. Comparison 1 LABA plus tiotropium versus tiotropium, Outcome 8 Serious adverse event (non-fatal)
Review: Long-acting beta2-agonist in addition to tiotropium versus either tiotropium or long-acting beta2-agonist alone for chronic obstructive pulmonary disease
Comparison: 1 LABA plus tiotropium versus tiotropium
Outcome: 8 Serious adverse event (non-fatal)
 |
 |
Analysis 1.9. Comparison 1 LABA plus tiotropium versus tiotropium, Outcome 9 Withdrawal
Review: Long-acting beta2-agonist in addition to tiotropium versus either tiotropium or long-acting beta2-agonist alone for chronic obstructive pulmonary disease
Comparison: 1 LABA plus tiotropium versus tiotropium
Outcome: 9 Withdrawal
 |
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 (the Cochrane Library) | Quarterly |
| PSYCHINFO (Ovid) | Monthly |
| CINAHL (Ebsco) | Monthly |
| AMED (Ebsco) | Monthly |
Handsearches: core respiratory conference abstracts
| Conference | Years searched |
|---|---|
| AmericanAcademy 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 PrimaryCareRespiratoryGroupCongress (IPCRG) | 2002 onwards |
| Thoracic Society of Australia and New Zealand (TSANZ) | 1999 onwards |
MEDLINE search strategy used to identify trials for the CAGR
COPD search
Lung Diseases, Obstructive/
exp Pulmonary Disease, Chronic Obstructive/
emphysema$.mp.
(chronic$ adj3 bronchiti$).mp.
(obstruct$ adj3 (pulmonary or lung$ or airway$ or airflow$ or bronch$ or respirat$)).mp.
COPD.mp.
COAD.mp.
COBD.mp.
AECB.mp.
or/1-9
Filter to identify RCTs
exp “clinical trial [publication type]”/
(randomised or randomised).ab,ti.
placebo.ab,ti.
dt.fs.
randomly.ab,ti.
trial.ab,ti.
groups.ab,ti.
or/1-7
Animals/
Humans/
9 not (9 and 10)
8 not 11
The MEDLINE strategy and RCT filter are adapted to identify trials in other electronic databases
Appendix 2. Search strategy for clinicaltrials.gov
COPD AND tiotropium AND salmeterol
COPD AND tiotropium AND formoterol
COPD AND tiotropium AND indacaterol
FEEDBACK
Feedback, 12 December 2013
Summary
We would like to provide the following feedback:
The risk of hospital admission with combination therapy can vary from 7.5% to 19%, given the assumed risk of 12% with monotherapy. Likewise, the risk of mortality can vary from 0.2% to 1.7%, assuming a baseline risk of 0.4%. With these wide confidence intervals, it may be more appropriate to say that the effect of combination therapy on these outcomes, compared with tiotropium monotherapy, is inconclusive due to the low event risk and small sample size. In other words, a clinically important increased or decreased risk of both outcomes cannot be ruled out based on current evidence. We feel this is clearer versus saying there is no difference versus monotherapy.
The addition of evidence for ipratropium, compared with placebo or tiotropium, would provide a more clear and complete rationale for the clinical question posed by the authors. Specifically, the authors could update their background to include a more recent Cochrane systematic review that compared tiotropium and ipratropium.
The mean difference was reported as -1.61 points [CI −2.93 to −0.29] on the St. George’s Respiratory Questionnaire (SGRQ). Since a clinically significant change in this score is 4 points, we can see that neither the point estimate nor the confidence interval approaches this difference. Also, the Aaron 2007 trial contributed significantly to this conclusion, but had 16% to 20% of missing outcome data that was not accounted for in a sensitivity analysis. This was also not addressed in the risk of bias table. We think it would be more appropriate to conclude there is insufficient data to show a change in the quality of life, using combination therapy.
In Analysis 1.5 the review authors included, from Aaron 2007, the number of patients who experienced an event and who remained in the study until completion. However, two sensitivity analyses were performed to include patients lost to follow-up. Given the high withdrawal rate from this trial, including this information as additional forest plots would provide a more conservative reflection of change in exacerbations. Additionally, it is unclear how the Aaron 2007 trial calculated the number of patients lost to follow-up for their sensitivity analyses. Perhaps the study authors could be contacted to clarify this.
The review did not indicate that Aaron 2007 had three treatment arms, one of which used a combination of tiotropium, fluticasone, and salmeterol. Also, over 70% of patients in each treatment arm were taking inhaled corticosteroids (ICS) at the time of randomisation. Therefore, there is potential for an increased proportion of COPD exacerbations in the treatment arms where patients discontinued prior ICS. Since patients in the other trials were allowed to continue on prior ICS, pooling those data with Aaron 2007 can complicate the interpretation of the change on exacerbation rates.
Reply
Thank you for your comments on our review.
Response 1: We agree that there is insufficient evidence to show that there is no difference between the treatments in terms of hospital admissions and mortality. That is why we in the conclusions wrote “Hospital admission and mortality have not been shown to be altered by adding long-acting beta2-agonists to tiotropium.” followed by the clarifying statement “There were not enough data to determine the relative efficacy and safety of tiotropium plus long-acting beta2-agonist compared to long-acting beta2-agonist.” However, to make this clearer it has been reworded.
Response 2: added a reference to the Cochrane review of ipratropium versus tiotropium (Cheyne 2013).
Response 3: We direct the writers to the review “Tiotropium versus placebo for chronic obstructive pulmonary disease” (Karner 2013) as this explains why it might be misleading to focus on the mean or the confidence interval when it comes to the minimal clinically important difference. Hence why we were cautious when describing the result: “but it is not clear how clinically important this mean difference may be”.
The missing data in Aaron 2007 is mentioned in the risk of bias assessment leading to the “unclear” risk of bias judgement. Also, it is unclear in what direction the potential bias may sway the result; the proportion of patients for whom there was no data was large in both treatment groups, but relatively even. If mainly people with negative effects drop out the treatment effect may be inflated those who remain in the study (though it’s not clear if it would be more inflated in one treatment group compared to the other). However, a large proportion of patients in both groups also switched from the treatment they were randomised to, which is likely to dilute the difference in treatment effect. No change made.
Response 4: Although the sensitivity analyses in Aaron 2007 are of interest, they were not specified in the protocol for the Cochrane Review and therefore we chose not to present them in the review.
Response 5: As the third treatment arm in Aaron 2007 wasn’t of interest for this Cochrane Review, we did not highlight it. We stated all of the included studies except for Aaron 2007 allowed concomitant ICS, and we have now added the percentages of people on ICS at baseline in characteristics of included studies tables (Aaron 2007 78% on either ICS alone of ICS/LABA; Mahler 2010 53%; Tashkin 2009 27%; Vogelmeier 2008 40-44%).
We hope these responses will clarify why we have chosen to present and describe the data as is written in the published review.
Contributors
Yin Gong and Jessie Yoon, Lower Mainland Pharmacy Services, Pharmacy Residents, UBC; Dr Aaron Tejani, Researcher, Therapeutics Initiative, UBC
HISTORY
Protocol first published: Issue 2, 2011
Review first published: Issue 4, 2012
| Date | Event | Description |
|---|---|---|
| 11 April 2013 | Amended | Funder acknowledgement added |
WHAT’S NEW
Last assessed as up-to-date: 11 January 2012.
| Date | Event | Description |
|---|---|---|
| 27 January 2014 | Amended | Feedback and rebuttal added. We added a reference to a Cochrane Review on ipratropium versus tiotropium, added the percentage of people taking ICS at baseline to the characteristics of included studies tables and made minor changes to the text |
Footnotes
DECLARATIONS OF INTEREST None known
References to studies included in this review
- Aaron 2007 {published data only} .Aaron SD, Vandemheen K, Ferguson D, FitzGerald M, Maltais F, Boureau J, et al. The Canadian optimal therapy of COPD trial: Design, organization and patient recruitment. Canadian Respiratory Journal. 2004;11(8):581–5. doi: 10.1155/2004/394710. [DOI] [PubMed] [Google Scholar]; *; Aaron SD, Vandemheen KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R, et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. [see comment][summary for patients in Ann Intern Med. 2007 Apr 17;146(8):I12. doi: 10.7326/0003-4819-146-8-200704170-00152. PMID: 17310044] [DOI] [PubMed] [Google Scholar]; Annals of Internal Medicine. 2007;146(8):545–55. doi: 10.7326/0003-4819-146-8-200704170-00152. [DOI] [PubMed] [Google Scholar]; Kaplan A. Effects of tiotropium combined with either salmeterol or salmeterol/fluticasone in moderate to severe COPD. Primary Care Respiratory Journal. 2007;16(4):258–60. doi: 10.3132/pcrj.2007.00055. [DOI] [PMC free article] [PubMed] [Google Scholar]; Najafzadeh M, Marra CA, Sadatsafavi M, Aaron SD, Sullivan SD, Vandemheen KL, et al. Cost effectiveness of therapy with combinations of long acting bronchodilators and inhaled steroids for treatment of COPD. Thorax. 2008;63(11):962–7. doi: 10.1136/thx.2007.089557. [DOI] [PubMed] [Google Scholar]; Roisman G. Tiotropium in combination with placebo, salmeterol, or fluticasone- salmeterol for treatment of chronic obstructive pulmonary disease. A randomized trial. Revue de Pneumologie Clinique. 2007;63(6):390–1. doi: 10.7326/0003-4819-146-8-200704170-00152. [DOI] [PubMed] [Google Scholar]
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- Mahler 2010b {published and unpublished data} . www.novctrd.com. [: CQAB149B2351]; Mahler DA, D’Urzo A, Peckitt C, Lassen C, Kramer B, Filcek S. Combining once-daily bronchodilators In COPD: Indacaterol plus tiotropium versus tiotropium alone. American Journal of Respiratory and Critical Care Medicine. 2011;(issue 183) [Google Scholar]; * A randomized, double-blind, controlled, parallel group, 12-week treatment study to compare the efficacy and safety of the combination of indacaterol 150 μg once daily with open label tiotropium 18 μg once daily versus open label tiotropium 18 μg once daily in patients with moderate-to-severe chronic obstructive pulmonary disease.
- Tashkin 2009 {published data only} .Tashkin D, Varghese S. Formoterol treatment plus tiotropium results in greater improvements in lung function compared with tiotropium administered alone in patients with COPD [Abstract] Journal of Allergy and Clinical Immunology. 2007;Vol. 119(issue 1 Suppl):S4. [13] [Google Scholar]; Tashkin D, Varghese S. The therapeutic effect of treatment with formoterol plus tiotropium was greater than the effect of treatment with tiotropium alone in COPD: findings from a 12-week, multicenter, double-blind, placebo-controlled, trial. Chest. 2007;Vol. 132(issue 4):529a. [Google Scholar]; Tashkin DP. Formoterol and tiotropium reduces rescue medication use more than tiotropium alone in patients with moderate COPD: findings from a 12 week randomized placebo controlled trial [Abstract]. American Thoracic Society International Conference; Toronto. May 16-21, 2008; 2008. p. A647. [#F5] [Google Scholar]; *; Tashkin DP, Pearle J, Iezzoni D, Varghese ST. Formoterol and tiotropium compared with tiotropium alone for treatment of COPD. COPD: Journal of Chronic Obstructive Pulmonary Disease. 2009;6(1):17–25. doi: 10.1080/15412550902724073. [DOI] [PubMed] [Google Scholar]; Tashkin DP, Pearle JL, Varghese S. Improvement of lung function with coadministered formoterol and tiotropium, regardless of smoking status in patients with chronic obstructive pulmonary disease [Abstract] Chest. 2008;Vol. 134(issue 4):103002s. [Google Scholar]
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References to studies excluded from this review
- Bateman 2001 {published data only} .*; Bateman ED, Hodder R, Miravitlles M, Lee A, Towse L, Serby C. A comparative trial of tiotropium, salmeterol and placebo: health-related quality of life. European Respiratory Journal. 2001;Vol. 18(issue Suppl 33):26s. [Google Scholar]
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