Shariq Rizvi First Year Graduate Student CS Division, UC Berkeley [email protected]
New decade, New approaches to AECOPD Prof. Nadeem Rizvi Head of Chest Medicine Jinnah Postgraduate...
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Transcript of New decade, New approaches to AECOPD Prof. Nadeem Rizvi Head of Chest Medicine Jinnah Postgraduate...
New decade, New approaches to AECOPD
Prof. Nadeem RizviHead 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
Social withdrawal
Worsening quality of life
More exacerbations
Increased risk of hospitalisation
Greater anxiety
Decline in lung function
Garcia-Aymerich J et al. 2001 Donaldson D et al. 2002
Gore JM et al. 2000 Seemungal T et al. 1998
Pauwels Pet al. 2001Seemungal T et al. 2000
Garcia-Aymerich J et al. 2003Anto JM et al. 2001
Increased symptoms (I.e. breathlessness)
Increased risk of mortality
Causes of AECB
Ball. CHEST 1995; 108: 43S–52S; Miravitlles & Niederman. Lectures in Respiratory Tract Infections. Science PressCommunications, 2004; Donaldson et al. Eur Respir J 1999; 13: 844–9
AECB
WeatherFall in temperature
InfectionBacterial
ViralAllergy
PollutionCigarette smokeIndustrial dusts
Epidemiology of Exacerbations: Frequency Increases with Declining FEV1
Donaldson GC, Wedzicha JA. Thorax. 2006;61:164-168.
FEV1 (1)
2.5
2.0
0.5
0< 1.25 1.25 – 1.54 > 1.54 2.40
3.0
1.5
Exa
cerb
atio
ns
per
Yea
r
2.50
1.0
5
Impact of Exacerbations in COPD
Wedzicha JA, Seemungal TA. Lancet. 2007;370:786-796. Wedzicha JA, Seemungal TA. Lancet. 2007;370:786-796.
Patients with Frequent Exacerbations
Higher Mortality
Faster Declinein Lung Function
Poorer Qualityof Life
Greater AirwayInflammation
6
More Rapid Decline in FEV1 With Higher Exacerbation Frequency
Donaldson GC, et al. Thorax. 2002;57:847-852.
Years
0.90
0.75
0
0.95
0.85
Per
cen
t C
han
ge
fro
m B
ase
lin
e in
FE
V1
0.80
1 2 3 4
Infrequent Exacerbators
Frequent Exacerbators
7
Frequent Exacerbations Are Associated With More Rapid Decline in Pulmonary Function
*
FEV1 (mL) PEF (L/minute)
An
nu
al C
ha
ng
e **
* 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. Kim S, et al. COPD. 2006;3:75-81. 10
Exacerbation Frequency and SeverityBoth Increase Mortality Risk
Soler-Cataluña JJ, et al. Thorax. 2005;60:925-931. Soler-Cataluña JJ, et al. Thorax. 2005;60:925-931.
Group A patients with no acute exacerbations Group B patients with 1–2 acute exacerbations
requiring hospital managementGroup C patients with >3 acute exacerbations
Group (1) no acute exacerbations Group (2) acute exacerbations requiring emergency
service visits without admissionGroup (3) patients with acute exacerbations requiring
one hospital admissionGroup (4) patients with acute exacerbations requiring
readmissions
1.0
0.8
0.6
0.4
0.2
0.00 10 20 30 40 50 60
Time (months)
A
p<0.0002
B
p=0.069
C
p<0.0
Pro
ba
bil
ity
of
su
rviv
ing
1.0
0.8
0.6
0.4
0.2
0.00 10 20 30 40 50 60
Time (months)
(1)
(3)
(4)
Pro
ba
bil
ity
of
su
rviv
ing
p<0.0001
(2)
NS
NS
p=0.005p<0.0001
11
Cost of Treatment for an Acute
Exacerbation of COPD
O'Reilly JF, et al. Int J Clin Pract. 2007;61:1112-1120. O'Reilly JF, et al. Int J Clin Pract. 2007;61:1112-1120. 123
Exacerbations Negatively Affect Quality of Life
Seemungal TA, et al. Am J Respir Crit Care Med. 2000;161:1608–1613.
* P<0.05 versus lower exacerbation rate
*
**
*
14
ISSUE OF ANTIBIOTIC USE IN EXACERBATION
Stratification of AECB patients – the Anthonisen criteria
Anthonisen et al. Ann Intern Med 1987 [Adapted from Woodhead et al. Eur Respir J 2005]
Increase in:• dyspnea
• sputum volume• sputum purulence
TYPE IAll three present,
antibiotic recommended
TYPE IITwo of three present,
antibiotic recommended if includes purulence
TYPE IIIOne of three present,
antibiotic not recommended
Relative Risk (95% Confidence Interval)Relative Risk (95% Confidence Interval)
Pooled summary(RR, 0.54; 95% CI, 0.32-0.92)
Pooled summary(RR, 0.54; 95% CI, 0.32-0.92)
Elmes et al, 1965Elmes et al, 1965
Pines et al, 1968Pines et al, 1968
Anthonisen et al, 1987Anthonisen et al, 1987
Jorgensen et al, 1992Jorgensen et al, 1992
Nouira et al, 2001Nouira et al, 2001
10100.10.1 0.20.2 0.50.5 22 5511
Favours PlaceboFavours PlaceboFavours AntibioticsFavours Antibiotics
Quon BS et al. Chest 2008; 133:756-766
Treatment failure is associated with increased acute exacerbation episodes and disease progression
23
Uncomplicated COPDNo risk factors:Age <65 years
FEV1 >50% predicted<3 exacerbations/year
No cardiac disease
Complicated COPD1 or More risk factors:
Age >65 yearsFEV1 <50% predicted>3 exacerbations/year
Cardiac disease
Advanced macrolide (azythromycin, clarithromycin)Cephalosporin (cefuroxime, cefpodoxime, cefdinir)DoxycyclineTrimethoprim–sulfamethoxazoleIf recent antibiotic exposure (<3 months), use alternative class
MILDOnly 1 of the 3 cardinal
symptoms:Increased dyspneaIncreased sputum volumeIncreased sputum purulence
Fluoroquinolone(moxi, gemi, levo)Amoxicillin-clavulanateIf at risk for Pseudomonas,consider ciprofloxacin andobtain sputum cultureIf recent antibiotic exposure (<3
months), use alternative class
MODERATE OR SEVEREAt least 2 of the 3 cardinal
symptoms:Increased dyspneaIncreased sputum volumeIncreased sputum purulence
A wind of change in AECOPD
Antibiotics for AECOPD: Risk Stratification
No antibioticsIncreased bronchodilatorSymptomatic therapyMonitoring symptoms
Reevaluate Consider sputum culture
Worsening clinical status or inadequate response in 72 hrs
Sethi S, Murphy TF. NEJM 2008;359:2355-65.
Uncomplicated COPDNo risk factors:Age <65 years
FEV1 >50% predicted<3 exacerbations/year
No cardiac disease
Complicated COPD1 or More risk factors:
Age >65 yearsFEV1 <50% predicted>3 exacerbations/year
Cardiac disease
Advanced macrolide (azythromycin, clarithromycin)Cephalosporin (cefuroxime, cefpodoxime, cefdinir)DoxycyclineTrimethoprim–sulfamethoxazoleIf recent antibiotic exposure (<3 months), use alternative class
Reevaluate Consider sputum culture
MILDOnly 1 of the 3 cardinal
symptoms:Increased dyspneaIncreased sputum volumeIncreased sputum purulence
Fluoroquinolone(moxi, gemi, levo)Amoxicillin-clavulanateIf at risk for Pseudomonas,consider ciprofloxacin andobtain sputum cultureIf recent antibiotic exposure (<3
months), use alternative class
MODERATE OR SEVEREAt least 2 of the 3 cardinal
symptoms:Increased dyspneaIncreased sputum volumeIncreased sputum purulence
A wind of change in AECOPD
No antibioticsIncreased bronchodilatorSymptomatic therapyMonitoring symptoms
Worsening clinical status or inadequate response in 72 hrs
Antibiotics for AECOPD: Risk Stratification
Sethi S, Murphy TF. NEJM 2008;359:2355-65.
Uncomplicated COPDNo risk factors:Age <65 years
FEV1 >50% predicted<3 exacerbations/year
No cardiac disease
Complicated COPD1 or More risk factors:
Age >65 yearsFEV1 <50% predicted>3 exacerbations/year
Cardiac disease
Advanced macrolide (azythromycin, clarithromycin)Cephalosporin (cefuroxime, cefpodoxime, cefdinir)DoxycyclineTrimethoprim–sulfamethoxazoleIf recent antibiotic exposure (<3 months), use alternative class
MILDOnly 1 of the 3 cardinal
symptoms:Increased dyspneaIncreased sputum volumeIncreased sputum purulence
Fluoroquinolone(moxi, gemi, levo)Amoxicillin-clavulanateIf at risk for Pseudomonas,consider ciprofloxacin andobtain sputum cultureIf recent antibiotic exposure (<3
months), use alternative class
MODERATE OR SEVEREAt least 2 of the 3 cardinal
symptoms:Increased dyspneaIncreased sputum volumeIncreased sputum purulence
A wind of change in AECOPD
No antibioticsIncreased bronchodilatorSymptomatic therapyMonitoring symptoms
Reevaluate Consider sputum culture
Worsening clinical status or inadequate response in 72 hrs
Antibiotics for AECOPD: Risk Stratification
Sethi S, Murphy TF. NEJM 2008;359:2355-65.
New Decade New Approaches to Treat AECB “The MAESTRAL Study”
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)
MAESTRAL
(moxifloxacin in acute exacerbations trial)
Current questions in management of AECB
Does the choice of antibiotic impact the clinical outcome of AECB?
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 ?
31
MAESTRAL STUDY DESIGN
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 EOT1Stratum 1: co-administration of systemic steroids for the current AECOPD
Stratum 2: no co-administration of systemic corticosteroids for the current AECOPD
PRIMARY ENDPOINT
8 weeks post- therapy (Day 63
±3)
4 weeks post-therapy
(Day 35 ±3)
EOT (Day 13 ±1)
Screening and
enrolment
Moxifloxacin400 mg qd
5 days
Moxifloxacin400 mg qd
5 days
Amoxicillin/clavulanic acid
875/125 mg bd7 days
Amoxicillin/clavulanic acid
875/125 mg bd7 days
MAESTRAL: a novel study vs a gold-standard therapy
Wilson R et al., Int J COPD 2011;6:373–83.
MAESTRAL patient selection1
Main inclusion criteria:60 years and olderModerate-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 monthExacerbation in previous month
1Wilson R et al., Int J COPD 2011;6:373–83.
2Anthonisen NR et al., Ann Intern Med 1987;106:196–204.
MAESTRAL used a novel primary endpoint
Wilson R et al., Int J COPD 2011;6:373–83.
Primary efficacy outcomeClinical 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/orhospitalisation with systemic antibiotics and/or systemic corticosteroids
Primary efficacy outcomeClinical 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/orhospitalisation with systemic antibiotics and/or systemic corticosteroids
MAESTRAL secondary outcomes
A wind of change in AECOPD Wilson R et al., Int J COPD 2011;6:373–83.
Secondary efficacy outcomesClinical 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 outcomesBacteriological eradication rates
Questionnaires outcomesImprovement 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 outcomesDirect and indirect healthcare costs outcomes
Safety outcomesSafety and tolerability
Secondary efficacy outcomesClinical 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 outcomesBacteriological eradication rates
Questionnaires outcomesImprovement 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 outcomesDirect and indirect healthcare costs outcomes
Safety outcomesSafety and tolerability
MAESTRAL: a global study
30 countries150 sites
Andorra, Belgium, Croatia, Czech Republic, Germany, Greece, Ireland, Italy, Latvia, Lithuania, Netherlands, Portugal, Spain, Switzerland, United
Kingdom
Australia
Argentina, Brazil, Chile, Colombia,
Peru
China, Hong-Kong, Indonesia, Pakistan,
Philippines, Thailand Canada, Mexico
South Africa
Wilson R et al., Int J COPD 2011;6:373–83.
Pakistan
Patient disposition: optimal randomisation of a large cohort
ITT with pathogensn=327
ITT with pathogensn=335
Amoxicillin/clavulanic acid
Moxifloxacin
ITT/safetyn=677
PPn=538
PP with pathogens
n=260
Randomisedn=686
ITT /safetyn=675
PPn=518
PP with pathogens
n=261
Randomisedn=686
Wilson R et al., Int J COPD 2011;6:373–83.
Enrolledn=1492
Not randomisedn=120
MAESTRAL:CLINICAL EFFICACY
0.4
6.7
13.8
20.6
1
7.7
16.0
22
0
5
10
15
20
25
During therapy EOT 4 weeks post-therapy 8 weeks post-therapy
Clin
ica
l fa
ilure
(%
pa
tie
nts
)
Avelox (n=538)
Amoxicillin/clavulanic acid (n=518)
Population
Moxifloxacin
n/N (%)
Amoxicillin/clavulanic acid
n/N (%)
95% CI2 P value
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
MAESTRAL met the primary endpoint
42
Per-protocol population
0
5
10
15
20
25
30
MoxifloxacinAmoxicillin/clavulanic acid
0
5
10
15
20
25
30
MoxifloxacinAmoxicillin/clavulanic acid
Populations Moxifloxacinn/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
Cli
nic
al
fail
ure
(%
pa
tie
nts
)
PP with pathogens
P=0.030
Cli
nic
al
fail
ure
(%
pa
tie
nts
)
ITT with pathogens
P=0.016
Moxifloxacin was superior in patients with confirmed bacterial exacerbations
Wilson et al., Eur Resp J 2011; in pressBayer Pharma AG; data on file
27.024.5
13.916.3
33.6 34.4
20.8 21.4
0
5
10
15
20
25
30
35
40
ITT with pathogens PP with pathogens ITT with pathogens PP with pathogens
Moxifloxacin Amoxicillin/clavulanic acid
1Failures and relapses are included in the failure rate calculation
95% CI stratified by region
34/126 40/119 23/94 32/93 28/201 45/216 27/166 36/168
Cli
nic
al
fail
ure
(%
pa
tie
nts
)
With corticosteroid use Without corticosteroid use
Clinical failure rates1 at 8 weeks post-therapy by systemic corticosteroid use
95% CI–20.8, 2.1P=0.110
95% CI–25.8, 0.21
P=0.055
95% CI–13.6, 3.2P=0.266
95% CI–13.9, 0.54
P=0.072
Wilson et al., Eur Resp J 2011; in press
MAESTRAL MICROBIOLOGICAL EFFICACY
Causative organisms at enrolment (ITT with pathogens)
19.7%
50.0%
30.2% Gram-positiveOther Gram-negativeEnterobacteriaceae
Most frequent pathogens by category
Gram-positiveOther Gram-
negativeEnterobacteriace
aeStreptococcus
pneumoniae 13%Haemophilus
influenzae 21%Klebsiella
pneumoniae 13%Staphylococcus
aureus 6% Pseudomonas
aeruginosa 17% Escherichia coli
6%Streptococcus sp.
1% Moraxella
catarrhalis 12%Serratia
marcescens 4%
662/1352 (49.0%) ITT patients had causative organisms isolated from sputum at baseline
Sethi et al. 51st Interscience Conference on Antimicrobial
Agents and Chemotherapy. Sept 17–20, 2011, Chicago, USA. Poster L1-269.
Organism Moxifloxacinmg/L
Amoxicillin/clavulanic acidmg/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
MIC distribution by key organism(ITT with pathogens population)
Wilson et al., Eur Resp J 2011; in press
92.389.2
80.0
72.385.3
66.7 65.3
56.0
0
20
40
60
80
100
During therapy End of therapy 4 weekspost-therapy
8 weekspost-therapy
Ba
cte
rio
log
ica
l s
uc
ce
ss
(%
pa
tie
nts
)
Moxifloxacin
Amoxicillin/clavulanic acid
Sustained advantage for Moxifloxacin against H. influenzae
Bacteriological success rates by organism and time-point Haemophilus influenzae (ITT with pathogens population)
Wilson et al., Eur Resp J 2011; in press
Clinical failure rates in patients with confirmed bacterial exacerbations
0
5
10
15
20
25
30
Duringtherapy
EOT 4 weekspost-therapy
8 weekspost-therapy
MoxifloxacinAmoxicillin/clavulanic acid
0
5
10
15
20
25
30
Duringtherapy
EOT 4 weekspost-therapy
8 weekspost-therapy
MoxifloxacinAmoxicillin/clavulanic acid
Cli
nic
al
fail
ure
(%
pa
tie
nts
)
Cli
nic
al
fail
ure
(%
pa
tie
nts
)
ITT with pathogens PP with pathogens
P=0.030P=0.016
Wilson et al., Eur Resp J 2011; in pressBayer Pharma AG; data on file
SAFETY
EventMedDRA Preferred Term (version 13.1)
MoxifloxacinN=677n (%)
Amoxicillin/clavulanic acid
N=675n (%)
Any adverse event (AE) 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)
P>0.05 for all categories
Overview of treatment-emergent adverse events through week 8 post-therapy (ITT/safety population)
Wilson et al., Eur Resp J 2011; in pressBayer 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.
Patients with confirmed bacterial exacerbations who received concomitant steroids generally had more severe disease and had a higher clinical failure rate than those who were not on steroids.
In this sicker population of patients with confirmed bacterial exacerbations who received steroids, there was a trend for lower clinical failure rates with Moxifloxacin vs amoxicillin/clavulanic acid.
The overall eradication rate at end-of-therapy 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.
Both treatments were well-tolerated and had similar safety profiles.
57
MAESTRAL Study Results Summary – 2/2
THANK YOU!