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1
ATTUALITA ED EVOLUZIONE NELLA GESTIONE CLINICA
DELLASMA

Aggiornamento Linee Guida GINA
2003 1/4/2004 Sala Congressi Hotel
Michelangelo Sassuolo Prof. Leonardo M.
Fabbri Clinica di Malattie dellApparato
Respiratorio Università degli Studi di Modena e
Reggio Emilia, Modena
2
Global INitiative for Asthma 2003
www.ginasthma.com
3
Executive CommitteeChair Paul OByrne, MD
GINA Structure
Dissemination Committee Chair Tan Wan-Cheng, MD
Science Committee 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.
4

• G lobal Initiative for Chronic
• O bstructive
• L ung
• D isease

www.goldcopd.com
5
Global Initiative on Obstructive Lung
DiseaseEXECUTIVE COMMITTEEChair 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

6
Global Initiative on Obstructive Lung
DiseaseSCIENTIFIC COMMITTEEChair 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

7

• 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

8
GOLD REPORT Section 4Page 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 Sep109(4)288-95
9
PATIENTS AT HIGH RISK OF DEATH AFTER
LUNG-VOLUMEREDUCTION SURGERY
National Emphysema Treatment Trial Research Group
N Engl J Med 2001 345 to be published on
October 11
10
Patients at High Risk of Death after
Lung-Volume-Reduction Surgery
NATIONAL EMPHISEMA TREATMENT TRIAL RESEARCH GROUP
P lt 0.001
Surgery
Probability of death
Medical therapy
Months since Randomization
New Engl J Med 2001 to be published next Oct 11
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
12
INSTITUTE OF SCIENTIFIC INFORMATION (ISI)
ISI JOURNAL CITATION REPORTS http//jcrweb.com/ I
mpact Factor Number of Citations in
2002 Number of articles 2000-2001
13
IMPACT FACTOR 2002
Medicine, General Internal 1) New Engl J
Med 31.74 2) JAMA J Am Med Assoc 16.78 3)
Lancet 15.39 4) Ann Intern Med 11.41 5)
Annu Rev Med 7.95 6) Brit Med J
7.58 7) Arch Intern Med 6.74 8)
Medicine 5.18
14
IMPACT FACTOR 2002
Respiratory System 1) Am J Resp Crit
Care 6.56 2) Am J Resp Cell Mol 4.17 3)
Thorax 4.08 4) Am J Physiol-Lung
C 3.90 5) Chest 2.97 6) Eur Respir
J 2.94 7) J Thorac Cardiov Sur 2.84 8)
Sarcoidosis Vasc Dif 2.83
15
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
16
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
17
Global INitiative for Asthma 2003
www.ginasthma.com
18
Executive CommitteeChair Paul OByrne, MD
GINA Structure
Dissemination Committee Chair Tan Chen Wan, MD
Science Committee 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.
19
Science Committee

• E. Bateman, South Africa, Chair
• P. Barnes, UK S. Holgate, UK
• J. Bousquet, France J. Kips, Belgium
• W. Busse, USA P. OByrne, Canada
• J. Drazen, USA K. Ohta, Japan
• M. FitzGerald, Canada S. Pedersen, Denmark
• P. Gibson, Australia E. von Mutius,Germany

20
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
21
Management of asthmaupdating the GINA guidelines
Mild Intermittent
Avoidance of risk factors, immunotherapy Short-act
ing beta-2 agonists as needed
Mild Persistent
Low-dose inhaled steroids
Combination of long-acting beta2 agonists with
low dose inhaled steroids
Moderate Persistent
Asthma severity
Moderate Persistent (Severe?)
Combination with higher doses inhaled
corticosteroids, theophylline, antileukotrienes
Severe Persistent (Very severe?)
Systemic steroids
22
Stepwise Approach to Asthma Therapy
Controlled by inhaled short-acting beta-2
agonists prn
Step 1 Mild Intermittent Asthma
Controller Not required
Reliever Inhaled beta2-agonist prn lt3-4x a
day Inhaled beta2-agonist or Cromolyn or
Leukotriene modifier prior to exercise or
exposure to antigen
Avoid or Control Triggers
23
START study outline
1
2
3
0
4
5
Year
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Pauwels R et a. Lancet 2003 371 1071-1076
24
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
25
Stepwise Approach to Asthma Therapy
Controlled by low-dose inhaled steroids
Step 2 Mild Persistent Asthma
Controller Daily inhaled cortico- steroid
(200-500 mcg) Cromolyn, Nedocromil,
sustained release Theophylline Consider
Leukotriene Modifiers
Reliever Inhaled beta2-agonist prn lt3-4x a
day Inhaled beta2-agonist or Cromolyn or
Leukotriene modifier prior to exercise or
exposure to antigen
Avoid or Control Triggers
26
Effects of Inhaled Beclomethasone Dipropionate in
Clinical Asthma
Bronchial Function
Bronchial Submucosa
PC20 methacholine (mg/ml)
Asthmatic symptoms
eosinophils
T lymphocytes
number of cells/mm2 of submucosa
Severity
mg/ml
Djukanovic et al, Am Rev Respir Dis 1992
Mar145(3)669-74
27
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
28
Low-dose Fluticasone is More Effective of
Montelukast in Mild Persistent Asthma








Mean change from baseline in FEV1
Endpoint
Baseline
Treatment week
Busse W et al., J Allergy Clin Immunol 2001 107
461-468
29
Low Dose Inhaled Budesonide and Formoterol in
Mild Persistent Asthma . The OPTIMA Randomized
Trial
Paul M. OByrne, Peter J. Barnes, Roberto
Rodriguez-roisin, Eva Runnerstrom,Thomas
Sandstrom, Klas Svensson, and Anne Tattersfield
OByrne et al. Am. J. Respir. Crit. Care Med.
2001164 1392-1397
30
Time to first severe exacerbation
Budesonide 200
34/226
Proportion
44/227
Budesonide 200 Formoterol
Placebo
79/237
Days
OByrne et al. Am. J. Respir. Crit. Care Med.
2001164 1392-1397
31
Rate for poorly controlled days
0.144
0.15
0.10
0.083
0.073
Rate
0.05
0.00
Placebo
Budesonide 200
Budesonide Formoterol
OByrne et al. Am. J. Respir. Crit. Care Med.
2001164 1392-1397
32
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-to-moderate persistent asthma previously
taking only ?2-agonists
Kemp et al, J Allergy Clin Immunol. 2000
Sep106(3)485-92
33
Stepwise Approach to Asthma Therapy
Controlled by inhaled steroids plus long-acting
bronchodilators
Step 3 Moderate Persistent Asthma
Controller Add long acting broncho- dilators
to low dose inhaled steroids Increase the
dose of inhaled corticosteroids
800-2,000?g Add leukotriene modifiers if
control is not achieved
Reliever Inhaled beta2-agonist prn lt3-4x a
day Inhaled beta2-agonist or Cromolyn or
Leukotriene modifier prior to exercise or
exposure to antigen
Avoid or Control Triggers
34
Addition of salmeterol to inhaled BDP is superior
to increased dose of BDP in persistent asthma
plt0.05, plt0.01, plt0.001 vs BDP
35
Salmeterol 50 ?g bid BDP 200 ?g bid
30



25


20
Mean change from baseline in morning PEF (L/min)

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
35
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
plt0.001, plt0.05
Change in FEV1 ( predicted)
5
4
3
BDP 1000 ?g bid
2
1
0
0
2
8
16
24
Weeks of treatment
Woolcock et al. Am J Respir Crit Care Med
1996 Adapted with permission
BDP, beclomethasone dipropionate
36
Changes in FEV1 during the study
90
85
FEV1 ( of predicted)
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
Pauwels RA et al., N Engl J Med 1997
FACET
37
Estimates of severe exacerbation rates
BUD200 h0.91 BUD800 h0.46
BUD200F h0.67 BUD800F h0.34
BUDH - 49 (plt0.001)
p0.031
FORM - 26 (p0.014)
Pauwels RA et al., N Engl J Med 1997
38
Estimates of mild exacerbation rates
BUD200 h35.4 BUD800 h22.3
BUD200F h21.3 BUD800F h13.4
BUDH - 37 (plt0.001)
p0.76
FORM - 40 (p0.001)
Pauwels RA et al., N Engl J Med 1997
FACET
39
Classification of Asthma Severity
Treatment
Intensity of treatment
40
Management of Asthma
Oral steroids
Long-acting bronchodilators and/or LTRA
Inhaled steroids
Short-acting ?2 agonists prn
Severity of asthma
IMMUNOTHERAPY ?
PREVENTION
41
Treatment Options for Patients Not Controlled on
Inhaled Steroids
Patients not controlled on inhaled steroids
Add leukotriene receptor antagonists
Increase the dose of inhaled steroid
Add theophylline
Add long-acting beta2-agonists
42
Montelukast Budesonide vs higher-dose budesonide
440
Montelukast budesonide 800 µg (n433)
430
Budesonide 1600 µg (n425)
420
AM PEF (L/min)
410
p0.367 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
43
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
44
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
45
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
46
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
47
Differences between asthma and COPD
ASTHMA Sensitizing agent
COPD Noxious agent
Asthmatic airway inflammation CD4
T-lymphocytes Eosinophils
COPD airway inflammation CD8 T-lymphocytes Marcro
phages Neutrophils
Airflow limitation
Completely reversible
Completely irreversible
Airflow limitation
48
Asthma
COPD
A
B
B
C
D
Fabbri LM et al Am J Respir Crit Care Med
2003167 418-424
49
Management of COPD and asthmaGOLD and GINA
guidelines
ASTHMA
COPD Mild Intermittent ?2 prn Mild
?2 prn Mild persistent iGCS
Moderate LABA Moderate persistent
Combination Severe Combination
LABAiGCS
LABAiGCS Severe persistent
Oral GCS Very
Oxygen, Sx
severe
Surgery
50
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
51
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-steroi
dal antiinflammatory agents Chemokine and
chemokine receptor antagonists Gene therapy
Modified by P.J. Barnes, 2003
52
IgE AND ITS INHIBITION IN ATOPY
IL-4, IL-13
Y
Y
Y
Y
IgE
Y
B lymphocyte
Modified by P.J. Barnes, 2003
53
ANTI-IgE IN STEROID-DEPENDENT ASTHMA
omalizumab iv. 2x weekly x 12 weeks then
reduction over 8 weeks
Oral steroids
Patients
L
L
gt50 reduction
Discontinuing
Milgrom H et al NEJM 1999
54
EFFECT OF ANTI-IgE IN ASTHMA
Moderate to severe allergic asthma
100
Omalizumab sc 28wks
plt0.001
80
Placebo
60

• FEV1, PEF
• ? Exacerbations (58)

40
20
0
Median BDP dose reduction ()
Soler M et al Eur Respir J 2001
55
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
56
Management of asthmaupdating the GINA guidelines
Mild Intermittent
Avoidance of risk factors, immunotherapy Short-act
ing beta-2 agonists as needed
Mild Persistent
Low-dose inhaled steroids
Combination of long-acting beta2 agonists with
low dose inhaled steroids
Moderate Persistent
Asthma severity
Moderate Persistent (Severe?)
Combination with higher doses inhaled
corticosteroids, theophylline, antileukotrienes
Severe Persistent (Very severe?)
Systemic steroids
57
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
58
ATTUALITA ED EVOLUZIONE NELLA GESTIONE CLINICA
DELLASMA

Aggiornamento Linee Guida GINA 2003 Prof.
Leonardo M. Fabbri Clinica di Malattie
dellApparato Respiratorio Università degli Studi
di Modena e Reggio Emilia, Modena