New decade, New approaches
to AECOPD
Prof. Nadeem Rizvi
Head of Chest Medicine
Jinnah Postgraduate Medical Center,
Karachi
Definition of COPD Exacerbations
An event in the natural course “of the disease characterized by a
change in the patient’s baseline dyspnea, cough, and/or sputum that is
beyond normal day-to-day variations, is acute in onset, and may
warrant a change in regular medication in a patient with underlying
COPD.”
From the Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for
Chronic Obstructive Lung Disease (GOLD) 2008. Available from: http://www.goldcopd.org.
2
What Does an Exacerbation Mean to a
Patient?
Decline in lung function
Increased symptoms
(I.e. breathlessness)
Greater anxiety
Worsening quality of life
Social withdrawal
Increased risk of
mortality
More exacerbations
Increased risk of
hospitalisation
Garcia-Aymerich J et al. 2001
Donaldson D et al. 2002
Gore JM et al. 2000
Seemungal T et al. 1998
Pauwels Pet al. 2001
Seemungal T et al. 2000
Garcia-Aymerich J et al. 2003
Anto JM et al. 2001
Causes of AECB
Infection
Allergy
Bacterial
Viral
AECB
Pollution
Cigarette smoke
Industrial dusts
Weather
Fall in temperature
Ball. CHEST 1995; 108: 43S–52S; Miravitlles & Niederman. Lectures in Respiratory Tract Infections. Science Press
Communications, 2004; Donaldson et al. Eur Respir J 1999; 13: 844–9
Epidemiology of Exacerbations:
Frequency Increases with Declining FEV1
Exacerbations per Year
3.0
2.5
2.0
1.5
1.0
0.5
0
< 1.25
1.25 – 1.54
> 1.54
2.40
2.50
FEV1 (1)
Donaldson GC, Wedzicha JA. Thorax. 2006;61:164-168.
5
Impact of Exacerbations in COPD
Patients with Frequent Exacerbations
Faster Decline
in Lung Function
Poorer Quality
of Life
Wedzicha JA, Seemungal TA. Lancet. 2007;370:786-796.
Greater Airway
Inflammation
Higher Mortality
6
Percent Change from Baseline in FEV1
More Rapid Decline in FEV1 With
Higher Exacerbation Frequency
0.95
Infrequent Exacerbators
Frequent Exacerbators
0.90
0.85
0.80
0.75
0
1
2
3
4
Years
Donaldson GC, et al. Thorax. 2002;57:847-852.
7
Frequent Exacerbations Are Associated
With More Rapid Decline in Pulmonary
Function FEV (mL)
PEF (L/minute)
Annual Change
1
**
* P<0.05 versus infrequent exacerbators; ** P<0.001 versus infrequent exacerbators
*
Donaldson GC, et al. Thorax. 2002;57:847-852.
8
Mortality Following Emergency
Department Visit for COPD Exacerbation
Kim S, et al. COPD. 2006;3:75-81.
10
Exacerbation Frequency and Severity
Both Increase Mortality Risk
1.0
0.8
A
p<0.0002
0.6
B
0.4
p<0.0
p=0.069
C
0.2
0.0
Probability of surviving
Probability of surviving
1.0
0.8
(1)
NS
0.6
(2)
p=0.005
0.4
p<0.0001
p<0.0001
(3)
NS
0.2
(4)
0.0
0
10
20
30
40
50
60
0
10
Time (months)
Group A
Group B
Group C
patients with no acute exacerbations
patients with 1–2 acute exacerbations
requiring hospital management
patients with >3 acute exacerbations
30
40
50
60
Time (months)
Group (1)
Group (2)
Group (3)
Group (4)
Soler-Cataluña JJ, et al. Thorax. 2005;60:925-931.
20
no acute exacerbations
acute exacerbations requiring emergency
service visits without admission
patients with acute exacerbations requiring
one hospital admission
patients with acute exacerbations requiring
readmissions
11
Cost of Treatment for an Acute
Exacerbation of COPD
O'Reilly JF, et al. Int J Clin Pract. 2007;61:1112-1120.
123
Exacerbations Negatively Affect
Quality of Life
*
*
*
*
* P<0.05 versus lower exacerbation rate
Seemungal TA, et al. Am J Respir Crit Care Med. 2000;161:1608–1613.
14
ISSUE OF ANTIBIOTIC USE IN
EXACERBATION
Stratification of AECB patients –
the Anthonisen criteria
Increase in:
• dyspnea
• sputum volume
• sputum purulence
TYPE I
All three present,
antibiotic recommended
TYPE II
TYPE III
Two of three present,
antibiotic recommended
if includes purulence
One of three present,
antibiotic
not recommended
Anthonisen et al. Ann Intern Med 1987 [Adapted from Woodhead et al. Eur Respir J 2005]
Using Antibiotics in AECB Prevents
Treatment Failure
Treatment failure is associated with increased acute exacerbation episodes and disease progression
Favours Antibiotics
Favours Placebo
Elmes et al, 1965
Pines et al, 1968
Anthonisen et al, 1987
Jorgensen et al, 1992
Nouira et al, 2001
Pooled summary
(RR, 0.54; 95% CI, 0.32-0.92)
0.1
0.2
0.5
1
2
5
Relative Risk (95% Confidence Interval)
Quon BS et al. Chest 2008; 133:756-766
10
23
Antibiotics for AECOPD: Risk Stratification
MILD
Only 1 of the 3 cardinal symptoms:
Increased dyspnea
Increased sputum volume
Increased sputum purulence
MODERATE OR SEVERE
At least 2 of the 3 cardinal symptoms:
Increased dyspnea
Increased sputum volume
Increased sputum purulence
Uncomplicated COPD
No risk factors:
Age <65 years
FEV1 >50% predicted
<3 exacerbations/year
No cardiac disease
No antibiotics
Increased bronchodilator
Symptomatic therapy
Monitoring symptoms
Advanced macrolide
(azythromycin, clarithromycin)
Cephalosporin (cefuroxime,
cefpodoxime, cefdinir)
Doxycycline
Trimethoprim–sulfamethoxazole
If recent antibiotic exposure (<3
months), use alternative class
Complicated COPD
1 or More risk factors:
Age >65 years
FEV1 <50% predicted
>3 exacerbations/year
Cardiac disease
Fluoroquinolone
(moxi, gemi, levo)
Amoxicillin-clavulanate
If at risk for Pseudomonas,
consider ciprofloxacin and
obtain sputum culture
If recent antibiotic exposure (<3
months), use alternative class
Worsening clinical status or inadequate response in 72 hrs
A wind of change in AECOPD
Sethi S, Murphy TF. NEJM 2008;359:2355-65.
Reevaluate
Consider sputum culture
Antibiotics for AECOPD: Risk Stratification
MILD
Only 1 of the 3 cardinal symptoms:
Increased dyspnea
Increased sputum volume
Increased sputum purulence
MODERATE OR SEVERE
At least 2 of the 3 cardinal symptoms:
Increased dyspnea
Increased sputum volume
Increased sputum purulence
Uncomplicated COPD
No risk factors:
Age <65 years
FEV1 >50% predicted
<3 exacerbations/year
No cardiac disease
No antibiotics
Increased bronchodilator
Symptomatic therapy
Monitoring symptoms
Advanced macrolide
(azythromycin, clarithromycin)
Cephalosporin (cefuroxime,
cefpodoxime, cefdinir)
Doxycycline
Trimethoprim–sulfamethoxazole
If recent antibiotic exposure (<3
months), use alternative class
Complicated COPD
1 or More risk factors:
Age >65 years
FEV1 <50% predicted
>3 exacerbations/year
Cardiac disease
Fluoroquinolone
(moxi, gemi, levo)
Amoxicillin-clavulanate
If at risk for Pseudomonas,
consider ciprofloxacin and
obtain sputum culture
If recent antibiotic exposure (<3
months), use alternative class
Worsening clinical status or inadequate response in 72 hrs
A wind of change in AECOPD
Sethi S, Murphy TF. NEJM 2008;359:2355-65.
Reevaluate
Consider sputum culture
Antibiotics for AECOPD: Risk Stratification
MILD
Only 1 of the 3 cardinal symptoms:
Increased dyspnea
Increased sputum volume
Increased sputum purulence
MODERATE OR SEVERE
At least 2 of the 3 cardinal symptoms:
Increased dyspnea
Increased sputum volume
Increased sputum purulence
Uncomplicated COPD
No risk factors:
Age <65 years
FEV1 >50% predicted
<3 exacerbations/year
No cardiac disease
No antibiotics
Increased bronchodilator
Symptomatic therapy
Monitoring symptoms
Advanced macrolide
(azythromycin, clarithromycin)
Cephalosporin (cefuroxime,
cefpodoxime, cefdinir)
Doxycycline
Trimethoprim–sulfamethoxazole
If recent antibiotic exposure (<3
months), use alternative class
Complicated COPD
1 or More risk factors:
Age >65 years
FEV1 <50% predicted
>3 exacerbations/year
Cardiac disease
Fluoroquinolone
(moxi, gemi, levo)
Amoxicillin-clavulanate
If at risk for Pseudomonas,
consider ciprofloxacin and
obtain sputum culture
If recent antibiotic exposure (<3
months), use alternative class
Worsening clinical status or inadequate response in 72 hrs
A wind of change in AECOPD
Sethi S, Murphy TF. NEJM 2008;359:2355-65.
Reevaluate
Consider sputum culture
New Decade New
Approaches to Treat
AECB
“The MAESTRAL Study”
MAESTRAL
(moxifloxacin in acute exacerbations trial)
A prospective, multinational, multicentre, randomised, double-blind,
double-dummy, controlled study comparing the efficacy and safety of
moxifloxacin to that of amoxicillin/clavulanic acid for the treatment of
subjects with acute exacerbations of chronic bronchitis (AECB)
Current questions in
management of AECB
Does the choice of antibiotic impact the clinical outcome
of AECB?
31
Is there adequate clinical evidence to support current
guidelines for the antibiotic management of AECB?
Are systemic steroids always beneficial in combination
with antibiotics in the out-patient management of AECB ?
MAESTRAL STUDY DESIGN
Stratification1 at enrolment
per steroid use
Randomisation
MAESTRAL: a novel study vs a
gold-standard therapy
Moxifloxacin
400 mg qd
5 days
Amoxicillin/clavulanic acid
875/125 mg bd
7 days
Screening
and
enrolment
EOT
(Day 13 ±1)
Wilson R et al., Int J COPD 2011;6:373–83.
4 weeks
post-therapy
(Day 35 ±3)
PRIMARY
ENDPOINT
8 weeks
post- therapy
(Day 63 ±3)
Primary endpoint: clinical failure at 8 weeks post-therapy - patient’s symptoms have not
improved or have worsened such that additional or alternate systemic antimicrobial and/or
corticosteroid therapy is required any time up to EOT
1Stratum 1: co-administration of systemic steroids for the current AECOPD
Stratum 2: no co-administration of systemic corticosteroids for the current AECOPD
MAESTRAL patient
1
selection
Main inclusion criteria:
60 years and older
Moderate-to-severe chronic bronchitis (COPD by definition)
• FEV1 ≤60% at enrolment
• History of ≥2 AECB (treated) in past 12 months
• At least 20 pack-year cigarette smoking history
– no fossil fuels, pollution, etc
Anthonisen Type 1: exacerbation has increased sputum
purulence, volume and dyspnea2
Main exclusion criteria:
Prior use of antibiotic and/or a short course of systemic
corticosteroids in previous month
Wilson R et al., Int J COPD 2011;6:373–83.
Exacerbation in previous month
1
2Anthonisen
NR et al., Ann Intern Med 1987;106:196–204.
MAESTRAL used a novel primary
endpoint
Primary efficacy outcome
Clinical failure rates at the 8-week post-therapy visit
Clinical failure defined as requirement of additional
treatment for an exacerbation of respiratory symptoms
(within 8 weeks post-therapy):
with systemic antibiotics and/or systemic corticosteroids
and/or
hospitalisation with systemic antibiotics and/or systemic
corticosteroids
Wilson R et al., Int J COPD 2011;6:373–83.
MAESTRAL secondary outcomes
Secondary efficacy outcomes
Clinical failure rates at different time points; clinical failure rates by
steroid strata; for patients with positive sputum culture at enrolment,
spirometry change; change in dosage/or additional respiratory
concomitant medication
Bacteriological outcomes
Bacteriological eradication rates
Questionnaires outcomes
Improvement of quality of life (SGRQ); rates and speed of symptom
relief (AECB-SS, a 7-item questionnaire on cough, phlegm consistency
and colour, breathing difficulties, sleep disturbances and daily life
disturbances)
Healthcare resource utilisation/consumption outcomes
Direct and indirect healthcare costs outcomes
Safety outcomes
Safety and tolerability
A wind of change in AECOPD
Wilson R et al., Int J COPD 2011;6:373–83.
MAESTRAL: a global study
Andorra, Belgium, Croatia, Czech
Republic, Germany, Greece, Ireland,
Italy, Latvia, Lithuania, Netherlands,
Portugal, Spain, Switzerland, United
Kingdom
China, Hong-Kong,
Indonesia, Pakistan,
Philippines, Thailand
Canada,
Mexico
Pakistan
Argentina, Brazil,
Chile, Colombia,
Peru
South Africa
30 countries
150 sites
Wilson R et al., Int J COPD 2011;6:373–83.
Australia
Patient disposition: optimal randomisation
of a large cohort
Enrolled
n=1492
Not randomised
n=120
Moxifloxacin
Randomised
n=686
Randomised
n=686
ITT with pathogens
n=327
ITT/safety
n=677
ITT /safety
n=675
PP
n=538
PP
n=518
PP with
pathogens
n=260
PP with
pathogens
n=261
Wilson R et al., Int J COPD 2011;6:373–83.
Amoxicillin/
clavulanic acid
ITT with pathogens
n=335
MAESTRAL:
CLINICAL EFFICACY
MAESTRAL met the primary
endpoint
Population
Moxifloxacin
Amoxicillin/
clavulanic acid
n/N (%)
95% CI2
P value
n/N (%)
Per-Protocol1
111/538 (20.6)
114/518 (22.0)
-5.89 to 3.83
N/A
ITT/Safety3
138/677 (20.4)
146/675 (21.6)
-5.50 to 3.03
0.571
25
Clinical failure (% patients)
22
20.6
20
16.0
15
13.8
Avelox (n=538)
Per-protocol population
Amoxicillin/clavulanic acid (n=518)
10
7.7
6.7
5
1
0
0.4
During therapy
EOT
4 weeks post-therapy
8 weeks post-therapy
42
Moxifloxacin was superior in patients with
confirmed bacterial exacerbations
Populations
Moxifloxacin
n/N (%)
Amoxicillin/clavulanic
acid
n/N (%)
P value
ITT with
pathogens
62/327 (19.0)
85/335 (25.3)
0.016
PP with
pathogens
50/260 (19.2)
68/261 (26.1)
0.030
PP with pathogens
ITT with pathogens
30
25
Moxifloxacin
Amoxicillin/clavulanic acid
20
15
10
5
0
P=0.016
Clinical failure (% patients)
Clinical failure (% patients)
30
25
Moxifloxacin
Amoxicillin/clavulanic acid
20
15
10
5
0
Wilson et al., Eur Resp J 2011; in press
Bayer Pharma AG; data on file
P=0.030
Clinical failure rates1 at 8 weeks post-therapy by
systemic corticosteroid use
Clinical failure (% patients)
Moxifloxacin
40
95% CI
–20.8, 2.1
P=0.110
33.6
35
30
Amoxicillin/clavulanic acid
95% CI
–25.8, 0.21
P=0.055
34.4
95% CI
–13.9, 0.54
P=0.072
27.0
95% CI
–13.6, 3.2
P=0.266
24.5
25
21.4
20.8
20
16.3
13.9
15
10
5
34/126 40/119
23/94
32/93
28/201
45/216
27/166
36/168
0
ITT with pathogens
PP with pathogens
With corticosteroid use
1Failures
Wilson et al., Eur Resp J 2011; in press
ITT with pathogens
PP with pathogens
Without corticosteroid use
and relapses are included in the failure
rate calculation
95% CI stratified by region
MAESTRAL
MICROBIOLOGICAL
EFFICACY
Causative organisms at enrolment (ITT with pathogens)
662/1352 (49.0%) ITT patients had causative organisms isolated from sputum at baseline
30.2%
19.7%
50.0%
Gram-positive
Other Gram-negative
Enterobacteriaceae
Most frequent pathogens by category
Gram-positive
Streptococcus
pneumoniae 13%
Staphylococcus aureus
6%
Streptococcus sp. 1%
Other GramEnterobacteriaceae
negative
Haemophilus
Klebsiella pneumoniae
influenzae 21%
13%
Pseudomonas
Escherichia coli 6%
aeruginosa 17%
Moraxella catarrhalis Serratia marcescens
12%
4%
Sethi et al. 51st Interscience Conference on
Antimicrobial
Agents and Chemotherapy. Sept 17–20, 2011,
Chicago, USA. Poster L1-269.
MIC distribution by key organism
(ITT with pathogens population)
Organism
Moxifloxacin
mg/L
Amoxicillin/clavulanic acid
mg/L
Median
MIC90
Range
Median
MIC90
Range
H. influenzae (N=122)
0.015
0.03
0.002−1.0
1.0
2.0
1.0−4.0
P. aeruginosa (N=103)
2.0
8.0
0.06−8.0
64.0
64.0
2.0−64.0
S.
pneumoniae1(N=80)
0.12
0.12
0.015−2.0
0.03
1.0
0.015−4.0
M. catarrhalis (N=69)
0.03
0.06
0.002−0.12
0.12
0.25
0.06−1.0
S. aureus (N=38)
0.06
2.0
0.03−2.0
0.75
4.0
0.06−4.0
1MIC
for S. pneumoniae vs penicillin 1.0 mg/L; range 0.015−2.0 mg/L
MIC changes during therapy or up to 8 weeks post-therapy were rare and were
not significant in both treatment groups
Wilson et al., Eur Resp J 2011; in press
Bacteriological success rates by organism and timepoint Haemophilus influenzae (ITT with pathogens
population)
Sustained advantage for Moxifloxacin against H. influenzae
Bacteriological success (% patients)
100
92.3
89.2
80.0
80
85.3
72.3
66.7
60
65.3
56.0
40
Moxifloxacin
Amoxicillin/clavulanic acid
20
0
During therapy
End of therapy
Wilson et al., Eur Resp J 2011; in press
4 weeks
post-therapy
8 weeks
post-therapy
Clinical failure rates in patients with confirmed
bacterial exacerbations
ITT with pathogens
PP with pathogens
30
30
20
15
10
P=0.016
5
0
Clinical failure (% patients)
Clinical failure (% patients)
25
Moxifloxacin
Amoxicillin/clavulanic acid
25
Moxifloxacin
Amoxicillin/clavulanic acid
20
15
10
P=0.030
5
0
During
therapy
EOT
4 weeks
8 weeks
post-therapy post-therapy
During
therapy
Wilson et al., Eur Resp J 2011; in press
Bayer Pharma AG; data on file
EOT
4 weeks
8 weeks
post-therapy post-therapy
SAFETY
Overview of treatment-emergent adverse events
through week 8 post-therapy (ITT/safety population)
Event
MedDRA Preferred Term
(version 13.1)
Moxifloxacin
N=677
n (%)
Amoxicillin/clavulani
c acid
N=675
n (%)
220 (32.5)
218 (32.3)
Drug-related AE
53 (7.8)
41 (6.1)
Serious AE (SAE)
46 (6.8)
51 (7.6)
Serious drug-related AE
4 (0.6)
2 (0.3)
Premature discontinuation due
to drug-related AE
12 (1.8)
9 (1.3)
Premature discontinuation due
to SAE
7 (1.0)
3 (0.4)
AE-related deaths
3 (0.4)
3 (0.4)
Any adverse event (AE)
P>0.05 for all categories
Wilson et al., Eur Resp J 2011; in press
Bayer Pharma AG; data on file
MAESTRAL Study Results Summary – 1/2
Moxifloxacin was equivalent to
amoxicillin/clavulanic acid in the treatment
of acute exacerbations in outpatients with
moderate-to-severe COPD.
Moxifloxacin was superior to
amoxicillin/clavulanic acid in terms of
clinical cure at 8 weeks post-therapy for
patients with confirmed bacterial
exacerbations at baseline.
MAESTRAL Study Results Summary – 2/2
The overall eradication rate at end-oftherapy was higher with Moxifloxacin than
with amoxicillin/clavulanic acid, mainly
explained by a better efficacy against H.
influenzae.
There was a clear correlation between
bacteriological response at end-of-therapy
and clinical cure at 8 weeks post-therapy –
overall and for the Moxifloxacin group.
57
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