Transcript aecopd
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 Increased risk of hospitalisation More exacerbations 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 Bacterial Viral Allergy 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 FEV
1
3.0
2.5
2.0
1.5
1.0
0.5
0 < 1.25
1.25 – 1.54
> 1.54
FEV 1 (1) 2.40
Donaldson GC, Wedzicha JA.
Thorax
. 2006;61:164-168.
2.50
5
Impact of Exacerbations in COPD
Patients with Frequent Exacerbations Faster Decline in Lung Function Poorer Quality of Life Greater Airway Inflammation Higher Mortality
Wedzicha JA, Seemungal TA.
Lancet
. 2007;370:786-796.
6
More Rapid Decline in FEV
1
With Higher Exacerbation Frequency
0.95
Infrequent Exacerbators Frequent Exacerbators 0.90
0.85
0.80
0.75
0 1 2 Years 3 4
Donaldson GC, et al.
Thorax.
2002;57:847-852.
7
Frequent Exacerbations Are Associated With More Rapid Decline in Pulmonary Function
FEV 1 (mL) PEF (L/minute) ** *
Donaldson GC, et al.
Thorax.
2002;57:847-852.
* P<0.05 versus infrequent exacerbators; ** P<0.001 versus infrequent exacerbators 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
0.6
0.4
0.2
A p<0.0002
B p=0.069
C p<0.0
0.0
0 10 20 30 40 Time (months) 50 60 Group A Group B Group C patients with no acute exacerbations patients with 1 –2 acute exacerbations requiring hospital management p atients with >3 acute exacerbations 1.0
0.8
0.6
0.4
0.2
(1) (2) NS p=0.005
(3) (4) NS p<0.0001
p<0.0001
0.0
0 10 Group (1) Group (2) Group (3) Group (4) 20 30 40 Time (months) 50 60 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
Soler Cataluña JJ, et al.
Thorax
. 2005;60:925-931.
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 Two of three present, antibiotic recommended if includes purulence
Anthonisen et al. Ann Intern Med 1987 [Adapted from Woodhead et al. Eur Respir J 2005]
TYPE III One of three present, antibiotic not recommended
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) 10
Quon BS et al. Chest 2008; 133:756-766
23
Antibiotics for AECOPD: Risk Stratification MILD Only 1 of the 3 cardinal symptoms: Increased dyspnea Increased sputum volume Increased sputum purulence No antibiotics Increased bronchodilator Symptomatic therapy Monitoring symptoms Uncomplicated COPD No risk factors: Age <65 years FEV1 >50% predicted <3 exacerbations/year No cardiac disease Advanced macrolide (azythromycin, clarithromycin) Cephalosporin (cefuroxime, cefpodoxime, cefdinir) Doxycycline Trimethoprim –sulfamethoxazole If recent antibiotic exposure (<3 months), use alternative class MODERATE OR SEVERE At least 2 of the 3 cardinal symptoms: Increased dyspnea Increased sputum volume Increased sputum purulence 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 A wind of change in AECOPD Worsening clinical status or inadequate response in 72 hrs
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 No antibiotics Increased bronchodilator Symptomatic therapy Monitoring symptoms Uncomplicated COPD No risk factors: Age <65 years FEV1 >50% predicted <3 exacerbations/year No cardiac disease Advanced macrolide (azythromycin, clarithromycin) Cephalosporin (cefuroxime, cefpodoxime, cefdinir) Doxycycline Trimethoprim –sulfamethoxazole If recent antibiotic exposure (<3 months), use alternative class MODERATE OR SEVERE At least 2 of the 3 cardinal symptoms: Increased dyspnea Increased sputum volume Increased sputum purulence 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 A wind of change in AECOPD Worsening clinical status or inadequate response in 72 hrs
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 No antibiotics Increased bronchodilator Symptomatic therapy Monitoring symptoms Uncomplicated COPD No risk factors: Age <65 years FEV1 >50% predicted <3 exacerbations/year No cardiac disease Advanced macrolide (azythromycin, clarithromycin) Cephalosporin (cefuroxime, cefpodoxime, cefdinir) Doxycycline Trimethoprim –sulfamethoxazole If recent antibiotic exposure (<3 months), use alternative class MODERATE OR SEVERE At least 2 of the 3 cardinal symptoms: Increased dyspnea Increased sputum volume Increased sputum purulence 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 A wind of change in AECOPD Worsening clinical status or inadequate response in 72 hrs
Sethi S, Murphy TF.
NEJM
2008;
359
:2355-65.
Reevaluate Consider sputum culture
New Decade New Approaches to Treat AECB
“The MAESTRAL Study”
MAESTRAL ( m oxifloxacin in a cute e xacerbations 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
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
Wilson R
et al.
,
Int J COPD
2011;
6 EOT
(Day 13 ± 1) :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 1 Stratum 1: co-administration of systemic steroids for the current AECOPD Stratum 2: no co-administration of systemic corticosteroids for the current AECOPD
MAESTRAL patient selection
1 Main inclusion criteria: 60 years and older Moderate-to-severe chronic bronchitis (COPD by definition) • • FEV 1 ≤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 dyspnea 2 Main exclusion criteria: Prior use of antibiotic and/or a short course of systemic corticosteroids in previous month Exacerbation in previous month 1 Wilson R
et al.
,
Int J COPD
2011;
6
:373 –83.
2 Anthonisen 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.
Canada, Mexico
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 Argentina, Brazil, Chile, Colombia, Peru Pakistan 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 ITT with pathogens n=327 Randomised n=686 ITT/safety n=677 Randomised n=686 ITT /safety n=675 Amoxicillin/ clavulanic acid ITT with pathogens n=335 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.
MAESTRAL: CLINICAL EFFICACY
MAESTRAL met the primary endpoint
Population Moxifloxacin
Per-Protocol 1 ITT/Safety 3 25 20 15 10 5 0
n/N (%)
111/538 (20.6) 138/677 (20.4) 1 0.4
During therapy
7.7
EOT
6.7
Amoxicillin/ clavulanic acid n/N (%)
114/518 (22.0) 146/675 (21.6) 16.0
13.8
95% CI
-5.89 to 3.83
-5.50 to 3.03
22
2
20.6
4 weeks post-therapy 8 weeks post-therapy P value
N/A 0.571
Avelox (n=538) Per-protocol population Amoxicillin/clavulanic acid (n=518) 42
Moxifloxacin was superior in patients with confirmed bacterial exacerbations Populations Moxifloxacin n/N (%) Amoxicillin/clavulanic acid n/N (%)
85/335 (25.3) ITT with pathogens PP with pathogens
ITT with pathogens
62/327 (19.0) 50/260 (19.2) 30 25 Moxifloxacin Amoxicillin/clavulanic acid 20 15 10 5 0
P
=0.016
30 25 20 15 10 5 0 68/261 (26.1)
PP with pathogens
Moxifloxacin Amoxicillin/clavulanic acid
P value
P
=0.030
0.016
0.030
Wilson
et al
.,
Eur Resp J
2011;
in press
Bayer Pharma AG; data on file
Clinical failure rates 1 at 8 weeks post-therapy by systemic corticosteroid use
Moxifloxacin Amoxicillin/clavulanic acid
40 35 30 25 20 15 10 5 0
95% CI –20.8, 2.1
P=0.110
33.6
27.0
34/126 40/119
95% CI –25.8, 0.21
P=0.055
34.4
24.5
23/94 32/93
95% CI –13.9, 0.54
P=0.072
13.9
20.8
28/201 45/216
95% CI –13.6, 3.2
P=0.266
16.3
21.4
27/166 36/168 ITT with pathogens PP with pathogens ITT with pathogens PP with pathogens With corticosteroid use Without corticosteroid use
1 Failures and relapses are included in the failure rate calculation 95% CI stratified by region Wilson
et al
.,
Eur Resp J
2011;
in press
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 Gram negative
Haemophilus
influenzae 21%
Pseudomonas
aeruginosa 17%
Moraxella catarrhalis
12%
Enterobacteriaceae
Klebsiella pneumoniae
13% Escherichia coli 6%
Serratia marcescens
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
H. influenzae (N=122) P. aeruginosa (N=103)
S. pneumoniae
1 (N=80) M. catarrhalis (N=69) S. aureus (N=38)
Median Moxifloxacin mg/L MIC 90 Range
0.015
2.0
0.12
0.03
8.0
0.12
0.002−1.0
0.06−8.0
0.015−2.0
0.03
0.06
0.06
2.0
0.002−0.12
0.03−2.0
1 MIC for
S. pneumoniae
vs penicillin 1.0 mg/L; range 0.015
−2.0 mg/L
Amoxicillin/clavulanic acid mg/L Median MIC 90 Range
1.0
64.0
0.03
2.0
64.0
1.0
1.0−4.0
2.0−64.0
0.015−4.0
0.12
0.75
0.25
4.0
0.06−1.0
0.06−4.0
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 time point Haemophilus influenzae ( ITT with pathogens population ) Sustained advantage for Moxifloxacin against H. influenzae 100 80 60 40 20
92.3
85.3
89.2
66.7
0 During therapy End of therapy
80.0
72.3
65.3
56.0
Moxifloxacin Amoxicillin/clavulanic acid
4 weeks post-therapy 8 weeks post-therapy
Wilson
et al
.,
Eur Resp J
2011;
in press
Clinical failure rates in patients with confirmed bacterial exacerbations ITT with pathogens
30 25 20 15 Moxifloxacin Amoxicillin/clavulanic acid 10 5 0 During therapy
P
=0.016
EOT 4 weeks post-therapy 8 weeks post-therapy
PP with pathogens
30 25 20 15 10 Moxifloxacin Amoxicillin/clavulanic acid 5 0 During therapy
P
=0.030
EOT 4 weeks post-therapy 8 weeks post-therapy Wilson
et al
.,
Eur Resp J
2011;
in press
Bayer Pharma AG; data on file
SAFETY
Overview of treatment-emergent adverse events through week 8 post-therapy ( ITT/safety population ) Event MedDRA Preferred Term (version 13.1)
Any adverse event (AE) Drug-related AE Serious AE (SAE) Serious drug-related AE Premature discontinuation due to drug-related AE Premature discontinuation due to SAE AE-related deaths
Moxifloxacin N=677 n (%)
220 (32.5) 53 (7.8) 46 (6.8) 4 (0.6) 12 (1.8) 7 (1.0) 3 (0.4)
Amoxicillin/clavulani c acid N=675 n (%)
218 (32.3) 41 (6.1) 51 (7.6) 2 (0.3) 9 (1.3) 3 (0.4) 3 (0.4) 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-of therapy was higher with Moxifloxacin than with amoxicillin/clavulanic acid, mainly explained by a better efficacy against H. influenzae.
57 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.