FormalPara Key Points

Uncontrolled asthma carries a significant financial and health burden on healthcare systems.

Advances in our knowledge of the role of the parasympathetic nervous system within the respiratory tract has resulted in more interest in the utility of long-acting muscarinic antagonists for patients with moderate to severe persistent asthma.

Approval of tiotropium as add-on therapy for patients with uncontrolled asthma brought a needed choice for healthcare providers.

1 Introduction

In the United States, asthma affects approximately 17.7 million adults and 6.3 million children with approximately 3500 deaths per year [1]. In 2011, an estimated 1.8 million visits to the emergency room were reported with asthma as the primary diagnosis. During 2010, 439,000 hospital discharges were due to asthma, with an average length of stay of 3.6 days. In 2013, asthma accounted for an estimated 13.8 million lost school days in children and 10.1 million lost work days in adults [2]. On average, 38.4 % of children and 50 % of adults with current asthma had uncontrolled symptoms between the years of 2006–2010 [2]. Asthma ranks within the top ten prevalent conditions causing limitation of activity and costs the US about $19.7 billion in healthcare dollars annually [3]. In order to grasp a better understanding as to why this disease has such healthcare implications, we need to pursue a better understanding of the disease and therapeutics available to clinicians.

Asthma is defined as an airway disease with airway inflammation, reversible obstruction, and airway hyperresponsiveness [3]. It is the underlying pathophysiology with dynamic interplay of cells that contributes to the phenotypic and endotypic heterogeneity associated with this disease. At the molecular level, asthma has been broken down into two major endotypes: type 2 high and type 2 low. Type 2 high individuals tend to have airway (and systemic) eosinophilia and usually respond to glucocorticoids or anti-eosinophilic therapies [4]. These patients tend to have a predominance of CD4+ cells, whereas in many patients with chronic obstructive pulmonary disease (COPD), CD8+ cells predominate [4]. Type 2 low asthmatics typically do not respond well to glucocorticoids and have either neutrophilic inflammation or paucigranulocytic findings. Recent attention has focused on the role of chronic inflammation and cytokine release from local inflammatory cells, with little emphasis on the role of neurogenic pathways and neurotransmitters. We know that both type 2 high and low patients respond to bronchodilators, including β-agonists and anticholinergics. This review will focus on the role of cholinergic pathways, acetylcholine, and muscarinic receptors on airway smooth muscle tone and inflammation and the importance of anticholinergics in the treatment of asthma.

For many centuries, Atropa belladonna and Dutura Stramonium were recommended for treatment of asthma by Ayurvedic medicine [5]. Atropine itself was used in either powder form or smoked as a cigarette or cigar to treat respiratory disease [6]. Atropine crosses the blood–brain barrier and has equal affinity to the three major muscarinic receptors, leading to its relatively high side-effect profile, especially when not inhaled. The development of quaternary agents that allow for targeted therapy in the lung with a limited side-effect profile has been important in the clinical utility of anticholinergics for asthma. Understanding the innervation of the lung and how these compounds impact airway tone, inflammation, and remodeling is essential to appropriately using these agents for asthma.

2 The Role of Acetylcholine and Muscarinic Receptors in the Airways

The parasympathetic nervous system in the lungs contributes to increased mucus production, inflammation, and smooth muscle contraction (Fig. 1) [7, 8]. In the airways, acetylcholine is the primary parasympathetic neurotransmitter. Increase in parasympathetic nervous system basal tone in the airway has been attributed to the development of airway hyperresponsiveness (AHR) seen in patients with asthma. Neuronal acetylcholine is under the effect of both afferent and efferent nerves interacting with surrounding cells. Ganglionic release of acetylcholine is enhanced by local inflammation of the airway epithelium due to local damage and inflammatory mediators that can directly cause or augment acetylcholine release. In the presence of viral infections or allergen-induced release of mediators, the M2 autoinhibitory receptor is down regulated allowing for further release of acetylcholine [9]. This contributes to increasing cholinergic tone (Fig. 2) [10].

Fig. 1
figure 1

Depicts the role of muscarinic receptors in the airways. M1, M2, M3 are differentially distributed among local cells. M1 facilitates neuronal release of acetylcholine (Ach). M2 located in the presynaptic region of the postganglionic nerve acts as an auto-receptor with inhibitory properties. Once neuronal Ach is released, it directly acts upon the M3 receptors on airway smooth muscle cells leading to increase in intracellular Ca2+ and subsequent contraction. The afferent fibers act as autonomic reflex where local inflammation or damage to epithelial cells cause an increase in cholinergic tone

Full size image
Fig. 2
figure 2

Modified from Wessler and Kirkpatrick [11]

Acetylcholine (Ach) itself has inflammatory properties. It is secreted in a paracrine/autocrine fashion by a multitude of cells in the bronchial airways including: epithelial cells, neutrophils, lymphocytes, macrophages, and fibroblasts. These cells also have muscarinic receptors. IL-2 interlukin-2, LTB4 leukotriene B4

Full size image

It is important to note that acetylcholine can be secreted from non-neural components in the airway. The airway epithelial cells, smooth muscle cells, lymphocytes, mast cells, eosinophils, and neutrophils all express the enzyme choline acetyltransferase, which allows the synthesis of choline and acetyle-CoA forming acetylcholine (Fig. 2) [11]. Acetylcholine in itself has inflammatory properties, possibly contributing to the underlying inflammation or remodeling in asthma [10], although it is unclear to date if non-neuronal acetylcholine has a direct role in bronchoconstriction. Acetylcholine acts upon both nicotinic and muscarinic receptors. We will focus on the role of muscarinic receptors for the purpose of this review.

Muscarinic receptors are found on the cholinergic nervous system, airway smooth muscle cells, epithelial cells, mucous cells, macrophages, neutrophils, and lymphocytes. The predominant muscarinic receptor directly involved in bronchoconstriction is M3 [7]. In proximal airway tissue, the M3 receptors are typically under cholinergic tone; however, in the peripheral airways they are typically activated by acetylcholine released from epithelial cells [12]. These Gq-coupled protein receptors, once stimulated, cause activation of phospholipase C (PLC) leading to hydrolysis of phosphatidylinositol 4.5-bisphosphate (PIP2) forming diacylglycerol (DAG) and 1,4,5-trisphosphate (IP3) [13]. IP3 causes mobilization of Ca2+ from the endoplasmic reticulum leading to increased intracellular Ca2+ [10] and muscle contraction [9]. M1 receptors are expressed on postganglionic nerves facilitating acetylcholine transmission [14]. M1 receptors are also found on epithelial cells, stimulating water and electrolyte secretion. M3 receptors primarily regulate smooth muscle contraction and mucus secretion by the sub-mucosal glands [10]. M2 receptors are Gi-coupled protein receptors that act as autoreceptors at the presynaptic junction, inhibiting the release of acetylcholine [7]. M2 receptors are also directly found on airway smooth muscle cells and display a small contribution to smooth muscle relaxation [15]. In animal models, decreased expression of M2 receptors induced an increase in acetylcholine from the vagal nerve, enhancing the cholinergic tone as seen in asthmatics [6, 10]. It has also been found that major basic protein secreted from eosinophils binds to the M2 receptor, eliminating the negative feedback mechanism which allows for increase in tone as well [10, 15]. Thus, airway inflammation can cause increased production and release of acetylcholine in patients with asthma.

Remodeling (manifested by increased airway smooth muscle, mucous metaplasia, collagen deposition, and inflammatory changes) is a major component of chronic asthma. Mucus secretion is stimulated by cholinergic pathways, and this contributes to airway obstruction [16]. In smokers with COPD and asthma, the overproduction of mucus has been attributed to MUC5AC overexpression in airway epithelial cells [16]. In vitro studies have illustrated a decrease in expression of MUC5A/C in bronchial tissue exposed to aclidinium or atropine [16, 17]. Arai et al. found that tiotropium inhibited the metaplasia of goblet cells [18]. Similar findings were seen in guinea pigs where a reduction in mucous gland hypertrophy was seen with the presence of tiotropium [16, 19]. Acetylcholine also increases the production of profibrotic cytokines including transforming growth factor (TGF)-β. In murine models, anticholinergics were found to inhibit the expression of these profibrotic cytokines [20]. Therefore, acetylcholine acting via muscarinic receptors can contribute to the inflammatory and remodeling changes seen in asthma, suggesting the importance of anticholinergics as therapeutic agents.

3 Crosstalk Between Muscarinic Receptors and Other Receptors in the Human Airway: Therapeutic Implications in Asthma

The crosstalk between the M2 and M3 receptors and the β2 adrenoceptors at the presynaptic and postsynaptic level is important and has potential therapeutic implications. The combination of long-acting antimuscarinics (LAMAs) and long-acting β2 agonists (LABAs) has been shown to have synergist effects for bronchodilation (Fig. 3) [7]. In guinea pig models, the addition of tiotropium to carmoterol (LABA) significantly enhanced bronchodilation [7, 21]. Also, improvements in lung function were noted after the addition of tiotropium to patients with asthma on LABA/inhaled corticosteroid [22]. At the postsynaptic level, the potential hypothesis for this interaction is that the M2 receptor-coupled activation of Gi, in the presence of inflammatory cytokines such as IL-1β, tumor necrosis factor (TNF-α)- and IL-13, may attenuate β2 adrenoceptor-mediated airway smooth muscle relaxation. In addition, multiple animal models have illustrated the functional antagonism of β2 agonist-induced relaxation by muscarinic receptor stimulation [9]. Muscarinic antagonists target the postsynaptic Gi-coupled M2 receptor leading to stabilization of adenylyl cyclase activity and airway smooth muscle relaxation induced by β2-agonist [23]. Furthermore, these agents can counteract the potassium calcium channels modulated by β2 adrenoceptors via the Gβγ protein of the M2 receptor [23]. Through M3 receptor stimulation, protein kinase C is formed which phosphorylates β2 adrenoceptor Gs causing uncoupling of the receptor. This downstream regulation contributes to the functional antagonism of β2-agonist-induced relaxation (Fig. 3). Therefore, the concomitant use of LAMAs and LABAs for obstructive airway diseases such as asthma has a sound pharmacological basis.

Fig. 3
figure 3

Schematic of proposed synergistic effect of long-acting muscarinic antagonist to β2-adrenoceptors. The interaction of M3 receptor in the presence of acetylcholine causes intracellular increase in calcium and subsequent bronchoconstriction. The diacylglycerol causes the activation of protein kinase C and the deactivation of the downstream components of the β2-adrenoceptors. The inhibition of the M3 receptor with anticholinergics contributes to an increase in cAMP and subsequent bronchodilation. Ach acetylcholine, AMP adenosine monophosphate, cAMP cyclic AMP, IP 3 1,4,5-trisphosphate, PKC protein kinase C, PLC phospholipase C

Full size image

In patients with asthma, a clinical benefit is observed with the addition of LAMAs to inhaled corticosteroids as well. A recent publication by Cazzola et al. described the possible pharmacological benefit and the synergistic activity of adding glycopyrronium to beclomethasone [24]. They found that in sensitized bronchi, the glycopyrronium/beclomethasone combination synergistically enhanced the relaxation of medium and small airways. This effect was attributed to higher concentrations of cyclic adenosine monophosphate (cAMP). This synergistic interaction was not noted in non-sensitized bronchi [24]. In summary, understanding the interaction of LAMAs, LABAs, and corticosteroids provides a basis for the appropriate use of these agents in patients with asthma.

4 Pharmacology of Short- and Long-Acting Antimuscarinics

Current muscarinic antagonists include the short-acting ipratropium and oxitropium, and the long-acting agents including tiotropium, glycopyrronium, aclidinium, and umeclidinium (Table 1). Currently published data for LAMAs in asthma include studies with tiotropium, unceclidinium, and aclidinium. As described above, muscarinic receptors are abundant throughout the airways with M2 receptors having a bronchoprotective role and M1 and predominantly M3 receptors having bronchoconstrictive roles [10]. A common characteristic of LAMAs is that they all have longer residence time at the M3 receptor and shorter residence time at the M2 receptor compared with the short-acting muscarinic antagonists, which have nonselective binding characteristics [25]. The longer residence time is consistent with longer duration of action of LAMAs. As seen in Table 1, tiotropium has a very prolonged dissociation time from M3 receptors. It is important to note that glycopyrronium dissociates from M3 faster than aclidinium; however, it is still also efficacious at once per day. This is suggestive that within the actual respiratory tract other underlying processes might be contributing. Most of this data is obtained with respect to patients with COPD. We will next discuss the current evidence on using LAMAs in asthma with a focus on tiotropium as the majority of published data is with this medication.

Table 1 Comparison of current muscarinic antagonists
Full size table

5 Asthma Studies Supporting the Use of Long-Acting Antimuscarinics

5.1 Tiotropium Bromide

Tiotropium is the most studied LAMA medication in asthma and has strong evidence of its effectiveness in COPD [26, 27]. Early evidence supporting tiotropium use in asthma came from a study by O’Connor et al. [28]. Subjects were treated with either tiotropium or placebo and subsequently underwent a methacholine challenge. Three doses of tiotropium (10, 40, and 80 μg) were used. Each dose of tiotropium produced mild bronchodilation as measured by an increase in the forced expiratory volume in 1 s (FEV1) sustained for 24 h, and the effects were dose-dependent. The authors reported the prolonged bronchodilator response and protection against methacholine challenge were suggestive of the usefulness of tiotropium in asthma. Later, Magnussen et al. in a double-blinded, placebo-controlled randomized trial of COPD patients with concomitant asthma further demonstrated the efficacy of tiotropium. They illustrated improvement in spirometric parameters as well as symptomatic benefit by reduction of need for rescue medications [29].

5.1.1 Safety and Efficacy of Different Doses of Tiotropium in Addition to Inhaled Corticosteroid (ICS)

Beeh et al. evaluated tiotropium respimat in multiple doses as add-on to an inhaled corticosteroid (ICS) in symptomatic moderate persistent asthma subjects [30]. In their 4-way crossover, randomized, double-blind, placebo-controlled study, 5, 2.5 or 1.25 μg of tiotropium respimat or placebo were examined for 4 weeks each. Analysis of peak FEV1 (0–3h) change from baseline at the end of each 4-week period demonstrated significant improvements across all tiotropium respimat doses compared with placebo (all p < 0.0001) with the greatest adjusted mean difference between tiotropium respimat 5 μg and placebo. All secondary endpoints including trough FEV1, FEV1 area under the curve (AUC)(0–3h), peak forced vital capacity (FVC)(0–3h), trough FVC, FVC AUC(0–3h), peak expiratory flow (PEF) AM/PM, and Asthma Control Questionnaire-7 (ACQ-7) score had significant improvements with all doses of tiotropium respimat except for trough FVC in the 1.25-μg group. Further analysis of the response difference among tiotropium doses showed the 5-μg dose to be somewhat better. Incidence of adverse events was comparable between placebo and all tiotropium respimat groups with no drug-related serious adverse events.

In an effort to demonstrate the best timing and frequency of tiotropium use, Timmer et al. assessed the efficacy and safety of once-daily tiotropium respimat 5 μg in comparison with 2.5 μg twice daily as add-on to medium dose ICS in asthmatic patients [31]. In this randomized, double-blind, placebo-controlled, crossover study, 4-week treatment periods of tiotropium 5 μg daily, 2.5 μg twice daily and placebo were examined. FEV1 AUC(0–24h) at the end of each treatment period was the primary end point. Peak FEV1 (0–24h), trough FEV1, PEFAM/PM and pharmacokinetic assessments were secondary points. Both tiotropium dosing regimens significantly improved FEV1 AUC(0–24h) response (once-daily 5 μg 158 ± 24 mL; twice-daily 2.5 μg 149 ± 24 mL and p < 0.01 for both) compared with placebo. There was no significant difference among both verum dosing regimens. There were prominent improvements (p < 0.01) in peak FEV1 (0–24h) (5 μg 131 ± 24 mL; 2.5 μg 132 ± 24 mL), trough FEV1 (5 μg 133 ± 29 mL; 2.5 μg 111 ± 30 mL), and pre-dose PEFAM/PM with both dosing regimens versus placebo. No statistical difference was observed among the tiotropium treatment regimens. Total systemic exposure and tolerability were comparable between treatment regimens. The mean ACQ-7 score showed a statistically significant improvement (p < 0.01) for both tiotropium dosing regimens when compared with placebo (once-daily 5 μg 0.274; twice-daily 2.5 μg 0.190). The authors concluded that tiotropium as add-on to medium-dose ICS has sustained and similar lung function improvement as once-daily 5 μg and twice-daily 2.5 μg in patients with symptomatic moderate asthma. It is likely that once-daily dosing would promote better patient adherence.

5.1.2 Safety and Efficacy of Tiotropium with ICS ± Long-Acting β2 Agonist (LABA) Compared with Placebo

Kerstjens et al. looked at the safety and efficacy of tiotropium respimat in asthma as add-on therapy to ICS ± LABA comparing two different doses (5 and 10 μg daily) with placebo in severe uncontrolled asthmatics [32]. After 8-week treatment periods in a crossover fashion, a significant difference in peak FEV1 was found among the tiotropium respimat 5- and 10-μg treatments compared with placebo. However, there was no significant difference between the tiotropium doses. Secondary endpoints FEV1 trough and daily home PEF rates were also significantly different compared with placebo. There were no noticeable differences in asthma-related health status or symptoms. Adverse reactions were balanced except for some anticholinergic effects at the higher dose of tiotropium. The authors concluded using tiotropium daily along with high-dose ICS plus LABA in severe uncontrolled asthmatics would significantly improve lung function. Subsequently, two replicate, randomized controlled trials (PrimoTinA-asthma 1 and PrimoTinA-asthma 2) involving 912 poorly controlled asthmatics were conducted [22]. After 24 weeks of tiotropium use, the mean peak FEV1 change from baseline was significantly greater in treated groups compared with placebo in both trials (p < 0.01 and p < 0.001, respectively). Also, trough FEV1 improved in the tiotropium arm compared with placebo (p < 0.01 and p < 0.001, respectively). Furthermore, the days to first exacerbation increased: 282 days compared with 226 days, and there was a 21 % overall reduction in the risk of a severe exacerbation (hazard ratio [HR] 0.79; p < 0.03) with tiotropium versus placebo. The adverse reactions reported were predominately anticholinergic in nature with dry mouth the most commonly reported. Drug-related cardiac events were reported in two patients (0.4 %) in the tiotropium group and one patient (0.2 %) in the placebo group. In a similar fashion, Paggiaro et al. evaluated the efficacy and safety of tiotropium as add-on to ICS in mild to moderate symptomatic asthma patients [33]. A phase III, double-blind, placebo-controlled trial of 464 mild to moderate asthmatics was conducted. After 12 weeks of receiving tiotropium respimat 5 or 2.5 μg, or placebo, there was a higher difference of peak FEV1 (0–3h) response among tiotropium groups compared with placebo (adjusted mean difference from placebo: 5 μg, 128 mL; 2.5 μg, 159 mL; both p < 0.001). Other studied parameters including trough FEV1, FEV1 AUC(0–3h), and PEFAM/PM also showed statistically significant improvements in comparison with placebo. Reported adverse events were similar across the treatment groups.

5.1.3 Effect of Tiotropium in Addition to ICS Compared with LABA plus ICS

In a three-way, double-blind, triple-dummy crossover trial, Peters et al. evaluated the addition of tiotropium bromide to ICS, as compared with doubling of ICS dose or the addition of LABA to ICS [34]. Two hundred and ten asthmatic subjects were enrolled in this trial. Tiotropium 18 μg once daily plus belcomethasone 80 μg twice daily versus belcomethasone 160 μg twice daily versus salmeterol plus belcomethasone 80 μg twice daily were used in this trial. The mean difference of 25.8 L/min (p < 0.001) in the PEFAM established the superiority of tiotropium use with ICS, as compared with a doubling of the dose of ICS. Additionally, PEFPM difference of 35.3 L/min (p < 0.001); the proportion of asthma-control days difference of 0.079 (p < 0.01); FEV1 before bronchodilation difference of 0.10 L (p < 0.004); and daily symptom scores difference of −0.11 points (p < 0.001) all supported the advantage of adding tiotropium to ICS. Moreover, the addition of tiotropium to ICS was not inferior to the LABA/ICS combination for all assessed outcomes. In fact, the tiotropium/ICS combination increased the prebronchodilator FEV1 more than did LABA, with a difference of 0.11 L (p < 0.003). Recently, Kerstjens and colleague studied effectiveness of tiotropium as add-on to moderate asthma therapy in comparison with LABA [35]. In 24-week, replicate, double-blind, placebo-controlled, parallel group studies (MezzoTinA-asthma®), the peak FEV1 (0–3) and trough FEV1 responses and responder rate by ACQ-7 were the primary endpoints. There were statically significant improvements in peak FEV1 and trough FEV1 with tiotropium and salmeterol versus placebo (Fig. 4). Moreover, a significant improvement in ACQ-7 responder rate was noticed with tiotropium 5 μg (odds ratio [OR] 1.32; 95 % CI 1.02–1.71; p < 0.035), 2.5 μg (OR 1.33; 95 % CI 1.03–1.72; p < 0.031), and salmeterol (OR 1.46; 95 % CI 1.13–1.89; p < 0.0039) compared with placebo (Fig. 5). However, this mean increase in ACQ-7 score did not reach the minimal clinical important difference for either drug. These findings supported the use of tiotropium as add-on to ICS in moderately severe adult asthmatics. Population-specific effects were evaluated in the BELT (Blacks and Exacerbations on LABA vs Tiotropium) trial. Wechsler et al. examined the superiority of LABAs in combination with ICS against tiotropium in combination with ICS in a Black moderate to severe asthmatic population and assessed any associated variation among genetic Arg16Gly alleles of the β2-adrenergic receptor (ADRB2) gene [36]. In this multicenter, randomized, open-label, and parallel-group study, the time to first asthma exacerbation was the primary outcome. Secondary outcomes included ACQ, Asthma Symptom Utility Index, and Asthma Symptom-Free Days questionnaire; FEV1; rescue medication use; asthma deteriorations; and adverse events. There was no difference between LABA/ICS versus tiotropium/ICS in time to first exacerbation (mean number of exacerbations/person-year 0.42 versus 0.37 [95 % CI 0.73–1.11]), change in FEV1 at 12 months and 18 months, ACQ score, and other patient-reported outcomes. No detected difference was found in the responses to tiotropium/ICS and LABA/ICS among the ADRB2 Arg16Gly allelic groups. With all these findings they concluded that combination therapy of LABA/ICS is not superior to tiotropium/ICS in Black asthmatic patients.

Fig. 4
figure 4

Adapted from Kerstjens et al. [35], with permission

Effectiveness of tiotropium as add-on to ICS in moderate asthma in comparison with LABA and placebo. Adjusted mean FEV1 over 24 weeks for peak (a) and trough (b) responses in the full analysis set (pooled data). For peak FEV1, all p values were <0.0001 for active drug versus placebo; for trough responses, all drugs were p < 0.0001 except salmeterol at week 16 (p = 0.0002). FEV 1 forced expiratory volume in 1 s, ICS inhaled corticosteroid, LABA long-acting β-agonist. Asterisk measured within the first 3 h after evening dosing. Dagger 0 h denotes the trough FEV1 value taken 10 min before inhalation of study drug, between 1800 and 2000 h

Full size image
Fig. 5
figure 5

Adapted from Kerstjens et al. [35] with permission

Effectiveness of tiotropium as add-on to ICS in moderate asthma in comparison with LABA and placebo. ACQ-7 responder rate at Week 24 in the full analysis set (pooled data). Mean ACQ-7 at baseline was 2.21 (SD 0.49) in the tiotropium 5-μg group, 2.17 (0.49) in the tiotropium 2.·5-μg group, 2.15 (0.47) in the salmeterol group, and 2.18 (0.50) in the placebo group. Adjusted mean ACQ-7 score responses versus placebo were −0.12 (SD 0.04; p = 0.0084) in the tiotropium 5-μg group, −0.16 (0.04; p = 0.0002) in the tiotropium 2.5-μg group, and −0.20 (0.04; p < 0.0001) in the salmeterol group. Dashed lines show the difference in responder rate (tiotropium vs placebo). ACQ-7 seven-question Asthma Control Questionnaire, ICS inhaled corticosteroid, LABA long-acting β-agonist

Full size image

5.1.4 Long-Term Safety of Tiotropium Use

Most of the previous efficacy studies showed comparable adverse effects between tiotropium and LABA as short-term therapy. Ohta et al. studied the safety of tiotropium use long term in a double-blind, randomized, placebo-controlled trial. They assessed the safety and efficacy of tiotropium in 285 moderate to severe asthmatics for 52 weeks [37]. They found the incidence of adverse events was similar across all the groups (5, 2.5 μg, and placebo). The most commonly reported adverse events were nasopharyngitis, asthma worsening, bronchitis, decreased PEF, pharyngitis, and gastroenteritis. Rates of drug-related adverse events were similar in the placebo and tiotropium 2.5-μg groups at 5.3 % versus tiotropium 5 μg at 8.8 % of subjects. Four percent of tiotropium 5-μg subjects had mild cardiac adverse events that were attributed to the medication. One subject each in the tiotropium 2.5- and 5-μg groups had worsening asthma symptoms which were documented as a serious adverse event. No deaths or life-threatening conditions were reported. The long-term efficacy at week 52 revealed a significantly higher difference in the mean trough FEV1 response of 112 mL (95 % CI 18–207; p < 0.0203) with tiotropium respimat 5 μg compared with placebo. Not much change was noted with tiotropium respimat 2.5 μg compared with placebo at week 52 with trough FEV1 change of 12 mL (95 % CI −82 to 106; p < 0.7971). Adjusted mean trough PEF response was significantly higher with tiotropium respimat 5 μg than with placebo but not with tiotropium respimat 2.5 μg. ACQ-7 responder rates were similar across treatment groups at Week 52.

5.1.5 Safety and Efficacy of Tiotropium in Children

In a shift in the population being studied, Vogelberg et al. studied tiotropium in adolescents with asthma. A randomized, double-blind, placebo-controlled, incomplete crossover, phase II trial was conducted in adolescents with moderate persistent asthma taking a moderate dose of ICS [38]. Subjects were assigned to different doses of tiotropium respimat of 5, 2.5, 1.25 μg, and placebo for 4 weeks each (total of 12 weeks). Noticeably, LABA was discontinued for each subject that was on it during the run-in period. They noted significant improvements in FEV1 3 h after using tiotropium respimat 5 μg and in trough FEV1 compared with placebo. This improvement was not seen in tiotropium respimat 2.5 and 1.25 μg. Morning PEF response for all three tiotropium respimat groups was superior compared with placebo. ACQ-7 scores improved during treatment to the same degree in all three groups of tiotropium and placebo. These findings suggest that tiotropium respimat 5 μg might be the most efficacious dose in an adolescent population. In a similar study design, Vogelberg et al. studied tiotropium in children aged 6–11 years old [39]. There was a statistically significant difference in peak FEV1 (0–3h) response across the tiotropium respimat dose group (5, 2.5 and 1.25 μg) versus placebo after 4 weeks of treatment. Furthermore, there was no dose-dependent response in patients treated with tiotropium respimat. The group treated with tiotropium respimat also showed improvements in trough FEV1 response, FEV1 AUC(0–3h) response, FEV1 response over 3 h after dosing, and morning PEF. There were positive trends in ACQ-7 and Pediatric Asthma Quality of Life Questionnaire (PAQLQ) scores, but these were not statistically significant. The safety and tolerability of tiotropium respimat groups were comparable with the placebo group.

5.1.6 Real-Life Trials

Although collective evidence from all the trials discussed here shows benefits of adding tiotropium in adult and pediatric populations (Table 2), these studies were more controlled and perhaps not indicative of actual asthma patients seen in clinic. Price et al. recently examined the effectiveness of LAMAs as add-on therapy in real-life asthma care [40]. Records of over 2000 asthmatics on ICS ± LABA (COPD excluded) were evaluated before (baseline) and after (outcome) starting tiotropium. They found a significant decrease in occurrence of acute exacerbations, oral corticosteroid use, and acute respiratory events that required antibiotics along with significant increases in the rate of asthma control (all p < 0.001). However, there was a significant increase in short-acting β2 agonist use and there were no significant changes in PEF, FEV1, or FEV1/FVC ratio. Despite some limitations in this real-life study, its findings were consistent with well controlled and randomized trials discussed above.

Table 2 Key efficacy and safety studies for long-acting muscarinic antagonists in asthma
Full size table

5.2 Umeclidinium

Although umeclidinium (UMEC) is approved for COPD as maintenance therapy in the US and EU, it is not approved for asthma. There are only a few small studies suggesting its effectiveness in asthma. Lee et al. evaluated the dose response, efficacy, and safety of UMEC in adults with asthma [41]. A randomized, double-blind, placebo-controlled, three-period crossover incomplete block study involved 350 steroid-naïve asthmatic subjects. A sequence of three of eight potential treatments (UMEC 15.6, 31.25, 62.5, 125, or 250 μg once daily, UMEC 15.6 or 31.25 μg twice daily, or placebo) were used. Trough FEV1 0–24h, weighted mean (WM) FEV1, and safety were assessed. Significant improvements in change from baseline trough FEV1 were observed for UMEC 15.6 μg once daily (0.066 L; p = 0.036) and UMEC 125 μg once daily (0.088 L; p = 0.005) versus placebo, but not other once-daily or twice daily doses. UMEC increased 0–24 h WM FEV1 versus placebo (0.068–0.121 L, p = 0.017) with no clear dose response. The incidence of adverse events was 9.21 % for UMEC and 12 % for placebo. There were no treatment-related effects on laboratory parameters. The authors concluded that, despite the modest trough FEV1 improvements, there was no therapeutic benefit of UMEC in non-ICS-treated patients with asthma. Lee et al. also studied the dose-response effect of UMEC in combination with fluticasone furoate (FF) in asthmatic subjects [42]. In their double-blind, three-period crossover study, 421 symptomatic asthma subjects were enrolled. A sequence of three of seven treatments (FF 100 μg alone, FF 100 μg combined with UMEC (15.6, 31.25, 62.5, 125, or 250 μg), or vilanterol [LABA] 25 μg) was inhaled once daily for 14 days. Trough FEV1, PEF, and safety were assessed. The researchers faced issues with carryover effect between treatment periods. Despite that, the trough FEV1 improved with FF/UMEC 125 and 250 μg versus FF (treatment difference 0.055 L [both doses]; p = 0.018). FF/UMEC increased morning (15.9–22.9 L/min) and evening (16.2–28.8 L/min) PEF versus FF. However, due to the carryover effect, a post hoc Period 1 data analysis was performed. This demonstrated significant increases in trough FEV1 with FF/UMEC 31.25, 62.5, and 250 μg versus FF. Interestingly, trough FEV1 improvements with FF/UMEC were higher in subjects with fixed (0.095–0.304 L) versus non-fixed (0.084–0.041 L) obstruction. Again, no treatment-related effects on laboratory parameters were found. The incidence of adverse events was 13–25 % across groups. Although there were clear carryover effects, ICS + UMEC may be an option for patients with symptomatic asthma, especially with fixed obstruction; however, further studies with better design are needed to confirm its effectiveness.

5.3 Glycopyrronium Bromide and Aclidinium Bromide

Despite glycopyrronium showing prolonged bronchodilatation effect, especially in an acute setting [43–45], to date there are no published clinical trials supporting the effectiveness of this or aclidinium in asthma. Previous trials have demonstrated their effectiveness in COPD as add-on therapy to ICS with or without LABA. The discussion of these studies is beyond this review.

6 Conclusion

Asthma is a heterogeneous disease that has been targeted with various treatment modalities. Unfortunately, many patients still remain symptomatic. Understanding the complex neuronal involvement of bronchoconstriction and inflammation in patients with asthma has allowed us to re-evaluate the clinical utility of antimuscarinics. Cumulative data have established the effectiveness of these agents as maintenance therapy. Evidence supports prescribing LAMA as add-on therapy to ICS in symptomatic asthma regardless of the severity in both adult and pediatric populations. Currently, tiotropium is the only LAMA approved for asthma. Tiotropium has been found to benefit patients as an add-on to ICS alone or in combination with LABAs. A daily dose of tiotropium 5 μg has the most sustainable effect and safety profile. Among different available formulations for tiotropium (powder or respimat), respimat has less local side effects, probably due to the delivery method. Emerging data for other LAMAs, such as aclidinium, will likely aid in the guideline-driven placement of LAMAs for asthma.