Asthma is a chronic inflammatory disease of the airways characterized by a complex pathophysiology and caused by different etiological factors which contribute to the heterogeneity of clinical presentation and to the severity of disease. Asthma can manifest both in childhood and in elderly patients [
1], the number of patients affected worldwide being estimated in 235 million [
2], ranging from 1 to 18% of the population in different countries [
3]. Asthma is characterized by a variable combination of symptoms such as wheeze, cough, shortness of breath, chest tightness and by different degrees of airflow obstruction and airway hyper-responsiveness that can vary in time and intensity [
3,
4]. The worsening of respiratory symptoms and thus disease exacerbations can be caused by direct or mediated mechanical, physical and infectious stresses that increase bronchial inflammation and cause an acute worsening of airflow obstruction [
3]. The latter circumstance, especially in elderly patients, can be complicated by comorbid conditions requiring a multidisciplinary therapeutic approach [
5,
6]. Poor control of symptoms and acute exacerbations requiring emergency room admittance and hospitalization expose patients to a poor quality of life, high mobility and a significant economic burden on the healthcare system and society [
7]. Although to a minor extent compared with chronic obstructive pulmonary disease (COPD) [
8,
9], severe and poorly controlled asthma still accounts for a significant in-hospital mortality, especially in children, elderly and mechanically ventilated patients [
10,
11], or patients from low income countries [
2]. For many years, important efforts have been spent to optimize asthma management; however, despite the availability of new treatment options [
12], international surveys continue to provide evidence for suboptimal asthma control in many countries [
13], with poor control of symptoms and exposure to risk of exacerbation in some cases affecting more than 50% of patients [
14,
15]. The need for new treatment approaches has led to reconsider anticholinergic drugs as a pharmacological treatment option for asthma [
16]. While also other muscarinic antagonists are currently being considered for approval in asthma [
16], the only anticholinergic drug introduced so far in the treatment algorithms of major international guidelines is represented by tiotropium bromide. In the last few years numerous clinical trials proved the efficacy of tiotropium both in adult and younger patients for the chronic treatment of asthma. Due to the numerous non-bronchodilator properties expressed by tiotropium, its efficacy may not completely rely on the reduction of the airways’ cholinergic bronchomotor tone, but also on anti-inflammatory and modulatory effects of the structures involved in the complex molecular and cellular pathophysiology of asthma. The aim of the present extensive narrative review is to highlight the pharmacological and non-bronchodilator properties of tiotropium and to present the data of clinical trials conducted so far to examine its role in connection with the current pharmacological treatment paradigm in patients with asthma.
Tiotropium bromide
The anticholinergic alkaloids contained in
Atropa belladonna,
Datura stramonium and
Hyosciamus niger plants have been used as popular remedies to alleviate respiratory symptoms since ancient Egyptians times and the Middle Ages, when in Europe the deadly nightshade was used [
76]. In the 19
th century atropine, a racemate of hyoscyamine [
77], was isolated from nightshade, and became the progenitor of the modern anticholinergic compounds such as ipratropium. Since the '70s there was a renewed interest in anticholinergics as alternative options for the treatment of obstructive diseases, but ipratropium bromide, although demonstrated good clinical efficacy during acute asthma exacerbations [
78], had a short duration of action and less bronchodilating effects compared with inhaled β2-agonists [
78]. In the '90s tiotropium bromide was developed [
79]. Tiotropium bromide is a synthetic quaternary ammonium anticholinergic agent derived from ipratropium bromide [
80] (molecular formula C
19H
22BrNO
4S
2 [
81]). Tiotropium demonstrated a high functional selectivity for specific M
R, with a long duration of action, being approximately 10-fold more potent than ipratropium in binding M
R in vitro and in vivo studies [
82]. Kinetic studies showed that tiotropium had a high selectivity for M
1R and M
3R and dissociated 100 times slower than ipratropium from M
1R (14.6 h vs 0.11 h) and M
3R (34.7 h vs 0.26 h) [
83]. At the same time it had dissociation time from M
2R 10 times faster than from M
3R, making it a selective functional antagonists of M
3R [
79]. Further labeling and functional in vitro studies on human lungs confirmed its selectivity over M
2R [
83]. Tiotropium is poorly absorbed from the gastro-intestinal tract and has very low systemic bioavailability [
84]. After a single dose inhalation, peak plasma levels are reached after a maximum of 5 min, with a subsequent rapid decline in 1 h to very low levels (in the 2 pg/mL range) [
85]. Tiotropium is than eliminated with a terminal half-life of 5 to 6 days, in a dose-dependent manner [
85]. In vitro functional studies demonstrated that, although with a slower onset of action compared with ipratropium, the offset of tiotropium is very long compared with atropine, with a half-life of 300 min. These results justify the prolonged inhibitory effect of tiotropium in pharmacological in vivo studies. In asthmatic patients treated with tiotropium in doses from 10 to 80 μg, it demonstrated a protection against methacholine challenge for up to 48 h [
86]; a prolonged and rapid onset of protection against methacholine challenge in patients with moderate airway hyper-responsiveness was later confirmed by Terzano and colleagues [
87]. Analysis of pooled data from phase II and phase III RCTs in patients with asthma exposed to tiotropium delivered via Respimat® shows that tiotropium is rapidly absorbed rapidly, with maximum plasma concentrations 5 min post-inhalation. Compared with COPD patients, the peak plasma concentration in patients with asthma was approximately 52%, with no difference in exposure comparing the once daily and twice daily administration regimens. Age, allergic status, race, geographical region and smoking history did not appeared to influence the systemic exposure to tiotropium in patients with asthma [
88]. In the numerous randomized clinical trials conducted in COPD [
89], tiotropium showed an excellent and sustained bronchodilator effect [
90], with proved efficacy in the reduction of static and dynamic volumes [
91], in the reduction of the incidence of acute exacerbations [
90], in the improvement of quality of life and symptoms [
90], together with a good safety profile [
91].
Approved for the long-term treatment of COPD since 2002 (2004 in the United States), tiotropium has been initially delivered via dry powder inhaler at the dosage of 18 μg qd; since 2014, tiotropium has been delivered also via Respimat® SoftMist™ inhaler technology, with lowered dosages (5 μg once daily). Following positive large efficacy and safety trials in asthma, in 2014 the European Medicines Agency has extended the indication of tiotropium Respimat® at a dose of 2.5 μg once daily (delivered in two inhalation of 1.25 μg each) to patients with asthma, which was also approved in more than 50 countries, including Japan. In September 2015 the Food and Drug Administration confirmed the same indication; the latter being extended for patients aged 6 and older since 16th February 2017.
Adults
Tiotropium 5 μg was demonstrated to be non-inferior to the dosage of 10 μg and superior to placebo in terms of lung function outcomes in a study involving patients with uncontrolled severe asthma despite treatment with high dose ICS/LABA [
125]. The higher dose of tiotropium, however, was associated with a higher rate of dry mouth occurrence [
125].
The pharmacokinetic profile of two regimens of inhaled tiotropium, 2.5 μg twice daily (TD) and 5 μg once daily (OD), was tested in a phase II randomized controlled two way crossed over trial involving asthmatic patients in maintenance therapy with budesonide 400–800 μg or equivalent [
126]. The geometric mean of pre-dose plasma concentrations of tiotropium at steady state ranged between 1.43 pg/mL (5 μg OD) and 1.59 pg/mL (2.5 μg TD) [
126], while the cumulative urinary excretion over 24 h was similar for both dosing regimens [
126]. Accordingly, functional outcomes from Beeh et al. [
126] and Timmer et al. [
127] demonstrated no difference in FEV
1AUC (0–24) for tiotropium 5 μg OD an d 2.5 μg TD, while both dose regimens lead to a significant improvement compared to placebo [
126,
127].
Efficacy and safety of three doses (namely 1.25 μg to 2.5 μg and 5 μg) of once-daily tiotropium Respimat® were tested in a phase II, randomized, double-blind, placebo controlled, crossover study conducted in a population of moderate asthma patients treated with stable medium-dose ICS (400–800 μg budesonide or equivalent), alone or in a fixed-dose combination with a LABA. Lung function measured as peak FEV
1 (0–3 h) improved for all doses of tiotropium Respimat® (
p < 0.0001 for all doses) with a largest mean difference from placebo observed for tiotropium 5 μg (188 mL, 95% confidence interval, CI: 140, 236) [
128].
Safety
Tiotropium long term safety as a primary outcome in asthma patients was specifically evaluated in a 52-weeks randomized controlled study in which tiotropium 5 μg, 2.5 μg and placebo were administered in symptomatic Japanese patients as add-on therapy to ICS/LABA. The most common AEs reported were nasopharyngitis (48.2%, 44.7%, 42.1%), asthma (28.9%, 29.8%, 38.6%), decreased PEF (15.8%, 7.9%, 21.1%), bronchitis (9.6%, 13.2%, 7.0%), pharyngitis (7.9%, 13.2%, 3.5%) and gastroenteritis (10.5%, 3.5%, 5.3%) for 5 μg, 2.5 μg and placebo respectively. The rate of serious adverse effects was
slow and not different between the study groups [
129]. In the majority of phase II and III trials that evaluated tiotropium in asthma, patients with narrow angle glaucoma and symptomatic prostatic hypertrophy were excluded; nonetheless, considering the importance of such comorbidities in late onset asthma, the administration of tiotropium was not related to an increased frequency of AEs involving the eye, reproductive and urinary tract apparatuses. In the study conducted by Ohta et al. [
129], the frequency of AEs related to eye disorders was usually very low, and lower in the tiotropium treated groups compared to placebo (5.3 and 6.1 vs 8.8% for patients treated with tiotropium 5 μg, 2.5 μg and placebo) [
129]. In the same trial, cystitis was reported respectively by 4.4% (tiotropium 5 μg), 2.6% (tiotropium 2.5 μg) and 1.8% (placebo) of patients. A recent pooled analysis of randomized, double blind parallel group phase II and III trials [
130] investigated the safety profile of tiotropium 5 μg and 2.5 μg, compared to placebo. Out of 3,474 patients analyzed, 2,157 received tiotropium. The overall percentage of patients reporting AEs was not different between groups, being 60.8% vs 62.5% for tiotropium 5 μg and placebo 5 μg and 57.1% vs 55.1 for tiotropium 2.5 μg and placebo 2.5 μg. The most common AEs were represented by a reduction in PEF and nasopharyngitis. Adverse cardiac events were comparable between active treatments and placebo. AEs typically associated with use of LAMAs such as dry mouth was very low, ranging from 0.4% for tiotropium 2.5 μg to 1.0% for tiotropium 5 μg. Serious AEs were similar between groups, albeit slightly higher for 5 μg dose compared to 2.5 μg (4.0% vs 2.0%, respectively) [
130].
Efficacy
Following proof of concept studies, the efficacy and safety of tiotropium delivered via Respimat® was investigated in a large scale clinical trial program (the UniTinA-asthma®) and in many independent studies, which included children, adolescents and adult patients. We summarized the main findings of the RCTs published so far dividing them by patients’ age (Table
3). If not differently stated, all tiotropium doses are meant to be delivered by Respimat® SofMist™ inhaler.
Table 3
Phase III RCTs that evaluated efficacy and safety of tiotropium in asthma
Children and adolescents |
| 2017 | FEV1 60–90%pred ACQ-7 > 1.5 and high dose ICS + 1 controller therapy or medium dose ICS + 2 controller therapies | 6–11 | 392 | Add on tiotropium 5 μg, 2.5 μg or placebo to chronic medium dose ICS (200–400 μg budesonide or eq.) + 2 controller or high dose ICS (≥400 μg) plus one controller | 12 weeks | Peak FEV1 (0–3 h) | 1) Trough FEV1
2) Peak FVC (0–3 h) 3) ACQ–IA score and responder rate 4) trough FVC 5) FEV1AUC (0–3h)
6) rescue medication use 7) time to first exacerbation 8) time to first severe exacerbation 9) ACQ-6 and ACQ-7 10) FEF25–75
11) weekly evening PEF 12) Tolerability | Primary and key secondary outcomes were significantly improved only for tiotropium 5 μg. Peak FVC (0–3 h) and trough FVC did not reach significance for any tiotropium dose. |
| 2016 | Moderate persistent asthma | 6–14 | 80 | 125 μg fluticasone propionate aerosol TD + placebo OD vs 125 μg fluticasone propionate aerosol TD + tiotropium 18 μg dry-powder OD | 12 weeks | (not clearly stated) | 1) FEV1, FVC and PEF at week 12. 2) Asthma exacerbation 3) Rescue medication use 4) Night time symptoms 5) Tolerability | Tiotropium 18 as add-on to maintenance therapy significantly improved lung function compared to maintenance therapy alone. |
| 2016 | FEV1 60–90%pred ACQ-7 > 1.5 and chronic treatment with ICS (200–800 μg for 12–14 years; 400–800 μg for 15–17 years) +/−LABA +/− LTRA | 12–17 | 376 | Add on tiotropium 5 μg, 2.5 μg or placebo to maintenance therapy, with ICS +/− LTRA (LABA not permitted) + open label SABA as rescue medication | 48 weeks | Peak FEV1 (0–3 h) | 1) Trough FEV1
2) Peak FVC (0–3 h) 3) FVC AUC (0–3h)
4) Trough FVC 5) FEV1AUC (0–3h)
6) time to first exacerbation 7) time to first severe exacerbation 8) ACQ-7 and ACQ-6 9) AQLQ (S) score and responder rate 10) Tolerability | All functional outcomes were significantly improved compared to placebo for all tiotropium doses. Greatest overall benefit was found for tiotropium 5 μg. A trend towards improvements was present for ACQ-7 |
| 2016 | ACQ-7 > 1.5 and high dose ICS + 1 controller therapy or medium dose ICS + 2 controller therapies | 12–17 | 388 | Add on tiotropium 5 μg, 2.5 μg or placebo to chronic ICS plus one or more controller therapies. | 12 weeks | Peak FEV1 (0–3 h) | 1) Trough FEV1
2) Peak FVC (0–3 h) 3) FVC AUC (0–3h)
4) trough FVC 5) FEV1AUC (0–3h)
6) rescue medication use 7) time to first exacerbation 8) time to first severe exacerbation 9) ACQ-6 and ACQ-7 10) FEF25–75
11) evening and morning PEF 12) Tolerability | Primary and secondary endpoint not met. Numerical greater response with tiotropium 5 μg compared to placebo. |
Adults |
Peters SP et al. [ 137] “TALC study” | 2010 | Symptomatic despite 160 μg daily beclomethasone with FEV1 < 70%pred | ≥18 | 174 | Tiotropium 18 μg + placebo vs beclomethasone 320 μg + placebo vs salmeterol 50 TD + beclomethasone 160 μg + placebo | 14 weeks – 3 period | Morning PEF | 1) Trough FEV1
2) asthma control days 3) rescue medication use 4) asthma symptoms 5) exacerbations 6) use of health care service 7) inflammatory biomarkers 8) ACQ 9) Tolerability | Tiotropium 18 μg is superior to doubling the ICS dose and non-inferior to salmeterol in patients with uncontrolled asthma |
| 2015 | Moderate asthma. FEV1 60–80%pred, daily use of SABA, PEF and FEV1variability of >30%. ACT 12–20 | ≥18 | 94 | Add on therapy with tiotropium 18 μg, LTRA or double dose ICS on salmeterol/fluticasone dry-powdre 50/250 μg TD | 16 weeks | Asthma control in terms of FeNO; daily PEF variability and ACT score | Not clearly stated | Tiotropium non inferior to doubling doses of ICS. Best response obtained with double dose ICS/LABA but higher risk of pneumonia and RTI. |
Kerstjens HA et al. [ 139] “PrimoTinA-asthma 1 & PrimoTinA-asthma 2“ | 2012 | Uncontrolled asthma defined with ACQ-7 > 1.5, FEV1 ≤ 80%pred and/or FVC ≤ 70%pred despite chronic treatment with ≥800 μg budesonide + LABA | 18–75 | 912 (456 per study) | Tiotropium 5 μg add on therapy or matching placebo. Teophylline, OCT and LTRA were permitted if part of maintenance therapy along with LABA/ICS. | Two replicate 48 weeks | 1) Peak FEV1 (0–3 h) 2) Trough FEV1 (24 weeks). 3) Time to first exacerbation (48 weeks) | At each visit: 1) Trough FEV1
2) Peak FEV1
4) trough FVC 5) Peak FVC 6) FEV1AUC (0–3h)
7) FVC AUC (0–3h)
8) time to first exacerbation 9) morning and evening PEF 10) asthma symptoms 11) ACQ-7 and AQLQ 12) Tolerability | Add on treatment with tiotropium to ICS/LABA sustained bronchodilation over 24 h, reduces severe exacerbations and episodes of worsening of disease. Improvements in asthma control scores and other secondary outcomes were not met. |
Kerstjens HA et al. [ 141] “MezzoTinA-asthma 1 & MezzoTinA-asthma 2“ | 2015 | Uncontrolled asthma defined with ACQ-7 > 1.5, FEV1 60–90%pred despite chronic treatment with 400–800 μg budesonide or eq. +/− LABA or SABA | 18–75 | 1972 (998 & 974 per study) | Tiotropium 5 μg, 2.5 μg, salmeterol 50 μg TD or placebo as add on therapy to 400–800 μg of budesonide or eq. | Two replicate 24 weeks | 1) Peak FEV1 (0–3 h) 2) Trough FEV1 (24 weeks). 3) ACQ-7 responder rate | 1) trough FVC 2) Peak FVC 3) morning weekly PEF 4) ACQ-7 5) time to first exacerbation 6) Tolerability | Add on treatment with tiotropium significantly improves lung function and asthma control compared with placebo, and has similar efficacy and tolerability to salmeterol |
| 2016 | Uncontrolled asthma defined with ACQ-7 > 1.5, FEV1 60–90%pred despite chronic treatment with 200–400 μg budesonide or eq. | 18–75 | 464 | Tiotropium 5 μg or tiotropium 2.5 μg or placebo as add on treatment to chronic low to medium ICS. | 12 week | Peak FEV1 (0–3 h) | 1) Trough FEV1
2) FEV1AUC (0–3h)
3) Use of rescue medication 4) ACQ-7 5) morning and evening PEF 6) Safety | Both doses of tiotropium were significantly superior to placebo for every lung function outcome. No effect size retrieved. No difference in reduction of ACQ-7 score between active and placebo groups. |
Children and adolescents
The efficacy of tiotropium was recently evaluated in patients <18 years old in four large, randomized double blind placebo controlled studies. A phase III, parallel-group 52 weeks RCT compared tiotropium 5 μg (administered by 2 inhalations of 2.5 μg), tiotropium 2.5 μg and placebo Respimat® given in the evening in adolescent patients with moderate symptomatic asthma. Symptomatic asthma was defined as an ACQ-7 mean score of at least 1.5. Patients had to be on maintenance therapy with ICSs, which was permitted during the study, with or without a LABA or a LTRA. Peak FEV
1 (0–3 h) after 24 weeks was the primary outcome. 376 patients completed the study. Peak FEV
1 (0–3 h) was significantly and similarly improved for both tiotropium doses (174 mL [95% CI, 76–272 mL] for tiotropium 5 μg and 134 mL [95% CI,34–234 mL] for tiotropium 2.5 μg) compared with placebo. A rapid improvement of the forced expiratory flow (FEF) between 25% and 75% of FVC (FEF
25–75) compared with placebo was also present beginning from 10 min post-dose for tiotropium 5 μg and 1 h post dose with the 2.5 μg dose. Trough FEV
1 was significantly improved compared to placebo only for tiotropium 5 μg: adjusted mean (standard error) 400 mL (41), +117 mL (54) vs placebo,
p = 0.03 [
131]. The same outcomes have been investigated by Hamelmann and coworkers [
132] in adolescent patients with severe symptomatic asthma (ACQ-7 mean score of ≥1.5) despite medium to high doses of ICS (from 400 μg to 1600 μg of budesonide or equivalent in patients aged 15–17 and >400 μg in those aged 12–14 years) and one or more controller therapies (LABA and/or LTRA). Peak FEV
1 (0–3 h) compared with placebo was significantly improved only with tiotropium 2.5 μg (111 mL;
p = 0.046), while all other outcomes, although showing a trend towards improvement, were not met [
132]. The first and only phase III trial to assess the efficacy and safety of once-daily tiotropium add-on therapy in children with severe symptomatic asthma was published by Szefler SJ and colleagues [
133]. Patients had to be symptomatic despite a maintenance therapy with medium ICS with two or more controller medications or high dose ICS with one or more controller medications and were randomized to receive tiotropium 5 μg, 2.5 μg or placebo for 12 weeks. Compared with placebo, only add-on tiotropium 5 μg significantly improved peak FEV
1 (0–3) (139 mL; 95% CI, 75–203), and trough FEV
1 (87 mL; 95% CI, 19–154) with a good safety profile [
133].
The efficacy of tiotropium 18 μg administered by dry powder inhaler was tested in children and adolescents with moderate persistent asthma and compared with fluticasone 125 μg via aerosol twice daily. After 12 weeks of treatment, the tiotropium/fluticasone group experienced significant improvements in FEV
1, FVC and PEF and a reduced usage of SABA on demand therapy and night-time symptoms compared with fluticasone alone [
134].
Adults
Initial proof of concept studies were conducted between late '90s and 2000 in adult asthmatic patients to prove tiotropium efficacy in protecting from methacholine-induced bronchoconstriction. O’Connor and colleagues [
86], using doses of 10 μg, 40 μg and 80 μg, demonstrated that tiotropium was able to produce and maintain for 48 h a dose-dependent protection against methacholine challenge at 2 h [mean (standard error): 5.0 (1.1); 7.1 (0.5) and 7.9 (0.7) doubling doses], despite a mild increase in FEV
1 that ranged between 5.5% and 11.1% from baseline [
86]. Later on, Terzano and coworkers showed that tiotropium at a dose of 18 μg delivered via HandiHaler® had a protective effect against methacholine-induced bronchoconstriction in asthma patients with airway hyper-responsiveness. In fact, compared with placebo, patients treated with tiotropium did not reach the provocative dose causing a 20% decrease in basal FEV
1 [
87]. Another double blind, randomized, placebo controlled crossover study investigated the possibility to introduce tiotropium in order to step-down the ICS doses in severe asthma patients (mean FEV
151% predicted). While in patients treated with fluticasone 1000 μg + LABA lung function improvements were limited to PEF and airway resistances, only patients treated with tiotropium 18 μg, fluticasone 500 μg + LABA experienced also significant improvements in FEV
1 (+170 mL) and FVC (+240 mL) which were associated also to a reduction in exhaled nitric oxide by 2.86 ppb compared to placebo [
135]. Iwamoto and colleagues demonstrated also that improvements in airway obstruction following administration of tiotropium (dose not reported) in patients with severe asthma were positively correlated with neutrophil inflammation assessed by induced sputum, suggesting that tiotropium would be more effective in asthma patients with a non-eosinophilic phenotype [
136].
The first large trial investigating the possibility to introduce tiotropium in the regular treatment in patients with uncontrolled asthma was the Tiotropium Bromide as an Alternative to Increased Inhaled Glucocorticoid in Patients Inadequately Controlled on a Lower Dose of Inhaled Corticosteroid (TALC) study [
137]. In 210 patients with moderate to severe uncontrolled asthma with low doses of beclomethasone (80 μg daily), the investigators evaluated the addition of tiotropium 18 μg to beclomethasone 80 μg daily as compared with doubling the dose of the ICS (primary superiority comparison) or with the addition of salmeterol to beclomethasone 80 μg (secondary non-inferiority comparison). The addition of tiotropium to low-dose ICS resulted in significant improvements in all lung function and clinical outcomes compared to doubling the ICS dosage. Compared to the latter group, the association of tiotropium improved both morning and evening PEF were improved with tiotropium (+25.8 l/min; 95% CI, 14.4–37.1;
p < 0.001 and +35.3 l/min; 95% CI, 24.6 – 46.0;
p < 0.001, respectively), the pre-dose FEV
1 (+100 mL,
p = 0.004), the proportion of asthma-control days, score for daily symptoms, and the ACQ-7 (−0.18 points;
p = 0.02). Moreover, tiotropium add-on therapy resulted to be non inferior to the LABA/ICS association in all outcomes [
137]. Confirmatory results came from a single-center study in which treatment with tiotropium + LABA + low dose ICS was non inferior in functional outcomes and nitric oxide reduction to LABA + double dose ICS in patients with uncontrolled asthma [
138].
Subsequently, two replicate, randomized, placebo-controlled 48-week period trials (PrimoTinA-asthma 1 and PrimoTinA-asthma 2) were designed to specifically assess if tiotropium 5 μg add on therapy to high dose ICS + LABA compared to add-on placebo was effective in improving disease control both in terms of lung function [peak FEV
1 (0–3 h) and through FEV
1] and of time to first exacerbation in patients poorly controlled with maintenance therapy [
139]. Patients had to have a FEV
1 < 80% predicted and a history of at least 1 severe asthma exacerbation in the previous year. Change in peak FEV
1 (0–3 h) from baseline was significantly greater with tiotropium than with placebo in both trials (vs placebo, mean ± SE: 86 ± 34 mL and 154 ± 32 mL), and this was true also for the trough FEV
1 (vs placebo: 88 ± 31 mL and 111 ± 30 mL). Time to the first severe exacerbation was increased in patients treated with add-on tiotropium (282 days vs. 226 days), with an overall reduction of 21% in the risk of a severe exacerbation (hazard ratio: 0.79;
p = 0.03) [
139]. The response to treatment with tiotropium was shown to be independent of baseline characteristics including gender, age, body mass index, disease duration, age at asthma onset, FEV
1% predicted at screening and reversibility [
140].
The non inferiority of tiotropium compared to LABA as add-on therapy to ICS in patients with moderate asthma was investigated in two 24-week, replicate, randomized, double-blind, placebo-controlled, parallel-group, active comparator trials (MezzoTinA-asthma 1 and MezzoTinA-asthma 2) [
141]. These two parallel trials randomized a total of 2,103 patients to receive tiotropium 5 μg OD, tiotropium 2.5 μg OD, salmeterol 50 μg BID or placebo on top of maintenance therapy with medium dose budesonide (400–800 μg). Again, the two functional co-primary end-points were peak FEV
1 (0–3 h) and through FEV
1 at the end of the 24-week treatment period, additionally, the study assessed the proportion of responders by means of the ACQ-7, i.e. patients that increased the ACQ-7 score more than 0.5. Pooled data of the 1,972 patients that completed the studies showed significant improvements for both doses of tiotropium and salmeterol compared to placebo in all functional outcomes. Compared to placebo, both doses of tiotropium and salmeterol significantly improved peak FEV
1 (0–3 h) and trough FEV
1, although results were numerically higher for tiotropium 2.5 μg. There were more ACQ-7 responders in the tiotropium 5 μg (OR 1.32; 95% CI: 1.02–1.71;
P = 0.035), 2.5 μg (1.33; 95% CI: 1.03–1.72;
P = 0.031) and the salmeterol group (1.46, 95% CI: 1.13–1.89;
p = 0.0039), compared to placebo. Although median time to first severe exacerbation could not be calculated because less than 50% of patients in each treatment group had one or more severe exacerbations, a statistically significant reduction in risk of first severe exacerbation was reported for tiotropium 2.5 μg and of first asthma worsening for tiotropium 2.5 μg and salmeterol [
141]. A recent phase III RCT compared tiotropium 2.5 μg and 5 μg OD versus placebo as add-on therapy to maintenance treatment with ICS in patients with moderate symptomatic asthma with a FEV
1 of 60 to 90% predicted. Data from 464 patients were analyzed. After 12 weeks of treatment, both dose regimens showed superiority over placebo in terms of through FEV
1and peak FEV
1 (0–3 h); however, numerically better results for peak FEV
1 (0–3 h) and FEV
1AUC (0–3 h) were found for tiotropium 2.5 μg compared to 5 μg [adjusted mean (SE): 293 mL (26) vs 262 mL (26) and 198 mL (24) vs 174 mL (25), respectively]. The frequency of AEs was not different across the treatment regimens [
142].
These large studies demonstrated the efficacy of tiotropium as add-on therapy both to moderate-to-high dose of ICS and to ICS/LABA maintenance therapy in terms of lung function, risk of exacerbation and disease worsening, goals that were achieved with a safety profile similar to LABA comparators and placebo. Further
post hoc analyses of pooled data from MezzoTinA-asthma 1, MezzoTinA-asthma 2, PrimoTinA-asthma 1 and PrimoTinA-asthma 2 suggested that the efficacy of tiotropium was independent of underlying allergic/eosinophilic inflammation and thus of the T-helper 2 asthma phenotype, as outcomes were reached in patients with a broad range of IgE and eosinophil values [
143].
The Arg16/Arg16 β2-adrenergic receptors polymorphism represents a common finding both in African Americans (20%) and Caucasians (15%) [
59] and is associated with a blunted sensitivity to the maintenance asthma treatment with SABAs thus justifying a worse disease control with long term treatment with ICS/LABA FDC both in adults [
144] and in children [
145]. This assumption led to investigate the predictors of response to therapy by means of a pharmacogenetic approach. Sequencing of eleven different nucleotide polymorphisms was performed in 138 asthmatic not controlled with their maintenance therapy in which tiotropium 18 μg was added once daily. The positive response to tiotropium in terms of lung function was found in 33% of patients and was predicted by the Arg16Gly polymorphism [
146]. When a cohort of asthmatic patients homozygous for the Arg16 β2 adrenergic receptor polymorphism were prospectively studied, tiotropium demonstrated to be non inferior to salmeterol in improving the morning PEF (mean ± SD; −3.9 ± 4.87 L/min for tiotropium and −3.2 ± 4.64 L/min for salmeterol) [
147]. Given the proportion of African-American patients with allelic variations associated with poor asthma control, a study specifically powered and designed to assess the risk of exacerbations in this particular population was set in 2011. The Blacks and Exacerbations on LABA vs Tiotropium (BELT study) [
148] was a parallel-group, randomized pragmatic trial that enrolled black adults with asthma from primary care and specialty practices in the United States. Participants were enrolled if on step 3 or step 4 combination ICS and LABA therapy, and were randomized to receive a LABA (salmeterol or formoterol) or tiotropium in addition to their chronic dose of ICS. The primary outcome was time to asthma exacerbation, secondary outcomes included patient-reported outcomes, lung function (FEV
1 changes), rescue medication use and AEs. The investigators found no difference between the two treatment regimens in terms of primary and secondary outcomes. Neither of the Arg16Gly β2-adrenergic receptors alleles was associated with differences in the effects of tiotropium + ICS vs LABA + ICS [
148].
Initial validations of these RCTs in real life settings can be found in two recent retrospective studies. An analysis of 64 patients with poor disease control despite treatment with high dose ICS/LABA showed that the introduction of tiotropium as add on therapy improved asthma control in 42.2% of cases, decreasing the number of emergency department visits and hospitalizations in 46.9% and 50.0% of cases, respectively [
149]. A larger cohort involving 2,042 outpatients from United Kingdom compared the number of exacerbations (emergency visits, hospitalizations and oral corticosteroids use) and acute asthma events (antibiotic use for lower respiratory tract infections) in the year before and in the year following the prescription of tiotropium. Patients experienced an overall significant decrease in exacerbations and acute asthma events by 10% and 11%; however, there was a significant increase in the as needed usage of SABA from a median (IQR) of 274 (110–548) to 329 (110–603) μg/day [
150].