Comparison add-on efficacies of formoterol and tulobuterol on budesonide
inhalation in elderly patients with asthma
Short title
Additional effects of Formoterol or Tulobuterol on budesonide for
elderly with asthma
Declarations of interest
The authors declare that they have no conflict of interest.
Abstract (232 words)
For asthma strategy, to avoid the aggravation of bronchial inflammation
and contraction, the long acting beta agonist (LABA) addition on inhaled
corticosteroids (ICS) has been recommended. To know whether there is any
clinical difference between the additional efficacies of formoterol
(FOR) and tulobuterol (TUL) onto budesonide (BUD) may be useful for the
elderly patients’ asthma treatment strategy. 18 outpatients with mild to
moderate bronchial asthma with FEV1.0% < 80% treated by
intermediate ICS dosages visited Respiratory Division of Nagasaki
University Hospital or Isahaya General Hospital, Japan Community Health
care Organization were subjected, and were randomly assigned (9 cases
per group) to either the FBC group (BUD/FOR 160/4.5 µg, 2 inhalations
twice daily) or BUD + TUL group (BUD 200 mcg: 2 inhalations twice daily
+ TUL 2mg daily) and were compared in parallel with 2 arms for 12 weeks
prospectively. Peak expiratory flow, forced expiratory volume in 1
second, impulse oscillometry (IOS), fractional exhaled nitric oxide
(FeNO), Asthma Control Questionnaire, mini-Asthma Quality of Life
Questionnaire (mini-AQLQ), and occurrence of adverse reactions were
compared. The “Fres” of IOS was improved in FBC group (p=0.03). The
“emotion” domain of mini-AQLQ was improved in BUD+TUL group (p=0.03).
By changing the drug formulation, the patch was superior in terms of
satisfaction, but it was thought that the inhaled combination was
superior in improving the respiratory function itself. It is necessary
to pay attention to the characteristics of the patient when selecting
treatment.
Keywords
bronchial inflammation, forced expiratory volume in 1 second (FEV1),
fractional exhaled nitric oxide (FeNO), impulse oscillometry (IOS),
mini-Asthma Quality of Life Questionnaire (mini-AQLQ), prospective
study, transdermal delivery system
Introduction
Because the essential pathology of bronchial asthma is bronchial
inflammation and airway smooth muscle contraction, inadequate treatments
result in increased airway hyperreactivity and future exacerbations due
to remodeling and/or smooth muscle hypertrophy (1, 2). The long acting
beta agonist (LABA) addition on inhaled corticosteroids (ICS) has been
recommended in Step2 onward to treat the bronchial inflammation and
contraction. Though ICS and LABA combination inhalation therapy has an
advantage as these materials goes to almost same area in the airways (3,
4), of which effects would be insufficient without adequate inhalation
technique, e.g. elder patients with lower respiratory function. Even for
such patients, the use of systemic steroids as a substitute for ICS
should be avoided in terms of adverse effects (5). Regarding LABA, the
tulobuterol patch (HokunalinTM Tape; TUL) with the
transdermal delivery system has been used for control of asthma and
chronic obstructive pulmonary disease (COPD) in Japan, Korea, and China
(6). This patch prevents excessive increase of the concentration in
blood that is useful to reduce the systemic adverse reactions (7, 8).
There are several studies reported the additional efficacies of TUL and
salmeterol (SAL) onto fluticasone propionate (FLU) inhalation (9-11),
and the results were inconsistent. There are little studies compared the
additional efficacies of TUL and formoterol (FOR), an LABA inhalation
onto budesonide (BUD) inhalation, an ICS. Because FOR/BUD combination
inhalation is quite popular for asthma control and BUD is known as an
ICS with less side effects (3, 4), to know any clinical difference
between the additional impacts efficacies of FOR and TUL onto BUD may be
useful for the elderly patients’ asthma treatment strategy. We compared
these strategies by a randomized prospective study with 2 arms for 12
weeks.
Methods
Subjects
In this study, 18 elderly outpatients 65 years of age or older, with
mild to moderate bronchial asthma, with FEV1.0% < 80%
treated by intermediate ICS dosages visited Respiratory Division of
Nagasaki University Hospital or Isahaya General Hospital, Japan
Community Health care Organization (JCHO) were recruited (Table 1). All
included patients fulfilled the Global Initiative for Asthma (GINA)
criteria (1), and had a history of asthmatic symptoms, including cough,
wheezing, or dyspnea (mean (SD) age was 72.8 (6.2), female/ male = 9/ 9,
Non-smoker/ Ex-smoker/ Current smoker = 7/ 11/ 0). All patients had no
findings of COPD on Chest X ray or high resolution CT. All patients
retained normal diffusion capacity. Anti-asthma drugs were discontinued
for at least 24 h prior to each examination. The intermediate dosages of
ICS were defined as follows: 1) SAL/FUL combination, 200 to 500 μg/ day
or 2) BUD, 400 to 800 μg/day; becromethason, FUL, cicresonide, or
mometasone, 200 to 400 μg/day. The ethics committee of Nagasaki
University Hospital approved this study protocol (#11042549), and all
the participants received verbal and written information and provided
the informed consent.
Study protocol
Subjects were randomly assigned to either the FBC group (n = 9, BUD/FOR,
160/4.5 µg, 2 inhalations twice daily) or BUD + TUL group (n = 9, BUD
200 µg, 2 inhalations twice daily + TUL 2 mg daily) and these groups
were compared. The treatment period was 12 weeks and the BUD dose of
both groups were set as equal. The short-acting inhaled β2-agonists
(SABA) was permitted to be used as needed (Fig1).
At the start of the study, a full medical interview was given and a
physical examination was performed. No patients had abnormal
electrocardiogram findings. During a 2 week run-in period, they were
asked to keep a daily diary card. This card was for record morning and
evening peak expiratory flow (PEF), symptom score and the rescue use of
SABA inhaler.
Measurements
PEF, forced expiratory volume in 1 second (FEV1), impulse oscillometry
(IOS), fractional exhaled nitric oxide (FeNO), Asthma Control
Questionnaire (ACQ) and mini-Asthma Quality of Life Questionnaire
(mini-AQLQ), and occurrence of adverse reactions were observed.
Pulmonary function test
Spirometry was measured using a Chestac-8900 (Chest Co., Ltd., Japan).
For the predicted values of FEV1 and vital capacity
(VC), the reference data developed by the Japanese Respiratory Society
were taken as the standard value (12).
Forced oscillation technique
The factors of IOS were measured using a forced oscillation technique
device (MostGraph-01; Chest Co., Ltd,) (13). During tidal breath about
60 seconds in the sitting position, respiratory impedance were measured.
To reduce upper airway shunting, the subject’s cheeks and mouth floor
were supported by the patient’s both hands. The levels of Rrs at 5 Hz
(R5), Rrs at 20 Hz (R20), the difference between R5 and R20 (R5–R20),
Xrs at 5 Hz (X5), resonant frequency (Fres), and also the differences of
the mean Rrs and Xrs in the expiratory phase to those in the inspiratory
phase were evaluated. Whole-breath analysis and within-breath analysis
were performed by programmed software automatically. These forced
oscillation technique measurements were performed prior to other
pulmonary function tests.
FeNO
FeNO was measured by portable sensor (NIOX MINO; Aerocrine AB, Solna,
Sweden) according to ATS/ERS recommendations on measurements of FeNO
(14), and the results were expressed as parts per billion. The
participants were asked to inhale through the device and exhale steadily
for 10 seconds at a flow rate of 50 ml/s and at a pressure of 10 cm
H2O. The measurements were done in a sitting position.
ACQ and mini-AQLQ
ACQ is a survey for asthma control contains seven items about limitation
due to asthma measured on a 7-point scale, from 0 (no impairment) to 6
(extreme impairment), using the past 7 days recall. The mean score
<= 0.75 was classified as “well controlled”,
>=1.5 as “uncontrolled”, and between these points as
“somewhat controlled”. A Minimal Clinically Important Difference
(MCID) of 0.5 was used (15).
Mini-AQLQ is simplified version with 15 questions with four domains
(symptoms, activities, emotions, and environment) from original AQLQ
with 32 questions, and ask each question to have “1” if there is a
serious impairment and “7” if there is no problem at all. The mean
score of ≥1.5 indicates uncontrolled asthma and <1.5 indicates
well controlled asthma. The MCID is a mean change in this mean score of
greater than 0.5 (16).
Evaluation of the treatment effects
The changes of the each factor (Δ factor) was defined by subtracking the
value of Visit 1 from that of Visit 4.
Statistical analysis
Mann-Whitney test was used for comparison of the background factors and
the changes of the factors (Δ factor) between the groups. The p-value
< 0.05 was considered as significant difference.
Results
Patient demographics
Regarding age, sex, classification of disease (atopic or non-atopic),
severity, ACQ, AQLQ, spirometry, FeNO, and IOS parameters, there were no
significant differences between the groups (Table 1).
The changes of parameters in ACQ, AQLQ, spirometry, FeNO, and IOS
3 cases (1 of FBC group and 2 of BUD+TUL group) had to use systemic
steroids within 2 weeks after the commencement of the study and
discontinued the trial. The remaining 15 cases were subjected for
efficacy analysis. The ”Fres” of IOS was improved (p=0.03) in FBC group.
The ”emotion” domain of AQLQ was improved (p=0.03) in BUD+TUL group
(Table 2). There were no differences between the groups in the changes
of each factor of ACQ, spirometry, or FeNO.
Adverse events
No drug-related adverse reactions were noted in both groups.
Discussion
In this study, FBC group had better improvement on ”Fres” of IOS
indicators, and BUF+TUL group had better improvement on ”emotion” domain
of mini-AQLQ. It may be suggested the characteristics of the additional
effects of each drug (FOR and TUL) differ.
By adding FOR to BUD (equal to FBC inhalation), the “Fres” associated
with large and small airway resistance was improved significantly (p =
0.03). FOR is a LABA and provides sustained action for 12 hours which
needs to be inhaled twice a day (17). It is reasonable for most patients
who can inhale the medicine properly, the ICS/LABA combination will be
suitable for asthma control (18).
In contrast, adding TUL to BUD improved ”emotion” domain significantly
(p = 0.03). Previously, the improvement of asthma control status of
patients with adult-onset mild to moderate asthma by additional TUL on
FLU inhalation was reported (9), and additional effect of TUL on
leukotriene receptor antagonist in children with asthma was also
reported (10). The efficacy of TUL addition to BUD inhalation was
firstly found by this study.
Other studies, however, reported that SAL addition achieved better
control after switching from TUL addition in asthmatic patients with FLU
treatment (10), or that SAL addition on FLU improved morning and evening
PEF rates and AQLQ score but TUL addition did not, in patients with
asthma on ICS therapy in 8 weeks observation (11). In our study, we have
found the addition of TUL or FOR on BUD respectively showed
characteristic improvements on “Fres” or “mini-AQLQ”.
For the patients with typical asthma, respiratory functions are most
severely suppressed from midnight to early morning, and it is called as
morning dip (19). Suppression of this morning dip may improve the
patient’s QOL. The therapeutic adherence of the TUL patch was
significantly higher than that of other inhaled drugs, as the patch was
easy to use and was applied once a day (6). TUL patch prolongs the
drug’s action to 24 hours, which may improve the circadian rhythm (8,
20). Improvements of QOL or treatment adherence are very important point
for chronic disease including asthma (21). Regarding the change in FeNO,
there was no difference between the groups, and the BUD dose was
consistently the same in both groups, so this was understandable.
In the study, there are some limitations. Firstly, the patients were
recruited from the asthma specialist outpatient department, which might
induce any bias compared with general medical clinics, and the numbers
were very small. Secondly, because the TUL may suppress the Rhinovirus
infection (22) and may be effective on upper respiratory tract infection
symptoms (23), the setting period include the winter season and for at
least half year might be desired.
In conclusion, by changing the drug formulation, the patch was superior
in terms of patients’ satisfaction, but it was thought that the inhaled
combination was superior in improving the respiratory function itself.
It is necessary to pay attention to the characteristics of the patient
when selecting treatment.
Acknowledgement
We would like to thank the physicians, patients, and volunteers for
participating in this study. This research was supported by a research
grant from the Non-profit Organization Aimed to Support Community
Medicine Research in Nagasaki.
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