INTERVENTIONS IN COPD
EXACERBATIONS: HOW DO
THEY WORK?
Professor Wisia Wedzicha
University College London, UK
EXACERBATION METRICS
• Exacerbation frequency – no/year
• Exacerbation severity
• Exacerbation length/recovery/days
• Time...
EXACERBATION SEVERITY
• How is exacerbation severity determined?
– TYPE OF EXACERBATION THERAPY
– SYMPTOM SCORES AND LENGT...
DEFINITIONS
• SYMPTOMATIC
(based on Anthonisen et al Ann Intern Med 1987)
• At least two of: increase in SOB, sputum
purul...
APRIL 1996
DATE 1 2 3 4 5 6 7 8 9 10 11
PEAK FLOW (BEST OF 3 READINGS)
CHANGE IN SYMPTOMS
DATE 12 13 14 15 16 17 18 19 20 ...
INSPIRE STUDY –
Exacerbation rates – HCU and Symptom
defined
SFC
n=641
Tio
n=650
Rate Ratio (CI) P value
HCU
exacerbations...
SGRQ
Total
< 25% > 75%
% Exacerbations Treated
Importance of Unreported Exacerbations
Wilkinson et all AJRCCM 2004
Rho = -...
From Wedzicha, JA, Seemungal T
Lancet 2007
REDUCTION IN
EXACERBATION TRIGGERS
Smoking cessation
Vaccination
Anti –virals
Pollution control
Occupational factors?
Long...
TORCH STUDY DATA - RATE OF
MODERATE AND SEVERE
EXACERBATIONS OVER THREE YEARS
p < 0.001 vs placebo; †
p = 0.002 vs SALM; ‡...
LOWER DOSE 250/50 SFC AND SALMETEROL
Ferguson et al Resp Med 2008
0
20
40
60
80
0 6 12 18 24 30 36 42 48
Probabilityofexacerbation(%)
Tiotropium Control
14% Reduction
in Risk
14% Reduction...
EFFECT OF TIOTROPIUM ON EXACERBATIONS
Powrie et al ERJ2007
UPLIFT – FURTHER SUB- ANALYSIS
Lancet 2009
INSPIRE STUDY - SFC and TIO have similar
magnitude of effect on exacerbation frequency
RateofHealthcareUtilisationExacerba...
RATE OF HEALTHCARE UTILIZATION
EXACERBATIONS
Wedzicha JA, et al. AJRCCM 2008
SFC 50/500
(n=658)
TIO 18
(n=665)
Rate Ratio
...
RESULTS: TIME TO FIRST
PNEUMONIA
Calverley P et al, ATS 2008
TRISTAN STUDY - Calverley et al Lancet 2003
1 exacerbation in previous year
TORCH STUDY – Calverley et al NEJM 2007 – No r...
ECLIPSE - DISTRIBUTION OF OBSERVED
EXACERBATIONS DURING YEAR 1 BY PRIOR
EXACERBATION HISTORY FOR GOLD STAGES 3-4
Wedzicha ...
ISOLDE - EXACERBATIONS AND INHALED STEROIDS
Jones et al ERJ 2004
NS
EFFECT OF EXACERBATION FREQUENCY
P=0.022
0.02
0.01
0.50
0.75
1.00
Days Until First Exacerbation of COPD
0 50 100 150 200 250 300 350
Tiotropium + Fluticasone/Salmeterol
Tiot...
Lancet 2009Patients had chronic bronchitis
Exacerbation history
EXACERBATION FREQUENCY AND
BACTERIAL COLONIZATION
Patel et al. Thorax 2002
Exacerbation frequency
Proportionofpatientswith...
LONG TERM ANTIBIOTICS
• Studies in 1960s showed effect on
“infections”
• Recent Pulse study with pulsed
moxifloxacin – som...
RATIONALE FOR MACROLIDE
USE IN COPD
• Macrolides in vitro may reduce the airway
inflammatory response to rhinovirus (1)
• ...
Time to First Exacerbation (Days)
4003002001000
CumSurvival
1.0
0.8
0.6
0.4
0.2
0.0
MACROLIDES – TIME TO 1ST
EXACERBATION
...
Symptom Duration is responsive to
Therapy (Macrolide Study)
Seemungal et al. AJRCCM 2008
Bacteria VirusesBacteria Viruses
NF-NF-κκB activationB activation
TNF-TNF-αα
CXCL8, CXCL5CXCL8, CXCL5
↑↑ NeutrophilsNeutro...
NON-PHARMACOLOGICAL
INTERVENTIONS
• Smoking cessation
• Home Oxygen Therapy
• Psychological therapies
• Home noninvasive v...
Figure 1
Prodrome
Exacerbation
Onset
Treatment
Delay
Treated Recovery Time
Total Recovery Time
Initiation of
Treatment
SIG...
SYMPTOM ONSET AND EARLY
START OFTHERAPY
P<0.001
Wilkinson et al. Am J Respir Crit Care Med. 2004;169:1298-1303.
Patients w...
Treatment Control
Thorax 2008
BENEFIT OF REHABILITATION ON
HOSPITALISATION
Griffiths T et al Lancet 2000
0
5
10
15
20
25
LOS LOS
Control
Rehab
• Reducti...
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
Hunsaker, A. R. et al. N Engl J Med
2003;348:2091
No Caption Found
UPPER LOBE
EMPHYSEMA
AND LUNG
VOLUME
REDUCTION
SURGERY
EFFECT OF LUNG VOLUME REDUCTION ON EXACERBATIONS
Washko et al AJRCCM2008
EFFECT OF LUNG VOLUME
REDUCTION ON EXACERBATIONS
Washko et al AJRCCM 2008
• Surgical cohort showed a 30% reduction in
exac...
RATIO INCIDENCE OF MI POST EXACERBATION TO
INCIDENCE IN STABLE STATE
Donaldson et al Chest in press
0
1
2
3
4
5
Day 1-5 Da...
CHALLENGES IN MANAGING
EXACERBATIONS
• Prospective exacerbation detection and
presentation
• New therapies for greater red...
COPD EXACERBATIONS
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COPD EXACERBATIONS

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  • ISOLDE / TRISTAN Studies: worsening of resp. symptoms requiring antibiotics or oral steroids
    Symbicort Study: mild – increased use of reliever (&amp;gt;= 4 above baseline at run-in)
    severe – use of oral steroid/antibiotic/hospital admission due to respiratory symptoms
    Tiotropium:new onset or increases at least one of sputum, dyspnoea, wheeze lasting at least 3 days and usually associated with therapeutic intervention.
  • Key point
    There was no significant difference between the two treatments in the annual rate of HCU exacerbations over the course of the study.
    There was no significant difference in the overall annual rate of exacerbations (1.28 vs 1.32; Rate ratio 0.97; 95% CI 0.84, 1.12; p=0.656).1
    Exacerbation rates were analysed using a negative binomial model with the number of exacerbations as the outcome and the log of time on treatment as an offset variable, with covariates of baseline smoking status, disease severity (percent predicted FEV1 at baseline), body mass index, number of exacerbations reported in the previous 12 months prior to screening, age, gender and country.2
    Seemungal TA, Stockley R, Calverley P, et al. Effect of salmeterol/fluticasone propionate versus tiotropium bromide on exacerbations: The INSPIRE study (Investigating New Standards for Prophylaxis In Reduction of Exacerbations). Eur Respir J 2007; 30 (suppl 51): 688s
    Seemungal TA, Stockley R Calverley PM, Hagan G, Wedzicha JA. Investigating New Standards for Prophylaxis in Reduction of Exacerbations – The INSPIRE study methodology. J. COPD 2007; 4 (3): 173 - 184
  • LEGEND
    Effect of early treatment on recovery of exacerbation symptoms. Patient mean total recovery time (days) plotted against patient mean treatment delay (ie, time from onset of exacerbation symptoms to initiation of therapy in days). In 108 patients (regression coefficient 0.42 day/day delay; CI, 0.19-0.65; P&amp;lt;0.001).
    SPEAKER&amp;apos;S NOTES
    Early treatment has a significant impact on COPD exacerbation outcome. Patients who receive prompt therapy after symptom onset are likely to recover more rapidly than are patients whose treatment is delayed. Additionally, patients who do not seek therapy for exacerbations have poorer health-related quality of life and are also more likely to be hospitalized for their exacerbations. For this reason, patient education and collaborative self-management are critical, as they enable patients to initiate treatment as soon as possible.
  • COPD EXACERBATIONS

    1. 1. INTERVENTIONS IN COPD EXACERBATIONS: HOW DO THEY WORK? Professor Wisia Wedzicha University College London, UK
    2. 2. 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
    3. 3. 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
    4. 4. 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 patient’s condition from stable state necessitating a change in regular medication • Used by most studies of therapies in COPD
    5. 5. APRIL 1996 DATE 1 2 3 4 5 6 7 8 9 10 11 PEAK FLOW (BEST OF 3 READINGS) CHANGE IN SYMPTOMS DATE 12 13 14 15 16 17 18 19 20 21 22 PEAK FLOW (BEST OF 3 READINGS) CHANGE IN SYMPTOMS DATE 23 24 25 26 27 28 29 30 PEAK FLOW (BEST OF 3 READINGS) CHANGE IN SYMPTOMS 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 DIARY CARD FOR EAST LONDON COPD COHORT
    6. 6. INSPIRE STUDY – Exacerbation rates – HCU and Symptom defined SFC n=641 Tio n=650 Rate Ratio (CI) P value HCU exacerbations (Rate) 1.28 1.32 0.976 (0.836,1.119) 0.651 Symptom defined exacerbations (Rate) 3.04 3.02 1.006 (0.901,1.123) 0.913
    7. 7. SGRQ Total < 25% > 75% % Exacerbations Treated Importance of Unreported Exacerbations Wilkinson et all AJRCCM 2004 Rho = -0.22, p = 0.018 =
    8. 8. From Wedzicha, JA, Seemungal T Lancet 2007
    9. 9. REDUCTION IN EXACERBATION TRIGGERS Smoking cessation Vaccination Anti –virals Pollution control Occupational factors? Long term antibiotics? Immunostimulants?
    10. 10. TORCH STUDY DATA - RATE OF MODERATE AND SEVERE EXACERBATIONS OVER THREE YEARS p < 0.001 vs placebo; † p = 0.002 vs SALM; ‡ p = 0.024 vs FP Mean number of exacerbations/year 1.13 0.97* 0.93* 0.85*†‡ 25% reduction 0 0.2 0.4 0.6 0.8 1 1.2 Placebo SALM FP SFC Treatment Calverley et al. NEJM 2007
    11. 11. LOWER DOSE 250/50 SFC AND SALMETEROL Ferguson et al Resp Med 2008
    12. 12. 0 20 40 60 80 0 6 12 18 24 30 36 42 48 Probabilityofexacerbation(%) Tiotropium Control 14% Reduction in Risk 14% Reduction in Risk Hazard ratio = 0.86, (95% CI, 0.81-0.91) p < 0.001 (log-rank test) UPLIFT STUDY – EFFECT ON EXACERBATIONS Tashkin et al NEJM 2008
    13. 13. EFFECT OF TIOTROPIUM ON EXACERBATIONS Powrie et al ERJ2007
    14. 14. UPLIFT – FURTHER SUB- ANALYSIS Lancet 2009
    15. 15. INSPIRE STUDY - SFC and TIO have similar magnitude of effect on exacerbation frequency RateofHealthcareUtilisationExacerbations SFC 50/500 TIO 18 0 2 4 6 Wedzicha JA, et al. AJRCCM 2008
    16. 16. RATE OF HEALTHCARE UTILIZATION EXACERBATIONS Wedzicha JA, et al. AJRCCM 2008 SFC 50/500 (n=658) TIO 18 (n=665) Rate Ratio (CI) P value Rate of all HCU exacerbations 1.28 1.32 0.97 (0.84 to 1.12) 0.656 HCU exacerbations requiring oral corticosteroids 0.69 0.85 0.81 (0.67 to 0.99) 0.039 HCU exacerbations requiring antibiotics 0.97 0.82 1.19 (1.02 to 1.38) 0.028 There is a shift in the character of the exacerbations: more antibiotics with SFC, more OCS with tiotropium
    17. 17. RESULTS: TIME TO FIRST PNEUMONIA Calverley P et al, ATS 2008
    18. 18. TRISTAN STUDY - Calverley et al Lancet 2003 1 exacerbation in previous year TORCH STUDY – Calverley et al NEJM 2007 – No requirement for exacerbation P Sal FC SFC
    19. 19. ECLIPSE - DISTRIBUTION OF OBSERVED EXACERBATIONS DURING YEAR 1 BY PRIOR EXACERBATION HISTORY FOR GOLD STAGES 3-4 Wedzicha et al Presented at ATS 2009 GOLD Stage 3-4 0 10 20 30 40 50 60 70 0 1 2 3+ n=559 n=317 n=176 n=150 Exacerbations During 12 Months Prior to Study %ofPatients No exb in Year 1 One exb in Year 1 Two exbs in Year 1 3+ exbs in Year 1
    20. 20. ISOLDE - EXACERBATIONS AND INHALED STEROIDS Jones et al ERJ 2004 NS EFFECT OF EXACERBATION FREQUENCY P=0.022 0.02 0.01
    21. 21. 0.50 0.75 1.00 Days Until First Exacerbation of COPD 0 50 100 150 200 250 300 350 Tiotropium + Fluticasone/Salmeterol Tiotropium + Placebo Tiotropium + Salmeterol ProbabilityofRemaining Exacerbation-Free P = 0.15 OPTIMAL STUDY TIME TO FIRST EXACERBATION Aaron et al Ann Intern Med 2007
    22. 22. Lancet 2009Patients had chronic bronchitis Exacerbation history
    23. 23. EXACERBATION FREQUENCY AND BACTERIAL COLONIZATION Patel et al. Thorax 2002 Exacerbation frequency ProportionofpatientswithLABC <2.58 per year (n=14) >2.58 per year (n=14) -0.2 0.0 0.2 0.4 0.6 0.8 1.0 1.2
    24. 24. 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?
    25. 25. 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; 163:A737 (3) Labro JAC 1989 (4) Kobayachi AJM 1995 (5) Blasi Thorax 2002
    26. 26. Time to First Exacerbation (Days) 4003002001000 CumSurvival 1.0 0.8 0.6 0.4 0.2 0.0 MACROLIDES – TIME TO 1ST EXACERBATION Seemungal et al AJRCCM 2008 ERYTHROMYCIN PLACEBO
    27. 27. Symptom Duration is responsive to Therapy (Macrolide Study) Seemungal et al. AJRCCM 2008
    28. 28. Bacteria VirusesBacteria Viruses NF-NF-κκB activationB activation TNF-TNF-αα CXCL8, CXCL5CXCL8, CXCL5 ↑↑ NeutrophilsNeutrophils Oxidative stressOxidative stress BacteriophagesBacteriophages Antimicrobial peptidesAntimicrobial peptides Antivirals: siRNAAntivirals: siRNA AntioxidantsAntioxidants CXCR2 antagonistsCXCR2 antagonists Anti-TNFAnti-TNF PDE4, p38 MAPK inhibitorsPDE4, p38 MAPK inhibitors IKK2 inhibitorsIKK2 inhibitors BLTBLT11 antagonistsantagonists Courtesy of Prof Peter Barnes POTENTIAL TARGETS FOR EXACERBATION THERAPY
    29. 29. NON-PHARMACOLOGICAL INTERVENTIONS • Smoking cessation • Home Oxygen Therapy • Psychological therapies • Home noninvasive ventilation and oxygen therapy • Pulmonary rehabilitation • ?Management of gastro-oesophageal reflux
    30. 30. Figure 1 Prodrome Exacerbation Onset Treatment Delay Treated Recovery Time Total Recovery Time Initiation of Treatment SIGNIFICANCE OF TREATMENT DELAY AND RECOVERY TIME Wilkinson et al AJRCCM 2004
    31. 31. SYMPTOM ONSET AND EARLY START OFTHERAPY P<0.001 Wilkinson et al. Am J Respir Crit Care Med. 2004;169:1298-1303. Patients who receive prompt therapy after symptom onset are likely to recover more rapidly than are patients whose treatment is delayed 24 18 12 6 0 0 7 14 Delay between onset and treatment (days) Symptomrecoverytime(days)
    32. 32. Treatment Control Thorax 2008
    33. 33. BENEFIT OF REHABILITATION ON HOSPITALISATION Griffiths T et al Lancet 2000 0 5 10 15 20 25 LOS LOS Control Rehab • Reduction of LOS • No reduction in hospital admissions • Fewer primary care visits
    34. 34. 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
    35. 35. Hunsaker, A. R. et al. N Engl J Med 2003;348:2091 No Caption Found UPPER LOBE EMPHYSEMA AND LUNG VOLUME REDUCTION SURGERY
    36. 36. EFFECT OF LUNG VOLUME REDUCTION ON EXACERBATIONS Washko et al AJRCCM2008
    37. 37. EFFECT OF LUNG VOLUME REDUCTION ON EXACERBATIONS Washko et al AJRCCM 2008 • Surgical cohort showed a 30% reduction in exacerbation frequency (p=0.0005) • 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
    38. 38. RATIO INCIDENCE OF MI POST EXACERBATION TO INCIDENCE IN STABLE STATE Donaldson et al Chest in press 0 1 2 3 4 5 Day 1-5 Day 5-10 Day10-15 Day 15-49 Days post exacerbation P=0.029 2.27 (1.1-4.7) increased risk at day 1-5
    39. 39. 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

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