Latest Update in Asthma

Management : Manage in a SMART Way

Heru Sundaru
Division of Allergy and Clinical Immunology
Department of Internal Medicine, Cipto Mangunkusumo Hospital

11
Patients are still at risk of preventable asthma attacks and global mortality
rates due to asthma are still high, despite improved treatment options1,2
asthma 2014/p5/p2) (Pavord 2018/p8/col1/p2)
(Global

Age-standardised country-specific asthma mortality

rates in the 5-34 year age group from the online WHO
Mortality Database for 46 countries (36 high-income
and 10 middle-income)
There was no appreciable change in global asthma
mortality rates from 2006 (0·19 deaths per 100 000
people (0·18-0·21) through to 2012 (also 0·19 deaths
per 100 000 people (0·16-0·21).3 (Ebmeier 2017/p1/p3)

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

22 1. The Global Asthma Report 2014. Available from http://globalasthmareport.org/resources/Global_Asthma_Report_2014.pdf

2. Pavord I et al. Lancet 2018; 391(10118):350–400.; 3. Ebmeier S et al. Lancet 2017; 390(10098):935-45.
Driven by inflammation: Asthma – a chronic disease with recurrent,
unpredictable flare-ups, despite maintenance treatment
 Asthma is a chronic inflammatory disease with recurrent, unpredictable flare-ups of worsening
inflammation (cause) and increased symptoms (consequence)1-4 (O’Byrne 2017/p2/p5)(GINA
2017/p16/p2)(Doeing 2013/p1/p1)(Ismael 2011/p3/Fig2)

 These flare-ups occur at all levels of asthma severity and, even in patients who are taking anti-
inflammatory maintenance therapy, can lead to full-blown asthma attacks (exacerbations)
Relaxed Air trapped in
smooth alveoli
muscles
Constricted
smooth
muscle

Wall inflamed
and thickened
Normal airway Asthmatic airway Asthmatic airway during exacerbation
In the asthmatic airway, the wall is During an asthma attack, smooth muscle
inflamed, thickened and excess mucus constriction further narrows the airway
is often present lumen

33 Figure adapted from Reference 4.

1. O’Byrne P, et al. Eur Respir J 2017;50. pii:1701103; 2. Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention, 2017. Available from:
http://www.ginasthma.org [Last accessed: September 2017]; 3. Doeing DC, Solway J. J Appl Physiol 2013;114:834–43; 4. Ishmael F, et al. J Am Osteopath Assoc
2011;111:S11–7.
Inflammation is main feature of asthma

Symptoms

Airflow
obstruction
Bronchial
Hyperresponsiveness

Inflammation

44
Currie, GP., Therapeutic modulation of allergic airways disease with leukotriene receptor
antagonists., Q J Med 2005; 98: 171 – 182h
Assessing asthma symptom control

Asthma symptom control Level of asthma symptom control

In the past 4 wewks, has the patient had: Partly
Well
• Daytime asthma symptoms more controlled Uncontrolled
□ Yes □ No controlled
than twice/week?
• Any night waking due to asthma? □ Yes □ No
• Reliever needed for symptoms*
□ Yes □ No None of 1-2 Yes
more than twice/week? 3-4 Yes
these
• Any activity limitation due to
□ Yes □ No
asthma?

55
Global Initiative for asthma report, updated 2018
Three large, population-based surveys highlight that almost half of
all treated asthma patients remain uncontrolled
of asthma

40% patients were

Not Well Controlled in large, US
survey (2009)1

of treated asthma patients

53% were assessed as Not Well

Controlled in a European
survey in France, Germany,
Italy, Spain and UK (2012)2

of patients were
Not Well Controlled (with 23%

46% Very Poorly Controlled) in a

large recent
Australian survey (2015)3

66
1. Fuhlbrigge A et al. Allergy Asthma Proc 2009;30:529–33. 2. Demoly P et al. Eur Respir Rev 2012;21:66–74. 3. Reddel H et al. TSANZ March 2015 (AstraZeneca Australia).
Asthma control is sub-optimal across all GINA
severity steps: The MAGIC study

Asthma control according to treatment step (n = 624)

Controlled asthma

Proportion of patients (%)

Partially controlled asthma
90 84.0

80 Uncontrolled asthma

70

60
52.4 51.1
50
43.4
40 37.4 36.2

28.0
30
19.5 19.2
20
12.7 12.0
10 4.0

0
Step 1 Step 2 Steps 3 & 4 Step 5
GINA treatment step
SABA as Low-dose ICS ICS/LABA Step 4 +
needed therapy systemic GCS
n=624 and/or IgE
antibodies

77 *Based on 2006 GINA guidelines.

GINA, Global Initiative for Asthma; GCS, glucocorticoids;
ICS, inhaled corticosteroid; IgE, immunoglobulin E; Olaguibel JM, et al. Respir Res 2012;13:50
LABA, long-acting β2-agonist; SABA, short-acting β2-agonist
Risk factors for asthma exacerbation

High SABA use (with increase mortality if >1 x 200-dose

canister/month)

Inadequate ICS: not prescribed ICS, poor adherene, incorrect

inhaler technique

• Low FEV1, especially if <60% predicted

• Higher bronchodilator reversibility
• Major psychological or socioeconomic problems
• Exposure: smoking, allergen exposure if sensitized
• Comorbidities: obesity, chronic rhinosinusitis, confirmed food
• Sputum or blood eosinophilia
• Elevated FENO (in adults with allergic asthma taking ICS)
• Pregnancy
88
Global Initiative for asthma report, updated 2018
Asthma Still Kills
The National Review of Asthma Deaths

 During the final attack 45% died without seeking assistance

 Only 23% had a personal action plan
 Only 43% had had an asthma review in the last year
 39% had more than 12 SABA inhalers in last year,
4% had more than 50 SABA inhalers
 38% had fewer than 4 prescriptions and 80% fewer than 12 prescriptions
for a preventer inhaler in the last year

99
Royal College of Physicians; confidential enquiry report, 2014
Key factors associated with asthma deaths

1. Over-reliance and overuse of SABA

2. Reluctance to take regular inhaled steroids

3. Lack of knowledge/education, including self management to

prevent exacerbation

10
10 Global Initiative for asthma report, updated 2018
Prof Tim Harrson at Jakarta Respi Summit 2017
1. Over-reliance and overuse of SABA

Overuse SABA

Patients believe daily SABA use is acceptable, and the

majority of patients with asthma who have been prescribed
ICS treatment still regularly (over) use SABA

11
11 Nathan J et al. Allergy Clin Immunol Pract 2015; 3:734–742.
Thomas and Bateman Prim Care Respir Med 2015; 25: 14105.
Patel M et al. Clin Exp Allergy 2013; 43: 1144–1151.
 90% patients want immediate ‘as and when’
relief
Proportion that agree with each statement

Prefer to take high dose of [ICS/combination]

No need to take my asthma medications every day

Fear of having a serious asthma attack

Concern too much medication when well

Concern side effects of higher doses

I manage my asthma myself

I prefer to adjust ICS to changes of my asthma

I am confident to intervene early

I use my medication as and when necessary

I want immediate relief

0 20 40 60 80 100
Agree strongly Agree somewhat
Patient number (%)
n=3415
Partridge MR, et al. BMC Pulm Med 2006;6:13
Over-reliance on SABA increases mortality

Over-reliance on SABA at the expense of ICS controller therapy is associated with an increased risk of asthma-related death, as a
result of under-treatment of inflammation1
Episodes of high reliever use are also predictive of an increased risk of exacerbations3

250 2.5

Rate ratio for death from asthma

Asthma deaths/10,000 patient- 200 2.0

150 1.5
years

100
1.0

50
0.5
0.0
0 1 2 3 4 5 6 7
0.0
0 1 2 3 4 5 6 7 8 9 10 11 12
Canisters of SABA per
month/20,000 μg1 Canisters of ICS per year2

13
13
ICS, inhaled corticosteroid;
1. Suissa S, et al. Am J Respir Crit Care Med 1994;149:604–10; 2. Suissa S, et al. N Engl J
SABA, short-acting β2-agonist Med 2000;343:332–6; 3. Buhl R, et al. Respir Res 2012;13:59
Potential problems with SABA’s

Regular use of SABAs has been shown to

• Worsen asthma control (Sears et al. Lancet 1990;
336:1391-6)
• promote airway inflammation (Gauvreau GM, et al.
AJRCCM 1997; 156:1738-45).
Overuse of SABAs is associated with increased
asthma mortality (Suissa S et al. Am J Respir Crit Care
Med 1994; 149: 604–10; 2).

14
14
Design

Run-in Randomisation Treatment

Allergen
Albuterol 200 µg QID Challenge

Plasebo

Hari 1 8 9 10
Pre-treatment Post-treatment 7 hour post allergen 24 hour post allergen
FEV1 FEV1 FEV1 FEV1
Sputum Sputum Sputum Sputum
Blood Blood
Methacline Methacline

N: 14 non smoker subjects

15
15
Gauvreau GM, et al. Am J Respir Crit Care Med 1997; 156:1738-45
 The allergen-induced late bronchoconstrictor response was
significantly enhanced after albuterol treatment when compared to
placebo

Diluent

Placebo + Allergen

Albuterol + Allergen

16
16
Gauvreau GM, et al. Am J Respir Crit Care Med 1997; 156:1738-45
Regular inhaled beta-agonist treatment in bronchial
asthma

“Thus, regular inhalation of a betasympathomimetic

agent was associated with deterioration of asthma
control in the majority of subjects”

17
17
Sears et al. Lancet 1990; 336:1391-6
Adherence to controller medication is poor and continued
reliance on SABA relievers leaves patients at risk of preventable
asthma attacks (exacerbations)
Even after asthma-related hospitalisation, electronically measured adherence to corticosteroids dropped to
approximately 50% within 7 days of discharge (real-world data)2 (Krishnan 2004/p2/fig1)

100

OCS: -5.2% per day, p<0.0001

ICS, N=49

75 OCS, N=48
Use (%)

50

25
ICS: -2.7% per day, p<0.0001

0
1 2 3 4 5 6 7 8 9 10 11 12 13
Days since discharge

18
18
ICS, inhaled corticosteroid; OCS, oral corticosteroids; SABA, short-acting β2-agonist.
1. Foster JM et al. J Allergy Clin Immunol 2014; 134:1260-68; 2. Krishnan JA, et al. Am J Respir Crit Care Med 2004; 170:1281–5.
19
19
Eur Respir J 2017; 50: 1701103
“The Paradoxes of Asthma Management”1 (O’Byne 2017/p1/title)
In step 1 treatment, a SABA bronchodilator alone is recommended despite the fact that
asthma is a disease of chronic airway inflammation with increased inflammation at the times
of exacerbations.

In step 1 treatment, the patient has autonomy and their perception of treatment as needed to control symptoms is accepted, whereas at
higher asthma treatment steps it is assumed that patients will adopt a fixed-dose approach.

There is a switch in recommendation from using a SABA alone as needed at step 1 to advising an ICS fixed-dose regimen at step 2 and
minimising SABA use. The medication that treats the underlying disease, which patients are encouraged to take (the ICS) is not the one that
the patient perceives is benefitting them (the SABA), which they are now discouraged from taking.

There is a different safety message in the advice given for the use of SABA and LABA within the guidelines; “SABA alone being safe and
LABA alone being unsafe”.

There is a dislocation between patients’ understanding of “asthma control” and the frequency, impact and severity of their symptoms.

20
20 1. O’Byrne et al. Eur Respir J 2017; 50: 1701103
Quotations taken directly from publication, referring to previous asthma guidelines, prior to 2018 updates (e.g. GINA and BTS/SIGN)
 The solution is a treatment approach
the combines regular with as-needed
treatment in the same inhaler!
STEP 5

STEP 4

STEP 3 Refer for

PREFERRED STEP 1 STEP 2 add-on
CONTROLLER treatment
CHOICE e.g.
Med/high tiotropium,*
anti-IgE,
ICS/LABA anti-IL5*
Low dose
Low dose ICS ICS/LABA**

Other Consider low Med/high dose ICS Add tiotropium* Add low
Leukotriene receptor antagonists (LTRA)
controller dose ICS Low dose ICS+LTRA High dose ICS dose OCS
Low dose theophylline*
options (or + theoph*) + LTRA
(or + theoph*)

RELIEVER As-needed short-acting beta2-agonist (SABA) As-needed SABA or

low dose ICS/formoterol#

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21
Eur Respir J 2017; 50: 1701103
 The goal of asthma management is:

Overall asthma control

achieving reducing

Current control Future risk

defined by defined by

Instability/
Symptoms Reliever use Exacerbations
worsening
SYM/020/Apr09-Apr10/LY

Loss of Adverse effects

Activity Lung function
lung function of medication

Bateman ED et al. J Allergy Clin Immunol 2010; 125(3):600–608.

NAEPP. Expert Panel Report 3. 2007.
Taylor DR, et al. Eur Respir J 2008; 32(3):545–554.
 Budesonide/Formoterol combination as morning, evening and as
needed manages flare-ups with additional doses when needed,
avoiding potential over-treatment and reducing future risk
Symptoms

Low dose ICS/LABA controller

Time
23
23 Adapted from Tattersfield et al.. Am J Respir Crit Care Med. 160. 1999
Osborne et al. Lancet 2004; 363:271-5b
 Budesonide/Formoterol combination as morning, evening and as
needed manages flare-ups with additional doses when needed,
avoiding potential over-treatment and reducing future risk

Potential over-treatment
and future risk
Symptoms

High dose ICS/LABA maintenance

Low dose ICS/LABA controller

Time
24
24 Adapted from Tattersfield et al.. Am J Respir Crit Care Med. 160. 1999
Osborne et al. Lancet 2004; 363:271-5b
 Budesonide/Formoterol combination as morning, evening and as
needed manages flare-ups with additional doses when needed,
avoiding potential over-treatment and reducing future risk
Dengan
Budesonide/formoterol

Potential over-treatment (Symbicort®) pagi, sore, dan

jika ada gejala:

and future risk • ICS tambahan yang

Symptoms

High dose ICS/LABA maintenance diperlukan diberikan

dalam kombinasi dengan
onset cepat
β2-agonist sebagai pelega
• Memberikan
bronkodilatasi cepat
& tambahan control
Low dose Budesonide/Formoterol morning and evening
inflamasi
Time
25
25 Rabe KF et al. Lancet 2006; 368: 744–53.
Adapted from Tattersfield et al.. Am J Respir Crit Care Med. 160. 1999
Osborne et al. Lancet 2004; 363:271-5b
 Increasing combination therapy earlier to prevent
exacerbations
FACET exacerbation profiles
% change from
day –14
100
Reliever β2-agonist
Morning PEF
80 Window of opportunity to
Night-time symptoms
prevent exacerbations?
60

40

SYM/021/Jul 11 – Jul 12/RD

20
SYM/020/Apr09-Apr10/LY

–15 –10 –5 0 5 10 15
Days before and after an exacerbation
Tattersfield AE, et al. Am J Respir Crit Care Med 1999;160:594–599.
SYM/020/Apr09-Apr10/LY
Studi COMPASS 2007: Effect of budesonide/formoterol
maintenance and reliever therapy on asthma exacerbations
Run-in Randomisation Treatment
Salmeterol/Flutikason 50/250 μg BID + Terbutaline as reliever (n=1123)
Regular ICS ≥500 µg +
terbutaline Symbicort 320/9 μg BID + Terbutaline as reliever (n=1105)
as reliever
Symbicort 160/4.5 μg BID + Symbicort as reliever (n=1107)
Week -2 0 8 16 24

Enrolled n=4399
Randomize n=3335

Primary objective:
To compare the efficacy of SMART [budesonide/formoterol (160/4.5
µg one inhalation bid) plus additional inhalations as needed], with
salmeterol/fluticasone (25/125 µg two inhalations bid) plus
terbutaline (0.4 mg/inhalation as needed).
Penelitian acak, buta-ganda selama 6 bulan terhadap 3335 pasien asma dewasa dan remaja yang memiliki gejala (FEV₁ rata-rata 73% terprediksi, dosis kortikosteroid hirup rata-rata adalah 745 µg/hari). Perawatan dan Pereda
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28 Symbicort® 160/4.5 µg satu kali penghirupan bd + penghirupan tambahan sesuai-kebutuhan. Perawatan dan Pereda Symbicort® memperpanjang waktu sampai ke eksaserbasi parah pertama yang membutuhkan perawatan
rumah sakit, ruang gawat darurat atau steroid oral (variabel primer) vs salmeterol/fluticasone dosis-tetap (p = 0,0034). Hasil penelitian juga menunjukkan bahwa salmeterol/fluticasone 25/125 µg dua kali penghirupan bd +
terbutaline sesuai-kebutuhan memiliki hasil hari-hari pelegaan asma yang serupa: Titik awal 5.7% vs Pengobatan 43.7%¹
1. Kuna P et al. Int J Clin Pract. 2007;61(5):725-736
The total number of severe exacerbation was reduced by 39% (P<0.001)
in the Budesonide/Formoterol maintenance & reliever compared with
fixed-dose Salmeterol/Fluticason
Hospitalization/
150 ER
SAL/FLU 50/250 µg bid +
SABA as needed (n = 1123)
39% reduction
p<0.0015 Symbicort® 320/9 µg bid +
SABA as needed (n = 1105)

39% 106

Number of events
Symbicort® 160/4.5 µg bid +
100 Symbicort® as needed (n = 1107)

(p< 0.0015) 72
64

50

29
29
1. Kuna P et al. Int J Clin Pract. 2007;61(5):725-736
Those benefit shown with 25% lower of ICS dosage in
budesonide/formoterol vs. Salmeterol/Flutikasone

Budesonide/formoterol 160/4.5 µg bd as maintenance &

reliver reduced severe exacerbation by 39% better vs.
Salmeterol/Flutikasone and improved asthma control days 7x

25%
vs. baseline, all those benefit with

25% lower of ICS

Vs. salmeterol/fluticasone
50/250 µg bd + SABA as reliever1

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30
1. Kuna P et al. Int J Clin Pract. 2007;61(5):725-736
 Maintenance and relief: selected study results vs GINA
criteria
Bud/form
Bud/form Seretide
Characteristic Study outcome maintenance and
regular regular
relief
% Symptom-free days
Daytime symptoms 44.2 44.6 46.0
(mean)
Inhalations/day 1.02 1.05 0.96
Need for rescue/
reliever treatment % Rescue-free days (mean) 56.0 57.8 59.1

Lung function
Change in am PEF (L/min)+ 26 27 29
(PEF or FEV1)
Exacerbations
Exacerbation (hospitalisations, ER visits, 0.24* 0.32 0.38
SYM/020/Apr09-Apr10/LY

≥3days OCS)†

*vs Seretide P<0.001, vs bud/form (budesonide/formeterol) regular P=0.0048

†Annualised rates based on 6 month data reported
+Calculated from baseline and endpoint data reported

Kuna P et al. Int J Clin Pract 2007;61:725–736

Replace SABA with ICS/formoterol in GINA 3-5
patients with SABA at higher risk for asthma exacerbaton
vs. patient with ICS/formoterol

Patel et al. Lancet Resp Med 2013;1:32-42

Prof Tim Harrison at Respi summit 2017
33
33
 Reviewing response & adjusting treatment
 How often should asthma be reviewed?
 1-3 months after starting treatment and every 3-12 months thereafter
 During pregnancy, every 4-6 week
 After exacerbation, a review visit within 1 week
 Stepping up asthma treatment
 Sustained step-up, for at least 2-3 month. If symptoms persist:
• Important: to check the common cause (for example: symptoms non asthma, inhaler technique, or
adherence)
 Short term step up (for 1-2 weeks), an occasional short term increase of maintenance dose for 1-2 weeks
may be necessary for example during viral infection or seasonal allergen exposure.
 Day to day adjustment
• For patients prescribed combination ICS/formoterol as maintenance & reliever treatment, the patients
adjusts the number of as needed ICS/formoterol from day to day according to their symptoms, while
continuing the maintenance dosage
 Stepping down treatment when asthma is well controlled
 Once good asthma control has been achieved & maintained for 3 months and lung function has reached a
plateau, treatment can often be successful reduced, without loss of asthma control.
 Find the effective minimum dose for each patients
34
34
Global Initiative for asthma report, updated 2018
Summary
1. Patients are still at risk of preventable asthma attacks and global mortality rates due to
asthma are still high, despite improved treatment options
2. Two key factor for exacerbation risk:
- Overuse SABA
- Underuse ICS
3. Patients are often provided a maintenance controller for the inflammation and a separate
SABA reliever for symptoms, which often leads to high reliever versus controller use
4. GINA 2018 recommend the use of ICS/Formoterol as maintenance & reliever for moderate-
severe asthma
5. With 25% lower of daily ICS dose, patients with budesonide/formoterol as reliever &
maintenance had better reduction of severe exacerbation 39% vs. Sal/Flu + SABA.
6. Asthma treatment should be reviewed 1-3 months after starting treatment and every 3-
12 months thereafter

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Thank you
4/6/2
019
SYM/020/Apr09-Apr10/LY