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Curriculum Vitae
DR. Dr. Arto Yuwono Soeroto, SpPD-KP, FINASIM, FCCP
E-mail: [email protected]
Pendidikan:
S1
Sp1
Konsultan Pulmonologi
S3
FK Universitas Padjadjaran
FK Universitas Padjadjaran
KIPD
FK Universitas Padjadjaran
Pekerjaan:
Kepala Divisi Respirologi & Penyakit Kritis IPD FKUP/RS Hasan Sadikin
Ketua Tim TB RSUP Dr. Hasan Sadikin
Ka IRJ RS Dr Hasan Sadikin Bandung
Organisasi:
PB Perhimpunan Dokter Spesialis Penyakit Dalam (PAPDI)
PB Perhimpunan Respirologi Indonesia (PERPARI)
Fellow American College of Chest Phisician (ACCP)
European Respiratory Society (ERS)
American Thoracic Society (ATS)
Achieving Asthma Control Based On
International Guideline With LABACS
Arto Yuwono Soeroto
Burden of asthma
• Asthma is one of the most common chronic diseases
worldwide with an estimated 300 million affected individuals
• Prevalence is increasing in many countries, especially in
children
• Asthma is a major cause of school and work absence
• Health care expenditure on asthma is very high
– Developed economies might expect to spend 1-2 percent of
total health care expenditures on asthma.
– Developing economies likely to face increased demand due to
increasing prevalence of asthma
– Poorly controlled asthma is expensive
– Investment in prevention medication is likely to yield cost
savings in emergency care
What is known about asthma ?
• Asthma is a common and potentially serious chronic disease that
can be controlled but not cured
• Asthma causes symptoms such as wheezing, shortness of
breath, chest tightness and cough that vary over time in their
occurrence, frequency and intensity
• Symptoms are associated with variable expiratory airflow,
i.e. difficulty breathing air out of the lungs due to
– Bronchoconstriction (airway narrowing)
– Airway wall thickening
– Increased mucus
• Symptoms may be triggered or worsened by factors such as viral
infections, allergens, tobacco smoke, exercise and stress
Definition of asthma
Asthma is a heterogeneous disease, usually characterized
by chronic airway inflammation.
It is defined by the history of respiratory symptoms such as
wheeze, shortness of breath, chest tightness and cough
that vary over time and in intensity, together with variable
expiratory airflow limitation.
Goals of asthma management
• The long-term goals of asthma
management are 
1. Symptom control: to achieve good control
of symptoms and maintain normal activity
levels
2. Risk reduction: to minimize future risk of
exacerbations, fixed airflow limitation and
medication side-effects
GINA assessment of symptom control
A. Symptom control
Level of asthma symptom control
In the past 4 weeks, has the patient had:
• Daytime asthma symptoms more
than twice a week?
• Any night waking due to asthma?
• Reliever needed for symptoms*
more than twice a week?
Wellcontrolled
Partly
controlled
Uncontrolled
None of
these
1-2 of
these
3-4 of
these
Yes No
Yes No
Yes No
• Any activity limitation due to asthma? Yes No
*Excludes reliever taken before exercise, because many people take this routinely
GINA assessment of symptom control
Level of asthma symptom control
A. Symptom control
In the past 4 weeks, has the patient had:
• Daytime asthma symptoms more
than twice a week?
Yes No
• Any night waking due to asthma?
Yes No
• Reliever needed for symptoms*
more than twice a week?
Yes No
• Any activity limitation due to asthma?
Yes No
Wellcontrolled
Partly
controlled
Uncontrolled
None of
these
1-2 of
these
3-4 of
these
B. Risk factors for poor asthma outcomes
ASSESS PATIENT’S RISKS FOR:
• Exacerbations
• Fixed airflow limitation
• Medication side-effects
Assessment of risk factors for poor asthma
outcomes
Risk factors for exacerbations include:
•
•
•
•
Ever intubated for asthma
Uncontrolled asthma symptoms
Having ≥1 exacerbation in last 12 months
Low FEV1 (measure lung function at start of treatment, at 3-6 months
to assess personal best, and periodically thereafter)
• Incorrect inhaler technique and/or poor adherence
• Smoking
• Obesity, pregnancy, blood eosinophilia
Assessment of risk factors for poor asthma outcomes
Risk factors for exacerbations include:
•
•
•
•
Ever intubated for asthma
Uncontrolled asthma symptoms
Having ≥1 exacerbation in last 12 months
Low FEV1 (measure lung function at start of treatment, at 3-6 months
to assess personal best, and periodically thereafter)
• Incorrect inhaler technique and/or poor adherence
• Smoking
• Obesity, pregnancy, blood eosinophilia
Risk factors for fixed airflow limitation include:
• No ICS treatment, smoking, occupational exposure, mucus
hypersecretion, blood eosinophilia
Risk factors for medication side-effects include:
• Frequent oral steroids, high dose/potent ICS, P450 inhibitors
Treating to control symptoms and minimize risk
• Establish a patient-doctor partnership
• Manage asthma in a continuous cycle:
– Assess
– Adjust treatment (pharmacological and
non-pharmacological)
– Review the response
• Teach and reinforce essential skills
– Inhaler skills
– Adherence
– Guided self-management education
• Written asthma action plan
• Self-monitoring
• Regular medical review
Stepwise management – pharmacotherapy (GINA 2016)
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
PREFERRED
CONTROLLER
CHOICE
STEP 1
STEP 2
Low dose ICS
Other
controller
options
RELIEVER
Consider low
dose ICS
Leukotriene receptor antagonists (LTRA)
Low dose theophylline*
As-needed short-acting beta2-agonist (SABA)
Low dose
ICS/LABA*
Med/high dose ICS
Low dose
ICS+LTRA
(or + theoph*)
Refer for
add-on
treatment
e.g.
Tiotroprium
*For children 6-11 years,
theophylline is not
recommended, and preferred
Step 3 is medium dose ICS
Med/high Omalizumab
ICS/LABA mepolizumab **For patients prescribed
BDP/formoterol or BUD/
formoterol maintenance and
reliever therapy
Add tiotropium#
High dose ICS
+ LTRA
(or + theoph*)
Add low
dose OCS
As-needed SABA or
low dose ICS/formoterol**
# Tiotropium by soft-mist
inhaler is indicated as add-on
treatment for adults
(≥18 yrs) with a history of
exacerbations
When asthma is well-controlled, patients can
Avoid troublesome symptoms during the day
and night
Need little or no reliever medication
Have productive, physically active lives
Have normal or near-normal lung function
Avoid serious asthma flare-ups (also called
exacerbations, or severe attacks)
GINA 2015
© Global Initiative for Asthma
Apakah Tujuan Tatalaksana Asthma Berdasar
GINA Dapat dicapai?
The Gaining Optimal Asthma Control
(GOAL) study
Bateman et al. Am J Respir Crit Care Med 2004;170:836-44
Definisi Asthma Terkontrol pada studi GOAL
Daytime symptoms
Rescue use
AM PEF (diary card)
Well Control
Total Control
Each week, two or more of
following:
Each week, all of following:
2 days per week with score >1
2 days & 4 occasions
80% predicted every day
None
None
80% predicted every day
Each week, all of following:
Night-time awakenings
Exacerbations (all grades)
Emergency visits
Treatment-related AEs
None
None
None
None enforcing change
in therapy
None
None
None
None enforcing change
in therapy
Bateman et al. Am J Respir Crit Care Med 2004;170:836-44
GOAL: Study design (1 of 2)
• Studi 1 tahun, berstrata, acak, samar-ganda, grup paralel (N=3421)
•
Dewasa dan remaja (≥12 sampai <80 tahun) dengan riwayat asma ≥6 bulan, reversibilitas VEP1
≥15% (dan ≥200 mL) setelah pemakaian SABA, riwayat merokok <10 tahun dan tidak
menggunakan LABA atau β2 agonis oral dalam waktu 2 minggu terakhir
• 3 strata berdasarkan penggunaan ICS dalam waktu 6 bulan sebelum randomisasi:
•
•
•
Stratum 1: steroid-naïf
Stratum 2: 500 µg BDP atau ekuivalen
Stratum 3: >500 to 1000 µg BDP atau ekuivalen
• Dua fase:
•
•
Fase I: terapi akan ditingkatkan (‘step-up’) setiap 12 minggu sampai mencapai Total Kontrol atau
maksimum dosis steroid (SFC 50/500 µg bid atau FP 500 µg bid) tercapai
Fase II: pasien tetap memakai dosis yang dicapai saat fase I sampai studi selesai, tidak perlu
dilakukan penurunan dosis (step-down)
• Objektif primer
•
Untuk menentukan proporsi pasien yang mencapai asma terkontrol baik (well-controlled)
dengan kombinasi salmeterol/fluticasone propionate dibandingkan FP tunggal selama fase I
BDP, beclomethasone dipropionate; bid, twice-daily; FEV1, forced expiratory volume in 1 second; FP, fluticasone
propionate; ICS, inhaled corticosteroid; LABA, long-acting β2 agonist; SABA, short-acting β2 agonist; SFC,
salmeterol/fluticasone propionate
Bateman et al. Am J Respir Crit Care Med 2004;170:836-44
GOAL: Primary outcome
Persentase pasien yang mencapai asma terkontrol baik atau total kontrol
• Proporsi pasien yang mencapai asma terkontrol baik (well-controll) atau total kontrol
secara statistik lebih tinggi pada grup SFC dibandingkan grup FP pada akhir fase I
(primary endpoint) pada semua strata
Well controlled Asthma (Primary Endpoint)
100
100
Patients, %
80
Totally controlled
FP
SFC
*
FP
SFC
80
**
60
**
60
**
**
40
40
**
20
20
0
0
Stratum 1
Stratum 2
Stratum 3
Stratum 1
Stratum 2
Stratum 3
*p=0.039; **p<0.001
Bateman et al. Am J Respir Crit Care Med 2004;170:836-44
GOAL: Peluang mencapai kontrol dengan SFC dibanding FP
pada dosis yang sama atau lebih rendah dari dosis (Fase I)
• Peluang SFC mencapai asma terkontrol baik meningkat 40% dan mencapai total kontrol
meningkat 78% dibandingkan FP (stratum 1)
• Pada strata 2 dan 3, peluang mencapai asma terkontrol baik dan total kontrol
meningkat lebih dari 2 kali.
SFC vs. FP Odds ratio (95% CI)
Well controlled
Totally controlled
Stratum 1
(steroid naïve)
1.40 (1.12 to 1.76); p=0.003
1.78 (1.38 to 2.30); p<0.001
Stratum 2
(low dose ICS)
2.20 (1.77 to 2.74); p<0.001
2.19 (1.66 to 2.89); p <0.001
Stratum 3
(mod dose ICS)
2.32 (1.82 to 2.95); p<0.001
2.95 (2.01 to 4.33); p<0.001
CI, confidence interval; FP, fluticasone propionate; ICS, inhaled corticosteroid; SFC, salmeterol/fluticasone
propionate
Bateman et al. Am J Respir Crit Care Med 2004;170:836-44
GOAL: Waktu untuk mencapai asma kontrol
• Minggu dimana 50% pasien pertama kali mencapai asma terkontrol-baik (wellcontrol) terjadi lebih cepat pada grup SFC dibandingkan grup FP saat minggu 1-12.
(semua strata p<0.001)
Stratum 3
(mod dose ICS)
Stratum 2
(low dose ICS)
SFC
FP
Stratum 1
(steroid naïve)
0
2
4
6
8
10
12
Time (weeks)
FP, fluticasone propionate; ICS, inhaled corticosteroid; SFC, salmeterol/fluticasone propionate
Bateman et al. Am J Respir Crit Care Med 2004;170:836-44
GOAL: Proporsi kumulatif pasien yang mencapai asma
terkontrol-baik (well-control) sepanjang fase I dan II
• Proporsi kumulatif pasien yang mencapai asma terkontrol-baik pada akhir fase II
secara signifikan lebih tinggi pada grup SFC dibandingkan grup PF pada stratum 1
(p=0.003) dan stratum 2 & 3 (keduanya p < 0.001)
Cumulative % patients
100
Phase I (step-up)
Phase II (constant dose)
80
60
40
20
0
SFC
FP
Stratum 1
(steroid naïve)
SFC
FP
Stratum 2
(low dose ICS)
SFC
FP
Stratum 2
(med dose ICS)
FP, fluticasone propionate; ICS, inhaled corticosteroid; SFC, salmeterol/fluticasone propionate
Bateman et al. Am J Respir Crit Care Med 2004;170:836-44
GOAL: Cumulative proportion of patients achieving Totallycontrolled asthma across phases I and II
• The cumulative proportion of patients achieving totally-controlled asthma at the end of
Phase II were significantly higher for SFC compared to FP for all strata (all p < 0.001)
Cumulative % patients
100
Phase I (step-up)
80
Phase II (constant dose)
60
40
20
0
SFC Stratum 1 FP
(steroid naïve)
SFC Stratum 2 FP
(low dose ICS)
SFC Stratum 2 FP
(med dose ICS)
FP, fluticasone propionate; ICS, inhaled corticosteroid; SFC, salmeterol/fluticasone propionate
Bateman et al. Am J Respir Crit Care Med 2004;170:836-44
GOAL: Efek terapi terhadap eksaserbasi sedang - berat¥
Weeks 1 – 52
* p < 0.01
Mean exacerbation rate
per patient per year
0.8
Baseline
0.6
0.4
*0.37
0.27
0.2
*0.17
0.07
*0.12
SFC
FP
0.12
0
Stratum 1
¥ Requiring
SFC
FP
Stratum 2
SFC
FP
Stratum 3
either oral steroids or hospitalisation / emergency visit
Bateman et al. Am J Respir Crit Care Med 2004;170:836-44
GOAL: Safety Data
AE (Adverse event) yang
umum terjadi (≥ 5%)
SFC*
FP*
Nasofaringitis, %
13
14
ISPA, %
13
13
Sakit kepala, %
5
7
Sinusitis, %
5
4
Influenza, %
5
4
SFC *
FP *
Kandidiasis oral, %
3
3
Suara serak, %
3
2
Nyeri faringolaringeal, %
<1
1
AE yang umum terjadi yang
berkaitan dengan obat
Pooled data for all strata
FP, fluticasone propionate; SFC, salmeterol/fluticasone propionate; URTI, upper respiratory tract infection
Bateman et al. Am J Respir Crit Care Med 2004;170:836-44
GOAL: Post-hoc analyses
Maintenance of control 1
Clinical symptoms and severe exacerbations 2
Factors affecting probability of control 3
1. Bateman et al. Allergy 2008: 63: 932–8
2. Woodcock et al. Prim Care Respir J 2007;16:155–61
3. Pedersen et al. J Allergy Clin Immunol 2007;120:1036–42
GOAL post-hoc analysis: stabilitas kontrol asma
•
•
Sebagian besar pasien yang mencapai total kontrol atau terkontrol-baik pada akhir fase I akan tetap
minimal terkontrol baik setiap minggu
Kira-kira 35-45% pasien yang tidak terkontrol pada akhir fase I, akan mencapai asma terkontrol-baik
pada akhir fase II
FP, fluticasone propionate; SFC, salmeterol/fluticasone
propionate; TC, totally controlled; WC, well controlled;
NWC, not well controlled
Stability of asthma control with regular treatment: an
analysis of the Gaining Optimal Asthma Control (GOAL)
study. Bateman et al. Allergy 2008: 63: 932–8. Copyright ©
2008 Blackwell Munksgaard
GOAL post-hoc analysis: Symptom Free Days
• Analisa gabungan (semua strata) menunjukkan peningkatan hari-hari bebas-gejala pada
kedua grup (SFC & FP) pada:
median % symptom free days
100
Minggu 1-12
Minggu 1-52
100
FP
SFC
80
OR 1.30§
(95% CI: 1.03, 1.64)
OR 2.06*
(95% CI: 1.66, 2.56)
80
OR 1.37#
(95% CI: 1.10, 1.71)
60
OR 1.78*
(95% CI: 1.43, 2.21)
60
OR 1.79*
(95% CI: 1.44, 2.24)
40
40
OR 1.76*
(95% CI: 1.39, 2.22)
20
20
0
0
Stratum 1
Stratum 2
Stratum 3
Stratum 1
Stratum 2
Stratum 3
SFC vs. FP: # p=0.005; * p<0.001; § p=0.025
OR and CI based on proportional odds logistic regression analysis
CI, confidence intervals; FP, fluticasone propionate; SFC, salmeterol/fluticasone propionate; OR, odds ratio;
Woodcock et al. Prim Care Respir J 2007;16:155–61
GOAL post-hoc analysis: Annual severe exacerbations
• There was a significant reduction for the SFC treated patients compared to FP
treated patients in strata 1 and 3 but not stratum 2
0.07
SFC
Mean exacerbation rate
per patient per year
0.06
FP
0.05
p=0.007
0.04
p=0.014
0.03
p=0.993
0.02
0.01
0
Stratum 1
(steroid naïve)
Stratum 2
(low dose ICS)
Stratum 3
(mod dose ICS)
FP, fluticasone propionate; ICS, inhaled corticosteroid; SFC, salmeterol/fluticasone propionate
Woodcock et al. Prim Care Respir J 2007;16:155–61
GOAL post hoc analysis: faktor-faktor yang mempengaruhi
kontrol
Karakteristik
Odds ratio [OR] (95% CI)
p value
Female vs. male sex
0.652 (0.527 to 0.806)
<0.0001
Age
1.002 (0.995 to 1.008)
0.6008
Height
1.210 (1.070 to 1.367)
0.0023
Former vs. never smoked
1.274 (1.031 to 1.574)
0.0273
Current vs. never smoked
2.757 (2.061 to 3.689)
<0.0001
No history of ICS use vs. history of ICS use
0.546 (0.437 to 0.683)
<0.0001
FP vs. SFC
1.972 (1.686 to 2.308)
<0.0001
Baseline mean PEFR
0.997 (0.995 to 0.998)
<0.0001
Baseline FEV1
0.829 (0.703 to 0.978)
0.0262
Baseline night-time awakenings
1.899 (1.688 to 2.135)
<0.0001
pooled data across all strata; 1669 patients in FP group and 1676 patients in SFC group
FEV1, forced expiratory volume in 1 second; FP, fluticasone propionate; ICS, inhaled corticosteroid; PEFR, peak expiratory
flow rate; SFC, salmeterol/fluticasone propionate
Pedersen et al. J Allergy Clin Immunol 2007;120:1036–42
One year double-blind1 followed by 2 year openlabel study2
1. Lundbäck et al. Respir Med 2006; 100:2-10
2. Lundbäck et al. Respir Med 2009; 103:348-355
Asthma control real-world
• Studi 12 bulan dengan samar ganda, diikuti fase label-terbuka (“real-world”) selama
2 tahun2
• Pasien dengan asma ringan – sedang.
• Dokter peneliti dapat meningkatkan atau menurunkan obat untuk mencapai dan
mempertahankan kontrol asma melalui penilaian klinis menggunakan kriteria berdasarkan
pedoman penatalaksanaan.
• Primary outcome – proporsi pasien yang memerlukan peningkatan obat studi
selama tahun pertama pengobatan
1. Lundbäck et al. Respir Med 2006; 100:2-10
2. Lundbäck et al. Respir Med 2009; 103:348-355
Asthma control real-world: primary variable at end of
year 11
• Dengan SFC lebih sedikit pasien yang memerlukan peningkatan dosis obat selama studi
tahun pertama, alasan utama adalah pasien mengalami ≥ 2 eksaserbasi*
• Dengan SFC, secara signifikan lebih sedikit pasien yang mengalami ≥2 eksaserbasi*
dibandingkan FP atau SAL
Primary outcome:
Increase in study medication, n (%)
SFC
(50/250µg)
N=95
FP
(250 µg)
N=92
SAL
(50 µg)
N=95
10 (10.5)
32 (34.8)
58 (61.1)
p<0.001
(SFC vs. FP and SAL)
4.2
17.4
40.0
p<0.01 SFC vs. FP
p<0.001 SFC vs. SAL
Patients experiencing ≥2
exacerbations, %**
p value
* Didefinisikan sebagai perburukan asma yang memerlukan peningkatan obat pelega >6 puff/hari untuk ≥ 2 hari
berturutan, atau peningkatan ≥ 2 dosis/hari dari obat inhalasi rutin (obat yang dipakai dalam studi ini atau
penambahan ICS) untuk ≥ 2 hari, atau ≥ 2 hari ketika gejala mengganggu aktivitas normal pasien
* *Tidak ada jumlah pasien dalam manuskrip, jadi hanya tertulis dalam persentase.
SAL tidak boleh digunakan tunggal untuk terapi asma 2,3
FP, fluticasone propionate; SAL, salmeterol; SFC,
salmeterol/fluticasone propionate
1. Lundbäck et al. Respir Med 2006; 100:2-10
2. Seretide Inhaler PI BPOM GDS32/IPI16
3. Seretide Diskus PI BPOM GDS32/IPI17
Asthma control real-world: Summary of increase in
medication over 3 years1
• Pada akhir studi 3 tahun, 73% (168/229) grup SFC yang tetap dalam studi ini untuk
mempertahankan kontrol asma, dibandingkan 21% (49/229) grup FP dan 5% (12/229)
grup SAL.
Jumlah pasien yang memerlukan
peningkatan dosis obat selama 3 tahun, n
(%)
Rasio peluang yang memerlukan
peningkatan terapi SFC vs monokomponen
SFC
(50/250µg)
N=95
FP
(250 µg)
N=92
SAL
(50 µg)
N=95
24 (25)
43 (47)
77 (81)
2.66
95% CI 1.43 to 4.96;
p=0.002
9.38
95% CI 4.68 to 18.80;
p<0.0001
SAL tidak boleh digunakan tunggal untuk terapi asma 2,3
FP, fluticasone propionate; SAL, salmeterol; SFC,
salmeterol/fluticasone propionate
1. Lundbäck et al. Respir Med 2009; 103:348-355
2. Seretide Inhaler PI BPOM GDS32/IPI16
3. Seretide Diskus PI BPOM GDS32/IPI17
Asthma control over 3 years: Safety*
•
Tidak ada perbedaan laporan AE (adverse event) antar kedua grup (96% dengan SFC [50/250
µg] 97% dengan FP [250 µg] dan 95% dengan SAL [50 µg])
•
AE yang paling sering terjadi adalah ISPA: 88% pada grup SFC, 87% pada grup FP dan 75% pada
grup SAL
•
AE lain yang umum terjadi adalah:
•
asma, infeksi virus, nyeri otot dan gastroenteritis; tidak ada perbedaan angka kejadian AE ini
pada semua grup terapi
•
Suara serak merupakaan AE yang diperkirakan berkaitan dengan obat yang paling sering dilaporkan:
9% pada grup SFC, 5% pada grup FP dan 15% pada grup SAL
•
Ada kejadian 19 AE yang serius; tidak ada yang dihubungkan dengan obat
•
Tidak ada laporan kematian
•
Kortisol rata-rata pagi hari: 433 nmol/L pada saat randomisasi dan 428 nmol/L pada akhir studi (3
tahun) pada grup SFC; 464 dan 435 nmol/L pada grup FP; 370 dan 452 nmol/L pada grup SAL.
* Patient numbers were not given in manuscript so just % presented
SAL should not be used (and is not sufficient alone) as the first treatment for asthma2,3
FP, fluticasone propionate; SAL, salmeterol; SFC,
salmeterol/fluticasone propionate
1. Lundbäck et al. Respir Med 2009; 103:348-355
2. Seretide Inhaler PI BPOM GDS32/IPI16
3. Seretide Diskus PI BPOM GDS32/IPI17
Take Home Massages
Goal of asthma management is to achieve
control and reduced future risk
When this Goal achieved
Avoid troublesome symptoms during the day and
night
Need little or no reliever medication
Have productive, physically active lives
Have normal or near-normal lung function
Avoid serious asthma flare-ups (also called
exacerbations, or severe attacks)
Asthma controlled can be achieved with
LABACS Combination
TERIMA KASIH