Data have shown that asthma is the most prevalent chronic respiratory disease, affecting
358 million people worldwide in 2015.1 While data show that the age-standardized asthma-related
death rate decreased by 58.8% from 1990–2015,1 asthma still represents a significant
burden in terms of morbidity.2 As such, there is an important role for utilizing add-on
therapy options. The focus of this review series is on the use of long-acting anticholinergic
add-on therapy to reduce asthma morbidity.
In the first article of this review series, Dr Kevin Gruffydd-Jones reviews the unmet
needs in the diagnosis, management, and treatment of asthma. There is no universally
accepted, gold-standard diagnostic test for asthma, so diagnosis relies on assessing
the probability of a patient’s symptoms being due to asthma and using objective tests.3,4
As a result, under-, over-, and misdiagnosis of asthma are common, with one study
finding no evidence of asthma in one-third of participants who had previously received
a physician’s diagnosis of asthma, and another prospective study in an adolescent
cohort showing that one-third of the diagnosed asthma patients had previously been
undiagnosed.5,6 In addition, a high proportion of patients with asthma are classified
as having guideline-defined uncontrolled asthma, and experience symptoms despite the
availability of different treatment options and guidelines.7 A move toward precision
medicine so as to provide more individualized treatment will go some way to meeting
the unmet needs in asthma diagnosis and management; however, for most patients with
asthma, this approach remains a long way off. Long-acting anticholinergics such as
tiotropium are an effective add-on therapy across a broad spectrum of severity and
age groups and are therefore helping to meet some of these unmet needs.
These add-on treatments are particularly important because many patients remain uncontrolled
with inhaled corticosteroids (ICS) and long-acting β2-agonists (LABAs).8,9 In line
with the Global Initiative for Asthma (GINA) strategy, there are several add-on therapy
options in patients who are uncontrolled despite medium- to high-dose ICS/LABA at
GINA Step 4, such as tiotropium delivered via Respimat®, a soft-mist inhaler.3 In
Professor Christine Jenkins’ article “Barriers to achieving asthma control in adults:
evidence for the role of tiotropium in current management strategies”, she explores
the interesting question of whether add-on therapy options are being utilized effectively
in clinical practice, with a focus on the extensive evidence for tiotropium add-on
therapy in current management strategies for adults with asthma. GINA recommends regular
reviews as part of the cycle of management and the stepwise approach to care;3 this
includes considering add-on therapy options to provide safe and efficacious treatment
according to individual patient needs.3 Furthermore, this regular review opens up
the opportunity for dialog between patients and health care professionals, encouraging
patients toward self-management. Treatment adherence remains problematic in asthma
management, yet studies have shown that interventions that aid dialog, such as professionals
undergoing communication skills training, can improve patient adherence.10 Regular
reviews also allow for ongoing inhaler technique training, as many studies show loss
of technique when it is only demonstrated once.11,12 Professor Jenkins concludes that
health care professionals should actively implement this cycle of asthma management
in regular reviews, and patients should be empowered with their health care provider
to be involved in their own care.
The 2018 GINA report also recommends tiotropium as add-on therapy in patients aged
≥12 years with a history of asthma exacerbations at Steps 4 and 5 of the stepwise
approach.3 In addition, approvals in patients aged ≥6 years were recently granted
by the US Food and Drug Administration and the European Medicines Agency.13,14 In
light of this, Professor Stanley Goldstein reviews the use of anticholinergics in
pediatric asthma, including the various challenges for selecting appropriate endpoints
in future clinical trials in a pediatric population. For example, traditional endpoints
such as forced expiratory volume in 1 second and peak expiratory flow do not correlate
well with asthma severity in children. Alternative endpoints, such as forced expiratory
flow between 25% and 75% of forced vital capacity, can be more sensitive measures
of small airway obstruction in a pediatric population. Of particular note is the focus
on the safety of anticholinergic therapies in pediatric patients. Four phase III and
one phase II/III clinical trials in adolescents and pediatric patients have shown
that tiotropium has a similar safety and tolerability to placebo.15–19
In the next article in the series, I review asthma in preschool children. Over half
of asthma cases develop before the age of 3 years, and 80% before the age of 6 years,
and yet there remain challenges in recognizing and treating asthma at this age. Frequently
cited complications include the maturity of the respiratory and immune systems, the
natural history of the disease, lack of reliable and reproducible tests, difficulty
in delivering treatment, unpredictable responses to treatment, and underestimation
of disease severity by parents, guardians, and patients. These difficulties with diagnosis
also mean that there are limited treatment options available and few clinical trials
investigating potential treatments in this age group. While pediatricians are familiar
with short-acting anticholinergics, especially in the context of treating acute asthma
attacks in young children,20 there is only very recent data on long-acting anticholinergics
in this age group. A recent trial assessing tiotropium vs placebo in preschool children
demonstrated a comparable safety and tolerability profile.19 However, further trials
are needed to establish the efficacy of tiotropium in this very young patient population.
So, what can be done to improve utilization of asthma therapies? One approach is the
selection of appropriate inhaler devices and improvements in inhaler technique. This
is explored in Dr Omar Usmani’s article “The importance of inhalation devices in the
management of asthma and COPD”, in which he recommends a tailored and personalized
approach to choosing an inhaler. This should be based not only on achieving better
clinical control and improved quality of life but also on factors such as pulmonary
function,21,22 device handling23 and patient preferences.24 It is important to note
that both the patient and the health care practitioner should receive training and
education on inhaler technique. Advances in electronic and digital health are likely
to provide additional support to inhaler use in obstructive airway diseases.
Finally, we look toward the future of asthma therapy. With the increasing number of
biologic agents entering the asthma treatment armamentarium, where do current treatments
such as tiotropium sit? Professors Roland Buhl and Eckard Hamelmann assess the future
position of anticholinergics – in particular tiotropium – for asthma treatment in
adults and children. The heterogeneous nature of asthma means that patients can respond
differently to the same treatment. This makes the concept of precision medicine an
attractive approach in asthma, although it should be noted that, currently, we do
not have all the tools to implement this in clinical practice.25 Newer biologic therapies
such as dupilumab have shown improved outcomes in adults with severe asthma.26 However,
use of these newer biologic therapies will need to be subjected to cost–benefit analysis,
taking into account the additional costs of patient phenotyping and biomarker analysis.27
Data have shown that tiotropium is efficacious in adults with asthma, irrespective
of baseline characteristics such as allergic status.28 This means that tiotropium
can be administered without the need for patient phenotyping, which will make it relatively
easy and cost-effective to incorporate into routine clinical practice. As an add-on
therapy, tiotropium can also provide a steroid-sparing alternative for patients who
are uncontrolled with ICS/LABA who would otherwise require higher ICS doses.29 The
review makes the important point that utilizing tiotropium effectively can help to
reduce the burden of asthma and improve patient outcomes, as shown by extensive clinical
trial data. Further data from real-world studies of tiotropium add-on therapy in asthma
should add additional insight.
This series of reviews raises many interesting questions – from how to ensure effective
implementation of guidelines, why training and regular dialog with patients is so
important, to the future position of long-acting anticholinergics in asthma therapy.