dr. chrispianoktafbipianmamudi, sppd-kp, finasimstep 1 step 2 steps 3 & 4 step 5) controlled...

dr. Chrispian Oktafbipian Mamudi, SpPD-KP, FINASIMJakarta, Sept 6th 1975e-mail: [email protected]

Education :MD Medical School, Atma Jaya, Jakarta, IndonesiaInternal Med Medical School, Sam Ratulangi, Manado, Indonesia Pulmonology Consultant Collegiums of Internal Medicine, Indonesia

Occupation :Staf of Respirology Division & Critical Care Internal Medicine, Faculty of Medicine Universitas

Kriten Krida Wacana, Indonesia

Organization :Indonesian Doctor’s Association, - IndonesiaSociety of Internal Medicine Jakarta, - IndonesiaSociety of Respirologi Indonesia (PERPARI)

CHRISPIAN O. MAMUDI

Treating Symptomatic Asthma Patients Beyond Inhaled Corticosteroid / Long

Acting B2 Agonist (ICS/LABA) :

The Role of Long Acting Anti Muscarinic Agent (LAMA)

DIVISI RESPIROLOGI DAN PENYAKIT KRITISDEPARTEMEN ILMU PENYAKIT DALAM

FAKULTAS KEDOKTERAN UNIVERSITAS KRISTEN KRIDA WACANA

PIT IDI JAKARTA UTARA

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

Goals of asthma management

• The long-term goals of asthma management are à1. Symptom control: to achieve good control of

symptoms and maintain normal activity levels2. 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 morethan twice a week? Yesq Noq

None ofthese

1-2 of these

3-4 of these

• Any night waking due to asthma? Yesq Noq• Reliever needed for symptoms*

more than twice a week? Yesq Noq

• Any activity limitation due to asthma? Yesq Noq

B. Risk factors for poor asthma outcomes

ASSESS PATIENT’S RISKS FOR:• Exacerbations• Fixed airflow limitation• Medication side-effects

Level of asthma symptom control

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 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

üAvoid troublesome symptoms during the day and night

üNeed little or no reliever medicationüHave productive, physically active livesüHave normal or near-normal lung functionüAvoid serious asthma flare-ups (also called

exacerbations, or severe attacks)

When asthma is well-controlled, patients can

GINA 2015

Meski banyak kemajuan dalam pengobatan,Secara Global risikoserangan asma dan angka mortalitas asma masih tinggi, 1,2

(Global asthma 2014/p5/p2) (Pavord 2018/p8/col1/p2)

1. The Global Asthma Report 2014. Available from http://globalasthmareport.org/resources/Global_Asthma_Report_2014.pdf2. Pavord I et al. Lancet 2018; 391(10118):350–400.; 3. Ebmeier S et al. Lancet 2017; 390(10098):935-45.

2,3 (Pavord 2018/ p4/fig1) (Ebmeier 2017/p4/fig1)

Angka mortalitas asma usia 5-34 tahun di 46 negara daridata online WHO Mortality Database (36 negara high-income dan 10 middle-income)

Tidak ada perubahan berartiangka mortalitas asma dari2006 (kematian 0-19 per 100.000 orang (0·18-0·21) ke2012 (juga kematian 0·19 per 100 000 orang (0·16-0·21).3

(Ebmeier 2017/p1/p3)

http://globalasthmareport.org/resources/Global_Asthma_Report_2014.pdf

MAGIC Study: Kontrol asma belum optimal di semua Step terapi GINA

19,5 19,212,7

4,0

28,0

37,4 36,2

12,0

52,4

43,451,1

84,0

0

10

20

30

40

50

60

70

80

90

Step 1 Step 2 Steps 3 & 4 Step 5

Prop

ortio

n of

pat

ient

s (%

) Controlled asthma

Partially controlled asthma

Uncontrolled asthma

*Based on 2006 GINA guidelines.GINA, Global Initiative for Asthma; GCS, glucocorticoids; ICS, inhaled corticosteroid; IgE, immunoglobulin E; LABA, long-acting β2-agonist; SABA, short-acting β2-agonist

GINA treatment step

Kontrol asma berdasarkan step terapi GINA (n = 624)

Low-dose ICS ICS/LABA therapy Step 4 + systemic GCS

and/or IgEantibodies

SABA as needed

Olaguibel JM, et al. Respir Res 2012;13:50

Eksaserbasi terjadi di semua Step terapi GINA

Eksaserbasi didefinisikan sebagai perburukan asma yang membutuhkan perawatan UGD/RS atau steroid oral (studi US: steroid oral yangdigunakan ekivalen dengan 20 mg/hari prednisone selama 3-28 hari; studi UK: peresepan steroid oral apapun dalam 2 minggu)

Suruki et al. BMC Pulmonary Medicine (2017) 17:74

Definisi Asma – Penyakit inflamasi kronis di setiap edisi GINA

Definisi asma – GINA 2002:

Asthma is a chronic inflammatory disorder of theairways in which many cells and cellular elements playa role

Definisi asma – GINA 2014

Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation.

Definisi asma – GINA 2018

Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation.

Global Initiative for Asthma (GINA) updated 2002, 2014, & 2018

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.

Definition of asthma

GINA 2018

Inflamasi adalah fitur yang mendasari penyakit asma

InflamasiSaluran napas

Obstruksisaluran napas

Hiperesponsifbronkial

Gejala

Currie, GP., Therapeutic modulation of allergic airways disease with leukotriene receptor

antagonists., Q J Med 2005; 98: 171 – 182h

© Global Initiative for Asthma

GINA 2018 – main treatment figure

GINA 2018, Box 3-5 (2/8) (upper part)

Previously, no controller was recommended for

Step 1, i.e. SABA-only treatment was ‘preferred’

Step 1 treatment is for patients with symptoms <twice/month and no risk factors for exacerbations

* Off-label; data only with budesonide-formoterol (bud-form)

† Off-label; separate or combination ICS and SABA inhalers

PREFERRED CONTROLLERto prevent exacerbations

and control symptoms

Other controller options

Other reliever option

PREFERRED RELIEVER

STEP 2

Daily low dose inhaled corticosteroid (ICS),

or as-needed low dose ICS-formoterol *

STEP 3

Low dose

ICS-LABA

STEP 4

Medium dose

ICS-LABA

Leukotriene receptor antagonist (LTRA), or low dose ICS taken whenever SABA taken †

As-needed low dose ICS-formoterol *

As-needed short-acting β2 -agonist (SABA)

Medium dose ICS, or low dose ICS+LTRA #

High dose ICS, add-on tiotropium, or add-on LTRA #

Add low dose OCS, but considerside-effects

As-needed low dose ICS-formoterol ‡

Box 3-5A

Adults & adolescents 12+ years

Personalized asthma management:Assess, Adjust, Review response

Asthma medication options: Adjust treatment up and down for

individual patient needs

STEP 5

High dose

ICS-LABA

Refer for

phenotypic

assessment

± add-on

therapy,

e.g.tiotropium,

anti-IgE,

anti-IL5/5R,

anti-IL4R

Symptoms Exacerbations Side-effects Lung functionPatient satisfaction

Confirmation of diagnosis if necessary Symptom control & modifiablerisk factors (including lung function)ComorbiditiesInhaler technique & adherence Patient goals

Treatment of modifiable risk factors & comorbiditiesNon-pharmacological strategies Education & skills training Asthma medications

1© Global Initiative for Asthma, www.ginasthma.org

STEP 1

As-needed

low dose

ICS-formoterol *

Low dose ICS taken whenever SABA is taken †

‡ Low-dose ICS-form is the reliever for patients prescribed

bud-form or BDP-form maintenance and reliever therapy

# Consider adding HDM SLIT for sensitized patients with

allergic rhinitis and FEV >70%predicted

‘Controller’ treatment means the treatment

taken to prevent exacerbations

Perubahan GINA 2019• Terapi SABA tunggal tidak direkomendasikan lagi jenjang awal

pengobatan• Pelega ICS/Formoterol menjadi pelega pilihan utama,

menggeser posisi SABA

GINA 2019 pocket guide

Choosing between controller options: individual patient decisions

Decisions for individual patientsUse shared decision-making with the patient/parent/carer to discuss:1. Preferred treatment for symptom control and for risk reduction2. Patient characteristics (phenotype)• Does the patient have any known predictors of risk or response?

(eg, smoker, history of exacerbations, blood eosinophilia) 3. Patient preference• What are the patient’s goals and concerns for their asthma?

4. Practical issues• Inhaler technique: can the patient use the device correctly after training?• Adherence: how often is the patient likely to take the medication?• Cost: can the patient afford the medication?

GINA 2014, Box 3-3 (2/2) Provided by H ReddelGlobal Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention, 2016.

Spectrum of actions of acetylcholine in the airway

Kummer K, et al. Histochem Cell Biol. 2008 130:219–234.

Pharmacological modulation of airway smooth muscle cell

Mechanism of action of anticholinergic bronchodilators

Barnes P. Physiol Rev. 1992; 72(3): 699 – 729.Ach Acetylcholine

Milestones in the development of anticholinergics

Cazzola M, et al. Pharmacol Rev. 2012;64:450–504.

IVisit 0

IVisit 1

(screening)

IVisit 2

(randomization)

IVisit 3–4

IVisit 5–8

IVisit 9

(end of treatment)

IVisit 10

Tiotropium 5 µg qd morning

Placebo

4-week screening

48-week double-blindtreatment period

4-weekfollow-up

-4I

0I

48I

52I

Three co-primary endpoints:

Kerstjens H, et al. N Engl J Med. 2012;367:1198–1207.FEV1, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; LABA, long-acting β2-agonist; qd, once daily.

All patients at least on ICS maintenance therapy (budesonide or equivalent)+LABA

FEV1 peak(0–3 h) after 24 weeks

FEV1 trough after 24 weeks

Time to first severe asthma exacerbation in pooled analysis after 48 weeks

148 centres, 5 continents

Patients on at least ICS+LABA

Perbaikan Fungsi Paru secara Signifikan melaluiFEV1 puncak(0–3 h) dan trough: Trial 1 dan 2

Baseline, mL PerubahanRerata(SE), mL

Perbandingan dengan Plasebo

RerataPerbedaan(SE),

mL

95% CI, mL

P-value

Trial 1

FEV1 peak(0–3h)

Tiotropium Respimat® (n=217)1578

401 (25)86 (34) 20, 152 <0.05

Placebo Respimat® (n=211) 315 (26)

FEV1 trough


144 (24)88 (31) 27, 149 <0.01


Trial 2

FEV1 peak(0–3h)


401 (25)154 (32) 91, 217 <0.0001


FEV1 trough


155 (23)111 (30) 53, 169 <0.001


Kerstjens H, et al. N Engl J Med. 2012;367:1198–1207.CI, confidence interval; FEV1, forced expiratory volume in 1 second; SE, standard error. Patients on at least ICS+LABA

FEV1 response results from Kerstjens H, et al. N Engl J Med. 2012;367:1198–1207.Error bars represent standard errors.FEV1, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; LABA, long-acting β2-agonist.

500

FEV

1 pe

ak: C

hang

e fr

om b

asel

ine

(mL)

FEV1 puncak(0–3 h) pada minggu ke- 24

Placebo Respimat® Trial 1 Placebo Respimat® Trial 2Tiotropium Respimat® 5 µg Trial 1 Tiotropium Respimat® 5 µg Trial 2Time post-dosing (h)

450

400

0

50

100

200

250

300

350

*****

*

**

0 0.5 1.0 2.0 3.0

***

150

Trial 1; mean difference 86±34 mL (P=0.01)

Trial 2; mean difference 154±32 mL (P<0.001)

P<0.0001 unless shown otherwise:*P<0.05

**P<0.01

Penambahan ke ICS+LABA


Perbaikan Fungsi Paru secara Signifikan melaluiFEV1 puncak(0–3 h): Trials 1 dan 2

Co-primary endpoint ketiga: Eksaserbasi Asma Berat

Kerstjens H, et al. N Engl J Med. 2012;367:1198–1207.ATS, American Thoracic Society; ERS, European Respiratory Society.

wDefinisi eksaserbasi asma berat: kebutuhan akaninisiasi atau penggandaan terapi kortikosteroid sistemikminimal 3 hari*

wWaktu terjadi eksaserbasi pertamawPer protokol: pooled analysis selama 48 minggu


*ATS/ERS Statement Asthma Control and Exacerbations: Standardizing Endpoints for Clinical Asthma Trials and Clinical Practice (Reddel H, et al, AJRCCM 2009)

Risiko eksaserbasi asma berat tiotropium vs

plasebo

Tiotropium Respimat® 5 µg qd n=122 (26.9%); placebo Respimat® qd n=149 (32.8%)

Tiotropium Respimat® 5 µg qd: 282 hari; placebo Respimat® qd: 226 hari (25th percentile)

Pasien berisiko:

453 430 409 401 389 378 363 353 348 339 331 319 308 298

250 50 75 100 125 150 175 200 225 250 275 300 325

Placebo Respimat® qd

Tiotropium Respimat® 5 µg qd

Pa

tie

nts

wit

h ≥

1 s

ev

ere

ast

hm

a e

xa

ce

rba

tio

n (

%)

Days

435 412 388 379 367 356 339 332 319 303 290 282 272454

HR=0.79 (95% CI: 0.62, 1.00); penurunan risiko21% (P=0.034)

Pasien yang memerlukan perawatan untuk mencegah satu eksaserbasi

berat selama 48 minggu periode penelitian: 15

20

0

10

30

40

50

Kerstjens H, et al. N Engl J Med. 2012;367:1198–1207. Full analysis set. Pooled data. Add-on to high-dose ICS+LABA. Severe exacerbation defined as asthma necessitating the initiation or doubling of systemic corticosteroid therapy for ≥3 days. CI, confidence interval; HR, hazard ratio; qd, once daily.

Placebo Respimat® qd

Tiotropium Respimat®5 µg qd

Meningkatkan waktu terjadinya eksaserbasi pertama hingga 56 hari


Kejadian perburukan asma

Kerstjens H, et al. N Engl J Med. 2012;367:1198–1207.CRF, case report form; PEF, peak expiratory flow.

wDefinisi Perburukan Asma:w Satu atau lebih gejala asma di luar rentang asma sehari-hari

pasien yang biasa berlangsung selama ≥2 hari berturut-turut.; dan/atau

w Penurunan PEF ≥30% pasien di pagi hari selama 2 hariberturut-turut

w Sesuai catatan pada CRF

wTermasuk eksaserbasi asma beratà Kehilangan kontrol

wWaktu terjadi perburukan asma pertamawPooled analysis selama 48 minggu


250 50 75 100 125 150 175 200 225 250 275 300 325

20

010

30405060708090

100

Pers

enta

sePa

sien

dega

nse

tidak

nya

satu

kali

keja

dian

perb

uruk

anas

ma

(%)

Hari

Placebo

Tiotropium 5 µg

Kerstjens H, et al. N Engl J Med. 2012;367:1198–1207 (supplementary information).ICS, inhaled corticosteroid; LABA, long-acting β2-agonist.

Kejadian Perburukan Asma

PenurunanRisiko31%

P<0.0001


Penambahan setelahICS+LABA

Waktu terjasi eksaserbasi asma berat pertamadilihat dengan keseluruhan status TH2

The height/width of the boxes in the forest plots represents the number of events proportionate to the number of events in PrimoTinA-asthma®. aIn PrimoTinA-asthma®, final P-value adjusted for interim analysis; bP-value adjusted for treatment-by-subgroup interaction. CI, confidence interval; HR, hazard ratio; TioR, tiotropium Respimat®.


•Subkelompok TH2-low and TH2-high pada baseline:

–TH2-low: total serum rendah IgE, ≤430 μg/L (equivalen dengan 179.2 IU/L), dan eosinofil darah rendah,

≤0.6×109/L (equivalen dengan 600/μL)

–TH2-high: total serum tinggi IgE, >430 μg/L, dan eosinofil darah tinggi, >0.6×109/L

Waktu terjadi eksaserbasi asma beratpertama dilihat dengan IgE dan status

eosinophil darah

The height/width of the boxes in the forest plots represents the number of events proportionate to the number of events in PrimoTinA-asthma®. aP-value adjusted for treatment-by-subgroup interaction. Patients on at least ICS+LABA

Waktu terjadi perburukan asma pertamadilihat dengan keseluruhan status TH2

The height/width of the boxes in the forest plots represents the number of events proportionate to the number of events in PrimoTinA-asthma®

aIn PrimoTinA-asthma®, final P value adjusted for interim analysis; bP value adjusted for treatment-by-subgroup interaction

Waktu terjadi perburukan asma pertamadilihat dengan status IgE dan status eosinofil

darah

The height/width of the boxes in the forest plots represents the number of events proportionate to the number of events in PrimoTinA-asthma®

aP value adjusted for treatment-by-subgroup interaction

Kerstjens H, et al. N Engl J Med. 2012;367:1198–1207 (supplementary information).

Kejadian Tidak Diinginkan


Profil keamanantiotropium setaradengan plasebo

Rangkuman• Tiotropium Respimat® sekali sehari pada asma

melengkapi penggunaan obat asma lainnya• Tiotropium memberikan pilihan terapeutik penting untuk

pasien dengan asma yang masih bergejala dengan ICS + LABA, tanpa memerlukan fenotip

• Penambahan tiotropium ke ICS/LABA pada pasiendengan asma berat yang masih bergejala menghasilkan:

31%risk reduction

in asthma worsening

Keamananyang setara

denganplasebo

Penurunanrisiko

eksaserbasiasma berat

hingga21%

Penurunanrisiko

perburukanasma hingga

31%

Perbaikanfungsi paru

hingga

154 mL

Thank you

dr. chrispianoktafbipianmamudi, sppd-kp, finasimstep 1 step 2 steps 3 & 4 step 5) controlled...

Documents