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INTERVENTIONS IN COPD EXACERBATIONS: HOW DO THEY WORK?

Professor Wisia Wedzicha University College London, UK. INTERVENTIONS IN COPD EXACERBATIONS: HOW DO THEY WORK?. EXACERBATION METRICS. Exacerbation frequency – no/year Exacerbation severity Exacerbation length/recovery/days Time to the next exacerbation

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INTERVENTIONS IN COPD EXACERBATIONS: HOW DO THEY WORK?

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  1. Professor Wisia Wedzicha University College London, UK INTERVENTIONS IN COPD EXACERBATIONS: HOW DO THEY WORK?

  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. 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. 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. 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

  6. INSPIRE STUDY – Exacerbation rates – HCU and Symptom defined

  7. Importance of Unreported ExacerbationsWilkinson et all AJRCCM 2004 Rho = -0.22, p = 0.018 = SGRQ Total < 25% > 75% % Exacerbations Treated

  8. From Wedzicha, JA, Seemungal T Lancet 2007

  9. REDUCTION IN EXACERBATION TRIGGERS Smoking cessation Vaccination Anti –virals Pollution control Occupational factors? Long term antibiotics? Immunostimulants?

  10. 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 < 0.001 vs placebo; †p = 0.002 vs SALM; ‡p = 0.024 vs FP

  11. LOWER DOSE 250/50 SFC AND SALMETEROL Ferguson et al Resp Med 2008

  12. UPLIFT STUDY – EFFECT ON EXACERBATIONS 14% Reductionin Risk Hazard ratio = 0.86, (95% CI, 0.81-0.91) p < 0.001 (log-rank test) Tashkin et al NEJM 2008

  13. EFFECT OF TIOTROPIUM ON EXACERBATIONS Powrie et al ERJ2007

  14. UPLIFT – FURTHER SUB- ANALYSIS Lancet 2009

  15. INSPIRE STUDY - SFC and TIO have similar magnitude of effect on exacerbation frequency 6 4 Rate of Healthcare Utilisation Exacerbations 2 0 SFC 50/500 TIO 18 Wedzicha JA, et al. AJRCCM 2008

  16. 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

  17. RESULTS: TIME TO FIRST PNEUMONIA Calverley P et al, ATS 2008

  18. 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

  19. ECLIPSE - DISTRIBUTION OF OBSERVED EXACERBATIONS DURING YEAR 1 BY PRIOR EXACERBATION HISTORY FOR GOLD STAGES 3-4Wedzicha et al Presented at ATS 2009

  20. ISOLDE - EXACERBATIONS AND INHALED STEROIDS Jones et al ERJ 2004 EFFECT OF EXACERBATION FREQUENCY P=0.022 0.01 0.02 NS

  21. Tiotropium + Fluticasone/Salmeterol Tiotropium + Placebo Tiotropium + Salmeterol 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

  22. Patients had chronic bronchitis Exacerbation history Lancet 2009

  23. EXACERBATION FREQUENCY AND BACTERIAL COLONIZATIONPatel 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 <2.58 per year(n=14) >2.58 per year(n=14) Exacerbation frequency

  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. 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. MACROLIDES – TIME TO 1ST EXACERBATION Seemungal et al AJRCCM 2008 ERYTHROMYCIN PLACEBO

  27. Symptom Duration is responsive to Therapy (Macrolide Study) Seemungal et al. AJRCCM 2008

  28. Bacteriophages Antimicrobial peptides Antivirals: siRNA Bacteria Viruses NF-κB activation IKK2 inhibitors Anti-TNF PDE4, p38 MAPK inhibitors TNF-α CXCL8, CXCL5 CXCR2 antagonists ↑ Neutrophils BLT1 antagonists Oxidative stress Antioxidants POTENTIAL TARGETS FOR EXACERBATION THERAPY Courtesy of Prof Peter Barnes

  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. SIGNIFICANCE OF TREATMENT DELAY AND RECOVERY TIME Wilkinson et al AJRCCM 2004

  31. SYMPTOM ONSET AND EARLY START OFTHERAPY 24 P<0.001 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. 2004;169:1298-1303.

  32. Thorax 2008 Treatment Control

  33. BENEFIT OF REHABILITATION ON HOSPITALISATIONGriffiths T et al Lancet 2000 • Reduction of LOS • No reduction in hospital admissions • Fewer primary care visits

  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. No Caption Found UPPER LOBE EMPHYSEMA AND LUNG VOLUME REDUCTION SURGERY Hunsaker, A. R. et al. N Engl J Med 2003;348:2091

  36. EFFECT OF LUNG VOLUME REDUCTION ON EXACERBATIONS Washko et al AJRCCM2008

  37. EFFECT OF LUNG VOLUME REDUCTION ON EXACERBATIONSWashko 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. 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 P=0.029 Days post exacerbation

  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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