Role of LABACS

Provides a simple and effective for

COPD and Asthma Management
GOLD Guideline
 GOLD 2017 Report: Chapters

1. Definition and Overview

2. Diagnosis and Initial Assessment

3. Evidence Supporting Prevention

& Maintenance Therapy

4. Management of Stable COPD

5. Management of Exacerbations

6. COPD and Comorbidities

2017 Global Initiative for Chronic Obstructive Lung Disease

 Global Strategy for Diagnosis, Management and Prevention of COPD

Definition of COPD
n COPD, a common preventable and treatable
disease, is characterized by persistent airflow
limitation that is usually progressive and
associated with an enhanced chronic
inflammatory response in the airways and the
lung to noxious particles or gases.
n Exacerbations and comorbidities contribute to
the overall severity in individual patients.
2016 Global Initiative for Chronic Obstructive Lung Disease
 Global Strategy for Diagnosis, Management and Prevention of COPD

Diagnosis and Assessment: Key Points

A clinical diagnosis of COPD should be

considered in any patient who has dyspnea,
chronic cough or sputum production, and a
history of exposure to risk factors for the
disease.
Spirometry is required to make the diagnosis;
the presence of a post-bronchodilator FEV1/FVC
< 0.70 confirms the presence of persistent
airflow limitation and thus of COPD.

2015 Global Initiative for Chronic Obstructive Lung Disease

 Global Strategy for Diagnosis, Management and Prevention of COPD

Diagnosis of COPD

EXPOSURE TO RISK
SYMPTOMS FACTORS
shortness of breath
tobacco
chronic cough occupation
sputum indoor/outdoor pollution

SPIROMETRY: Required to establish

diagnosis
2015 Global Initiative for Chronic Obstructive Lung Disease
 Global Strategy for Diagnosis, Management and Prevention of COPD

Manage Exacerbations : Definition

An exacerbation of COPD is:

an acute event characterized by a
worsening of the patients respiratory
symptoms that is beyond normal day-
to-day variations and leads to a
change in medication.

2015 Global Initiative for Chronic Obstructive Lung Disease

 Global Strategy for Diagnosis, Management and Prevention of COPD

Manage Exacerbations: Key Points

The most common causes of COPD exacerbations
are viral upper respiratory tract infections and
infection of the tracheobronchial tree.
Diagnosis relies exclusively on the clinical
presentation of the patient complaining of an acute
change of symptoms that is beyond normal day-to-
day variation.
The goal of treatment is to minimize the impact of
the current exacerbation and to prevent the
development of subsequent exacerbations.
2015 Global Initiative for Chronic Obstructive Lung Disease
 FEV1 decline over 4 years and
exacerbation frequency
0.95

Frequent exacerbators

0.90 Infrequent exacerbators

FEV1 (l)

25% of FEV1 DECLINE ATTRIBUTED TO EFFECT

0.85

OF EXACERBATIONS
0.80

0.75
0 1 2 3 4

Years

Donaldson et al Thorax. 2002 ;57(10):847-52

 Frequent exacerbations impair
health status in COPD
Exacerbation frequency
Worse 02/year
100 38/year

P =0.001
P < 0.0005
80
P < 0.0005
SGRQ score

60 P = 0.002

40

20

0
Total Symptoms Activities Impacts

SGRQ = St. Georges Respiratory Questionnaire Seemungal TA, et al. Am J Respir Crit Care Med 1998;157:14181422.
 Increased frequency of exacerbations
increases the risk of mortality in COPD
1.0 0 exacerbations
12 exacerbations
3 exacerbations
0.8
Survival probability

P < 0.0002
0.6

P < 0.0001
0.4 P = 0.069

0.2

0
0 10 20 30 40 50 60
Time (months)

Soler-Cataluna JJ, et al. Thorax 2005;60:925931.

 ECLIPSE Survival curves related to prior
hospitalization history

100% 100%

95% 95%
Percent Survival

90% 90%

85% 85%

80% 80%

No COPD Hospitalization, prior year (n=1813)

75% COPD Hospitalization, prior year (n=325) 75%

0 6 12 18 24 30 36
Months Observed

Anzueto et al ATS (abstract 5374) 2011

 Exacerbation history: powerful predictor of exacerbations
1 exacerbation in year 1 1 exacerbation in year 2
Year 1 Year 2 Year 3
23%
6%
Exacerbations in the following year 2%
0 20 40 60 80 100
6%
3%
Patients with no exacerbation 2%
Patients with 1 exacerbation
0 20 40 60 80 100
Patients with 2 exacerbations 2%
0 20 40 60 80 100 2%
1%
Percent
0 20 40 60 80 100
5%
3%
1%
0 20 40 60 80 100
3%
2%
2%

0 20 40 60 80 100 2%
0 20 40 60 80 100 0 20 40 60 80 100 2%
3%
Percent Percent
0 20 40 60 80 100
2%
1%
1%
N=1679 patients who 0 20 40 60 80 100
completed the 3-year study 2%
2%
3%

The percentages at right denote the proportions of 0 20 40 60 80 100 1%

all patients with no exacerbations, one 0 20 40 60 80 100 4%
exacerbation, or two or more exacerbations Percent 12%
Hurst JR et al. N Engl J Med 2010;363:1128-1138 0 20 40 60 80 100
 ECLIPSE - COPD hospitalizations by
GOLD Stage
GOLD II GOLD III GOLD IV
60%

50%

40%

30%

20%

10%

0%
Year 1 Year 2 Year 3 Overall

Anzueto et al ATS (abstract 5374) 2011

 Frequent exacerbations drive
disease progression
PATIENTS WITH
FREQUENT EXACERBATIONS

Lower quality of life Increased mortality

Increased Increased risk of

recurrent exacerbations
inflammation

Faster disease Increased likelihood

progression of hospitalisation

Adapted from Wedzicha JA and Seemungal TA. Lancet 2007;370:786-796.;

and Donaldson GC and Wedzicha JA. Thorax 2006;61:164-168.
 Global Strategy for Diagnosis, Management and
Prevention of COPD

Combined Assessment
of COPD
When assessing risk, choose the highest risk
according to GOLD grade or exacerbation
history. One or more hospitalizations for COPD
exacerbations should be considered high risk.)

Patient Characteristic Spirometric Exacerbations CAT mMRC

Classification per year
Low Risk
A GOLD 1-2 1 < 10 0-1
Less Symptoms
Low Risk
B GOLD 1-2 1 > 10 >2
More Symptoms
High Risk
C GOLD 3-4 >2 < 10 0-1
Less Symptoms
High Risk >2
D GOLD 3-4 >2 > 10
More Symptoms
2015 Global Initiative for Chronic Obstructive Lung Disease
Global Strategy for Diagnosis, Management and
Prevention of COPD, 2015: Chapters

n Definition and Overview

n Diagnosis and Assessment
n Therapeutic Options
n Manage Stable COPD
n Manage Exacerbations
n Manage Comorbidities
Updated 2015 n Asthma COPD Overlap
Syndrome (ACOS)
2015 Global Initiative for Chronic Obstructive Lung Disease
 Global Strategy for Diagnosis, Management and Prevention of COPD
Therapeutic Options: Smoking Cessation

Counseling delivered by physicians and other health

professionals significantly increases quit rates over self-
initiated strategies. Even a brief (3-minute) period of
counseling to urge a smoker to quit results in smoking
quit rates of 5-10%.
Nicotine replacement therapy (nicotine gum, inhaler,
nasal spray, transdermal patch, sublingual tablet, or
lozenge) as well as pharmacotherapy with varenicline,
bupropion, and nortriptyline reliably increases long-
term smoking abstinence rates and are significantly
more effective than placebo.
2015 Global Initiative for Chronic Obstructive Lung Disease
 Brief Strategies to Help the
Patient Willing to Quit Smoking

ASK Systematically identify all

tobacco users at every visit
ADVISE Strongly urge all tobacco
users to quit
ASSESS Determine willingness to
make a quit attempt
ASSIST Aid the patient in quitting
ARRANGE Schedule follow-up contact.
2015 Global Initiative for Chronic Obstructive Lung Disease
 Global Strategy for Diagnosis, Management and Prevention of COPD
Therapeutic Options: COPD Medications

Beta2-agonists
Short-acting beta2-agonists
Long-acting beta2-agonists
Anticholinergics
Short-acting anticholinergics
Long-acting anticholinergics
Combination short-acting beta2-agonists + anticholinergic in one inhaler
Combination long-acting beta2-agonist + anticholinergic in one inhaler
Methylxanthines
Inhaled corticosteroids
Combination long-acting beta2-agonists + corticosteroids in one inhaler
Systemic corticosteroids
Phosphodiesterase-4 inhibitors
2015 Global Initiative for Chronic Obstructive Lung Disease
 Pharmacologic Therapy

2017 Global Initiative for Chronic Obstructive Lung Disease

 Pharmacologic Therapy

2017 Global Initiative for Chronic Obstructive Lung Disease

 Global Strategy for Diagnosis, Management and Prevention of COPD
Therapeutic Options: Bronchodilators

Bronchodilator medications are central to the

symptomatic management of COPD.
Bronchodilators are prescribed on an as-needed or on a
regular basis to prevent or reduce symptoms.
The principal bronchodilator treatments are beta2-
agonists, anticholinergics, theophylline or combination
therapy.
The choice of treatment depends on the availability of
medications and each patients individual response
in terms of symptom relief and side effects..
2015 Global Initiative for Chronic Obstructive Lung Disease
 Global Strategy for Diagnosis, Management and Prevention of COPD
Therapeutic Options: Bronchodilators

Long-acting inhaled bronchodilators are

convenient and more effective for symptom relief
than short-acting bronchodilators.
Long-acting inhaled bronchodilators reduce
exacerbations and related hospitalizations and
improve symptoms and health status.
Combining bronchodilators of different
pharmacological classes may improve efficacy and
decrease the risk of side effects compared to
increasing the dose of a single bronchodilator.
2015 Global Initiative for Chronic Obstructive Lung Disease
 Global Strategy for Diagnosis, Management and Prevention of COPD
Therapeutic Options: Inhaled
Corticosteroids
Regular treatment with inhaled corticosteroids
improves symptoms, lung function and quality of life
and reduces frequency of exacerbations for COPD
patients with an FEV1 < 60% predicted.

Inhaled corticosteroid therapy is associated with an

increased risk of pneumonia.

Withdrawal from treatment with inhaled

corticosteroids may lead to exacerbations in some
patients.
2015 Global Initiative for Chronic Obstructive Lung Disease
 Global Strategy for Diagnosis, Management and Prevention of COPD
Therapeutic Options: Combination
Therapy
An inhaled corticosteroid combined with a long-acting
beta2-agonist is more effective than the individual
components in improving lung function and health
status and reducing exacerbations in moderate to very
severe COPD.
Combination therapy is associated with an increased risk
of pneumonia.
Addition of a long-acting beta2-agonist/inhaled
glucorticosteroid combination to an anticholinergic
(tiotropium) appears to provide additional benefits.

2015 Global Initiative for Chronic Obstructive Lung Disease

 Global Strategy for Diagnosis, Management and Prevention of COPD
Therapeutic Options: Systemic
Corticosteroids

Chronic treatment with systemic

corticosteroids should be avoided
because of an unfavorable benefit-to-
risk ratio.

2015 Global Initiative for Chronic Obstructive Lung Disease

 Global Strategy for Diagnosis, Management and Prevention of COPD

Therapeutic Options: Theophylline

Theophylline is less effective and less well tolerated than

inhaled long-acting bronchodilators and is not
recommended if those drugs are available and affordable.

There is evidence for a modest bronchodilator effect and

some symptomatic benefit compared with placebo in stable
COPD. Addition of theophylline to salmeterol produces a
greater increase in FEV1 and breathlessness than
salmeterol alone.

Low dose theophylline reduces exacerbations but does not

improve post-bronchodilator lung function.

2015 Global Initiative for Chronic Obstructive Lung Disease

 Global Strategy for Diagnosis, Management and Prevention of COPD
Therapeutic Options: Other
Pharmacologic Treatments

Influenza vaccines can reduce serious illness.

Pneumococcal polysaccharide vaccine is recommended
for COPD patients 65 years and older and for COPD
patients younger than age 65 with an FEV1 < 40%
predicted.

The use of antibiotics, other than for treating infectious

exacerbations of COPD and other bacterial infections, is
currently not indicated.

2015 Global Initiative for Chronic Obstructive Lung Disease

 Global Strategy for Diagnosis, Management and Prevention of COPD
Therapeutic Options: Other
Pharmacologic Treatments
Alpha-1 antitrypsin augmentation therapy: not
recommended for patients with COPD that is unrelated
to the genetic deficiency.
Mucolytics: Patients with viscous sputum may
benefit from mucolytics; overall benefits are very small.
Antitussives: Not recommended.
Vasodilators: Nitric oxide is contraindicated in stable
COPD. The use of endothelium-modulating agents for
the treatment of pulmonary hypertension associated
with COPD is not recommended.
2015 Global Initiative for Chronic Obstructive Lung Disease
 Global Strategy for Diagnosis, Management and Prevention of COPD
Therapeutic Options: Rehabilitation

All COPD patients benefit from exercise training

programs with improvements in exercise tolerance
and symptoms of dyspnea and fatigue.

Although an effective pulmonary rehabilitation

program is 6 weeks, the longer the program
continues, the more effective the results.

If exercise training is maintained at home, the

patient's health status remains above pre-
rehabilitation levels.
2015 Global Initiative for Chronic Obstructive Lung Disease
 Global Strategy for Diagnosis, Management and Prevention of COPD
Therapeutic Options: Other Treatments

Oxygen Therapy: The long-term administration of

oxygen (> 15 hours per day) to patients with chronic
respiratory failure has been shown to increase
survival in patients with severe, resting hypoxemia.

Ventilatory Support: Combination of noninvasive

ventilation (NIV) with long-term oxygen therapy may
be of some use in a selected subset of patients,
particularly in those with pronounced daytime
hypercapnia.

2015 Global Initiative for Chronic Obstructive Lung Disease

 Global Strategy for Diagnosis, Management and Prevention of COPD
Therapeutic Options: Surgical
Treatments

Lung volume reduction surgery (LVRS) is more

efficacious than medical therapy among patients
with upper-lobe predominant emphysema and low
exercise capacity.

LVRS is costly relative to health-care programs not

including surgery.

In appropriately selected patients with very severe

COPD, lung transplantation has been shown to
improve quality of life and functional capacity.
2015 Global Initiative for Chronic Obstructive Lung Disease
Global Strategy for Diagnosis, Management and
Prevention of COPD, 2015: Chapters

n Definition and Overview

n Diagnosis and Assessment
n Therapeutic Options
n Manage Stable COPD
n Manage Exacerbations
n Manage Comorbidities
Updated 2015 n Asthma COPD Overlap
Syndrome (ACOS)
2015 Global Initiative for Chronic Obstructive Lung Disease
 Global Strategy for Diagnosis, Management and Prevention of COPD

Manage Stable COPD: Goals of Therapy

Relieve symptoms
Improve exercise tolerance Reduce
symptoms
Improve health status

Prevent disease progression

Reduce
Prevent and treat exacerbations risk
Reduce mortality
2015 Global Initiative for Chronic Obstructive Lung Disease
 Global Strategy for Diagnosis, Management and Prevention of COPD
Manage Stable COPD: All COPD Patients

Avoidance of risk factors

- smoking cessation
- reduction of indoor pollution
- reduction of occupational exposure
Influenza vaccination
2015 Global Initiative for Chronic Obstructive Lung Disease
 Global Strategy for Diagnosis, Management and Prevention of COPD
Manage Stable COPD: Non-pharmacologic

Patient Essential Recommended Depending on local

Group guidelines

Smoking cessation (can Flu vaccination

A include pharmacologic Physical activity Pneumococcal
treatment) vaccination

Smoking cessation (can

Flu vaccination
include pharmacologic
B, C, D Physical activity Pneumococcal
treatment)
vaccination
Pulmonary rehabilitation

2015 Global Initiative for Chronic Obstructive Lung Disease

 Global Strategy for Diagnosis, Management and Prevention of COPD
Manage Stable COPD: Pharmacologic Therapy
RECOMMENDED FIRST CHOICE

C D

Exacerbations per year

GOLD 4 ICS + LABA ICS + LABA 2 or more
or and/or or
LAMA LAMA > 1 leading
GOLD 3 to hospital
admission

A B
GOLD 2 1 (not leading
SAMA prn LABA to hospital
or or admission)
GOLD 1 SABA prn LAMA
0

CAT < 10 CAT > 10

mMRC 0-1 mMRC > 2
2015 Global Initiative for Chronic Obstructive Lung Disease
 Global Strategy for Diagnosis, Management and Prevention of COPD
Manage Stable COPD: Pharmacologic Therapy
ALTERNATIVE CHOICE

C D
LAMA and LABA ICS + LABA and LAMA

Exacerbations per year

GOLD 4 or
or
2 or more
ICS + LABA and PDE4-inh
LAMA and PDE4-inh or or
or LAMA and LABA > 1 leading
GOLD 3 LABA and PDE4-inh or to hospital
LAMA and PDE4-inh. admission
A B
GOLD 2 LAMA 1 (not leading
or LAMA and LABA to hospital
LABA admission)
GOLD 1 or
SABA and SAMA 0

CAT < 10 CAT > 10

mMRC 0-1 mMRC > 2
2014 Global Initiative for Chronic Obstructive Lung Disease
 Global Strategy for Diagnosis, Management and Prevention of COPD
Manage Stable COPD: Pharmacologic Therapy
OTHER POSSIBLE TREATMENTS

C D
SABA and/or SAMA Carbocysteine

Exacerbations per year

GOLD 4 2 or more
N-acetylcysteine or
Theophylline
SABA and/or SAMA > 1 leading
GOLD 3 to hospital
Theophylline admission
A B
GOLD 2 1 (not leading
SABA and/or SAMA to hospital
Theophylline
admission)
GOLD 1 Theophylline
0

CAT < 10 CAT > 10

mMRC 0-1 mMRC > 2
2015 Global Initiative for Chronic Obstructive Lung Disease
WHICH COPD PATIENTS BENEFIT
FROM ICS TREATMENT?
The Eosinophil Story
 Bud/Form: Efficacy in COPD Treatment
produces maintained improvement in lung
function vs. LABA alone
SYMBICORT
104
Formoterol
102 Budesonide
100
Mean FEV1 (% of baseline)

Placebo
98
96
94
92
90
88
86
84
82
80
0.5 0 1 2 3 4 5 6 7 8 9 10 11 12
Time from randomisation (months)

P < 0.001 SYMBICORTvs. placebo and budesonide;

P = 0.002 SYMBICORTvs. formoterol; P < 0.001 formoterol vs. placebo Calverley PM, et al. Eur Respir J 2003;22:912919.
Bud/Form significantly improves symptoms
within 1 week vs. LABA alone
0.35
Mean change in symptom score vs.

SYMBICORT
placebo after 1 week of treatment

0.30 -0.13
Formoterol
P=0.038
0.25
-0.20 -0.17
P=0.005 P= 0.012
0.20 -0.12
P= 0.047

0.15

0.10

0.05

0
Night-time Shortness Cough Chest
awakening of breath tightness

Patients had more rapid symptom relief with Symbicort due

to the addition of ICS
Szafranski W, et al. Eur Respir J 2003;21:7481.
 Bud/Form reduces the rate of exacerbations
requiring medical intervention vs. LABA alone
5 +3%
Rate of exacerbations/patient/year

0
3

Number needed to treat

5
2.1
10 2
12%
15
1
20

25 24%
0
Symbicort vs.
* formoterol
30
Symbicort Budesonide Formoterol

Treating 100 patients with COPD (GOLD stage IIIIV) with Symbicort
instead of formoterol alone may prevent 47 exacerbations in 1 year

*P < 0.05 vs. placebo;

P = 0.015 Symbicort vs. formoterol Calverley PM, et al. Eur Respir J 2003;22:912919.
Bud/Form as a combine therapy
Rate of severe exacerbations reduced by 62% with
budesonide/formoterol plus tiotropium compared
with tiotropium alone
Budesonide/formoterol + tiotropium
0.4 Placebo + tiotropium
Exacerbations/patient

0.3

0.2

0.1

0.0
62%
0 15 30 45 60 75 90
Days since randomisation
CLIMB study
Cox-proportional hazards: rate ratio 0.38 (95% CI 0.25, 0.57, p<0.001)
Figure reproduced from Welte T et al. Am J Respir Crit Care Med 2009; 180: 741750.
Official Journal of the American Thoracic Society. American Thoracic Society.
Budesonide/formoterol plus tiotropium reduced COPD
symptom scores compared with tiotropium alone

0.165
Mean difference in symptom score

p<0.001

0.160 p<0.001

0.155

0.150

0.145 p<0.001 p<0.001

0.140

0.135

0.130
Breathlessness Chest Cough Night-time
tightness awakenings

CLIMB study
p values, comparison between budesonide/formoterol plus tiotropium versus
placebo plus tiotropium
Welte T et al. Am J Respir Crit Care Med 2009; 180: 741750.
 Bud/Form reduces the need for oral steroids
Symbicort Budesonide Formoterol
0

5
Hazard ratio for time to first oral
steroid course vs. placebo (%)

10

15 13% 30.5%
14%

20
30.5%
25 reduction in
rate of
30 oral
steroid
use
35

40 vs. LABA alone

42%
45 *

*P < 0.001 vs. placebo;

P = 0.009 SYMBICORT vs. budesonide;
P = 0.007 SYMBICORT vs. formoterol Calverley PM, et al. PM,
Calverley EuretRespir J 2003;
al. Eur Respir 22: 912-919
J 2003;22:912919.
 Bud/Form improves health status
within 4 weeks
9

8 SYMBICORT-treated
patients
7
Health status

5
Clinically
4 meaningful
improvement
3

0
Symptoms Activity Impact Total

Symbicort leads to clinically relevant improvements in SGRQ scores vs baseline within

just 4 weeks of treatment in patients with moderate-to-severe COPD

SGRQ = St Georges Respiratory Questionnaire Bourbeau J, et al. Eur Respir J 2005;26(Suppl 49):296s.
 Prescriptions of COPD related medications

ICS, inhaled corticosteroids; LABA, long-acting 2 agonists; SABA, short-acting 2 agonists

Yearly rate of events calculated using Poisson regression

AZ data on file These data are communicated for scientific purpose only. Confidential slide set
 COPD Exacerbations
Events per 100 patient/years for exacerbations in propensity matched COPD patients treated
with BUD/FORM (n=2734) or FLU/SAL (n=2734)

NNT = 3.4

NNT = 16

Adjusted yearly rates of healthcare utilisation events were compared using Poisson regression analysis.
**P<0.0001; *P=0.0003 for difference.
CI, confidence intervals; BUD/FORM, budesonide/formoterol; FLU/SAL, fluticasone/salmeterol
AZ data on file These data are communicated for scientific purpose only. Confidential slide set
 Pneumonia-related events
Pneumonia events in propensity matched COPD patients
BUD/FORM (n=2734) or FLU/SAL (n=2734)

Adjusted yearly pneumonia event rates compared using Poisson regression analysis. P<0.001 for all.
CI, confidence intervals; BUD/FORM, budesonide/formoterol; FLU/SAL, fluticasone/salmeterol

AZ data on file These data are communicated for scientific purpose only. Confidential slide set
GINA 2016 Updated

These data are communicated for scientific purpose only. Confidential slide set
These data are communicated for scientific purpose only. Confidential slide set
 Stepwise management - pharmacotherapy
UPDATED!

Diagnosis
Symptom control & risk factors
(including lung function)
Inhaler technique & adherence
Patient preference

Symptoms
Exacerbations
Side-effects Asthma medications
Patient satisfaction Non-pharmacological strategies
Lung function Treat modifiable risk factors

STEP 5

STEP 4

STEP 3 Refer for *Not for children <12 years

PREFERRED STEP 1 STEP 2 add-on **For children 6-11 years, the
CONTROLLER treatment preferred Step 3 treatment is
CHOICE e.g.
Med/high tiotropium,* medium dose ICS
ICS/LABA omalizumab,
#For patients prescribed
Low dose mepolizumab*
Low dose ICS BDP/formoterol or BUD/
ICS/LABA**
formoterol maintenance and
reliever therapy
Other Consider low Leukotriene receptor antagonists (LTRA) Med/high dose ICS Add tiotropium* Add low
controller dose ICS Low dose theophylline* Low dose ICS+LTRA High dose ICS dose OCS Tiotropium by mist inhaler is
+ LTRA
options (or + theoph*)
(or + theoph*)
an add-on treatment for
patients 12 years with a
As-needed short-acting beta2-agonist (SABA) As-needed SABA or history of exacerbations
RELIEVER
low dose ICS/formoterol#

GINA 2016, Box 3-5 (2/8) (upper part) These data are communicated for scientific purpose only. Confidential slide set
 Step 1 as-needed inhaled short-acting
beta2-agonist (SABA)

STEP 5

STEP 4

STEP 3 Refer for

PREFERRED STEP 1 STEP 2 add-on
CONTROLLER treatment
CHOICE e.g.
Med/high tiotropium,*
omalizumab,
ICS/LABA mepolizumab*
Low dose
Low dose ICS ICS/LABA**

Other Add tiotropium* Add low

Consider low Leukotriene receptor antagonists (LTRA) Med/high dose ICS
controller High dose ICS dose OCS
dose ICS Low dose theophylline* Low dose ICS+LTRA
options + LTRA
(or + theoph*)
(or + theoph*)

As-needed short-acting beta2-agonist (SABA) As-needed SABA or

RELIEVER low dose ICS/formoterol#

*Not for children <12 years

**For children 6-11 years, the preferred Step 3 treatment is medium dose ICS
#For patients prescribed BDP/formoterol or BUD/ formoterol maintenance and reliever therapy
Tiotropium by mist inhaler is an add-on treatment for patients 12 years with a history of exacerbations
GINA 2016, Box 3-5, Step 1 (4/8) These data are communicated for scientific purpose only. Confidential slide set
 Step 2 low-dose controller + as-needed
inhaled SABA

STEP 5

STEP 4

STEP 3 Refer for

STEP 1 STEP 2 add-on
treatment
e.g.
Med/high tiotropium,*
omalizumab,
ICS/LABA mepolizumab*
Low dose
Low dose ICS ICS/LABA**

Other Consider low Med/high dose ICS Add tiotropium* Add low
Leukotriene receptor antagonists (LTRA)
controller dose ICS Low dose ICS+LTRA High dose ICS dose OCS
Low dose theophylline*
options (or + theoph*) + LTRA
(or + theoph*)

RELIEVER As-needed short-acting beta2-agonist (SABA) As-needed SABA or

low dose ICS/formoterol#

*Not for children <12 years

**For children 6-11 years, the preferred Step 3 treatment is medium dose ICS
#For patients prescribed BDP/formoterol or BUD/ formoterol maintenance and reliever therapy
Tiotropium by mist inhaler is an add-on treatment for patients 12 years with a history of exacerbations
GINA 2016, Box 3-5, Step 2 (5/8) These data are communicated for scientific purpose only. Confidential slide set
 Step 3 one or two controllers + as-needed
inhaled reliever

STEP 5

STEP 4

STEP 3 Refer for

STEP 1 STEP 2 add-on
treatment
PREFERRED e.g.
CONTROLLER Med/high tiotropium,*
CHOICE omalizumab,
ICS/LABA mepolizumab*
Low dose
Low dose ICS ICS/LABA**

Other Consider low Leukotriene receptor antagonists (LTRA) Med/high dose ICS Add tiotropium* Add low
controller Low dose ICS+LTRA High dose ICS dose OCS
dose ICS Low dose theophylline*
options (or + theoph*) + LTRA
(or + theoph*)

As-needed short-acting beta2-agonist (SABA) As-needed SABA or

low dose ICS/formoterol#
RELIEVER

*Not for children <12 years

**For children 6-11 years, the preferred Step 3 treatment is medium dose ICS
#For patients prescribed BDP/formoterol or BUD/ formoterol maintenance and reliever therapy
Tiotropium by mist inhaler is an add-on treatment for patients 12 years with a history of exacerbations
GINA 2016, Box 3-5, Step 3 (6/8) These data are communicated for scientific purpose only.Initiative
Global Confidential slide set
for Asthma
 Fixed combinations of inhaled steroids
plus long-acting 2-agonists
Logical, effective, and well tolerated

Acceptance of inhaled steroid

Only one inhaler: simplified therapy

user friendly
patients adherence

Acceptance of long-term treatment

 Bud / Form SMART: 6 double-blind studies
in > 14 000 patients
STEAM1
6 months: Bud / Form SMART vs. 2x budesonide
Bud / Form SMART clinical trial

+ SABA; n = 697

STEP2
12 months: Bud / Form SMART vs. 2x budesonide Proof of concept
+ SABA; n = 1890

STAY3
12 months: Bud / Form SMART vs. 4 x ICS or
Bud / Form + SABA; n = 2760 Value of
reliever
SMILE4 component
12 months: Bud / Form + Bud / Form, formoterol
or SABA; n = 3394

COMPASS5 Superior to higher

6 months: Bud / Form SMART vs. Bud / Form or fixed-dose
Salm / FP + SABA; n = 3335 ICS/LABA
AHEAD6
6 months: Bud / Form SMART vs.
Salm / FP + SABA; n = 2309

2001 2002 2003 2004 2005 2006 2007

Years of clinical trial
1. Rabe et al. Chest 2006; 129:246256
2. Scicchitano et al. Curr Med Res Opin 2004; 20:14031418
STEAM not included in pooled analysis as primary 3. OByrne et al. Am J Respir Crit Care Med 2005; 171:129136
endpoint was morning PEF; time to first severe 4. Rabe et al. Lancet 2006; 368:744753
5. Kuna et al. Int J Clin Pract 2007; 61:72573.
exacerbation was primary endpoint in other 5 studies 6. Bousquet et al. Respir Med 2007; 101:24372446
 Severe exacerbations requiring intervention
in 6 double-blind studies (n = 14 351)
BUD + SABA Salm-FP + SABA
Exacerbations Bud-Form + SABA Bud-Form SMART
[/100 patients/yr] Bud-Form + formoterol *ICS dose of comparator
250*
(BDP equivalents)
40 1000*
500*
500* 1000*
1000* 1000*
2000*
500*
30

20

10

0
STEAM STEP AHEAD STAY COMPASS SMILE
 OVERALL ASTHMA CONTROL: Achieving Current Clinical Control

100 Budesonide + SABA

Budesonide/Formoterol + SABA
90
Salmeterol/Fluticasone + SABA
Percent of days with reliever use

Budesonide/Formoterol SMART
80

70

60 50% of days

50

40
Budesonide 400 g/d

Fluticasone 1000 g/d

Budesonide 800 g/d

Budesonide 800 g/d

Budesonide 640 g/d

Budesonide 160 g/d

Fluticasone 500 g/d

30

BUD 792 g/d

BUD 483 g/d
20

10

0
Rabe et al. Scicchitano et al. OByrne et al. Kuna et al. Bousquet et al.

Patients treated with SMART use no reliever on most days

1. Rabe KF, et al. Chest 2006; 2. Scicchitano R, et al. Curr Med Res Opin 2004;
3. OByrne PM, et al. Am J Respir Crit Care Med 2005; 4. Kuna P, et al. Int J Clin Pract 2007;
5. Bousquet J, et al. Respir Med 2007
 OVERALL ASTHMA CONTROL: Reducing Future Risk

45 Bud/Form using the SMART approach 2 x BUD + SABA

Bud/Form + SABA Fluticasone/salmeterol
40 Bud/Form + SABAl + SABA
Exacerbations/100 patients/year

35

30

*** *
25 **
20 *** **

15

10 ***

0
Rabe et al.1+ Scicchitano et al.2 O' Byrne et al.3 Rabe et al.4+ Kuna et al.5+ Bousquet et al.6+

*p<0.05 vs all controls; **p<0.01 vs all controls; ***p<0.001 vs all controls; +Filipino patients participated in the trial

SMART reduces the rate of severe exacerbations as reported in

numerous clinical trials (Filipino patients included)
1. Rabe et al. Chest 2006; 2. Scicchitano et al. Curr Med Res Opin 2004;
3. OByrne et al. Am J Respir Crit Care Med 2005; 4. Rabe et al. Lancet 2006;
5. Kuna et al. Int J Clin Pract 2007; 6. Bousquet et al. Respir Med 2007
 REDUCE INCREASE
TREATMENT STEPS
STEP STEP STEP STEP STEP

1 2 3 4 5
asthma education
Budesonide / Formoterol (SMART)
environmental
RELIEVERcontrol
as needed
rapid-acting as needed rapid acting -agonist
2 -agonist
ADD ONE OR ADD ONE OR
SELECT ONE SELECT ONE MORE BOTH
CONTROLLER OPTIONS

low dose ICS*plus medium dose oral

low dose ICS* long acting 2 - ICS*plus long glucocorticosteroid
agonist acting 2 -agonist (lowest dose)

leukotriene medium- or leukotriene anti-IgE

modifier** high dose ICS modifier treatment

Budesonide /low
Formoterol
dose ICS plus
leukotriene
(SMART)
sustained - release
theophylline
CONTROLLER
modifier

low dose ICS plus

sustained release
theophylline

* inhaled corticosteroid ** receptor antagonist or synthesis inhibitors

1. GINA 2009 guidelines 2. PCCP PCRADM 2009
 CONCLUSIONS
Inhaled corticosteroids affect lung function,
exacerbation rate and health status in COPD
Other treatments work as well on average as LABA-ICS
combinations but may benefit different patients
Eosinophils predict acute exacerbation response to
steroids and may identify those with the greatest
reductions in exacerbations on ICS.
Inhaled corticosteroids have a role in some COPD
patients
In Asthma, SMART regimen has showed a significant
result Vs other ICS/LABA
THANK YOU