Respiratory Medicine 162 (2020) 105859

Contents lists available at ScienceDirect

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

One-year follow up of asthmatic patients newly initiated on treatment with

medium- or high-dose inhaled corticosteroid-long-acting β2-agonist in UK
primary care settings
Roland Buhl a, *, Liam G. Heaney b, Emil Loefroth c, Michael Larbig d, 1, Konstantinos Kostikas e, 1,
Valentino Conti f, 1, Hui Cao g
a
Pulmonary Department, Mainz University Hospital, Mainz, Germany
b
Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, United Kingdom
c
Novartis Sverige AB, Kista, Sweden
d
Novartis Pharma AG, Basel, Switzerland
e
Respiratory Medicine Department, University of Ioannina Medical School, Ioannina, Greece
f
Novartis Ireland Limited, Dublin, Ireland
g
Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States

A R T I C L E I N F O A B S T R A C T

Keywords: Introduction: Global Initiative for Asthma (GINA) recommends medium- or high-dose inhaled corticosteroid-long-
Uncontrolled asthma acting β2-agonist (ICS-LABA) as preferred treatments for patients with moderate-to-severe asthma. Limited data
Retrospective study is available on how step 4/5 patients respond to ICS-LABA and how they step up/down in clinical practice.
Treatment pathways
Methods: This retrospective cohort study assessed the characteristics, control status, treatment pathways, and
Inhaled corticosteroid-long-acting β2-agonist
(ICS-LABA)
healthcare resource utilization in patients with asthma during one year after initiating medium- or high-dose ICS-
Clinical practice research datalink (CPRD) LABA. Data from the United Kingdom Clinical Practice Research Datalink were analysed between January 01,
2006 and February 28, 2016.
Results: Overall, 29,229 and 16,575 patients initiated medium- and high-dose ICS-LABA, and 35.1% and 45.7% of
patients, respectively, remained uncontrolled. The proportions of patients who were adherent to treatment
(Medication Possession Ratio �80%) were 37.8% and 49.1% in the medium- and high-dose ICS-LABA cohorts,
respectively. Among these adherent patients, 63.8% in the medium- and 70% in the high-dose cohorts remained
uncontrolled. In patients who stepped up therapy in the medium-dose cohort (19.0%), the common step-up
choices were add-on leukotriene receptor antagonist (LTRA) (42.2%), long-acting muscarinic antagonist
(LAMA) (23.3%), and increase in ICS dose (22.9%). In patients who stepped up therapy in the high-dose cohort
(26.1%), the common step-up choices were add-on LAMA (43.8%) and LTRA (42.1%). Healthcare resource
utilization was higher in uncontrolled patients, regardless of the ICS-LABA dose.
Conclusions: Many patients remain uncontrolled on both medium- or high-dose ICS-LABA, highlighting the need
for timely assessment of asthma control to increase treatment intensity, following evidence-based treatment
pathways.

1. Introduction high-dose inhaled corticosteroids (ICS)-long-acting β2-agonist (LABA) as

preferred controller treatments for patients with moderate to severe
Asthma is the most common form of chronic respiratory disease with asthma [2]. However, many patients seem to remain uncontrolled
more than 358 million people affected worldwide [1]. The Global despite receiving ICS-LABA therapies. A real-world study of over 5 years
Initiative for Asthma (GINA) 2019 guidelines recommend low- to showed that exacerbation rates remained constant over time, despite

* Corresponding author. Pulmonary Department, Universit€atsmedizin Mainz Langenbeckstr. 1, 55131, Mainz, Germany.
E-mail address: Roland.Buhl@unimedizin-mainz.de (R. Buhl).
1
ML and KK were the employees of Novartis Pharma AG, Basel, Switzerland and VC was an employee of Novartis Ireland Limited, Dublin, Ireland, during the
conduct of this study.

https://doi.org/10.1016/j.rmed.2019.105859
Received 14 August 2019; Received in revised form 7 November 2019; Accepted 28 December 2019
Available online 30 December 2019
0954-6111/© 2020 Elsevier Ltd. All rights reserved.
R. Buhl et al.
patients being treated with continuous ICS-LABA therapy for 4 months
in a year [3]. These patients with uncontrolled asthma on ICS-LABA
have higher rates of morbidity, mortality and healthcare resource uti­
lization compared with patients who achieved control [3,4].
GINA recommends an increase in the dose of ICS or the addition of
one or more controllers, such as a long-acting muscarinic antagonist
(LAMA) or a leukotriene receptor antagonist (LTRA), before stepping up
to biologics and/or low-dose maintenance oral corticosteroid (OCS), if
patients are not controlled on ICS-LABA. This GINA recommendation
leaves primary care physicians (PCPs) with multiple options for the
management of moderate to severe asthma. How physicians choose the
step-up options post medium- or high-dose ICS-LABA in the real-world
clinical practice is largely unknown [5]. Patient adherence is a signifi­
cant factor in asthma treatment success. However, improved adherence
does not always have a substantial positive effect on health outcomes
[6]. Treatment adherence in patients with difficult-to-treat asthma itself
can be an outcome of lack of treatment response [2]. Nevertheless,
adherence is not the only reason for treatment failure in asthma patients
and the absence of asthma control in many patients may largely be
attributed to the refractory nature of their asthma.
In order to understand the level of control in moderate to severe
asthma patients initiated on medium- or high-dose ICS-LABA therapy
and treatment pathways followed in primary care, we conducted a
retrospective cohort study using the United Kingdom (UK) Clinical
Practice Research Datalink (CPRD) linked to the Hospital Episode Sta­
tistics (HES). We specifically examined also the control status of a sub­
group of patients who were adherent to their ICS-LABA treatment, in
order to further understand treatment pathways in these patients with
treatment-refractory asthma.
2. Methods
2.1. Data source
CPRD is a UK database of anonymized longitudinal medical records
data collected from a network of general physicians (GP) practices
across the UK. The patient population in CPRD is representative of the
UK primary care population. HES is a database containing details of all
admissions, outpatient appointments and accident and emergency
(A&E) attendances at National Health Services (NHS) hospitals in UK
[7].
2.2. Patients and study design
This was a retrospective cohort study on patients newly initiated on
Fig. 1. Study design.
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Respiratory Medicine 162 (2020) 105859
medium- or high-dose ICS-LABA therapy, identified in CPRD with linked
HES data between January 01, 2006 and February 28, 2016. Patients
were excluded if they had a diagnostic code of chronic obstructive
pulmonary disease (COPD) or other chronic respiratory disease such as
cystic fibrosis during the study period. ICS-LABA initiators were divided
into two cohorts, medium- and high-dose ICS-LABA cohorts [5]). The
classification of medium- or high-dose ICS-LABA was based on GINA
definitions and is presented in Table S1 in the online supplementary
material. ICS-LABA initiators were defined as patients without a pre­
scription for the specified medication in the year prior to cohort entry.
Patients could be included in both cohorts in different time periods. The
index date is the initiation date of medium- or high-dose ICS-LABA (from
January 01, 2007 to February 28, 2015). All patients were followed up
for a minimum of 12 months (Fig. 1). The study period for each patient
comprised 2 sequential periods: a 1-year baseline period preceding and
inclusive of the index date for patient baseline characterization and a
minimum 1-year follow-up period after the index date.
2.3. Baseline characteristics and outcome measures
Patient characteristics such as demographics, body mass index,
smoking status, use of asthma drugs, asthma exacerbation history,
concomitant medications, comorbidities and Charlson Comorbidity
Index were evaluated in the pre-index baseline period.
The outcome measure - asthma control in the follow-up period was
assessed using a composite outcome including moderate or severe ex­
acerbations, treatment step-up, and SABA use �450 μg Defined Daily
Dose (DDD) per year [8]. Patients with any occurrence of one or more of
these events were identified as uncontrolled. An exacerbation was
considered as moderate if managed in primary care, i.e. asthma-related
GP visit and OCS burst (within 7 days of GP visit, one fill only). Severe
exacerbations were defined as asthma-related hospitalization or A&E
visit. Exacerbation events occurring within 14 days were considered as
one exacerbation. Treatment step-up was either addition of one or more
asthma controllers, including LAMA, LTRA, theophylline, or mainte­
nance OCS in patients of both ICS-LABA cohorts, and increase in ICS
dose only in the medium-dose ICS-LABA cohort.
Adherence to treatment was defined as Medication Possession Ratio
(MPR) of �80%. Changes in asthma treatments post medium- or high-
dose ICS-LABA implemented by GPs, percentage of patients who step­
ped up or stepped down, and medications that patients stepped up/
down to were also examined during the follow-up period. Healthcare
resource utilization in medium- and high-dose ICS-LABA cohorts was
assessed in terms of asthma-specific prescriptions and rates of specialist
referral and hospitalizations.
R. Buhl et al. Respiratory Medicine 162 (2020) 105859

2.4. Statistical analysis 3.3. Asthma control in the follow-up period

Baseline characteristics of patients were presented as counts (n) and
proportions (%); summary statistics were presented for continuous data.
The unequal variance two-sample t-test was used for continuous data,
the Wilcoxon rank sum test was used for ordinal data, and the chi-square
test was used for categorical data to compare uncontrolled patients with
controlled patients. Two-tailed P values were reported.
3. Results
3.1. Patient characteristics
A total of 29,229 and 16,575 patients initiated medium- and high-
dose ICS-LABA, respectively, during the study period (Table S2 in the
online supplementary material). In both medium- and high-dose ICS-
LABA cohorts, proportions of men (40.3% and 38.2%) and women
(59.7% and 61.8%) were similar. Patients on medium-dose ICS-LABA
were slightly younger, with mean age of 48.8 years at index date
compared with 54.7 years in the high-dose ICS-LABA cohort. Never-
smokers were more prevalent in the medium-dose ICS-LABA group
than in the high-dose ICS-LABA cohort (51.1% versus 45.7%). De­
mographics and baseline clinical characteristics of patients who were
controlled and uncontrolled in medium- and high-dose ICS-LABA during
the post-index period are presented in Table 1.
3.2. Treatment adherence
On medium- and high-dose ICS-LABA, 37.8% (n ¼ 11,061) and
49.1% (n ¼ 8,144) of the patients were considered to be adherent (MPR
�80%).
3.3.1. Medium-dose ICS-LABA cohort
Among all patients, 35.1% remained uncontrolled in the follow-up
period (Fig. 2A), 14.2% had exacerbations, 15.2% stepped up treat­
ment and 7.0% used SABA �450 μg DDD/year (Fig. 2B). Among patients
who were adherent to treatment, 63.8% remained uncontrolled, 24.4%
had exacerbations, 28.5% stepped up and 13.6% used SABA �450 μg
DDD/year (Fig. 2B).
3.3.2. High-dose ICS-LABA cohort
Among all patients, 45.7% of patients remained uncontrolled
(Figs. 2A), 15.9% had exacerbations, 22.9% stepped up treatment, and
9.3% used SABA �450 μg DDD/year (Fig. 2B). Among adherent patients,
70% remained uncontrolled, 22.8% had exacerbations, 36.8% stepped
up, and 14.9% used SABA �450 μg DDD/year (Fig. 2B).
The prevalence of comorbidities was greater in uncontrolled patients
compared with controlled patients; the most common comorbidities in
both cohorts were anxiety/depression, eczema and gastroesophageal
reflux disease. The data on comorbidities is presented in Table S3 in the
online supplementary material.
3.4. Changes in asthma treatments
3.4.1. Medium-dose ICS-LABA cohort
In the medium-dose ICS-LABA cohort, 15.2% of all patients and
28.5% of adherent patients stepped up treatment (Fig. 3A). In all pa­
tients and adherent patients, respectively, the most common step-ups
from medium-dose ICS-LABA were addition of LTRA (42.2%, 44.7%),
addition of LAMA (23.4%, 25.1%), and increased ICS dose (22.9%,
17.8%). In total, 19.0% of all patients and 28.9% of adherent patients
stepped down their treatment (Fig. 3C). In these step-down patients,
58.0% stepped down to mono-ICS and 42.0% lowered ICS dose.

Table 1
Demographic and baseline clinical characteristics of patients with asthma who were controlled and uncontrolled during the post-index period.
Parameters Medium-dose ICS-LABA High-dose ICS-LABA
N ¼ 29,229 N ¼ 16,575

Controlled Uncontrolled P value Controlled Uncontrolled P value

N ¼ 18,965 N ¼ 10,264 N ¼ 9001 N ¼ 7574

Gender
Women 11,171 (58.9%) 6269 (61.1%) 5572 (61.9%) 4675 (61.7%)
Age (years) at index, mean � SD 47.7 � 20.07 50.8 � 21.39 <0.0001z 53.4 � 18.47 56.3 � 19.01 <0.0001z
Smoking status
Current smoker 3451 (18.2%) 2017 (19.7%) <0.0001a 1755 (19.5%) 1619 (21.4%) <0.0001a
Former smoker 4874 (25.7%) 2812 (27.4%) 2652 (29.5%) 2585 (34.1%)
Never smoker 9918 (52.3%) 5026 (49.0%) 4352 (48.4%) 3226 (42.6%)
Missing/Unknown 722 (3.8%) 409 (4.0%) 242 (2.7%) 144 (1.9%)
BMI, mean � SD 29.0 � 6.94 29.2 � 7.47 0.0921z 29.5 � 6.97 29.6 � 7.40 0.5794z
Baseline asthma medications
Medium-dose ICS-LABA free-dose combination 858 (4.5%) 614 (6.0%) <0.0001a 310 (3.4%) 322 (4.3%) 0.0069a
High-dose ICS-LABA free-dose combination 409 (2.2%) 419 (4.1%) <0.0001a 375 (4.2%) 472 (6.2%) <0.0001a
Low-dose ICS-LABA fixed-dose combination 3437 (18.1%) 2200 (21.4%) <0.0001a 821 (9.1%) 776 (10.3%) 0.0145a
Medium-dose ICS-LABA fixed-dose combination 0 0 NE 3764 (41.8%) 3423 (45.2%) <0.0001a
SABA 15,923 (84.0%) 9141 (89.1%) <0.0001a 7823 (86.9%) 6930 (91.5%) <0.0001a
Asthma exacerbations pre-Index, mean � SD 0.3 � 0.71 0.6 � 2.43 <0.0001z 0.4 � 0.90 0.8 � 2.77 <0.0001z
Number of asthma exacerbations pre-index
0 15,436 (81.4%) 7098 (69.2%) <0.0001x 6794 (75.5%) 4602 (60.8%) <0.0001x
�1 3529 (18.6%) 3166 (30.9%) 2207 (24.5%) 2972 (39.2%)
Concomitant medications
β-blockers 870 (4.6%) 576 (5.6%) 0.0001a 497 (5.5%) 376 (5.0%) 0.1096a
NSAIDs 3549 (18.7%) 2180 (21.2%) <0.0001a 1832 (20.4%) 1684 (22.2%) 0.0032a
Paracetamol 4792 (25.3%) 3467 (33.8%) <0.0001a 2823 (31.4%) 3111 (41.1%) <0.0001a
Charlson Comorbidity Index, mean � SD 1.5 � 1.24 1.7 � 1.48 <0.0001z 1.6 � 1.44 1.9 � 1.71 <0.0001z

Data are presented as n (%) unless otherwise specified. Percentages are based on the number of patients in each cohort.
BMI, body mass index; ICS, inhaled corticosteroid; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist; LTRA, leukotriene receptor antagonist; NE,
not estimated; NSAID, non-steroidal anti-inflammatory drug; SABA, short-acting β2-agonist; SAMA, short-acting muscarinic antagonist.
a
Chi-square test; zUnequal variance 2-sample t-test; xWilcoxon rank sum test.

3
R. Buhl et al.
Fig. 2. Exacerbations distribution observed in uncontrolled and controlled patients with asthma during one-year follow-up.
3.4.2. High-dose ICS-LABA cohort
In the high-dose ICS-LABA cohort, 22.9% of all patients and 36.8% of
adherent patients stepped up treatment (Fig. 3B). In all and adherent
patients, respectively, the most common step-ups from high-dose ICS-
LABA were addition of LAMA (43.8%, 45.8%) and addition of LTRA
(42.1%, 39.0%). In total, 26.1% of all patients and 32.6% of adherent
patients stepped down (Fig. 3D). In all step-down patients, 70.5% low­
ered the ICS dose of ICS-LABA and 29.5% stepped down to mono-ICS.
Interestingly, among adherent, uncontrolled patients who could be
followed up for an additional year post the first episode indicating un­
controlled status, 41.1% in the medium-dose and 31.2% in the high-dose
ICS-LABA cohort had no treatment step-up. Referral to specialists was
also rare among these patients. Overall, 3.6% (n ¼ 1046) patients who
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Respiratory Medicine 162 (2020) 105859
were uncontrolled in the medium-dose ICS-LABA cohort, shifted to high-
dose ICS-LABA regimen. Among them, 35.0% of patients remained
uncontrolled.
3.5. Healthcare resource utilization
Healthcare utilization rates (per 100 person-years) were lower in
patients in the medium-dose ICS-LABA cohort compared with the high-
dose cohort for both asthma-specific and non-asthma items. Asthma-
specific hospitalization rate (per 100 person-years) was 14.4 vs 18.2.
The number of systemic corticosteroid and lower respiratory tract
infection (LRTI) prescriptions on the same date (per 100 person-years)
was 6.7 vs 11.9, and the number of non-asthma prescriptions (per 100
R. Buhl et al.
Fig. 3. Treatment patterns followed by physicians to manage uncontrolled and controlled patients with asthma during one-year follow-up.
person-years) was 3184.9 versus 4288.8. The rate of asthma-specific
specialist referrals/visits (per 100 person-years) was slightly higher in
medium-dose versus high-dose ICS-LABA patients (278.3 vs 267.5).
However, in the subgroup of adherent patients, the rate of specialist
referrals/visits was higher in the high-dose ICS-LABA cohort (434.9)
compared with medium-dose ICS-LABA (418.3) (Table S4 in the online
supplementary material).
Uncontrolled patients had significantly higher rates for all non-
asthma-specific healthcare utilization related items as well as asthma-
specific GP-related items when compared with controlled patients.
Asthma-specific specialist referrals/visits (per 100 person-years) were
5
Respiratory Medicine 162 (2020) 105859
more than doubled among the uncontrolled patients, compared to
controlled patients (574.0 vs 224.3). A similar pattern was observed for
all-cause (excluding asthma-related) healthcare resource utilization
items. For example, non-asthma specific A&E attendances (per 100
person-years) was almost 3-times greater in the uncontrolled group,
compared to the controlled group (69.8 vs 25.6) (Table S5 in the online
supplementary material).
4. Discussion
To the best of our knowledge, our study is the largest cohort study
R. Buhl et al.
Fig. 3. (continued).
investigating the outcomes of asthma patients in primary care who were
initiated on medium- or high-dose ICS-LABA, a preferred treatment
option for step 4 patients by the latest GINA document [5]. Our data
provide evidence on the current clinical practice in the UK and improve
our understanding of patients’ asthma control and physicians’ attitudes
in the primary care setting.
Our study results showed that, despite receiving guideline-
recommended treatments, many patients in UK primary care remain
uncontrolled. Our data are consistent with other real-world studies
showing that 30–50% of asthma patients continue to experience poor
control of their symptoms or exacerbations. Our study showed addi­
tionally that the overall adherence to medium- or high-dose ICS-LABA is
6
Respiratory Medicine 162 (2020) 105859
low; however, adherence does not seem to be a main factor for the
medium or high-dose ICS-LABA treatment failure.
Among the uncontrolled patients in both cohorts, about 70% were
highly adherent. The high adherence in these uncontrolled patients
might be reflective of their higher symptom burden and disease severity,
both actual and perceived. Higher adherence may also suggest their
greater dependency on asthma medication for controlling their symp­
toms. While examining patients’ adherence to their asthma medication
is important during their clinical visit, physicians should not neglect the
refractory nature of asthma and step up patients to appropriate treat­
ments on time. We were also able to identify treatment pathways for
step-up and step-down from medium/high doses of ICS-LABA,
R. Buhl et al.
contributing to our understanding of asthma management in primary
care in the UK.
The physicians’ top choice of adding LTRA or LAMA to patients
uncontrolled on medium-dose ICS-LABA is supported by some evidence
from previous randomized controlled trials suggesting that the addition
of tiotropium or LTRA to ICS-LABA may reduce asthma exacerbations
and/or improve asthma control in patients with uncontrolled asthma
[9–12]. However, a recent meta-analysis has suggested that the addition
of a LAMA to ICS-LABA combinations provides a modest improvement
in lung function but does not reduce asthma exacerbations [13]. The
existing evidence base creates challenges for physicians to choose an
appropriate step-up option in patients uncontrolled on
medium/high-dose ICS-LABA. Among 1,046 patients who were uncon­
trolled in the medium-dose ICS-LABA cohort and stepped up to
high-dose ICS-LABA, 34.9% patients remained uncontrolled. This sug­
gests that some moderate-to-severe asthma patents are less responsive to
steroids. Increased ICS dose did not result in asthma control. Interest­
ingly, we observed more than 15 different treatment pathways for
managing patients with uncontrolled asthma in medium- or high-dose
ICS-LABA. This indicates that the current evidence base does not pro­
vide clarity on how to step-up asthma medications post ICS-LABA,
creating challenges for physicians in deciding step-up treatment op­
tion. Studies identifying responders to specific treatment options are
certainly needed.
Our study also shows approximately 41% of uncontrolled patients in
the medium-dose and 31% in the high-dose ICS-LABA cohort had no
treatment step-up, and these were patients who experienced severe ex­
acerbations and/or had excessive use of SABAs. This finding suggests
that physicians and patients may have a poor perception of asthma
control. This is supported by the findings from a cross-sectional UK study
comparing patient and healthcare professionals’ (HCP) assessment of
asthma control with validated Asthma Control Test (ACT) scores. This
study demonstrated that high proportions of patients and HCPs had
incorrect perceptions of asthma control, especially in relation to asthma
patients in step 4 and 5. The global asthma physician survey (GAPS) [14]
revealed that there is a high variance in physician practices for assessing
asthma control across all countries included in GAPS. In these countries,
use of validated patient-reported questionnaires was very low, and there
was a noticeable discrepancy between the measurements recommended
by GINA and those used in clinical practices. These studies together with
the findings from our study suggest there is a great room for improve­
ment in physicians’ assessment of asthma control.
In the current study, patients with uncontrolled asthma tended to be
older, with a history of smoking and were more likely to have had pre-
index exacerbations as well as multiple comorbidities including
ischemic heart disease, rhinosinusitis, depression and anxiety. These
findings concur with the evidence from the previous reports [2,15],
suggesting that uncontrolled patients represent a more medically
“at-risk” group with a higher rate of exacerbations and are therefore
more susceptible to the negative consequences of poor disease control.
Our investigation of healthcare resource utilization of asthma pa­
tients showed similar results to previous reports [3,4]. As expected,
healthcare resource utilization was higher among uncontrolled asthma
patients in both medium- and high-dose ICS-LABA groups. Uncontrolled
patients also had significantly higher rates for all-cause healthcare uti­
lization related items, compared with controlled patients.
Asthma-specific hospitalizations accounted for approximately 38% of all
hospitalizations in the medium- and high-dose ICS-LABA cohorts and
reached up to 50% among patients who were adherent to treatment.
This clearly shows the high burden of asthma to the health care system.
As a retrospective study, our study has a few limitations. Our results
suggest that a significant proportion of adherent patients (with a MPR �
80%) were refractory to treatment with ICS-LABA. MPR is a rather crude
measure of adherence. Use of EMR data precludes evaluation of inha­
lation techniques in these patients, which play a significant role in
ensuring effective drug delivery. In this study, exacerbations were
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Respiratory Medicine 162 (2020) 105859
defined based on a previous report [8]. In the real-world practice setting,
patients may visit GP or the ER department for their worsening condi­
tion due to multiple reasons, which may not reflect the severity of their
exacerbations. Furthermore, findings of this analysis reflect asthma
control status in UK primary care and cannot be generalized to other
populations.
5. Conclusions
A significant proportion of patients newly initiated to medium- or
high-dose ICS-LABA therapy remain uncontrolled and at risk of exac­
erbation even when adherent to these treatments, highlighting the need
for timely assessment of asthma control and treatment adjustment.
Healthcare resource utilization was higher in uncontrolled patients
compared with controlled patients. Addition of a controller such as
LAMA or LTRA was preferred by physicians as a step-up strategy for
uncontrolled patients, however the multiple treatment pathways fol­
lowed by practicing primary care physicians suggest that more evidence
is needed to support treatment decisions on top of medium-/high-dose
ICS-LABA.
Authors’ contributions
All authors contributed to the interpretation of the data and the
writing and reviewing of all drafts of the manuscript. All authors
approved the final version to be published and agree to be accountable
for all aspects of this work.
Funding
This study was funded by Novartis Pharma AG, Basel, Switzerland.
Data disclosure statement
Novartis is committed to sharing with qualified external researchers,
access to patient-level data and supporting clinical documents from
eligible studies. These requests are reviewed and approved by an inde­
pendent review panel on the basis of scientific merit. All data provided is
anonymized to respect the privacy of patients who have participated in
the trial in line with applicable laws and regulations. This trial data
availability is according to the criteria and process described on www.
clinicalstudydatarequest.com.
Declaration of competing interest
RB reports personal fees from AstraZeneca, Chiesi, GSK and Teva,
and grants and personal fees from Boehringer Ingelheim, Novartis and
Roche. LGH has received grants from Northern Ireland Chest, Heart &
Stroke Association and Genentech; has consultant arrangements with
Hoffman la Roche, AstraZeneca, Novartis, GlaxoSmithKline, and TEVA;
has received grants from/has grants pending with Novartis UK, Roche/
Genentech, MedImmune, and GlaxoSmithKline; has received payment
for lectures, including service on speakers’ bureaus, from Hoffman la
Roche, Novartis, and TEVA; and has received travel/accommodation/
meeting expenses unrelated to activities listed from AstraZeneca,
Boehringer Ingelheim, GlaxoSmithKline, TEVA, Chiesi, and Napp. EL
and HC are employees and shareholders of Novartis. KK and ML were
employees of Novartis Pharma AG at the time of conduct of the study. KK
has received grants and/or personal fees from AstraZeneca, Boehringer
Ingelheim, Chiesi, ELPEN, Innovis and Novartis. VC was an employee of
Novartis.
Acknowledgements
Editorial and writing support was provided by Santanu Bhadra, PhD,
Archana Jayaraman, PhD, and Rahul Lad, PhD (Novartis), funded by
R. Buhl et al.
Novartis AG, Basel, Switzerland in accordance with Good Publication
Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.rmed.2019.105859.
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