The effect of indacaterol during an acute exacerbation of COPD

Andrea Segreti
a
, Enrica Fiori
b
, Luigino Calzetta
c
, Marco Sabatini
b
, Vincenzo Segreti
b
,
Paola Rogliani
a
, Mario Cazzola
a,
*
a
Department of System Medicine, University of Rome Tor Vergata, Rome, Italy
b
Emergency Department and Observation Medicine Unit, Santo Spirito Hospital, Rome, Italy
c
Department of Pulmonary Rehabilitation, San Raffaele Pisana Hospital, IRCCS, Rome, Italy
a r t i c l e i n f o
Article history:
Received 4 February 2013
Received in revised form
16 March 2013
Accepted 29 March 2013
Keywords:
COPD
Exacerbation
Indacaterol
Salbutamol
a b s t r a c t
Some clinical trials have suggested that the inhaled long-acting b
2
-agonists (LABAs) may be effective in
the treatment of acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Since inda-
caterol, the rst once-daily LABA to be developed for the regular treatment of COPD, exhibits fast onset of
action and 24-h duration of bronchodilation, we have investigated its effects in patients with AECOPD
managed in the emergency department.
In a randomised controlled pilot trial, we have enrolled 29 consecutive patients with a recent
(i.e., within 4 d) history of AECOPD and requiring hospitalization. All patients received a standard
protocol consisting of ipratropium bromide aerosol 500 mg three times a day, intravenous methylpred-
nisolone 20 mg twice-daily and, if indicated, oral levooxacin 500 mg once-daily. Moreover, they were
randomly allocated to one of the two 5-day treatment groups (indacaterol maleate 300 mg once-daily or
salbutamol nebulizer 1250 mg three times a day).
The administration of indacaterol 300 mg to patients admitted to emergency department for an
AECOPD resulted in a greater improvement of pulmonary function compared with traditional therapy,
without cardiovascular side effects.
Our results suggest that indacaterol could be a useful option in the treatment of AECOPD. However,
further larger double-blinded randomized clinical trials are needed to validate the intriguing results
obtained in this setting.
2013 Elsevier Ltd. All rights reserved.
1. Introduction
Patients with acute exacerbations of chronic obstructive
pulmonary disease (AECOPD) managed in the emergency depart-
ment must be treated proactively to prevent rapid respiratory
deterioration [1]. All guidelines recommend using bronchodilators
because they relieve dyspnoea and airow obstruction during
exacerbations [2,3]. Nebulizers and hand-held inhalers can be used
to administer inhaled bronchodilators during AECOPDs and the
choice of delivery method should consider the ability of the patient
to use the device and the dose of drug required [1e3].
Short-acting inhaled b
2
-agonists (SABAs) are usually the
preferred bronchodilators for the initial treatment of AECOPD [2,3].
There is a great deal of controversy regarding the timing and
optimal dose of inhaled b
2
-agonists in the treatment of AECOPD.
Regrettably, the duration of the bronchodilator effect of SABAs is
decreased in AECOPD [4]. In order to overcome the reduced func-
tional half-life of b
2
-agonists, several authors have suggested the
use of larger-than-usual doses that are sometimes necessary to
relieve airway obstruction, but also to dose more frequently [5,6].
The use of LABAs has been suggested as another potential option
to overcome the reduced functional half-life of b
2
-agonists in
AECOPD [7]. Our group has previously demonstrated that for-
moterol can be considered an alternative to SABAs in the treatment
of AECOPD due to its fast onset of action that further increases by
increasing the inhaled dose [8].
Indacaterol is the rst once-daily LABA for the regular treatment
of COPD [9]. In patients with stable moderate-to-severe COPD,
single doses of indacaterol 150 and 300 mg demonstrated a fast
onset of action similar to that for salbutamol 200 mg [10].
In consideration of the fast onset of action exhibited by inda-
caterol and its duration of bronchodilation, we have investigated
the effects of this once-daily LABA in patients with AECOPD
managed in the emergency department.
* Corresponding author. Unit di Farmacologia Clinica Respiratoria, Dipartimento
di Medicina dei Sistemi, Universit di Roma, Tor Vergata, Via Montpellier 1, 00133
Rome, Italy.
E-mail address: mario.cazzola@uniroma2.it (M. Cazzola).
Contents lists available at SciVerse ScienceDirect
Pulmonary Pharmacology & Therapeutics
j ournal homepage: www. el sevi er. com/ l ocat e/ ypupt
1094-5539/$ e see front matter 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.pupt.2013.03.020
Pulmonary Pharmacology & Therapeutics 26 (2013) 630e634
2. Methods
2.1. Patients
Twenty-nine consecutive patients with a recent (i.e., within
4 d) history of AECOPD and requiring hospitalization according to
their attending physician were enrolled in the study. COPD was
diagnosed, and its severity was assessed in accordance with the
2006 guidelines of the Global Initiative for Chronic Obstructive
Lung Disease [11]. The study was carried out at the Emergency
Department of Santo Spirito Hospital in Rome fromSeptember 2011
to April 2012 according to Good Clinical Practice and the Declara-
tion of Helsinki. Each patient gave informed consent for
participation.
Patients with cor pulmonale, pneumonia, diabetes mellitus,
renal failure, lung cancer, atherosclerotic or congenital cardiac
disease, left ventricular failure, need for non invasive mechanical
ventilation, or inability to perform spirometry due to poor clinical
conditions within 24 h of emergency admission were excluded.
Patients were also excluded if they had a personal history of
asthma, allergic rhinitis, or atopy.
2.2. Methods
This was a non-blinded, randomised, controlled pilot trial. We
must highlight that our study was spontaneous, without any nan-
cial and organizational support of Pharma Companies. Therefore, it
was impossible for us to prepare treatments to be administered in
double-blind, double-dummy fashion. After consenting to participate
inthe study, consecutive eligible patients were randomly allocated to
one of the two treatment groups (groupAand B) using the sequential
randomization scheme ABA. Group A received inhaled indacaterol
maleate 300 mg once a day administered before the spirometry and,
in the following days, at 8 AM using Breezhaler device. Group B
received salbutamol nebulizer 1250 mg three times a day.
All patients also received therapy with ipratropium bromide
aerosol 500 mg three times a day, intravenous methylprednisolone
20 mg twice day and oral levooxacin 500 mg once a day. These
drugs and salbutamol nebulizer 1250 mg three times a day are the
usual therapeutic regimen at the Emergency Department of the
Santo Spirito Hospital in Rome for treating patients suffering from
AECOPD.
All participants underwent clinical and radiological examina-
tions, pulmonary function testing, arterial blood gas analysis, and
echocardiographic assessment. Plasma levels of Brain Natriuretic
Peptide (BNP), troponin I, creatinine, and C-reactive protein (CRP)
were measured. All examinations were carried out at admission
(T0) and day 5 (T5).
At day 5, pulmonary function testing was carried out 24 h or 8 h
after the last administration of indacaterol or salbutamol,
respectively.
2.3. Statistical analysis
Inplanning this trial there were a number of uncertainties, mainly
the feasibility of the study, the sample size required, and the consent
rate. Therefore, we decided to undertake a pilot study to test as many
elements of the researchproposal as possible. Thus, no formal sample
size calculations were done. Statistical analysis was conducted using
GraphPad Prism (CA, USA) and SPSS (Chicago, IL, USA) software. The
values of the variables were expressed as mean and 95% condence
interval (95%CI) andthedifferencebetweenT0andT5was considered
statistically signicant for P < 0.05, employing the Students t-test
and/or the analysis of variance (ANOVA) associated, when necessary,
with the Bonferroni post hoc test.
3. Results
Twenty-nine patients with COPD exacerbation were enrolled, 19
were treated with indacaterol (armA) and 10 with salbutamol (arm
B) (Table 1). The gender distribution was 58.62% (17) males and
41.38% (12) females. There were no statistically signicant differ-
ences in the study population with respect to age (average 75.9
years, 95% CI 73.2e78.5) and BMI (average 28.2, 95% CI 25.8e30.6).
All patients completed the study. There was not statistically sig-
nicant difference (p > 0.05) between the two treatment arms
(salbutamol and indacaterol) at T0 (baseline, before treatment) with
regard to variables considered in this study but BNP concentration,
which was signicantly higher in salbutamol arm (P < 0.001).
In the salbutamol arm, after 5 days of treatment, respiratory rate
signicantly improved (Table 3). The changes in all other respira-
tory variables did not reach statistical signicance (P > 0.05) (Fig. 1,
Table 1).
In the indacaterol arm, after 5 days of treatment (T5), lung
function improved signicantly (P < 0.05) from baseline (Fig. 1).
Also other variables such as respiratory rate, pO
2
and pO
2
/FiO
2
improved in a statistically signicant manner (Table 2).
In both groups we observed a reduction of pCO
2
values and an
improvement of arterial pH but these changes did not reach sta-
tistical signicance (P > 0.05) (Table 2).
Heart rate was stable during both treatments (Table 3). After 5
days, a reduction of troponin I was reported in both arms, but the
change in both arms was not statistically signicant (P > 0.05)
(Table 4). Levels of serum BNP were signicantly reduced
(P < 0.001) in the population B (salbutamol) while there was a not
signicant reduction in the population A (indacaterol) (Table 4).
However, the baseline BNP levels in the salbutamol arm were
signicantly higher than in the indacaterol arm.
No modication of echocardiographic parameters (Table 3) and/
or sings of acute coronary syndrome were recorded during treat-
ment in either treatment arm.
However, in one patient treated with indacaterol, an episode of
paroxysmal atrial brillation was reported, which regressed spon-
taneously after 6 h and in conjunction with the improvement of the
respiratory condition. The administration of indacaterol was not
suspended, as we did not assign any causal relationship between
the drug and the onset of the arrhythmia.
4. Discussion
Our study suggests that indacaterol could be a useful option in
the treatment of AECOPD. This is a novel nding and, to the best of
our knowledge, the present trial is the rst that has evaluated the
effect of indacaterol in patients suffering from an AECOPD.
In our study, 5-day therapy with indacaterol 300 mg o.d.
signicantly improved pulmonary function. Furthermore, indaca-
terol reduced respiratory rate and, more importantly, improved
pO
2
/FiO
2
ratio, suggesting an amelioration of ventilation-perfusion
ratio. It is noteworthy that the improvements in pulmonary func-
tion and respiratory exchanges were more marked in the
Table 1
Anthropometric characteristics of the studied patients. Regardless of gender, all
values are mean and 95% condence interval.
Indacaterol Salbutamol
Gender F 10 M 9 F 2 M 8
Age 75.37 (72.59e78.15) 76.80 (71.13e82.47)
Weight 78.37 (69.54e84.19) 73.00 (65.57e80.43)
Height 164.32 (159.90e168.73) 166.40 (162.13e170.67)
BMI 29.18 (25.80e32.56) 26.38 (23.80e28.95)
F, female; M, male; BMI, Body mass index.
A. Segreti et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 630e634 631
indacaterol arm compared with the salbutamol arm. In fact, in
patients treated with salbutamol, improvements in pulmonary
function (through-FEV
1
% e PEF%) and pO
2
/FiO
2
ratio did not reach
statistical signicance.
AECOPD represent an increased burden to the heart, and
myocardial injury with release of cardiac-specic troponin may
occur [12]. Clinical safety of b
2
-agonists in COPD is an issue widely
discussed in literature [13]. Patients affected by COPD may be at
increased risk of cardiovascular complications because this disease
Fig. 1. Inuence of a 5-day treatment with salbutamol (A and C) or indacaterol (B and D) on the through forced expiratory volume in the 1st second (FEV
1
), forced vital capacity
(FVC), peak expiratory ow (PEF) expressed in litres and %predicted, and FEV
1
/FVC ratio. *P < 0.05 vs T0.
Table 2
Inuence of a 5-day treatment for with salbutamol or indacaterol on respiratory
rate, partial pressure of oxygen (pO
2
), partial pressure of CO
2
(pCO
2
), pH and the
ratio between partial pressure of oxygen and fractional inspired oxygen concen-
tration (pO
2
/FiO
2
).
T0 T5
Mean Lower
limit
Upper
limit
Mean Lower
limit
Upper
limit
Salbutamol population
Respiratory rate 37.20 33.78 40.62 26.80*** 23.33 30.27
pO2 (mmHg) 70.60 51.58 89.62 71.40 64.34 78.46
pCO
2
(mmHg) 59.90 48.31 71.49 51.30 44.52 58.08
pH 7.35 7.30 7.40 7.39 7.37 7.42
pO
2
/FiO
2
252.87 200.01 305.74 319.86 272.81 366.90
Indacaterol population
Respiratory rate 32.53 29.38 35.67 23.35*** 20.59 26.12
pO
2
(mmHg) 62.68 57.54 67.83 73.00** 68.35 77.65
pCO
2
(mmHg) 49.74 42.53 56.94 44.00 40.27 47.73
pH 7.38 7.34 7.42 7.41 7.39 7.42
pO
2
/FiO
2
288.65 259.57 317.73 340.91* 316.30 365.51
Values are mean and 95% condence interval. *P < 0.05, **P < 0.01 and ***P < 0.001
vs T0.
Table 3
Inuence of a 5-day treatment with salbutamol or indacaterol on heart rate,
tricuspid annular plane systolic excursion (TAPSE), pulmonary artery pressures
(PAPS), pulmonary artery occlusion pressure (PAOP) and ejection fraction (EF).
T0 T5
Mean Lower
limit
Upper
limit
Mean Lower
limit
Upper
limit
Salbutamol population
Heart rate 80.10 69.40 90.80 70.50 66.26 74.74
TAPSE (mm) 24.00 20.23 27.77 23.17 18.77 27.56
PAPS (mmHg) 40.63 30.03 51.22 39.83 32.51 47.16
PAOP (mmHg) 9.20 8.04 10.36 9.92 8.17 11.68
EF (%) 53.56 48.01 59.10 55.14 46.32 63.96
Indacaterol population
Heart rate 87.26 80.08 94.44 80.12 73.62 86.62
TAPSE (mm) 21.69 18.85 24.54 21.31 17.67 24.94
PAPS (mmHg) 35.79 30.66 40.91 41.45 38.85 44.06
PAOP (mmHg) 13.05 11.49 14.62 13.07 9.86 16.28
EF (%) 60.94 57.56 64.32 58.42 53.84 63.00
Values are mean and 95% condence interval. All values at T5 were non-signicantly
different (P > 0.05) vs T0.
A. Segreti et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 630e634 632
amplies the impact of b
2
-agonists on the heart and, unfortunately,
is a confounding factor when this impact is evaluated [13]. In
particular, the proarrhythmic effects of b
2
-agonists may be ampli-
ed by hypoxaemia and acidosis [14].
In our study, troponin I levels remained stable during treatment
in both groups and no event of acute coronary syndrome occurred
in both arms. This is an important nding because it has been
shown that many patients hospitalised for AECOPD have elevated
troponin levels [15], and troponin elevation has been associated
with worse prognosis [16]. In fact, in this setting, hypoxia and
tachycardia may result in an imbalance between oxygen demand
and delivery, causing a type 2 myocardial infarction [15]. This risk
must always be considered when prescribing b
2
-agonists to a pa-
tient suffering from AECOPD because the administration of b
2
-ag-
onists to patients with airways obstruction usually results in an
increase in heart rate [14] and often in a transient decrease in their
PaO
2
despite concomitant bronchodilation [17].
As above-mentioned, a patient treated with indacaterol experi-
enced an episode of paroxysmal atrial brillation, but this episode
ended spontaneously 6 h after its clinical onset and in conjunction
with the improvement in respiratory state. Although results from a
meta-analysis of 33 randomized placebo-controlled trials evaluating
the arrhythmogenic potential of b
2
-agonists suggest that inhaled b
2
-
agonists have a potential to increase heart rate and the incidence of
ventricular arrhythmias in patients with obstructive airway disease
[18], the administration of indacaterol was not discontinued because
the onset of the episode of paroxysmal atrial brillation was asso-
ciated with the presence of respiratory failure with hypoxaemia and
acidosis, and we assumed that there was not a causal relationship
with indacaterol administration.
Our nding corroborates those of analyses of pooled safety data
from recent clinical trials with indacaterol that also evaluated the
cardiac safety of this b
2
-agonist in stable COPD[19,20]. In particular,
Holter monitoring in patients chronically treated with indacaterol
did not showany increased incidence of arrhythmic episodes when
compared to traditional therapies [19].
The available data suggest that in COPD patients experiencing
an exacerbation the prevalence of left ventricular systolic
dysfunction is common [21]. In patients with left ventricular
systolic dysfunction, sympathetic activation is an important part
of the pathophysiologic mechanism in the progression of disease
[22]. A limited number of studies suggested that oral and inhaled
b
2
-agonists do seem to increase the risk of mortality and number
of heart failure exacerbations in patients with left ventricular
dysfunction [23,24]. For this reason, it has been suggested that
clinicians should consider evaluation for the possibility of
worsening heart failure in patients with known left ventricular
systolic dysfunction taking high doses of inhaled b
2
-agonists
[22,24], also because the adverse effects of b
2
-agonists are likely
to be exacerbated in COPD patients with coexistent chronic heart
failure [25].
Recognising heart failure in COPD patients, particularly in acute
settings, remains a clinical challenge, but monitoring of changes in
plasma BNP may provide an important method for assessing ven-
tricular function [26]. Plasma concentrations of BNP are elevated
when patients experience AECOPD [26,27]. Our study documented
that both treatments were able to induce a rapid reduction in BNP
levels, although the fall on the fth day was signicantly greater in
the group treated with salbutamol. We do not believe that the
differential impact of salbutamol compared with indacaterol has a
real clinical signicance. As already highlighted, the plasma basal
BNP levels were higher in the salbutamol group compared
with indacaterol group. This difference due to chance, i.e. chance
maldistribution, was an unintended consequence of allocation
concealment that we have followed.
It is not easy to explain why there has been a decrease in BNP
levels in our patients. The most plausible hypothesis is that both
drugs have been able to inuence the pulmonary haemodynamics.
This is only a hypothesis because there are still no studies that have
examined the potential vasodilating effect of indacaterol on pul-
monary circulation. In any case, a small trial on the acute effects of
inhaled LABAs in patients with COPD has clearly shown that these
agents are able to elicit benecial acute effects on pulmonary
haemodynamics [28].
However, since echocardiography appears more reliable than BNP
levels to detect unsuspected left ventricular systolic dysfunction in
patients with stable COPD [29] and also to document an effect of
indacaterol and salbutamol on pulmonary circulation, we also
included in our study an echocardiographic assessment before and
after 5 days of therapy with particular regard to those parameters
that express the function and the workload of the right ventricle. We
were unable to record variations of these parameters during both
treatments and, consequently, we cannot conrm our hypothesis.
Alternatively, we can suggest that both bronchodilators were
able to cause an attenuation of air trapping, leading to a reduction
of intrathoracic pressure, including pressure on the whole heart,
and, consequently, to an improvement of right ventricular overload
and left ventricular diastolic dysfunction. Unfortunately, we did not
evaluate the impact of indacaterol and salbutamol on pulmonary
hyperination.
We must highlight that the lowand unequal number of patients
in each separate group might not have allowed obtaining statisti-
cally meaningful differences in many explored parameters. None-
theless, the administration of indacaterol 300 mg to patients
admitted to emergency department for AECOPD resulted in a
greater improvement of pulmonary function compared with tradi-
tional therapy without cardiovascular side effect. Therefore, it canbe
argued that in this condition the drug is effective and safe. However,
larger double-blinded randomized clinical trials are needed to
validate the intriguing results obtained in our explorative study.
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