Apichart Khanichap MD. Department of Medicine, Faculty of Medicine, Thammasat University
Definition of COPD www.themegallery.com <ul><li>Its pulmonary component is characterized by  airflow limitation that is no...
 
Future trend of COPD: Development of mortality worldwide Murray CJL, Lopez AD. Lancet. 1997;349;1269-76. Diseases 1990 Dis...
Prevalence of COPD: geographical variation <ul><li>Global 3.9% 1 </li></ul><ul><li>Europe 4 –6% 2 </li></ul><ul><li>United...
Worldwide burden of COPD: Asia-Pacific 1. Ko FW et al.  Int J Tuberc Lung Dis  2008; 12: 713–717. Asia-Pacific study area ...
<ul><li>Relieve symptoms  </li></ul><ul><li>Prevent disease progression </li></ul><ul><li>Improve exercise tolerance </li>...
 
 
Health status changes following  an exacerbation Spencer et al. Thorax 2003 *at presentation with acute exacerbation 30 35...
Therapy at Each Stage of COPD * Company name www.themegallery.com *  Postbronchodilator FEV 1  is recommended for the diag...
COPD: a multi-component airway disease Mucociliary dysfunction Airway inflammation Airflow limitation Systemic component S...
COPD is a Disease Characterised  by Inflammation Reproduced from  The Lancet , Vol 364, Barnes PJ & Hansel TT, &quot;Prosp...
Inflammation and Airway Destruction Normal COPD Reproduced from  The Lancet , Vol 364, Hogg JC. &quot;Pathophysiology of a...
Volume of Airway Wall Tissue Correlates Significantly with Disease Progression Hogg et al.  New Engl J Med.  2004;350:2645...
Inflammation in COPD occurs even in the early stages Hogg et al. N Engl J Med 2004  0 20 40 60 80 100 Neutrophils Macropha...
Anti-inflammatory effects of salmeterol/fluticasone propionate in chronic obstructive lung disease End of double-blind pha...
Summary - absolute changes in biopsy endpoints -500 -300 0 100 SALM/FP 50/500 – placebo (cells/mm 2 ) -100 -400 -200 CD8 p...
Sputum: neutrophil differential count  * Adjusted for multiplicity (p=0.01 unadjusted) 0 74 76 78 80 82 84 86 Placebo   (n...
www.themegallery.com Adjusted mean changes from baseline in prebronchodilator FEV 1 Barnes NC et al. AJRCCM 2006 0 0 1 2 3...
 
 
What do COPD patients die from? Mannino. Respir Med 2006 ASCVD=atherosclerotic cardiovascular disease 5.4 COPD deaths per ...
Effects of fluticasone with or without salmeterol on systemic biomarkers of inflammation in COPD + p=0.016 comparison plac...
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
Circulating SP-D levels related to changes in health status scores in COPD Change in circulating SPD in quintiles (median ...
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 R...
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 ....
N Engl J Med 2004;350:1005
 
TOwards a Revolution in COPD Health – the TORCH trial
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 ...
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 (week...
Primary analysis: all-cause mortality at 3 years TORCH FEB 07 Vertical bars are standard errors 1524 1533 1464 1487 1399 1...
Rate of moderate and severe exacerbations over three years TORCH FEB 07 *p < 0.001 vs placebo;  † p = 0.002 vs SALM;  ‡ p ...
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 (uni...
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...
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 R...
Age and rates of decline in FEV1 <ul><li>Celli BR et al.  Am J Respir Crit Care Med  2008; 178: 332–338   </li></ul>
% Predicted FEV1 and rates of decline in FEV1 Rate of FEV1 decline (ml/yr) <ul><li>Celli BR et al.  Am J Respir Crit Care ...
Exacerbations occur even in patients with FEV 1  ≥ 50% predicted O’Reilly et al. COPD4 2004 Number of exacerbations vs. FE...
TORCH : Exacerbation rate (patients with FEV1> 50% pred) Jone P. presented in APSR 2008
UPLIFT study design 1. Decramer M  et al. J COPD  2004; 1: 303–312.  All study medications delivered via HandiHaler ®  dev...
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; 35...
UPLIFT: endpoints  <ul><li>Co-primary Endpoints </li></ul><ul><ul><li>Yearly rate of decline in the morning pre-dose  FEV ...
Co-primary UPLIFT endpoint: yearly rate of decline in pre-dose FEV 1   <ul><li>Rate of decline in mean FEV 1  before and a...
UPLIFT: Post bronchodilator FEV 1  decline (ITT population) Placebo Tiotropium p=0.21 1. Tashkin DP  et al. N Engl J Med  ...
UPLIFT: rate of decline in health-related quality of life (SGRQ)  1. Tashkin DP  et al. N Engl J Med  2008; 359: 1543–54. ...
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 UPLI...
UPLIFT: all-cause mortality 1. Tashkin DP  et al. N Engl J Med  2008; 359: 1543–54. Years Mortality at 1470 days: Predefin...
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 ...
INSPIRE  Wedzicha JA, et al. AJRCCM 2008;177:19-26
A 2 year multicenter, randomized, double-blind, double dummy controlled trial   2 week Run-in 2-years treatment Oral predn...
Wedzicha JA, et al. AJRCCM 2008;177:19-26 Rate of HCU exacerbations
All Cause Mortality Time to death on treatment from Cox’s proportional hazards model ** *  Includes all patients for whom ...
Wedzicha JA, et al. AJRCCM 2008;177:19-26 Time to death on treatment in SFC and TIO 52% risk reduction p=0.012
All cause mortality Wedzicha JA, et al. AJRCCM 2008;177:19-26
Pneumonia reported Wedzicha JA, et al. AJRCCM 2008;177:19-26 *Includes events of pneumonia, lobar pneumonia and bronchopne...
COPD treatment: Overview 1. Calverley PMA et al.  N Engl J Med  2007; 356: 775–789.  2.  Wedzicha JA et al . Am J Crit Car...
Conclusion <ul><li>COPD treatment paradigm has change  from symptomatic to prevention </li></ul><ul><li>Anti-inflammatory ...
 
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TAEM10: How To Help Copd Patients Feel Better And

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  • TAEM10: How To Help Copd Patients Feel Better And

    1. 1. Apichart Khanichap MD. Department of Medicine, Faculty of Medicine, Thammasat University
    2. 2. Definition of COPD www.themegallery.com <ul><li>Its pulmonary component is characterized by airflow limitation that is not fully reversible . </li></ul><ul><li>The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases. </li></ul><ul><li>COPD is a preventable and treatable disease with some significant extrapulmonary effects that may contribute to the severity in individual patients </li></ul>GOLD 2008
    3. 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
    4. 5. Prevalence of COPD: geographical variation <ul><li>Global 3.9% 1 </li></ul><ul><li>Europe 4 –6% 2 </li></ul><ul><li>United States 3.6% 3,4 </li></ul><ul><li>Latin America ~15% of adults over 40 years 5 </li></ul><ul><li>Asia Pacific 6.3% 6 </li></ul>1. Murray et al. Science 1996. 2. European White Lung Book, 2003. 3. American Lung Association Report, 2005. 4. U.S Census Bureau. www.census.gov (accessed February 2006). 5. Hallal et al. Poster presented at ATS 2005. 6. Chan-Yeung et al. Int J Tuberc Lung Dis 2004.
    5. 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
    6. 7. <ul><li>Relieve symptoms </li></ul><ul><li>Prevent disease progression </li></ul><ul><li>Improve exercise tolerance </li></ul><ul><li>Improve health status </li></ul><ul><li>Prevent and treat complications </li></ul><ul><li>Prevent and treat exacerbations </li></ul><ul><li>Reduce mortality </li></ul><ul><li>Prevent and minimize side effects from treatment </li></ul>GOALS of COPD MANAGEMENT VARYING EMPHASIS WITH DIFFERING SEVERITY
    7. 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
    8. 11. Therapy at Each Stage of COPD * Company name www.themegallery.com * Postbronchodilator FEV 1 is recommended for the diagnosis and assessment of severity of COPD GOLD 2008 I: Mild II: Moderate III: Severe IV: Very Severe <ul><li>FEV 1 /FVC < 0.7 </li></ul><ul><li>FEV 1  80% predicted </li></ul><ul><li>FEV 1 /FVC < 0.7 </li></ul><ul><li>50% ≤ FEV 1 < 80% predicted </li></ul><ul><li>FEV 1 /FVC < 0.7 </li></ul><ul><li>30% ≤ FEV 1 < 50% predicted </li></ul><ul><li>FEV 1 /FVC < 0.7 </li></ul><ul><li>FEV 1 <30% predicted or FEV 1 < 50% predicted plus chronic respiratory failure </li></ul>Active reduction of risk factor(s); influenza vaccination Add short-acting bronchodilator (when needed) Add regular treatment with one or more long-acting bronchodilators (when needed); Add rehabilitation Add inhaled glucocorticosteroids if repeated exacerbations Add long-term oxygen if chronic respiratory failure Consider surgical treatments
    9. 12. COPD: a multi-component airway disease Mucociliary dysfunction Airway inflammation Airflow limitation Systemic component Structural changes
    10. 13. COPD is a Disease Characterised by Inflammation Reproduced from The Lancet , Vol 364, Barnes PJ & Hansel TT, &quot;Prospects for new drugs for chronic obstructive pulmonary disease&quot;, 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
    11. 14. Inflammation and Airway Destruction Normal COPD Reproduced from The Lancet , Vol 364, Hogg JC. &quot;Pathophysiology of airflow limitation in chronic obstructive pulmonary disease&quot;, pp709-721. Copyright © 2004, with permission from Elsevier. These images airway destruction in COPD. Airway Narrowing, Collagen, Mucus, Small Airway
    12. 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
    13. 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
    14. 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
    15. 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
    16. 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
    17. 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
    18. 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
    19. 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 +*
    20. 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
    21. 26. Circulating SP-D levels related to changes in health status scores in COPD Change in circulating SPD in quintiles (median values in ngml 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.
    22. 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
    23. 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
    24. 29. N Engl J Med 2004;350:1005
    25. 31. TOwards a Revolution in COPD Health – the TORCH trial
    26. 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
    27. 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
    28. 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%
    29. 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
    30. 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 ††
    31. 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)
    32. 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
    33. 39. Age and rates of decline in FEV1 <ul><li>Celli BR et al. Am J Respir Crit Care Med 2008; 178: 332–338 </li></ul>
    34. 40. % Predicted FEV1 and rates of decline in FEV1 Rate of FEV1 decline (ml/yr) <ul><li>Celli BR et al. Am J Respir Crit Care Med 2008; 178: 332–338 </li></ul>
    35. 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
    36. 42. TORCH : Exacerbation rate (patients with FEV1> 50% pred) Jone P. presented in APSR 2008
    37. 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
    38. 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
    39. 45. UPLIFT: endpoints <ul><li>Co-primary Endpoints </li></ul><ul><ul><li>Yearly rate of decline in the morning pre-dose FEV 1 from day 30 (steady state) until completion of double-blind treatment </li></ul></ul><ul><ul><li>Yearly rate of decline in post-bronchodilator FEV 1 from day 30 until completion of double-blind treatment. </li></ul></ul><ul><li>Secondary Endpoints </li></ul><ul><ul><li>Adverse events </li></ul></ul><ul><ul><li>Exacerbations </li></ul></ul><ul><ul><li>Hospitalisations due to exacerbations </li></ul></ul><ul><ul><li>Spirometric other than co-primaries </li></ul></ul><ul><ul><li>St George’s Respiratory Questionnaire </li></ul></ul><ul><ul><li>Mortality at 1470 days (all-cause and lower respiratory) </li></ul></ul>1. Tashkin DP et al. N Engl J Med 2008; 359: 1543–54.
    40. 46. Co-primary UPLIFT endpoint: yearly rate of decline in pre-dose FEV 1 <ul><li>Rate of decline in mean FEV 1 before and after bronchodilation beginning on day 30 </li></ul>1. Tashkin DP et al. N Engl J Med 2008; 359: 1543–54. 1.50 1.40 1.30 1.20 1.10 1.00 0.00 FEV 1 (litres) 0 1 6 12 18 24 30 36 42 48 Month Day 30 Tiotropium (n=2516) Placebo (n=2374) Tiotropium (n=2494) Placebo (n=2363) Before bronchodilation After bronchodilation p=0.95 p=0.21 CRM: Concomitant respiratory medication * * * * * * * * * * * * * * * * * *
    41. 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)
    42. 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
    43. 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.).
    44. 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
    45. 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
    46. 52. INSPIRE Wedzicha JA, et al. AJRCCM 2008;177:19-26
    47. 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
    48. 54. Wedzicha JA, et al. AJRCCM 2008;177:19-26 Rate of HCU exacerbations
    49. 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
    50. 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
    51. 57. All cause mortality Wedzicha JA, et al. AJRCCM 2008;177:19-26
    52. 58. Pneumonia reported Wedzicha JA, et al. AJRCCM 2008;177:19-26 *Includes events of pneumonia, lobar pneumonia and bronchopneumonia
    53. 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
    54. 60. Conclusion <ul><li>COPD treatment paradigm has change from symptomatic to prevention </li></ul><ul><li>Anti-inflammatory therapy with salmeterol/fluticasone </li></ul><ul><ul><li>Reduces exacerbation </li></ul></ul><ul><ul><li>Maintains improvement in health status </li></ul></ul><ul><ul><li>Slows loss of FEV1 </li></ul></ul><ul><ul><li>Reduces mortality </li></ul></ul><ul><li>Salmeterol/fluticasone are also seen in milder patients </li></ul><ul><ul><li>Without frequent exacerbations </li></ul></ul><ul><ul><li>FEV1 50-60% predicted (GOLD stage II) </li></ul></ul>

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