Current pharmacological treatment

of COPD

Zen Ahmad
Medical Faculty, Sriwijaya University
 COPD IS A MAJOR BURDEN ON HEALTHCARE
RESOURCES AND THE ECONOMY
 COPD is a leading cause of morbidity and mortality
 COPD affects 384 million people worldwide (2010)1 and
causes 3 million deaths annually (5% of all deaths
worldwide)2
 It is predicted to become the third leading cause of global
mortality by 20303
 The economic burden of COPD is high, with costs increasing
as the disease progresses
 Severe COPD costs are up to 17 times higher than mild COPD4
 High costs are associated with treatment of exacerbations and loss of
productivity in the workplace 4
1. Diette GB, Orr P, McCormack MC et al. Population Health Management 2010;13:21-26.
2. WHO. COPD Fact Sheet No 315. 2011. Available from www.who.int/mediacentre/factsheets/fs315/en/index.html
3. WHO. Chronic respiratory diseases. Accessed 2011. http://www.who.int/respiratory/copd/burden/en/index.html
4. Wouters EFM. Respir Med 2003;97:S3-S14.
GOLD Guideline
Definition of COPD

Global Initiative for Chronic Obstructive Lung Disease

(GOLD) defines COPD as:

“a common preventable and treatable disease is characterized by

persistent respiratory symptoms and airflow limitation that is due
to airway and/or alveolar abnormalities usually caused by signifi-
cant exposure to noxious particles or gases”

Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global
Initiative for Chronic Obstructive Lung Disease (GOLD) 2017. Available from www.goldcopd.org
Risk Factors for COPD

Nutrition

Infections

Socio-economic
status

Aging Populations
Gene, Gender, Comorbidities
 COPD has pulmonary and systemic components

Inhaled substances +
Genetic susceptibility

Airway Mucociliary Structural

inflammation dysfunction changes Systemic
inflammation

Airway limitation

Breathlessness Weight changes

Bronchitis: coughing, sputum production Co-morbidities
Emphysema: hyperinflation, wheezing (e.g. diabetes, cardiovascular disease)
Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease
(GOLD) 20107Available from www.goldcopd.org
Pathogenesis of COPD

Chemotactic factors
IL8; CXC chemokines
LTB4

TGFβ
CTG

Neutrophil elastase; MMP; Cathepsins

 COPD is diagnosed based on symptoms, risk
factors and spirometry

RISK FACTORS
SYMPTOMS
Host factors
Dyspnea
Chronic cough + Tobacco
Occupational hazards
Sputum production
Indoor/outdoor pollution

Spirometry;
The presence of FEV1/FVC < 0.70 confirms the presence
of the persistent airflow limitation and thus of COPD.

Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease
(GOLD) 2017. Available from www.goldcopd.org
 ABCD assessment of COPD
The ABCD assessment grid has been refined to utilize exclusively
respiratory symptoms and exacerbation history to assign categories

Spirometrically Assessment Assessment of

confirmed of airflow symptoms/risk
diagnosis limitation of exacerbations
Exacerbation
history
FEV ≥ 2 or ≥ 1
(% predicted) leading to
Post-bronchodilator GOLD 1 ≥ 80
hospital C D
admission
FEV1/FVC < 0.7 GOLD 2 50 – 79
0 or 1 (not
GOLD 3 leading to
30 – 49
hospital A B
GOLD 4 <30 admission)

mMRC 0-1 mMRC ≥ 2

CAT < 10 CAT ≥ 10
Symptoms
@2017 Global Initiative for Chronic Obstructive Lung Disease, all rights reserved. Use is by express license from the owner
 GOALs OF COPD MANAGEMENT

PATIENT CHARACTERISTICS

Prevent and treat symptom Prevent and treat exacerbations

Improve exercise tolerance Prevent and treat complications
Improve health status Prevent disease progression

Reduce mortality

MANAGEMENT PLAN

Adapted from:
1. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD)
2016. Available from www.goldcopd.org
2. Postma D, Anzueto A, Calverley P et al . Prim Care Respir J 2011; 20:205-209.
Management of COPD Non-
pharmacological
Management of COPD (pharmacologic)

Anti
cholinergics

SAMA
LAMA

PDE4 inhibitors
Antibiotics
Mucolytics COPD
Immunoregulators
Others
Pharmacologic algorithm (GOLD group)
Grup C Grup D
Consider roflumilast if FEV1 < 50% Consider macrolide
LABA + ICS pred. and patient has chronic (in former smokers)
LAMA+LABA bronchitis
Further exacerbation(s)

LAMA+LABA+ICS
Further Persistent
Exacerbation(s) symptoms/further
Further
exacerbation(s)
Exacerbation(s)

LAMA LABA
LAMA LAMA+LABA
+ ICS

Grup B
Grup A
Continue, stop or try LAMA+LABA
alternative class of
bronchodilator
Persistent Symptoms
Evaluate effect

A long-acting bronchodilator
A bronchodilator (LABAor LAMA )

@2017 Global Initiative for Chronic Obstructive Lung Disease, all rights reserved. Use is by express license from the owner
ICS/LABA pada PPOK
LABA/ICS dapat menjadi pilihan pertama pada pasien
• Riwayat dan/atau diketahui Asthma-COPD Overlap (ACO)
• Pasien dengan eosinofil tinggi pada darah

Penggunaan jangka panjang ICS dapat dipertimbangkan

dengan LABA untuk pasien dengan riwayat eksaserbasi,
walaupun pasien sudah menggunakan LABA yang sesuai

GOLD 2017 Global Strategy for the Diagnosis, Management and Prevention of COPD. Available online at http://goldcopd.org/. Accessed 21stNovember 2016.
Penggunaan ICS/LABA pada PPOK

Penghentian ICS pada pasien PPOK, di beberapa penelitian, menunjukkan

peningkatan eksaserbasi dan/atau gejala pada pasien, walaupun ada
beberapa yang tidak.

Ada bukti yang menunjukkan terjadi penurunan FEV1 (~ 40 mL) ketika ICS
dihentikan, yang dapat dikaitkan dengan peningkatan kadar Eosinofil.

GOLD 2017 Global Strategy for the Diagnosis, Management and Prevention of COPD. Available online at http://goldcopd.org/. Accessed 21stNovember 2016.
Corticosteroid
• ICS/LABA is more effective than monotherapy in improving
lung function and health status; reducing exacerbations in
patients with exacerbations, moderate-very severe COPD
• Regular treatment with ICS increases the risk of pneumonia
especially in those with severe disease
• Triple inhaled therapy of ICS/LAMA/LABA improve lung
function, symptoms and health status and reduces
exacerbations compared to ICS/LABA or LAMA monotherapy
• Long term use of oral steroids has numerous side effects with
no evidence of benefit
Problem pada PPOK

Pada pagi hari, pasien PPOK lebih tinggi mengalami

gangguan gejala sesak napas, dan gangguan
kemampuan aktivitas, dibandingkan dengan jam lainnya
di hari yang sama

Partridge, Martyn R., et al., Effect on lunch function and morning activities of Budesonide/formoterol versus salmeterol/fluticasone in patients
with COPD. Ther Adv Respir Dis (2009), 3(4); 147-157
 Partridge, Martyn R., et al., Effect on lunch function and morning activities of Budesonide/formoterol versus salmeterol/fluticasone in patients
with COPD. Ther Adv Respir Dis (2009), 3(4); 147-157
19
Desain penelitian

Random, buta ganda, multi-centres, double-dummy, cross-over, 442 pasien dengan PPOK usia ≥40 tahun (Prebronkodilator
FEV1 ≤ 50%; FEV1/VC <70%) dengan 2x periode pengobatan 1 minggu, dilakukan dalam 66 pusat di 9 negara
(Argentina, Australia, Belgium, Brazil, Denmark, Jerman, India, Filipin, dan UK

Partridge, Martyn R., et al., Effect on lunch function and morning activities of Budesonide/formoterol versus salmeterol/fluticasone in patients
with COPD. Ther Adv Respir Dis (2009), 3(4); 147-157
 PEF 5 menit setelah dosis:
Budesonide/Formoterol 15.1 L/menit
Salmeterol/Fluticasone 14.2 L/menit
P = 0.603

Perbaikan lebih nyata terlihat pada

Budesonide/Formoterol Vs Sal/Flu untuk
menit ke – 5 dan menit ke – 15 FEV1 rata-rata
di pagi hari

(P< 0.09 dan P<0.05)

Partridge, Martyn R., et al., Effect on lunch function and morning activities of
Budesonide/formoterol versus salmeterol/fluticasone in patients with COPD. Ther
Adv Respir Dis (2009), 3(4); 147-157
 Budesonide/Formoterol lebih signifikan
menunjukkan perbaikan aktivitas pagi hari
Vs. Sal/Flu

Total skor CDLM*

Bud/For Vs Sal/Flu
0.22 Vs 0.12 (P<0.05)

Partridge, Martyn R., et al., Effect on lunch function and morning activities of Budesonide/formoterol versus salmeterol/fluticasone in patients
with COPD. Ther Adv Respir Dis (2009), 3(4); 147-157

22 *CDLM: Capacity of Daily Living during the Morning Questionnaire

 Budesonide/Formoterol memiliki onset kerja yang
lebih cepat dan memberikan perbaikan yang lebih besar
bagi kemampuan pasien melakukan aktivitas pagi hari Vs.
Sal/Flu
The Paradigm Continues:
Real World Experience to complement RCTs

A retrospective propensity score matched cohort study comparing

combination budesonide/formoterol vs. fluticasone/salmeterol in chronic
obstructive pulmonary disease.
 Kejadian eksaserbasi per 100 pasien/tahun pada pasien PPOK yang
diobati dengan BUD/FORM (n=2734) atau FLU/SAL (n=2734)

**P<0.0001
*P=0.0003

• Kejadian eksaserbasi per 100 pasien/tahun pada pasien PPOK yang diobati dengan BUD/FORM (n=2734) atau FLU/SAL (n=2734)
• Jumlah rata – rata penggunaan pelayanan kesehatan disesuaikan dibandingkan dengan menggunakan analisis regresi poisson.
**P<0.0001; *P=0.0003 for difference.
• CI, confidence intervals; BUD/FORM, budesonide/formoterol; FLU/SAL, fluticasone/salmeterol
Larrson, K., et al., J of Int Med, 2013, 273; 584-594
 Bud/Formoterol memiliki onset
kerja lebih cepat daripada Sal/Flu,
sehingga lebih cepat dalam
meredakan gejala akut.

Larrson, K., et al., J of Int Med, 2013, 273; 584-594

 Kematian yang terkait dengan
Pneumonia lebih tinggi pada
fluticasone/salmeterol
dibandingkan dengan
Symbicort®(peningkatan risiko
sebesar 76% pada
fluticasone/salmeterol)

Kejadian Pneumonia lebih tinggi pada pasien yang diobati

dengan fluticasone/salmeterol dibandingkan dengan Symbicort®
(peningkatan risiko sebesar 73% pada fluticasone/salmeterol)

Perawatan di rumah sakit karena Pneumonia lebih tinggi pada

pasien yang diobati dengan fluticasone/salmeterol
dibandingkan dengan Symbicort® (peningkatan risiko sebesar
74% pada fluticasone/salmeterol)
Janson C et al. BMJ 2013; 346:f3306 doi: 10.1136/bmj.f3306
ES pneumonia ICS pada GOLD 2017

Efek samping pneumonia pada ICS dikonfirmasi berdasarkan studi ICS yang
menggunakan Flutikason furoate, bahkan pada dosis rendah.

Pada penelitian dengan pasien COPD moderate, ICS monoterapi atau dalam
kombinasi LABA tidak meningkatkan resiko pneumonia

GOLD 2017 Global Strategy for the Diagnosis, Management and Prevention of COPD. Available online at http://goldcopd.org/. Accessed 21stNovember 2016.
Simpulan

• COPD tetap menjadi masalah besar, dikarenakan tingginya

angka kesakitan/kematian dan beban ekonomi yang besar
• Panduan GOLD edisi 2017, perubahannya signifikan
• Diagnosis COPD berdasarkan gejala, faktor resiko dan
bukti adanya obstruksi pada spirometri
• Dua tahapan assessment; derajat obstruksi; keluhan dan
resiko eksaserbasi
• Pengobatan terdiri atas farmakologik dan non farmakologik
Simpulan
• Pengobatan non farmakologik al; henti rokok, pembe-rian
vaksin (influenzae; pneumonia) dan rehabilitasi
• Pengobatan farmakologik al; bronkodilator, anti infla-masi
(CS; PDE4 inhibitor), antibiotik ataupun mukolitik
• Pilar utama pengobatan adalah bronkodilator
• ICS/LABA direkomendasikan pada group C & D, terutama
pasien dengan riwayat eksaserbasi dan jumlah
eosinophil yang dominan
Simpulan
 Budesonide/Formoterol
 Memiliki onset kerja yang lebih cepat dan memberikan
perbaikan yang lebih besar untuk kemampuan melakukan
aktivitas pagi hari Vs. Sal/Flu
 Studi PATHOS menyatakan Budesonide/Formoterol lebih
efektif dalam menurunkan resiko eksaserbasi
dibandingkan kombinasi Salmeterol/Flutikason3