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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 (firstname.lastname@example.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. In light of the REFERENCES evidence, we believe that anticholinergic bronchodilators will be a useful add-on therapy for patients at high risk of future worsening 1 Masoli M, Fabian D, Holt S, Beasley R, The Global Initiative for Asthma. Global burden of asthma. Available at http://www.ginasthma.org/local/uploads/ﬁles/ or exacerbations, and in patients whose asthma remains GINABurdenReport_1.pdf (accessed 6 December 2013). uncontrolled on a broad range of treatments and/or for whom 2 Global Initiative for Asthma. Global strategy for asthma management and pre- other alternative therapies are unsuitable. vention. Updated 2012. Available at http://www.ginasthma.org/local/uploads/ Whether tiotropium or other long-acting anticholinergic ﬁles/GINA_Report_2012Feb13.pdf (accessed 6 December 2013). bronchodilators will offer clinical advantages in younger patients, 3 Reddel HK, Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW et al. An or in those with less severe asthma than studied thus far, is under ofﬁcial American Thoracic Society/European Respiratory Society statement: investigation. As we gain clinical experience in asthma with long- asthma control and exacerbations: standardizing endpoints for clinical asthma acting anticholinergics, if approved, it will be interesting to see trials and clinical practice. Am J Respir Crit Care Med 2009; 180:59–99. whether and to what extent certain subgroups and phenotypes 4 National Heart, Lung, and Blood Institute. Expert Panel Report 3: Guidelines for the diagnosis and management of asthma. Available at http://www.nhlbi.nih.gov/ beneﬁt from their use as controller medications. guidelines/asthma/asthgdln.htm (accessed 15 November 2013). 5 Barnes PJ. New therapies for asthma: is there any progress? Trends Pharmacol Sci 2010; 31:335–343. ACKNOWLEDGEMENTS 6 Canonica GW, Baena-Cagnani CE, Blaiss MS, Dahl R, Kaliner MA, Valovirta EJ, The authors acknowledge the medical writing assistance received from Sam GAPP Survey Working Group. Unmet needs in asthma: Global Asthma Physician Yarwood, PhD, of Complete HealthVizion, in the form of literature searches and and Patient (GAPP) Survey: global adult ﬁndings. Allergy 2007; 62:668–674. preparation and revision of the draft manuscript. 7 Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJ, Pauwels RA et al. Can guideline-deﬁned asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med 2004; 170:836–844. CONTRIBUTIONS 8 Adams RJ, Fuhlbrigge A, Guilbert T, Lozano P, Martinez F. Inadequate use of asthma medication in the United States: results of the asthma in America national The authors take full responsibility for the scope, direction, content of, and population survey. 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. Ingelheim, Chiesi, GlaxoSmithKline, Meda, Merck, Mundipharma, Napp, 15 Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON et al. Mepolizumab Novartis, Nycomed, Pﬁzer, Sandoz and Teva; grants and support for research for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo- controlled trial. Lancet 2012; 380:651–659. in respiratory disease from the following organisations in the past 5 years: UK 16 Corren J, Lemanske RF Jr, Hanania NA, Korenblat PE, Parsey MV, Arron JR et al. National Health Service, Aerocrine, AstraZeneca, Boehringer Ingelheim, Chiesi, Lebrikizumab treatment in adults with asthma. N Engl J Med 2011; 365: GlaxoSmithKline, Merck, Mundipharma, Novartis, Nycomed, Orion, Pﬁzer and 1088–1098. Teva; consultancy for Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, 17 Restrepo RD. Use of inhaled anticholinergic agents in obstructive airway disease. GlaxoSmithKline, Meda, Merck, Mundipharma, Napp, Novartis, Nycomed, Pﬁzer, Respir Care 2007; 52:833–851. Sandoz and Teva; speaker fees from Activaero, Almirall, AstraZeneca, 18 Meier CR, Jick H. Drug use and pulmonary death rates in increasingly sympto- Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Merck, Mundi- matic asthma patients in the UK. Thorax 1997; 52:612–617. pharma, Novartis, Pﬁzer and Teva; payment for manuscript preparation from 19 Westby MJ, Benson MK, Gibson PG. Anticholinergic agents for chronic asthma Merck, Mundipharma and Teva; payment for the development of educational in adults. Cochrane Database Syst Rev 2004: (3)CD003269. © 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 20 Novelli F, Malagrinò L, Dente FL, Paggiaro P. Efﬁcacy of anticholinergic drugs 47 Gosens R, Bos IST, Zaagsma J, Meurs H. Protective effects of tiotropium bromide in in asthma. Expert Rev Respir Med 2012; 6:309–319. the progression of airway smooth muscle remodeling. Am J Respir Crit Care Med 21 Vogelmeier C, Hederer B, Glaab T, Schmidt H, Rutten-van Mölken MP, Beeh KM 2005; 171:1096–1102. et al. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. 48 Milara J, Serrano A, Peiró T, Gavaldà A, Miralpeix M, Morcillo EJ et al. Aclidinium inhibits human lung ﬁbroblast to myoﬁbroblast transition. Thorax 2012; 67: N Engl J Med 2011; 364: 1093–1103. 22 Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S et al. A 4-year trial of 229–237. 49 Baker B, Peatﬁeld AC, Richardson PS. Nervous control of mucin secretion into tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008; 359: human bronchi. J Physiol 1985; 365: 297–305. 1543–1554. 50 Bos IST, Gosens R, Zuidhof AB, Schaafsma D, Halayko AJ, Meurs H et al. Inhibition 23 O'Connor BJ, Towse LJ, Barnes PJ. Prolonged effect of tiotropium bromide on of allergen-induced airway remodelling by tiotropium and budesonide: a com- methacholine-induced bronchoconstriction in asthma. Am J Respir Crit Care Med parison. Eur Respir J 2007; 30:653–661. 1996; 154(4 Pt 1): 876–880. 51 Bateman ED, Rennard S, Barnes PJ, Dicpinigaitis PV, Gosens R, Gross NJ 24 Fardon T, Haggart K, Lee DKC, Lipworth BJ. A proof of concept study to evaluate et al. Alternative mechanisms for tiotropium. Pulm Pharmacol Ther 2009; 22: stepping down the dose of ﬂuticasone in combination with salmeterol and tio- 533–542. tropium in severe persistent asthma. Respir Med 2007; 101: 1218–1228. 52 Belmonte KE. Cholinergic pathways in the lungs and anticholinergic therapy for 25 Bateman ED, Kornmann O, Schmidt P, Pivovarova A, Engel M, Fabbri LM. chronic obstructive pulmonary disease. Proc Am Thorac Soc 2005; 2:297–304. Tiotropium is noninferior to salmeterol in maintaining improved lung function 53 Cazzola M, Matera MG. Emerging inhaled bronchodilators: an update. Eur Respir J in B16-Arg/Arg patients with asthma. J Allergy Clin Immunol 2011; 128: 2009; 34: 757–769. 315–322. 54 Sykes DA, Dowling MR, Leighton-Davies J, Kent TC, Fawcett L, Renard E et al. The 26 Kerstjens HAM, Disse B, Schröder-Babo W, Bantje TA, Gahlemann M, Sigmund R inﬂuence of receptor kinetics on the onset and duration of action and the ther- et al. Tiotropium improves lung function in patients with severe uncontrolled apeutic index of NVA237 and tiotropium. J Pharmacol Exp Ther 2012; 343: asthma: a randomized controlled trial. J Allergy Clin Immunol 2011; 128: 520–528. 308–314. 55 Rossoni G, Manfredi B, Razzetti R, Civelli M, Berti F. Positive interaction of the 27 Peters SP, Kunselman SJ, Icitovic N, Moore WC, Pascual R, Ameredes BT et al. novel β -agonist carmoterol and tiotropium bromide in the control of airway Tiotropium bromide step-up therapy for adults with uncontrolled asthma. NEngl J 2 changes induced by different challenges in guinea-pigs. Pulm Pharmacol Ther Med 2010; 363: 1715–1726. 2007; 20: 250–257. 28 Kerstjens HAM, Engel M, Dahl R, Paggiaro P, Beck E, Vandewalker M et al. Tio- 56 Kume H, Imbe S, Iwanaga T, Tohda Y. Synergistic effects between glycopyrronium tropium in asthma poorly controlled with standard combination therapy. N Engl J bromide and indacaterol on a muscarinic agonist-induced contraction in airway Med 2012; 367: 1198–1207. smooth muscle. Abstract P4835 presented at the European Respiratory Society 29 Canning BJ. Reﬂex regulation of airway smooth muscle tone. J Appl Physiol 2006; Annual Congress: Vienna, Austria, 2012. 101: 971–985. 57 Gaultier C, Reinberg A, Girard F. Circadian rhythms in lung resistance and dynamic 30 Molﬁno NA, Slutsky AS, Julià-Serdà G, Hoffstein V, Szalai JP, Chapman KR et al. lung compliance of healthy children. Effects of two bronchodilators. Respir Physiol Assessment of airway tone in asthma. Comparison between double lung trans- 1977; 31: 169–182. plant patients and healthy subjects. Am J Respir Crit Care Med 1993; 148: 58 Furlan R, Guzzetti S, Crivellaro W, Dassi S, Tinelli M, Baselli G et al. Continuous 24- 1238–1243. hour assessment of the neural regulation of systemic arterial pressure and RR 31 Barnes PJ. Neural mechanisms in asthma. Br Med Bull 1992; 48: 149–168. variabilities in ambulant subjects. Circulation 1990; 81:537–547. 32 Cazzola M, Page CP, Calzetta L, Matera MG. Pharmacology and therapeutics of 59 Cox ID, Hughes DTD, McDonnell KA. Ipratropium bromide in patients with bronchodilators. Pharmacol Rev 2012; 64:450–504. nocturnal asthma. Postgrad Med J 1984; 60:526–528. 33 Douglas NJ, Sudlow MF, Flenley DC. Effect of an inhaled atropinelike agent on 60 Morrison JF, Pearson SB. The parasympathetic nervous system and the diurnal normal airway function. J Appl Physiol 1979; 46:256–262. variation of lung mechanics in asthma. Respir Med 1991; 85:285–289. 34 Rodrigo G, Rodrigo C, Burschtin O. A meta-analysis of the effects of ipratropium 61 Larj MJ, Bleecker ER. Effects of β -agonists on airway tone and bronchial bromide in adults with acute asthma. Am J Med 1999; 107:363–370. responsiveness. J Allergy Clin Immunol 2002; 110(6 Suppl): S304–S312. 35 Hashimoto A, Maeda H, Yokoyama M. Augmentation of parasympathetic nerve 62 Haney S, Hancox RJ. Recovery from bronchoconstriction and bronchodilator tol- function in patients with extrinsic bronchial asthma—evaluation by coefﬁciency erance. Clin Rev Allergy Immunol 2006; 31:181–196. of variance of R-R interval with modiﬁed long-term ECG monitoring system. Kobe 63 Abramson MJ, Walters J, Walters EH. Adverse effects of beta-agonists: are they J Med Sci 1996; 42: 347–359. clinically relevant? Am J Respir Med 2003; 2:287–297. 36 Kesler BS, Canning BJ. Regulation of baseline cholinergic tone in guinea-pig air- 64 Casarosa P, Pieper MP, Gantner F. Cross-talk between the human muscarinic M3 way smooth muscle. J Physiol 1999; 518:843–855. and β receptors: evidence for heterologous desensitization. Am J Respir Crit Care 37 Jammes Y, Mei N. Assessment of the pulmonary origin of bronchoconstrictor Med 2010; 181 (abs A6373). vagal tone. J Physiol 1979; 291: 305–316. 65 Rodrigo GJ, Rodrigo C. First-line therapy for adult patients with acute asthma 38 Barnes PJ. Neuroeffector mechanisms: the interface between inﬂammation and receiving a multiple-dose protocol of ipratropium bromide plus albuterol in the neuronal responses. J Allergy Clin Immunol 1996; 98(5 Pt 2): S73–S81. emergency department. Am J Respir Crit Care Med 2000; 161: 1862–1868. 39 Goyal M, Jaseja H, Verma N. Increased parasympathetic tone as the underlying 66 Rodrigo GJ, Rodrigo C. The role of anticholinergics in acute asthma treatment: an cause of asthma: a hypothesis. Med Hypotheses 2010; 74:661–664. evidence-based evaluation. Chest 2002; 121: 1977–1987. 40 Ayala LE, Ahmed T. Is there loss of protective muscarinic receptor mechanism in 67 Grifﬁths B, Ducharme FM. Combined inhaled anticholinergics and short-acting asthma? Chest 1989; 96: 1285–1291. beta -agonists for initial treatment of acute asthma in children. Cochrane Data- 41 Barnes PJ. Modulation of neurotransmission in airways. Physiol Rev 1992; 72: base Syst Rev 2013: (8)CD000060. 699–729. 68 Plotnick L, Ducharme F. Combined inhaled anticholinergics and beta -agonists for 42 Kanazawa H, Kawaguchi T, Shoji S, Fujii T, Kudoh S, Hirata K et al. Synergistic effect initial treatment of acute asthma in children. Cochrane Database Syst Rev 2000: (3) of nitric oxide and vasoactive intestinal peptide on bronchoprotection against CD000060. histamine in anesthetized guinea pigs. Am J Respir Crit Care Med 1997; 155: 69 Hansel TT, Neighbour H, Erin EM, Tan AJ, Tennant RC, Maus JG et al. Glyco- 747–750. pyrrolate causes prolonged bronchoprotection and bronchodilatation in patients 43 Park HW, Yang MS, Park CS, Kim TB, Moon HB, Min KU et al. Additive role of with asthma. Chest 2005; 128: 1974–1979. tiotropium in severe asthmatics and Arg16Gly in ADRB2 as a potential marker to 70 Terzano C, Petroianni A, Ricci A, D'Antoni L, Allegra L. Early protective effects of predict response. Allergy 2009; 64:778–783. tiotropium bromide in patients with airways hyperresponsiveness. Eur Rev Med 44 Lundgren R, Söderberg M, Hörstedt P, Stenling R. Morphological studies of Pharmacol Sci 2004; 8:259–264. bronchial mucosal biopsies from asthmatics before and after ten years of treat- 71 Israel E, Chinchilli VM, Ford JG, Boushey HA, Cherniack R, Craig TJ et al. Use of ment with inhaled steroids. Eur Respir J 1988; 1:883–889. regularly scheduled albuterol treatment in asthma: genotype-stratiﬁed, rando- 45 An SS, Bai TR, Bates JHT, Black JL, Brown RH, Brusasco V et al. Airway smooth mised, placebo-controlled cross-over trial. Lancet 2004; 364: 1505–1512. muscle dynamics: a common pathway of airway obstruction in asthma. 72 Kazani S, Israel E. Long-acting β-agonists and inhaled corticosteroids: is the whole Eur Respir J 2007; 29:834–860. greater than the sum of its parts? J Allergy Clin Immunol 2010; 125: 357–358. 46 Gosens R. Inhibition of allergen-induced airway remodeling by tiotropium and 73 Bleecker ER, Postma DS, Lawrance RM, Meyers DA, Ambrose HJ, Goldman M. budesonide: a comparative study. Abstract A269 presented at the 103rd Annual Effect of ADRB2 polymorphisms on response to longacting β -agonist therapy: a International Conference of the American Thoracic Society: San Francisco, CA, pharmacogenetic analysis of two randomised studies. Lancet 2007; 370: USA, 2007. 2118–2125. 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 74 Bleecker ER, Nelson HS, Kraft M, Corren J, Meyers DA, Yancey SW et al. β -receptor 82 Ullah MI, Newman GB, Saunders KB. Inﬂuence of age on response to ipratropium polymorphisms in patients receiving salmeterol with or without ﬂuticasone pro- and salbutamol in asthma. Thorax 1981; 36: 523–529. pionate. Am J Respir Crit Care Med 2010; 181:676–687. 83 Connolly MJ. Ageing, late-onset asthma and the beta-adrenoceptor. Pharmacol 75 Beeh KM, Ablinger O, Moroni-Zentgraf P, Hollaenderova Z, Pivovarova A, Ther 1993; 60:389–404. 84 Partridge MR, Saunders KB. Site of action of ipratropium bromide and clinical and Engel M et al. Tiotropium in asthma: a dose-ﬁnding study in adult patients physiological determinants of response in patients with asthma. Thorax 1981; 36: with moderate persistent asthma. Poster A1283 presented at the American 530–533. Thoracic Society International Conference: Philadelphia, PA, USA, 2013. 85 Berry M, Morgan A, Shaw DE, Parker D, Green R, Brightling C et al. Pathological 76 Kerstjens HAM, Bleecker E, Meltzer E, Casale T, Pizzichini E, Schmidt O et al. features and inhaled corticosteroid response of eosinophilic and non- Tiotropium as add-on therapy to inhaled corticosteroids for patients with eosinophilic asthma. Thorax 2007; 62: 1043–1049. symptomatic asthma: lung function and safety. Eur Respir J 2013; 42(Suppl 57): 86 Pavord ID, Brightling CE, Woltmann G, Wardlaw AJ. Non-eosinophilic corticos- 980s (abs 4629). teroid unresponsive asthma. Lancet 1999; 353: 2213–2214. 77 Kerstjens HAM, Bleecker E, Meltzer E, Casale T, Pizzichini E, Schmidt O et al. 87 Bradding P, Green RH. Subclinical phenotypes of asthma. Curr Opin Allergy Clin Tiotropium as add-on to inhaled corticosteroids signiﬁcantly improves asthma Immunol 2010; 10:54–59. control as reﬂected by the ACQ responder rate. Eur Respir J 2013; 42(Suppl 57): 88 Lazarus SC, Chinchilli VM, Rollings NJ, Boushey HA, Cherniack R, Craig TJ et al. 876s (abs 4130). Smoking affects response to inhaled corticosteroids or leukotriene receptor 78 Bateman ED, Esser D, Chirila C, Fernandez M, Fowler A, Moroni-Zentgraf P et al. antagonists in asthma. Am J Respir Crit Care Med 2007; 175:783–790. Systematic review and meta-analysis of the magnitude of the effect on the AQLQ 89 Chaudhuri R, Livingston E, McMahon AD, Lafferty J, Fraser I, Spears M et al. Effects and ACQ in asthma clinical trials. Poster P4113 presented at the European of smoking cessation on lung function and airway inﬂammation in smokers Respiratory Society Annual Congress: Barcelona, Spain, 2013. with asthma. Am J Respir Crit Care Med 2006; 174:127–133. 79 Powell H, Gibson PG. 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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