Abstract
Exacerbations of chronic obstructive pulmonary disease (COPD) have important consequences for lung function, health status and mortality. Furthermore, they are associated with high economic costs, predominantly related to hospitalization. They are managed acutely with short-acting bronchodilators, systemic corticosteroids or antibiotics; however, a large proportion of COPD exacerbations are unreported and therefore untreated or self-managed. There is evidence to suggest that these unreported exacerbations also have important consequences for health status; therefore, reducing exacerbation risk is an important goal in the management of COPD.
Current guidelines recommend long-acting muscarinic antagonists (LAMAs) as first-line bronchodilator therapy in patients with stable COPD who have a high risk of exacerbation or increased symptoms. To date, three LAMAs, tiotropium bromide, aclidinium bromide and glycopyrronium bromide, have been approved as maintenance bronchodilator treatments for stable COPD. These all provide clinically significant improvements in lung function, reduce symptoms and improve health status compared with placebo in patients with COPD. This paper reviews evidence from randomized, controlled clinical trials demonstrating that tiotropium, aclidinium and glycopyrronium reduce exacerbation risk in patients with COPD. Reductions were seen irrespective of the exacerbation measure used, whether time to first event or annualized exacerbation rate. Furthermore, studies with aclidinium suggest LAMAs can reduce exacerbation risk irrespective of whether exacerbation events are assessed, using an event-based approach or a symptom-based method which includes unreported events. Together these results demonstrate that LAMAs have the potential to provide clinical benefit in the management of exacerbations in patients with stable COPD.
Introduction
In the UK it is estimated that approximately 3 million people have chronic obstructive pulmonary disease (COPD), with two-thirds of these being undiagnosed [National Institute for Health and Clinical Excellence, 2011]. In contrast, there is little information about the incidence of exacerbations of COPD, defined by the Global initiative for chronic Obstructive Lung Disease (GOLD) as ‘an acute event characterized by a worsening of the patient’s respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medication’ [Global Initiative for Chronic Obstructive Lung Disease, 2014]. While not all patients with COPD experience exacerbations, rates and severity increase with disease severity, although the best predictor of a future exacerbation is the patient’s own history of exacerbations in the preceding year [Hurst et al. 2010].
COPD exacerbations are heterogeneous but are associated with the onset of, or an acute increase in, dyspnoea, wheeze, chest discomfort, cough and increased sputum production [Jones et al. 2011]. Consistent with this, respiratory tract infections (viral and bacterial) are believed to be the underlying cause of most COPD exacerbations [Global Initiative for Chronic Obstructive Lung Disease, 2014; Sapey and Stockley, 2006]. However, environmental pollution has also been shown to induce exacerbations in some patients, and the aetiology of approximately one-third of exacerbations is unknown [Global Initiative for Chronic Obstructive Lung Disease, 2014; Sapey and Stockley, 2006].
GOLD guidelines recommend that exacerbations of COPD are assessed based on the patient’s medical history and clinical signs of exacerbation severity (Table 1) [Global Initiative for Chronic Obstructive Lung Disease, 2014]. Furthermore, according to the National Institute for Health and Clinical Excellence, a variety of factors including the patient’s level of breathlessness, their ability to cope at home, their general condition and level of activity and the presence of significant comorbidities (e.g. cardiac disease or insulin-dependent diabetes) are among the factors that should be considered when assessing the need to treat patients with exacerbations in hospital [National Institute for Health and Care Excellence, 2010]. In clinical trials of COPD treatments, exacerbations are commonly assessed based on healthcare resource utilization (HCRU) and changes in therapy to manage worsening of symptoms [Burge and Wedzicha, 2003; Cazzola et al. 2008; Rodriguez-Roisin, 2000]. There are a number of limitations of this event-based method, including differences in access to healthcare and variability in the individual patient’s awareness of changes in symptoms. As a consequence, symptom-based approaches, which use patient-completed diaries to record changes in COPD symptoms, have also been used to identify exacerbations [Jones et al. 2014; Langsetmo et al. 2008; Seemungal et al. 1998; Trappenburg et al. 2011; Vijayasaratha and Stockley, 2008; Xu et al. 2010].
GOLD guidelines for assessment of COPD exacerbations.
From the ‘Global strategy for diagnosis, management and prevention of COPD’ [Global Initiative for Chronic Obstructive Lung Disease, 2014]. © Global Initiative for Chronic Obstructive Lung Disease (GOLD) all rights reserved.
COPD, chronic obstructive pulmonary disease.
The impact of COPD exacerbations and their management in the clinic
Exacerbations of COPD have important consequences for patients as they accelerate the rate of decline of lung function [Celli et al. 2008; Donaldson et al. 2002; Halpin et al. 2012], impair health status [Halpin et al. 2012; Jones et al. 2014; Langsetmo et al. 2008; Seemungal et al. 1998; Spencer et al. 2004; Xu et al. 2010] and increase mortality [Global Initiative for Chronic Obstructive Lung Disease, 2014; Halpin et al. 2012]. Furthermore, they result in considerable economic costs, most of which are related to hospitalization [Toy et al. 2010]. A significant proportion are unreported, and therefore untreated, and there is evidence to demonstrate that these unreported exacerbations also have important implications for health status [Jones et al. 2014; Langsetmo et al. 2008; Seemungal et al. 1998; Xu et al. 2010]. As a consequence, unreported exacerbations may contribute to increased healthcare costs in the longer term [Toy et al. 2010], and a key goal in the management of COPD is to minimize the impact of exacerbations or stop exacerbations reoccurring [Global Initiative for Chronic Obstructive Lung Disease, 2014]. There is evidence to demonstrate that early treatment of exacerbations is associated with faster recovery times and better health status [Wilkinson et al. 2004]. Current guidelines recommend treatment with short-acting bronchodilators (β2-agonists or muscarinic antagonists) and systemic corticosteroids or antibiotics as appropriate [Global Initiative for Chronic Obstructive Lung Disease, 2014; National Institute for Health and Care Excellence, 2010].
Long-acting muscarinic antagonists (LAMAs) are recommended as first-line maintenance bronchodilator therapy in patients with stable COPD who have a high risk of exacerbations or more symptoms [Global Initiative for Chronic Obstructive Lung Disease, 2014; National Institute for Health and Care Excellence, 2010]. Here, we review evidence demonstrating the efficacy of LAMAs for preventing COPD exacerbations. To give a representative account of the available evidence for the efficacy of LAMAs in COPD exacerbations we reviewed the literature for LAMAs approved for use in COPD. Literature searches, using the following terms, were conducted on PubMed: aclidinium AND COPD (74 articles identified; four reported exacerbation data); glycopyrronium OR NVA237 (the formulation of glycopyrronium approved for the treatment of COPD) AND COPD (80 articles identified; five reported exacerbation data); tiotropium AND COPD AND exacerbation; no limits (152 articles identified; nine reported exacerbation data); abstracts presented at the American Thoracic Society, the British Thoracic Society and the European Respiratory Society in the last year (2012–2013) were also reviewed. All articles reporting exacerbation outcomes from randomized, controlled studies of aclidinium and glycopyrronium at the licenced dose were selected for review, in addition to key publications (Cochrane review and the two largest clinical trials) reporting exacerbations outcomes from tiotropium studies.
Evidence for the use of LAMAs for the prevention of COPD exacerbations
There is now a large body of evidence from randomized, double-blind, placebo- or active comparator-controlled clinical studies indicating a clinical benefit of LAMAs in reducing COPD exacerbations. Results from these studies are reviewed below and key outcomes related to exacerbations are summarized in Table 2.
Summary of key data for efficacy of LAMAs in reducing exacerbation risk.
ACCORD COPD, AClidinium in Chronic Obstructive Respiratory Disease; ATTAIN, Aclidinium To Treat Airway obstruction In COPD PatieNts; CI, confidence interval; COPD, chronic obstructive pulmonary disease; EXACT, EXAcerbations of Chronic obstructive pulmonary disease Tool; GLOW, GLycopyrronium bromide in COPD AirWays; HCRU, healthcare resource utilization; HR, hazard ratio; LAMA, long-acting muscarinic antagonists; OR, odds ratio; POET-COPD, Prevention Of Exacerbations with Tiotropium in COPD; RR, rate ratio; SE, standard error; UPLIFT, Understanding Potential Long-term Impact on lung Function with Tiotropium
Tiotropium bromide
The tiotropium clinical development programme has demonstrated the efficacy of tiotropium 18 µg once daily, administered via the dry powder inhaler HandiHaler® (Boehringer Ingelheim GmbH, Ingelheim am Rhein, Germany), to improve clinical outcomes in patients with COPD. Tiotropium 18 µg once daily provides clinically significant improvements in lung function and breathlessness and improves health status compared with active comparators or placebo [Brusasco et al. 2003; Casaburi et al. 2002; Tashkin et al. 2008; Vincken et al. 2002]. Similar improvements in clinical outcomes are also seen with lower doses of tiotropium (5 µg once daily) administered via Respimat® (Boehringer Ingelheim GmbH, Ingelheim am Rhein, Germany) [Bateman et al. 2010].
The effect of tiotropium on COPD exacerbations has also been assessed in a series of studies. In all of them, a similar event-based approach (new onset or increase in cough, sputum, dyspnoea or wheeze that lasted at least 3 days and was treated with antibiotics or inhaled corticosteroids) was used to assess exacerbations. A Cochrane review of 22 randomized, controlled, parallel-group studies of tiotropium (minimum duration 12 weeks) found that significantly fewer patients randomized to tiotropium experienced at least one exacerbation versus placebo (38% versus 44%, respectively; odds ratio [OR] 0.78, 95% confidence interval 0.70–0.87; p < 0.001), and fewer patients had at least one exacerbation that led to hospitalization (10.4% versus 13.1%, respectively; p < 0.05) [Karner et al. 2012]. There was no significant relationship between risk of exacerbation and length of study; the OR (95% CI) for tiotropium versus placebo was 0.74 (0.66–0.84) in studies of less than 1 year and 0.82 (0.70–0.95) in studies of at least 1 year. There was also no significant relationship between risk of exacerbation and disease severity or inhaler type (HandiHaler or soft mist inhaler [Respimat]). Based on this analysis, the number needed to treat (NNT) for prevention of one exacerbation with tiotropium 18 µg once daily was 16 over the period of 1 year [Karner et al. 2012]. A large-scale, randomized, event-based study, Tiotropium Safety and Performance In Respimat (TIOSPIR; n = 17 183), demonstrated that the effects of tiotropium 5 µg via Respimat or tiotropium 18 µg via HandiHaler on exacerbation risk were comparable when assessed as time to first exacerbation [hazard ratio (HR) 0.98, 95% CI 0.93–1.03), time to first severe exacerbation (HR 1.02, 95% CI 0.93–1.03) or overall annualized exacerbation rates (0.59 versus 0.59) [Wise et al. 2013].
In the large 4-year Understanding Potential Long-term Impact on Lung Function with Tiotropium (UPLIFT) study (n = 5993), in which patients continued on all respiratory medication except inhaled anticholinergic drugs, tiotropium 18 µg once daily significantly delayed both time to first exacerbation and time to first hospitalization for an exacerbation compared with placebo (Table 2). Figure 1 shows Kaplan–Meier curves of the probability of a COPD exacerbation over 4 years. In tiotropium-treated patients, the mean number of exacerbations per patient-year was 14% lower than in placebo-treated patients (HR 0.86, 95% CI 0.81–0.91; p < 0.001) [Tashkin et al. 2008].
Kaplan–Meier estimates of the probability of a chronic obstructive pulmonary disease (COPD) exacerbation in patients treated with tiotropium 18 µg once daily and placebo in the UPLIFT trial [Tashkin et al. 2008]. From N Engl J Med, Tashkin et al, A 4-Year Trial of Tiotropium in Chronic Obstructive Pulmonary Disease, 359., 1543. Copyright © 2008 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. The numbers of patients who continued to receive the study drug (including those at 30 days after the last dose) are listed for each time point. All patients who received at least one dose of study drug were included. COPD, chronic obstructive pulmonary disease; UPLIFT, Understanding Potential Long-term Impact on lung Function with Tiotropium.
Two 6-month phase III studies (n = 1207) compared tiotropium with the long-acting β2-agonist salmeterol 50 µg twice daily and placebo [Brusasco et al. 2003]. In these studies, there was no significant difference between the efficacy of tiotropium and salmeterol to reduce exacerbations. However, in a large 1-year trial (Prevention Of Exacerbations with Tiotropium in COPD [POET-COPD]; n = 7384) in patients with moderate to severe COPD who had a history of exacerbations, there was a 17% reduction in the risk of moderate or severe exacerbations with tiotropium 18 µg once daily versus salmeterol 50 µg twice daily (HR 0.83, 95% CI 0.77–0.90; p < 0.001), as assessed by time to first exacerbation. The annualized rate of all exacerbations was also 11% lower with tiotropium 18 µg once daily than with salmeterol 50 µg twice daily (rate ratio [RR] 0.89, 95% CI 0.83–0.96; p < 0.01), with a significant reduction in the rate of both moderate exacerbations and severe exacerbations [Vogelmeier et al. 2011]. The risk of exacerbations leading to treatment with systemic glucocorticoids, antibiotics or both was also lower with tiotropium than with salmeterol (all p < 0.001; Table 2).
The studies described above were performed in the secondary care setting; however, most patients are managed in a primary setting. In a 3-month study, carried out in 44 primary care centres throughout the UK (n = 395), significantly fewer patients randomized to tiotropium 18 µg once daily had at least one exacerbation versus patients randomized to placebo (9.5% versus 17.9%, respectively; p < 0.05) [Freeman et al. 2007].
Aclidinium bromide
Aclidinium bromide, administered via the Genuair®/Pressair® inhaler (AstraZeneca, Mӧlndal, Sweden; registered trademarks of AstraZeneca A.B., Mӧlndal, Sweden, for use within the USA as Pressair and Genuair within all other licensed territories), is a novel, inhaled LAMA with low systemic bioavailability, which has recently been approved in the European Union and the USA as a maintenance bronchodilator treatment for patients with COPD. In two pivotal phase III studies in patients with moderate to severe COPD Clidinium in Chronic Obstructive Respiratory Disease [ACCORD] COPD I, n = 561; 12 weeks; and Aclidinium To Treat Airway obstruction In COPD PatieNts (ATTAIN), n = 819; 24 weeks], aclidinium 400 µg twice daily provided statistically and clinically significant improvements in bronchodilation, breathlessness and health status versus placebo [Jones et al. 2012a; Kerwin et al. 2012a].
Neither ACCORD COPD I nor ATTAIN were powered for exacerbations as an endpoint; however, the effect of aclidinium on exacerbations was assessed in both. In the 6-month ATTAIN study, aclidinium 400 µg twice daily significantly delayed the time to first exacerbation compared with placebo (p < 0.05; Figure 2(b)) and reduced the annualized rate of exacerbations by 33% (RR 0.67, 95% CI 0.48–0.94; p < 0.05 versus placebo) [Jones et al. 2014]. Fewer patients experienced at least one exacerbation with aclidinium 400 µg twice daily compared with placebo, but this reduction did not reach statistical significance. In ATTAIN, the NNT for prevention of one exacerbation event per patient-year with aclidinium 400 µg twice daily was 5.1 [Jones et al. 2014]. The annualized rate of exacerbations was also reduced with aclidinium 400 µg twice daily in ACCORD COPD I (RR 0.52; p < 0.01 versus placebo) [Kerwin et al. 2012a] and the NNT with aclidinium 400 µg twice daily was 2.7 (AstraZeneca, data on file).
Kaplan–Meier plot of time to first (a) EXACT-identified event, and (b) HCRU event in patients treated with aclidinium 400 µg twice daily or placebo in the ATTAIN study [Jones et al. 2014]. Reproduced with permission of the European Respiratory Society: Eur Respir J November 2014 44(5):1156-1165. doi:10.1183/09031936.00038814. Analyses were performed in the ITT population (all treated patients with both a baseline and a post-baseline FEV1 assessment). ATTAIN, Aclidinium To Treat Airway obstruction In COPD patieNts; BID, twice daily; EXACT, Exacerbations of Chronic obstructive pulmonary disease Tool; FEV1, forced expiratory volume in 1 s; HCRU, healthcare resource utilization; ITT, intent to treat.
In both ACCORD COPD I and ATTAIN, there was a trend towards a reduction in the annualized rate of moderate or severe exacerbations (defined based on HCRU criteria) with aclidinium 400 µg twice daily, but this did not reach statistical significance versus placebo [Jones et al. 2012b; Kerwin et al. 2012a]. However, when data from both studies were pooled, the rates of moderate or severe exacerbations were significantly lower with aclidinium 400 µg twice daily compared with placebo (29%, RR 0.71; p = 0.01) [Jones et al. 2012b].
In ATTAIN, COPD exacerbations were also assessed using the EXAcerbations of Chronic pulmonary disease Tool (EXACT) patient diary, an electronic personal digital assistant. The EXACT is a standardized patient-reported outcome instrument designed to evaluate the frequency, severity and duration of COPD exacerbations, based on changes in symptoms reported directly by the patient [Leidy et al. 2010, 2011], and was developed as a result of a collaboration between experts in instrument development and validation, specialists in COPD and the Food and Drug Administration. The EXACT is now being used in clinical trials to assess the efficacy of novel COPD treatments to reduce exacerbation risk [Jones et al. 2014; Singh et al. 2013]. Time to first exacerbation, assessed using the EXACT, was significantly delayed with aclidinium 400 µg twice daily compared with placebo [p < 0.05; Figure 2(a)] and the annualized rate of EXACT events was reduced by 29% (RR 0.71, 95% CI 0.54–0.93; p < 0.05 versus placebo). The reduction in the rate of EXACT events with aclidinium 400 µg twice daily was comparable to the reduction in the rate of HCRU-defined exacerbations observed in the same study (29% versus 33%, respectively) [Jones et al. 2014]. As with HCRU-defined exacerbations, using EXACT, fewer patients experienced at least one exacerbation with aclidinium 400 µg twice daily compared with placebo, but again this reduction did not reach statistical significance. The NNT for prevention of one exacerbation event per patient-year with aclidinium 400 µg twice daily was 2.5 for EXACT events.
Glycopyrronium bromide
NVA237 is a formulation of glycopyrronium bromide, which is administered using the Seebri Breezhaler® (Novartis AG, Basal, Switzerland) and has recently been approved by the European Medicines Agency as a once-daily inhaled maintenance bronchodilator treatment to relieve symptoms in COPD. In two phase III studies, the 6-month GLycopyrronium bromide in COPD AirWays study 1 (GLOW1) (n = 822) and the 1-year GLOW2 study (n = 1066), glycopyrronium 50 µg once daily provided statistically significant improvements in bronchodilation, breathlessness and health status compared with placebo [D’Urzo et al. 2011; Kerwin et al. 2012b].
In both GLOW1 and GLOW2, glycopyrronium 50 µg once daily significantly increased the time to first moderate or severe exacerbation. In GLOW1, there was a 31% reduction in risk compared with placebo (HR 0.69, 95% CI 0.50–0.95; p < 0.05) [D’Urzo et al. 2011]. The risk of severe exacerbations leading to hospitalization and the percentage of hospitalizations due to exacerbations was also significantly lower (both p < 0.05; Table 2) [D’Urzo et al. 2011]. In the longer GLOW2 study, a similar reduction in time to first moderate or severe exacerbation versus placebo was observed (34%, HR 0.66, 95% CI 0.52–0.85; p = 0.001 versus placebo), which was comparable to that seen with tiotropium 18 µg once daily in this study (39%, HR 0.61, 95% CI 0.46–0.87; p = 0.001; Figure 3) [Kerwin et al. 2012b]. Both glycopyrronium and tiotropium also significantly reduced moderate exacerbations requiring systemic corticosteroids or antibiotics versus placebo (Table 2). NNTs to avoid one moderate or severe exacerbation over 1 year were comparable between glycopyrronium and tiotropium (13.3 versus 10.0, respectively) in GLOW2 [Kerwin et al. 2012b]. The GLOW2 study used open-label tiotropium as a comparator; however, in the 12-week GLOW5 study (n = 657), in which tiotropium was blinded, improvements in annualized exacerbation rates were also comparable between glycopyrronium 50 µg once daily and tiotropium 18 µg once daily (RR 1.10, 95% CI 0.062–1.93; p = 0.754) [Chapman et al. 2014].
Kaplan–Meier plot of the time to first moderate or severe COPD exacerbation in patients treated with glycopyrronium (NVA237) 50 µg once daily, tiotropium 18 µg once daily and placebo in the GLOW2 study [Kerwin et al. 2012b]. Reproduced with permission of the European Respiratory Society. Eur Respir J. 2012 Nov;40(5):1106-14. doi: 10.1183/09031936.00040712. COPD, chronic obstructive pulmonary disease; GLOW, GLycopyrronium bromide in COPD airWays study.
As with aclidinium, there was a trend towards a reduction in the rate of moderate or severe exacerbations with glycopyrronium in GLOW1, which did not reach statistical significance versus placebo [D’Urzo et al. 2011]. However, the rate of moderate to severe exacerbations was significantly reduced versus placebo in GLOW2 (RR 0.66, 95% CI 0.50–0.87; p < 0.01) [Kerwin et al. 2012b]. When data from GLOW1 and GLOW2 were pooled, glycopyrronium significantly prolonged the time to first moderate or severe exacerbation versus placebo over 26 weeks (HR 0.64, 95% CI 0.52–0.80; p < 0.001) and 1 year (HR 0.67, 95% CI 0.55–0.81; p < 0.001) [D’Urzo et al. 2014]. This was comparable to the reduction in exacerbation risk over both periods with tiotropium 18 µg once daily versus placebo (HR 0.70, 95% CI 0.52–0.96; p < 0.05 and 0.61, 95% CI 0.46–0.80; p < 0.001, respectively) [D’Urzo et al. 2014]. Furthermore, based on pooled data, the rate of moderate or severe exacerbations over 26 weeks and 1 year was 34% lower with glycopyrronium 50 µg once daily compared with placebo (RR 0.66 for both; p < 0.005 versus placebo) [Banerji et al. 2012]. Glycopyrronium also significantly reduced severe exacerbations leading to hospitalization, and moderate exacerbations requiring treatment with systemic corticosteroids or antibiotics (all p < 0.001; Table 2) [D’Urzo et al. 2014].
Is the efficacy of different LAMAs to prevent COPD exacerbations the same?
All LAMAs approved for maintenance treatment of patients with COPD reduced the risk of COPD exacerbations. Direct comparison of the benefits of each is restricted due to differences in study design, the endpoints assessed and the number of trials that directly compared drugs of this class. Only the GLOW2 study directly compared two different LAMAs. In this study, the reduction in risk of moderate or severe exacerbations and NNTs was comparable between glycopyrronium and tiotropium [Kerwin et al. 2012b]. Whilst the NNT for aclidinium 400 µg twice daily, when assessed using event-based (HCRU-defined) exacerbations in the ATTAIN study, was lower than those reported for glycopyrronium and tiotropium in GLOW2 [Jones et al. 2014], care should be taken when comparing NNTs from different studies. NNTs are a useful parameter, but the methods used to determine these as a measure of a reduction in exacerbations are not standardized [Suissa, 2013]. For example, ATTAIN was a 6-month study whereas GLOW2 was a 1-year study, and differences in study length, patient populations or study designs may impact on the assessment of NNTs. Despite all of the possible confounding factors, the available data suggest that all three of these drugs appear to have similar efficacy in terms of reducing moderate or severe exacerbations.
Comparing results from clinical trials can be a challenge due to other factors that may confound analyses of exacerbation risk and the comparison of efficacy across clinical studies. These include: study length (which may not take into account seasonal variations in exacerbation rates), nonstandardized definitions and differences in the endpoints selected to determine efficacy [Beeh et al. 2009; Gillissen et al. 2009]. The effect of therapy on exacerbation rate might also be dependent on the mean exacerbation rate prior to inclusion in the clinical trial, although this might be difficult to test since experience has shown that exacerbation rates during a trial are often lower than the patients’ reported historical rate, even in patients receiving placebo. However, time to first exacerbation is considered a robust endpoint, although perhaps not clinically the most useful, and may be less biased by differential dropout than other endpoints; all the approved LAMAs have been shown to reduce exacerbation risk when assessed in this way. All of the published studies employed a similar event-based method to measure exacerbations, but there are a number of limitations with using event-based approaches to assess exacerbation risk, including the potential for underestimating exacerbation frequency. Studies using symptom-based approaches to detect exacerbations have shown that a high proportion of exacerbations are unreported, and unreported exacerbations have a negative impact on health status [Jones et al. 2014; Langsetmo et al. 2008; Seemungal et al. 1998; Xu et al. 2010], but more needs to be understood about these events before this can be used as a primary outcome in clinical trials.
Translating the results of clinical trials into clinical practice can be difficult, since in reality patients do not usually stop their preventative therapy for exacerbations in routine practice, whereas they do in clinical trials when they withdraw. Withdrawal from a trial induces a bias that is especially pronounced when calculating the frequency of exacerbations, since patients who remain in the study have a lower rate of exacerbations than those who withdraw [Vestbo et al. 2011]. This could lead to an underestimate of treatment. Another problem is the effect of pharmacotherapy on exacerbations, since patients may be on a range of concomitant therapy that would not be allowed in a clinical trial.
Overall, the safety profile of all three LAMAs has been reported to be similar [D’Urzo et al. 2011; Jones et al. 2012a; Kerwin et al. 2012a, 2012b]. Whilst there was a suggestion from meta-analyses that tiotropium was linked with an increased risk of mortality when administered via Respimat [Dong et al. 2013; Karner et al. 2012; Singh et al. 2011], the UPLIFT study demonstrated lower all-cause mortality versus placebo when tiotropium was given via HandiHaler [Tashkin et al. 2008]. Furthermore, results from the TIOSPIR study found no difference in mortality risk between tiotropium 18 µg via HandiHaler and 5 µg via Respimat [Wise et al. 2013]. In this study, the incidence of major cardiovascular events was also comparable between the two treatments. No cardiovascular safety issues have been identified for aclidinium and glycopyrronium, although the number of patients treated with these drugs, and the number of years of treatment, are much less than with tiotropium. Overall, this class of compounds is well tolerated. Together, these results suggest a positive risk–benefit profile for LAMAs in the prevention of COPD exacerbations.
Summary and conclusion
Preventing exacerbations is an important goal in the management of COPD, not only for those exacerbations for which patients seek medical attention, but also unreported events that can also impact on clinical outcomes. There is now well-documented evidence, from randomized, blinded and appropriately controlled clinical trials, that tiotropium, aclidinium and glycopyrronium reduce exacerbations in patients with COPD. Whilst comparison between different LAMAs is difficult due to differences in study design and lengths, these results indicate that they appear to be broadly comparable in terms of preventing exacerbations.
Footnotes
Acknowledgements
I thank Deborah McGregor, PhD, of Complete Medical Communications, who assisted in preparing the first draft of the article based on author direction, and with subsequent changes. This contribution does not meet the ICMJE criteria for authorship. Paul W. Jones directed the content of the article and interpretation of the literature, reviewed the first draft of the article and revised subsequent drafts for intellectual content and provided final approval of the manuscript.
Conflict of interest statement
Paul W. Jones has received lecture fees, research grants or payment for consultancy or advisory boards from Almirall, Amgen, AstraZeneca, Chiesi, GlaxoSmithKline, Medimmune, Novartis, Roche, Spiration and Evidera. All fees were contracted via his institution.
Funding
Paul W. Jones received no funding for this manuscript. Medical writing/editing support was provided by Deborah McGregor, PhD, of Complete Medical Communications, and was funded by Almirall S.A., Barcelona, Spain.