Chronic Obstructive Pulmonary Disease
Management
Focus on Bronchodilator
Mulyadi
Pulmonology & Respiratory Medicine Dept.
Faculty of Medicine Syiah Kuala University
Dr. Zainoel Abidin General Hospital
Banda Aceh
2019
Updated COPD definition includes persistent respiratory symptoms
Chronic Obstructive Pulmonary Disease
(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
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 usually
caused by significant exposure to
noxious particles or gases
COPD = chronic obstructive pulmonary disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease
1. GOLD 2016
2. GOLD 2017
Faktor Risiko:
Diagnosis PPOK
Gejala :
•
•
•
•
•
•
•
Sesak napas
Batuk kronis
Sputum
Faktor
individu
Tembakau
Pekerjaan
Polusi di
dalam atau
luar ruangan
Spirometri :
Dibutuhkan untuk
menentukan
diagnosis
4
GOLD 2019
The changing role of spirometry
•
•
•
Post-bronchodilator spirometry is required for the diagnosis and
assessment of COPD
However, assessing the degree of reversibility of airflow limitation (e.g.
measuring FEV1 before and after bronchodilator or corticosteroids) to
inform therapeutic decisions is no longer recommended
Spirometry remains key in the diagnosis, prognostication and
treatment with non-pharmacological therapies
COPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory volume in 1 second
GOLD = Global Initiative for Chronic Obstructive Lung Disease
Symptoms and exacerbation risk should be assessed to determine
appropriate treatment
1.
Diagnose COPD and determine the severity of airflow limitation (GOLD Grade 1–4) using spirometry
2.
Determine GOLD Group (A–D) and subsequent appropriate pharmacological treatment by assessing
symptoms and exacerbation history (including prior hospitalizations)
Spirometrically
confirmed diagnosis
Assessment of
airflow limitation
Assessment of symptoms/
risk of exacerbations
Exacerbation
history
Post-bronchodilator
FEV1/FVC <0.7
Grade
FEV1
(% pred.)
1
≥80
2
50–79
3
30–49
4
<30
>2 or ≥1
leading to
hospitalization
C
D
0 or 1
(not leading to
hospital admission)
A
B
mMRC 0–1
CAT <10
CCQ <1
CAT = COPD Assessment Test; CCQ = Clinical COPD Questionnaire; COPD = chronic obstructive pulmonary disease
FEV1 = forced expiratory volume in 1 second; GOLD = Global Initiative for Chronic Obstructive Lung Disease
mMRC = modified Medical Research Council
mMRC 2+
CAT 10+
CCQ 1+
Tujuan utama terapi pada pasien PPOK
• Meringankan gejala
• Meningkatkan toleransi olah-raga
• Meningkatkan status kesehatan
Mengurangi gejala
dan
• Mencegah progresivitas penyakit
• Mencegah dan mengobati
eksaserbasi
• Mengurangi mortalitas
Mengurangi risiko
Components of COPD management
1. Assess and monitor disease
2. Reduce risk factors
3. Manage stable COPD

Education

Pharmacologic

Non-pharmacologic
4. Manage exacerbations
Tak pernah merokok atau
tidak peka terhadap rokok
FEV1 (% value of age 25)
100
75
Perokok dan peka
terhadap rokok
50
DISABILITAS
25
KEMATIAN
0
Fletcher dan Peto (1977) :
Faal paru menurun landai
pada awal, curam pd lanjut
25
50
75
Umur (tahun)
Cohort study with 792 working men, 8-year follow-up period, measurement of FEV1 every 6 months
Modified version of the Fletcher and Peto graph showing the decline in FEV1
Fletcher C, Peto R. BMJ 1977; 1: 1645–1648
Paradigma – percepatan penurunan faal paru terutama pada stadium awal PPOK
100
Tantucci (2012) :
penurunan FEV1
GOLD 2 paling tinggi
dibanding pada
stadium akhir COPD1,2
FEV1 (% predicted)
GOLD 1
80
 40 mL/th
 47–79 mL/th
GOLD 2
50
 56–59 mL/th
GOLD 3
30
GOLD 4
 <35 mL/th
0
Tahun
Analysis based on randomized control arms of longitudinal studies with a follow-up period ≥3 years
Dashed lines indicate any stage or portion for which consistent information is lacking
1. Tantucci C, Modina D. Int J Chron Obstruct Pulmon Dis 2012; 7: 95–99;
2. Welte T, et al. Int J Clin Pract; 2015; 69:336–349
Eksaserbasi berat merupakan awal lingkaran setan (vicious circle) , waktu
pemulihan lebih pendek dan peningkatan risiko eksaserbasi lebih berat
Hazard function of the time terhadap eksaserbasi selanjutnya untuk 10 eksaserbasi berat
setelah rawat inap karena PPOK pertamakali.
< 4 bulan
Median waktu antara eksaserbasi berat
Jumlah eksaserbasi berat seanjutnya
per 10000 perhari
100
menurun dengan setiap eksaserbasiberat baru ①
dari sekitar 4,5 tahun sejak pertama ke kedua
n= 73106;
sampai < 4 bulan dari ke 9 ke 10.
80
①
Risiko terjadi eksaserbasi meningkat ②
dan tidak dapat kembali ke risiko baseline ③.
60
40
5.4 tahun
20
②+③
0
0
2
4
6
8
10
Waktu setelah eksaserbasi berat pertama (tahun)
12
Suissa et al. Thorax 2012; 67: 957-963.
Group D
Group C
LAMA +
LABA
LABA + ICS
Consider roflumilast
if FEV1 <50% pred.
and patient has
chronic bronchitis
Consider
macrolide
Further
exacerbation(s)
LAMA +
LABA + ICS
Further
exacerbation(s)
Further
exacerbation(s)
Persistent
symptoms/further
exacerbations
LAMA
LAMA
Group A
LAMA + LABA
LABA + ICS
Group B
Continue, stop or
try alternative class
of bronchodilator
Evaluate
effect
A bronchodilator
FEV1 = forced expiratory volume in 1 second; GOLD = Global Initiative for Chronic Obstructive Lung Disease
ICS = inhaled corticosteroid; LABA = long-acting β2-agonist; LAMA = long-acting muscarinic antagonist
LAMA + LABA
Persistent
symptoms
A long-acting bronchodilator
(LABA or LAMA)
Tata laksana PPOK GOLD 2019 : Terapi farmakologi awal
B
• Eksaserbasi: perburukan akut dari gejala pernafasan yang membutuhkan terapi
tambahan.Ringan: SABDs only; Moderat: SABDs + abtibiotik dan atau OCS; Berat:
membutuhkan perawatan RS
• Definisi Abreviasi: eos: blood eosinophil count in cells per microliter; mMRC:
modified Medical Research Council dyspnea questionnaire; CAT™: COPD
Assessment Test™.
Paradigma pemakaian LAMA/LABA dan pembatasan ICS pada PPOK1
!
LAMA/LABA pilihan yang
disukai untuk terapi
simtomatik *
Regimen yang mengandung ICS
dibatasi
LABA/ICS dan triple
therapy TIDAK
direkomendasi
sebagai terapi lini
pertama*
LAMA/LABA pilihan
yang disukai untuk
terapi simtomatik*
Eskalasi ke triple
therapy dianjurkan
hanya pada grup D
yang masih
eksaserbasi dengan
LAMA/LABA
GRUP
GRUP
GRUP
A,B,C,D
B,D
D
*LABA/ICS may be the first choice in some patients. For example, those with a history and/or findings suggestive of asthmaCOPD overlap.
©2018 Global Initiative for Chronic Obstructive Lung Disease, all rights reserved. Use is by express license from the owner.
This overview is based on the GOLD Report 2018 (chapter 4, management of stable COPD). The new pharmacologic treatment
recommendations provided on this page should not be considered as making a claim of a complete listing of all potential
treatments recommended by GOLD 2018. It should rather be considered as a contribution from Boehringer Ingelheim to help
healthcare professionals to familiarize themselves with the new key recommendations provided by GOLD 2018.
1. @2018 Global Initiative forChronic Obstructive Lung Disease, all rights reserved. Use is by
express license from the owner
10
Bronchodilators: the cornerstone of COPD treatment
• Meningkatkan fungsi paru (dilihat dari nilai FEV1)
• Meningkatkan kapasitas fisik
• Mengurangi sesak napas
• Meningkatkan kualitas hidup
• Mengurangi eksaserbasi
FEV1 = forced expiratory volume in 1 second
EXHALEID
Kombinasi LABA/LAMA memberi perbaikan klinis lebih baik
dibandingkan satu komponen pada pasien dengan gejala pada
baseline berat .
(Martinez et al, 2017)
9
17
Kombinasi bronkodilator pada pasien PPOK
Berdasarkan GOLD 2019, beberapa studi mendukung
penggunaan kombinasi LABA dan LAMA pada PPOK1,2
•
Kombinasi bronkodilator dari kelas yang berbeda, dapat meningkatkan efikasi dan
menurunkan efek samping, dibandingkan dengan meningkatkan dosis dari terapi tunggal1,2
•
Penelitian mengenai kombinasi bebas LABA dan LAMA menunjukkan peningkatan yan
signifikan bagi pasien2
•
Saat obstruksi aliran udara semakin parah, pasien disarankan untuk ,menggunakan
kombinasi LABA dan LAMA2
GOLD = Global initiative for chronic Obstructive Lung Disease;
LABA = long-acting β2-agonist;
LAMA = long-acting muscarinic antagonist
1. GOLD 2019
2. Tashkin DP, et al. Respir Res 2013
DUAL BRONKHODILATOR : FLAME STUDY
Indacaterol Glycopyronium, superiority thdp Salmeterol Fluticasone
•
52-minggu , multicenter, randomized, double-blind, double-dummy, non-inferiority study pada
pasien obstruksi SN sedang-sangat berat,*, mMRC ≥2 dan riwayat eksaserbasi PPOK tahun
sebelumnya ≥1
Rate ratio (95% Cl)
Superiority
margin
0.83
Per-protocol set
(Primary analysis)
0.96
p=0.003
IND/GLY N=1518; SFC N=1544
Full analysis set
(Supportive analysis)
0.89
Non-inferiority
margin
0.82
0.88
0.94
p<0.001
IND/GLY N=1651; SFC N=1656
0.8
0.9
1.0
1.15
Favors IND/GLY
Favors SFC
110/50 μg q.d.
50/500 μg b.i.d.
*FEV1 of at least 25% to <60% predicted; †mild/moderate/severe
GLY = glycopyrronium; ICS = inhaled corticosteroid; IND = indacaterol LABA = long-acting β2-agonist; mMRC = modified Medical Research
Criteria SFC = salmeterol fluticasone
Wedzicha JA, et al. N Engl J Med 2016
FLAME STUDY :
IND/GLY menunda time to first exacerbation vs Salmeterol Fluticasone
Analysis of the FAS. GLY = glycopyrronium; HR = hazard ratio; ICS = inhaled corticosteroid; IND = indacaterol;
LABA = long-acting β2-agonist; mMRC = modified Medical Research Criteria; SFC = salmeterol fluticasone
Wedzicha JA, et al. N Engl J Med 2016
26
FLAME: IND/GLY Lebih Efektif Mencegah Eksaserbasi Sedang-Berat Dibanding SFC
dengan Eosinofil Darah pada Randomisasi
Moderate to severe exacerbations
(annualized rate)
1.5
SFC 50/500 µg b.i.d
IND/GLY 110/50 µg q.d
RR (95% CI)
0.80 (0.68, 0.93), P=0.004
1.25
RR (95% CI)
0.85 (0.75, 0.96), P=0.010
1
0.75
0.5
0.25
0
1.24
0.99
1.15
0,98
≥2
<2
Percentage blood eosinophils (%)
Analysis of the mITT
Wedzicha JA, et al. N Engl J Med 2016
Shine Study :
26-minggu, studi multisenter, acak, double-blind, grup paralel, kontrol plasebo aktif
Plasebo, n=234
Periode pra-randomisasasi
QVA149 110/50 μg sekali sehari, n=475
Periode praskrining
Glycopyrronium 50 μg sekali sehari, n=477
Periode skrining
Indacaterol 150 μg sekali sehari n=475
OL Tiotropium 18 μg sekali sehari, n=483
Visit 1
Hari 1 ke Hari 184
Hari -14 ke Hari -1
Hari -21 ke Hari -15
Visit 2
Randomisasi visit 3
Bateman et al. Eur Respir J 2013;42:1484-1494
Shine Study :
Trough FEV1 pada minggu 26 perbaikan bermakna pada Glycopyrronium/Indacaterol dibanding grup lain
∆=0.13 L, p<0.001
∆=0.12 L, p<0.001
∆=0.13 L, p<0.001
∆=0.2 L, p<0.001
∆=0.08 L, p<0.001
∆=0.09 L, p<0.001
Primary
endpoint
Trough FEV1 (L)
1,5
∆=0.07 L, p<0.001
1,4
1,3
1,2
1,25
1,45
1,38
1,36
1,37
Placebo
Glycopyrronium/Indacaterol
110/50 µg
Indacaterol 150 µg
Glycopyrronium 50 µg
OL Tiotropium 18 µg
n=232
n=474
n=476
n=473
n=480
Values are least squares mean ± SE
Bateman et al. Eur Respir J 2013;42:1484-1494
Shine Study :
Perbaikan bermakna trough FEV1 bertahan sampai periode terapi selama 26-minggu
Terapi
Treatment
LS mean of FEV1 (L)
Placebo n=232
Glycopyrronium/Indacaterol 110/50 µg n=474
Indacaterol 150 µg n=476
Glycopyrronium 50 µg n=473
OL Tiotropium 18 µg n=480
Glycopyrronium/Indacaterol was superior to all active treatments and placebo at all timepoints (all p<0.001)
Bateman et al. Eur Respir J 2013;42:1484-1494
Shine Study :
Serial spirometri menunjukkan bronkodilatasi Glycopyrronium/Indacaterol pada hari 1
Terapi
LS mean of FEV1 (L)
Placebo n=31
Glycopyrronium/Indacaterol 110/50 µg n=66
Indacaterol 150 µg n=64
Glycopyrronium 50 µg n=63
OL Tiotropium 18 µg n=70
Glycopyrronium/Indacaterol superior to placebo and tiotropium at all assessed timepoints (p<0.001); superior to indacaterol at all assessed timepoints (p<0.01),
except at 5 min post dose; superior to glycopyrronium at all assessed timepoints (p<0.05), except 1 h post dose; n, number per treatment group in the serial
spirometry subset of the full analysis set
Bateman et al. Eur Respir J 2013;42:1484-1494
Shine Study :
Serial spirometri menunjukkan bronkodilatasi Glycopyrronium/Indacaterol cepat dan bertahan pada minggu 26
LS mean of FEV1 (L)
Treatment
Placebo n=31
Glycopyrronium/Indacaterol 110/50 µg n=66
Indacaterol 150 µg n=64
Glycopyrronium 50 µg n=63
OL Tiotropium 18 µg n=70
Glycopyrronium/Indacaterol superior to placebo (p<0.001) and indacaterol (p<0.05) at all assessed timepoints; superior to glycopyrronium at all assessed timepoints
(p<0.05), except 23 h 45 min; superior to tiotropium at all assessed timepoints (p<0.05), except 22 h and 23 h 45 min.; n, number per treatment group in the serial
spirometry subset of the full analysis set
Bateman et al. Eur Respir J 2013;42:1484-1494
• Glycopyrronium/Indacaterol menunjukkan :
– Perbaikan superior pada faal paru dibanding
monokomponen Indacaterol atau Glycopyronium.
– Pasien PPOK dengan riwayat eksaserbasi pada tahun sebelumnya,
Indacaterol–Glycopyrronium konsisten
lebih efektif daripada
Salmeterol–Fluticasone untuk
pencehagan eksasebasi dan
berhubungan dengan efek samping yang tidak terdeteksi.
(FLAME study , Wedzicha, 2017)
27
Profil keamanan dari kombinasi LABA dan LAMA1,2
• Kombinasi LABA/LAMA menunjukkan profil keamanan yang baik pada pasien
PPOK
• Sejauh ini, kombinasi kedua bronkodilator ini tidak meningkatkan masalah
keamanan
• Kombinasi bebas LABA dan LAMA juga menunjukkan profil keamanan yang
baik

LABA = long-acting β2-agonist;
LAMA = long-acting muscarinic antagonist

1. Tashkin DP, et al. Respir Res 2013
2. van der Molen T, Cazzola M. Prim Care Respir J 2012
Tata laksana PPOK GOLD 2019: siklus manajemen
1.
2.
Jika respon terhadap terapi awal sudah baik, lanjutkan terapi pengobatan
Jika tidak :
Pertimbangkan sifat yang lebih dominan, dyspnea atau eksaserbasi. Jika keduanya dominan, ikuti jalur eksaserbasi
Ikuti indikasi sesuai dengan posisi terapi pasien
Nilai respon, sesuaikan dan review
Rekomendasi ini tidak bergantung pada penilaian ABCD saat diagnosis
eos: blood eosinophil count. Kadar eosinophil pada darah (sel/µL)
*pertimbangkan jika eos ≥300 atau eos≥100 DAN ≥2 eksaserbasi sedang/1 rawat inap
**pertimbangkan de-eskalasi atau penggantian terapi jika terjadi pneumonia, adanya penggunaan indikasi tidak sesuai, atau
respon kecil terhadap ICS
29
Peran LABA/ICS pada pasien PPOK
GOLD 2019:
Terapi dengan penggunaan LABA/ICS sebagai terapi awal dapat
dipertimbangkan pada pasien Grup D, dengan jumlah eosinophil ≥ 300
sel/µL dan pasien dengan riwayat asma
•
Penggunaan ICS pada pasien PPOK dengan indikasi yang tidak sesuai dapat meningkatkan
risiko pasien terkena efek samping seperti pneumonia, osteoporosis, diabetes, dan katarak2
•
Penggunaan ICS pada terapi awal harus mempertimbangkan risk dan benefit untuk pasien1
ICS = inhaled corticosteroid
LABA = long-acting β2-agonist
GOLD 2019
Price D, et al. Prim Care Respir J 2013
Mekanisme LABA/LAMA menurunkan frekuensi eksaserbasi
LAMA / LABA
Pengurangan
hiperinflasi
(stabilisasi SN)
Pengurangan produksi
mukus dan peningkatan
klirens mukosilier
Perbaikan
keparahan gejala
Aktivitas
antiinflamasi*
(langsung & tak
langsung)
*Anti-inflammatory mechanisms have been demonstrated in vitro and in animal models, but have not been demonstrated yet in patients with COPD
Beeh, KM. Et al. AJRCCM 2016 Article in Press. Published on 06-December-2016 as
10.1164/rccm.201609-1794CI.
22
Summary:
 Definition of COPD
 Refined to place more emphasis on symptoms and comorbidities
 ABCD assessment tool
 Refined to assess both symptom level and risk of future exacerbations following
the revised role of spirometry in COPD
 Pharmacological management
 Pharmacological algorithms added
 Dual bronchodilation recommended as a first-line therapy for a majority
of symptomatic patients
 ICS therapy only recommended in a minority of patients as an alternative to
preferred LABA/LAMA treatment
 Focus on inhaler technique
 Emphasizes the importance of patient education
 Management of comorbidities
 Emphasizes the importance of identifying and treating comorbidities
COPD = chronic obstructive pulmonary disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease
LABA = long-acting β2-agonist; LAMA = long-acting muscarinic antagonist
GOLD 2017
THANK YOU