See discussions, stats, and author profiles for this publication at: [Link]

net/publication/356666648

Salmeterol-Fluticasone: The Role Revisited

Article  in  The Journal of the Association of Physicians of India · December 2021

CITATIONS READS

0 291

5 authors, including:

Lancelot Mark Pinto Parvaiz A Koul

P.D Hinduja National Hospital & Medical Research Centre Sher-i-Kashmir Institute of Medical Sciences
105 PUBLICATIONS   1,713 CITATIONS    529 PUBLICATIONS   70,609 CITATIONS   

SEE PROFILE SEE PROFILE

Some of the authors of this publication are also working on these related projects:

GIHSN project View project

Enhancing Biorisk mitigation awareness in public health community and creating laboratory networks for enhanced diagnostic capabilities to deal with surveillance
and outbreaks of high-risk group viral pathogens causing vhf and respiratory infections View project

All content following this page was uploaded by Parvaiz A Koul on 01 December 2021.

The user has requested enhancement of the downloaded file.

 Journal of The Association of Physicians of India ■ Vol. 69 ■ December 2021 81

update article

Salmeterol-Fluticasone: The Role Revisited

Agam Vora1, Raja Dhar2, Lancelot Pinto3, Parvaiz Koul4, Pratyusha Gaonkar 5

Since the use of ICS along with LABA

Abstract encompasses 70% of the COPD cases, 3
particularly at high doses, the interest
Apart from the individual diseases, some patients also show overlapping
in its associated events of pneumonia
manifestations of asthma and COPD. Nevertheless, the diagnosis of COPD is
h a s b e e n r e i g n i t e d . We s o u g h t t o
often delayed due to inaccessibility to spirometry; the prevalence of the asthma
evaluate the available evidence to
COPD overlap phenotype is rather high given the exposure to biomass smoke.
infer whether pneumonia is a true risk
Furthermore, the rates of exacerbations are twice as high compared to the patients and ICS use should be considered,
with either of the diseases. A treatment strategy that would reduce the risk of since the benefit risk ratio of SFC
exacerbations would contribute immensely to the management of such patients. in COPD is high, given its effect on
Evidence of eosinophilia (marker of inflammation) in patients with asthma, the reduction in exacerbations and
asthma COPD overlap phenotype or COPD alone should prompt treatment improvement in the respiratory and
with a combination of inhaled corticosteroids (ICS)/ long-acting β-agonists HR-QoL. SFC was associated with no
(LABA); several studies have shown improvement in the airflow limitation and increased risk of mortality. On the
reduction in the rate of exacerbations with salmeterol-fluticasone combination contrary, there was a deceleration in
(SFC). Considering the association of COPD and cardiovascular diseases (CVD), the decline of the lung function, which
it is critical to determine the cardiovascular safety of the LABA in such patients. c o u l d i m p r o ve s u r v i va l . T h i s wa s
Salmeterol is a highly selective partial b-2 agonist; the TORCH study and the well-substantiated by a 3-year survival
studies comparing formoterol and salmeterol infer that there is no increased risk study conducted by Soriano et al. which
of new cardiovascular adverse events either with Salmeterol or SFC. Furthermore, showed significantly greater survival
the combination may provide certain degree of cardio-protection. Since COPD per in the SFC group when compared with
se increases the risk of CVD, the cardio-safety of salmeterol outweighs its onset non-ICS/non-LABA pharmacotherapy. 4
of action. SFC has well substantiated benefits in patients with asthma, COPD and Asthma patients with COPD phenotype
high-risk patients such as those with an overlap of COPD and asthma symptoms, and COPD: Eosinophilia
patients with elevated eosinophils and pre-existing CVD. An advisory board was Asthma is often under-diagnosed,
hence conducted, which discussed the role of combination of salmeterol and which creates a substantial burden on
fluticasone (SFC) not only in asthma and COPD but also in asthma COPD overlap individuals and disrupts their quality of
phenotype. Based on the panel’s clinical experience and the expertise derived life. 5 In a survey which aimed to study
thereof, the propositions regarding the place of SFC therapy in patients with the prevalence of asthma in the elderly,
stable and uncontrolled asthma, asthma COPD overlap phenotype and COPD Parameswaran et al. found that 24% of
has been put forth. the 390 patients were diagnosed with
asthma. Of the 95 patients diagnosed
w i t h a s t h m a , m o s t o f t h e m we r e
lifelong never-smokers and only 7%
Introduction Based on our clinical experience and the reported a previous diagnosis of
expertise derived thereof, we have also asthma. In spite of concrete indication

S almeterol, a LABA and

fluticasone propionate, an ICS,
have demonstrated individual
put forth our propositions regarding
place of SFC therapy in patients with
stable and uncontrolled asthma, asthma
of reversible and significant airflow
limitation, only 21 were receiving
inhaled glucocorticoid therapy. 6 Even
and synergistic pharmacodynamic COPD overlap phenotype and COPD. if one assumed that all the ex-smokers
advantages in the management of Pa t i e n t s w i t h a s t h m a a n d C O P D had COPD rather than asthma, this
obstructive airway diseases such as inherently are at an increased risk of suggests that more than 70 percent of
asthma and COPD. 1 Therefore, the cardiovascular diseases and vice-versa; the asthma patients were undiagnosed.7
combination of these two drugs could we sought to review evidence regarding Underdiagnosis may be due to an
be particularly effective in patients with its safety in these high-risk patients absence of a standardised method of
characteristics of both these diseases, given the very high β 2 -selectivity of diagnosis for asthma. 7 In India, wherein
based on levels of a biomarker, which its LABA component, salmeterol. 2
can be easily determined. An advisory
board was hence conducted, which 1
Pulmonologist & Medical Director, Vora Clinic, Mumbai, Maharashtra; 2Director, Center of Excellence in Lung Care, Fortis
discussed the role of combination of Hospital, Kolkata, West Bengal; 3PD Hinduja Hospital, Mumbai, Maharashtra; 4Professor & Head, Internal & Pulmonary Medicine,
salmeterol and fluticasone (SFC) not Sher-i-Kashmir Institute of Medical Sciences, Srinagar, Jammu & Kashmir; 5Medical Advisor, Medical Affairs Dept., Lupin Limited,
only in asthma and COPD but also Mumbai, Maharashtra

in asthma COPD overlap phenotype. Received: 02.09.2021; Accepted: 02.11.2021

82 Journal of The Association of Physicians of India ■ Vol. 69 ■ December 2021

the prevalence of COPD is likely to expenses that individual diseases. 12 energy is in the form of biomass, an
be high due to exposure to biomass Also, given the higher morbidity in estimated ~66% of Indian families use
smoke (BMS), COPD is underdiagnosed this condition exceeding either disease biomass fuel as the main resource for
partly because diagnosis is mostly alone, the clinicians might want to domestic cooking. 28 Biomass fuel can
based on symptoms and also due to focus more on the treatment facets be accounted for 5-6% of the national
the fact that symptomatic people are than flawless phenotyping. Hence, burden of disease. 28 A cross-sectional
often late in seeking care because control of exacerbation should be the study in India found confirmed cases
of insufficient disease awareness. 8 primary target of pharmacotherapy. 13 of COPD in 18.4% among 2868 women
Underutilization of spirometry is Notwithstanding, studies have exposed to BMS for 10-25 years. 29
regarded as the most robust indicator demonstrated that sputum and blood Further, a meta-analysis found that
for inappropriate diagnosis of COPD. eosinophilia also help predict the women exposed to BMS were 2.4 time
Additionally, factors such as knowledge clinical response to ICS and thus help more likely to develop COPD. 30 Given
of associated risk factors, patient in the prevention of exacerbations. 14,15 the higher exposure to BMS, the ratio of
demographics, language barriers and Cross-sectional and observational male to female COPD patients in India
comorbid diseases like bronchiectasis, studies world over including India 1.5 : 1.0 seems realistic. 31 In a cross-
heart failure and formerly treated have found the prevalence of asthma sectional study in India, significant
t u b e rculosis s hould b e t aken int o patients with COPD phenotype to eosinophilia (eosinophils ≥3%) was
consideration. 9 A worrisome lack of be approximately 20% (21.8%, 16 18- found in subjects exposed to BMS (non-
spirometry usage and a high percentage 23%, 17 7.02-27.49% 18 ); however, it is smokers) than smokers (71% vs 49.4%,
of misdiagnosis, has been reported in not consistent due to the criteria used p=0.04). Thus, even after adjusting
patients with suspected chronic airway to define it. 11 The GINA, COPD-Gene, for severity and clinical symptoms,
inflammatory diseases and in those the PLATINO, Spanish Consensus significant eosinophilic inflammation
who are managed by primary care document, GesEPOC, Soler-Cataluna was observed in stable BMS-COPD
physicians. 10 e t a l . , R h e e e t a l . h a ve d i s s i m i l a r compared to smokers. 32
Earlier known as asthmatiform criteria for identifying the combined FP reduces eosinophils, CD8:CD4
bronchitis which is currently referred phenotype, and therefore return ratio in bronchial epithelium,
to as Asthma- chronic obstructive divergent prevalence rates. 11,18 neutrophils in sputum and systemic
pulmonary disease overlap or asthma The GINA/GOLD and GEMA have markers of inflammation. 33 Similar
patients with COPD phenotype developed algorithms for identifying results have also been found for SFC and
was based on the proposed Dutch this phenotype, however, its peculiar a reduction of inflammatory markers
hypothesis of a common basis of asthma i n f l a m m a t o r y a t t r i b u t e s h a ve n o t may also be correlated to a drop in
and COPD. 11 It has been suggested that been taken into consideration. 11 COPD the exacerbation rates. 33 Two studies,
even in milder cases, determination of patients with asthma phenotype I N S P I R E a n d T R I S TA N o f 2 - a n d
phenotypic traits should be attempted represents a large proportion of COPD 1-year duration respectively analysed
so that the clinician can concur if patients with absolute eosionophil moderate and severe exacerbation rates
asthma or COPD carry more weight count (AEC) as an important biomarker based on same eosinophils cut-offs. For
in such patients. But in the clinical to distinguish the former from COPD patients with ≥2% eosinophils, SFC was
practice, even experienced clinicians (peripheral eosinophilia (36% vs 7.6%, associated with significant reductions
opine that it is seldom possible to p=0.002) as corroborated by Sharma in exacerbation rates versus LAMA
perform sophisticated phenotyping. et al. in a retrospective, observational (rate ratio (RR)=0.75, 95% CI 0.60 to
Hence, approaching asthma patients study. 16 Unlike asthma in which some 0 . 9 2 , p = 0 . 0 0 6 ) a n d vers u s pl a c e b o
with COPD phenotype or vice versa as phenotypes are eosinophilic and others (RR=0.63, 95% CI 0.50 to 0.79, p<0.001).34
a single disease would not be rational are neutrophilic or both, in COPD In INSPIRE, a 25% reduction in annual
owing to the heterogeneity of both 10 to 40% of subjects have sputum moderate/severe exacerbation rate
asthma and COPD. eosinophilia. 19 Earlier identification with SFC versus LAMA was observed
The panel of advisors opined that will facilitate apposite treatment in the ≥2% eosinophils subgroup
per their clinical experience, a patient of this discrete clinical phenotype (p=0.006). 14 Statistically significant
with features of both asthma and COPD not clearly represented in clinical reductions in the rate of exacerbations
tends to exacerbate more than patients trials particularly, in the most severe were observed in the ≥2% eosinophils
with either of the features. Asthma f o r m s . 1 1 - 1 7 M o r e o ve r , e o s i n o p h i l i c subgroup in the TRISTAN study with
patients with COPD phenotype or vice COPD has been recognized as a distinct SFC and monotherapies compared
versa can experience up to 2- or 2.5-times phenotype. 20 Globally, eosinophilia to placebo [(SFC 37%; p<0.001) (FP
the number of exacerbations/ year in COPD (sputum eosinophil counts 28%; p=0.005) (SAL 30% p=0.002)]. 35
experienced by those with COPD and ≥3%) has also been reported during No significant difference was seen
asthma, alone. These patients generally acute exacerbations in nearly 28% in the <2% eosinophil subgroup in
are found to have more respiratory of cases and in ~34-38% of patients either of the studies. The 44-week
symptoms, lower physical capacity, with COPD in stable condition. 21-26 A randomized, double-blind parallel-
poorer quality of life, and a greater risk study conducted in Thrissur, India g r o u p s t u d y - V I VA C E ( I m p a c t o f
for exacerbations and hospitalizations. found peripheral blood eosinophilia Salmeterol/Fluticasone Propionate
Furthermore, patients with asthma and in 39% of the COPD patients. 27 Further, versus Salmeterol on Exacerbations
COPD phenotype may require more in a developing country like India, in Severe COPD) showed that ICS
health-care utilization and related where three-fourth of the domestic added to LABA reduces exacerbation
 Journal of The Association of Physicians of India ■ Vol. 69 ■ December 2021 83

only 18% of asthma patients with

COPD phenotype not receiving an ICS.
Reviews of therapy for asthma patients
with COPD phenotype recommend an
ICS as an imperative early maintenance
t h e r a p y . 41 A l s o , s i n c e t h e a s t h m a
patients with COPD phenotype have
more of a Th2 mechanism of disease
than the Th1-based COPD patient,
ICS therapy largely precedes LAMA
therapy in treatment algorithms. 41
In the Korean COPD subgroup
study cohort, asthma patients with
COPD phenotype were assessed and
followed up for a year and exacerbation
analysis was conducted. ICS treatment
Fig. 1: COPD and Cardiovascular diseases: the commonalities51-45 significantly decreased exacerbation in
asthma patients with COPD phenotype
risk by 35%. Another randomized and combined bronchodilators, since
according to the specialists’ diagnoses
clinical trial, ISOLDE conducted in 751 diagnosis with COPD). Even after
and the GOLD/GINA criteria. The
patients treated with FP for 3 years, adjusting for confounders, the survival
only factor linked to decreased
when analysed on the basis of baseline benefit observed was maximum in
exacerbation after ICS treatment was
blood eosinophil count found that SFC group versus the non-ICS group.
a blood eosinophil count of ≥300 cells/
unlike patients with eosinophils <2%, in Mortality decreased with the increasing
mL (IRR=0.52, P=0.03) regardless of
patients with eosinophils ≥2%, the rate use of SFC. 4
the diagnostic criteria of the combined
of post-bronchodilator FEV1 decline GOLD has stated that the blood phenotype. 42 Another cohort of the
decreased significantly by 33.9 mL/year eosinophil count ≥100 cells/μL or 1% KOLD study with mild-to-moderate air
versus placebo (p=0.003). 36 should be contemplated not only for flow limitation, showed a significant
Compared to the non-ICS/ICS ICS treatment in patients with COPD increase in FEV1 following 3 months
withdrawal/placebo group, a recent experiencing one exacerbation despite of treatment with ICS/LABA including
meta-analysis revealed a statistically LAMA/LABA but also for gauging SFC in the combined phenotype group
significant reduction (17%; P=0.03) the efficacy of ICS for precluding compared with COPD alone. 43
in the exacerbations of moderate- exacerbations. For COPD patients with
A randomized, open-label study
severe COPD patients with ≥2% (200/ high eosinophil counts and no history
showed that a 4-week treatment
mm 3 AEC cut-off ) blood eosinophils of pneumonia, ICS is recommended as
with SFC improved lung function in
undergoing ICS therapy. 37 Thus, the part of therapy, as treatment benefits
asthma patients with COPD phenotype,
indication of using ICS in COPD is more l i k e i m p r o ve d l u n g f u n c t i o n a n d
without inducing change in heart rate
substantiated in patients with increased decreased symptoms and rate of
or any other cardiovascular symptoms.
blood eosinophils levels. 38 Accordingly, exacerbations are high while risk of
These findings indicate that SFC has
a baseline blood eosinophil count of pneumonia relatively low. 40 However,
the potential to be used as a regular
≥2% (identified the high sensitivity when high eosinophil counts are
treatment for asthma patients with
of this cut-off point for the presence found and history of pneumonia is
C O P D p h e n o t y p e o r v i c e ve r s a . 4 4
of a raised sputum eosinophil count) documented, the benefits and risks
Current guidelines recommend ICS/
identifies a group of COPD patients must be individualized for optimal
LABA in patients with severe airflow
with slower rates of decline in FEV1 benefit. An ICS should be included
limitation and frequent exacerbations
when treated with ICS like FP. There is in such patients who suffer persistent
based on the evidence from clinical
a greater reduction in the exacerbation exacerbations, resulting in frequent
trials, but in real clinical practice,
rate with ICS/LABA, compared to hospital admissions when being treated
ICS/LABA are also used in COPD
placebo or LAMA, in individuals with with dual bronchodilator therapy. 40
patients with mild-to-moderate airflow
a pre-treatment blood eosinophil level The benefits of ICS have been found
limitation. 44
≥2%. to outweigh the risks. 39 The GOLD
2021 strategy also recommends use There are several salient pragmatic
The addition of fluticasone to
of ICS/LABA in COPD patients with grounds to use FDC inhalers in asthma
salmeterol not only reduces the rate
e o s i n o p h i l s ≥ 3 0 0 c e l l / m L . 40 S i n c e patients with COPD phenotype
of exacerbation but it also improves
asthma patients with COPD phenotype and patients with COPD alone
the airflow limitation and quality of
is associated with a higher exacerbation including patient acceptance and
life compared with the use of a LABA
rate compared to either of the diseases.38 cost-effectiveness. Inhaler preference
alone in a randomised controlled
when tested in both groups found
trial. 14,38 Moreover, the 3-year survival Per the analysis of the data from large
th a t on e- th i rd of th e pa t i e n t s f e l t
was significantly greater in SFC users COPD registries in the US and Europe,
‘extremely satisfied’ with their device.
(78.6%) compared to the non-ICS asthma patients with COPD phenotype
The ‘ease of use/suitability of inhaler
(63.6%) group (prescribed short-acting were prescribed similar treatments as
d e v i c e ’ wa s c i t e d a s a p r e m i s e t o
b-agonists, xanthines, anticholinergics, compared to the COPD patients with
prescribe the device by physician with
84 Journal of The Association of Physicians of India ■ Vol. 69 ■ December 2021

of atherosclerosis, thus consequently

leading to coronary heart disease and
heart failure. 51 Therefore, systemic
inflammatory response in COPD
increases the risk for CVD. 52-54 Apart
from the systemic inflammation, the
processes that are believed to link CVD
and COPD include lung hyperinflation,
hypoxaemia, pulmonary hypertension
and oxidative stress, exacerbations and
genetics as well as COPD phenotype 54
Figure 1.
Conversely, CVD risk factors of
systemic and vascular inflammation,
such as abdominal obesity, diabetes and
physical inactivity are also correlated
with diminished pulmonary function,
airway hyper-reactivity and ultimately
COPD, corroborating the premise that
systemic inflammation related to CVD
may affect COPD. 54
PH-pulmonary hypertension,
LVH-left ventricular hypertrophy,
LV S D - l e f t v e n t r i c u l a r s y s t o l i c
Fig. 2: CV comorbidities (%) in patients with COPD from several published studies.46-51 dysfunction, LVDD-left ventricular
diastolic dysfunction, HF-heart failure,
other device features such as ‘simple such patients it is reasonable to choose
IHD-ischemic heart disease, CV-
instructions and easy to follow’ serving salmeterol over formoterol considering
cardiovascular
a predominant role in asthma patients its favourable cardio-safety profile.
with COPD phenotype and patients The high prevalence of cardiovascular
Asthma, COPD and Cardiovascular
COPD alone. 45 co-morbidities in patients with COPD
Comorbidities
was discussed by the board members
Stable and Uncontrolled Asthma Chronic, systemic inflammation and has been estimated by prospective
Based on their clinical experience, underlies the pathogenic mechanism case-control, retrospective and cross-
the panel of advisors opined that not only of asthma and COPD but also sectional studies. Patients with COPD
dose flexibility or adjustable dosing of several cardiovascular diseases. 2 demonstrate an increased risk of carotid
is unnecessary in patents with stable Asthma is not only characterized plaque formation, IHD, HF, arrhythmia,
asthma. This opinion is substantiated by chronic airway inflammation but right and left ventricular dysfunction,
by a long-term efficacy study, which also beyond it. Many studies have left ventricular systolic dysfunction
found that a stable-dose regimen shown that inflammatory processes and pulmonary hypertension55-59 Figure
of SFC provided significantly are common to the pathophysiology of 2. Pulmonary artery systolic pressure,
greater symptom-free days, reduced asthma, atherosclerosis and endothelial systemic hypertension, pulmonary
exacerbation rates and offered greater dysfunction. Additionally, the data hypertension and LV dysfunction also
HRQoL benefits compared with confirming the association between increased with the severity of COPD.55,60
formoterol/budesonide adjustable the pathogenesis of asthma and A m e t a - a n a l y s i s o f o b s e r va t i o n a l
maintenance dosing (FOR/BUD AMD).46 coagulation, anticoagulant pathways, studies inferred that there is twice
Though the various bodies recommend the fibrinolytic system, and platelets has as much rise in the probability of
formoterol over salmeterol owing to its significantly increased. A retrospective a diagnosis of any CVD in people
faster onset, there is adequate reason registry showed the overall prevalence with COPD compared to non-COPD
to believe that onset wouldn’t hold of asthma with CVD to be more than patients. 61 Another meta-analysis of ten
any additional clinical significance in 88%. 50 Several studies have found studies with 40,6426 participants found
stable asthmatics. Hence, the panel that asthma is related to an increased that asthma patients were associated
of advisors believe that there is no incidence of CVD compared to the non- with an increased risk of CVD and
reason that stable patients should not asthmatics.2 However, the correlation of all-cause mortality, albeit greater in
be continued on SFC. Moreover, in COPD and CVD is more prominent as women than men. 2
patients with tremors and tachycardia compared to the association of asthma
Since IHD, ventricular hypertrophy,
that are related to formoterol may be with CVD. 51 In COPD, the two main
and arrhythmias are rather common
administered salmeterol fluticasone etiological causes namely smoking
in patients with chronic symptoms of
combination instead. and BMS, may give rise to various
COPD and asthma, such patients may
Furthermore, in patients with inflammatory responses in predisposed
be at an increased risk of cardiovascular
uncontrolled and long-standing individuals. Inflammatory mediators
events which may occur from
asthma, there lies a risk of several in the systemic circulation chronically
β-adrenergic stimulation with LABA.2,62
comorbidities, particularly CVD. 47-49 In may cause progressive development
 Journal of The Association of Physicians of India ■ Vol. 69 ■ December 2021 85

In patients with cardiovascular determines the heart rhythm showed (24.3%). Compared to placebo,
comorbidities, an otherwise tolerable no effect on the mean or maximum treatment with SFC was related to a
level of side-effects to attain therapeutic 24-h heart rates, signifying that significant reduction in the possibility
benefit in an emergency may not be salmeterol does not induce significant of a CV AE by 3 years in patients
acceptable and instead may be a factor sympathetic stimulation of the heart on CV therapy at baseline (27.9%
worth receiving more caution. 63 Due in patients with COPD. No clinically versus 33.5%, respectively; p<0.05). 72
to low receptor density of nontarget pertinent variations were observed The probability of patients having a
tissues, full β-agonists may cause more i n t h e i n c i d e n c e o f ve n t r i c u l a r o r serious CV AE by 3 years was lowest
severe side effects, such as higher supraventricular tachycardia or for SFC compared to the placebo and
rate of tachycardia and drop in serum qualitative ECG measurements, QT the monotherapies, respectively (12.5%
potassium, than partial agonists. intervals, pulse rates, and SBP/DBP vs 15.4%, 13.6%, 14.7%). Likewise,
Salmeterol is a highly selective partial between the salmeterol and placebo regarding the ischaemic CV AE, the
β2 agonist.64 A multicentre, randomized groups. Thus, the pooled analysis probability was lowest for SFC (11.3%
study comparing salmeterol and concluded that the cardiovascular vs 14.6%,13.4%, 13.8%). There was
placebo in patients with asthma found safety profile of salmeterol is not n o s i g n i f i c a n t d i f f e r e n c e b e t we e n
n o c l i n i c a l l y s i g n i f i c a n t b e t we e n - dissimilar to placebo, in patients with placebo and SFC in terms of overall
group differences either in pulse COPD. 62 and CV-related mortality. 73 Thus, SFC
rate, ECG QTc interval, ventricular Several other studies have evaluated might have advantageous effects on
or supraventricular ectopic events or the cardiovascular safety of salmeterol decreasing CV events in patients being
arterial BP or frequency of adverse either alone or with ICS (fluticasone). treated with CV medications at baseline
c a r d i o va s c u l a r e ve n t s . S a l m e t e r o l Cazzola et al. in a randomized double- or with moderate COPD. However, the
was well tolerated through the blind, double-dummy study measured SUMMIT study comparing fluticasone
year, with a cardiovascular safety sPAP using transthoracic Doppler furoate/vilanterol (FV) with the
profile indistinguishable from that echocardiography and found that it respective monotherapies and placebo
of placebo. 65 A randomized, single- significantly (p<0.05) decreased in did not find significant reduction in
blind, study in COPD patients with comparison with baseline at 15, 30, the risk of mortality compared to the
pre-existing cardiac arrhythmias and and 60min post inhalation. 69 The study placebo. Thus, FV in the SUMMIT
hypoxemia showed a higher heart did not find any association between study did not replicate the results of
rate, more frequent supraventricular the maximum increase in FEV(1) the TORCH post hoc analysis.
or ventricular premature beats with and maximum decline in sPAP after Thus, both pooled analysis of a
formoterol than salmeterol. Tremor inhalation of salmeterol (r(2)=0.071). large safety database and the large
was noted in lesser number of patients The heart rate did not change in a prospective TORCH study in patients
taking salmeterol than formoterol significant manner (p>0.05). 69 Aortic with moderate to severe COPD and
(2 vs 5) and palpitation occurred pulse wave velocity (APWV) which studies comparing formoterol and
in four patients taking formoterol is a marker of arterial stiffness and a salmeterol infer that there is no
but none with salmeterol. 66 Adverse good predictor for the cardiovascular increased risk of new cardiovascular
effects, such as tachycardia, tremor events 70 was found to be significantly AEs either with Salmeterol or SFC. On
and hypokalaemia, are minimal with reduced (−0.49 m·s−1, p=0.045) with the contrary, its combination with an
salmeterol at standard doses. 66 Less SFC compared to placebo in a 12-week, ICS like Fluticasone may provide certain
tremors were noted even when highest multicentre, randomised, double- degree of cardioprotection.54,62,71,73 These
doses of salmeterol and formoterol were blind, placebo-controlled study. 71 A data suggest a protective effect of
compared. 67 Hence, salmeterol allows a meta-analysis by Rodrigo et al, found ICS and highlight the cardiovascular
better safety edge than formoterol. 68 that compared to LAMA, use of SFC safety of salmeterol; hence, SFC can
Pooled analysis of seven clinical was associated with a lower incidence be used to manage asthma and COPD
trials was conducted to evaluate the in CV mortality and MI incidence. without increased risk of CVE. When
cardiovascular safety of salmeterol Further, Wedzicha et al., in a 2-year, we consider these diseases, which by
(50 μg bid), in patients with COPD double-blind, double-dummy parallel themselves are a risk factor for CVD,
by Ferguson et al. and compared study showed a significant decrease the difference in side effect profile
to placebo. This analysis included in the all-cause mortality rate (6% vs would take precedence over the onset of
the use of a sizeable safety database 3%; P=0.032) compared with LAMA. 14 action; therefore, salmeterol should be
t h a t wa s d i s t i n c t l y i l l u s t r a t i ve o f Cardiac disorder associated deaths preferred over formoterol in ICS/LABA
the COPD population, with patient were also higher in LAMA than SFC combination. Lastly, the duration of
profile encompassing various (3% vs 1%). In those subjects with pre- action of salmeterol is longer than
important subgroups namely the existing co-morbid CVD, the mortality formoterol since the long side-chain
e n t i r e g a m u t o f d i s e a s e s e ve r i t y , rate was higher in the LAMA compared of salmeterol binds to the exosite at
smokers, geriatric patients and to the SFC group (8% vs 3%). 14 the receptor site, which allows it to
those with comorbid cardiovascular Post-hoc analysis of the TORCH repetitively fasten and unfasten with
conditions. 62 This analysis did not find study, suggested that the probability the active site, resulting in a long
any significant difference between of patients having a CV AE by 3 duration of action. 74-76
salmeterol and placebo for any of years was the lowest for SFC (20.8%) Secondary Pneumonia with ICS
the parameters assessed. 62 Analysis versus placebo (24.2%), salmeterol In asthma and COPD, ICS has
of the Holter monitoring data which (22.7%) and fluticasone propionate demonstrated decrease in the total
86 Journal of The Association of Physicians of India ■ Vol. 69 ■ December 2021

frequency of exacerbations and Fluticasone users, notwithstanding difference in the mortality associated
enhancement in the quality of life. 77- i n c r e a s e d r i s k o f p n e u m o n i a . 86,89 with pneumonia between SFC and
80
The correlation between use of ICS A s t u d y o f Ve t e r a n s A f f a i r s ( VA) Non-ICS group. 33 A single case of
and predisposition to pneumonia has hospitals evaluated the correlation of p n e u m o n i a wa s d o c u m e n t e d a s a
been better described in patients with ICS (including fluticasone) exposure secondary cause of death in each group,
COPD than in asthma. 81 Incongruously, with mortality in hospitalized COPD however, whether the alleged cases of
studies have reported higher incidence subjects with pneumonia. The use pneumonia were true cases or simply a
of pneumonia with fluticasone use in o f I C S d e m o n s t r a t e d a p r o t e c t i ve different clinical picture of an episode
asthma and COPD patients. 33,72,89,94,82 effect against 30-day mortality. The of exacerbation is uncertain; while
Nevertheless, these data should be retrospective analysis of VA healthcare there was a definite and significant
reviewed on the basis of certain factors database found no significant decrease in overall exacerbations with
which cast a doubt whether these association between ICS use including the addition of fluticasone to salmeterol
studies reflect the true incidences of fluticasone and clinical outcomes in (-35%; p< 0.0001). 14 The INSPIRE study,
pneumonia. The studies which have patients with COPD who suffered which compared SFC with a LAMA
reported higher incidence of pneumonia from pneumonia. 86 When a nested (tiotropium) found that though there
with fluticasone were not designed case-control study was evaluated, it was a small rise in pneumonia, the
to evaluate the risk of pneumonia also demonstrated a lesser 30-day mortality was lower in the SFC group
and hence did not confirm the same mortality risk of after hospitalization (3% vs 6%; P=). 14 Also, a nested case-
radiographically. The diagnosis in for pneumonia [13.3% vs 17.2% (p < control design that included greater
most of the relevant studies was based 0.001)]. 87 A single-center cohort study than one lakh seventy-five thousand
on clinical judgement of signs and observed that ICS use particularly patients with COPD failed to show
symptoms. However, clinical signs fluticasone was associated with fewer increased risk of mortality in spite of
and symptoms of COPD exacerbations complications and lower mortality, higher incidence of pneumonia with
and pneumonia often overlap which since it was evidently the most ICS use including fluticasone. 89 Rather,
may result in under or over-diagnosis commonly used ICS in Spain during on performing regression analyses
of pneumonia, especially when chest this study period. 88 Studies comparing of the results of data of hospitalised
radiographs are not used for the COPD exacerbation rates between COPD patients with pneumonia from
confirmation of the clinical diagnosis. patients being treated with either US Veterans Affairs hospitals, mortality
Hence, true incidence of pneumonia salmeterol or SFC demonstrated that was found to be significantly lower at
with fluticasone may be different from all-cause mortality was comparable for 30- and 90-days (9% at 30 days and 16%
what has been reported.  patients hospitalized with pneumonia at 90 days). 92
A recent open-label randomized irrespective of the previous use of ICS.89 Even with the increased pneumonia
study in 194 patients with COPD found In the TORCH study, although incidence, COPD patients on fluticasone
that in the formoterol/budesonide t h e r e wa s a s i g n i f i c a n t l y h i g h e r therapy have lower mortality due to
treated group, pneumonia (7.8% vs frequency of pneumonia, it did not the blunted systemic inflammatory
1.1; P=0.038) was more common than lead to an increased risk of mortality. 35 r e s p o n s e . T h e i n ve s t i g a t o r s h a ve
with SFC. 83 A meta-analysis of clinical With further subgroup analysis, the shown that inhaled fluticasone
randomized trials of asthmatics using probability of pneumonia with SFC in propionate helps decrease the invasion
fluticasone propionate and budesonide COPD patients (GOLD stage II) was o f e p i t h e l i a l c e l l s i n t h e a i r wa y
found that patients did not have an lesser than that observed in the total by microbes such as Streptococcus
elevated risk of pneumonia, even at population. The number of deaths in pneumoniae and Haemophilus
higher doses or between the various patients on treatment were very less influenzae thereby decreasing the
I C S s . 84 S e c o n d a r y a n a l y s i s o f t h e and hence could not be analysed by bacterial load. 91,92 Studies have also
Lung Injury Prediction Score (LIPS) GOLD stage. 90 In a post hoc analysis of demonstrated reduced hazard of
cohort, which included patients with TORCH, the reports of serious adverse parapneumonic effusion due to
COPD (N=589) and patients with events with pneumonia namely death, the reduction of excessive local
asthma (N=440), prehospital ICS use hospitalisation or prolongation inflammatory responses and necessity
was not individualistically related of hospitalisation as a percentage for mechanical ventilation. 86 Of note is
to an increased risk for pneumonia o f t h e t o t a l p n e u m o n i a s we r e n o t a trial conducted for a year in patients
needing hospitalization after more frequent in the fluticasone or with COPD with budesonide 640 μg
correcting for various confounders. SFC groups compared with placebo and 320 μg, which found rise in the
There were no statistically significant (∼60%). This finding suggests that the pneumonia adverse events, these doses
differences between COPD, asthma, probability of pneumonia leading to an were comparable to fluticasone 400
and non-COPD/asthma subgroups. 85 arduous clinical situation is unlikely. μg and 200 μg. 93 Also, given its lower
Though randomized controlled trials Absence of opportunistic pathogens potency than fluticasone, budesonide
of ICS use in COPD have suggested in any pneumonia episode further may have been favourably advised
an unadjusted risk of mortality related corroborates this finding. 91 to patients with COPD of a lesser
to pneumonia; none of these found Also, in the patients with COPD severity who are at a lower risk of
a difference between ICS users and r a n d o m i s e d t o r e c e i ve e i t h e r S F C pneumonia, compared to those with
non-users. 33,72,89,94 Further even various o r s a l m e t e r o l a l o n e i n a 4 4 - we e k greater severity. 94
observational studies reported largely randomized, double-blind, parallel- Even geriatric patients and
similar or reduced mortality among group multicentre study, there was no those with severe COPD are at an
 Journal of The Association of Physicians of India ■ Vol. 69 ■ December 2021 87

increased risk of pneumonia. 95 COPD are foundational approaches for the Initiative for Chronic Obstructive
per se increases the susceptibility to treatment of asthma patients with Lung Disease; HR-QoL:Health-
pneumonia based on the presence COPD phenotype or vice versa. Patients related quality of life; ICS:inhaled
of chronic bronchitis with tenacious with COPD, such as those with blood corticosteroid; IHD:Ischemic heart
mucus production, and the presence eosinophilia or asthma, respond well disease; INSPIRE:Investigating New
of potential pathogenic bacteria in to SFC even at low doses. 100 ICS/LABA Standards for Prophylaxis in Reducing
the airways. 96 Also, the existence of like SFC could be a basic maintenance Exacerbations; LABA:long-acting β2-
bacteria in the airway of patients with therapy in asthma patients with COPD adrenoceptor agonist; LAMA:Long-
stable COPD and higher numbers phenotype or vice versa. 41 Given the acting muscarinic antagonists;
during exacerbations have been linked established efficacy and cardiovascular PLATINO:Spanish acronym for the
with greater inflammation. 96 Further, safety of the LABA component of Latin American Project for Research
COPD also increases the pneumonia SFC in COPD, it would also be a in Pulmonary Obstruction; SBP/
associated hospitalization more so preferred ICS/LABA combination in DBP:Systolic blood pressure/diastolic
for patients with severe underlying COPD and asthma patients with COPD blood pressure; SFC:Salmeterol-
disease. Further, the dose of ICS phenotype with pre-existing CVD fluticasone combination; sPAP:systolic
prescribed for severe cases of COPD including arterial stiffness, pulmonary pulmonary arterial pressure;
to prevent exacerbation is also likely hypertension, arrhythmia. In COPD T O R C H : T O wa r d s a R e v o l u t i o n i n
to be high. 92 patients, pneumonia is much less C O P D H e a l t h ; T R I S TA N : T R i a l o f
There was no increase in mortality common than exacerbations. Though Inhaled STeroids ANd long-acting β2
with SFC even in patients with there appears to be a slightly higher agonists.
pneumonia and reduced exacerbation increased risk of pneumonia, treatment Conflict of Interest
rates were observed compared to LABA with ICS does not cause an increase in
This paper forms part of a
and LAMA alone, the impact of this all-cause mortality. These data indicate
supplement commissioned and funded
combination on the overall health status that such adverse effects may occur
by Lupin Limited. The supplement
and quality of life is noteworthy. The inconsistently. Rather there was no
contains papers based on presentations
pivotal studies, TORCH and INSPIRE difference in ICS and non-ICS users
from an Advisory Board of health-care
suggested no association with the with regard to mortality. There was
professionals held on 6th December,
incidence of pneumonia and overall significantly a higher survival rate
2020, which was sponsored by Lupin
change in health status assessed by St among SFC users compared to non-ICS
Limited. All participants received an
George’s Respiratory Questionnaire.33,72 users with an absolute difference of
honorarium from Lupin Limited for
15%. 4,101
A recent meta-analysis of more their participation in the Advisory
than thirteen thousand patients with Adding fluticasone to salmeterol meeting. Pratyusha Gaonkar is an
COPD demonstrated that ICS including contributes important benefits, such employee of Lupin Ltd.
fluticasone use of for more than 6 as preventing exacerbations and
Acknowledgment
months duration slowed the rate of slowing pulmonary function decline.
SFC also has a significant effect on The authors express their sincere
decline in quality of life as measured
improvement in HR-QoL with more thanks to all the advisory board
by the St George’s Respiratory
than four-unit change in the SGRQ members – Dr. A G Ghoshal, Dr Narayan
Questionnaire. 97 Though there are
score in 35% patients. 33 Thus, SFC Mishra, Dr Rajesh Swarnakar, Dr Nitin
different quality-of-life measures in
has proven and validated benefits Abhyankar, Dr S K Jindal, Dr Vikram
studies included in the meta-analysis,
in patients with asthma, COPD and Jaggi, and Dr K. S. Satish.
more than 70% studies reported a
statistically significant improvement in high-risk patients such as those with
overlapping symptoms, patients with
References
St George’s Respiratory Questionnaire
scores. 97 A new-user cohort study elevated eosinophils, pre-existing CVD. 1. Fenton C, Keating GM. Inhaled salmeterol/fluticasone

suggested weakening of the risk of Use of a fixed-dose combination like propionate: a review of its use in chronic obstructive
pulmonary disease. Drugs 2004; 64:1975-96.
pneumonia subsequent to continual salmeterol and fluticasone has been
2. Xu M, Xu J, Yang X. Asthma and risk of cardiovascular disease
use for a minimum of six months, found to be extremely satisfactory or all-cause mortality: a meta-analysis. Ann Saudi Med 2017;
whereas RCTs require about 6 months given its ease of use, which is critical for 37:99-105.

of use before treatment differences the end-users suffering from asthma, 3. Suissa S, Barnes PJ. Inhaled corticosteroids in COPD: the case

surface. Meta-analyses of RCTs show COPD and asthma patients with COPD against. Eur Respir J 2009; 34:13–16.

attenuation of the risk of pneumonia phenotype or vice versa. 4. Soriano JB, Vestbo J, Pride NB, Kiri V, Maden C, Maier WC.
Survival in COPD patients after regular use of fluticasone
after >2 years of ICS usage. 98,99 Thus, Abbreviations propionate and salmeterol in general practice. Eur Respir J
the apparent increased pneumonia risk ACO: Asthma COPD overlap;
2002; 20:819-25.

associated with fluticasone therapy is aPWV:Aortic pulse wave velocity;

5. Singh SK, Gupta J, Sharma H, Pedgaonkar SP, Gupta N.
Socio-economic Correlates and Spatial Heterogeneity in
balanced with the known favourable BMS:Biomass smoke; COPD:Chronic the Prevalence of Asthma among Young Women in India.
effects of ICS use on quality of life and obstructive pulmonary disease; BMC Pulmonary Medicine 2020; 20:1-2.
reduction of morbidity. 98 CVD:Cardiovascular disease; FDC:Fixed 6. Parameswaran K, Hildreth AJ, Chadha D, Keaney NP, Taylor
IK, Bansal SK. Asthma in the elderly: underperceived,
Conclusion dose combination; FEV:Forced underdiagnosed and undertreated; a community
Basic treatment strategies that focus expiratory volume; FV:Fluticasone/ survey. Respir Med 1998; 92:573-7. doi: 10.1016/s0954-
6111(98)90311-0.
on the use of inhalers utilized in the Vilanterol; GesPOC:The Spanish
treatment of both asthma and COPD Guidelines for COPD; GINA:Global 7. Kavanagh J, Jackson DJ, Kent BD. Over- and under-diagnosis
in asthma. Breathe (Sheff) 2019; 15:e20-e27.
Initiative for Asthma; GOLD:Global
 88 Journal of The Association of Physicians of India ■ Vol. 69 ■ December 2021

8. Salvi S, Kumar GA, Dhaliwal RS, Paulson K, Agrawal A, Koul formoterol in chronic obstructive pulmonary disease. Am J or asthma-COPD overlap syndrome consulting for routine
PA, Mahesh PA, Nair S, Singh V, Aggarwal AN, Christopher Respir Crit Care Med 2015; 192:523–525. care. Int J Chron Obstruct Pulmon Dis 2018; 13:927–936.
DJ. The burden of chronic respiratory diseases and their
27. Ajithkumar CS. Peripheral blood eosinophilia in COPD: 46. Price DB, Williams AE, Yoxall S. Salmeterol/fluticasone stable-
heterogeneity across the states of India: the Global Burden
prevalence and clinical characteristics. Indian J Basic Appl dose treatment compared with formoterol/budesonide
of Disease Study 1990–2016. The Lancet Global Health 2018;
Med Res 2018; 7:223-228. adjustable maintenance dosing: impact on health-related
6:e1363-74.
quality of life. Respir Res 2007; 8:46. Published 2007 Jul 4.
28. Prasad R, Singh A, Garg R, Giridhar GB. Biomass fuel
9. Ho T,  Cusack RP, Chaudhary N, Satia I, Kurmi OP. Under- doi:10.1186/1465-9921-8-46.
exposure and respiratory diseases in India. Biosci Trends
and over-diagnosis of COPD: a global perspective.
2012; 6:219-28. 47. Cazzola M, Calzetta L, Bettoncelli G, Cricelli C, Romeo F,
Breathe 2019; 15:24-35.
Matera MG, Rogliani P. Cardiovascular disease in asthma
29. Kalagouda Mahishale V, Angadi N, Metgudmath V, Lolly
10. Heffler E, Crimi C, Mancuso S, Campisi R, Puggioni F, Brussino and COPD: a population-based retrospective cross-
M, Eti A, Khan S. The Prevalence of Chronic Obstructive
L, Crimi N. Misdiagnosis of asthma and COPD and underuse sectional study. Respir Med 2012; 106:249-56. doi: 10.1016/j.
Pulmonary Disease and the Determinants of Underdiagnosis
of spirometry in primary care unselected patients. Respir rmed.2011.07.021.
in Women Exposed to Biomass Fuel in India- a Cross Section
Med 2018; 142:48-52.
Study. Chonnam Med J 2016; 52:117-122. 48. Tattersall MC, Dasiewicz AS, McClelland RL, Gepner AD,
11. Cosío BG, Dacal D, Pérez de Llano L. Asthma-COPD overlap: Kalscheur MM, Field ME, Heckbert SR, Hamdan MH,
30. Po JY, FitzGerald JM, Carlsten C. Respiratory disease
identification and optimal treatment. Ther Adv Respir Dis Stein JH. Persistent Asthma Is Associated With Increased
associated with solid biomass fuel exposure in rural women
2018; 12:1753466618805662. Risk for Incident Atrial Fibrillation in the MESA. Circ
and children: systematic review and meta-analysis. Thorax
Arrhythm Electrophysiol 2020; 13:e007685. doi: 10.1161/
12. Maselli DJ, Hardin M, Christenson SA, Hanania NA, Hersh CP, 2011; 66:232-9.
CIRCEP.119.007685.
Adams SG, Anzueto A, Peters JI, Han MK, Martinez FJ. Clinical
31. Jindal SK, Aggarwal AN, Gupta D. A review of population
Approach to the Therapy of Asthma-COPD Overlap. Chest 49. Ingebrigtsen TS, Marott JL, Vestbo J, et alCoronary heart
studies from India to estimate national burden of chronic
2019; 155:168-177. disease and heart failure in asthma, COPD and asthma-COPD
obstructive pulmonary disease and its association with
overlap. BMJ Open Respiratory Research 2020; 7:e000470. doi:
13. Louie S, Zeki AA, Schivo M, Chan AL, Yoneda KY, Avdalovic smoking. Indian J Chest Dis Allied Sci 2001; 43:139-47. PMID:
10.1136/bmjresp-2019-000470.
M, Morrissey BM, Albertson TE. The asthma-chronic 11529432.
obstructive pulmonary disease overlap syndrome: 50. Demko IV, Gordeeva NV, Petrova MM, Artiukhov IP. [Clinical
32. Fernandes L, Rane S, Mandrekar S, Mesquita AM.
pharmacotherapeutic considerations. Expert Rev Clin picture and treatment of bronchial asthma comorbid with
Eosinophilic Airway Inflammation in Patients with Stable
Pharmacol 2013; 6:197-219. cardiovascular diseases]. Ter Arkh 2007; 79:60-5.
Biomass Smoke- versus Tobacco Smoke-Associated Chronic
14. Wedzicha JA, Calverley PM, Seemungal TA, Hagan G, Ansari Obstructive Pulmonary Disease. J Health Pollut 2019; 51. Morgan AD, Zakeri R, Quint JK. Defining the relationship
Z, Stockley RA. The prevention of chronic obstructive 9:191209. between COPD and CVD: what are the implications for clinical
pulmonary disease exacerbations by salmeterol/fluticasone practice? Ther Adv Respir Dis 2018; 12:1753465817750524.
33. Kardos P, Wencker M, Glaab T, Vogelmeier C. Impact of
propionate or tiotropium bromide. Am J Respir Crit Care Med
salmeterol/fluticasone propionate versus salmeterol 52. Sin DD, Man SF. Why are patients with chronic obstructive
[Internet] 2008; 177:19–26.
on exacerbations in severe COPD.  Am J Respir Crit Care pulmonary disease at increased risk of cardiovascular
15. Kreindler JL, Watkins ML, Lettis S, et al. Effect of inhaled Med 2007; 175:144–149. diseases? The potential role of systemic inflammation in
corticosteroids on blood eosinophil count in steroidnaïve chronic obstructive pulmonary disease. Circulation 2003;
34. Pavord ID, Lettis S, Locantore N, Pascoe S, Jones PW,
patients with COPD. BMJ Open Resp Res 2016; 3:e000151. 107:1514-9.
Wedzicha JA, Barnes NC. Blood eosinophils and inhaled
16. Sharma R, Jha O, Prajapat O et al. Prevalence and profile of corticosteroid/long-acting β-2 agonist efficacy in COPD. 53. Roversi S, Roversi P, Spadafora G, Rossi R, Fabbri LM. Coronary
asthma copd overlap (ACO) in previously diagnosed COPD Thorax 2016; 71:118-25. artery disease concomitant with chronic obstructive
patients – an observational study from North India. Respirol pulmonary disease. Eur J Clin Invest 2014; 44:93-102.
35. Calverley P, Pauwels R, Vestbo J, et al. Combined salmeterol
2017; 22(Suppl.3):244-245.
and fluticasone in the treatment of chronic obstructive 54. Rabe KF, Hurst JR, Suissa S. Cardiovascular disease and COPD:
17. Krishnan JA, Nibber A, Chisholm A, Price D, Bateman ED, pulmonary disease: a randomised controlled trial. Lancet dangerous liaisons? Eur Respir Rev 2018; 27:180057.
Bjermer L, et al. Prevalence and Characteristics of Asthma- 2003; 361:449–56.
55. Kaushal M, Shah PS, Shah AD, Francis SA, Patel NV, Kothari
Chronic Obstructive Pulmonary Disease Overlap in Routine
36. Barnes NC, Sharma R, Lettis S, Calverley PM. Blood eosinophils KK. Chronic obstructive pulmonary disease and cardiac
Primary Care Practices. Ann Am Thorac Soc 2019; 16:1143-
as a marker of response to inhaled corticosteroids in COPD. comorbidities: A cross-sectional study. Lung India 2016;
1150.
Eur Respir J 2016; 47:1374-82. 33:404-9.
18. Ye W, Li X, Gu W, Guo X, Han F, Liu S. A comparison of
37. Cheng SL. Blood eosinophils and inhaled corticosteroids in 56. Vizza CD, Lynch JP, Ochoa LL, Richardson G, Trulock EP. Right
diagnostic consistency for asthma-chronic obstructive
patients with COPD: systematic review and meta-analysis. and left ventricular dysfunction in patients with severe
pulmonary disease overlap and clinical characteristics study.
Int J Chron Obstruct Pulmon Dis 2018; 13:2775-2784. pulmonary disease. Chest 1998; 113:576-83.
BMC Pulm Med 2019; 19:249.
38. Janson C. Treatment with inhaled corticosteroids in chronic 57. Vattanatt G and Supriya Adiyodi. Comorbidities associated
19. Woodruff PG, van den Berge M, Boucher RC, Brightling
obstructive pulmonary disease. J Thorac Dis 2020; 12:1561- with chronic obstructive pulmonary disease (COPD) – A
C, Burchard EG, Christenson SA, et al. American Thoracic
1569. clinical study. Eur Resp J 2011; 38:3577.
Society/National Heart, Lung, and Blood Institute Asthma-
Chronic Obstructive Pulmonary Disease Overlap Workshop 39. Izquierdo JL, Cosio BG. The dose of inhaled corticosteroids in 58. Chindhi S, Thakur S, Sarkar M, Negi PC. Subclinical
Report. Am J Respir Crit Care Med 2017; 196:375-381. patients with COPD: when less is better. Int J Chron Obstruct atherosclerotic vascular disease in chronic obstructive
Pulmon Dis 2018; 13:3539–47. pulmonary disease: Prospective hospital-based case control
20. Tworek D, Antczak A. Eosinophilic COPD-a distinct
study. Lung India 2015; 32:137-141.
phenotype of the disease. Advances in Respiratory Medicine 40. Global Strategy for Diagnosis, management and prevention
2017; 85:271-6. of COPD 2021 Update. Accessed at [Link] 59. Alexander V, R. Pajanivel VR, Menon SK, Prasath A. Prevalence
wp-content/uploads/2020/11/GOLD-REPORT-2021-v1.1- of cardiac comorbidities and its relation to severity staging
21. Bafadhel M, McKenna S, Terry S, et al. Acute exacerbations
25Nov20_WMV.pdf on 11 Jan 2021. of chronic obstructive pulmonary disease. Int J Cur Res Rev
of chronic obstructive pulmonary disease: identification of
2015; 727-33.
biologic clusters and their biomarkers. Am J Respir Crit Care 41. Albertson TE, Chenoweth JA, Pearson SJ, Murin S.
Med 2011; 184:662–671. The pharmacological management of asthma-chronic 60. Rao VK, Naseer MA, Reddy KS, Bhaskar L, Waghray P. Chronic
obstructive pulmonary disease overlap syndrome (ACO). Obstructive Pulmonary Disease and Cardiac Comorbidities.
22. McDonald VM, Higgins I, Wood LG, Gibson PG.
Expert Opin Pharmacother 2020; 21:213-231. Int J Sci Stud 2018; 5:53-56.
Multidimensional assessment and tailored interventions
for COPD: respiratory utopia or common sense? Thorax 42. Jo YS, Hwang YI, Yoo KH, Kim TH, Lee MG, Lee SH, Shin 61. Chen W, Thomas J, Sadatsafavi M, et al. Risk of cardiovascular
2013; 68:691–694. KC, In KH, Yoon HK, Rhee CK; Korean Asthma Research comorbidity in patients with chronic obstructive pulmonary
Group & KOCOSS cohort. Effect of Inhaled Corticosteroids disease: a systematic review and meta-analysis. Lancet Respir
23. Leigh R, Pizzichini MM, Morris MM, Maltais F, Hargreave
on Exacerbation of Asthma-COPD Overlap According to Med 2015; 3:631–639.
FE, Pizzichini E. Stable COPD: predicting benefit from
Different Diagnostic Criteria. J Allergy Clin Immunol Pract
high-dose inhaled corticosteroid treatment. Eur Respir J 62. Ferguson GT, Funck-Brentano C, Fischer T, Darken P, Reisner
2020; 8:1625-1633.e6.
2006; 27:964–971. C. Cardiovascular safety of salmeterol in COPD. Chest 2003;
43. Lee SY, Park HY, Kim EK, et al. Combination therapy of inhaled 123:1817-24.
24. Bafadhel M, McKenna S, Terry S, et al. Blood eosinophils to
steroids and long-acting beta2-agonists in asthma-COPD
direct corticosteroid treatment of exacerbations of chronic 63. Hanania NA, Sharafkhaneh A, Barber R, Dickey BF. Beta-
overlap syndrome.  Int J Chron Obstruct Pulmon Dis 2016;
obstructive pulmonary disease: a randomized placebo- agonist intrinsic efficacy: measurement and clinical
11:2797-2803.
controlled trial. Am J Respir Crit Care Med 2012; 186:48–55. significance. Am J Respir Crit Care Med 2002; 165:1353-8.
44. Ishiura Y, Fujimura M, Shiba Y, Ohkura N, Hara J, Kasahara
25. Pascoe S, Locantore N, Dransfield MT, Barnes NC, Pavord 64. Baker JG. The selectivity of beta-adrenoceptor agonists
K. A comparison of the efficacy of once-daily fluticasone
ID. Blood eosinophil counts, exacerbations, and response at human beta1-, beta2- and beta3-adrenoceptors.  Br J
furoate/vilanterole with twice-daily fluticasone propionate/
to the addition of inhaled fluticasone furoate to vilanterol Pharmacol 2010; 160:1048-1061.
salmeterol in asthma-COPD overlap syndrome. Pulm
in patients with chronic obstructive pulmonary disease: a 65. Chervinsky P, Goldberg P, Galant S, Wang Y, Arledge T, Welch
Pharmacol Ther 2015; 35:28-33.
secondary analysis of data from two parallel randomised MB, Stahl E. Long-term cardiovascular safety of salmeterol
controlled trials. Lancet Respir Med 2015; 3:435–442. 45. Ding B, Small M, Scheffel G, et al. Maintenance inhaler
powder pharmacotherapy in adolescent and adult patients
preference, attribute importance, and satisfaction in
26. Siddiqui SH, Guasconi A, Vestbo J, et al. Blood eosinophils: with chronic persistent asthma: a randomized clinical trial.
prescribing physicians and patients with asthma, COPD,
a biomarker of response to extrafine beclomethasone/ Chest 1999; 115:642-8. doi: 10.1378/chest.115.3.642.
 Journal of The Association of Physicians of India ■ Vol. 69 ■ December 2021 89

66. Drugs Acting on the Respiratory System. Karen S. Gregson, COPD overlap. Allergol Int 2018; 67:187–190. randomised, placebo-controlled TORCH study.  Respir Res
Jeffrey D. Bennett, in Pharmacology and Therapeutics for 2009; 10:59.
80. Price DB, Williams AE, Yoxall S. Salmeterol/fluticasone stable-
Dentistry (Seventh Edition), 2017. Accessed at [Link]
dose treatment compared with formoterol/budesonide 91. Crim C, Calverley PM, Anderson JA, Celli B, Ferguson GT,
[Link]/topics/immunology-and-microbiology/
adjustable maintenance dosing: impact on health-related Jenkins C, Jones PW, Willits LR, Yates JC, Vestbo J. Pneumonia
salmeterol on 05-01-2021.
quality of life. Respir Res 2007; 8:46. Published 2007 Jul 4. risk in COPD patients receiving inhaled corticosteroids alone
67. Meyler’s Side Effects of Drugs (Sixteenth Edition), 2016. doi:10.1186/1465-9921-8-46). or in combination: TORCH study results. Eur Respir J 2009;
Accessed at [Link] 34:641-7.
81. Sibila O, Soto-Gomez N, Restrepo MI. The risk and outcomes
immunology-and-microbiology/salmeterol on 05-01-2021.
of pneumonia in patients on inhaled corticosteroids. Pulm 92. Malo de Molina R, Mortensen EM, Restrepo MI, Copeland
68. Cazzola M, Imperatore F, Salzillo A, Di Perna F, Calderaro F, Pharmacol Ther 2015; 32:130-136. doi:10.1016/j. LA, Pugh MJ, Anzueto A. Inhaled corticosteroid use is
Imperatore A, Matera MG. Cardiac effects of formoterol and pupt.2015.04.001. associated with lower mortality for subjects with COPD and
salmeterol in patients suffering from COPD with preexisting hospitalised with pneumonia. Eur Respir J 2010; 36:751-7.
82. McKeever T, Harrison TW, Hubbard R, Shaw D. Inhaled
cardiac arrhythmias and hypoxemia. Chest 1998; 114:411-5.
corticosteroids and the risk of pneumonia in people with 93. Sharafkhaneh A, Southard JG, Goldman M, et al. Effect of
69. Cazzola M, Mantero A, Santus P, Carlucci P, Mondoni asthma: a case-control study. Chest 2013; 144:1788–1794. budesonide/formoterol pMDI on COPD exacerbations:
M, Bosotti L, Centanni S. Doppler echocardiographic doi: 10.1378/chest.13-0871. a double-blind, randomized study. Respir Med 2012;
assessment of the effects of inhaled long-acting beta2- 106:257–68.
83. Muiser S, Luijk B, Braunstahl GJ, Heijink I, Reddel H, Kerstjens
agonists on pulmonary artery pressure in COPD patients.
H, Van Den Berge M. Eur Res J 2020; 56:Suppl. 64, 5237. DOI: 94. Suissa S, Patenaude V, Lapi F, Ernst P. Inhaled corticosteroids
Pulm Pharmacol Ther 2007; 20:258-64.
10.1183/[Link]-2020.5237. in COPD and the risk of serious pneumonia. Thorax 2013;
70. Ranjith R, Binu TG, George V, et al. Aortic pulse wave velocity 68:1029-36.
84. O’Byrne PM, Pedersen S, Carlsson LG, et al. Risks of
and its relationship with complexity of coronary artery
pneumonia in asthmatic patients taking inhaled 95. Müllerova H, Chigbo C, Hagan GW, Woodhead MA,
disease based on SYNTAX score. Heart Asia 2014; 6:109-115.
corticosteroids. Am J Respir Crit Care Med 2011; 183:589–595. Miravitlles M, Davis KJ, Wedzicha JA. The natural history
71. Dransfield MT, Cockcroft JR, Townsend RR, et al. Effect of doi: 10.1164/rccm.201005-0694OC. of community-acquired pneumonia in COPD patients: a
fluticasone propionate/salmeterol on arterial stiffness in population database analysis. Respir Med 2012; 106:1124-33.
85. Festic E, Bansal V, Gajic O, Lee AS; United States Critical
patients with COPD. Respir Med 2011; 105:1322–1330.
Illness and Injury Trials Group: Lung Injury Prevention Study 96. Restrepo MI, Sibila O, Anzueto A. Pneumonia in Patients
72. Calverley PM, Anderson JA, Celli B, et al. Salmeterol and Investigators (USCIITG-LIPS). Prehospital use of inhaled with Chronic Obstructive Pulmonary Disease. Tuberc Respir
fluticasone propionate and survival in chronic obstructive corticosteroids and point prevalence of pneumonia at Dis (Seoul) 2018; 81:187-197.
pulmonary disease. N Engl J Med 2007; 356:775–789. the time of hospital admission: secondary analysis of a
97. Yang IA, Fong KM, Sim EH, Black PN, Lasserson TJ. Inhaled
multicenter cohort study. Mayo Clin Proc 2014; 89:154-62.
73. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins corticosteroids for stable chronic obstructive pulmonary
doi: 10.1016/[Link].2013.10.028.
C, Jones PW, Crim C, Willits LR, Yates JC, Vestbo J; TORCH disease. Cochrane Database Syst Rev 2007; (2):CD002991.
Investigators. Cardiovascular events in patients with COPD: 86. Chen D, Restrepo MI, Fine MJ, et al. Observational study of
98. Drummond MB, Dasenbrook EC, Pitz MW, Murphy DJ, Fan
TORCH study results. Thorax 2010; 65:719-25. inhaled corticosteroids on outcomes for COPD patients with
E. Inhaled corticosteroids in patients with stable chronic
pneumonia. Am J Respir Crit Care Med 2011; 184:312-316.
74. Naline E, Zhang Y, Qian Y, et al. Relaxant effects and durations obstructive pulmonary disease: a systematic review and
of action of formoterol and salmeterol in the isolated human 87. Joo MJ, Au DH, Fitzgibbon ML, Lee TA. Inhaled corticosteroids meta-analysis [published correction appears in JAMA. 2009
bronchus. Eur Respir J 1994; 7:914–920. and risk of pneumonia in newly diagnosed COPD.  Respir Mar 11;301(10):1024]. JAMA. 2008;300(20):2407-2416.
Med 2010; 104:246–252.
75. Nials AT, Coleman RA, Johnson M, Magnussen H, Rabe KF, 99. DiSantostefano RL, Sampson T, Le HV, Hinds D, Davis KJ,
Vardey CJ. Effects of β-adrenoceptor agonists in human 88. Sellares J, López-Giraldo A, Lucena C, Cilloniz C, Amaro Bakerly ND. Risk of pneumonia with inhaled corticosteroid
bronchial smooth muscle. Br J Pharmacol 1993; 110:1112– R, Polverino E, et al. Influence of previous use of inhaled versus long-acting bronchodilator regimens in chronic
1116. corticoids on the development of pleural effusion in obstructive pulmonary disease: a new-user cohort
community-acquired pneumonia. Am J Respir Crit Care Med study. PLoS One 2014; 9:e97149.
76. Johnson M. Salmeterol. Med Res Rev 1995; 15:225–257.
2013; 187:1241-8.
100. Yasui H, Inui N, Fujisawa T, Karayama M, Enomoto N,
77. Araujo D, Padrao E, Morais-Almeida M, et al. Asthma-
89. Ernst P, Gonzalez AV, Brassard P, Suissa S.  Inhaled Nakamura Y, et al. Low-dose Fluticasone Propionate in
chronic obstructive pulmonary disease overlap syndrome
corticosteroid use in chronic obstructive pulmonary disease Combination With Salmeterol in Patients With Chronic
– Literature review and contributions towards a Portuguese
and the risk of hospitalization for pneumonia. Am J Respir Obstructive Pulmonary Disease. Clin Med Insights Circ Respir
consensus. Rev Port Pneumol 2017; 23:90–99.
Crit Care Med 2007; 176:162–166. Pulm Med 2018; 12:1179548418771702.
78. Lau EMT, Roche NA, Reddel HK. Therapeutic approaches
90. Jenkins CR, Jones PW, Calverley PM, et al. Efficacy of 101. Sin DD, Wu L, Anderson JA, et al. Inhaled corticosteroids and
to asthma chronic obstructive pulmonary disease overlap.
salmeterol/fluticasone propionate by GOLD stage of mortality in chronic obstructive pulmonary disease. Thorax
Expert Rev Clin Immunol 2017; 13:449–455.
chronic obstructive pulmonary disease: analysis from the 2005; 60:992–997.
79. Kondo M, Tamaoki J. Therapeutic approaches of asthma and

TM

my

Journal of

The Association of Physicians of India

JAPI app
Available for Android and Apple mobiles
Visit playstore
Search: myjapi
Download and Install
Prof. Milind Y. Nadkar
Editor-in-Chief, JAPI

View publication stats