1. Can We offer COPD Patients better life? ครรชิต ปิยะเวชวิรัตน์ แผนกโรคปอดและเวชบำบัดวิกฤต รพ . พระมงกุฎเกล้า 24 พ . ค . 51

4. World’s Top Ten Killers: WHO

5. World’s Top Ten Killers: WHO

6. Of the six leading causes of death in the United States, only COPD has been increasing steadily since 1970 Source : Jemal A. et al. JAMA 2005

8. Chiangmai INNER CITY Population COPD Prevalence 2004 ( n=553/66,000) Chaicharn Pothirat et al. Chiangmai Lung Health Study 2004 0% Smokers 11.2% Non-smokers 0.55% COPD 3.7% Asthma 10%

9. Pack-years and diseases Chaicharn P et al. WAM 2004 0 5-15 15-30 30-70 pack-yrs Chronic smokers of Chiang Daw elderly club 0/108 7/75 14/110 47/224 Chiang Daw COPD in population

10. The prevalence of COPD among at risk smokers 21 / 185 ( 11.4 %) Chaicharn P et al. WAM 2004 OR=1.71 (0.69-4.25) Mean pack-yrs 24.7 26.3

11. Chaicharn P et al. WAM 2004 N=209 Frequency of Hospitalized Exacerbation during the past year

12. Healthcare Resource Burden 1 yr hospitalization May 2003-2004(n=271 episodes) M:F 44.6%:55.4% Age 70.33 + 9.33 yr Cause of admission AECOPD 153 (56.5%) CAP 39(14.4%) Others 29(29.3%) LOS 11.7 + 9.57 d MV use 218/271(80.4%) MV duration 7.6(1-44) d Direct hospital cost(bill)(n265) 52,229.8 (1,122-352,500) Universal coverage 149(55%) goverment insurance 91(33.6%) Dead /expected dead 71(26.2%) Chaicharn Pothirat et al. Economic impact study of COPD2004

13. N 153 39 LOS 10.25 + 8.6 16.92 + 13.14 0.004 Hosp charge * 41217 + 39,385 94,884 + 87,315 0.004 Dead 17.7 41.0 0.002 Healthcare Resource Burden 1 yr hospitalization study May2003-2004 AECOPD COPD pneumonia p-value * Cost-to-Charge ratio > 0.80 Chaicharn Pothirat et al. Economic impact study of COPD2004

16. Risk Factors for COPD Nutrition Infections Socio-economic status Aging Populations

17. 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 55 (severe COPD)

18. Loss of connective tissue support results in dynamic airway collapse

19. Pathophysiological features of COPD Mucus hyper-secretion Increased mucus viscosity Reduced mucociliary transport Mucosal damage Muco-ciliary Dysfunction Mucociliary dysfunction Airway inflammation Systemic component Structural changes Airflow limitation

20. หลอดลมของผู้ป่วยที่ไม่ใช่ COPD

21. หลอดลมของผู้ป่วย COPD

22. Mucociliary dysfunction Healthy H. influenzae

23. Pathophysiological features of COPD Increased numbers / activation: Neutrophils Macrophages CD8+ Elevated: IL-8, TNF- α , LTB4 Protease/anti-protease imbalance Mucosal edema Airway Inflammation Mucociliary dysfunction Airway inflammation Systemic component Structural changes Airflow limitation

24. Pathophysiological features of COPD Airway obstruction Smooth muscle contraction Increased cholinergic tone Bronchial hyperreactivity? Loss of elastic recoil Normal COPD

25. Pathophysiological features of COPD Systemic Component Mucociliary dysfunction Airway inflammation Systemic component Structural changes Airflow limitation

26. Respiratory system Target organs Systemic inflammation

27. Cardiac risk factors* in COPD patients *adjusted for age, sex, BMI, smoking status, race and comorbidity (Data are mean +/- SEM) Sin D and Man P. Circulation 2003 3 4 5 6 7 Neutrophils (10 3 /µL) 400 2.5 0 0.5 1 1.5 2 CRP (mg/dL) STAGE 3- 4 STAGE 2 STAGE 1 NORMAL COPD severity 400 200 250 300 350 Platelets (10 3 /µL) 250 300 350 Fibrinogen (mg/dL)

28. Skeletal muscle apoptosis in COPD Agustí AGN et al. Eur Respir J 2000 COPD patient Healthy control

29. Prevalence of osteoporosis in COPD Bolton. Am J Respir Crit Care Med 2004 FEV 1 <50% pred n=46 FEV 1 >50% pred n=35 Healthy subjects n=38 Percentage of subject group

30. Osteoporosis in COPD Low BMI low FFMI n=16 Normal BMI low FFMI n=17 Normal BMI Normal FFMI n=44 Healthy subjects n=38 Percentage of subject group Bolton. Am J Respir Crit Care Med 2004

34. Disease progress vs Exacerbation Progression Exacerbation

35. COPD: Progressive Disease อาการ / lung function ระยะเวลา Normal daily activity Acute exacerbation

36. Outcome of COPD exacerbations Seneff et al. JAMA 1995 Murata et al. Ann Emerg Med 1991 Adams et al. Chest 2000 Patil et al. Arch Intern Med 2003 Percent of patients 2.5%-10% (within 5 days) Hospital mortality In hospitalized patients 22%-32% (within 14 days) Relapse (repeat ER visit) In ER patients 24% (within 1 year) Hospital mortality In ICU patients 13%-33% (within 14 days) Treatment failure rate In outpatients

56. TO wards a R evolution in C OPD H ealth - the TORCH trial

57. TORCH: study design 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) Calverley et al . NEJM 2007

58. Worldwide participation in TORCH 42 countries

62. Premature study drug discontinuation 0 4 8 12 16 20 24 28 32 36 40 44 48 0 12 24 36 48 60 72 84 96 108 120 132 144 156 Probability of withdrawal (%) Placebo 1524 1521 1534 1533 Number at risk 1141 1240 1247 1296 1005 1093 1112 1164 884 986 971 1042 Time to withdrawal from study medication (weeks) SFC Statistical comparisons: SALM/FP, SAL & FP vs placebo p < 0.001; SALM/FP vs SAL p = 0.048; SALM/FP vs FP p = 0.01 Vertical bars are standard errors Calverley et al. NEJM 2007 SALM FP

63. Primary analysis: all-cause mortality at 3 years 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%

65. Impact of smoking cessation programme on mortality All-cause 14.5 year survival from the Lung Health Study (LHS) Anthonisen et al . Ann Intern Med 2005 1.00 0.95 0.90 0.85 0.80 Proportion of patients with no event 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Time since LHS baseline (years) Special intervention group Usual care group 15%

68. Secondary and other efficacy endpoints

70. 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

71. Rate of exacerbations requiring systemic corticosteroids over three years *p < 0.001 vs placebo; † p < 0.001 vs SALM; ‡ p = 0.017 vs FP 0.64 * 0.52 * Mean number of exacerbations/year 0.46 * †‡ 43% reduction 0.80 0 0.2 0.4 0.6 0.8 1 1.2 Placebo SALM FP SFC Treatment Calverley et al. NEJM 2007

72. Exacerbations requiring hospitalisation over three years *p = 0.016 vs placebo; † p = 0.028 vs placebo Mean number of exacerbations/year 0.19 0.16 * 0.17 0.16 † 0 0.05 0.1 0.15 0.2 0.25 Placebo SALM FP SFC Treatment

73. SGRQ total score – 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 ††

74. Post-bronchodilator FEV 1 Adjusted mean change FEV 1 (mL) 0 24 48 72 96 120 156 Time (weeks) Calverley et al. NEJM 2007 – 150 – 100 – 50 0 50 100 Placebo SALM FP * * * † SFC 1524 1521 1534 1533 1248 1317 1346 1375 Number of subjects 1128 1218 1230 1281 1049 1127 1157 1180 979 1054 1078 1139 906 1012 1006 1073 819 934 908 975 *p < 0.001 vs placebo; † p < 0.001 vs SALM and FP

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

78. 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 μ g b.d. Tiotropium bromide 18 μ g o.d. via Handihaler (n=665) SFC 50/500 μ g b.d. via Accuhaler (n=658) Study design Discontinued all existing COPD maintenance medications Wedzicha JA, et al. AJRCCM 2008;177:19-26

80. Patient characteristics Wedzicha JA, et al. AJRCCM 2008;177:19-26 * Baseline following treatment intensification period

81. Time to withdrawal on treatment in SFC and TIO Cox Hazard Ratio 95% CI p-value TIO vs SFC 1.29 (1.08 – 1.54) 0.005 Probability of withdrawal prior to wk 104 SFC 34.5% TIO 41.7% More subjects withdrew from the TIO arm Wedzicha JA, et al. AJRCCM 2008;177:19-26 Number at Risk 0 13 26 39 52 65 78 91 104 0 4 8 12 16 20 24 28 32 36 40 44 Probability of withdrawing (%) Time to withdrawal (weeks) Treatment SFC 50/500 TIO 18

82. Rate of exacerbations (mean no./year) Wedzicha JA, et al. AJRCCM 2008;177:19-26 HCU = Health care utilization 0.028 1.19 (1.02 to 1.38) 0.82 0.97 Requiring antibiotics 0.039 0.81 (0.67 to 0.99) 0.85 0.69 Requiring oral corticosteroids 0.656 0.97 (0.84 to 1.12) 1.32 1.28 HCU P value Rate Ratio (95% CI) TIO 18 (n=665) SFC 50/500 (n=658) Variable

83. Quality of Life (Total SGRQ score over 2 years) Wedzicha JA, et al. AJRCCM 2008;177:19-26 The total SGRQ was significantly lower in the SFC group compared with the tiotropium group, although this difference did not reach the minimum clinically importance difference SGRQ = St. George’s Respiratory Questionnaire

84. Health status: Total SGRQ score Wedzicha JA, et al. AJRCCM 2008;177:19-26 The proportion of patients achieving a clinically significant improvement in SGRQ was greater in the SFC group than in the Tio group SGRQ = St. George’s Respiratory Questionnaire 1.29 1.34 1.29 1.24 Odds ratio (SFC vs TIO) 193 (32%) 198 (33%) 194 (32%) 211 (35%) SFC (N=658) 169 (27%) 171 (27%) 180 (29%) 190 (30%) TIO (N=665) 0.021 1.04, 1.60 Week 104 0.008 1.08, 1.67 Week 80 0.021 1.04, 1.60 Week 56 0.045 1.01, 1.54 Week 32 p-value 95% CI SGRQ – number of patients (%) with a change from baseline ≥ 4 units

85. 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 0.032 38 (6%) 21 (3%) Number of deaths* p-value TIO 18 SFC 50/500 0.012 (0.27 to 0.85) 0.48 SFC vs TIO p-value 95% CI Hazard Ratio

86. Time to death on treatment in SFC and TIO Number at Risk 0 13 26 39 52 65 78 91 104 0 1 2 3 4 5 6 7 Probability of death (%) Time to death (Weeks) Treatment SFC TIO 52% risk reduction p=0.012 Wedzicha JA, et al. AJRCCM 2008;177:19-26 0.012 (0.27, 0.85) 0.48 SFC vs TIO p-value 95% CI Hazard Ratio

87. Summary of events associated with death * , n (%) Wedzicha JA, et al. AJRCCM 2008;177:19-26 * Deaths can be associated with more than one adverse event 19 (3) 6 (<1) 7 (1) 2 (<1) 0 2 (<1) 0 1 (<1) 0 9 (1) 5 (<1) 2 (<1) 5 (<1) 4 (<1) 1 (<1) 2 (<1) 0 1 (<1) Cardiac disorders Respiratory, thoracic and mediastinal disorders Neoplasms benign, malignant and unspecified General disorders & administration site conditions Infections and infestations Nervous system disorders Vascular disorders Gastrointestinal disorders Hepatobiliary disorders TIO 18 (n = 665) SFC 50/500 (n = 658) Events (grouped by body system)

88. Top 5 most commonly reported AEs that began during treatment, n (%) *Includes events of pneumonia, lobar pneumonia and bronchopneumonia Wedzicha JA, et al. AJRCCM 2008;177:19-26 414 (62) 104 (16) 98 (15) 60 (9) 24 (4) 26 (4) 435 (66) 122 (19) 115 (17) 48 (7) 50 (8) 34 (5) All events COPD Nasopharyngitis Headache Pneumonia* Pharyngolaryngeal pain TIO 18 (n = 665) SFC 50/500 (n = 658)

92. Thank you for your attention