Apichat Kanichap

1. Apichart Khanichap MD. Department of Medicine, Faculty of Medicine, Thammasat University

4. Future trend of COPD: Development of mortality worldwide Murray CJL, Lopez AD. Lancet. 1997;349;1269-76. Diseases 1990 Diseases 2020 1. Coronary disease 1. Coronary disease 2. Stroke 2. Stroke 3. Pneumonia 3. COPD 4. Diarrhea 4. Pneumonia 5. Infant mortality 5. Lung cancer 6. COPD 6. Traffic accident 7. TB 7. TB 8. Measles 8. Stomach cancer 9. Traffic accident 9. HIV/AIDS 10. Lung cancer 10. Suicide

6. Worldwide burden of COPD: Asia-Pacific 1. Ko FW et al. Int J Tuberc Lung Dis 2008; 12: 713–717. Asia-Pacific study area Overall prevalence of COPD (%) 0 2 4 6 8 10 12 Japan Hong Kong China Thailand Taiwan Prevalence assessed using the International Classification of Disease Prevalence assessed by community surveys utilising spirometry

10. Health status changes following an exacerbation Spencer et al. Thorax 2003 *at presentation with acute exacerbation 30 35 40 45 50 55 60 4 Weeks 12 Weeks 26 Weeks 65 No Further Exacerbation Baseline* Further Exacerbation Within 6 months SGRQ Score

12. COPD: a multi-component airway disease Mucociliary dysfunction Airway inflammation Airflow limitation Systemic component Structural changes

13. COPD is a Disease Characterised by Inflammation Reproduced from The Lancet , Vol 364, Barnes PJ & Hansel TT, "Prospects for new drugs for chronic obstructive pulmonary disease", pp985-96. Copyright © 2004, with permission from Elsevier. Cigarette Smoke Epithelial Cells CD8+ Tc Cell Emphysema Proteases Mucus Hypersecretion Macrophage/Dendritic Cell Neutrophil Monocyte Fibroblast Obstructive Bronchiolitis Fibrosis This slide illustrates that COPD is a complex disease with many inflammatory pathways that initiate and potentiate the disease process. CD8+, Cigarette, Emphysema, Epithelial, Macrophage, Monocyte, Mucus, Neutrophil

14. Inflammation and Airway Destruction Normal COPD Reproduced from The Lancet , Vol 364, Hogg JC. "Pathophysiology of airflow limitation in chronic obstructive pulmonary disease", pp709-721. Copyright © 2004, with permission from Elsevier. These images airway destruction in COPD. Airway Narrowing, Collagen, Mucus, Small Airway

15. Volume of Airway Wall Tissue Correlates Significantly with Disease Progression Hogg et al. New Engl J Med. 2004;350:2645-2653. Copyright © 2004 Massachusetts Medical Society. All rights reserved. This graph illustrates the association between total airway wall thickness and lung function (FEV 1 ). Airway Wall Thickness, FEV 1 , GOLD Stage 0 20 40 60 80 100 120 0.25 0.20 0.15 0.10 0.05 0 GOLD Stage 4 FEV 1 V:SA (mm) GOLD Stage 3 GOLD Stage 2 GOLD Stages 0 and 1

16. Inflammation in COPD occurs even in the early stages Hogg et al. N Engl J Med 2004 0 20 40 60 80 100 Neutrophils Macrophages Eosinophils CD4 cells CD8 cells Airways with measurable cells (%) GOLD Stage 0 GOLD Stage 1 GOLD Stage 2 & 3 GOLD Stage 4

17. Anti-inflammatory effects of salmeterol/fluticasone propionate in chronic obstructive lung disease End of double-blind phase = Sputum = Biopsy Run-In Seretide 50/500 μ g bd Randomisation Screen Week: Placebo bd -4 0 4 8 12 13 -1 * * Any previous ICS/OCS withdrawal 4 weeks Barnes et al. Am J Respir Crit Care Med 2006

18. Summary - absolute changes in biopsy endpoints -500 -300 0 100 SALM/FP 50/500 – placebo (cells/mm 2 ) -100 -400 -200 CD8 p=0.015 * CD68 p=0.255 * TNF-  p=0.003 Mast cells p=0.083 *p-value has been adjusted for multiplicity (Data are median, 95% CI) Change favours SALM/FP Change favours placebo Barnes et al. Am J Respir Crit Care Med 2006 IFN-  p=0.026

19. Sputum: neutrophil differential count * Adjusted for multiplicity (p=0.01 unadjusted) 0 74 76 78 80 82 84 86 Placebo (n = 60) Seretide (n = 51) Sputum neutrophil differential counts (%) Baseline Week 13 Week 8 Baseline Week 13 Week 8 p = 0.04* Barnes et al. Am J Respir Crit Care Med 2006

20. www.themegallery.com Adjusted mean changes from baseline in prebronchodilator FEV 1 Barnes NC et al. AJRCCM 2006 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Weeks - 0.1 - 0.05 0 0.1 0.2 0.05 0.15 Adjusted mean change (L) Placebo SALM/FP * * * * * p < 0.001 173 ml

23. What do COPD patients die from? Mannino. Respir Med 2006 ASCVD=atherosclerotic cardiovascular disease 5.4 COPD deaths per 1,000 patient years 9.1 COPD deaths per 1,000 patient years 21.6 COPD deaths per 1,000 patient years 0% 20% 40% 60% 80% 100% GOLD 2/3/4 GOLD 1 No COPD COPD ASCVD Lung Cancer Pneum/Inf Other

24. Effects of fluticasone with or without salmeterol on systemic biomarkers of inflammation in COPD + p=0.016 comparison placebo and fluticasone * p= 0.002 comparison placebo and fluticasone/salmeterol Sin DD, et al. Am J Respir Crit Care Med 2008;177:1207-1214 Placebo (n=39) Fluticasone (n=85) Fluticasone/salmeterol (n=88) P value CRP (mg/L) -0.145 (-1.923 to 1.732) -0.168 (-1.385 to 0.691) 0.074 (-1.205 to 2.674) 0.537 IL-6 (pg/ml) -0.2 (-1.3 to 0.5) 0.1 (-0.6 to 0.9) 0.2 (-0.5 to 1.1) 0.120 SP-D (ng/ml) -1.9 (9.8 to 15.2) -7.3 (-22.8 to -1.1) -12.3 (-28.4 to 0.4) 0.002 +*

25. Circulating SP-D levels related to changes in FEV 1 in COPD Sin DD, et al. Am J Respir Crit Care Med 2008;177:1207-1214

26. Circulating SP-D levels related to changes in health status scores in COPD Change in circulating SPD in quintiles (median values in ngl for each quintile) Test for trend p=0.002 Improved health status Change in total SGRQ score 1 (-39.2) 2 (-19.6) 3 (-8.8) 4 (-1.1) 5 (17.9) 4.0 2.0 0.0 -2.0 -4.0 -6.0 -8.0 Sin DD et al. Am J Respir Crit Care Med 2008; 177: 1207–1214.

27. Survival by lung function impairment Years 12 10 8 6 4 2 0 Survival 1.0 0.9 0.8 0.7 0.6 GOLD 3 or 4 GOLD 2 GOLD 0 Normal Restricted GOLD 1 Mannino et al. Respir Med 2006

28. Survival by respiratory symptoms Mannino et al. Respir Med 2006 0 2 4 6 8 10 12 Follow up in years Survival 1.0 .9 .8 .7 .6 .5 Gold stage 3 or 4 No Symptoms Symptoms

29. N Engl J Med 2004;350:1005

31. TOwards a Revolution in COPD Health – the TORCH trial

32. TORCH: study design TORCH FEB 07 SFC 50/500 µ g bd (N=1533) SAL 50 µg bd (N=1521) Placebo (N= 1524) 3-year study duration 2 week run-in FP 500 µg bd (N=1534) Vestbo et al . Eur Respir J 2004; Calverley et al . NEJM 2007

33. TORCH FEB 07 All-cause mortality at 3 years Vertical bars are standard errors 18 16 14 12 10 8 6 4 2 0 Time to death (weeks) Probability of death (%) 1524 1533 1521 1534 1464 1487 1481 1487 1399 1426 1417 1409 1293 1339 1316 1288 Placebo SFC Number alive 0 12 24 36 48 60 72 84 96 108 120 132 144 156 Calverley et al. NEJM 2007 SALM FP

34. Primary analysis: all-cause mortality at 3 years TORCH FEB 07 Vertical bars are standard errors 1524 1533 1464 1487 1399 1426 1293 1339 Number alive 0 2 4 6 8 10 12 14 16 18 0 12 24 36 48 60 72 84 96 108 120 132 144 156 Time to death (weeks) Probability of death (%) HR 0.825, p=0.052 17.5% risk reduction 2.6% absolute reduction Calverley et al. NEJM 2007 SFC 12.6% Placebo 15.2%

35. Rate of moderate and severe exacerbations over three years TORCH FEB 07 *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

36. SGRQ total score TORCH FEB 07 – 5 – 4 – 3 – 2 – 1 0 1 2 3 0 24 48 72 96 120 156 Adjusted mean change SGRQ total score (units) Time (weeks) Calverley et al. NEJM 2007 Placebo SALM * FP † *p = 0.057 vs placebo; † p < 0.001 vs placebo; †† p < 0.001 vs placebo, SALM and FP; v ertical bars are standard errors Number of subjects 1149 1148 1155 1133 854 906 942 941 781 844 848 873 726 807 807 814 675 723 751 773 635 701 686 731 569 634 629 681 SFC ††

37. Age 40-50 50-55 55-60 60-70 Courtesy of D. O’Donnell. Adapted from Fletcher CM, Peto R. BMJ 1977 FEV 1 (%) Relative to Age 25 Age (years) Death Disability Symptoms 30 40 50 60 70 80 90 0 20 40 60 80 20 100 Not Susceptible Susceptible Smokers Stopped smoking at 45 (mild COPD) Stopped smoking at 65 (severe COPD)

38. SFC slows the rate of decline of lung function over 3 years (TORCH) 1350 1300 1250 1200 1150 1100 Celli BR et al. Am J Respir Crit Care Med 2008; 178: 332–338. FEV 1 (mL) 0 24 48 72 96 120 156 Weeks -39 mL/yr -42 mL/yr -55 mL/yr -42 mL/yr SFC versus placebo: 16 ml/year, p<0.001 Salmeterol versus placebo: 13 ml/year, p=0.003 FP versus placebo: 13 ml/year, p=0.003 Placebo SALM FP SFC

41. Exacerbations occur even in patients with FEV 1 ≥ 50% predicted O’Reilly et al. COPD4 2004 Number of exacerbations vs. FEV 1 % predicted 0 20 40 60 80 100 120 0 5 10 15 20 25 Number of exacerbations FEV 1 % predicted (L) <50% predicted >=50% predicted

42. TORCH : Exacerbation rate (patients with FEV1> 50% pred) Jone P. presented in APSR 2008

43. UPLIFT study design 1. Decramer M et al. J COPD 2004; 1: 303–312. All study medications delivered via HandiHaler ® device. *Patients permitted to use all previously prescribed respiratory medications. No restrictions for medications prescribed for exacerbations. † Active smokers advised to discontinue smoking and offered a smoking cessation program. 37 countries, 475 investigational sites Every 6 Months Spriometry SGRQ Review Patient Diary End of Study Spriometry SGRQ Review Patient Diary Tiotropium 18 mcg QD + concomitant respiratory medications* Placebo QD + concomitant respiratory medications* Ipratropium 30 days 4 years R Screening † Spriometry Randomisation Spriometry SGRQ Review Patient Diary Day 30 Spriometry SGRQ n = 5993

44. Study design: TORCH vs UPLIFT 1 . Tashkin D. Am J Med 2006; 119: S63–72. 2. Calverley PMA et al. N Eng J Med 2007; 356: 775-789. Design TORCH UPLIFT Patients (n) 6,112 5,993 Design – 3 years – 6184 patients (four arms, twice-daily dosing) – Salmeterol 50 mcg – Fluticasone 500 mcg – Fluticasone 500 mcg/salmeterol 50 mcg – Placebo – 4 years – 5993 patients (two arms, once-daily dosing) – TIO 18 mcg – Placebo Primary endpoint All-cause mortality (placebo vs SFC) Rate of lung function decline SGRQ Score 49 ± 17 46 ± 17 Baseline & predicted post-bronchodilator FEV 1 ~44% ~47% Concomitant medication – ICS: 0% – LABA: 0% – Long-term OCS: 0% – Theophylline permitted – ICS: ~75% – LABA: ~70% – Theophylline: ~35% Withdrawals – SFC: 34% – Placebo: 44% – Analysis including withdrawals – Tiotropium: 36% – Placebo: 45% – Analysis including withdrawals

47. UPLIFT: Post bronchodilator FEV 1 decline (ITT population) Placebo Tiotropium p=0.21 1. Tashkin DP et al. N Engl J Med 2008; 359: (Online Suppl.). -45 -40 -35 -30 -25 -20 -15 -10 -5 0 FEV 1 decline (ml/yr)

48. UPLIFT: rate of decline in health-related quality of life (SGRQ) 1. Tashkin DP et al. N Engl J Med 2008; 359: 1543–54. Improvement SGRQ Total Score (units) Placebo (n=2337) Tiotropium (n=2478) 0 35 40 45 50 p=0.78 0 6 12 18 24 30 36 42 48 Month CRM: Concomitant respiratory medication

49. HR 0.86 (95%CI 0.81, 0.91) 14% 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 Exacerbations Number per year Placebo Tiotropium UPLIFT: COPD exacerbations 1. Tashkin DP et al. N Engl J Med 2008; 359: (Online Suppl.).

50. UPLIFT: all-cause mortality 1. Tashkin DP et al. N Engl J Med 2008; 359: 1543–54. Years Mortality at 1470 days: Predefined secondary analysis 20 15 10 5 0 Probability of death from any cause (%) 0 1 2 3 4 Hazard ratio, 0.89 (95% Cl, 0.79-1.02) Tiotropium Placebo p<0.09

51. UPLIFT and TORCH: Mortality UPLIFT 1 TORCH 2 1. Tashkin DP et al. N Engl J Med 2008; 359: 1543–54. 2. Calverley PMA et al. N Engl J Med 2007; 356: 775–789 Tiotropium Placebo Hazard Ratio (HR) N (%) N (%) HR 95% CI P-value ITT 1470 days 446 (14.9) 495 (16.9) 0.89 0.79-1.02 0.086 ITT 1440 days 430 (14.4) 491 (16.3) 0.87 0.76-0.99 0.034 On-treatment 381 (12.8) 411 (13.7) 0.84 0.73-0.97 0.016 SFC Placebo Hazard Ratio (HR) N (%) N (%) HR 95% CI P-value Log-rank adjusted 193 (12.6) 231 (15.2) 0.825 0.68-1.00 0.052 Cox proportional 193 (10.3) 231 (12.6) 0.811 0.67-0.98 0.03

52. INSPIRE Wedzicha JA, et al. AJRCCM 2008;177:19-26

53. A 2 year multicenter, randomized, double-blind, double dummy controlled trial 2 week Run-in 2-years treatment Oral prednisolone 30mg/day + inhaled salmeterol 50  g b.d. Tiotropium bromide 18  g o.d. via Handihaler (n=665) SFC 50/500  g b.d. via Accuhaler (n=658) Study design Discontinued all existing COPD maintenance medications Wedzicha JA, et al. AJRCCM 2008;177:19-26

54. Wedzicha JA, et al. AJRCCM 2008;177:19-26 Rate of HCU exacerbations

55. All Cause Mortality Time to death on treatment from Cox’s proportional hazards model ** * Includes all patients for whom mortality was known during the study ** Time to death on treatment excludes 7 deaths (3 SFC, 4 TIO) which occurred > 2 weeks after treatment cessation Wedzicha JA, et al. AJRCCM 2008;177:19-26 SFC 50/500 TIO 18 Number of deaths* p-value 21 (3%) 38 (6%) 0.032 Hazard Ratio 95% CI p-value SFC vs TIO 0.48 (0.27 to 0.85) 0.012

56. Wedzicha JA, et al. AJRCCM 2008;177:19-26 Time to death on treatment in SFC and TIO 52% risk reduction p=0.012

57. All cause mortality Wedzicha JA, et al. AJRCCM 2008;177:19-26

58. Pneumonia reported Wedzicha JA, et al. AJRCCM 2008;177:19-26 *Includes events of pneumonia, lobar pneumonia and bronchopneumonia

59. COPD treatment: Overview 1. Calverley PMA et al. N Engl J Med 2007; 356: 775–789. 2. Wedzicha JA et al . Am J Crit Care Med 2008; 177: 19–26. SFC treats symptoms and disease progression 1 Tiotropium SFC Reduces inflammation 1,2 X Reduces breathlessness 1,2 Reduces exacerbations 1,2 Slows the rate of decline in lung function 1,2 X Improves and sustains quality of life 1,2 Potential to improve survival 1,2