2. LE BASI DELL’USO DEGLI ICS/LABA NELLA BRONCOPNEUMOPATIA CRONICA OSTRUTTIVA G IAN G ALEAZZO R IARIO S FORZA P NEUMOLOGIA RIABILITATIVA A.O. I STITUTI C LINICI DI P ERFEZIONAMENTO - M ILANO

3. CCOPD Management WWhat guidelines suggest IICS/LABA combination therapy IICS/LABA drawbacks WWhich ICS/LABA? WWhich COPD patient will benefit from ICS? Agenda

4.  Disease Management should now be focusing on 2 key areas 1.Reducing Symptoms 2.Reducing Risk 2.Reducing Risk. COPD Management

5.  Pharmacologic treatment is used to:  Reduce Symptoms  Reduce frequency and severity of exacerbations  Improve health status  Improve exercise tolerance GOLD 2014 Disease management: Pharmacologic Treatment

6. Pharmacologic options for COPD

7. CCOPD Management WWhat guidelines suggest IICS/LABA combination therapy IICS/LABA drawbacks WWhich ICS/LABA? WWhich COPD patient will benefit from ICS? Agenda

8. National Institute for Health Care and Excellence National Institute for Health and Clinical Excellence. NICE clinical guideline 101.

9. Ann Intern Med. 2011;155:179-191. symptomatic patients with stable COPD and FEV<60% Recommendation 5: clinicians may administer combination inhaled therapies (LAMA, LABA or ICS) for symptomatic patients with stable COPD and FEV<60% predicted. (Grade: weak recommendation, moderate-quality evidence)

10. FEV1 pre-broncodilatatore < 60% Nelle persone con BPCO, sintomatiche nonostante l’uso regolare di broncodilatatori a lunga durata d’azione, con VEMS o FEV1 pre-broncodilatatore < 60% del valore teorico e storia di frequenti riacutizzazioni (2/anno), considerare l ’ associazione LABA + CSI. L’utilizzo della combinazione fissa può migliorare in modo significativo l’aderenza della persona alla terapia. Linee Guida AGENAS

11. recommended as first choice in patients The combination ICS + LABA or LAMA was recommended as first choice in patients group C and D Global initiative for chronic Obstructive Lung Disease

12. GOLD 2014 Combined assessment of COPD Adapted from GOLD 2014

13. Treatment Options Less symptoms High risk Less symptoms High risk MMRC 0  1 CAT <10 GOLD 3 GOLD 4 First Recommended choice: ICS + LABA or LAMA Alternative choice: LABA and LAMA Or LABA and PDE4-inh LAMA and PDE4-inh Other Possible Choices*: SABA and/or SAMA Theophylline Adapted from GOLD 2014 *Other Possible Choices can be used alone or in combination with other options in the First and Second columns ≥1 Or ≥2 leading to hospital admission Patient Type (C)

14. Treatment Options More symptoms high risk More symptoms high risk MMRC ≥2 CAT ≥10 GOLD 3 GOLD 4 First Recommended choice: ICS + LABA And/ or LAMA Alternative choice: ICS + LABA and LAMA or ICS+LABA and PDE4-inh. or LABA and LAMA or LAMA and PDE4-inh Other Possible Choices*: Carbocysteine SABA and/or SAMA Theophylline Adapted from GOLD 2014 *Other Possible Choices can be used alone or in combination with other options in the First and Second columns ≥1 Or ≥2 leading to hospital admission Patient Type (D)

15. CCOPD Management WWhat guidelines suggest IICS/LABA combination therapy IICS/LABA drawbacks WWhich ICS/LABA? WWhich COPD patient will benefit from ICS? Agenda

16. The LABA/ICS combination addresses the multicomponent nature of COPD more than does LABA or ICS treatment alone. Cazzola M, Dahl R. CHEST 2004; 126:220–237 A I R F L O W L I M I T A T I O N

17. ICS/LABA vs. LABA monotherapy  Significant improvement in lung function  Significantly improves quality of life  Significant reduction in the rate of exacerbations

18. Combination therapy ICS/LABA improves lung function (TORCH)

19. The FORWARD study: Adjusted mean change from baseline in pre-dose morning FEV1 Respir Med. 2014 Aug;108(8):1153-62. The pre-dose morning FEV1 increase from baseline to Week 12 was significantly larger in the beclomethasone/formoterol (BDP/FOR) group. BDP/FOR FOR

20. Cochrane Database Syst Rev. 2014;3, CD010844 Trough forced expiratory volume in one second (FEV 1 ) change from baseline—six-month and 12-month class results.

21. Combination therapy ICS/LABA significantly improves quality of life (TORCH)

22. St George's Respiratory Questionnaire (SGRQ) change from baseline—six-month and 12-month class results. Cochrane Database Syst Rev. 2014;3, CD010844

23. Combination therapy ICS/LABA reduces the rate of exacerbations requiring systemic corticosteroids over three years (TORCH)

24. Annual exacerbation rates on selected randomized clinical trials Current Drug Targets, 2013, Vol. 14, No. 2

25. Respir Med. 2014 Aug;108(8):1153-62. The FORWARD study: Kaplan-Meier plot of time to first COPD exacerbation Beclomethasone/formoterol (BDP/FOR) reduced the adjusted exacerbation rate ratio by 28%. ICS/LABA combination therapy is more effecting in reducing exacerbation in severe COPD patients over LABA alone. This demonstrates the antiinflammatory effect of ICS, suggesting also a complementary and synergistic interaction at the molecular level. BDP/FOR FOR

26. When added to LABA in COPD, ICS reduce exacerbations only in patients with FEV1 ≤ 40%. Puhan MA, et al. BMC Medicine 2009, 7:2

27. N Engl J Med Oct 2, 2014;371:1285-94. Withdrawal of Inhaled Glucocorticoids and Exacerbations of COPD Withdrawal of Inhaled Steroids during Optimized Bronchodilator Management (WISDOM)

28. Combination therapy ICS/LABA versus LABA monotherapy

29. CCOPD Management WWhat guidelines suggest IICS/LABA combination therapy IICS/LABA drawbacks WWhich ICS/LABA? WWhich COPD patient will benefit from ICS? Agenda

30. Compared to no treatment with ICS, ICS use was associated with a significant, potentially dose-related increase in risk of pneumonia in patients with COPD Inhaled corticosteroid use in patients with chronic obstructive pulmonary disease and the risk of pneumonia: a retrospective claims data analysis International Journal of COPD 2013:8 295–304

31. Inhaled corticosteroids in COPD and the risk of serious pneumonia Thorax 2013;68:1029-1036

32. ICS had no impact on hospitalisation for community-acquired pneumonia, and had no association with ICU admission, days-to-clinical recovery or mortality. Almirall J, et al. PLoS ONE 2013 8(9): e73271. Relationship between inhaled steroids and Community-Acquired Pneumonia

33. ICS/LABA had the lowest risk of mortality when compared with placebo, tiotropium or LABA only Thorax 2013 Jan;68(1):48-56

34. CCOPD Management WWhat guidelines suggest IICS/LABA combination therapy IICS/LABA drawbacks WWhich ICS/LABA? WWhich COPD patient will benefit from ICS? Agenda

35. Clin Ther 2010 Jul;32(7):1320-8. Relative effectiveness of budesonide/formoterol and fluticasone propionate/salmeterol Patients treated with BUD/FM were less likely to have ED visits and hospitalizations for COPD and used fewer doses of anticholinergic medication in the year after treatment initiation. However, due to the observational nature of the study design, we cannot conclude with certainty that the medication was the only factor responsible for the observed differences.

36. Rapid onset of bronchodilation with formoterol/beclomethasone and formoterol/budesonide as compared to formoterol alone in patients with COPD Cazzola M, et al. Pulm Pharmacol Ther. 2011;24(1):118–22 Rapid effect of the inhaled corticosteroid component when combined with formoterol. Onset of bronchodilation of formoterol/beclomethasone (Form/BDP) and formoterol/budesonide (Form/Bud) are similar and greater than formoterol alone.

37. The efficacy and safety of the novel once- daily combination of FF/VI 100/25 mcg in patients with moderate to very severe COPD over 12 weeks is not significantly different to that of the currently available FP/SAL 500/50 mcg twice daily dose. Agustì A, et al. Eur Respir J 2014; 43: 763–772 A comparison of the efficacy and safety of once-daily fluticasone furoate/vilanterol with twice-daily fluticasone propionate/salmeterol in moderate to very severe COPD

38. CS corticosteroid, CV cardiovascular, FF fluticasone furoate, LRTI lower respiratory tract infection, PL placebo, VI vilanterol, ø indicates <1 % Adverse events of special interest with once-daily fluticasone furoate/vilanterol compared with individual components and placebo in patients with moderate to severe COPD Drugs (2014) 74:1509–1522

39. International Journal of COPD 2012:7 73–86 Efficacy and safety characteristics of mometasone furoate/formoterol fumarate (MF/F) fixed-dose combination in subjects with moderate to very severe COPD

40. Conclusion of ICS/LABA choice it is currently difficult to recommend any of ICS/LABA combination over another Because there are insufficient trials of head-to-head comparison design, adequate duration (>12 weeks) or with clinically relevant outcomes, it is currently difficult to recommend any of ICS/LABA combination over another Curr Respir Care Rep (2014) 3:121–132

41. CCOPD Management WWhat guidelines suggest IICS/LABA combination therapy IICS/LABA drawbacks WWhich inhaled corticosteroid? WWhich COPD patient will benefit from ICS? Agenda

42. In many cases COPD is an outdated term that does not fully recognize the molecular and clinical heterogeneity of the disease. There is a strong need for going toward a new taxonomy and personalized approach to COPD Consequently, it is becoming increasingly important to identify those subjects with COPD with or without a favorable response to ICSConsequently, it is becoming increasingly important to identify those subjects with COPD with or without a favorable response to ICS Moving from the Oslerian paradigm to the postgenomic era: are asthma and COPD outdated terms? Vanfleteren LEGW, et al. Thorax 2014;69:72–79.

43. Marc Miravitlles, et al. Prim Care Respir J 2013; 22(1): 117-121 A new approach to grading and treating COPD based on clinical phenotypes Infrequent exacerbators with either chronic bronchitis or emphysema Overlap COPD-asthma Frequent exacerbators with emphysema predominant Frequent exacerbators with chronic bronchitis predominant Phenotypes of COPD

44. A new approach to grading and treating COPD based on clinical phenotypes Prim Care Respir J 2013; 22(1): 117-121 There is room for the use of ICS in COPD, at least in some subtypes of COPD

45. The question, now, is no longer whether and when to add an ICS in the treatment of COPD patients, but: ICSs are really useful in COPD patients without chronic bronchitis? Which of the anti-inflammatory treatments available (ICSs or phosphodiesterase 4 inhibitors) are the most effective in subjects with COPD and chronic bronchitis? In frequent exacerbators, long-lasting bronchodilators may prevent exacerbations even in the absence of an ICS? In non-frequent exacerbators, what is the utility of combined therapy that include ICS? The answer to these questions would allow us to optimize the use of ICSs in COPD Conclusions Cazzola M, et al. Expert Opin. Pharmacother. (2013) 14(18):2489-2499