Curriculum Vitae DR. Dr. Arto Yuwono Soeroto, SpPD-KP, FINASIM, FCCP E-mail: aysoeroto@yahoo.co.id Pendidikan: S1 FK Universitas Padjadjaran Sp1 FK Universitas Padjadjaran Konsultan Pulmonologi KIPD S3 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) Date of preparation Sept 2007. Prescribing Information can be found at the end of this presentation and is available on request. Symbicort® and Turbuhaler® are trademarks owned by the AstraZeneca Group.

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  Symptom control: to achieve good control of symptoms and maintain normal activity levels Risk reduction: to minimize future risk of exacerbations, fixed airflow limitation and medication side-effects

GINA assessment of symptom control A. Symptom control In the past 4 weeks, has the patient had: Well-controlled Partly controlled Uncontrolled Daytime asthma symptoms more than twice a week? Yes No None of these 1-2 of these 3-4 of these 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 Level of asthma symptom control *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: Well-controlled Partly controlled Uncontrolled Daytime asthma symptoms more than twice a week? Yes No None of these 1-2 of these 3-4 of these 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 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 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 REVIEW RESPONSE ASSESS ADJUST TREATMENT

Stepwise management – pharmacotherapy (GINA 2016) Diagnosis Symptom control & risk factors (including lung function) Inhaler technique & adherence Patient preference REVIEW RESPONSE ASSESS Symptoms Exacerbations Side-effects Patient satisfaction Lung function ADJUST TREATMENT Asthma medications Non-pharmacological strategies Treat modifiable risk factors STEP 5 STEP 4 Refer for add-on treatment e.g. Tiotroprium Omalizumab mepolizumab STEP 3 *For children 6-11 years, theophylline is not recommended, and preferred Step 3 is medium dose ICS **For patients prescribed BDP/formoterol or BUD/ formoterol maintenance and reliever therapy # Tiotropium by soft-mist inhaler is indicated as add-on treatment for adults (≥18 yrs) with a history of exacerbations STEP 1 STEP 2 PREFERRED CONTROLLER CHOICE Med/high ICS/LABA Low dose ICS/LABA* Low dose ICS Other controller options Add tiotropium# High dose ICS + LTRA (or + theoph*) Consider low dose ICS Leukotriene receptor antagonists (LTRA) Low dose theophylline* Med/high dose ICS Low dose ICS+LTRA (or + theoph*) Add low dose OCS As-needed short-acting beta2-agonist (SABA) As-needed SABA or low dose ICS/formoterol** RELIEVER

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

Apakah Tujuan Tatalaksana Asthma Berdasar GINA Dapat dicapai 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 Well Control Each week, two or more of following: Total Control Each week, all of following: Daytime symptoms Rescue use AM PEF (diary card) 2 days per week with score >1 2 days & 4 occasions 80% predicted every day None 80% predicted every day Each week, all of following: Night-time awakenings Exacerbations (all grades) Emergency visits Treatment-related AEs None None enforcing change in therapy 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) 16/10/2017 14:04 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 Notes.

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) *p=0.039; **p<0.001 ** * Stratum 1 Totally controlled ** Patients, % Stratum 2 Stratum 3 Stratum 1 Stratum 2 Stratum 3 Bateman et al. Am J Respir Crit Care Med 2004;170:836-44

SFC vs. FP Odds ratio (95% CI) 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 (well-control) terjadi lebih cepat pada grup SFC dibandingkan grup FP saat minggu 1-12. (semua strata p<0.001) FP SFC 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) Phase II (constant dose) Phase I (step-up) Cumulative % patients Stratum 1 (steroid naïve) Stratum 2 (low dose ICS) 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 Totally-controlled 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) Phase II (constant dose) Phase I (step-up) Cumulative % patients Stratum 1 (steroid naïve) Stratum 2 (low dose ICS) 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: Efek terapi terhadap eksaserbasi sedang - berat¥ Baseline Weeks 1 – 52 * p < 0.01 Mean exacerbation rate per patient per year *0.37 0.27 *0.17 *0.12 0.12 0.07 ¥ Requiring 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, % Sakit kepala, % 5 7 Sinusitis, % 4 Influenza, % AE yang umum terjadi yang berkaitan dengan obat SFC * FP * Kandidiasis oral, % 3 Suara serak, % 2 Nyeri faringolaringeal, % <1 1 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: Minggu 1-12 Minggu 1-52 OR 1.30§ (95% CI: 1.03, 1.64) FP SFC OR 2.06* (95% CI: 1.66, 2.56) OR 1.37# (95% CI: 1.10, 1.71) OR 1.78* (95% CI: 1.43, 2.21) median % symptom free days OR 1.79* (95% CI: 1.44, 2.24) OR 1.76* (95% CI: 1.39, 2.22) 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 p=0.007 Mean exacerbation rate per patient per year p=0.014 p=0.993 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) No history of ICS use vs. history of ICS use 0.546 (0.437 to 0.683) FP vs. SFC 1.972 (1.686 to 2.308) Baseline mean PEFR 0.997 (0.995 to 0.998) Baseline FEV1 0.829 (0.703 to 0.978) 0.0262 Baseline night-time awakenings 1.899 (1.688 to 2.135) 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 open-label study2 Lundbäck et al. Respir Med 2006; 100:2-10 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 Lundbäck et al. Respir Med 2006; 100:2-10 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 SFC (50/250µg) N=95 FP (250 µg) N=92 SAL (50 µg) p value Primary outcome: Increase in study medication, n (%) 10 (10.5) 32 (34.8) 58 (61.1) p<0.001 (SFC vs. FP and SAL) Patients experiencing ≥2 exacerbations, %** 4.2 17.4 40.0 p<0.01 SFC vs. FP p<0.001 SFC vs. SAL * 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 Lundbäck et al. Respir Med 2006; 100:2-10 Seretide Inhaler PI BPOM GDS32/IPI16 Seretide Diskus PI BPOM GDS32/IPI17

SAL tidak boleh digunakan tunggal untuk terapi asma 2,3 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. SFC (50/250µg) N=95 FP (250 µg) N=92 SAL (50 µg) Jumlah pasien yang memerlukan peningkatan dosis obat selama 3 tahun, n (%) 24 (25) 43 (47) 77 (81) Rasio peluang yang memerlukan peningkatan terapi SFC vs mono-komponen 2.66 95% CI 1.43 to 4.96; p=0.002 9.38 95% CI 4.68 to 18.80; p<0.0001 By the end of the 3 year study 73% (168/229) of the subjects remaining in the study were receiving SFC to maintain control of their asthma, compared with 21% (49/229) receiving FP and 5% (12/229) receiving SAL SAL tidak boleh digunakan tunggal untuk terapi asma 2,3 FP, fluticasone propionate; SAL, salmeterol; SFC, salmeterol/fluticasone propionate Lundbäck et al. Respir Med 2009; 103:348-355 Seretide Inhaler PI BPOM GDS32/IPI16 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 Lundbäck et al. Respir Med 2009; 103:348-355 Seretide Inhaler PI BPOM GDS32/IPI16 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

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