Optimising treatment for COPD

Children’s Healthcare of Atlanta

By

What can we do ???What can we do ???COPD

Disease Management should now be focusing on
2 key areas
1.
Goal of COPD Management

Road Map

• Smoking cessation is the single most effective
and cost-effective intervention to reduce the
risk of developing COPD and stop its
progression (Evidence A) .

COPD progression
Age (year)
FEV1%ofvalueatage25yr
100
75
50
25
5025 75
Death
Disability
Adapted from:Fletcher C,et al.Br Med J.1977;1:1645-1648
Nonsmokers
20-30 ml/year
COPD
60 mL/year
Symptoms

Children’s Healthcare of Atlanta 10

15
Role of Bronchodilators in COPD

V
BD
 Air flowDeflation
 Improvement in flow – FEV1
 Improvement in volumes – FVC and IC
Bronchodilator therapy deflates the lung
BD = bronchodilator; V = ventilation; FEV1= forced expiratory volume in 1 second;
FVC= forced vital capacity; IC = inspiratory capacity

17
Expiratory flow-limitation and lung hyperinflation that are only partially reversible to
bronchodilator therapy are pathophysiological hallmarks of COPD

• Bronchodilators have been shown to have beneficial
effects in COPD patients on:
Bronchodilators
Symptoms
Quality of life
Exacerbations
(sudden worsening)
COPD, chronic obstructive pulmonary disease
Ferro TJ. Clinical Pulmonary Medicine 2005;12(4 Suppl):S13-S15;
Decramer M. Eur Respir Rev 2006;15(99):51-57.

28
LABA
DPI Diskus Serevent®
(Salmeterol)
DPI Aerolizer Foradil®
(Formoterol)
DPI Breezhaler Onbrez®
(Indacaterol)
SMI Respimat Striverdi®
(Olodaterol)
LABA inhalers for COPD

39
LAMA
DPI HandiHaler/
SMI Respimat
Spiriva®
(Tiotropium)
DPI Breezhaler Seebri®
(Glycopyrronium)
DPI Genuair Eklira®
(Aclidinium)
DPI Ellipta Incruse®
(Umeclidinium)
LAMA inhalers for COPD

Proskocil BJ et al. Proc Am Thorac Soc. 2005;2(4):305-310.
SMC relaxationSMC contraction
M3- muscarinic
receptors
Beta Agonists
(LABA)Antocholinergics
(LAMA)
β2-adrenergic
receptors
Mechanisms of action of bronchodilators
on airway smooth muscle

46
Fixed-dose
combination
LABA/LAMA
DPI Ellipta Anoro®
(vilanterol/umeclidinium)
DPI Breezhaler Ultibro®
(indacaterol/glycopyrronium)
SMI Respimat Inspiolto®
(olodaterol/tiotropium)
DPI Genuair Duaklir®
(formoterol/aclidinium)
Combination LABA/LAMA inhalers for COPD

53
ICS/LABA
DPI Diskus Advair®
(Fluticasone/salmeterol)
DPI Turbuhaler Symbicort®
(Budesonide/formoterol)
DPI Ellipta Relvar®
(Fluticasone/vilanterol)

63
GOLD2001GOLD2001
GOLD2011GOLD2011
GOLD2017GOLD2017

COPD: Management
Clinical diagnosis
Spirometry
Gold Severity stage
Drugs a/t stages

SYMPTOMS
Cough
Sputum
Shortness of breath
EXPOSURE TO RISK
FACTORS
Tobacco
Occupation
Indoor/outdoor pollution
SPIROMETRY
Diagnosis of COPD

Pharmacological treatment of stable COPD based on GOLD
guidelines 2001.

72
ABCD assessment (GOLD 2011)

73

GOLD report 2017:
Current pathways to the diagnosis of COPD
Symptoms to
consider
COPD
•Dyspnoea
•Chronic cough
or
•Sputum
production
Symptoms to
consider
COPD
•Dyspnoea
•Chronic cough
or
•Sputum
production
Spirometry (post-bronchodilator)
FEV1/FVC <0.7 confirms the presence of airway limitation
and/or
history of
exposure to
risk factors
and/or
history of
exposure to
risk factors
Spirometry: Required to establish diagnosis
Symptoms
•Shortness of
breath
•Chronic cough
•Sputum
Risk factors
•Host factors
•Tobacco
•Occupation
•Indoor/outdoor
pollution

(Diagnosis and initial assessment)
Refined A, B, C, D assessment tool: overview
(C) (D)
(A) (B)
FEV1 (%
predicted)
GOLD 1 ≥ 80%
GOLD 2 50-79
GOLD 3 30-49
GOLD 4 < 30
Post-
bronchodilator
FEV1/FVC < 0.7
Post-
bronchodilator
FEV1/FVC < 0.7
≥ 2 or ≥ 1
leading to
hospital
admission
≥ 2 or ≥ 1
leading to
hospital
admission
0 or 1
(not leading
to hospital
admission)
0 or 1
(not leading
to hospital
admission)
Spirometrically
confirmed
diagnosis
Spirometrically
confirmed
diagnosis
Assessment of
airflow
limitation
Assessment of
airflow
limitation
Assessment of
symptoms/risk
of exacerbations
Assessment of
symptoms/risk
of exacerbations
Exacerbation
history
Symptoms
CAT < 10 CAT > 10
mMRC 0–1 mMRC > 2

ABCD assessment 2017 has been refined: Spirometry
Spirometry is still relevant
for:
•Diagnosis
•Prognostication
•Treatment with non-
pharmacological therapies
Classification unchanged!
FEV1 (%
predicted)
GOLD 1 ≥ 80%
GOLD 2 50-79
GOLD 3 30-49
GOLD 4 < 30
Post-
bronchodilator
FEV1/FVC < 0.7
Post-
bronchodilator
FEV1/FVC < 0.7
Spirometrically
confirmed
diagnosis
Spirometrically
confirmed
diagnosis
Assessment of
airflow
limitation
Assessment of
airflow
limitation

ABCD assessment 2017 has been refined:
(C) (D)
(A) (B)
0 or 1
(not leading
to hospital
admission)
0 or 1
(not leading
to hospital
admission)
Assessment of
symptoms/risk
of exacerbations
Assessment of
symptoms/risk
of exacerbations
Exacerbation
history
Symptoms
CAT < 10 CAT > 10
mMRC 0–1 mMRC > 2
Assessment of A, B, C, D and
therapy recommendations
are based exclusively on:
Respiratory symptoms
Exacerbation history
≥ 2 or ≥ 1
leading to
hospital
admission
≥ 2 or ≥ 1
leading to
hospital
admission

82
0-1 = less breathlessness
>2 = more breathlessness

83
Cough
Sputum
Chest tightness
Walking up hill
ADLs
Leaving the house
Sleep
Energy levels

85
Bronchodilators
Continue , stop or
try alternative
class of
bronchodilators
Evaluate effect
Group A Group B
A long – acting bronchodilators
( LABA or LAMA )
LAMA + LABA
Persistent
Symptoms
Group C
LAMA
LAMA + LABA LABA + ICS
Further
exacerbation(s)
Group D
LAMA LAMA + LABA LABA + ICS
LAMA
+ LABA
+ ICS
Consider Roflumilast
if FEV1 50% pred.˂
And patient has
chronic bronchitis
Consider
macrolides in
former smokers
Further exacerbation(s)
Further
exacerbation(s)
Persistent
Symptoms / further
exacerbation(s)

Pharmacologic treatment in detail:
GOLD Group A patients
(A)
Continue, stop or try
alternative class of
bronchodilator
Continue, stop or try
alternative class of
bronchodilator
A bronchodilatorA bronchodilator
Evaluate effect
GOLDGroup A
As a preferred choice all group
A patients should be offered a
short- or a long-acting
bronchodilator (dependent on its
effect on breathlessness).
Continuation with treatment if
symptomatic benefit is
documented
If necessary, an alternative class
of bronchodilator can be used if
benefit is not achieved with the
first.
GOLDGroup A
As a preferred choice all group
A patients should be offered a
short- or a long-acting
bronchodilator (dependent on its
effect on breathlessness).
Continuation with treatment if
symptomatic benefit is
documented
If necessary, an alternative class
of bronchodilator can be used if
benefit is not achieved with the
first. In patients with a majordiscrepancy between the perceived level of
symptoms
and severity of airflow limitation, furtherevaluation is warranted

Preferred
treatment
GOLD Group B patients
(B)
A long-acting
bronchodilator
(LABA or LAMA)
A long-acting
bronchodilator
(LABA or LAMA)
Persistent
symptoms
LAMA + LABALAMA + LABA
GOLD Group B
Although a long-acting
bronchodilator is yet
recommended as initial
therapy, LAMA/LABA are
recommended
- if symptoms persist
or
- from the start in patients with
severe breathlessness
GOLD Group B
Although a long-acting
bronchodilator is yet
recommended as initial
therapy, LAMA/LABA are
recommended
- if symptoms persist
or
- from the start in patients with
severe breathlessness
In patients with a majordiscrepancy between the perceived level of
symptoms

88
 For Group B patients, therapy should begin with a long-
acting bronchodilator LABA or LAMA , (no evidence to
recommend one over another), and should be escalated
to two bronchodilators if breathlessness continues with
monotherapy.
 If breathlessness is severe, starting the patient on dual
long-acting bronchodilators can be considered, however
if the second therapy does not improve symptoms, the
guidelines suggest stepping down to one bronchodilator.

(C)
LAMA + LABALAMA + LABA LABA + ICSLABA + ICS
LAMALAMA
Further
exacerbation(s)
GOLD Group C patients
Preferred
treatment
GOLD Group C
Starting therapy with a LAMA
In case of persistent
exacerbations addition of a
LABA  LAMA/LABA as
first choice
(LABA/ICS could be an
alternative but patients are on
higher risk for developing
pneumonia)
GOLD Group C
Starting therapy with a LAMA
In case of persistent
exacerbations addition of a
LABA  LAMA/LABA as
first choice
(LABA/ICS could be an
alternative but patients are on
higher risk for developing
pneumonia)
symptoms

90
 For Group C patients, it is recommended that treatment be
started with a single long-acting bronchodilator,
preferably a LAMA (LAMA was superior to the LABA
regarding exacerbation prevention).
 A second long-acting bronchodilator or the combination of
LABA/ICS may be used for persistent exacerbations;
 The guidelines recommend LABA/LAMA as the addition of
ICS has been shown to increase pneumonia risk in some
patients.

The use of ICS-containing therapies in COPD
• Compared to non-ICS-containing therapies in COPD,
therapies containing ICS, eg, LABA/ICS FDC are
associated with greater risk of:
– Pneumonia1-6
– Bone density decline and fractures7-10
– Candidiasis and skin lesions6,11,12
– Cataracts13
• Evidence linking ICS-containing therapies with
increased risk of diabetes mellitus14,15
1. Calverley PM, et al. N Engl J Med. 2007;356:775-789. 2. Crim C, et al. Eur Respir J. 2009;34:641-647;
3. Drummond MB, et al. JAMA. 2008;300:2407-2416;
4. Rodrigo GJ, et al. Chest. 2009;136:1029-1038. 5. Singh S, Loke YK. Curr Opin Pulm Med. 2010;16:118-122;
6. Yang IA, et al. Cochrane Database Syst Rev. 2012;7:CD002991. 7. Lung Health Study Research Group. N Engl J Med. 2000;343:1902-1909;
8. Scanlon PD, et al. Am J Respir Crit Care Med. 2004;170:1302-1309. 9. Hubbard R, et al. Chest. 2006;130:1082-1088;
10. Loke YK, et al. Thorax. 2011;66:699-708. 11. Alsaeedi A, et al. Am J Med. 2002;113:59-65;
12. Mahler DA, et al. Am J Respir Crit Care Med. 2002;166:1084-1091;
13. Weatherall M, et al. Respirology. 2009;14:983-990;
14. O’Byrne PM, et al. Respir Med. 2012;106:1487-1493;
15. Suissa S, et al. Am J Med. 2010;123:1001-1006.
COPD, chronic obstructive pulmonary disease; FDC, fixed-dose combination;
ICS, inhaled corticosteroid; LABA, long-acting β2-agonist

GOLD Group D patients
(D)
LAMA + LABALAMA + LABALAMALAMA
LAMA +
LABA + ICS
LAMA +
LABA + ICS
Further
exacerbation(s)
Further
exacerbation(s)
Consider roflumilast
if FEV1 <50% pred.
and patient has
chronic bronchitis
Consider roflumilast
if FEV1 <50% pred.
and patient has
chronic bronchitis
Consider
macrolide
(in former
smokers)
Consider
macrolide
(in former
smokers)
Persistent
symptoms/further
exacerbation(s)
De-escalation from ICS containing to
LAMA/LABA treatments if ICS
shows lack of efficacy!
GOLD Group D
•LAMA/LABA is recommended from the
start
-Since a LAMA/LABA combination was superior to a
LABA/ICS combination in preventing exacerbations and
other patient reported outcomes in group D patients
-as the default treatment for patients who are de-
escalated from ICS-containing treatments
•For patients with a history and/or findings of
concurrent asthma, LABA/ICS may be the first
choice
•For patients who develop further exacerbations
on LAMA/LABA two alternatives are suggested
-Escalation to triple therapy
-Switch to LABA/ICS (but no evidence that switching from
LAMA/LABA results in better exacerbation prevention)
GOLD Group D
•LAMA/LABA is recommended from the
start
-Since a LAMA/LABA combination was superior to a
LABA/ICS combination in preventing exacerbations and
other patient reported outcomes in group D patients
-as the default treatment for patients who are de-
escalated from ICS-containing treatments
•For patients with a history and/or findings of
concurrent asthma, LABA/ICS may be the first
choice
•For patients who develop further exacerbations
on LAMA/LABA two alternatives are suggested
-Escalation to triple therapy
-Switch to LABA/ICS (but no evidence that switching from
LAMA/LABA results in better exacerbation prevention)
symptoms
and severity of airflow limitation, further evaluation is warranted
LABA + ICSLABA + ICS

93
 For Group D patients, a LABA/LAMA combination is
preferred as initial therapy over LABA/ICS as these patients
may be at higher risk of developing pneumonia with ICS
use.
 For patients with high blood eosinophil counts or those
with asthma-COPD overlap, LABA/ICS could be considered
first-line therapy.

94
In patients who develop further exacerbations on
LABA/LAMA therapy we suggest two alternative
pathways:
1.Escalation to LABA/LAMA/ICS (Triple therapy).
2.Switch to LABA/ ICS
If LABA/ICS therapy does not positively impact
exacerbations/symptoms a LAMA can be added.

95
• For patients who still have exacerbations with
LABA/LAMA/ICS, the following three options can be
considered:
• 1) adding roflumilast (for patients with FEV1<50% predicted
and chronic bronchitis)
• 2) adding a macrolide (azithromycin preferred, however,
antibiotic resistance should be factored in decision-
making)
• 3) discontinuing ICS.

The use of ICS-containing therapies in COPD
• Bronchodilators are central to symptom management in
COPD
– GOLD 2017 guidelines recommend bronchodilators in all
patients with COPD
• ICS-containing therapies currently over-used in management of COPD
– More than 70% of patients with COPD are currently receiving an
ICS-containing therapybut, based on GOLD guidelines, this should be
less than 20%
– ICS should be reserved for those patients in whom additional
bronchodilation is failing to control their exacerbations
• ICS in combination with LABA have limited role in COPD
1. Barnes PJ. Chest. 2000;117(2 Suppl):10S-14S;
2. Global Strategy for the

100
Is ICS Withdrawal or Step Down
Therapy Possible
in COPD?

102
WISDOM (Withdrawal of Inhaled Steroids During
Optimised bronchodilator Management) study

103
6-7 0
S
C
R
E
E
N
I
N
G
Treatment
52Week -6
ICS
(remained on triple therapy from run-in)
Stepwise ICS withdrawal
(remained on dual bronchodilator)
Run-in
Triple
therapy
12
R
A
N
D
O
M
I
S
A
T
I
O
N
ICS stepwise withdrawal Stable
treatment
Reduced to 250 µg BID
Reduced to 100 µg BID
Reduced to 0 µg (placebo)
Fluticasone propionate 12-week
withdrawal schedule
500 µg BID
18
• Tiotropium 18 µg QD
• Salmeterol 50 µg BID
• Fluticasone propionate 500 µg BID
Triple therapy
regimen
WISDOM: Study design

104
 With a controlled, stepwise withdrawal of ICS , the risk
of exacerbation would be similar to that with continued
use of ICS in patients with severe or very severe COPD
who were receiving a combination of a LAMA
(tiotropium) and a LABA (salmeterol).
WISDOM Study Results

105
Stepping Down ICS: A Proposed Algorithm
Kaplan AG. Int J COPD. 2015;10:2535-2548.

106

107
 ICS are not recommended as monotherapy in COPD .
 ICS-containing pharmaceutical regimens no longer
recommended as first-choice treatments for COPD of any
severity .
 In addition, the new GOLD Strategy suggests that ICS therapy
may be withdrawn safely (de-escalation path ) in people with
COPD who are in GOLD group D and stable, by using a
LAMA/LABA regimen.

108
 The updated 2017 GOLD Strategy now positions a combination
of a LAMA (long-acting muscarinic receptor antagonists ) and
a LABA (long-acting beta2-agonist), as a mainstay treatment
for people with COPD in GOLD groups B-D.
 This represents a significant change versus previous GOLD
guidelines.

109
LAMA/LABA combination plays a central role in COPD management in GOLD
2017 updates and with more restriction on ICS use
LAMA/LAB
A plays a
critical,
central role
for GOLD
groups B-D
Limited role
of ICS in
Group C and
D
Group A
and B
completely
ICS-free

Optimising treatment for COPD

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