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Is there a rationale and role for long-acting anticholinergic bronchodilators in asthma?

Is there a rationale and role for long-acting anticholinergic bronchodilators in asthma? www.nature.com/npjpcrm All rights reserved 2055-1010/14 REVIEW ARTICLE OPEN Is there a rationale and role for long-acting anticholinergic bronchodilators in asthma? 1,2 3 4 5 6 David Price , Leonard Fromer , Alan Kaplan , Thys van der Molen and Miguel Román-Rodríguez Despite current guidelines and the range of available treatments, over a half of patients with asthma continue to suffer from poor symptomatic control and remain at risk of future worsening. Although a number of non-pharmacological measures are crucial for good clinical management of asthma, new therapeutic controller medications will have a role in the future management of the disease. Several long-acting anticholinergic bronchodilators are under investigation or are available for the treatment of respiratory diseases, including tiotropium bromide, aclidinium bromide, glycopyrronium bromide, glycopyrrolate and umeclidinium bromide, although none is yet licensed for the treatment of asthma. A recent Phase III investigation demonstrated that the once-daily long- acting anticholinergic bronchodilator tiotropium bromide improves lung function and reduces the risk of exacerbation in patients with symptomatic asthma, despite the use of inhaled corticosteroids (ICS) and long-acting β -agonists (LABAs). This has prompted the question of what the rationale is for long-acting anticholinergic bronchodilators in asthma. Bronchial smooth muscle contraction is the primary cause of reversible airway narrowing in asthma, and the baseline level of contraction is predominantly set by the level of ‘cholinergic tone’. Patients with asthma have increased bronchial smooth muscle tone and mucus hypersecretion, possibly as a result of elevated cholinergic activity, which anticholinergic compounds are known to reduce. Further, anticholinergic compounds may also have anti-inflammatory properties. Thus, evidence suggests that long-acting anticholinergic bronchodilators might offer benefits for the maintenance of asthma control, such as in patients failing to gain control on ICS and a LABA, or those with frequent exacerbations. npj Primary Care Respiratory Medicine (2014) 24, 14023; doi:10.1038/npjpcrm.2014.23; published online 17 July 2014 INTRODUCTION glucocorticosteroids and anti-immunoglobulin E (omalizumab) are all further or alternative treatment options. Asthma affects over 300 million individuals worldwide, a figure Despite these guidelines and the wide range of therapies that is estimated to grow by 100 million by 2025. A chronic available, poor control of current asthma symptoms, and of future inflammatory disease of the airways, asthma has multifactorial 5–9 asthma exacerbations, continues to affect 450% of patients, pathophysiological causes and considerable heterogeneity in the with exacerbations placing significant strain on their quality of life classification of the disease by phenotype, aetiology, severity and and on health-care systems. Risk factors associated with future interventional control. exacerbations include previous exacerbations, poor control, Current guidelines recommend stepwise management to gain inhaler technique and adherence, co-morbid allergic rhinitis, and maintain control, in which the clinical definition of full gastro-oesophageal reflux disease, psychological dysfunction, ‘control’ is daytime symptoms or use of reliever medication less smoking and obesity. The same factors, in addition to incorrect than twice a week, no limitations of activity, no nocturnal diagnosis, poor choice of inhaler, variation in individual treatment symptoms and normal lung function. Furthermore, the American responses or genetic components, have been attributed to the Thoracic Society and the European Respiratory Society state that underlying poor control. There are a number of actions available any definition or measure of control must take into account the in the primary care setting to reduce the impact of these factors management of a patient’s future risk. Thus, in clinical manage- 10,11 (Figure 1). ment of asthma, consideration must be given to reducing the In the light of such concerns around risk and poor control, it is frequency of exacerbations, preserving lung function, preventing appropriate to consider the rationale for investigating additional reduced lung growth in children and minimising the adverse controller medications. A number of new therapies are under effects of any treatment. investigation, including long-acting anticholinergic bronchodi- For those receiving low-dose inhaled corticosteroids (ICS), lators (the focus of this review), anti-prostaglandin D2 CRTH2 13 5 current step-up treatment involves the addition of a long-acting antagonists, phosphodiesterase-4 inhibitors, anti-leukotriene 5- β -agonist (LABA) or leukotriene receptor antagonist as 2 lipoxygenase-activating protein antagonists and the monoclonal controller therapy. In patients unable to attain or maintain control antibodies mepolizumab and lebrikizumab (which are raised 15 16 with ICS and LABA—those in Global Initiative for Asthma against interleukin-5 and interleukin-13, respectively). treatment steps 3–5 (Figure 1)—upward titration of ICS Short-acting anticholinergic agents, particularly ipratropium dose, leukotriene modifiers, sustained-release theophylline, oral bromide (ipratropium) and oxitropium bromide (oxitropium), have 1 2 3 Centre of Academic Primary Care, University of Aberdeen, Aberdeen, UK; Research in Real Life Ltd, Cambridge, UK; Department of Family Medicine, David Geffen School of 4 5 Medicine at UCLA, Los Angeles, CA, USA; Family Physician Airways Group of Canada, Richmond Hill, ON, Canada; Department of General Practice, University of Groningen, University Medical Center, Groningen, The Netherlands and Son Pisa Primary Health Care Centre, Balearic Health Service, Palma de Mallorca, Spain. Correspondence: D Price (david@respiratoryresearch.org) Received 19 July 2013; revised 14 February 2014; accepted 28 March 2014 © 2014 Primary Care Respiratory Society UK/Macmillan Publishers Limited Long-acting anticholinergic bronchodilators in asthma D Price et al Potential additions to the current Risk management Current symptom management treatment paradigm STEP 1: Correct diagnosis As-needed SABA Investigation for co-morbid rhinitis • Long-acting anticholinergic STEP 2: bronchodilators Correct inhaler selection Low-dose ICS • FLAP inhibitors OR leukotriene modifier • CRTH2 inhibitors Correct inhaler technique • PDE4 inhibitors STEP 3: • Anti-IL-5 antibodies Better adherence Low-dose ICS plus LABA OR medium- to high-dose ICS • Anti-IL-13 antibodies OR low-dose ICS plus leukotriene modifier Allergic trigger avoidance OR low-dose ICS plus theophylline Smoking cessation if applicable STEP 4: Medium- to high-dose ICS plus LABA: Weight management with or without leukotriene modifier OR theophylline Tailoring of ICS/alternative treatment for non-ceasing smokers STEP 5: In addition to STEP 4 therapy, add (In future): Individual tailoring oral glucocorticosteroid of therapy according to OR anti-immunoglobulin E genotype or phenotype? Current and future control 2,5,10–16 Figure 1. Combined approaches for the management of control in asthma. FLAP, 5-lipoxygenase-activating protein; ICS, inhaled corticosteroids; IL, interleukin; LABA, long-acting β -agonist; PDE4, phosphodiesterase-4; SABA, short-acting β -agonist. 2 2 17,18 been used in asthma for many years, although they have not THE ROLE OF CHOLINERGIC ACTIVITY IN THE become widespread because they are generally considered to be PATHOPHYSIOLOGY OF ASTHMA less effective than short-acting β -agonists (SABAs) for acute The symptoms of asthma, and of acute exacerbations, are bronchodilation. This, coupled with a perception that longer- attributed to airway narrowing that occurs as a consequence of term antagonism of cholinergic receptors induces little broncho- chronic inflammation and associated hyper-responsiveness. Local 19,20 dilation above that induced by LABAs, has meant that, in influx of inflammatory cells and high levels of inflammatory 21,22 contrast to chronic obstructive pulmonary disease, long-acting mediators result in airway oedema, airway thickening, mucus anticholinergic bronchodilators have not been considered or hypersecretion and bronchial smooth muscle contraction thoroughly investigated as potential controller medication in 2 (Table 1). Although multiple pathophysiological mechanisms asthma. Early studies demonstrated mild bronchodilation and are thought to contribute to the characteristic narrowing of protection, over 48 h, against methacholine-induced bronchocon- airways and the hyper-responsiveness found in asthma (Table 1), striction in male patients with asthma, and, in patients with bronchial smooth muscle contraction represents the primary severe persistent asthma, small improvements in lung function 29,30 cause of reversible airway obstruction in asthma. The degree were observed with the LABA salmeterol plus the long-acting of basal airway smooth muscle contraction (airway smooth muscle anticholinergic bronchodilator tiotropium bromide (tiotropium), 24 ‘tone’) is under autonomic nervous regulation (Figure 2), although with a halved dose of fluticasone propionate. the mechanisms are not fully understood. During normal Recently, Phase I–III clinical investigation with long-acting ventilation, adrenergic sympathetic nerves and parasympathetic anticholinergic bronchodilators in asthma has begun: two Phase 29,31,32 cholinergic and non-cholinergic nerves are all active, but II trials of umeclidinium bromide (umeclidinium) have completed cholinergic activity is thought to be the predominant driver of (NCT01641692; NCT01573624), and Phase II and III trials with bronchoconstriction (Figure 2, Box 2). Acute treatment with the tiotropium, as add-on therapy, have demonstrated improvements anticholinergic compounds atropine and ipratropium is known to in lung function and a reduction in exacerbation risk in patients 33,34 reduce basal airway smooth muscle tone. with poorly controlled asthma despite the use of ICS or ICS plus a 25–28 Patients with asthma have increased basal airway smooth LABA. muscle tone, and there is evidence to suggest that this is a result In this review, we consider the pathophysiological and clinical of increased basal activity of pulmonary parasympathetic choli- rationales for use of long-acting anticholinergic agents in the nergic nerves, hereinafter described as ‘cholinergic tone’. Molfino broader management of asthma, and the clinical evidence et al. demonstrated that bronchoconstriction induced by breath- reported to date. Please see Box 1 for a description of the literature search and appraisal methods. holding is significantly inhibited by ipratropium in asthmatic npj Primary Care Respiratory Medicine (2014) 14023 © 2014 Primary Care Respiratory Society UK/Macmillan Publishers Limited Long-acting anticholinergic bronchodilators in asthma D Price et al Box 1 Literature evaluation methods Table 1. Mechanisms of airway narrowing and hyper-responsiveness in asthma Clinical evidence around long-acting anticholinergic broncho- Process Consequence dilators We performed searches in November 2013 of PubMed, Google Increased volume and/or Excessive contractility of airway Scholar and Cochrane databases and ClinicalTrials.gov (www. contractility of airway smooth smooth muscle muscle cells clinicaltrials.gov). Secretion of multiple Airway smooth muscle PubMed searches bronchoconstriction mediators contraction All terms restricted to title and abstract, with restriction of results such as histamine, prostaglandin to clinical trials: D and neurotransmitters (1) Asthma* AND (anticholinergic OR antimuscarinic OR Uncoupling of airway smooth Excessive narrowing of the cholinergic OR muscarinic OR parasympathetic) muscle contraction as a result airways; loss of maximum plateau (2) Asthma* AND (tiotropium OR umeclidinium OR aclidi- of inflammatory changes in of contraction when a the airway wall bronchodilator is administered nium OR glycopyrronium OR darotropium OR QVA149 OR glycopyrrolate) Oedema due to microvascular Thickening of airway wall; In November 2013 the searches yielded 209 results; search leakage in response to amplification of airway narrowing 2 yielded 25 results. PubMed search results were manually inflammatory mediators and due to contraction of airway structural changes to airway smooth muscle for geometric reviewed for articles or studies relevant to the topic of smooth muscle reasons short-acting muscarinic agonists or long-acting muscarinic agonists for acute or maintenance therapy Sensitisation of sensory nerves Increased parasympathetic, leading to afferent activity and cholinergic and airway smooth autonomic reflex muscle tone, with consequent Cochrane database searches exaggerated bronchoconstriction ‘Asthma AND anticholinergic’, limited to title, abstract and in response to sensory stimuli keywords, yielding 39 hits, the titles and abstracts of which were manually reviewed In November 2013 the searches yielded one review relating to the use of anticholinergics for asthma manage- Autonomic regulation ment, and eight reviews of anticholinergics in a variety of acute settings Indirect sympathetic Airway www.clinicaltrials.gov searches influence smooth Asthma AND tiotropium OR umeclidinium OR aclidinium muscle OR glycopyrronium OR darotropium OR glycopyrrolate OR QVA149 Airway smooth Pathophysiology and pharmacology muscle tone PubMed and Google scholar searches Mucus secretion ● Epithelial The following terms in Boolean strings: asthma; respiratory; cells cholinergic; muscarinic; parasympathetic; autonomic; tone; pathophysiology; anticholinergic; antimuscarinic; β-agonist; phenotype; genotype; inflammation; bronchoconstriction; Airway and bronchodilation M As this article is not a systematic review, certain articles Ganglion within the pathophysiology and pharmacology sections were reviewed and cited based on their adjudged relevance to the topic Figure 2. Autonomic regulation of airway smooth muscle 29,32,49,50 tone. M ,M ,M , muscarinic acetylcholine receptors 1, 2 1 2 3 and 3. + and − symbols represent signals increasing and decreasing airway smooth muscle tone, respectively. Note that non-adrenergic patients but not in healthy volunteers. It is thought that non-cholinergic autonomic pathways have been omitted for cholinergic tone, at least, is driven by afferent nervous activity simplicity. Adapted from the study by Cazzola, et al., with 29,36,37 permission from the American Society for Pharmacology and arising in the airways, and it has been hypothesised that Experimental Therapeutics. local airway inflammatory mediators may have a role in inducing afferent activity and an autonomic reflex response, thereby driving 31,38,39 an increase in cholinergic tone (Figure 2). Other proposed persist in asthmatic patients, possibly even in the absence of mechanisms for increased cholinergic tone in asthmatic patients airway inflammation following long-term ICS use, suggests that include abnormal muscarinic receptor expression, increased other pathophysiological factors, such as increased cholinergic 39,45 release of acetylcholine from cholinergic nerve endings and and smooth muscle tone, have a role in asthma. It has been reduced levels of neuromodulators that attenuate cholinergic proposed that acetylcholine has a prominent role in allergen- 42,43 46–48 neurotransmission. induced airway smooth muscle remodelling. In a guinea pig The degree to which cholinergic tone contributes to airway model of ongoing allergic asthma, treatment with tiotropium narrowing in asthma, either at basal state or during exacerbations, inhibited increases in airway smooth muscle mass and contractility is unclear. However, the fact that airway hyper-responsiveness can induced by allergic challenge; it has thus been hypothesised that © 2014 Primary Care Respiratory Society UK/Macmillan Publishers Limited npj Primary Care Respiratory Medicine (2014) 14023 Sensory nerve Parasympathetic nerve Long-acting anticholinergic bronchodilators in asthma D Price et al Currently, there are five anticholinergic drugs available for Box 2 Possible pathophysiological reasons why long-acting anti- bronchodilation in respiratory disease. Ipratropium and oxitro- cholinergic bronchodilators may be beneficial for the control of asthma pium are short-acting non-selective antagonists of M ,M and 1 2 M receptors. In contrast, tiotropium, aclidinium bromide ● 3 Cholinergic activity is the predominant driver of bronchial (aclidinium) and glycopyrronium bromide (glycopyrronium) are smooth muscle contraction, the primary cause of reversible 29–31 long-acting compounds, with comparative selectivity for the airway obstruction in asthma 17,53,54 M /M ,M /M and M receptors, respectively. 1 3 2 3 3 Patients with asthma have increased basal airway smooth Short-acting anticholinergics are generally considered less muscle tone, possibly as a result of increased cholinergic effective acute bronchodilators than SABAs, and their short 30,35 tone duration of action makes them broadly unsuitable as controller Acute treatment with anticholinergic compounds reduces medication. Thus, evidence of increased cholinergic tone in 33,34 basal airway smooth muscle tone patients with asthma indicates that the longer-acting bronchodi- Local airway inflammatory mediators may have a role in lator compounds may be more suitable as controller medications 29,31,36–39 inducing increased cholinergic tone in asthma. Cholinergic activity may have a prominent role in airway There is some rationale to suggest that the addition of long- 17,46,47 smooth muscle remodelling acting anticholinergic bronchodilators to LABAs might provide Cholinergic receptors on lung submucosal cells regulate advantages in the treatment of asthma (Box 2). It is reasonable to 49,50,52 mucus secretion hypothesise that by simultaneously antagonising parasympathetic Increased cholinergic and smooth muscle tone may con- smooth muscle contraction and stimulating adrenergic smooth 39,44,45 tribute to airway hyper-responsiveness muscle relaxation, it is possible to achieve greater bronchodilation Cholinergic antagonists may have non-neuronal anti-inflam- compared with either strategy in isolation. To date, there has matory actions been little thorough clinical investigation of this hypothesis in Patients with asthma may have abnormal muscarinic asthma, but a study in a guinea pig model found that receptor expression bronchodilation induced by the LABA carmoterol was significantly Patients with asthma may have increased release of augmented by the addition of tiotropium. In vitro studies acetylcholine from cholinergic nerve endings have also found that the LABA indacaterol can synergistically Patients with asthma may have reduced levels of neuro- increase the inhibitory effects of glycopyrronium on 42,43 56 modulators that attenuate cholinergic neurotransmission methacholine-induced airway smooth muscle contraction. As discussed below, improvements in lung function have been observed in asthmatic patients receiving tiotropium as add-on 26,28 therapy to LABA plus ICS. anticholinergic drugs could help prevent airway smooth muscle It has been suggested that anticholinergic/LABA combination remodelling in human asthma. therapy might offer advantages in mitigating daily variation, Cholinergic activity is also believed to regulate non-smooth based on evidence that sympathetic activity may be elevated muscle and non-neuronal cells within the lungs, including during the daytime, relative to the parasympathetic system, which 49,50 57–60 inflammatory cells and those controlling mucus secretion. In may predominate at night. For example, it was shown in a a guinea pig model, tiotropium was shown to reduce allergen- small study in patients with nocturnal asthma that ipratropium is induced mucus gland hypertrophy and goblet cell number, more effective than salbutamol in the prevention of morning suggesting that anticholinergic bronchodilators might also reduce reductions in peak expiratory flow. It is also possible that a airflow obstruction by reducing mucus hypersecretion. Expression combined approach to bronchodilation might reduce the impact of cholinergic receptors on inflammatory cells raises the additional of inter-patient variability in the relative responses to anti- question of whether there are any non-neuronal anti-inflamma- cholinergic or adrenergic interventions. Finally, tachyphylaxis to tory actions of cholinergic antagonists, although a review of the effects of β-agonists is known to occur (although the clinical 61–63 studies on chronic obstructive pulmonary disease failed to identify relevance of this remains unclear), and it has been proposed robust evidence of this. that crosstalk between muscarinic receptor signalling and adrenergic receptor signalling in smooth muscle cells might interfere with tachyphylactic mechanisms. This would provide a PHARMACOLOGY OF ANTICHOLINERGIC BRONCHODILATORS further rationale for the investigation of LABA/long-acting anti- Anticholinergic bronchodilators are antagonistic to parasympa- cholinergic bronchodilator combination therapy in asthma, as thetic activity and exert their effects on acetylcholine receptors on add-on to ICS. airway smooth muscle and pulmonary parasympathetic nerves (Figure 2). Acetylcholine receptors fall into two families—nicotinic CLINICAL EVIDENCE OF ANTICHOLINERGIC and muscarinic—and it is the M ,M and M subtypes of the latter 1 2 3 BRONCHODILATORS IN ASTHMA that are thought to be primarily involved in the regulation of bronchoconstriction. All subtypes of muscarinic receptors are Historically, short-acting anticholinergic bronchodilators have not widely expressed in the brain, the parasympathetic nervous been considered appropriate for the control of asthma, except in system and the body’s smooth muscle tissues. M receptors are some cases for the acute treatment of asthma attacks in patients 17,18 broadly distributed throughout the parasympathetic ganglia and with chronic stable asthma, and in those who experience regulate cholinergic transmission. M receptors are found in adverse events from SABAs, such as tachycardia, arrhythmia and 1,43 prejunctional membranes of neuromuscular junctions of airway tremor. Although short-acting anticholinergics are considered smooth muscle and regulate negative feedback to reduce less effective rapid bronchodilators than SABAs such as 17,19 acetylcholine transmission. In a pulmonary context, M receptors salbutamol, there are data to suggest that, for acute are predominantly expressed in smooth muscle cells, where they exacerbations, ipratropium in combination with a SABA as reliever regulate contraction, and also within lung submucosal glands, medication improves lung function to a greater extent than a 52 34,65,66 where they regulate mucus secretion (Figure 2). Thus, it is SABA alone. In a double-blind, randomised trial, Rodrigo preferable for antimuscarinic bronchodilators to have a relatively and Rodrigo investigated the effects of high-dose ipratropium high affinity for M and M receptors and low affinity for the M plus the SABA albuterol (registered generic name for salbutamol 1 3 2 receptor. in the USA) in adults with acute asthma, in the emergency npj Primary Care Respiratory Medicine (2014) 14023 © 2014 Primary Care Respiratory Society UK/Macmillan Publishers Limited Long-acting anticholinergic bronchodilators in asthma D Price et al department. Patients receiving high-dose ipratropium plus albu- (values provided in Table 2). Small but statistically significant terol had a greater improvement in peak expiratory flow and improvements in lung function were also observed. Surprisingly, forced expiratory volume in 1 s compared with patients who given the changes in lung function and exacerbation rate, received albuterol alone. The risk of hospital admission was 49% improvements in symptomatic benefit (seven-question Asthma lower in the ipratropium/albuterol arm. Further, a meta-analysis Control Questionnaire [ACQ-7] and Asthma Quality of Life has indicated that the addition of a short-acting anticholinergic to Questionnaire) were small and inconsistent. Of adverse events a SABA is associated with a significant reduction in the risk of reported in ⩾ 2% of patients, only allergic rhinitis occurred at a hospitalisation in children. Thus, in adults or children, the main statistically significantly higher rate in the tiotropium group justification for the use of short-acting anticholinergic drugs in compared with the placebo group. Dry mouth, a typical side acute asthma is reduction of the elevated airway smooth muscle effect associated with anticholinergic drugs, was reported in ⩽ 2% and cholinergic tone during an acute crisis, although administra- of patients. tion of multiple doses has been associated with a reduction in More recently, a Phase III replicate trial of once-daily tiotropium 34,65–68 hospitalisations and risk of hospitalisation. at a dose of 5 or 2.5 μg, versus placebo, as add-on to medium- Although tiotropium has been indicated for the treatment of dose ICS (400–800 μg budesonide or equivalent) was conducted 76,77 chronic obstructive pulmonary disease for over a decade, no long- in 2,103 patients with poorly controlled asthma. An active acting anticholinergic bronchodilators are currently approved in comparator arm of salmeterol 50 μg versus placebo was also asthma. A number of compounds exist, including aclidinium, included. Again, statistically significant improvements in lung glycopyrronium, glycopyrrolate and darotropium bromide, but, as function were observed with tiotropium, which were comparable mentioned, presently only tiotropium and umeclidinium have in magnitude with those seen with salmeterol. A statistically clinical trials in asthma listed on ClinicalTrials.gov. The latter has significant improvement over placebo in ACQ-7 responder rate been under investigation in two dose-ranging Phase II trials in was observed in all three active arms, although, as is common in patients with asthma, as a monotherapy (NCT01641692) and in analyses of ACQ-7 in asthma clinical trials, there was also a large 76,77 combination with fluticasone furoate (NCT01573624), although to placebo effect. We await the full primary publication from our knowledge no results from these trials have yet been this trial. published. Early studies with long-acting anticholinergics in asthma were IS THERE A ROLE FOR LONG-ACTING ANTICHOLINERGIC small and underpowered, and failed to detect meaningful BRONCHODILATORS IN ASTHMA? responses. However, studies of tiotropium and of glycopyrrolate indicated that long-acting anticholinergics can provide sustained Is it possible to determine to which patients, and in which clinical 23,24,69,70 bronchodilation and bronchoprotection. situations, long-acting anticholinergic bronchodilators might offer To date, more thorough clinical evaluation has been performed clinical benefits? Phase III investigation has found that tiotropium with tiotropium only, in six Phase II or III studies, involving over add-on therapy offers advantages to adults with severe asthma 3,500 patients (Table 2). In an investigator-initiated three-way who are failing to gain control on ICS and LABA combinations. crossover trial (14 weeks per treatment) in 210 patients with This, and the fact that the benefit:risk ratio of ICS falls at high ICS 2,7,17,79,80 asthma inadequately controlled by low-dose ICS (twice-daily doses, suggests that addition of long-acting anticholiner- beclomethasone 80 μg), tiotropium delivered via the Spiriva gic bronchodilators to ICS plus a LABA is likely to be a useful HandiHaler device (Boehringer Ingelheim Pharmaceuticals, Ridge- option for patients with poorly controlled severe asthma, and an field, CT, USA) was shown to be superior to a doubling of ICS dose alternative to further increases in ICS dose. and equal to the addition of salmeterol, as assessed by Whether long-acting anticholinergics will be appropriate as improvements in lung function (Table 2). alternatives to LABAs is a harder question to answer. Nevertheless, Subsequent published investigations of tiotropium have all tiotropium add-on to medium-dose ICS has been shown to involved administration via the Respimat SoftMist inhaler (Boeh- provide lung function and ACQ-7 improvements that were 76,77 ringer Ingelheim Pharma, Ingelheim am Rhein, Germany). In an 8- comparable with those of salmeterol, indicating that, in week crossover trial, once-daily tiotropium at a dose of 5 or 10 μg patients for whom LABAs may be unsuitable, long-acting antic- improved lung function, compared with placebo, in 107 patients holinergics could be a helpful alternative. with severe persistent poorly controlled asthma already receiving Although the ACQ-7 effects reported in clinical trials thus far are ICS and LABA (Table 2). In a 16-week trial in patients with relatively small, it will be interesting to see to what extent in arginine/arginine homozygosity at amino acid 16 of the β - practice patients gain clinically relevant benefits in control or adrenergic receptor (B16-Arg/Arg) and moderate poorly con- future risk. Further, one might expect that the demonstrated trolled asthma (already receiving ICS), once-daily tiotropium at a reduction of exacerbation risk with tiotropium as add-on to ICS dose of 5 μg was superior to placebo and non-inferior to twice- plus LABA might translate into long-term improvements in daily salmeterol at a dose of 50 μg for maintenance of overall control. We anticipate that lung function improvements of improvements in lung function (Table 2). The rationale for the magnitude observed in the trials we have described will performing the latter study was based on suggestions that the translate into clinically relevant benefits to patients in a real-world adverse-event profile of β -agonists is worse, and the efficacy setting. At the time of writing, few real-world studies have been 71,72 lower, in patients with the B16-Arg/Arg polymorphism, performed, as long-acting anticholinergic bronchodilators are yet although prospective investigation has revealed that there are to be approved in asthma. However, in a retrospective study of the 73,74 no such concerns. A subsequent Phase II dose-ranging study UK Optimum Patient Care Research Database, off-label use of tested tiotropium at doses of 5 μg, 2.5 μg and 1.25 μg as add-on to tiotropium in patients predominantly in Global Initiative for ICS and found the 5 μg dose to provide the greatest bronchodi- Asthma step 3 or 4 was found to be associated with a reduction lator effect. in the number of exacerbations and a reduced risk of severe Data from the first Phase III trial on a long-acting anticholinergic exacerbation or lower respiratory tract infection. bronchodilator in asthma were published in 2012. In two It is yet to be determined in Phase III investigation whether replicate trials including a total of 912 patients with poorly long-acting anticholinergic bronchodilators offer similar benefits controlled asthma despite the use of LABA and high-dose ICS to adults with mild asthma or to children or adolescents, although (⩾800 μg budesonide or equivalent), tiotropium 5 μg administered several Phase III trials are underway with tiotropium in via the Respimat SoftMist inhaler as add-on therapy significantly these populations (NCT01316380; NCT01634139; NCT01634152; reduced the risk of severe exacerbations compared with placebo NCT01277523). © 2014 Primary Care Respiratory Society UK/Macmillan Publishers Limited npj Primary Care Respiratory Medicine (2014) 14023 Long-acting anticholinergic bronchodilators in asthma D Price et al Table 2. Comparison of lung function and clinical findings from clinical trials with long-acting anticholinergic bronchodilators in asthma Authors Severity Duration per N Study drug(s) Comparator(s) Primary and key Difference from treatment, secondary end points comparator weeks Peters Mild to moderate 14 210 Once-daily Doubling Morning PEF 25.8 l/min (95% CI: et al. asthma tiotropium 18 μg, via ICS dose 14.4–37.1; Po0.001) inadequately Spiriva HandiHaler controlled by Doubling Daily symptom − 0.11 points (Po0.001) low-dose ICS ICS dose score Salmeterol Morning PEF No significant difference Salmeterol Daily symptom score No significant difference Kerstjens Severe asthma 8 107 Once-daily Placebo Tiotropium 5 μg, 139 ml (95% CI: 96–181; et al. inadequately tiotropium 5 μg, via peak FEV Po0.0001) controlled by high- Respimat SoftMist dose ICS + LABA Asthma-related No significant difference health status or symptoms Once-daily Tiotropium 10 μg, 170 ml (95% CI: 128–213; tiotropium 10 μg, via peak FEV Po0.001) Respimat SoftMist Asthma-related No significant difference health status or symptoms Bateman Mild to moderate 16 38 Once-daily Placebo Morning − 20.70 l/min (95% CI: et al. asthma tiotropium 5 μg, via (following run-in pre-dose − 33.24 to − 8.16; uncontrolled by Respimat SoftMist with salmeterol) PEF P= 0.001 for superiority) ICS alone Salmeterol Morning − 0.78 l/min (95% (following run-in pre-dose CI: −13.096 to 11.530; with salmeterol) PEF P= 0.002 for non-inferiority) Kerstjens Poorly controlled 48 912 Once-daily Placebo Peak FEV 86± 34 ml (P= 0.01) et al. asthma despite use tiotropium 5 μg, via at week 24 (trial 1); 154± 32 ml of ICS + LABA Respimat SoftMist (Po0.001) (trial 2) Trough FEV 88± 31 ml (P= 0.01) at week 24 (trial 1); 111± 30 ml (P= 0.001) (trial 2) Reduction in risk of 21% (hazard ratio 0.79; severe exacerbation Po0.03) (pooled at week 48 population) Difference in AQLQ 0.04 units, NS (trial 1) 0.18 units, P= 0.02 (trial 2) Difference in ACQ-7 − 0.13, NS (trial 1) − 0.2, P= 0.003 (trial 2) Abbreviations: ACQ-7, seven-question Asthma Control Questionnaire; AQLQ, Asthma Quality of Life Questionnaire; CI, confidence interval; FEV , forced expiratory volume in 1 s; ICS, inhaled corticosteroids; LABA, long-acting β -agonist; NS, not significant; PEF, peak expiratory flow. a 76,77 75 Only studies published in journal primary publication format have been included (Kerstjens et al. and Beeh et al. not shown). All studies were in adults. All lung function values are mean change from baseline, unless otherwise stated. Active treatments were evaluated as maintenance therapies following a 4-week run-in period with salmeterol. Minimal clinically important difference not achieved. 85,86 There are some physiological (Box 2) and clinical rationales that patients with non-eosinophilic sputum profiles or neutrophilic allow us to suggest groups of patients for whom long-acting inflammation do not gain the same benefit from ICS as those with anticholinergic bronchodilators might be appropriate. A few small eosinophilic inflammation, and hence may be candidates for studies with short-acting anticholinergic bronchodilators have additional treatments such as long-acting anticholinergic bronch- indicated that responses to anticholinergics are more likely in older odilators, as may groups in which steroid resistance is known to 82,83 84 88,89 patients or in those with intrinsic (non-allergic) asthma. It has occur, such as smokers or obese patients. also been suggested that patients intolerant of β -adrenergic It is currently unclear why long-acting anticholinergic agents or with nocturnal asthma might respond better to bronchodilators might reduce the rate of exacerbations. anticholinergic bronchodilators. Further, there is evidence that However, one can hypothesise that a contributing factor to npj Primary Care Respiratory Medicine (2014) 14023 © 2014 Primary Care Respiratory Society UK/Macmillan Publishers Limited Long-acting anticholinergic bronchodilators in asthma D Price et al exacerbations might be an increase in afferent sensory materials from GlaxoSmithKline; stock/stock options in AKL International; nerve activity, resulting in an increase in parasympathetic payment for travel/accommodations/meeting expenses from Boehringer tone and subsequent bronchoconstriction. If this were the Ingelheim, Mundipharma, Napp and Novartis. LF: speaker bureau for Boehringer case, treatment with long-acting anticholinergic therapies Ingelheim. AK: advisory boards or speaker bureau for AstraZeneca, Boehringer may attenuate such autonomic effects and provide additional Ingelheim, Merck Frosst, Novartis, Pfizer, Purdue, Sanofi and Takeda. TvdM: bronchodilation. research grants from Almirall, AstraZeneca, GlaxoSmithKline, MSD and Nycomed; consultancy fees for advisory boards from Almirall, AstraZeneca, MDS, Novartis and Nycomed; speaker fees from AstraZeneca, GlaxoSmithKline, CONCLUSIONS MDS, Novartis and Nycomed. MRR: consultancy for Almirall, Boehringer It has long been apparent from clinical and preclinical investiga- Ingelheim, Chiesi and Novartis; speaker fees from Almirall, AstraZeneca, tions of the pathophysiology of asthma that cholinergic para- Boehringer Ingelheim, Chiesi, GlaxoSmithKline and Novartis. sympathetic tone contributes to contraction of bronchial smooth muscle and narrowing of the airways. The extent to which FUNDING increased parasympathetic tone is a consequence of reflex to the inflammatory state or is a pathophysiological mechanism in itself Medical writing assistance, in the form of literature searches and preparation is unclear. Regardless, the raised parasympathetic tone does and revision of the draft manuscript, was funded by Boehringer Ingelheim. provide a rationale for the use of long-acting anticholinergic Boehringer Ingelheim personnel were given the opportunity (by the authors bronchodilators in asthma, and recent Phase III trial results have prior to submission) to check the data used in the review for factual accuracy demonstrated clinical benefits and lung function improvements only. with tiotropium as add-on therapy to ICS alone or ICS plus LABA in adult patients with poorly controlled asthma. 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Inhaled corticosteroid doses in asthma: an evidence-based approach. Med J Aust 2003; 178:223–225. 80 Szefler SJ, Martin RJ, King TS, Boushey HA, Cherniack RM, Chinchilli VM et al. This work is licensed under a Creative Commons Attribution- Significant variability in response to inhaled corticosteroids for persistent asthma. NonCommercial-NoDerivatives 4.0 International License. The images J Allergy Clin Immunol 2002; 109:410–418. or other third party material in this article are included in the article’s Creative Commons 81 Price DB, Kaplan A, Jones R, Freeman D, Burden A, Gould SE et al. Real-life license, unless indicated otherwise in the credit line; if the material is not included under prescribing and outcomes of long-acting anticholinergic therapy in adult the Creative Commons license, users will need to obtain permission from the license asthma patients in UK clinical practice. Am J Respir Crit Care Med 2013; 187 holder to reproduce the material. 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Is there a rationale and role for long-acting anticholinergic bronchodilators in asthma?

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www.nature.com/npjpcrm All rights reserved 2055-1010/14 REVIEW ARTICLE OPEN Is there a rationale and role for long-acting anticholinergic bronchodilators in asthma? 1,2 3 4 5 6 David Price , Leonard Fromer , Alan Kaplan , Thys van der Molen and Miguel Román-Rodríguez Despite current guidelines and the range of available treatments, over a half of patients with asthma continue to suffer from poor symptomatic control and remain at risk of future worsening. Although a number of non-pharmacological measures are crucial for good clinical management of asthma, new therapeutic controller medications will have a role in the future management of the disease. Several long-acting anticholinergic bronchodilators are under investigation or are available for the treatment of respiratory diseases, including tiotropium bromide, aclidinium bromide, glycopyrronium bromide, glycopyrrolate and umeclidinium bromide, although none is yet licensed for the treatment of asthma. A recent Phase III investigation demonstrated that the once-daily long- acting anticholinergic bronchodilator tiotropium bromide improves lung function and reduces the risk of exacerbation in patients with symptomatic asthma, despite the use of inhaled corticosteroids (ICS) and long-acting β -agonists (LABAs). This has prompted the question of what the rationale is for long-acting anticholinergic bronchodilators in asthma. Bronchial smooth muscle contraction is the primary cause of reversible airway narrowing in asthma, and the baseline level of contraction is predominantly set by the level of ‘cholinergic tone’. Patients with asthma have increased bronchial smooth muscle tone and mucus hypersecretion, possibly as a result of elevated cholinergic activity, which anticholinergic compounds are known to reduce. Further, anticholinergic compounds may also have anti-inflammatory properties. Thus, evidence suggests that long-acting anticholinergic bronchodilators might offer benefits for the maintenance of asthma control, such as in patients failing to gain control on ICS and a LABA, or those with frequent exacerbations. npj Primary Care Respiratory Medicine (2014) 24, 14023; doi:10.1038/npjpcrm.2014.23; published online 17 July 2014 INTRODUCTION glucocorticosteroids and anti-immunoglobulin E (omalizumab) are all further or alternative treatment options. Asthma affects over 300 million individuals worldwide, a figure Despite these guidelines and the wide range of therapies that is estimated to grow by 100 million by 2025. A chronic available, poor control of current asthma symptoms, and of future inflammatory disease of the airways, asthma has multifactorial 5–9 asthma exacerbations, continues to affect 450% of patients, pathophysiological causes and considerable heterogeneity in the with exacerbations placing significant strain on their quality of life classification of the disease by phenotype, aetiology, severity and and on health-care systems. Risk factors associated with future interventional control. exacerbations include previous exacerbations, poor control, Current guidelines recommend stepwise management to gain inhaler technique and adherence, co-morbid allergic rhinitis, and maintain control, in which the clinical definition of full gastro-oesophageal reflux disease, psychological dysfunction, ‘control’ is daytime symptoms or use of reliever medication less smoking and obesity. The same factors, in addition to incorrect than twice a week, no limitations of activity, no nocturnal diagnosis, poor choice of inhaler, variation in individual treatment symptoms and normal lung function. Furthermore, the American responses or genetic components, have been attributed to the Thoracic Society and the European Respiratory Society state that underlying poor control. There are a number of actions available any definition or measure of control must take into account the in the primary care setting to reduce the impact of these factors management of a patient’s future risk. Thus, in clinical manage- 10,11 (Figure 1). ment of asthma, consideration must be given to reducing the In the light of such concerns around risk and poor control, it is frequency of exacerbations, preserving lung function, preventing appropriate to consider the rationale for investigating additional reduced lung growth in children and minimising the adverse controller medications. A number of new therapies are under effects of any treatment. investigation, including long-acting anticholinergic bronchodi- For those receiving low-dose inhaled corticosteroids (ICS), lators (the focus of this review), anti-prostaglandin D2 CRTH2 13 5 current step-up treatment involves the addition of a long-acting antagonists, phosphodiesterase-4 inhibitors, anti-leukotriene 5- β -agonist (LABA) or leukotriene receptor antagonist as 2 lipoxygenase-activating protein antagonists and the monoclonal controller therapy. In patients unable to attain or maintain control antibodies mepolizumab and lebrikizumab (which are raised 15 16 with ICS and LABA—those in Global Initiative for Asthma against interleukin-5 and interleukin-13, respectively). treatment steps 3–5 (Figure 1)—upward titration of ICS Short-acting anticholinergic agents, particularly ipratropium dose, leukotriene modifiers, sustained-release theophylline, oral bromide (ipratropium) and oxitropium bromide (oxitropium), have 1 2 3 Centre of Academic Primary Care, University of Aberdeen, Aberdeen, UK; Research in Real Life Ltd, Cambridge, UK; Department of Family Medicine, David Geffen School of 4 5 Medicine at UCLA, Los Angeles, CA, USA; Family Physician Airways Group of Canada, Richmond Hill, ON, Canada; Department of General Practice, University of Groningen, University Medical Center, Groningen, The Netherlands and Son Pisa Primary Health Care Centre, Balearic Health Service, Palma de Mallorca, Spain. Correspondence: D Price (david@respiratoryresearch.org) Received 19 July 2013; revised 14 February 2014; accepted 28 March 2014 © 2014 Primary Care Respiratory Society UK/Macmillan Publishers Limited Long-acting anticholinergic bronchodilators in asthma D Price et al Potential additions to the current Risk management Current symptom management treatment paradigm STEP 1: Correct diagnosis As-needed SABA Investigation for co-morbid rhinitis • Long-acting anticholinergic STEP 2: bronchodilators Correct inhaler selection Low-dose ICS • FLAP inhibitors OR leukotriene modifier • CRTH2 inhibitors Correct inhaler technique • PDE4 inhibitors STEP 3: • Anti-IL-5 antibodies Better adherence Low-dose ICS plus LABA OR medium- to high-dose ICS • Anti-IL-13 antibodies OR low-dose ICS plus leukotriene modifier Allergic trigger avoidance OR low-dose ICS plus theophylline Smoking cessation if applicable STEP 4: Medium- to high-dose ICS plus LABA: Weight management with or without leukotriene modifier OR theophylline Tailoring of ICS/alternative treatment for non-ceasing smokers STEP 5: In addition to STEP 4 therapy, add (In future): Individual tailoring oral glucocorticosteroid of therapy according to OR anti-immunoglobulin E genotype or phenotype? Current and future control 2,5,10–16 Figure 1. Combined approaches for the management of control in asthma. FLAP, 5-lipoxygenase-activating protein; ICS, inhaled corticosteroids; IL, interleukin; LABA, long-acting β -agonist; PDE4, phosphodiesterase-4; SABA, short-acting β -agonist. 2 2 17,18 been used in asthma for many years, although they have not THE ROLE OF CHOLINERGIC ACTIVITY IN THE become widespread because they are generally considered to be PATHOPHYSIOLOGY OF ASTHMA less effective than short-acting β -agonists (SABAs) for acute The symptoms of asthma, and of acute exacerbations, are bronchodilation. This, coupled with a perception that longer- attributed to airway narrowing that occurs as a consequence of term antagonism of cholinergic receptors induces little broncho- chronic inflammation and associated hyper-responsiveness. Local 19,20 dilation above that induced by LABAs, has meant that, in influx of inflammatory cells and high levels of inflammatory 21,22 contrast to chronic obstructive pulmonary disease, long-acting mediators result in airway oedema, airway thickening, mucus anticholinergic bronchodilators have not been considered or hypersecretion and bronchial smooth muscle contraction thoroughly investigated as potential controller medication in 2 (Table 1). Although multiple pathophysiological mechanisms asthma. Early studies demonstrated mild bronchodilation and are thought to contribute to the characteristic narrowing of protection, over 48 h, against methacholine-induced bronchocon- airways and the hyper-responsiveness found in asthma (Table 1), striction in male patients with asthma, and, in patients with bronchial smooth muscle contraction represents the primary severe persistent asthma, small improvements in lung function 29,30 cause of reversible airway obstruction in asthma. The degree were observed with the LABA salmeterol plus the long-acting of basal airway smooth muscle contraction (airway smooth muscle anticholinergic bronchodilator tiotropium bromide (tiotropium), 24 ‘tone’) is under autonomic nervous regulation (Figure 2), although with a halved dose of fluticasone propionate. the mechanisms are not fully understood. During normal Recently, Phase I–III clinical investigation with long-acting ventilation, adrenergic sympathetic nerves and parasympathetic anticholinergic bronchodilators in asthma has begun: two Phase 29,31,32 cholinergic and non-cholinergic nerves are all active, but II trials of umeclidinium bromide (umeclidinium) have completed cholinergic activity is thought to be the predominant driver of (NCT01641692; NCT01573624), and Phase II and III trials with bronchoconstriction (Figure 2, Box 2). Acute treatment with the tiotropium, as add-on therapy, have demonstrated improvements anticholinergic compounds atropine and ipratropium is known to in lung function and a reduction in exacerbation risk in patients 33,34 reduce basal airway smooth muscle tone. with poorly controlled asthma despite the use of ICS or ICS plus a 25–28 Patients with asthma have increased basal airway smooth LABA. muscle tone, and there is evidence to suggest that this is a result In this review, we consider the pathophysiological and clinical of increased basal activity of pulmonary parasympathetic choli- rationales for use of long-acting anticholinergic agents in the nergic nerves, hereinafter described as ‘cholinergic tone’. Molfino broader management of asthma, and the clinical evidence et al. demonstrated that bronchoconstriction induced by breath- reported to date. Please see Box 1 for a description of the literature search and appraisal methods. holding is significantly inhibited by ipratropium in asthmatic npj Primary Care Respiratory Medicine (2014) 14023 © 2014 Primary Care Respiratory Society UK/Macmillan Publishers Limited Long-acting anticholinergic bronchodilators in asthma D Price et al Box 1 Literature evaluation methods Table 1. Mechanisms of airway narrowing and hyper-responsiveness in asthma Clinical evidence around long-acting anticholinergic broncho- Process Consequence dilators We performed searches in November 2013 of PubMed, Google Increased volume and/or Excessive contractility of airway Scholar and Cochrane databases and ClinicalTrials.gov (www. contractility of airway smooth smooth muscle muscle cells clinicaltrials.gov). Secretion of multiple Airway smooth muscle PubMed searches bronchoconstriction mediators contraction All terms restricted to title and abstract, with restriction of results such as histamine, prostaglandin to clinical trials: D and neurotransmitters (1) Asthma* AND (anticholinergic OR antimuscarinic OR Uncoupling of airway smooth Excessive narrowing of the cholinergic OR muscarinic OR parasympathetic) muscle contraction as a result airways; loss of maximum plateau (2) Asthma* AND (tiotropium OR umeclidinium OR aclidi- of inflammatory changes in of contraction when a the airway wall bronchodilator is administered nium OR glycopyrronium OR darotropium OR QVA149 OR glycopyrrolate) Oedema due to microvascular Thickening of airway wall; In November 2013 the searches yielded 209 results; search leakage in response to amplification of airway narrowing 2 yielded 25 results. PubMed search results were manually inflammatory mediators and due to contraction of airway structural changes to airway smooth muscle for geometric reviewed for articles or studies relevant to the topic of smooth muscle reasons short-acting muscarinic agonists or long-acting muscarinic agonists for acute or maintenance therapy Sensitisation of sensory nerves Increased parasympathetic, leading to afferent activity and cholinergic and airway smooth autonomic reflex muscle tone, with consequent Cochrane database searches exaggerated bronchoconstriction ‘Asthma AND anticholinergic’, limited to title, abstract and in response to sensory stimuli keywords, yielding 39 hits, the titles and abstracts of which were manually reviewed In November 2013 the searches yielded one review relating to the use of anticholinergics for asthma manage- Autonomic regulation ment, and eight reviews of anticholinergics in a variety of acute settings Indirect sympathetic Airway www.clinicaltrials.gov searches influence smooth Asthma AND tiotropium OR umeclidinium OR aclidinium muscle OR glycopyrronium OR darotropium OR glycopyrrolate OR QVA149 Airway smooth Pathophysiology and pharmacology muscle tone PubMed and Google scholar searches Mucus secretion ● Epithelial The following terms in Boolean strings: asthma; respiratory; cells cholinergic; muscarinic; parasympathetic; autonomic; tone; pathophysiology; anticholinergic; antimuscarinic; β-agonist; phenotype; genotype; inflammation; bronchoconstriction; Airway and bronchodilation M As this article is not a systematic review, certain articles Ganglion within the pathophysiology and pharmacology sections were reviewed and cited based on their adjudged relevance to the topic Figure 2. Autonomic regulation of airway smooth muscle 29,32,49,50 tone. M ,M ,M , muscarinic acetylcholine receptors 1, 2 1 2 3 and 3. + and − symbols represent signals increasing and decreasing airway smooth muscle tone, respectively. Note that non-adrenergic patients but not in healthy volunteers. It is thought that non-cholinergic autonomic pathways have been omitted for cholinergic tone, at least, is driven by afferent nervous activity simplicity. Adapted from the study by Cazzola, et al., with 29,36,37 permission from the American Society for Pharmacology and arising in the airways, and it has been hypothesised that Experimental Therapeutics. local airway inflammatory mediators may have a role in inducing afferent activity and an autonomic reflex response, thereby driving 31,38,39 an increase in cholinergic tone (Figure 2). Other proposed persist in asthmatic patients, possibly even in the absence of mechanisms for increased cholinergic tone in asthmatic patients airway inflammation following long-term ICS use, suggests that include abnormal muscarinic receptor expression, increased other pathophysiological factors, such as increased cholinergic 39,45 release of acetylcholine from cholinergic nerve endings and and smooth muscle tone, have a role in asthma. It has been reduced levels of neuromodulators that attenuate cholinergic proposed that acetylcholine has a prominent role in allergen- 42,43 46–48 neurotransmission. induced airway smooth muscle remodelling. In a guinea pig The degree to which cholinergic tone contributes to airway model of ongoing allergic asthma, treatment with tiotropium narrowing in asthma, either at basal state or during exacerbations, inhibited increases in airway smooth muscle mass and contractility is unclear. However, the fact that airway hyper-responsiveness can induced by allergic challenge; it has thus been hypothesised that © 2014 Primary Care Respiratory Society UK/Macmillan Publishers Limited npj Primary Care Respiratory Medicine (2014) 14023 Sensory nerve Parasympathetic nerve Long-acting anticholinergic bronchodilators in asthma D Price et al Currently, there are five anticholinergic drugs available for Box 2 Possible pathophysiological reasons why long-acting anti- bronchodilation in respiratory disease. Ipratropium and oxitro- cholinergic bronchodilators may be beneficial for the control of asthma pium are short-acting non-selective antagonists of M ,M and 1 2 M receptors. In contrast, tiotropium, aclidinium bromide ● 3 Cholinergic activity is the predominant driver of bronchial (aclidinium) and glycopyrronium bromide (glycopyrronium) are smooth muscle contraction, the primary cause of reversible 29–31 long-acting compounds, with comparative selectivity for the airway obstruction in asthma 17,53,54 M /M ,M /M and M receptors, respectively. 1 3 2 3 3 Patients with asthma have increased basal airway smooth Short-acting anticholinergics are generally considered less muscle tone, possibly as a result of increased cholinergic effective acute bronchodilators than SABAs, and their short 30,35 tone duration of action makes them broadly unsuitable as controller Acute treatment with anticholinergic compounds reduces medication. Thus, evidence of increased cholinergic tone in 33,34 basal airway smooth muscle tone patients with asthma indicates that the longer-acting bronchodi- Local airway inflammatory mediators may have a role in lator compounds may be more suitable as controller medications 29,31,36–39 inducing increased cholinergic tone in asthma. Cholinergic activity may have a prominent role in airway There is some rationale to suggest that the addition of long- 17,46,47 smooth muscle remodelling acting anticholinergic bronchodilators to LABAs might provide Cholinergic receptors on lung submucosal cells regulate advantages in the treatment of asthma (Box 2). It is reasonable to 49,50,52 mucus secretion hypothesise that by simultaneously antagonising parasympathetic Increased cholinergic and smooth muscle tone may con- smooth muscle contraction and stimulating adrenergic smooth 39,44,45 tribute to airway hyper-responsiveness muscle relaxation, it is possible to achieve greater bronchodilation Cholinergic antagonists may have non-neuronal anti-inflam- compared with either strategy in isolation. To date, there has matory actions been little thorough clinical investigation of this hypothesis in Patients with asthma may have abnormal muscarinic asthma, but a study in a guinea pig model found that receptor expression bronchodilation induced by the LABA carmoterol was significantly Patients with asthma may have increased release of augmented by the addition of tiotropium. In vitro studies acetylcholine from cholinergic nerve endings have also found that the LABA indacaterol can synergistically Patients with asthma may have reduced levels of neuro- increase the inhibitory effects of glycopyrronium on 42,43 56 modulators that attenuate cholinergic neurotransmission methacholine-induced airway smooth muscle contraction. As discussed below, improvements in lung function have been observed in asthmatic patients receiving tiotropium as add-on 26,28 therapy to LABA plus ICS. anticholinergic drugs could help prevent airway smooth muscle It has been suggested that anticholinergic/LABA combination remodelling in human asthma. therapy might offer advantages in mitigating daily variation, Cholinergic activity is also believed to regulate non-smooth based on evidence that sympathetic activity may be elevated muscle and non-neuronal cells within the lungs, including during the daytime, relative to the parasympathetic system, which 49,50 57–60 inflammatory cells and those controlling mucus secretion. In may predominate at night. For example, it was shown in a a guinea pig model, tiotropium was shown to reduce allergen- small study in patients with nocturnal asthma that ipratropium is induced mucus gland hypertrophy and goblet cell number, more effective than salbutamol in the prevention of morning suggesting that anticholinergic bronchodilators might also reduce reductions in peak expiratory flow. It is also possible that a airflow obstruction by reducing mucus hypersecretion. Expression combined approach to bronchodilation might reduce the impact of cholinergic receptors on inflammatory cells raises the additional of inter-patient variability in the relative responses to anti- question of whether there are any non-neuronal anti-inflamma- cholinergic or adrenergic interventions. Finally, tachyphylaxis to tory actions of cholinergic antagonists, although a review of the effects of β-agonists is known to occur (although the clinical 61–63 studies on chronic obstructive pulmonary disease failed to identify relevance of this remains unclear), and it has been proposed robust evidence of this. that crosstalk between muscarinic receptor signalling and adrenergic receptor signalling in smooth muscle cells might interfere with tachyphylactic mechanisms. This would provide a PHARMACOLOGY OF ANTICHOLINERGIC BRONCHODILATORS further rationale for the investigation of LABA/long-acting anti- Anticholinergic bronchodilators are antagonistic to parasympa- cholinergic bronchodilator combination therapy in asthma, as thetic activity and exert their effects on acetylcholine receptors on add-on to ICS. airway smooth muscle and pulmonary parasympathetic nerves (Figure 2). Acetylcholine receptors fall into two families—nicotinic CLINICAL EVIDENCE OF ANTICHOLINERGIC and muscarinic—and it is the M ,M and M subtypes of the latter 1 2 3 BRONCHODILATORS IN ASTHMA that are thought to be primarily involved in the regulation of bronchoconstriction. All subtypes of muscarinic receptors are Historically, short-acting anticholinergic bronchodilators have not widely expressed in the brain, the parasympathetic nervous been considered appropriate for the control of asthma, except in system and the body’s smooth muscle tissues. M receptors are some cases for the acute treatment of asthma attacks in patients 17,18 broadly distributed throughout the parasympathetic ganglia and with chronic stable asthma, and in those who experience regulate cholinergic transmission. M receptors are found in adverse events from SABAs, such as tachycardia, arrhythmia and 1,43 prejunctional membranes of neuromuscular junctions of airway tremor. Although short-acting anticholinergics are considered smooth muscle and regulate negative feedback to reduce less effective rapid bronchodilators than SABAs such as 17,19 acetylcholine transmission. In a pulmonary context, M receptors salbutamol, there are data to suggest that, for acute are predominantly expressed in smooth muscle cells, where they exacerbations, ipratropium in combination with a SABA as reliever regulate contraction, and also within lung submucosal glands, medication improves lung function to a greater extent than a 52 34,65,66 where they regulate mucus secretion (Figure 2). Thus, it is SABA alone. In a double-blind, randomised trial, Rodrigo preferable for antimuscarinic bronchodilators to have a relatively and Rodrigo investigated the effects of high-dose ipratropium high affinity for M and M receptors and low affinity for the M plus the SABA albuterol (registered generic name for salbutamol 1 3 2 receptor. in the USA) in adults with acute asthma, in the emergency npj Primary Care Respiratory Medicine (2014) 14023 © 2014 Primary Care Respiratory Society UK/Macmillan Publishers Limited Long-acting anticholinergic bronchodilators in asthma D Price et al department. Patients receiving high-dose ipratropium plus albu- (values provided in Table 2). Small but statistically significant terol had a greater improvement in peak expiratory flow and improvements in lung function were also observed. Surprisingly, forced expiratory volume in 1 s compared with patients who given the changes in lung function and exacerbation rate, received albuterol alone. The risk of hospital admission was 49% improvements in symptomatic benefit (seven-question Asthma lower in the ipratropium/albuterol arm. Further, a meta-analysis Control Questionnaire [ACQ-7] and Asthma Quality of Life has indicated that the addition of a short-acting anticholinergic to Questionnaire) were small and inconsistent. Of adverse events a SABA is associated with a significant reduction in the risk of reported in ⩾ 2% of patients, only allergic rhinitis occurred at a hospitalisation in children. Thus, in adults or children, the main statistically significantly higher rate in the tiotropium group justification for the use of short-acting anticholinergic drugs in compared with the placebo group. Dry mouth, a typical side acute asthma is reduction of the elevated airway smooth muscle effect associated with anticholinergic drugs, was reported in ⩽ 2% and cholinergic tone during an acute crisis, although administra- of patients. tion of multiple doses has been associated with a reduction in More recently, a Phase III replicate trial of once-daily tiotropium 34,65–68 hospitalisations and risk of hospitalisation. at a dose of 5 or 2.5 μg, versus placebo, as add-on to medium- Although tiotropium has been indicated for the treatment of dose ICS (400–800 μg budesonide or equivalent) was conducted 76,77 chronic obstructive pulmonary disease for over a decade, no long- in 2,103 patients with poorly controlled asthma. An active acting anticholinergic bronchodilators are currently approved in comparator arm of salmeterol 50 μg versus placebo was also asthma. A number of compounds exist, including aclidinium, included. Again, statistically significant improvements in lung glycopyrronium, glycopyrrolate and darotropium bromide, but, as function were observed with tiotropium, which were comparable mentioned, presently only tiotropium and umeclidinium have in magnitude with those seen with salmeterol. A statistically clinical trials in asthma listed on ClinicalTrials.gov. The latter has significant improvement over placebo in ACQ-7 responder rate been under investigation in two dose-ranging Phase II trials in was observed in all three active arms, although, as is common in patients with asthma, as a monotherapy (NCT01641692) and in analyses of ACQ-7 in asthma clinical trials, there was also a large 76,77 combination with fluticasone furoate (NCT01573624), although to placebo effect. We await the full primary publication from our knowledge no results from these trials have yet been this trial. published. Early studies with long-acting anticholinergics in asthma were IS THERE A ROLE FOR LONG-ACTING ANTICHOLINERGIC small and underpowered, and failed to detect meaningful BRONCHODILATORS IN ASTHMA? responses. However, studies of tiotropium and of glycopyrrolate indicated that long-acting anticholinergics can provide sustained Is it possible to determine to which patients, and in which clinical 23,24,69,70 bronchodilation and bronchoprotection. situations, long-acting anticholinergic bronchodilators might offer To date, more thorough clinical evaluation has been performed clinical benefits? Phase III investigation has found that tiotropium with tiotropium only, in six Phase II or III studies, involving over add-on therapy offers advantages to adults with severe asthma 3,500 patients (Table 2). In an investigator-initiated three-way who are failing to gain control on ICS and LABA combinations. crossover trial (14 weeks per treatment) in 210 patients with This, and the fact that the benefit:risk ratio of ICS falls at high ICS 2,7,17,79,80 asthma inadequately controlled by low-dose ICS (twice-daily doses, suggests that addition of long-acting anticholiner- beclomethasone 80 μg), tiotropium delivered via the Spiriva gic bronchodilators to ICS plus a LABA is likely to be a useful HandiHaler device (Boehringer Ingelheim Pharmaceuticals, Ridge- option for patients with poorly controlled severe asthma, and an field, CT, USA) was shown to be superior to a doubling of ICS dose alternative to further increases in ICS dose. and equal to the addition of salmeterol, as assessed by Whether long-acting anticholinergics will be appropriate as improvements in lung function (Table 2). alternatives to LABAs is a harder question to answer. Nevertheless, Subsequent published investigations of tiotropium have all tiotropium add-on to medium-dose ICS has been shown to involved administration via the Respimat SoftMist inhaler (Boeh- provide lung function and ACQ-7 improvements that were 76,77 ringer Ingelheim Pharma, Ingelheim am Rhein, Germany). In an 8- comparable with those of salmeterol, indicating that, in week crossover trial, once-daily tiotropium at a dose of 5 or 10 μg patients for whom LABAs may be unsuitable, long-acting antic- improved lung function, compared with placebo, in 107 patients holinergics could be a helpful alternative. with severe persistent poorly controlled asthma already receiving Although the ACQ-7 effects reported in clinical trials thus far are ICS and LABA (Table 2). In a 16-week trial in patients with relatively small, it will be interesting to see to what extent in arginine/arginine homozygosity at amino acid 16 of the β - practice patients gain clinically relevant benefits in control or adrenergic receptor (B16-Arg/Arg) and moderate poorly con- future risk. Further, one might expect that the demonstrated trolled asthma (already receiving ICS), once-daily tiotropium at a reduction of exacerbation risk with tiotropium as add-on to ICS dose of 5 μg was superior to placebo and non-inferior to twice- plus LABA might translate into long-term improvements in daily salmeterol at a dose of 50 μg for maintenance of overall control. We anticipate that lung function improvements of improvements in lung function (Table 2). The rationale for the magnitude observed in the trials we have described will performing the latter study was based on suggestions that the translate into clinically relevant benefits to patients in a real-world adverse-event profile of β -agonists is worse, and the efficacy setting. At the time of writing, few real-world studies have been 71,72 lower, in patients with the B16-Arg/Arg polymorphism, performed, as long-acting anticholinergic bronchodilators are yet although prospective investigation has revealed that there are to be approved in asthma. However, in a retrospective study of the 73,74 no such concerns. A subsequent Phase II dose-ranging study UK Optimum Patient Care Research Database, off-label use of tested tiotropium at doses of 5 μg, 2.5 μg and 1.25 μg as add-on to tiotropium in patients predominantly in Global Initiative for ICS and found the 5 μg dose to provide the greatest bronchodi- Asthma step 3 or 4 was found to be associated with a reduction lator effect. in the number of exacerbations and a reduced risk of severe Data from the first Phase III trial on a long-acting anticholinergic exacerbation or lower respiratory tract infection. bronchodilator in asthma were published in 2012. In two It is yet to be determined in Phase III investigation whether replicate trials including a total of 912 patients with poorly long-acting anticholinergic bronchodilators offer similar benefits controlled asthma despite the use of LABA and high-dose ICS to adults with mild asthma or to children or adolescents, although (⩾800 μg budesonide or equivalent), tiotropium 5 μg administered several Phase III trials are underway with tiotropium in via the Respimat SoftMist inhaler as add-on therapy significantly these populations (NCT01316380; NCT01634139; NCT01634152; reduced the risk of severe exacerbations compared with placebo NCT01277523). © 2014 Primary Care Respiratory Society UK/Macmillan Publishers Limited npj Primary Care Respiratory Medicine (2014) 14023 Long-acting anticholinergic bronchodilators in asthma D Price et al Table 2. Comparison of lung function and clinical findings from clinical trials with long-acting anticholinergic bronchodilators in asthma Authors Severity Duration per N Study drug(s) Comparator(s) Primary and key Difference from treatment, secondary end points comparator weeks Peters Mild to moderate 14 210 Once-daily Doubling Morning PEF 25.8 l/min (95% CI: et al. asthma tiotropium 18 μg, via ICS dose 14.4–37.1; Po0.001) inadequately Spiriva HandiHaler controlled by Doubling Daily symptom − 0.11 points (Po0.001) low-dose ICS ICS dose score Salmeterol Morning PEF No significant difference Salmeterol Daily symptom score No significant difference Kerstjens Severe asthma 8 107 Once-daily Placebo Tiotropium 5 μg, 139 ml (95% CI: 96–181; et al. inadequately tiotropium 5 μg, via peak FEV Po0.0001) controlled by high- Respimat SoftMist dose ICS + LABA Asthma-related No significant difference health status or symptoms Once-daily Tiotropium 10 μg, 170 ml (95% CI: 128–213; tiotropium 10 μg, via peak FEV Po0.001) Respimat SoftMist Asthma-related No significant difference health status or symptoms Bateman Mild to moderate 16 38 Once-daily Placebo Morning − 20.70 l/min (95% CI: et al. asthma tiotropium 5 μg, via (following run-in pre-dose − 33.24 to − 8.16; uncontrolled by Respimat SoftMist with salmeterol) PEF P= 0.001 for superiority) ICS alone Salmeterol Morning − 0.78 l/min (95% (following run-in pre-dose CI: −13.096 to 11.530; with salmeterol) PEF P= 0.002 for non-inferiority) Kerstjens Poorly controlled 48 912 Once-daily Placebo Peak FEV 86± 34 ml (P= 0.01) et al. asthma despite use tiotropium 5 μg, via at week 24 (trial 1); 154± 32 ml of ICS + LABA Respimat SoftMist (Po0.001) (trial 2) Trough FEV 88± 31 ml (P= 0.01) at week 24 (trial 1); 111± 30 ml (P= 0.001) (trial 2) Reduction in risk of 21% (hazard ratio 0.79; severe exacerbation Po0.03) (pooled at week 48 population) Difference in AQLQ 0.04 units, NS (trial 1) 0.18 units, P= 0.02 (trial 2) Difference in ACQ-7 − 0.13, NS (trial 1) − 0.2, P= 0.003 (trial 2) Abbreviations: ACQ-7, seven-question Asthma Control Questionnaire; AQLQ, Asthma Quality of Life Questionnaire; CI, confidence interval; FEV , forced expiratory volume in 1 s; ICS, inhaled corticosteroids; LABA, long-acting β -agonist; NS, not significant; PEF, peak expiratory flow. a 76,77 75 Only studies published in journal primary publication format have been included (Kerstjens et al. and Beeh et al. not shown). All studies were in adults. All lung function values are mean change from baseline, unless otherwise stated. Active treatments were evaluated as maintenance therapies following a 4-week run-in period with salmeterol. Minimal clinically important difference not achieved. 85,86 There are some physiological (Box 2) and clinical rationales that patients with non-eosinophilic sputum profiles or neutrophilic allow us to suggest groups of patients for whom long-acting inflammation do not gain the same benefit from ICS as those with anticholinergic bronchodilators might be appropriate. A few small eosinophilic inflammation, and hence may be candidates for studies with short-acting anticholinergic bronchodilators have additional treatments such as long-acting anticholinergic bronch- indicated that responses to anticholinergics are more likely in older odilators, as may groups in which steroid resistance is known to 82,83 84 88,89 patients or in those with intrinsic (non-allergic) asthma. It has occur, such as smokers or obese patients. also been suggested that patients intolerant of β -adrenergic It is currently unclear why long-acting anticholinergic agents or with nocturnal asthma might respond better to bronchodilators might reduce the rate of exacerbations. anticholinergic bronchodilators. Further, there is evidence that However, one can hypothesise that a contributing factor to npj Primary Care Respiratory Medicine (2014) 14023 © 2014 Primary Care Respiratory Society UK/Macmillan Publishers Limited Long-acting anticholinergic bronchodilators in asthma D Price et al exacerbations might be an increase in afferent sensory materials from GlaxoSmithKline; stock/stock options in AKL International; nerve activity, resulting in an increase in parasympathetic payment for travel/accommodations/meeting expenses from Boehringer tone and subsequent bronchoconstriction. If this were the Ingelheim, Mundipharma, Napp and Novartis. LF: speaker bureau for Boehringer case, treatment with long-acting anticholinergic therapies Ingelheim. AK: advisory boards or speaker bureau for AstraZeneca, Boehringer may attenuate such autonomic effects and provide additional Ingelheim, Merck Frosst, Novartis, Pfizer, Purdue, Sanofi and Takeda. TvdM: bronchodilation. research grants from Almirall, AstraZeneca, GlaxoSmithKline, MSD and Nycomed; consultancy fees for advisory boards from Almirall, AstraZeneca, MDS, Novartis and Nycomed; speaker fees from AstraZeneca, GlaxoSmithKline, CONCLUSIONS MDS, Novartis and Nycomed. MRR: consultancy for Almirall, Boehringer It has long been apparent from clinical and preclinical investiga- Ingelheim, Chiesi and Novartis; speaker fees from Almirall, AstraZeneca, tions of the pathophysiology of asthma that cholinergic para- Boehringer Ingelheim, Chiesi, GlaxoSmithKline and Novartis. sympathetic tone contributes to contraction of bronchial smooth muscle and narrowing of the airways. The extent to which FUNDING increased parasympathetic tone is a consequence of reflex to the inflammatory state or is a pathophysiological mechanism in itself Medical writing assistance, in the form of literature searches and preparation is unclear. Regardless, the raised parasympathetic tone does and revision of the draft manuscript, was funded by Boehringer Ingelheim. provide a rationale for the use of long-acting anticholinergic Boehringer Ingelheim personnel were given the opportunity (by the authors bronchodilators in asthma, and recent Phase III trial results have prior to submission) to check the data used in the review for factual accuracy demonstrated clinical benefits and lung function improvements only. with tiotropium as add-on therapy to ICS alone or ICS plus LABA in adult patients with poorly controlled asthma. 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J Allergy Clin Immunol 2002; 110:58–64. editorial decisions relating to, the manuscript; they were involved at all stages 9 Partridge MR, van der Molen T, Myrseth SE, Busse WW. Attitudes and actions of of development and have approved the submitted manuscript. DP provided asthma patients on regular maintenance therapy: the INSPIRE study. BMC Pulm the initial scope, flow, topics and search term areas to be included in the Med 2006; 6:13. manuscript outline. DP, LF, AK, TvdM and MRR all provided input and guidance 10 Sims EJ, Price D, Haughney J, Ryan D, Thomas M. Current control and future risk in on content, style, flow, figures and reference sources on all subsequent drafts of asthma management. Allergy Asthma Immunol Res 2011; 3:217–225. the outline and the full manuscript. All authors provided their approval of the 11 Haughney J, Price D, Kaplan A, Chrystyn H, Horne R, May N et al. Achieving asthma final draft of the manuscript. Medical writing assistance, in the form of literature control in practice: understanding the reasons for poor control. Respir Med 2008; 102: 1681–1693. searches and preparation and revision of the draft manuscript, was provided by 12 O'Byrne PM, Naji N, Gauvreau GM. Severe asthma: future treatments. Clin Exp Sam Yarwood, PhD, of Complete HealthVizion, under the authors' conceptual Allergy 2012; 42:706–711. direction and based on feedback from all authors. 13 Barnes N, Pavord I, Chuchalin A, Bell J, Hunter M, Lewis T et al. A randomized, double-blind, placebo-controlled study of the CRTH2 antagonist OC000459 in moderate persistent asthma. Clin Exp Allergy 2012; 42:38–48. COMPETING INTERESTS 14 Iwona S, Tomasz G. Antileukotriene treatment in children with asthma - new DP: a member of advisory boards for Almirall, AstraZeneca, Boehringer patents. Recent Pat Inflamm Allergy Drug Discov 2008; 2:202–211. 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