Pierluigi Paggiaro Cardio-Thoracic and Vascular Department, University of Pisa, Italy

1. EARLY TREATMENT: USE THE BEST FIRSTEarly treatment with pharmacological approachFocus on COPD Stage II Pierluigi Paggiaro Cardio-Thoracic and Vascular Department, University of Pisa, Italy Annual Meeting ACCP – Capitolo Italiano Honolulu, Hawaii, 23 oct 2011

2. Main characteristics of COPD Non completely reversible airway obstruction Variable combination of chronic bronchitis and emphysema Progressive decline in FEV1 Progressive deterioration in dyspnoea exercise limitation Relevant role of exacerbations in progression of the disease in quality of life

3. The natural history of FEV1 decline in COPD patients Fletcher and Peto, BMJ 1977

4. Recent long-term trial have confirmed the progressive decline in FEV1 in untreated moderate-severe COPD Miravitlles et al, IJCOPD 2009

5. Long-term longitudinal studies have only partially confirmed the rate of FEV1 decline at different baseline FEV1 Decramer and Cooper, Thorax 2010

6. GOLD stage II has a greater FEV1 decline than GOLD stage III and GOLD stage IV Decramer and Cooper, Thorax 2010

7. Several interventional studies Lung Health Study I (ipratropium bromide) ICS treatment Euroscope (budesonide) Copenhagen City Heart Study (budesonide) LHS II (triamcinolone) ISOLDE(fluticasone) UPLIFT study (tiotropium) TORCH study (Salm/Fluti) Negative results in the primary outcome Is it possible to modify the natural history of COPD ?

8. Long-term smoking cessation may modify the FEV1 decline Scanlon et al, AJRCCM 2000

9. Effective in reducing number and/or severity of exacerbations Several studies, with different but consistent results (Paggiaro et al, Lancet 1997) Effect associated with: Improvement in FEV1 Improvement in quality of life In subjects with FEV1 < 50% and frequent exacerbations Studies over 3-4 years, with the aim to modify natural history of the disease All studies negative on improving the progressive decline of FEV1 (Euroscop, ISOLDE, LHS-II, CCLS) Confirmation of the positive effect on exacerbations and other secondary outcomes Short and long-term studies with inhaled corticosteroids (ICS)

10. No effect of regular use ICS on FEV1 decline in COPD patients Soriano, Chest 2007

11. In the Uplift study, tiotropium induces an important improvement in FEV1 which persists over 4 years 1,50 Tiotropium Control * * * * 1,40 * * Post-Bronch FEV1  = 47 – 65 mL * * 1,30 * (L) (n=2516) * 1 * * * FEV (n=2374) * 1,20 * * * * 1,10 (n=2494) Pre-Bronch FEV1  = 87 – 103 mL (n=2363) 1,00 0 1 0 6 42 48 12 18 24 30 36 Day 30 (steady state) Month *P<0.0001 vs. control. Repeated measure ANOVA was used to estimate means. Means are adjusted for baseline measurements. Baseline trough FEV1 (observed mean) = 1.116 (trough), 1.347 (peak). Patients with ≥3 acceptable PFTs after day 30 were included in the analysis.

12. Different response to tiotropium, according to: Gender: male vs female Tashkin et al, Respir Med 2010 Smoking habit: current vs ex vs intermittent Tashkin et al, ERJ 2010 GOLD II stage ** Decramer et al, Lancet 2009 Acute reversibility; reversible vs non reversible Hanania et al, Resp Res 2011 No additional therapies (ICS/LABA) ** Troosters et al, ERJ 2010 Age: lower than 50 yrs vs higher than 50 yrs ** Morice et al, Respir Med 2010 Sub-analysis of the UPLIFT study

13. Reversible and non reversible COPD patients had similar results from tiotropium addition Hanania et al, Resp Res 2011

14. In moderate COPD, tiotropium significantly reduces the decline in post-bronc FEV1 Decramer et al, Lancet 2009

15. Post-hoc analysis of TORCH study Salm/Fluti decreases the decline in FEV1 Celli et al, AJRCCM 2008

18. Symptoms and limitation in daily life Present also in mild airway obstruction and/or hyperinflation Decline in FEV1 Greater in early phases Positive effect of treatment easier to be observed Airway and lung inflammation / exacerbations Present in the early stages More steroid-sensitive in early stage (?) Need to identify “rapid decliners” Rationale for early treatment in COPD

19. May early treatment effectively prevent progressive deterioration in COPD ? Decramer et al, Respir Med 2011

20. Persistence of smoking habit Pulmonary function FEV1 IC Exercise capacity 6MWT, physical activity Nutritional status BMI, FFM Rate of exacerbations Factors contributing to the progression of COPD

21. COPD patients may have exacerbations, which increase in number and severity with the increase in the severity of the pathology of the disease The impact of exacerbations increases over time, leading to: Greater decline in pulmonary function 1 Increase in symptoms 2 Deterioration in health status 3 Increased risk of hospitalization 4 Severe exacerbations increase the risk of mortality 4,5 COPD exacerbations represent an important outcome, among the PROs 1. Donaldson GC et al. Thorax 2002; 57: 847-852; 2. Donaldson GC et al. Eur Respir J 2003; 22: 931-936;3. Seemungal TA et al. Am J Respir Crit Care Med 1998; 157: 1418-1422; 4. Groenewegen KH et al. Chest 2003; 124: 459-467; 5. Soler-Cataluna JJ et al. Thorax 2005; 60: 925-931

22. Frequent exacerbations are related to a greater decline in FEV1 Donaldson et al, Thorax 2002

23. 0 riacutizzazioni/anno 1–2 riacutizzazioni/anno ≥ 3 riacutizzazioni/anno 1,0 0,8 p<0,0002 0,6 p<0,0001 Probabilità di sopravvivenza 0,4 p=0,069 0,2 0 0 10 20 30 40 50 60 Tempo (mesi) High frequency of exacerbations increases the risk of mortality in COPD Soler-Cataluna JJ et al. Thorax 2005

24. ECLIPSE: 3-year longitudinal observational study 2165 COPD patients, GOLD II-IV 246 non smokers 336 ‘healthy’ smokers baseline 3 Months 6 M 12 M 18 M 24 M 30 M 36 M V1 V2 V3 V4 V5 V6 V7 V8 Vestbo et al. ERJ 2008

25. Frequent exacerbators are represented in all GOLD stages Hurst et al, NEJM 2010

26. Frequent exacerbators represent a specific constant phenotype Hurst et al, NEJM 2010

27. Inhaled corticosteroids reduce the risk of exacerbations in COPD Alsaeedi et al, Am J Med 2002

28. Moderate-severe exacerbation in 3 yrs Mean number of exacerbation/year 25% reduction 1.2 1.13 0.97* 0.93* 1 0.85*†‡ 0.8 0.6 0.4 0.2 0 Placebo SALM FP SALM/FP Trattamenti *p < 0.001 vs placebo; †p = 0.002 vs SALM; ‡p = 0.024 vs FP Calverly et al, NEJM 2007

29. Salm/Fluti reduces all causes of mortality of COPD in comparison with placebo Calverly et al, NEJM 2007

31. Sputum eosinophilia During acute exacerbations In up to 50% of AE Mainly in virus-induced AE In stable COPD In 30% about of patients Associated with exhaled NO, acute reversibility (?) Non associated with age, smoke, atopy, etc Different response to inhaled or oral CS “Asthma” pattern in COPD

32. Virus-induced exacerbations of COPD are associated with greater sputum eosinophilia Papi et al, AJRCCM 2006

33. Observed in up to 30-40% of patients Lower than in asthma Not related to other clinical features Chronic bronchitis ? Acute reversibility ? How to select these patients ? Sputum eosinophilia in stable COPD

34. High frequency of sputum eosinophils in COPD patients

36. COPD patients with partial airway reversibility have higher levels of exhaled NO Papi et al, AJRCCM 2000

37. Sputum eosinophilia predicts a better response to CS in COPD patients Brightling et al, Thorax 2005

39. A strategy aiming to minimize sputum eosinophilia reduces the number of severe exacerbations of COPD Siva et al, ERJ 2007

41. Airway inflammation is present in COPD, also in earlier stages Hogg et al, NEJM 2004

42. Malondealdehayde (MDA), a marker of oxidative stress in EBC, is increased in stable moderate COPD patients Bartoli et al, Med Inflamm 2011

43. Progression of COPD is more evident in early phase In GOLD I-II stages Exacerbations represent a major target of treatment Efficacy of ICS and ICS/LABA Also in earlier stages Early treatment Better chance of modifying natural history Phenotyping of COPD “asthmatic” feature  role of ICS Conclusions

44. A more flexible approach, based on symptoms and exacerbations, and not only on FEV1, has been now considered in the future GOLD guidelines