Combination

Therapies in
COPD
Speaker :
Dr. Kaushik Saha
Associate Professor
Medical College Kolkata
Respiratory Medicine Department
 COPD – Chronic Obstructive Pulmonary
Disease
COPD is a common, preventable and treatable disease that is
characterized by persistent respiratory symptoms and airflow
limitation that is due to airway and/or alveolar abnormalities
GOLD 2022
Definition usually cause by significant exposure to noxious particles or gases
and influenced by host factors including abnormal lung
development

Global initiative for chronic obstructive lung disease 2022 Report. https://goldcopd.org/.
 What is Chronic Obstructive Pulmonary
Disease?
Patient is usually greater
than age 45
Respiratory symptoms of
cough, shortness of
breath
Post-bronchodilator
FEV1/FVC ratio <0.7
History of cigarette
smoking and/or other
pollutants
COPD – Burden in India

From 1990 to 2016:1,2

Number of cases of COPD
increased from 28·1 million to
55·3 million
Prevalence of COPD increased
by 29.2%
DALYs due to COPD increased by
36.3%

2021: Pooled estimate COPD

Salvi S et al. Lancet Glob Health, 6 (2018), pp. e1363-e1374
prevalence in India: 7.4% Daniel RA et. al. Lung India. 2021;38:506–13.
Hossain MM et al. Int J Pul & Res Sci. 2018; 2(5):1-4.
Risk factors
for COPD
What happens? Air Trapping & Poor
Gas Exchange
Small airway
inflammation
(obstruction)
and

Parenchyma
destruction
(emphysema)
What is Emphysema?
The lungs are made up of
several tiny air sacs
called alveoli.
These air sacs are
normally stretchy and
springy. When you
breathe in, the airs sacs
expand like tiny balloons.
In emphysema, the walls
of the air sacs (alveoli) of
the lung are damaged and
lose their stretchiness.
 Symptoms
Chronic and progressive dyspnea - most characteristic symptom of
COPD.
o A sense of increased effort to breathe, chest heaviness, air hunger, or
gasping.
Cough with sputum production - up to 30% of patients.
Often the first symptom of COPD, frequently discounted by the
patient as an expected consequence of smoking and/or
environmental exposures.
Initially, may be intermittent, - present every day, often throughout
the day (later stages).
May be productive or unproductive.
COPD patients commonly raise small quantities of tenacious sputum
with coughing
Significant airflow limitation may develop without the presence of a
cough.
Regular production of sputum for three or more months in two
consecutive years is usually typical for COPD patients.
Wheezing and chest tightness - may vary between days, and over the
course of a single day.
Additional features in severe disease include
Fatigue,
 Additional investigations as part of diagnosis and assessment
of COPD:
Imaging (chest X-ray, CT)
Lung volumes and diffusing capacity
Oximetry and arterial blood gas measurement
Exercise testing and assessment of physical activity
Composite scores (BODE method)

BODE: Body mass index, Obstruction, Dyspnea, and Exercise GOLD

2020
GOLD 2023
5th major revision of GOLD report
(4th was in 2017)
Several novel and updated
recommendations
ABCD assessment tool modified
to ABE Assessment Tool
New definitions of COPD and
exacerbations
New information on the choice of
inhaler device
https://goldcopd.org/2023-gold-report-2/; last accessed on 16th November
GOLD 2023

https://goldcopd.org/2023-gold-report-2/; last accessed on 16th November

GOLD 2023

https://goldcopd.org/2023-gold-report-2/; last accessed on 16th November

 GOLD 2023

https://goldcopd.org/2023-gold-report-2/;
last accessed on 16th November
GOLD 2022 Report
Commonly used maintenance medications in COPD

Inhaler based
therapy
Fixed-Dose Combination LAMA/LABAs
Approved by US-FDA

Umeclidinium Vilanterol Aclidiniu Formoterol

m
Once daily; dry powder inhaler Twice daily; dry powder inhaler

Tiotropium Olodaterol Glycopyrrolate Formoterol

Once daily; soft mist inhaler Twice daily; pressurized metered dose inhaler

FDCs have the potential to: Glycopyrrolate Indacaterol

Maximize bronchodilation Twice daily*; dry powder inhaler
Provide synergistic effects
Simplify treatment regimen *In Europe, once daily dose/formulation

Singh D. Br J Clin Pharmacol. 2014;79:695-

708.
COPD Exacerbations
Defined as an acute worsening of respiratory symptoms that
result in additional therapy

Acute exacerbation – A serious event triggering a catastrophic cascade -

potentially overwhelming & life-threatening, akin to a ‘stroke of the lungs’

Characterized by an increase in airway inflammation, edema, mucus production,

bronchoconstriction
Even mild COPD patients can have life-threatening exacerbations
Exacerbations risk significantly higher with GOLD 3 (severe) & GOLD 4 (very severe)
COPD
COPD exacerbations account for the greatest proportion of the total COPD burden

Global strategy for the diagnosis, management, and prevention of Chronic Obstructive Pulmonary Disease (2022 Report).
Sandelowsky H et. al. BMC Family Practice. 2021 Dec;22(1):1-7.
Impact of Exacerbations
COPD exacerbations associated with
x More rapid decline in FEV1
x Poorer QoL
x Hospitalizations
x Disease progression
x Increased risk of CVD
x Risk of further exacerbations
x Increased mortality

Downward spiral of COPD

exacerbations
Sandelowsky H et. al. BMC Family Practice. 2021 Dec;22(1):1-7. Hurst JR et. al. Eur J Internal Med. 2020;73:1–6.
Impact of Exacerbations on Outcomes
Lung Health Study – in smokers, each
additional exacerbation caused a
greater annual decline in FEV1 by 7
mL
London COPD cohort study –
increased rate of decline of 8 mL/year
in more frequent exacerbators vs.
infrequent exacerbators
In severe acute exacerbation of
COPD, 180-day mortality rate – 33%
and 2-yr mortality rate – 49%
Am J RespirCrit Care Med 2001;164:358-64.
Thorax 2002; 57: 847–852.
Am J Respir Crit Care Med 1996; 154: 959–
967.
Economic burden of COPD Exacerbations

Observational study conducted

in a tertiary care hospital
located in Srinagar, India
129 patients admitted to the
hospital with severe AECOPD
were enrolled in the study
Median total cost per
exacerbation episode – INR
44,390
Annals of Global Health. 2019; 85(1): 13, 1–5.
Combination
Pharmacotherapy
in COPD
 ICS + LABA

ICS with LABA

More effective than either
component alone in
improving lung function,
health status & reducing
exacerbations

Global strategy for the diagnosis, management, and prevention of Chronic Obstructive Pulmonary Disease (2022 Report).
Barnes PJ Pharmaceuticals, 3 (2010), pp. 514-540
Global initiative for chronic obstructive lung disease. https://goldcopd.org/ (04.01.2022).
LAMA + LABA

Synergistic effect rather than just being

additive
Greater degree of bronchodilation potentially
at lower doses of individual components thus
minimizing side effects
At least 15% increase in post-bronchodilator
FEV1 reversibility with β2 agonist + Muscarinic
antagonist
No meaningful PK interactions - whether
drug–drug or due to formulation

Cazzola M et al. Pulmonary pharmacology & therapeutics. 2010 Aug 1;23(4):257-67.

Nardini S. et. al. Multidiscip Respir Med. 2014;9(1):50
Ferguson GT et al. International journal of chronic obstructive pulmonary disease. 2018;13:945.
Tamura G. Respir Med 2007; 101: 1895–902.
 LABA + LAMA + ICS

Three different drug classes

have synergistic effect on
increasing receptor expression
& binding amongst them
Enhances anti-inflammatory
effect and modulates the
release of mediators
Three different pharmacological
mechanisms of action:
Maximize clinical benefits &
prevent exacerbations

Global strategy for the diagnosis, management, and prevention of Chronic Obstructive Pulmonary Disease (2022 Report).
Micheletto C et. al. Curr Respir Med Rev 2019; 15: 102-11.
Global initiative for chronic obstructive lung disease. https://goldcopd.org/ (04.01.2022).
 PRIMUS Study: Prompt Initiation
of Maintenance therapy in the US
Real-world evaluation in 24,770 patients ≥40 years old with
COPD who initiated triple therapy after ≥2 moderate or ≥1
severe exacerbation in the prior year
Patients were stratified by triple therapy timing: prompt
(≤30 days post-index exacerbation), delayed (31–180 days),
very delayed (181–365 days)
Nearly one third (30.6%) of patients had prompt, 39.1%
delayed, and 30.3% very delayed initiation of triple therapy

Int J Chr Obstruct Pulm Dis. 2022:17:329-42.

 PRIMUS Study
Each 30-day delay in initiation of
triple therapy associated with
11% increased odds of any
exacerbation
7% increased odds of severe
exacerbation
4.3% increase in the number of
exacerbations
5.5% increased odds of any
hospitalization
2.1% increase in COPD-related costs

Int J Chr Obstruct Pulm Dis. 2022:17:329-42.

PRIMUS Study
Initiation of triple therapy 4 months after index-
exacerbation compared to initiation <30 days after
exacerbation leads to:
44% greater odds of an exacerbation ( 1 in 2 )
26% greater odds of a severe exacerbation ( 1 in 4 )
22% greater odds of an all-cause inpatient
admission ( 1 in 5 )
13% greater odds of a 90-day COPD readmission

Int J Chr Obstruct Pulm Dis. 2022:17:329-42.

PRIMUS Study
Conclusions
Prompt initiation of triple therapy decreases risk of
future exacerbations
Timely consideration of triple therapy after a single
severe exacerbation or two moderate exacerbations
could decrease overall patient morbidity and lessen
the economic burden of COPD

Int J Chr Obstruct Pulm Dis. 2022:17:329-42.

Pragmatic Positioning of Triple
Therapy
Triple Therapy with ICS/LAMA/LABA may be the immediate
choice in
Patients who present for the first time, and have severe airway
obstruction (FEV1 <50%) and are symptomatic
Patients who have had frequent (≥2) moderate or severe
exacerbations (≥1 hospitalisation) in the previous
year
Patients who have peripheral eosinophilia (>300 cells/μL)
Patients with significant lung function decline
Patients discharged from hospital after a COPD exacerbation

Int J Chron Obstruct Pulmon Dis. 2022

Jan 14;17:165-80.
Triple Therapy – Issues
Triple therapy has been prescribed with two separate inhalers
ICS/LABA inhaler and a LAMA inhaler or
LABA/LAMA inhaler and an ICS inhaler

Factors contributing to poor adherence among COPD patients

Treatment complexity
Dosing frequency
Number of medications
Ease of use of the inhalers
Learning different techniques for different inhalers may reduce
adherence: Many patients fail to use even one inhaler correctly

SITT could help address poor adherence with COPD medications, which is common
leading to increased exacerbations, persistent symptoms & poor economic outcomes

Gaduzo S et. al. Int J Chron Obstruct Pulmon Dis. 2019;14:391

Issues with using Multiple Inhalers

J Med Econ. 2011;14(4):486-96

 Clinical Characteristics, Treatment Persistence
and Outcomes among Patients with COPD treated
with SITT or MITT
Real-world, observational, retrospective cohort study from
Spain recently published in CHEST
Compared the effectiveness of SITT vs MITT in not just
treatment persistence, but also on mortality, exacerbation
prevention, and economic consequences in COPD patients
4,625 COPD patients starting triple therapy (LAMA, LABA, ICS),
either with SITT (n=1,011; 21.9%) or MITT using two or three
inhalers (n=3,614; 78.1%) included
Patients were followed up until treatment discontinuation or
for a maximum of 12 months

Chest. 2022 Jul 1:S0012-

3692(22)01212-0.
 Clinical Characteristics, Treatment Persistence
and Outcomes among Patients with COPD treated
with SITT or MITT

Patients initiating SITT had

37% higher persistence vs.
MITT during 12-month
follow-up (HR=1.37; 95%
CI=1.22 to 1.53; P<0.001)
Treatment persistence
rates in SITT vs. MITT
cohort were higher at both
6 months (80.6% vs. 76.7%;
P=0.008) and 12 months
(62.4% vs. 53.8%; P<0.001)
Chest. 2022 Jul 1:S0012-
3692(22)01212-0.
 Clinical Characteristics, Treatment Persistence
and Outcomes among Patients with COPD treated
with SITT or MITT
Patients in the SITT group vs.
MITT had
32% lower risk of
exacerbations (HR=0.68; 95%
CI=0.61 to 0.77; P=0.001)
Significantly lower mean
number of exacerbations
(0.56 vs. 0.71; P<0.001)
Prolonged mean time to first
exacerbation (203 vs.179
days; P<0.001)

Chest. 2022 Jul 1:S0012-

3692(22)01212-0.
 Clinical Characteristics, Treatment Persistence
and Outcomes among Patients with COPD treated
with SITT or MITT

Patients initiating SITT had

a 33% reduced risk of 12-
month all-cause mortality
vs. MITT (HR=0.67; 95%
CI=0.63 to 0.71, P=0.027)
SITT was associated with
significant reductions in
the use of COPD related
healthcare resources and
costs
Chest. 2022 Jul 1:S0012-
3692(22)01212-0.
Advantages of Triple Therapy FDC –
SITT
Synergistic effect of three different drug classes

Shown to improve lung function, patient reported outcomes

& reduce exacerbations vs. LAMA alone, LABA/LAMA &
LABA/ICS

Reduce mortality vs. LABA/LAMA

Improve patient convenience, adherence and compliance

Therapeutic Options in COPD Patient Journey

Vanfleteren LEGW et. al. ERJ Open Res 2019; 5: 00185–02018.

 Take Home Messages
There is mounting evidence from clinical trials and meta-
analysis that dual combination of LAMA/LABA is the highest
ranking therapy for patients irrespective of history of
exacerbations
ICS can be a useful add-on in specific set of patients
Recently, several trials have evaluated efficacy and safety
of fixed dose triple therapy ICS/LAMA/LABA – SITT
Clinical evidence from meta-analyses and real-world studies
suggest that SITT has advantages over dual combination as
well as over MITT in terms of exacerbations and mortality
Thank You