1. A 1 Physician’s Perspective: The Impact

2. A 2 Clinician’s Perspective Bartolome R. Celli, MD Professor of Medicine Tufts University Boston, MA

3. A 3 COPD: Presentation Outline COPD mortality and the clinician COPD mortality and the clinician Mortality can be modified in COPD - Oxygen therapy - Smoking cessation - TORCH Mortality can be modified in COPD - Oxygen therapy - Smoking cessation - TORCH Lessons from other fields - Cardiovascular Lessons from other fields - Cardiovascular Useful clinical comparisons Useful clinical comparisons Summary Summary Lessons from yesterday Lessons from today

4. A 4 Age-adjusted Death Rate 0 0.5 1 1.5 2 2.5 3 Proportion of 1970 rate 1970 2002 +103% COPD -63% CHD-Stroke -32% All Causes Adapted from Jemal et al. JAMA. 2005;294:1255-1259.

5. A 5 Lessons from Yesterday

6. A 6 1. NOTT Group. Ann Intern Med 1980 2. MRC Working Party. Lancet 1981 COPD Survival: Oxygen - 21%* * ARR

7. A 7 1. NOTT Group. Ann Intern Med 1980 2. MRC Working Party. Lancet 1981 COPD Survival: Oxygen - 34%* * RRR

8. A 8 Impact of smoking cessation intervention on all-cause mortality: 14.5 year survival from the Lung Health Study (LHS) Anthonisen et al. Ann Intern Med 2005 Special intervention group Usual care group

9. A 9 Impact of smoking cessation intervention on all-cause mortality: 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 0123456789101112131415 Time since LHS baseline (years) Special intervention group Usual care group 15%* * RRR

10. A 10 New Lessons TORCH

11. A 11 Primary Analysis: All-cause Mortality At 3 Years Vertical bars are standard errors 0 2 4 6 8 10 12 14 16 18 01224364860728496108120132144156 Time to death (weeks) Probability of death (%) PlaceboAdvair 500/50 -17.5% NNT = 39 RR Adapted from Calverley, et al. N Engl J Med 2007; 356: 775-789.

12. A 12 Rate of exacerbations requiring systemic corticosteroids *p < 0.001 vs placebo; † p < 0.001 vs SAL; ‡ 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 PlaceboSALFPAdvair 500/50 Treatment Adapted from Calverley, et al. N Engl J Med 2007; 356: 775-789.

13. A 13 Post-bronchodilator FEV 1 Adjusted mean change FEV 1 (mL) 024487296120156 Time (weeks) –150 –100 –50 0 50 100 Placebo SALFP * * *†*† Advair 500/50 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 SAL and FP Calverley, et al. N Engl J Med 2007; 356: 775-789.

14. A 14 SAL Placebo FP Results - SGRQ Total Score -5 -4 -3 -2 0 1 2 3 024487296120156 1149 1148 1155 1133 Number of Subjects 854 906 942 941 781 844 848 873 726 807 814 675 723 751 773 635 701 686 731 569 634 629 681 Adjusted mean Change SGRQ Total Score (Units) Advair 500/50 Weeks Vertical bars represent standard errors Calverley, et al. N Engl J Med 2007; 356: 775-789.

15. A 15 Candida & dysphonia Eye Effects Bone Effects FEV 1 Quality of Life Exacerbations Survival Favorable Benefit / Risk Profile for Advair 500/50 in COPD Risk Benefit Pneumonia

16. A 16 Lessons from others Cardiovascular trials

17. A 17 CHF: Beta blocker vs Placebo 4.6%* Packer et al NEJM 1996;334:1349 n = 1094 n = 1094 * ARR

18. A 18 CHF: Beta blocker vs Placebo 65%* Packer et al NEJM 1996;334:1349 n = 1094 n = 1094 * RR

19. A 19 Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Artery trial: GUSTO MC, R, in 15 countries MC, R, in 15 countries Four Thrombolytics in MI Four Thrombolytics in MI n = 41,021 n = 41,021 F/U = 30 days F/U = 30 days Deaths = 2870 (7.4%) Deaths = 2870 (7.4%) The GUSTO Investigators. NEJM 1993

20. A 20 1%* The GUSTO Investigators. NEJM 1993 * ARR Thirty-day Mortality in the Four Treatment Groups: GUSTO Trial

21. A 21 10%* NNT = 100 The GUSTO Investigators. NEJM 1993 * RRR Thirty-day Mortality in the Four Treatment Groups: GUSTO Trial

22. A 22 Statins Analysis Studies = 5 (between 4 and 9 thousand) Studies = 5 (between 4 and 9 thousand) Number 30,602 Number 30,602 Mean follow up time of 5.4 years Mean follow up time of 5.4 years Mean Relative Reduction in mortality by 21% (0 to 31%) Mean Relative Reduction in mortality by 21% (0 to 31%) Mean Absolute RR = 1.6 (-0.1, 0.8, 0.9, 3.0, 3.3) Mean Absolute RR = 1.6 (-0.1, 0.8, 0.9, 3.0, 3.3) La Rosa et al. JAMA 1999

23. A 23 Useful Clinical Comparisons Number Needed to Treat

24. A 24 NNT to save 1 life tPA 100 once x 30 days Statins 61 x 5 yrs Advair 500/50 39 x 3 yrs Smoking cessation 62 x 14 yrs Beta-blocker 20 x 6 months Oxygen 5 x 36 months 0255075100

25. A 25 Summary

26. A 26 TORCH FEV1 QOL EXACERBATION St George’s is 3.1 better than placebo and better than baseline 92 ml difference from placebo 25% reduction in Exacerbations Survival

27. A 27 The Future

28. A 28 Age-adjusted Death Rate COPD 1970 Other causes CHD-Stroke 20022020 0 0.5 1 1.5 2 2.5 3 Proportion of 1970 rate