ATTUALITA’ ED EVOLUZIONE NELLA
GESTIONE CLINICA DELL’ASMA
Aggiornamento Linee Guida
GINA 2003
1/4/2004
Sala Congressi Hotel Michelangelo
Sassuolo
Prof. Leonardo M. Fabbri
Clinica di Malattie dell’Apparato Respiratorio
Università degli Studi di Modena e Reggio Emilia, Modena
Global
INitiative for
Asthma 2003
www.ginasthma.com
GINA Structure
Executive Committee
Chair: Paul O’Byrne, MD
Dissemination
Committee
Science
Committee
Chair: Tan Wan-Cheng, MD
Chair: Eric Bateman, MD
GINA reports prepared during workshops conducted in cooperation with
the U.S. National Heart, Lung, and Blood Institute, NIH and the World
Health Organization.
G lobal Initiative for Chronic
O bstructive
L ung
D isease
www.goldcopd.com
Global Initiative on Obstructive
Lung Disease
EXECUTIVE COMMITTEE
Chair: Romain Pauwels
S.Buist, US
P.Calverley, UK
B.Celli, US
L.Fabbri, Italy
Y.Fukuchi, Japan
L.Grouse, US
S.Hurd, US
C.Jenkins, Australia
C.Lenfant, US
J.Luna, Guatemala
W.McNee, UK
E.Nizankowska-Mogilnicka,
Poland
K.Rabe, NL
R.Rodriguez Roisin, E
P.Van Der Molen, NL
N.Zhong, China
Global Initiative on Obstructive Lung Disease
SCIENTIFIC COMMITTEE
Chair: Leonardo M. Fabbri
P. Barnes, UK
S. Buist, US
P. Calverley, UK
Y. Fukuchi, Giappone
W. McNee, UK
R. Pauwels, Belgium
K. Rabe, Germany
Roberto Rodrigues Roisin, Spain
N. Zielinski, Poland
Third Quarter, 2000: Publication Date from 2000/07/01 to 2000/09/30
Search COPD NOT ASTHMA: All Fields.
Limits: All Adult: 19+ years, only items with abstracts, English, Clinical Trial, Human
Sort by: Authors (20 citations)
No star = Clinical Trial, One * = Randomized Clinical Trials (15 citations)
Two ** = Randomized Clinical Trials and Core Clinical Journals (7 citations)
ASSIGNMENTS, REVIEWER, PUBLICATION NUMBER
Peter Barnes, 8
Sonia Buist, 16, 17
Leo Fabbri, 14, 20, 10, 19
Yoshi Fukuchi, 5, 7, 10, 12, 19, 20
Bill MacNee, 1, 5, 8, 15
Romain Pauwels, 16, 17
Klaus Rabe, 2, 3, 4, 11, 14
Roberto Rodriguez-Roisin, 2, 3, 4, 11, 13, 18
Jan Zielinski, 1, 7, 10, 15, 19
GOLD REPORT – Section 4
Page 32, left column, end of para 2,
ORIGINAL TEXT
…. tract inflammation57-61. It is likely that
indoor air pollution derived from the
burning of biomass fuels will prove to
have similar effects.
SUGGESTED REVISION
…. tract inflammation57-61. It is likely that
indoor air pollution derived from the
burning of biomass fuels will prove to
have similar effects. Also bacterial
colonization contributes to the
airway inflammation in patients with
stable COPD. The degree of
inflammation also relating to the
bacterial load and to the bacterial
species (Hill at et al, 2000).
Consequences of such colonization
and enhanced inflammation on
morbidity and lung function is not
clear
Hill AT, Campbell EJ, Hill SL, Bayley DL, Stockley RA. Association between airway
bacterial load and markers of airway inflammation in patients with stable chronic
bronchitis. Am J Med 2000 Sep;109(4):288-95
PATIENTS AT HIGH RISK OF DEATH
AFTER LUNG-VOLUME–REDUCTION SURGERY
National Emphysema Treatment Trial Research Group
N Engl J Med 2001; 345: to be published on October 11
Patients at High Risk of Death after
Lung-Volume-Reduction Surgery
1
NATIONAL EMPHISEMA TREATMENT TRIAL RESEARCH GROUP
Probability of death
0,9
0,8
P < 0.001
0,7
0,6
Surgery
0,5
Medical therapy
0,4
0,3
0,2
0,1
0
0
6
12
18
24
30
36
42
Months since Randomization
New Engl J Med 2001; to be published next Oct 11
Levels of evidence
Level
Source
A
Randomized clinical trials
(RCT). Several, consistent
B
Randomized clinical trials
(RCT). Few, inconsistent
C
Non-randomized clinical
trials. Small and/or
observational studies
D
Opinion of experts
INSTITUTE OF SCIENTIFIC
INFORMATION (ISI)
ISI JOURNAL CITATION REPORTS
http://jcrweb.com/
Impact Factor Number of Citations in 2002
Number of articles 2000-2001
IMPACT FACTOR 2002
Medicine, General & Internal:
1) New Engl J Med
2) JAMA – J Am Med Assoc
3) Lancet
4) Ann Intern Med
5) Annu Rev Med
6) Brit Med J
7) Arch Intern Med
8) Medicine
31.74
16.78
15.39
11.41
7.95
7.58
6.74
5.18
IMPACT FACTOR 2002
Respiratory System
1) Am J Resp Crit Care
2) Am J Resp Cell Mol
3) Thorax
4) Am J Physiol-Lung C
5) Chest
6) Eur Respir J
7) J Thorac Cardiov Sur
8) Sarcoidosis Vasc Dif
6.56
4.17
4.08
3.90
2.97
2.94
2.84
2.83
Le linee guida GINA in Italia:
passare dalla teoria ai fatti
Prof. L.M. Fabbri
Processo di aggiornamento delle linee guida
Trattamento farmacologico: 2003-2004
Asma grave/BPCO
Nuovi farmaci antiasmatici
Le linee guida GINA in Italia:
passare dalla teoria ai fatti
Prof. L.M. Fabbri
Processo di aggiornamento delle linee guida
Trattamento farmacologico: 2003-2004
Asma grave/BPCO
Nuovi farmaci antiasmatici
Global
INitiative for
Asthma 2003
www.ginasthma.com
GINA Structure
Executive Committee
Chair: Paul O’Byrne, MD
Dissemination
Committee
Science
Committee
Chair: Tan Chen Wan, MD
Chair: Eric Bateman, MD
GINA reports prepared during workshops conducted in cooperation with
the U.S. National Heart, Lung, and Blood Institute, NIH and the World
Health Organization.
Science Committee
E. Bateman, South Africa, Chair
P. Barnes, UK
J. Bousquet, France
W. Busse, USA
J. Drazen, USA
M. FitzGerald, Canada
P. Gibson, Australia
S. Holgate, UK
J. Kips, Belgium
P. O’Byrne, Canada
K. Ohta, Japan
S. Pedersen, Denmark
E. von Mutius,Germany
Le linee guida GINA in Italia:
passare dalla teoria ai fatti
Prof. L.M. Fabbri
Processo di aggiornamento delle linee guida
Trattamento farmacologico: 2003-2004
Asma grave/BPCO
Nuovi farmaci antiasmatici
Management of asthma:
updating the GINA guidelines
Mild
Intermittent
Avoidance of risk factors, immunotherapy
Short-acting beta-2 agonists as needed
Mild
Persistent
Low-dose inhaled steroids
Moderate
Persistent
Moderate
Persistent
(Severe?)
Severe
Persistent
(Very severe?)
Combination of long-acting beta2 agonists
with low dose inhaled steroids
Combination with higher
doses inhaled corticosteroids,
theophylline, antileukotrienes
Systemic
steroids
Stepwise Approach to Asthma Therapy
Controlled by inhaled
short-acting beta-2 agonists prn
Step 1: Mild Intermittent Asthma
Controller
Reliever
• Not required
• Inhaled beta2-agonist
prn <3-4x a day
• Inhaled beta2-agonist or
Cromolyn or Leukotriene
modifier prior to exercise
or exposure to antigen
Avoid or Control Triggers
START – study outline
Part A – Budesonide therapy
Adults
Budesonide 400 g once daily
+ usual asthma therapy
Part B
Children (6–10 yrs)
Budesonide 200 g once daily
+ usual asthma therapy
Adults
Budesonide 400 g once daily
+ usual asthma therapy
Part A – Reference therapy
Children (6–10 yrs)
Budesonide 200 g once daily
+ usual asthma therapy
Adults and Children
Placebo once daily
+ usual asthma therapy
Year
Visit
0
1
1 2 3 4 5 6
2
7
8
3
4
5
9 10 11 12 13 14 15 16 17 18 19 20 21 22
Pauwels R et a. Lancet 2003; 371: 1071-1076
START
Conclusions
• Long-term, once-daily treatment
with low-dose budesonide
decreases the risk of severe
exacerbations by 44% and improves
asthma control compared with
placebo in patients with recent
onset, mild persistent asthma.
Pauwels R et a. Lancet 2003; 371: 1071-1076
Stepwise Approach to Asthma Therapy
Controlled by low-dose
inhaled steroids
Step 2: Mild Persistent Asthma
Controller
Reliever
• Daily inhaled corticosteroid (200-500 mcg)
• Cromolyn, Nedocromil,
sustained release
Theophylline
• Consider Leukotriene
Modifiers
• Inhaled beta2-agonist
prn <3-4x a day
• Inhaled beta2-agonist or
Cromolyn or Leukotriene
modifier prior to exercise
or exposure to antigen
Avoid or Control Triggers
Effects of Inhaled Beclomethasone
Dipropionate in Clinical Asthma
PC20
methacholine
(mg/ml)
Asthmatic
symptoms
100
6
4
mg/ml
Severity
10
1
2
0,1
0
Pre-BD
6 wk
0,01
Pre-BD 6 wk
Bronchial Submucosa
number of cells/mm2 of submucosa
Bronchial Function
mast cells eosinophilsT lymphocytes
760
720
240
200
160
120
80
40
0
Pre-BD6 wk Pre-BD6 wk Pre-BD6 wk
Djukanovic et al, Am Rev Respir Dis 1992 Mar;145(3):669-74
LONG-ACTING b2-AGONIST
MONOTHERAPY VS CONTINUED
THERAPY WITH INHALED
CORTICOSTEROIDS IN PATIENTS
WITH PERSISTENT ASTHMA
A Randomized Controlled Trial
Patients with persistent asthma well controlled by low doses of
triamcinolone cannot be switched to salmeterol monotherapy
without risk of clinically significant loss of asthma control.
Lazarus SC et al.
JAMA 2001; 285: 2583-2593
Mean % change from baseline
in FEV1
Low-dose Fluticasone is More Effective of
Montelukast in Mild Persistent Asthma
30
25
20
*
*
*
*
*
*
*
*
15
10
FP 88 µg BID
5
MON 10 mg BID
0
Baseline
4
8
12
16
20
24
Endpoint
Treatment week
Busse W et al., J Allergy Clin Immunol 2001; 107: 461-468
Low Dose Inhaled Budesonide and Formoterol
in Mild Persistent Asthma . The OPTIMA
Randomized Trial
Paul M. O‘Byrne, Peter J. Barnes, Roberto Rodriguez-roisin,
Eva Runnerstrom,Thomas Sandstrom, Klas Svensson,
and Anne Tattersfield
O’Byrne et al. Am. J. Respir. Crit. Care Med. 2001;164 1392-1397
Proportion
Time to first severe exacerbation
Budesonide
34/226
200
44/227 Budesonide 200
+ Formoterol
79/237
Placebo
Days
O’Byrne et al. Am. J. Respir. Crit. Care Med. 2001;164 1392-1397
Rate for poorly controlled days
0.15
0.144
0.10
0.083
0.073
Rate
0.05
0.00
Placebo
Budesonide
200
Budesonide +
Formoterol
O’Byrne et al. Am. J. Respir. Crit. Care Med. 2001;164 1392-1397
Mometasone furoate administered once daily
is as effective as twice-daily administration for
treatment of mild-to-moderate persistent
asthma
_________________________________________________
This is the first study demonstrating that a total
daily dose of 400 g of mometasone furoate
(MF) administered by dry powder inhaler is an
effective treatment for patients with mild-tomoderate persistent asthma previously taking
only b2-agonists
Kemp et al, J Allergy Clin Immunol. 2000 Sep;106(3):485-92
Stepwise Approach to Asthma Therapy
Controlled by inhaled steroids
plus long-acting bronchodilators
Step 3: Moderate Persistent Asthma
Controller
Reliever
• Add long acting bronchodilators to low dose inhaled
steroids
• Inhaled beta2-agonist prn
<3-4x a day
• Inhaled beta2-agonist or
Cromolyn or Leukotriene
• Increase the dose of inhaled
modifier prior to exercise or
corticosteroids 800-2,000g
exposure to antigen
• Add leukotriene modifiers if
control is not achieved
Avoid or Control Triggers
Addition of salmeterol to inhaled BDP is superior to
increased dose of BDP in persistent asthma
*p<0.05, **p<0.01, ***p<0.001 vs BDP
35
30
Salmeterol 50 g bid
+ BDP 200 g bid
**
**
***
25
*
**
20
***
15
10
BDP 500 g bid
5
0
0
3
6
9
12
15
18
21
Time (weeks)
BDP, beclomethasone dipropionate; ICS, inhaled corticosteroid
PEF, peak expiratory flow
Greening et al. Lancet 1994
Change in FEV1 (% predicted)
Addition of salmeterol to inhaled BDP is superior to
increased dose of BDP in moderate/severe asthma
10
9
8
*
*
**
** Salmeterol 50 g bid
+ BDP 500 g bid
7
6
*p<0.001, **p<0.05
5
4
3
BDP 1000 g bid
2
1
0
0
2
8
16
24
Weeks of treatment
BDP, beclomethasone dipropionate
Woolcock et al. Am J Respir Crit Care Med 1996
Adapted with permission
Changes in FEV1 during the study
FEV1 (% of predicted)
90
85
80
75
Higher-dose budesonide plus formoterol
Lower-dose budesonide plus formoterol
Higher-dose budesonide
Lower-dose budesonide
-1
0
1
2
3
6
9
12
Month
FACET
Pauwels RA et al., N Engl J Med 1997
Estimates of severe exacerbation rates
BUDH:
- 49%
(p<0.001)
BUD200
h=0.91
BUD200+F
h=0.67
BUD800
h=0.46
BUD800+F
h=0.34
p=0.031
FORM: - 26% (p=0.014)
Pauwels RA et al., N Engl J Med 1997
Estimates of mild exacerbation rates
BUDH:
- 37%
(p<0.001)
BUD200
h=35.4
BUD200+F
h=21.3
BUD800
h=22.3
BUD800+F
h=13.4
FORM: - 40% (p=0.001)
FACET
p=0.76
Pauwels RA et al., N Engl J Med 1997
Classification of Asthma Severity
CLASSIFY SEVERITY
Clinical Features Before Treatment
Symptoms
Nighttime Symptoms
PEF
STEP 4
Severe
Persistent
Continuous
Limited physical Frequent
activity
≤60% predicted
Variability >30%
STEP 3
Moderate
Persistent
Daily
>1 time week
Use b2-agonist daily
Attacks limit activity
60-80% predicted
Variability >30%
STEP 2
Mild
Persistent
≥1 time a week
but <1 time a day
>2times a months
≥80% predicted
Variability 20-30%
≤2 times a month
≥80% predicted
Variability <20%
<1 time a week
STEP 1
Intermittent Asymptomatic and
normal PEF between
attacks
One of the features of severity is sufficient to place a patient in that category
Treatment
Management of Asthma
Oral steroids
Long-acting bronchodilators and/or LTRA
Inhaled steroids
Short-acting b2 agonists prn
Severity of asthma
IMMUNOTHERAPY ?
PREVENTION
Treatment Options for Patients
Not Controlled on Inhaled Steroids
Patients not controlled on inhaled steroids
Add long-acting
beta2-agonists
Increase the
dose of inhaled
steroid
Add
theophylline
Add leukotriene
receptor
antagonists
Montelukast + Budesonide vs higher-dose
budesonide
440
Montelukast + budesonide 800 µg
(n=433)
Budesonide 1600 µg
(n=425)
430
420
AM
PEF
410
(L/min)
p=0.367
between groups
during the last 10 weeks of the
12-week treatment period
400
390
Days relative to start of trial
-14 -7
0
7 14 21 28 35 42 48 56 63 70 77 84
Run-in
Price et al., Thorax 2003
COMPARISON OF INHALED SALMETEROL
AND ORAL ZAFIRLUKAST IN PATIENTS
WITH ASTHMA
In patients with persistent asthma, most of whom currently
using inhaled corticosteroids, treatment with inhaled
salmeterol provided significantly greater improvement that
oral zafirlukast in overall clinical control over the 4-week
treatment period
Busse WW et al. J Allergy Clin Immunol 1999; 103: 1075-80
A ONE-YEAR COMPARATIVE TRIAL OF
MONTELUKAST AND FLUTICASONE VS
SALMETEROL AND FLUTICASONE IN
PROTECTING AGAINST ASTHMA ATTACKS
The study demonstrates the equal clinical benefit of including
montelukast or salmeterol in asthma therapy for protection
against asthma exacerbations of patients inadequately
controlled by inhaled corticosteroids.
Biermer L t al. BMJ 2003; in press
ADDITION OF LEUKOTRIENE ANTAGONISTS
TO THERAPY IN CHRONIC PERSISTENT
ASTHMA: A RANDOMISED DOUBLE-BLIND
PLACEBO-CONTROLLED TRIAL
Used as additional therapy in a hospital outpatient clinic setting,
montelukast did not provide such additional benefit in patients
with moderate or severe asthma
Robinson DS et al Lancet 2001; 357: 2007-11
Le linee guida GINA in Italia:
passare dalla teoria ai fatti
Prof. L.M. Fabbri
Processo di aggiornamento delle linee guida
Trattamento farmacologico: 2003-2004
Asma grave/BPCO
Nuovi farmaci antiasmatici
Differences between asthma and COPD
ASTHMA
Sensitizing agent
COPD
Noxious agent
Asthmatic airway
inflammation
CD4+ T-lymphocytes
COPD airway inflammation
CD8+ T-lymphocytes
Marcrophages
Eosinophils
Neutrophils
Completely
reversible
Airflow limitation
limitation
Airflow
Completely
irreversible
COPD
A
Asthma
B
B
C
D
Fabbri LM et al Am J Respir Crit Care Med 2003;167 418-424
Management of COPD and asthma:
GOLD and GINA guidelines
ASTHMA
Mild Intermittent
COPD
b2 prn
Mild persistent iGCS
Moderate persistent
Combination
Mild
b2 prn
Moderate
LABA
Severe
Combination
LABA+iGCS
Severe persistent
Oral GCS
LABA+iGCS
Very
severe
Oxygen, Sx
Surgery
Le linee guida GINA in Italia:
passare dalla teoria ai fatti
Prof. L.M. Fabbri
Processo di aggiornamento delle linee guida
Trattamento farmacologico: 2003-2004
Asma grave/BPCO
Nuovi farmaci antiasmatici
TREATMENT OPTIONS IN ASTHMA
CURRENT OPTIONS
Inhaled corticosteroids
Long acting beta2-agonists
Leukotriene receptor antagonists
FUTURE OPTIONS
Better corticosteroids and bronchodilators
Phosphodiesterase inhibitors
Anti-IgE
FUTURISTIC OPTIONS
Mediator antagonists
Non-steroidal antiinflammatory agents
Chemokine and chemokine receptor antagonists
Gene therapy
Modified by P.J. Barnes, 2003
IgE AND ITS INHIBITION IN ATOPY
FcRI
IL-4, IL-13
Mast cell
Histamine
Cys-LTs
PGD2
FcRII (CD23)

Y
IgE
Macrophage
Chronic
inflammation
B lymphocyte
rhuMAb-E25,
omalizumab
Modified by P.J. Barnes, 2003
T lymphocyte
Eosinophil
ANTI-IgE IN STEROID-DEPENDENT ASTHMA
omalizumab: iv. 2x weekly x 12 weeks then reduction over 8 weeks
Oral steroids
% Patients
80
Placebo
Anti-IgE (low dose)
Anti-IgE (high dose)
60
40
20
L0
L
>50% reduction
Milgrom H et al: NEJM 1999
Discontinuing
EFFECT OF ANTI-IgE IN
ASTHMA
100
Moderate to severe allergic asthma
p<0.001
Omalizumab sc 28wks
80
Placebo
 FEV1, PEF
 Exacerbations (58%)
60
p<0.001
40
20
0
Median BDP dose
reduction (%)
Complete BDP
withdrawal (%)
Soler M et al: Eur Respir J 2001
POSITION OF ANTI-IgE IN THE
TREATMENT OF ASTHMA
•
•
Patients with more severe asthma
steroid-dependent, steroid-resistant, brittle
Patients with severe concomitant allergic
diseases
•
Poor compliance with existing therapy ?
•
Cover for immunotherapy ?
Modified by P.J. Barnes, 2003
Management of asthma:
updating the GINA guidelines
Mild
Intermittent
Avoidance of risk factors, immunotherapy
Short-acting beta-2 agonists as needed
Mild
Persistent
Low-dose inhaled steroids
Moderate
Persistent
Moderate
Persistent
(Severe?)
Severe
Persistent
(Very severe?)
Combination of long-acting beta2 agonists
with low dose inhaled steroids
Combination with higher
doses inhaled corticosteroids,
theophylline, antileukotrienes
Systemic
steroids
Le linee guida GINA in Italia:
passare dalla teoria ai fatti
Prof. L.M. Fabbri
Processo di aggiornamento delle linee guida
Trattamento farmacologico: 2003-2004
Asma grave/BPCO
Nuovi farmaci antiasmatici
ATTUALITA’ ED EVOLUZIONE NELLA
GESTIONE CLINICA DELL’ASMA
Aggiornamento Linee Guida
GINA 2003
Prof. Leonardo M. Fabbri
Clinica di Malattie dell’Apparato Respiratorio
Università degli Studi di Modena e Reggio Emilia, Modena