1. UPDATE ON ASTHMA
MANAGEMENT
Lunch Hour Talk
12th July, 2005
Rashidi Ahmad
Lecturer/Emergentist
Department of Emergency Medicine

2. Outline
• Global Burden of asthma – good @ bad
news?
• Definition of asthma, what is new?
• Pathogenesis of asthma, what is new?
• What is persistent asthma?
• Scientific rationale of LABA + CS and
LABACS inhaler
• Formoterol/Budesonide as AMD & single
inhaler therapy

3. Global Burden of Asthma
• Asthma prevalence 2 - 7% internationally (ECRHS studies)
• Asthma prevalence on the rise for > 20 year (Vollmer
1998), 74% increase 1980 - 96 (Mannino 1998) & may be
stabilizing (Braun-Fahrlander ERS 2004)
• 50% of male cases Dx by 3 y.o, 50% of female cases
Dx by 8 y.o (Yunginger et al ARRD 1992)
• Factors for persistent & relapsed asthma:
atopic exposure, bronchial hyperreactivity, female sex,
smoking, early age at onset (Sears et al NEJM 2003)
• Highest absence rate from school (Weiss et al NEJM 1992)
• Costly: 12.6 billion /year direct med costs (Weiss JACI 2000)

4. Asthma Exacerbations
• In the relatively undertreated 1999 U.S. asthma
population (N= 10,488,000 persons)
– School absence: 14.0 million days
– Work absence: 14.5 million days
– Asthma ER visits: 2 million
– Asthma Hospitalizations: 478,000
– Asthma Deaths: 4657
MMWR Surveillance Summaries March 29, 2002 / 51(SS01);1-13

5. Frequency Adverse Event is Likely to Occur..
- Absenteeism: At least once in every asthmatic
(Average: 3.7 days/year)
- ER visit: Once in every 5 asthmatics
- Hospital visit: Once in every 26 asthmatics
- Death: Once in every 2252 asthmatics
MMWR Surveillance Summaries March 29, 2002 / 51(SS01);1-13

6. Asthma Definition
• Chronic Airway Inflammatory Disease
• Occurs only in Susceptible Individuals
• Recurrent Episodes of Symptoms
• Variable and Reversible Airflow
Obstruction
• Increased Bronchial Hyperreactivity
NHLBI 1997

7. Asthma Definition – NHLBI 2002
• Chronic Airway Inflammatory Disease
• Occurs only in Susceptible Individuals
• Recurrent Episodes of Symptoms
• Variable and Reversible Airflow Obstruction
• Increased Bronchial Hyperreactivity
• May have an incomplete response to
therapy
• May coexist with chronic bronchitis

8. Pathogenesis of Asthma
Holgate ST. The cellular and mediator basis of asthma in relation to natural history.
Lancet 1997;350(suppl 2):5-9.

9. Asthma Pathology - Modern view
Allergen
Macrophage/
dendritic cell Mast cell
Th2 cell Neutrophil
Eosinophil
Mucus plug
Epithelial shedding
Nerve activation
Subepithelial
fibrosis
Plasma leak
Sensory nerve
Oedema activation
Vasodilatation Cholinergic
Mucus reflex
New vessels
hypersecretion
Hyperplasia Bronchoconstriction
Hypertrophy/hyperplasia
Barnes PJ (1999:2000)

10. Airway remodeling overview

11. Bronchial morphology
• Inflammation
• Eosinophils
• Gland hyperplasia
• Mucous plug in lumen
• Hypertrophy of muscle layer

12. Normal bronchial mucosa
Goblet-cell hyperplasia in the
epithelial-cell lining
Sub-basement membrane: thickened,
collagen deposition in the submucosal
area, cellular infiltrattion
Busse et al NEJM 2001

13. Cellular Mechanisms Involved in Airway Inflammation

14. Mediators of Airflow Obstruction
• Bronchoconstriction (histamine, PAF, PGD2,
LTC4, LTD4)
• Edema (as above plus bradykinin)
• Increased mucus secretion (cysteinyl
leukotrienes)
• Airway remodeling (toxic eosinophil
eosinophil, TNF-alpha)

15. What is Persistent Asthma?
Asthma severity
Classified by:
4 Severe Persistent • Symptoms
• Activity levels
3 Moderate Persistent
• Exacerbations
2
• FEV1/PEFR
Mild Persistent
• PEFR variability
1 Mild Intermittent “Severity is classified before
therapy begins”
Global INitiative for Asthma (1998)Asthma Management and Prevention Report,
NHLBI and World Health Organization (WHO)

16. Mild Intermittent
Clinical features before Rx
• Symptoms < 2x per week
• Brief exacerbations
• Night time symptoms < 2x per
month
• Asymptomatic with normal lung
function between exacerbations
1 Mild
Intermittent
• FEV1 and PEF > 80% predicted
• PEF variability < 20%

17. Mild Persistent
Clinical features before Rx
• Sx > 2x/week but <1x/day
• Exacerbations may affect activity
• Night time asthma Sx > 2x/month
2 • FEV1 and PEF > 80% predicted
• PEF variability 20 - 30%
Mild
Persistent

18. Moderate Persistent
Clinical features before Rx
• Daily symptoms
• Exacerbations > 2x/week
3 affect activity
• Night time asthma sx > 1x/week
Moderate • Daily use of short-acting ß agonist
Persistent • FEV1 and PEF > 60% and < 80%
predicted
• PEF variability > 30%

19. Severe Persistent
Severe
4 Persistent
Clinical features before Rx
• Continuous symptoms
• Frequent exacerbations
• Frequent night time symptoms
• Limited activity
• FEV1 and PEF < 60% predicted
• PEF variability > 30%

20. Principles of Asthma MX
Acute Chronic Airway
Inflammation Inflammation Remodelling
Bronchoconstriction Cell recruitment
Cellular proliferation
Oedema Epithelial damage
Extra-cellular matrix
Secretions Early structural
increase
Cough changes

21. Asthma Continuum
)
dose 00 µg
aily 20
(d µg
id 0
stero 100
+ Prednisone
tico
β2-agonist cocor 00 µg
CS d glu 5
le
(mainstay of asthma MX) Inha
g
0µ Additional therapy
Short-acting β2-agonist on demand
Environmental control and education
Severity of asthma
Very mild Mild Moderate Moderately Severe
severe
Symptom characteristics
Subclinical Intermittent Persistent
Canadian Consensus on Asthma 1999

22. Questions to be answer?
• How CS works in asthma?
• What is the maximum effective dose?
• How β2-agonist works in asthma?
• What are the effects of combination therapy
between LABA and CS?
• What is the rationale of LABACS in asthma
management?

23. Steroid Effects in Asthma
Enhanced innate immunity
Barnes PJ Am J Resp Crit Care Med 1998; 157: S1-S53

24. Therapeutic response to CS
Laitinen et al JACI 1992; 90: 32-42

25. What is the maximum dose?
• Those asthmatics who were not controlled on a low
dose of ICS (beclomethasone dipropionate 400 µg
daily), had little improvement in asthma control even
the dose was increased (1000 µg daily)
Greening AP et al. Lancet 1994;344:219–224
• Dose/response studies have demonstrated that in
patients with moderate asthma there is a relatively flat
dose/response curve, with most of the benefit obtained
at the lowest doses
Holt S et al. Dose-response relation of inhaled fluticasone propionate in
adolescents and adults with asthma: meta-analysis. BMJ 2001;323:253–256

26. Beclomethasone dipropionate 400 µg daily
Optimum dosage

27. Revolution in Asthma MX
• Landmark study (Lancet 1994)
• To examine the benefits of adding salmeterol compared
with increasing dose of inhaled corticosteroids.
• Systematic review of randomised, double blind clinical
trials
• 3685 symptomatic patients aged >/= 12 y.o
• Results and conclusions (compared with response to
increased steroids)
• In patients receiving salmeterol morning PEFR was
greater at 3 months (difference 22.4 (95% confidence interval
15.0 to 30.0) L/min, P<0.001) and 6 months (27.7 (19.0 to 36.4) L/min,
P<0.001).

28. Cont…
• FEV1 was also increased at 3/12 (0.10 L/min (0.04 to 0.16),
P<0.001) and 6/12 (0.08 L/min (0.02 to 0.14), P<0.01),
• Mean percentage of days and nights without symptoms
(3 months: days 12% (9% to 15%), nights 5% (3% to 7%); 6 months: days
15% (12% to 18%), nights 5% (3% to 7%); all P<0.001)
• Mean percentage of days and nights without need for
rescue treatment (3 months: days 17% (14% to 20%), nights 9% (7%
to 11%); 6 months: days 20% (17 to 23%), nights 8% (6% to 11%); all
P<0.001).
• Fewer patients experienced any exacerbation with
salmeterol (difference 2.73% (0.43% to 5.04%), P=0.02)
• The proportion of patients with moderate or severe
exacerbations was also lower (2.42% (0.24% to 4.60%), P=0.03).
Greening AP, Ind PW, Northfield M, Shaw G. Added salmeterol versus higher-dose
corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid.
Lancet 1994;344:219–224

29. Kips JC, O'Connor BJ, Inman MD, Svensson K, Pauwels RA, O'Byrne PM. A long-term
study of the antiinflammatory effect of low-dose budesonide plus formoterol versus high-
dose budesonide in asthma. Am J Respir Crit Care Med 2000;161:996–1001

30. Kips JC, O'Connor BJ, Inman MD, Svensson K, Pauwels RA, O'Byrne PM. A long-term study of
the antiinflammatory effect of low-dose budesonide plus formoterol versus high-dose budesonide
in asthma. Am J Respir Crit Care Med 2000;161:996–1001

31. Formoterol minimises systemic burden
arbitrary
units
Oxis Turbuhaler®
Short-acting β2-agonist
Effects in the lung
after inhaled
administration
0 6 12 hours
Systemically
derived
effects
1. Löfdahl & Svedmyr, Allergy 1989 2. Palmqvist et al, Eur Respir J 1997 3. Borgström et al, AJRCCM 1996
4. Tötterman et al, Eur Respir J 1998 5. Lötvall et al, Eur Respir J 1997

32. Questions
• Why CS have ceiling effects in inflammation
process? I don’t have the answer. ?saturated
• How LABA improve the symptoms & lung
function beside no inflammatory properties?
• Can LABA causes intolerance or mask the
exacerbations?

34. Non-bronchodilatory effects of
β2-agonists
• Inhibit mediator release from mast cells
• inhibit plasma exudation by preventing
separation of endothelial cells in postcapillary
venules
• inhibit excitatory non-adrenergic non-cholinergic
(NANC) bronchoconstrictor responses in
guinea-pig bronchi in vitro

35. Formoterol does not mask exacerbations
% Pulmicort Turbuhaler® 100 mg bid
fall in mPEF
before, during Pulmicort Turbuhaler® 100 mg bid + Oxis Turbuhaler® 9 mg bid
10 Pulmicort Turbuhaler® 400 mg bid
and after
severe Pulmicort Turbuhaler® 400 mg bid + Oxis Turbuhaler® 9 mg bid
exacerbation
0
-10
-20
-30
-15 -10 -5 0 5 10 15
Days
Tattersfield et al, AJRCCM 1999

36. No tolerance with long term use of formoterol
Pulmicort® 100 mg bid Pulmicort® 100 mg bid + Oxis® 9 mg bid
Pulmicort® 400 mg bid Pulmicort® 400 mg bid + Oxis® 9 mg bid
FEV1 90
(%
predicted)
85
80
75
70
-1 0 1 2 3 6 9 12
run-in Months
Pauwels R et al, NEJM 1997

37. Summary of the effects of LABA & CS

38. Interaction between formoterol & budesonide
P J Barnes ERJ 2002; 19:182-191

39. Desensitization of ß2 receptor
Stimulatory G-protein
G-protein receptor
kinase-2
Uncoupling

40. CS - increased the expression of ß2-receptors
↑ transcriptase
GRE: Glucocorticoid response elements

41. Interaction of ß2-agonists with
corticosteroid effects
PKA: protein Kinase A
MAPK: mitogen-activated protein kinases

42. Clinical implications
• LABA & CS have different targets
• Complementary effects – CS preventing the
loss of function of β2-agonists with chronic use
& β2-agonists may potentiate the local
inflammatory actions of CS
• Combination of LABA + CS more superior than
high dose CS in overall control of asthma
especially moderate to severe persistent
asthma

43. Stepwise Approach to Therapy for
Children ≤5 Years
Step 4
Severe Persistent
Step 3 High-dose ICS +
Moderate Persistent LABA
Step 2 Preferred: (+ systemic
Mild Persistent Low-dose ICS + LABA corticosteroids
or if needed)
Medium-dose ICS
Step 1 Preferred:
(+ LABA if needed)
Mild Intermittent Low-dose ICS
Alternative: Alternative:
No Daily
Cromolyn Low- to Med-dose ICS
Medication
or + LTRA or
LTRA Theophylline
NIH/NHLBI Guideline Update. June 2002. NIH Publication No. 02-5075.

44. Stepwise Approach to Therapy for Adults
and Children > 5 Years
Step 4
Severe Persistent
Step 3
Moderate Persistent High-dose ICS +
LABA
Preferred:
Step 2 Low- to Medium-dose
Mild Persistent (+ systemic
ICS + LABA corticosteroids
Preferred: (↑ to med-dose ICS+ if needed)
Step 1 Low-dose ICS LABA if needed)
Mild Intermittent
Alternative:
Alternative: ↑ ICS With No LABA
No Daily
Cromolyn, LTM, or Low- to Med-dose
Medication
Nedocromil, or ICS + LTM or
SR Theophylline Theophylline
NIH/NHLBI Guideline Update. June 2002. NIH Publication No. 02-5075.

45. The Rationale of Inhaler combination
therapy (LABACS)
• ß2-agonists & CS interact in a beneficial way (CS
preventing the loss of function of ß2-agonists with
chronic use, whereas ß2-agonists may potentiate
the local anti-inflammatory actions of CS)
• Therefore it is a powerful scientific rationale for
combining ß2-agonists and CS in a single inhaler
(LABACS), as most patients with asthma will need
both treatments
• LABACS inhalers – better overall control of
asthma
• LABACS inhalers – new “gold standard” of therapy

46. Patients with asthma control day (%) Symbicort® improves asthma control* days
Additional two
60 months per year
55 of asthma
50 control
45 p<0.001
40
Symbicort® 160/4.5 μg
35
30 Pulmicort® 200 μg +
Oxis® 4.5 μg
25
Pulmicort® 200 μg
20
15
-10 0 10 20 30 40 50 60 70 80 90
Treatment Days
*Asthma control day = no day/night symptoms, no rescue bronchodilator, no night awakenings
Zetterström et al, WCLH/ERS 2000b

47. Symbicort® improves morning PEF
Symbicort® 160/4.5 μg Pulmicort® 200 μg + Oxis® 4.5 μg Pulmicort® 200 μg
400
390
(L / min)
380
370 p<0.001
360
350
-10 0 10 20 30 40 50 60 70 80 90
Treatment Days
Zetterström et al, WCLH/ERS 2000a

48. Symbicort® is more effective than a higher
dose of ICS in Moderate Asthma
30
Change in morning PEF (L/min)
25
20
15 p<0.001
10
5
0
-5
-10 0 10 20 30 40 50 60 70 80 90
Treatment days
Symbicort® 160/4.5 µg bid fluticasone DPI 250 µg bid
Bateman et al, Am J Respir Crit Care Med 2001

49. Combination inhaler therapy
(LABACS)
• Symbicort (standard dose (160/4.5µg)
and low-dose (80/4.5µg)
• Seretide (50 µg of salmeterol (as
salmeterol xinafoate) and 100, 250 or 500 µg
of fluticasone propionate)

50. SABA versus LABA. Anderson et al Eur Respir J 1994; 7: 569-578

51. Revolution in single inhaler
LABACS
• Fixed dosing
• Adjustment maintenance dosing
• Single inhaler (controller + reliever)

52. Aiming for earlier and simpler adjustment in
controller treatment to prevent attacks
Asthma
Worsening Exacerbation
Reliever use prior to and
after 425 exacerbations
(data from FACET)
Symbicort
-15 -10 -5 0 5 10 15
Days before and after severe exacerbation
Adapted from Tattersfield et al: AJRCCM 1999

53. Symbicort Ajustable Maintenance Dosing (AMD)
compared to fixed-dosing
(Canadian, Swedish and SUND Studies)
Patients with Patients with Number of exacerbations
exacerbation (%) exacerbation (%)
10 10 60
8 8 p<0.05
45 vs
p<0.05
Seretide
6 6
P<0.01
30
4 4
2 2 15
0 0
Symbicort Symbicort Symbicort Symbicort Seretide Symbicort Symbicort
Fixed AMD Fixed AMD Fixed Fixed AMD
Fitzgerald M, et al (2003) Ställberg B, et al (2003) Aalbers R, et al (2004)
N=995 N=1034 N=658

54. STAY: Study Design
4 x Budesonide + SABA n=926
Run-in Budesonide 320 μg bid a + terbutaline 0.4 mg as needed
Previous
regular ICS + Symbicort® Fixed Dose + SABA n=909
SABA as
R
needed Symbicort 80/4.5 μg bid a + terbutaline 0.4 mg as needed
Symbicort® Single inhaler Therapy n=925
Symbicort 80/4.5 μg bid a + as needed
Visit: 1 2 3 4 5 6 7
Month: -0.5 0 1 3 6 9 12
a Children <12 years received half the daily maintenance dose with a once daily regimen
O’Byrne ATS 2004

55. Patient Characteristics
4 x BUD Symbicort Symbicort
Characteristic + SABA + SABA SiT
N=926 N=909 N=925
Males, n (%) 416 (45) 394 (43) 421 (46)
Mean age, years (range) 36 (4–79) 36 (4–79) 35 (4–77)
Mean FEV1, % predicted 73 73 73
Mean ICS at entry, μg/day 620 598 619
Long-acting β2-agonists (%) 27 28 27
Mean reliever
inhalations/24 hours (no.) 2.4 2.4 2.5
Mean total asthma symptom 1.5 1.4 1.5
score (0–6)
O’Byrne ATS 2004

56. Severe Exacerbations
Total exacerbations
p<0.001 Exacerbation
600 subtypes
564
553
500
PEF falls Steroid courses Hospitalisations/
ER treatment
400
350 350 40
303
300
250 250 30
200
150 150 20
100
50 50 10
0
4 x BUD + SABA Symbicort + SABA Symbicort SiT
O’Byrne ATS 2004

57. Total Asthma Exacerbations
280
4 x BUD + SABA
200
Individual patients with exacerbations
= 294 events
120
40
requiring intervention
0 3 6 9 12 15 19 23 27 31 35 39 43 47 51 55
280
Symbicort + SABA
200 = 330 events
120
40
0 3 6 9 12 15 19 23 27 31 35 39 43 47 51 55
280 Symbicort SiT # rate reduction 46 to 53% vs both
200 = 160 events # groups; p<0.001
120
40
0 3 6 9 12 15 19 23 27 31 35 39 43 47 51 55
Weeks since randomisation
O’Byrne ATS 2004

58. Sustained improvements in lung
function
Morning PEF (L/min) Mean change am p<0.001
PEF (L/min)
370 Symbicort SiT 29.9
Symbicort + SABA 30
p<0.001
4 x BUD + SABA
360
22.0
350 20
13.0
340
10
330
320 0
0 40 80 120 160 200 240 280 320 360 4 x BUD Symbicort Symbicort
+ SABA + SABA SiT
Days since randomisation
O’Byrne ATS 2004

59. As-needed Medication Use
Change from run-in Mean daily inhalations of as
(inhalations/day) needed medication per group
0.4 4 x BUD + SABA 1.6 1.45
Symbicort + SABA
-0 1.20
Symbicort SiT
1.2
1.0
-0.4
*** both groups p<0.001
0.8
-0.8
-1.2 0.4
***
-1.6
0
0 40 80 120 160 200 240 280 320 360 4 x BUD + Symbicort Symbicort
SABA + SABA SiT
Days since randomisation
O’Byrne ATS 2004

60. Night-time awakenings
Increase in % of nights
undisturbed by asthma
14
***
12.7
12 *** p<0.001 vs both
groups
10 8.8
8.4 difference of at least
8 14 extra nights
undisturbed per year
6
4
2
0
4 x BUD + Symbicort Symbicort SiT
SABA + SABA
O’Byrne ATS 2004

61. Steroid load during 1 year of
treatment
Days with systemic steroid Mean daily ICS μg/day
3500 700
600
2500 500
400
1500 300
200
500 100
0
4 x BUD Symbicort Symbicort 4 x BUD Symbicort Symbicort
+ SABA SiT + SABA SiT
O’Byrne ATS 2004

62. Rate of severe exacerbations requiring medical
intervention
Events/patient/year 2–4 x BUD + SABA
Symbicort + SABA
0.6 Symbicort SiT
0.5
0.40
0.4 0.35
0.3
0.2 0.19 ***
0.1
0
STAY
moderate
*** p<0.001 vs both Symbicort + SABA and 2 to 4x BUD + SABA

63. Numbers needed to treat (NNT) to prevent one
severe exacerbation per year
Comparison NNT Exacerbation reduction
/100 patients per year
Symbicort SiT vs BUD + SABA
STAY (vs 4x BUD) 6.1 16
Symbicort SiT vs Symbicort + SABA
STAY 4.7 21
NNT to prevent one severe exacerbation requiring medical intervention

64. Incidence of high as-needed use and association with
emergency treatment (hospitalisation/ER visit) for asthma
No. of patients with high
No. of patients with high as-needed use *
as-needed use *
and at least one hospitalisation/ER visit
150 25
120 20
90 15
60 10
30 5
0 0
4x BUD Symbicort Symbicort 4x BUD Symbicort Symbicort
+ SABA + SABA SiT + SABA + SABA SiT
*>8 as-needed doses/day on any day in the year (STAY study only)

65. Incidence of high as-needed use and exacerbation
treatment in the STAY study (paediatric data)
No. of children with No. of children with high as-needed use*
high as-needed use * and at least one exacerbation requiring
medical intervention
25 25
20 20
15 15
10 10
5 5
0 0
4 xBUD Symbicort Symbicort 4 xBUD Symbicort Symbicort
+SABA + SABA SIT +SABA + SABA SIT
* >7 as-needed doses on any day in the year (STAY paediatric data)

66. Other add on therapies
• Low dose theophylline
• Antileukotrienes (Montelukast)
• Few trials documented above drugs do have
some benefit when added to low doses of ICS
• However, it is less effective as an add-on
therapy than salmeterol

67. Summary
• It is unlikely that bronchodilators more
effective than ß2-agonists can be discovered,
and new classes of bronchodilator have had
major problems with vasodilator side effects
• Most of the new treatments are more specific
inhibitors of the inflammatory process than
corticosteroids and are therefore less likely to
be as effective, at least in a broad range of
asthmatic patients

68. Conclusions
• LABACS inhalers have shown tremendous
results in asthma management (moderate to
severe persistent asthma) especially
symbicort (AMD + single inhaler therapy)
• LABACS inhalers are likely to remain the
most effective treatment for asthma over at
least the next 10 years (it takes 15 years to
bring a novel drug to the market)

69. PREVENTERS CONTROLLERS RELIEVERS
Anti-inflammatory action to Sustained bronchodilator For quick relief of symptoms
prevent asthma attacks action but weak or unproven and use in acute attacks as PRN
anti-inflammatory effect dosage only
Inhaled corticosteroids∗ Long-acting β2 agonists∗ Short-acting β2 agonists∗
1. beclomethasone 1. salmeterol 1. salbutamol
2. budenoside 2. formoterol 2. fenoterol
3. fluticasone 3. terbutaline
4. flunisolide 4. hexoprenaline
5. triamcinolone 5. orciprenaline
Sustained release theophylline
tablets
| Anti-cholinergics
aminophylline
Oral corticosteroids ipratropium bromide
1.prednisone
2.prednisolone Leukotriene antagonists∗∗ Short-acting theophyllines
3.methylprednisone 1. montelukast several preparations
4.methylprednisolone 2. zafirlukast