Respiratory Medicine 143 (2018) 82–90

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Respiratory Medicine
journal homepage: www.elsevier.com/locate/rmed

Review article

Tiotropium add-on to inhaled corticosteroids versus addition of long-acting T

β2-agonists for adults with asthma
Roland Buhla,∗, J. Mark FitzGeraldb, William W. Bussec
a
University Hospital Mainz, Langenbeckstraße 1, D-55131, Mainz, Germany
b
Centre for Heart and Lung Health, 7th Floor, 2775 Laurel Street, Vancouver, V5Z 1M9, Canada
c
University of Wisconsin School of Medicine and Public Health, Allergy, Pulmonary and Critical Care Medicine, 600 Highland Avenue, Madison, WI, 53792, USA

A R T I C LE I N FO A B S T R A C T

Keywords: Additional management options, and better use of current options, are needed to help support a large proportion
Tiotropium of patients with asthma whose symptoms remain uncontrolled on inhaled corticosteroids (ICS). Here, we aim to
Long-acting muscarinic antagonist review the safety and efficacy of adding tiotropium to ICS compared with adding a long-acting β2-agonist (LABA)
Long-acting β2-agonist for adults whose asthma is not well controlled on ICS alone. Adding tiotropium to a background of ICS provides
Inhaled corticosteroids
beneficial effects that are comparable with addition of a LABA in terms of lung function measures, exacerbations,
Asthma
asthma control and other endpoints. In addition, tiotropium and LABAs are both well tolerated. Some patients
respond to either tiotropium or LABA treatment, but not both, suggesting that there are groups of patients that
may respond better to one of these drugs. Currently, tiotropium is recommended as an add-on therapy in patients
with severe asthma (Global Initiative for Asthma Steps 4 and 5) whose asthma is uncontrolled despite treatment
with ICS/LABA. Tiotropium is also effective in patients with less severe disease and may benefit patients who
experience adverse events from LABA treatment or where LABAs are ineffective. Tiotropium is therefore an
important therapeutic option in asthma, not only as recommended as an add-on treatment with ICS/LABA, but
also as an alternative to the addition of LABA to maintenance therapy with an ICS.

1. Introduction
Asthma continues to be a burden for individuals and health services
worldwide [1]. The Global Initiative for Asthma (GINA) recommends a
stepwise increase in dose of inhaled corticosteroids (ICS), followed by
the addition of inhaled β2-agonists and further therapeutic options as
necessary to gain control [2]. However, even with updated guidelines,
between 45 and 55% of patients with asthma remain uncontrolled
[3–5]. Therefore, more active assessment and consideration of optimal
use of additional add-on therapies are needed to help support patients
whose asthma remains uncontrolled.
The most recent addition to our armamentarium of inhaled anti-
asthmatic drugs is the long-acting anticholinergic agent tiotropium. The
aim here is to review the safety and efficacy of tiotropium added onto
ICS compared with adding a long-acting β2-agonist (LABA) for adults
whose asthma is not well controlled on ICS alone. A systematic review
of trials on this topic was conducted over 2 years ago [6]. Here, we
include those trials and also look at the most recent evidence. Data are
drawn from six trials that have included both a tiotropium/ICS and a
LABA/ICS treatment arm: MezzoTinA-asthma® (two replicate studies)
[7]; the Blacks and Exacerbations on LABA vs. Tiotropium (BELT) [8];
Bateman et al. (2011) [9]; Tiotropium Bromide as an Alternative to
Increased Inhaled Glucocorticoid in Patients Inadequately Controlled
on a Lower Dose of Inhaled Corticosteroid (TALC) [10]; and Zhang et al.
(2018) [11]. This review will also consider whether there are instances
and potential clinical benefits to using tiotropium instead of a LABA as
an add-on to ICS.

Abbreviations: ACRN, Asthma Clinical Research Network; AE, adverse event; B16-Arg/Arg, arginine single nucleotide polymorphism at amino acid 16 in the β2-
adrenergic receptor gene; BELT, Blacks and Exacerbations on LABA vs. Tiotropium; CI, confidence interval; COPD, chronic obstructive pulmonary disease; FEV1,
forced expiratory volume in 1 s; FVC, forced vital capacity; GINA, Global Initiative for Asthma; GOAL, Gaining Optimal Asthma ControL study; ICS, inhaled cor-
ticosteroids; IgE, anti-immunoglobulin E; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist; NHLBI, National Heart, Lung, and Blood Institute;
OCS, oral corticosteroids; PEF, peak expiratory flow; QoL, quality of life; RR, relative risk; SMART, Salmeterol Multicenter Asthma Research Trial; TALC, Tiotropium
Bromide as an Alternative to Increased Inhaled Glucocorticoid in Patients Inadequately Controlled on a Lower Dose of Inhaled Corticosteroid
∗
Corresponding author. University Hospital Mainz, Langenbeckstraße 1, D-55131, Mainz, Germany.
E-mail addresses: Roland.Buhl@unimedizin-mainz.de (R. Buhl), Mark.Fitzgerald@vch.ca (J.M. FitzGerald), wwb@medicine.wisc.edu (W.W. Busse).

https://doi.org/10.1016/j.rmed.2018.08.014
Received 17 May 2018; Accepted 27 August 2018
Available online 29 August 2018
0954-6111/ © 2018 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).
R. Buhl et al.
2. Lay summary
Many people with asthma continue to suffer despite taking their
usual medication. Taking inhaled corticosteroids (ICS) is an important
way to control symptoms. However, more treatments can be added on if
symptoms continue. Here we review and compare two other types of
inhaled medicines to take with ICS: 1) tiotropium, a newer drug for
asthma; and 2) long-acting β2-agonists (LABAs), a group of drugs that
have been used for a long time. Both have been tested and are used to
treat asthma. Only a few trials have directly compared the two. These
trials show that both tiotropium and LABAs improve how well lungs
work, prevent asthma attacks, and help with asthma symptoms. Both
treatments have few side effects. One study showed that some patients
benefited more from one drug or the other, but not always from both.
At the moment tiotropium is recommended for people with moderate-
to-severe disease, but studies show it also helps people with milder
asthma too. Tiotropium is an important treatment option. It can be
taken in addition to ICS and LABA, or with ICS instead of LABA.
3. Add-on therapies to ICS
ICS is the primary treatment recommended for the long-term man-
agement of symptomatic asthma that remains uncontrolled on as-needed
short-acting bronchodilators alone. Treatment with regular daily low-
dose ICS is highly effective in reducing asthma symptoms, the risk of
asthma-related exacerbations, hospitalization, and death [2]. However,
some patients with asthma continue to have symptoms. In such cases,
stepping up to moderate-dose ICS is an option, but addition of a LABA to
low-dose ICS is considered to be more effective. High-dose ICS is only
recommended if good control cannot be achieved with medium-dose ICS/
LABA and/or a third controller [2]. It has been well documented that
long-term use of high-dose ICS may lead to adverse events (AEs) in some
cases, such as reduction in bone density, ocular hypertension, glaucoma,
and adrenal suppression [12]. Furthermore, the dose–response curve to
treatment with ICS plateaus at relatively low doses of ICS [13]; for ex-
ample, in adults with moderate-to-severe asthma, the maximum benefit of
the ICS fluticasone, in terms of all major clinical outcomes, is achieved by
100–200 μg/day [14]. Add-on therapies are therefore always considered
preferable to high-dose monotherapy with ICS [2].
In the GINA Strategy for Asthma Management and Prevention re-
port, LABAs are currently the preferred add-on therapy for patients
uncontrolled on ICS alone [2]. There is a substantial evidence base for
these drugs, with a recent review comparing LABAs as an add-on to ICS
that comprised 77 studies and over 20,000 patients [15]. For patients
who remain uncontrolled on ICS/LABA treatment, GINA suggests ad-
ditional therapies, including a leukotriene modifier, tiotropium and/or
theophylline [2]. For the most severe patients, further options also in-
clude anti-immunoglobulin E (IgE), anti-interleukin-5, and low-dose
oral corticosteroids (OCS) [2].
As the only long-acting muscarinic antagonist (LAMA) approved for the
treatment of asthma, tiotropium has been extensively studied and will be
the focus of this review. Tiotropium as an add-on to ICS, with and without
additional controllers, has demonstrated many clinical benefits for patients
with asthma [16]. An extensive clinical trial program including over 6000
patients has shown that tiotropium provides a bronchoprotective effect
with a positive impact on measures of lung function, exacerbations,
symptom control, and quality of life (QoL) [16,17]. A systemic review with
meta-analysis showed that tiotropium as add-on to ICS significantly in-
creased baseline morning and evening peak expiratory flow (PEF) by
22–24 L/min and forced expiratory volume in 1 s (FEV1) by 140–150 mL
compared with ICS alone [18]. It is worth noting that clinical studies using
other LAMAs, such as aclidinium bromide, glycopyrronium bromide, and
umeclidinium, although smaller in size, have also shown potential clinical
benefits of LAMA add-on treatment to ICS [17].
Tiotropium is included in the latest GINA strategy report as an add-on
option to ICS plus a LABA at Steps 4 and 5 in adolescents and adults (≥12
83
Respiratory Medicine 143 (2018) 82–90
years) with a history of exacerbations [2]. Once-daily tiotropium deliv-
ered via the Respimat® Soft Mist™ inhaler is the only LAMA approved in
the USA (patients aged ≥6 years), Japan (patients aged ≥15 years),
Canada (patients aged ≥18 years), the EU (patients aged ≥6 years), and
several other countries. In adult patients with asthma, tiotropium Re-
spimat® is indicated as an add-on maintenance bronchodilator treatment
who are currently treated with the maintenance combination of ICS
(≥800 μg budesonide/day or equivalent) and LABA, and who experi-
enced one or more severe exacerbations in the previous year [19].
4. Asthma therapies have different mechanisms of action
LAMAs exert a bronchodilator effect via a different mechanism to
both LABAs and ICS: LABAs stimulate airway β2-receptors to trigger
smooth muscle relaxation, and thereby prevent bronchoconstriction [15];
ICS work mainly through anti-inflammatory mechanisms, including
switching off inflammatory gene transcription [20]. In contrast, LAMAs
reduce bronchoconstriction in the lungs by binding to airway muscarinic
acetylcholine receptors, leading to a reduction in smooth muscle con-
traction and mucus secretion and thus producing a bronchodilator effect
[17]. The M3 acetylcholine receptor is the primary pharmacologic target
for bronchodilation [21]. Of all the LAMAs so far studied, tiotropium is
the most potent antagonist for the M3 receptor, with the slowest dis-
sociation rate at this receptor, which allows for a once-daily dosing
schedule [21]. In vitro studies and animal models suggest that LAMAs
additionally reduce inflammation and inhibit airway remodeling induced
by allergens [22,23]. Recent data from allergic airway inflammation
models show that tiotropium is also capable of directly reducing mucus
production and inflammation in the airways [24]. Furthermore, clinical
data from patients with symptomatic asthma despite ICS and LABA
treatment suggest that tiotropium may also reduce airway thickness to
improve airflow obstruction [25]. The pharmacologic mechanisms that
lead to the anti-inflammatory and anti-remodeling benefits of tiotropium
in asthma are still under investigation [26].
5. Efficacy of tiotropium versus LABAs
There is a large body of evidence supporting the use of a LABA as an
add-on treatment to ICS in asthma, where it has been shown that the ad-
dition of LABA is superior compared with: the same dose of ICS, increasing
the dose of ICS monotherapy, and other add-on therapies such as theo-
phylline and leukotriene receptor antagonists [15,27–29]. A meta-analysis
has shown that LABA add-on therapy to ICS improved a range of clinical
features; compared with high-dose ICS treatment, the addition of LABA
therapy reduced the risk of exacerbations requiring OCS from 11.45% to
10%, improved lung function (FEV1 endpoint improved by 80 mL, 95%
confidence interval [CI] 30, 130), reduced the need for daytime rescue
inhalations by −0.48 puffs/day (95% CI –0.77, −0.20), and improved
daytime symptom score (a change of −0.26, 95% CI –0.35, −0.17) [27].
Efficacy data from Phase III, double-blind, placebo-controlled trials
have shown that adding tiotropium to ICS from low-to high-dose is
superior to placebo in patients with mild-to-severe asthma [7,30,31].
Significant improvements were seen in lung function in terms of peak
and trough FEV1, morning and evening PEF, and in other measures,
such as improved asthma control, reduced time to first severe exacer-
bation and a reduction in risk of severe exacerbations [7,30,31].
However, only six asthma studies have investigated ICS with tio-
tropium and LABA as add-on treatment arms (Table 1). These trials
have mostly been carried out in patients with moderate asthma and
have explored a variety of clinical endpoints.
The largest studies with both of these treatments were the MezzoTinA-
asthma® trials, with over 500 patients in each treatment arm. These were
two parallel-group, 24-week, multisite, replicate, randomized, double-
blind, placebo-controlled trials, which used the LABA salmeterol 50 μg as
an active-comparator treatment versus tiotropium 5 μg and 2.5 μg in pa-
tients with symptomatic moderate asthma [7]. All patients were
 Table 1
Summary of efficacy data from trials comparing tiotropium with LABA as add-on therapy to ICS.
Trial details Lung function endpoints Questionnaire Other endpoints
R. Buhl et al.

endpoints

MezzoTinA-asthma® NCT01172808/NCT01172821 in Treatment difference versus placebo at Week 24

patients with moderate asthma [7]

Treatment arms ICS background Peak FEV1, mean, mL* Trough FEV1, mean, mL* Morning PEF, mean, L/min ACQ-7, score Time to first severe asthma Time to first asthma
medication responses, mean exacerbation,** HR (95% worsening,† HR (95% CI)
(SD)* CI)

Tiotropium 5 μg once daily
Tiotropium 2.5 μg once daily
Salmeterol 50 μg twice daily
Budesonide 400–800 μg or 185 (P < 0.0001, 146 ( P < 0.0001, 24.3 ( P < 0.0001, n = 472) −0.12 (0.04) 0.72 (0.45–1.14) P = 0.16, 0.87 (0.69–1.09) P = 0.22,
equivalent n = 481) n = 481) P = 0.0084, n = 513 n = 513 n = 513
223 (P < 0.0001, n = 492) 180 ( P < 0.0001, 25.4 ( P < 0.0001, n = 485) −0.16 (0.04) 0.50 (0.30–0.84) 0.66 (0.52–0.84) P = 0.0007,
n = 492) P = 0.0002, n = 515 P = 0.0084, n = 515 n = 515
196 (P < 0.0001, 114 (P < 0.0001, 24.8 (P < 0.0001, n = 501) −0.20 (0.04) 0.75 (0.48–1.18) P = 0.21, 0.75 (0.60–0.94) P = 0.013,
n = 510) n = 510) P < 0.0001, n = 535 n = 535 n = 535

BELT NCT01290874 in Black patients with moderate-to- Change from baseline at Month 18§
severe asthma (open-label, no placebo arm) [8]

Treatment arms ICS background FEV1, mean, mL ACQ Number of exacerbations** per person-year, mean
medication

Tiotropium 18 μg once daily Patients continued their −78 P = 0.49 (tiotropium vs −0.72 P = 0.70 (tiotropium 0.37 P = 0.31 (tiotropium vs
(n = 532) baseline moderate–high salmeterol) vs salmeterol) salmeterol)
Salmeterol 50 μg, or ICS dose −53 −0.68 0.42
formoterol 9 μg, twice

84
daily (n = 538)

Bateman et al. (2011) NCT00350207 in patients with Estimated treatment difference versus placebo; change from baseline to Week 16
moderate asthma and the B16-Arg/Arg genotype [9]

Treatment arms ICS background Morning weekly pre-dose Evening weekly pre-dose Morning weekly pre-dose Mini-AQLQ, overall Asthma symptoms Rescue medication use,
medication FEV1, mean, mL FEV1, mean, mL PEF, mean, L/min* score daytime, score puffs/24-h period

Tiotropium 5 μg once daily Budesonide 400–1000 μg 113 (P = 0.04) 128 (P = 0.02) 20.70 (P = 0.001) 0.091 (P = 0.302) −0.102 (P = 0.155) −0.368 (P = 0.146)
(n = 128) or equivalent
Salmeterol 50 μg twice daily 91 (P = 0.19) 76 (P = 0.059) 21.48 (P = 0.001) 0.240 (P = 0.006) −0.235 (P = 0.001) −0.567 (P = 0.024)
(n = 134)

TALC NCT00565266 in patients (n = 210) || with moderate Treatment difference versus beclomethasone 160 μg twice daily treatment, modeled change from baseline to Week 14††
asthma [10]

Treatment arms ICS background FEV1 before FEV1 after 4 puffs of Morning PEF, mean, L/ ACQ, mean Daily symptoms, mean, Rescue medication
medication bronchodilation, mean, albuterol, mean, mL min* score (albuterol) use, mean,
mL puffs/day

Tiotropium 18 μg once daily Beclometha-sone 80 μg 100 (P = 0.004) 40 (P = 0.01) 25.8 (P < 0.001) −0.18 (P = 0.02) −0.11 (P < 0.001) −0.05 (P = 0.63)
Salmeterol 50 μg twice daily twice daily 0 (P = 0.89) −30 (P = 0.06) 19.4 (P < 0.001) −0.28 (P < 0.001) −0.07 (P = 0.005) −0.09 (P = 0.33)

Zhang et al. (2018) in patients with moderate persistent Treatment difference at Week 8 versus baseline
asthma [11]

(continued on next page)

Respiratory Medicine 143 (2018) 82–90
R. Buhl et al. Respiratory Medicine 143 (2018) 82–90

ACT, asthma control test; ACQ, Asthma Control Questionnaire; ACQ-7, ACQ seven-question; B16-Arg/Arg, arginine single nucleotide polymorphism at amino acid 16 in the β2-adrenergic receptor gene; BELT, Blacks and

published manuscript, and therefore could not be presented in this table. The time to first exacerbation did not differ significantly between groups. ||This was a crossover study with 210 patients in total, who each
received each treatment in turn. ††Due to the 3-way crossover design, a restricted maximum-likelihood model was performed to determine the treatment effects based on the change between beginning and end of each
Exacerbations on LABA vs. Tiotropium; CI, confidence interval; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; HR, hazard ratio; Mini-AQLQ, Mini-Asthma Quality of Life Questionnaire; ICS, inhaled

morning PEF response of 30% or more of the mean morning response, and lasting for ≥2 consecutive days. §The primary outcome, time to first exacerbation, and other endpoints were presented graphically in the
Corticosteroid. *Primary or co-primary endpoints. **Defined as a worsening asthma event requiring oral or parenteral corticosteroids. †Defined as either a progressive increase in asthma symptoms, or a decrease in best
corticosteroids; PEF, peak expiratory flow; SD, standard deviation; TALC, Tiotropium Bromide as an Alternative to Increased Inhaled Glucocorticoid in Patients Inadequately Controlled on a Lower Dose of Inhaled
maintained on a course of ICS budesonide (400–800 μg or equivalent)
throughout the trial. This design enabled the trial to be performed with

(salbutamol) use, over

2.20 (P < 0.05 vs ICS)

Rescue medication
matching treatment-placebos in a controlled blinded fashion, although in
daily practice ICS and LABA would likely be given in the form of a
treatment period combination inhaler. The results showed that once-daily tiotropium pro-
vided significant improvements in the three co-primary endpoints (lung
function measures of peak and trough FEV1 responses and seven-question
1.20

1.50

3.90
Asthma Control Questionaire-7 responder rate) versus placebo that were
similar to those for twice-daily salmeterol versus placebo (Table 1). In
terms of the secondary endpoints considered in this study, time to first
Night-time symptom score

severe asthma exacerbation (defined as an asthma worsening event re-

2.20 (P < 0.05 vs ICS)

quiring OCS) and time to first asthma worsening, tiotropium 2.5 μg sig-
nificantly improved both measures compared with placebo (Table 1).
Other endpoints

BELT was an open-label study conducted in a population of African-

American patients with moderate-to-severe asthma [8]. The context
and results of this study will be further discussed later in this review,
2.38

2.40

1.50

although in summary, a LABA did not add any benefit or superiority

compared with tiotropium in this population in terms of the primary
outcome (time to first exacerbation) or other endpoints (Table 1).
8.90 (P < 0.05 vs

Bateman et al. (2011) carried out a small placebo-controlled study

Questionnaire

(NCT00350207) to compare tiotropium with salmeterol in patients with

ACT score
endpoints

moderate asthma and a genetic polymorphism in the β2-adrenoceptor [9].

10.12

This study will be further discussed later, but briefly, the authors concluded
9.50

5.90
ICS)

that tiotropium was non-inferior to salmeterol and superior to placebo in

relation to both the primary endpoint (change in mean weekly morning
pre-dose PEF) and other lung function measures in these patients (Table 1).
1.93 (P < 0.05 vs ICS)

TALC was a double-blind, three-way crossover trial overseen by the

National Heart, Lung, and Blood Institute (NHLBI) Asthma Clinical
Research Network (ACRN). This was the first trial to include both tio-
tropium and LABA add-on treatment arms; it explored the response to
PEF, L/s

twice-daily salmeterol 50 μg versus once-daily tiotropium 18 μg (de-

1.98

1.91

1.30

livered via HandiHaler®) when added to an ICS (twice-daily beclo-

methasone 160 μg) in patients with asthma [10]. In terms of the pri-
mary outcome, morning PEF, the effects of tiotropium and salmeterol
13.73 (P < 0.05 vs ICS)

were comparable and both were superior to a doubling of the dose of

ICS (Table 1). While this was a small study, and no treatment period
lasted longer than 14 weeks, pre-bronchodilator FEV1 favored tio-
FEV1/FVC, %

tropium compared with salmeterol (Table 1).

The most recent trial reviewed here was that conducted by Zhang
11.98

13.28

6.80

et al. (2018) [11]. The 8-week study with 160 patients compared four
treatment arms: ICS (twice-daily fluticasone propionate 250 μg) alone;
ICS and tiotropium 18 μg; ICS and LABA (salmeterol 50 μg twice daily);
Lung function endpoints

0.73 (P < 0.05 vs ICS)

and ICS, LABA, and tiotropium (Table 1). This small trial also concluded
that tiotropium was superior to ICS alone, and similar to LABA add-on
therapy, in terms of improved pulmonary function (FEV1, forced vital
capacity [FVC], FEV1/FVC, PEF), asthma control, night-time scores,
and rescue medication use.
FEV1, L

It is difficult to make comparisons between absolute numerical values

0.75

0.68

0.38

in lung function measures from individual trials conducted in different

populations and with varying protocols. A Cochrane review recently
compared the use of LAMA add-on to ICS versus the addition of a LABA,
Fluticasone propionate

using available clinical data up to April 2015 [6]. This quantitative meta-
250 μg twice daily
ICS background

analysis reviewed the evidence of four double-blind, double-dummy stu-

medication

dies, with approximately 2000 patients in total, all of which were under 6
months in duration (NCT00350207; MezzoTinA-asthma® [NCT01172808/
NCT01172821]; and the ACRN TALC trial [NCT00565266]) [7,9,32]. All
the studies used the LAMA tiotropium, comparing it with the LABAs sal-
meterol or formoterol as an add-on drug to medium doses of ICS. The
Salmeterol 50 μg twice daily
Tiotropium 18 μg once daily

Tiotropium 18 μg once daily

authors concluded that tiotropium and LABAs are comparable in most

and salmeterol 50 μg
twice daily (n = 40)

Fluticasone propionate
250 μg twice daily

aspects. The differences found in this meta-analysis were small; tiotropium

Table 1 (continued)

showed slight benefits over LABAs on some measures of lung function such
treatment period.
Treatment arms

as trough FEV1, whereas LABAs showed benefit in terms of QoL measures

(n = 40)

(n = 40)

(n = 40)
Trial details

[6]. The benefit in QoL may arise from the more rapid onset of action
produced by LABAs (in particular, formoterol) and ICS/LABA combina-
tions, which can often lead to patients and physicians suggesting that
LABAs are more effective than LAMAs [33–36].

85
R. Buhl et al.
The Cochrane review found no differences in treatment outcomes
for asthma patients in terms of rate of exacerbations (including ex-
acerbations that led to hospitalization) and serious AEs between tio-
tropium and LABA [6]. The analysis performed in the Cochrane review
was based on results available at the time, and the authors of the review
acknowledge that there were results pending for the use of LAMAs at
the time of analysis. Since the publication of the Cochrane review, the
MezzoTinA-asthma® trials, as discussed above, have been fully pub-
lished, and show that in patients with moderate asthma, tiotropium
improves lung function and asthma control compared with placebo, and
has similar efficacy and tolerability to salmeterol [7]. Tiotropium may
therefore offer an alternative add-on therapy in patients where LABAs
are unsuitable or in those who have complained about LABA-related
side effects.
6. Safety of tiotropium versus LABAs
Tiotropium has a long history of use in the treatment of chronic
obstructive pulmonary disease (COPD), as well as its more recent use in
asthma; there are now over 50 million patient-years of clinical experi-
ence with tiotropium [16]. It is regarded as a safe and well-tolerated
LAMA for use in patients with asthma, regardless of age or disease se-
verity [37]. A recent pooled safety analysis study, which included 3474
adult patients with mild-to-severe asthma, showed that as an add-on to
ICS therapy, tiotropium Respimat® demonstrates safety and tolerability
comparable with placebo [38]. This is evidenced by the number of
patients reporting AEs, serious AEs and treatment-related AEs, which
were comparable between the tiotropium and placebo treatment arms.
Overall, the most commonly reported AEs were asthma and decreased
PEF rate, both of which were reported in fewer patients treated with
tiotropium versus placebo.
Previous safety concerns were raised over the use of LABAs in
asthma [39]; these were addressed by safety studies, which conclude
that LABAs in combination with an ICS do not produce a higher risk of
serious asthma-related AEs or increased risk of death compared with
treatment with ICS alone [40,41].
A summary of the safety outcomes from the six trials that have in-
cluded both tiotropium and LABA treatment arms as add-on to ICS are
shown in Table 2. MezzoTinA-asthma®, BELT, Bateman et al. (2011),
TALC, and Zhang et al. (2018) reported safety findings over a treatment
period of between 8 weeks and 18 months in patients with moderate
asthma. Both classes of drug are generally well tolerated. Common AEs
associated with both drugs include asthma worsening, nasopharyngitis,
upper respiratory tract infection, and bronchitis. Frequency of patients
reporting any AEs, serious AEs, and drug-related AEs is comparable
between tiotropium, LABA, and placebo treatment arms for the in-
dividual trials [7–11].
Certain other AEs have attracted attention due to their association
with LAMA or LABA treatment of respiratory disease. For example, dry
mouth is an AE of special interest due to its association with LAMA
therapies; in asthma trials, dry mouth is reported by more patients
treated with tiotropium compared with placebo; however, overall fre-
quency of patients reporting this is low (tiotropium 5 μg, 1.0%; placebo
5 μg pool, 0.5%; tiotropium 2.5 μg, 0.4%; placebo 2.5 μg pool, 0.5%)
and reported less often than in studies of patients with COPD [38]. Dry
mouth can be a concern for elderly patients in whom it may impair
communication [42]. However, in the pooled safety analyses of tio-
tropium in asthma, dry mouth was not described as a serious AE nor did
it lead to trial discontinuation [38]. LABA usage may lead to some
patients experiencing tremor (relative risk [RR] 1.74, 95% CI 0.72,
4.20; in ICS and LABA versus ICS alone meta-analysis of 16 studies; 33
events in 2133 patients in the LABA and ICS group vs 9 events in 1700
patients in the ICS alone group) and palpitation or tachycardia (RR
2.11, 95% CI 0.83, 5.37; in ICS and LABA versus ICS alone meta-ana-
lysis of 12 studies; 13 events in 1791 patients in the LABA and ICS
group vs 5 events in 1700 patients in the ICS alone group) [15]. Thus, in
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Respiratory Medicine 143 (2018) 82–90
patients who experience side effects with LABA treatment, an alter-
native add-on treatment such as tiotropium may be a consideration.
7. Safety and efficacy in population subgroups
Given the heterogeneous nature of asthma, there is increasing re-
cognition of the necessity to address patient needs and provide treat-
ment solutions that are safe and efficacious in different population
subgroups, as well as in the general population. Post hoc analyses of the
PrimoTinA-asthma® trials in patients with severe asthma showed that
tiotropium is an effective add-on treatment to ICS plus LABA, in-
dependent of many baseline characteristics [43]. These included
gender, age, body mass index, disease duration, age at asthma onset,
smoking status, allergic status, FEV1 reversibility, leukotriene receptor
antagonist use at baseline, B16 genotype combination, race, ethnicity,
and country/region. Likewise, a recent post hoc analysis has been
performed on the MezzoTinA-asthma® trials in patients with moderate
asthma, and have also concluded that tiotropium is effective irrespec-
tive of baseline characteristics and phenotypes [44]. Furthermore, a
subsequent post hoc analysis of 912 patients with severe asthma and
2100 patients with moderate asthma showed that clinical benefits of
add-on tiotropium treatment were independent of T2 phenotype, as
assessed by IgE levels or blood eosinophil counts [45]. Although these
were all post hoc subgroup analyses, and therefore not powered for
statistical significance, this suggests that tiotropium may be appropriate
among different patient groups without the need for phenotyping.
Tiotropium may be a useful alternative to LABA in particular sub-
groups of patients based on their ethnicity. The use of tiotropium versus
LABA in the African-American population was investigated in the BELT
trial [8]. The BELT trial was set up to address concerns raised from the
early termination of the Salmeterol Multicenter Asthma Research Trial
(SMART) study when safety concerns were raised that the African-
American population had a potential increased risk of respiratory-re-
lated deaths or life-threatening experiences with LABA treatment [39].
Research had shown an association between rare variants of the β2-
adrenergic receptor gene and AEs during LABA therapy, including an
increased likelihood of a severe asthma exacerbation requiring hospi-
talization. This occurs specifically among LABA-treated African Amer-
icans with the −376 insertion-deletion rare variant and among LABA-
treated Whites with the Thr164Ile rare variant [46]. Furthermore,
African-American individuals may not benefit from LABA treatment to
the same degree as individuals of other races [47]. In the 18-month long
BELT study, the authors concluded that a LABA plus ICS did not add any
benefit or superiority compared with tiotropium plus ICS in the African-
American population.
A 52-week study of patients from Japan that were symptomatic
despite ICS with or without LABA therapy was conducted. This study
showed that the long-term use of tiotropium has a safety profile com-
parable with that of placebo. Lung function and symptoms were sig-
nificantly improved in this patient population with tiotropium 5 μg
compared with placebo [48].
The safety and efficacy of LABAs has been questioned in patients
with asthma with an arginine single nucleotide polymorphism at amino
acid 16 (B16-Arg/Arg) in the coding region of the β2-adrenergic re-
ceptor gene [49,50]. This polymorphism is found in a substantial pro-
portion of the asthmatic population; for example, approximately
10–12% of White patients and 20–25% of African-American patients
[9]. The 2011 study by Bateman et al. concluded that tiotropium was
non-inferior to salmeterol and superior to placebo in maintaining im-
proved lung function in patients with moderate asthma with the B16-
Arg/Arg genotype [9]. This suggests that tiotropium is a useful alter-
native to LABA in patients with asthma who are not adequately con-
trolled on ICS alone irrespective of β-receptor polymorphisms.
There is also evidence that LABA treatment is not effective across all
patients with asthma. A study of over 3000 patients with uncontrolled
disease, Gaining Optimal Asthma ControL study (GOAL), showed that
 R. Buhl et al.

Table 2
Summary of safety data from clinical trials with tiotropium or LABA as add-on therapy to ICS.
Study Treatment arm Patients, n Patients with an AE, n (%) Patients reporting common AEs, n (%)

Any AE Serious Drug- Asthma/exacerbation/ Decreased PEF Nasopharyngitis Upper respiratory Bronchitis
AEs* related AEs hospitalization** rate tract infection

MezzoTinA-asthma® [7] Tiotropium 5 μg once daily 517 296 (57) 11 (2) 38 (7) 111 (22) 59 (11) 41 (8) 19 (4) 11 (2)
NCT01172808/NCT01172821 Tiotropium 2.5 μg once daily 519 302 (58) 12 (2) 36 (7) 82 (16) 49 (9) 49 (9) 27 (5) 9 (2)
Salmeterol 50 μg twice daily 541 294 (54) 11 (2) 28 (5) 105 (19) 47 (9) 41 (8) 41 (8) 9 (2)
Placebo 523 309 (59) 14 (3) 28 (5) 115 (22) 79 (15) 48 (9) 41 (8) 5 (1)
BELT [8] NCT01290874 Tiotropium 18 μg once daily 532 NR 67 (13) NR 19 (3.6) NR NR NR NR
Salmeterol 50 μg, or formoterol 9 μg, twice 538 NR 58 (11) NR 10 (1.9) NR NR NR NR
daily
Bateman et al. (2011) [9] Tiotropium 5 μg once daily 128 51 (39.8) 2 (1.6) 6 (4.7) 16 (12.5) NR 5 (3.9) 2 (1.6) 4 (3.1)
NCT00350207 Salmeterol 50 μg twice daily 134 56 (41.8) 7 (5.2) 3 (2.2) 17 (12.7) NR 3 (2.2) 4 (3.0) 5 (3.7)
Placebo 126 52 (41.3) 1 (0.8) 4 (3.2) 17 (13.5) NR 9 (7.1) 3 (2.4) 1 (0.8)
TALC [10] NCT00565266 Tiotropium 18 μg once daily, and 210† NR 3† NR 9† NR NR NR NR

87
beclomethasone 80 μg twice daily
Salmeterol 50 μg twice daily, and 210† NR 4† NR 16† NR NR NR NR
beclomethasone 80 μg twice daily
Beclomethasone 160 μg twice daily 210† NR 4† NR 5† NR NR NR NR
Zhang et al. (2018) [11] Tiotropium 18 μg once daily and fluticasone 40 NR 0 1 NR NR NR NR NR
propionate 250 μg twice daily
Tiotropium 18 μg once daily and salmeterol 40 NR 0 2 NR NR NR NR NR
50 μg/fluticasone propionate 250 μg twice
daily
Salmeterol 50 μg and fluticasone propionate 40 NR 0 2 NR NR NR NR NR
250 μg twice daily
Fluticasone propionate 250 μg twice daily 40 NR 0 NR NR NR NR NR NR

AE, adverse event; BELT, Blacks and Exacerbations on LABA vs Tiotropium; NR, not reported; PEF, peak expiratory flow; TALC, Tiotropium Bromide as an Alternative to Increased Inhaled Glucocorticoid in Patients
Inadequately Controlled on a Lower Dose of Inhaled Corticosteroid. *A serious drug-related AE was defined slightly differently between the trials, but is generally one that required an emergency room visit or
hospitalization of the patient. **The term ‘asthma’ as an AE was defined differently in the individual trials: for MezzoTinA asthma®, the definition includes several preferred terms, but in the majority of cases the reported
term was ‘exacerbation of asthma’; for BELT, asthma-related hospitalizations were reported; and for Bateman et al. (2011) and TALC, asthma exacerbations were coded as asthma. †This was a crossover study with 210
patients in total, who each received each treatment in turn.
Respiratory Medicine 143 (2018) 82–90
R. Buhl et al.
Fig. 1. Response of patients in the TALC study to either LABA or tiotropium
treatment in terms of A) FEV1 response and B) asthma control days (from Peters
et al. [32]). FEV1, forced expiratory volume in 1 second.
approximately one-third of these patients were unable to gain sufficient
control despite treatment with an ICS/LABA combination treatment
[51]. Furthermore, a large number of patients in the TALC study re-
sponded to treatment with either salmeterol or tiotropium, but not both
agents, indicating that there are groups of patients who, due to the
nature of their disease, may respond better to LAMA or LABA (Fig. 1).
The authors suggested that this may be due to different mechanisms at
play in the two groups of patients [32].
8. Practical aspects of adherence to add-on therapy
Adherence is a well-recognized challenge in asthma therapy, and
furthermore, not all patients have the same reasons for poor adherence
and therefore many approaches are required [52]. Further to working
with the patient to provide optimal asthma management through pa-
tient education, there are also practical concerns to be taken into ac-
count that relate to the treatment regimen and delivery device.
The benefit of a once-daily administration of tiotropium over a
twice-daily treatment should simplify the patient's treatment regimen.
Furthermore, tiotropium is available via the Respimat® Soft Mist™ de-
vice, which has been developed to provide an easy-to-use inhalable
aerosol that results in higher drug deposition in the lung compared with
dry powder inhalers or pressurized metered-dose inhalers [53].
However, while there exists a range of ICS/LABA combination
products, there are currently no fixed ICS/LAMA combination devices.
In daily practice, the lack of a combination product is a potential barrier
88
Respiratory Medicine 143 (2018) 82–90
to the ease of uptake of tiotropium compared with using a LABA as an
add-on therapy in asthma.
9. Real-world studies
Tiotropium has only recently been licensed for use as add-on
therapy in asthma; hence the number of real-world studies investigating
tiotropium is limited. However, one study that has been carried out
revealed that UK primary care physicians have been prescribing tio-
tropium for the treatment of asthma since 2002 [54]. In this study,
physicians were shown to be prescribing tiotropium predominantly as
add-on to ICS/LABA therapy in older patients with poorly controlled
asthma despite good treatment adherence, of whom over half were
current or former smokers (patients with a diagnosis of COPD were
excluded). In this real-life population, tiotropium add-on therapy re-
duced exacerbation rate and improved outcomes for other respiratory
events.
10. Expanding the clinical use of tiotropium
The use of tiotropium may benefit particular subgroups of patients,
such as those who have experienced on-treatment tremor or palpita-
tions, a characteristic AE of LABAs [55]. For these patients, an alter-
native treatment with a different mode of action, such as a LAMA, may
be clinically relevant. The efficacy of tiotropium added onto ICS in
GINA Step 3 patients has now been demonstrated in both industry-
sponsored and independent trials [7,10,30]. As further evidence
emerges, tiotropium has the potential to be an alternative therapy as an
add-on to ICS in patients with less severe disease.
It is worth emphasizing that GINA recommend considering tio-
tropium as an add-on to ICS/LABA for patients at Step 5 prior to the use
of monoclonal antibodies [2]. Indeed, tiotropium may be of particular
benefit for patients with Type 2-low asthma, where monoclonal anti-
bodies are ineffective [56], and tiotropium should be added to the
treatment regimen before methotrexate, antifungals, and bronchial
thermoplasty are considered. Tiotropium also confers cost benefits
compared to the more expensive options such as omalizumab [57]. As
tiotropium becomes more widely used in the clinic, further insights into
the use of this treatment will emerge.
11. Conclusions
To conclude, the differences in terms of improvements in lung
function and measures of asthma control between adding tiotropium
compared with adding a LABA are small, and depend on the trial design
and the outcome measured. Tiotropium is currently recommended as an
add-on therapy in patients with moderate-to-severe asthma and a his-
tory of exacerbations who are uncontrolled despite treatment with ICS/
LABA. However, with further clinical and real-world evidence, its use
may be expanded in the future. Based on the evidence, tiotropium may
be a suitable add-on option to ICS treatment for patients uncontrolled
on ICS alone, and as an alternative add-on in patients where LABAs are
not well tolerated or are ineffective.
Disclosures
RB has received grants and personal fees from Boehringer
Ingelheim, GlaxoSmithKline, Novartis, and Roche, and personal fees
from AstraZeneca, Chiesi, and Teva.
JMF reports being a member of advisory boards for AstraZeneca,
Boehringer Ingelheim, Novartis, Sanofi-Regeneron, Circassia, and Teva,
has been paid honoraria for lecturing at symposia organized by
AstraZeneca, Boehringer Ingelheim, Novartis, Merck, and has also un-
dertaken clinical trials through his employer, the University of British
Columbia, for these companies and GlaxoSmithKline.
WWB reports consulting fees from Novartis, Roche,
R. Buhl et al.
GlaxoSmithKline, AstraZeneca, Genentech, Sanofi, Regeneron,
Boehringer Ingelheim, Boston Scientific (Data Safety Monitoring
Board), and ICON Clinical Research Limited (Study Oversight
Committee), and grants from NIH-NIAID and NIH-NHLBI.
Acknowledgments
The authors take full responsibility for the scope, direction, content
of, and editorial decisions relating to the manuscript, were involved at
all stages of development, and have approved the submitted manu-
script. Medical writing assistance, in the form of the preparation and
revision of the draft manuscript, was supported financially by
Boehringer Ingelheim and provided by Helen Moore, PhD, of MediTech
Media, under the authors' conceptual direction and based on feedback
from the authors. Boehringer Ingelheim was given the opportunity to
review the manuscript for factual accuracy only.
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