WHAT SHOULD BE THE MARKERS OF AN EFFECTIVE TREATMENT FOR GOLD I-II?

1. WHAT SHOULD BE THE MARKERS OF AN EFFECTIVE TREATMENT FOR GOLD I-II? Prof Dr Nurhayat YILDIRIM

2. Are GOLD I-II important?

3. LATIN AMERICAN STUDY %7.1-18.9

4. ADANA STUDY GOLD phases I II III-IV Male (%) 13.1 13.1 2.3 Female (%) 4.3 5.3 0.7 Total(%) 8.6 9.1 1.5 Total(%) pbFEV1/FVC<%70 19.1 Total (%) pbFEV1/VC<LLN 14.3 Kocabas A, Hancioglu A, Turkyilmaz S, Unalan T, Umut S, Cakir B, Vollmer W, Buist S. Prevalence of COPD in Adana, Turkey (BOLD-Turkey Study). Proceedings of the American Thoracic Society 2006; 3 : A543 

5. Female GOLD II GOLD I Hoogendoorn M. ERJ 2005;26:223-233.

6. Male GOLD II GOLD I Hoogendoorn M. ERJ 2005;26:223-233.

7. EXACERBATIONS FEV1≥%50 FEV1<%50 Jones PW. ERJ 2003;21:68-73.

8. Mortality GOLD 0 1.5 (95% CI, 1.3-1.8) GOLD I 1.4 (95% CI, 1.1-2.8) GOLD II 2.4 (95% CI, 2.0-2.9) GOLD III-IV 5.7 (95% CI, 4.4-7.3) Mannino DM. Respir Med 2006;100:115-122.

9. LHS Study Res Fail CA CVD Mortality risk in smoker stage I and II cases HR 2.04 (1.34-3.11) and 3.16 (1.38-7.23) #Garcia-Aymerich J. Thorax 2003;58:100-105. ¶Celli BR. NEJM 2004;350:1005-1012. +Waterhouse JC. ERJ 1999:14:387s. §Anthonisen NR. Ann Intern Med 2005;142:233-239. Ekberg-Aronsson M. Respir Res 2005;6:98-107.

10. LHS Study S Respiratory Failure DC S D S AC K Cancer CVD #Garcia-Aymerich J. Thorax 2003;58:100-105. ¶Celli BR. NEJM 2004;350:1005-1012. +Waterhouse JC. ERJ 1999:14:387s. §Anthonisen NR. Ann Intern Med 2005;142:233-239.

11. Hoogendoorn M. ERJ 2005;26:223-233.

12. Hoogendoorn M. ERJ 2005;26:223-233.

13. TREATMENT of GOLD I - II

14. IV Very Severe GOLD 2007 III Severe II Moderate I Mild pbd FEV1/FVC < 70 % pbdFEV1>80% 80%>FEV1>50% 50%>FEV1>30%FEV1<30% Chronic respiratory failure or right cardiac failure Symptoms or not Long Term Oxygen Therapy, Surgical Assessment ICS TREATMENT LONG TERMby One or More Long acting BRONCHODILATOR Short acting Bronchodilator if necessary Retreat from risk factors, Flu vaccine, Rehabilitation

15. TREATMENT MARKERS

16. Symptoms: Cough, expectoration, dispnea, Weight loss, Exercise intolerance, İmpaired health-related quality of life, İncreased health resource use, Death Health-rlated Quality of life scores Exercise capacity FEV1, IC, ΔFEV1,DLCO Biological markers Patient-Specific Outcomes “outcome” Markers

17. MRC respiratory Questionnaire MRC Dyspnoea sclae, Borg scale, BDI/TDI CRDQ, SGRQ, BPQ,PFSDQ, PFSS, CCQ SF-36, NHP, EQ-5D Cognitive functions FEV1, IC, DLCO FEV1/FVC normal + lung hyperinflation, ΔFEV1 6DYT BHR Muscle functions CT, PET, hyperpolarised gas MR Exacerbation rate and type Symptomatic markers Physiological markers

18. Expec materyel; Neut, macr, lymp, eo, mast Expec solb; TNF-α, IL-8, ECP, MPO Expec air; NO, CO, H2O2 Expec air cond; LTB4, cytokines Per blood; neut, TNF-α, IL-6, IL-8, CRP Sputum; MMPs, α1-AT, SLPI, TIMPs Biological markers

19. FEV1, IC, DLCO FEV1/FVC normal + lung hyperinflation, ΔFEV1 6DYT BHR Muscle functions CT, PET, hyperpolarised gas MR Exacerbation rate and type MRC respiratory Questionnaire MRC Dyspnoea sclae, Borg scale, BDI/TDI CRDQ, SGRQ, BPQ,PFSDQ, PFSS, CCQ SF-36, NHP, EQ-5D Cognitive functions BODE Symptomatic markers Physiological markers Patient- Specific Outcomes; BMI

20. SYMPTOMS

21. DYNAMIC ve STATIC HYPERINFLATION Inspiratory Capacity LABA, LAAC, ICS/LABA Exercise endurance Dispnoea O’Donnell DE. Chest 2004;23:832-840. O’Donnell DE. Am J Respir Crit Care Med 1998;158:1557-1559. O’Donnell DE. Am J Respir Crit Care Med 1999;160:542-549.

22. 5 year survival according to staging ATS guideline by the percentage of predicted FEV1 Nishimura K. Chest 2002;121:1434-1440.

23. Dispnea Grading • Grade I. Are you ever troubled by breathlessness except on strenuous exertion? • Grade II. Are you short of breath when hurrying on the level or walking up a slight hill? • Grade III. Do you have to walk slower than most people on the level? Do you have to stop after a mile or so onthe level at your own pace? • Grade IV. Do you have to stop for breath after walking about 100 yard on the level? • Grade V. Are you too breathless to leave the house, or breathless after undressing? Fletcher CM. BMJ 1959;2:257-266. Nishimura K. Chest 2002;121:1434-1440.

24. 5 year survival according to dyspnoea Nishimura K. Chest 2002;121:1434-1440.

25. QUALITY OF LIFE

26. SGRQ, which is a life quality marker, is related to all-cause and respiratory related mortality. It is an independant risk factor. • A 4 point increase in SGRQ causes 5.1 (%95 CI, 0.97-9.4) increase in all-cause mortality risk. Domingo-Salvany A. AJRCCM 2002;166:680-685.

27. Minimum Clinically Important Difference for COPD patients • 4 point decrease in SGRQ system Jones PW. J COPD 2005;2:75-79

28. Donohue JF. Chest 2002;122:47-55.

29. FUNCTIONAL PARAMETERS

30. Minimum Clinically Important Difference for COPD patients • Pr brd FEV1 post-treatment increase ≥100 mL Patient perception 112 mL After exacerbations 100-120 mL • Post brd FEV1 post-treatment increase ̴ 200 mL • IC de 100 mL increase Donohue JF. J COPD 2005;2:111-124.

31. FEV1 Tiotropium (n=329) 150mL  FEV1 (mL) start Ipratropium (n=161) 0 8 50 92 182 273 364 ControlDay p<0.0001

32. 12 WEEKS LATER F12 F24 İPR PL Dahl R. AJRCCM 2001;164:778-784.

33. FEV1,Sin DD. Chest 2005;127:1952-1959. Stavem K. ERJ 2005;25:618-625. Schunemann GD. Chest 2000;118:656-664. • BODE score (BMI, FEV1, 6DYT, MMRC) Celli BR. NEJM 2004;350:1005-1010. Freeborne N. J Am Geriatr Soc 2000;48:S199-205. and mortality are related. Sin DD. ERJ 2006;28:1245-1257.

34. PROGRESSION

35. FEV1ΔFEV1 PL Vestbo 86-87% 49 mL/year Pauwels 79 % 60 mL/year LHS 67 % 47 mL/year Burge (ISOLDE) 50 % 59 mL/year Van Grunsven 44 % - Weir 41 % 57 mL/year Sudherland ER. Thorax 2003;58:937-941.

36. Anzueto A. Pulm Pharmacol Ther 2005;18:75-81.

37. Sudherland ER. Thorax 2003;58:937-941.

38. In subjects with a fast annual FEV1 decrease, the cardiac mortality is 3 to 5 times more frequent than in subjects with a slower FEV1 decrease, independent from, smoking, hypertension, BMI and serum cholesterol level. Tockman MS. AJRCCM 1995;151:390-398.

39. EXACERBATIONS

40. FEV1≥50% FEV1<50% Jones PW. ERJ 2003;21:68-73.

41. Minimum Clinically Important Difference for COPD patients • Decrease in exacerbations by 20% or to 1 per year Calverley PMA. J COPD 2005;2:143-148.

42. Annual exacerbation average according to basic FEV1 3.0 Placebo ICS 2.5 Annual exacerbation average 1.8 2.0 1.6 1.4 1.5 1.0 1.0 0.7 0.7 0.5 0.0 2.4 2.5 <1.125 1.125 -1.54 >1.54 FEV1 ISOLDE 2000 BMJ CCLS Euroscop

43. Jones PW. ERJ 2003;21:68-73.

44. EUROSCOP STUDY • 49 (%4.2) patients had a total 60 ischaemic cardiac events, 3/49 died due to MI • 18/593 (%3) with BUD therapy , 22 ischemic exacerbations 31/582 (%5.3) with Pls therapy, 38 ischemic exacerbations p=0.043 • ICS, reduced severe exacerbations that require oral steroids use by 37% (p=0.002), Löfdall C-G. ERJ 2007;29:1115-1119.

45. INFLAMATION

46. Stage 2 Stage 1 Stage 3-4 Hogg JC. NEJM 2004;350:2645-2653.

47. Expec materyel; Neut, macr, lymp, eo, mast Expec solb; TNF-α, IL-8, ECP, MPO Expec air; NO, CO, H2O2 Expec air cond; LTB4, cytokines Per blood; neut, TNF-α, IL-6, IL-8, CRP Sputum; MMPs, α1-AT, SLPI, TIMPs Biological markers

48. COPD and Systemic Inflamation Sin DD. Thorax 2006;61:1-3.

49. Hospitalization and mortality are higher in serum CRP level>3 mg/L patients than CRP level<3 mg/L patients (p<0.001) Dahl M. AJRCCM 2007;175:250-255.

50. Baseline CRP and risk of first cardiovascular events Paul M Ridker, Circulation 2003