INTERVENTIONS IN COPD EXACERBATIONS: HOW DO THEY WORK?

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INTERVENTIONS IN COPD EXACERBATIONS HOW DO THEY
WORK?

• Professor Wisia Wedzicha
• University College London, UK

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EXACERBATION METRICS

• Exacerbation frequency no/year
• Exacerbation severity
• Exacerbation length/recovery/days
• Time to the next exacerbation
• Numbers of patients with 1 or more exacerbations
• Number of patients with no exacerbations
• Hospital admission

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EXACERBATION SEVERITY

• How is exacerbation severity determined?
• TYPE OF EXACERBATION THERAPY
• SYMPTOM SCORES AND LENGTH OF EXACERBATION
• HOSPITAL ADMISSION
• RESPIRATORY FAILURE
• DEATH
• BIOMARKERS? LUNG FUNCTION

DISEASE SEVERITY
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DEFINITIONS

• SYMPTOMATIC
• (based on Anthonisen et al Ann Intern Med 1987)
• At least two of increase in SOB, sputum
  purulence, sputum volume
• Or any one above and one of URTI, Wheeze, Cough,
  Increase in resp. / pulse rate
• HEALTH CARE UTILIZATION
• (Rodriguez-Roisin Chest 2000)
• Sustained worsening of COPD patients condition
  from stable state necessitating a change in
  regular medication
• Used by most studies of therapies in COPD

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DIARY CARD FOR EAST LONDON COPD COHORT
A Increased shortness of breath, B1 Increased
sputum colour, B2 Increased sputum amount, C
Colds runny nose or nasal congestion, D
Increased wheeze and/or chest feels tighter, E1
Sore throat , E2 Increased cough
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INSPIRE STUDY Exacerbation rates HCU and
Symptom defined
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Importance of Unreported ExacerbationsWilkinson
et all AJRCCM 2004
Rho -0.22, p 0.018
SGRQ Total
lt 25
gt 75
Exacerbations Treated
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From Wedzicha, JA, Seemungal T Lancet 2007
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REDUCTION IN EXACERBATION TRIGGERS

• Smoking cessation
• Vaccination
• Anti virals
• Pollution control
• Occupational factors?
• Long term antibiotics?
• Immunostimulants?

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TORCH STUDY DATA - RATE OF MODERATE AND SEVERE
EXACERBATIONS OVER THREE YEARS
Mean number of exacerbations/year
25 reduction
1.2
1.13
0.97
0.93
1
0.85
0.8
0.6
0.4
0.2
0
Placebo
SALM
FP
SFC
Treatment

• Calverley et al. NEJM 2007

p lt 0.001 vs placebo p 0.002 vs SALM p
0.024 vs FP
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LOWER DOSE 250/50 SFC AND SALMETEROL Ferguson et
al Resp Med 2008
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UPLIFT STUDY EFFECT ON EXACERBATIONS
14 Reductionin Risk
Hazard ratio 0.86, (95 CI, 0.81-0.91) p lt
0.001 (log-rank test)
Tashkin et al NEJM 2008
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EFFECT OF TIOTROPIUM ON EXACERBATIONS Powrie et
al ERJ2007
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UPLIFT FURTHER SUB- ANALYSIS
Lancet 2009
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INSPIRE STUDY - SFC and TIO have similar
magnitude of effect on exacerbation frequency
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4
Rate of Healthcare Utilisation Exacerbations
2
0
SFC 50/500
TIO 18
Wedzicha JA, et al. AJRCCM 2008
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RATE OF HEALTHCARE UTILIZATION EXACERBATIONS
There is a shift in the character of the
exacerbations more antibiotics with SFC, more
OCS with tiotropium
Wedzicha JA, et al. AJRCCM 2008
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RESULTS TIME TO FIRST PNEUMONIA
Calverley P et al, ATS 2008
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TRISTAN STUDY - Calverley et al Lancet 2003 1
exacerbation in previous year
TORCH STUDY Calverley et al NEJM 2007 No
requirement for exacerbation
SFC
P
Sal
FC
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ECLIPSE - DISTRIBUTION OF OBSERVED
EXACERBATIONS DURING YEAR 1 BY PRIOR EXACERBATION
HISTORY FOR GOLD STAGES 3-4Wedzicha et al
Presented at ATS 2009
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ISOLDE - EXACERBATIONS AND INHALED STEROIDS
Jones et al ERJ 2004
EFFECT OF EXACERBATION FREQUENCY
P0.022
0.01
0.02
NS
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OPTIMAL STUDY TIME TO FIRST EXACERBATION
Aaron et al Ann Intern Med 2007
1.00
0.75
Probability of Remaining Exacerbation-Free
0.50
P 0.15
0
50
100
150
200
250
300
350
Days Until First Exacerbation of COPD
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Lancet 2009
Patients had chronic bronchitis Exacerbation
history
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EXACERBATION FREQUENCY AND BACTERIAL
COLONIZATION Patel et al. Thorax 2002
1.2
1.0
0.8
0.6
Proportion of patients with LABC
0.4
0.2
0.0
-0.2
lt2.58 per year(n14)
gt2.58 per year(n14)
Exacerbation frequency
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LONG TERM ANTIBIOTICS

• Studies in 1960s showed effect on infections
• Recent Pulse study with pulsed moxifloxacin
  some effect on exacerbation prevention
• Problems which antibiotic? resistance?
  Continuous or pulsed? Inhaled?

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RATIONALE FOR MACROLIDE USE IN COPD

• Macrolides in vitro may reduce the airway
  inflammatory response to rhinovirus (1)
• LPS-stimulated primary COPD airway epithelial
  cells pre-treatment with the macrolide
  clarithromycin
• 68.6 reduction in IL-6 production (2)
• Neutrophil function ?oxidant production (3)
• Bacterial adhesion (4)
• Anti-Chlamydia activity (5)

(1) Suzuki AJRCCM 2002 (2) Roland et al AJRCCM
2001 163A737 (3) Labro JAC 1989 (4) Kobayachi
AJM 1995 (5) Blasi Thorax 2002
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MACROLIDES TIME TO 1ST EXACERBATION Seemungal
et al AJRCCM 2008
ERYTHROMYCIN
PLACEBO
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Symptom Duration is responsive to Therapy
(Macrolide Study)
Seemungal et al. AJRCCM 2008
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POTENTIAL TARGETS FOR EXACERBATION THERAPY
Courtesy of Prof Peter Barnes
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NON-PHARMACOLOGICAL INTERVENTIONS

• Smoking cessation
• Home Oxygen Therapy
• Psychological therapies
• Home noninvasive ventilation and oxygen therapy
• Pulmonary rehabilitation
• ?Management of gastro-oesophageal reflux

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SIGNIFICANCE OF TREATMENT DELAY AND RECOVERY
TIME Wilkinson et al AJRCCM 2004
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SYMPTOM ONSET AND EARLY START OFTHERAPY
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Plt0.001
18
12
Symptom recovery time (days)
6
0
0
7
14
Delay between onset and treatment (days)
Patients who receive prompt therapy after symptom
onset are likely to recover more rapidly than
are patients whose treatment is delayed
Wilkinson et al. Am J Respir Crit Care Med.
20041691298-1303.
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Thorax 2008
Treatment
Control
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BENEFIT OF REHABILITATION ON HOSPITALISATIONGriff
iths T et al Lancet 2000

• Reduction of LOS
• No reduction in hospital admissions
• Fewer primary care visits

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RCT OF HOME NIV VERSUS LONG TERM OXYGEN THERAPY
(LTOT) McEvoy et al Thorax 2009
P 0.045 for ITT P 0.0036 for PP
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No Caption Found
UPPER LOBE EMPHYSEMA AND LUNG VOLUME REDUCTION S
URGERY
Hunsaker, A. R. et al. N Engl J Med 20033482091
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EFFECT OF LUNG VOLUME REDUCTION ON
EXACERBATIONS Washko et al AJRCCM2008
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EFFECT OF LUNG VOLUME REDUCTION ON
EXACERBATIONSWashko et al AJRCCM 2008

• Surgical cohort showed a 30 reduction in
  exacerbation frequency (p0.0005)
• Greatest effect with improvement in FEV1
• Time to 1st exacerbation increased in patients
  with and without history of exacerbations
• No evidence that LVRS affects airway inflammation
• Possible mechanisms, reduction in dyspnoea,
  effect on mucous secretion

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RATIO INCIDENCE OF MI POST EXACERBATION TO
INCIDENCE IN STABLE STATEDonaldson et al Chest
in press
2.27 (1.1-4.7) increased risk at day 1-5
P0.029
Days post exacerbation
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CHALLENGES IN MANAGING EXACERBATIONS

• Prospective exacerbation detection and
  presentation
• New therapies for greater reduction of
  exacerbation frequency and severity
• Faster exacerbation recovery and preventing
  recurrence
• Which phenotype of COPD patients respond best to
  preventative exacerbation therapy?
• Exacerbations in mild COPD
• Statistical analysis of exacerbations is complex