New decade, New approaches to AECOPD

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

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


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.



No cardiac disease



Cardiac disease














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 ?

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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


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


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


Pakistan

Patient disposition: optimal randomisation of a large cohort

ITT with pathogensn=327

ITT with pathogensn=335


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


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 (%)


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


Populations Moxifloxacinn/N (%)


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)


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


Sustained advantage for Moxifloxacin against H. influenzae

Bacteriological success rates by organism and time-point Haemophilus influenzae (ITT with pathogens population)


Clinical failure rates in patients with confirmed bacterial exacerbations

0

5

10

15

20

25

30

Duringtherapy

EOT 4 weekspost-therapy

8 weekspost-therapy


0

5

10

15

20

25

30

Duringtherapy

EOT 4 weekspost-therapy

8 weekspost-therapy


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


SAFETY

EventMedDRA Preferred Term (version 13.1)

MoxifloxacinN=677n (%)


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)


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.

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MAESTRAL Study Results Summary – 2/2

THANK YOU!

New decade, New approaches to AECOPD

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