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Role of ICS in Asthma and COPD

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Oral presentation at world Asthma Day, Cairo, 5/5/2016

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Role of ICS in Asthma and COPD

  1. 1. Prof. Gamal Rabie Agmy, MD, FCCP Professor of Chest diseases, Assiut University Fairmont Nile City, Cairo 5/5/2016 Role of ICS in Asthma & COPD
  2. 2.  Asthma is a heterogeneous disease, usually characterized by airflow inflammation.  It is defined by the presence of respiratory symptoms such as • Wheezes. • Shortness of breath. • Cough . • that vary overtime and in intensity, together with variable airflow limitation. What is Asthma? (GINA 2014) Global strategy for Asthma management and prevention guidelines 2014.
  3. 3. Asthma: Burden  Asthma is a problem worldwide, with an estimated 300 million affected individuals  The global prevalence of asthma ranges from 1% to 18% of the population in different countries  The World Health Organization has estimated that asthma represents 1% of the total global disease burden  Annual worldwide deaths from asthma have been estimated at 250,000. Global strategy for Asthma management and prevention guidelines 2014.
  4. 4. | Asthma Medical Training | Raed Darwish | Dec 2015 | Business Use Only Severe allergic asthma is a chronic condition, which, when uncontrolled, has a serious impact on quality of life, morbidity, mortality and health expenditure Asthma has serious consequences ~50,0000 hospitalisations each year in Europe for people with severe asthma2 40% of patients with asthma have moderate-severe disease1 Inflammation causing: 1. Wheezing 2. Breathlessness 3. Chest tightness 4. Coughing 15,000 people die each year from asthma attacks in Europe2 • Of 195 UK asthma-related deaths 2012-13: • 17% = allergic asthma3 • 39% = severe asthma3 $6,022 mean cost over 12 months for a patient with asthma that is uncontrolled despite ICS+LABA5Severe asthma accounts for >50% of total costs despite being 5-10% of total asthma patients 6,7 ~300 million people have asthma worldwide4 22nd in the ranking of disease burden worldwide4 1| Asthma Medical Training | Raed Darwish | Dec 2015 | Business Use Only 5
  5. 5. GINA GUIDLINES 2014 Step 1 Step 2 Step 3 Step 4 Step 5 Consider low dose ICS low dose ICS Leukotrienereceptorantagonist(LTRA) Low dose theophylline As-neededshort-acting beta2-agonist (SABA) Low dose ICS/LABA Med/high dose ICS Low dose ICS+LTRA (or + theo.) Med/high ICS/LABA High dose ICS+LTRA (or + theo.) Refer for add-on treatment e.g. Anti-Ige Add low dose OCS As neededSABAor low dose ICS/Formoterol Preferred controller choice Other controller choice Reliever Before stepping up, always check inhaler technique, adherence and key issues first Global strategy for Asthma management and prevention guidelines 2014. Stepwise Approach for Optimal Asthma management
  6. 6. ICS in Asthma  ICS with or without LABA, continue to be the mainstay of pharmacological treatment for mild to moderate asthma.  Inhaled corticosteroids (ICS) are by far the most effective controllers used in the treatment of asthma.  The only drugs that can effectively suppress the characteristic inflammation in asthmatic airways, even in very low doses. Pharmaceuticals 2010, 3, 514-540
  7. 7. ICS in Asthma (cont’d)  ICS are the recommended first-line therapy for persistent asthma of all severities and patients of all ages and are the most effective asthma medications currently available. Pharmaceuticals 2010, 3, 514-540
  8. 8. Role of ICS in Asthma  ICS can reverse the specific chronic airway inflammation present in asthma.  ICS reduce the number of mast cells, macrophages, T-lymphocytes and Eosinophils in the sputum, broncho- alveolar lavage and bronchial wall.  ICS reverse the shedding of epithelial cells, goblet-cell hyperplasia and basement-membrane thickening characteristic of the airway mucosa of patients with asthma. Eur J Clin Pharmacol (2009) 65:853–871
  9. 9. Source: Peter J. Barnes, MD Asthma Inflammation: Cells and Mediators
  10. 10. ICS in Asthma Pharmaceuticals 2010, 3, 514-540 Cellular Effects
  11. 11.  When taken regularly, inhaled corticosteroids: • Effectively control everyday asthma symptoms. • Improve lung function. • Decrease the risk for exacerbations. ICS in Asthma (cont’d) Fernando D Martinez et al,Lancet 2013; 382: 1360–72
  12. 12.  Controlled trials have consistently shown that inhaled corticosteroids are better than leukotriene receptor antagonists, such as montelukast, at : • Controlling symptoms • Improving lung function • Reducing exacerbations ICS in Asthma (cont’d) Fernando D Martinez et al, Lancet 2013; 382: 1360–72
  13. 13.  Several clinical trials have shown that patients who are still symptomatic after treatment with inhaled corticosteroids benefit from the addition of a LABA.  A larger proportion of such patients respond better to adding LABAs than to doubling the dose of inhaled corticosteroids or adding a leukotriene receptor antagonist. Adding LABA is better than increasing ICS dose Fernando D Martinez et al,Lancet 2013; 382: 1360–72
  14. 14. LABA with ICS for Asthma Management  ICS therapy in combination with long acting inhaled beta agonists (LABA) represents the most important treatment for asthma.  ICS therapy forms the basis for treatment of asthma of all severities, improving asthma control, lung function and preventing exacerbations of disease. Eur J Clin Pharmacol (2009) 65:853–871
  15. 15. Anti-inflammatory Effects of β2-agonists in Asthma  β2-agonists not only cause bronchodilation, but also exert anti- inflammatory effects as has been shown in many in vitro studies.  These effects include: • Inhibition of the oxidative burst and release of thromboxane and leukotriene C4 from Eosinophils. • Inhibition of mediator release from circulating neutrophils. M van den Berge at al ,Clinical Medicine:Therapeutics 2009:1 77–93
  16. 16. LABA / ICS for Asthma Management  Adding a LABA is more effective than increasing the dose of ICS in terms of improving asthma control and reducing exacerbations.1  Use of inhaled corticosteroids plus Formoterol, a fast- onset LABA, has proven to be effective in preventing exacerbations.2 1- Pharmaceuticals 2010, 3, 514-540 2-Fernando D Martinez et al,Lancet 2013; 382: 1360–72
  17. 17. Interaction between β2-agonists and ICS  Corticosteroids can interact with β2-agonists in a beneficial way, since they prevent desensitization. Effects of β2-receptors on Corticosteroids  β2-agonists are capable of potentiating the anti- inflammatory actions of corticosteroids. Effects of corticosteroids on β2-receptors M van den Berge at al ,Clinical Medicine:Therapeutics 2009:1 77–93
  18. 18. April 2015_GMCC_NP4_GLRESP/COPD/0012o ICS role in COPD
  19. 19. Recommendations for ICS are largely based on preventative effect on exacerbations  Use of ICS is associated with an 18% relative risk reduction in occurrence of exacerbations1 • The commonly cited MCID for change in exacerbation frequency is a 20% reduction2 CI = confidence interval; ICS = inhaled corticosteroid MCID = minimal clinically important difference 1. Agarwal et al. Chest 2010; 2. Calverley. COPD 2005 1 20.5 Study 1: 1.00 Study 2: 1.00 Study 3: 0.63 Study 4: 0.75 Study 5: 0.66 Study 6: 0.93 Study 7: 0.66 Study 8: 0.51 Study 9: 0.82 Study 10: 1.11 Study 11:0.91 Fixed:0.84 Random: 0.82 ICS Placebo Rateratio
  20. 20. COPD exacerbation phenotypes and responsiveness to steroids  This observational, 1-year study of 182 exacerbations in 86 patients identified four distinct biologic COPD exacerbation phenotypes • Eosinophil-predominant phenotype is most responsive to corticosteroid treatment COPD = chronic obstructive pulmonary disease Bafadhel et al. Am J Respir Crit Care 2011 Th 2 Th 1 Proinflammatory Bacteria predominant (sputum IL-1β) Eosinophilpredominant (% peripheral eosinophils) Viral predominant (CXCL10) Pauci-inflammatory Biologic phenotype (clinical biomarker)
  21. 21. Post-hoc analysis suggests that blood eosinophils are a potential biomarker of ICS effectiveness in reducing exacerbation rates  Further research is required to help establish blood eosinophilia as a biomarker for treatment response COPD = chronic obstructive pulmonary disease EOS = eosinophil; FF/VI = fluticasone furoate/vilanterol ICS = inhaled corticosteroid; VI = vilanterol Pascoe et al. Lancet Respir Med 2015 0.7 0.9 1.1 1.3 1.5 EOS <2% EOS ≥2% Annualexacerbationrate (patient/year) FF/VI all doses VI 25 μg 0.79 n=795 0.89 n=299 0.91 n=1,583 1.28 n=500 29% difference p<0.0001 10% difference p=0.283 0
  22. 22. Sputum eosinophilia and response to budesonide in COPD  Changes in post-bronchodilator FEV1 in patients with or without sputum eosinophilia Leigh et al. Eur Respir J 2006 Δpost-BDFEV1(L) ‒0.05 0.05 0.10 * † 0 0.15 * † PrednisoneBudesonidePlacebo Withoutsputum eosinophiliaWith sputum eosinophilia *p<0.05 within group (sputum eosinophilia) vs placebo; †p<0.05 between groups (with vs without sputum eosinophilia). Data are mean (SE) BD = bronchodilator; COPD = chronic obstructive pulmonary disease FEV1 = forced expiratory volume in 1 second; SE = standard error
  23. 23. Sputum eosinophilia and response to mometasone in COPD  Response to treatment with mometasone compared with placebo for each tertile of eosinophils in induced sputum *p<0.05 vs placebo. Data are mean (SE). BD = bronchodilator COPD = chronic obstructive pulmonary disease; CRQ = chronic respiratory disease questionnaire; FEV1 = forced expiratory volume in 1 second Brightling et al. Thorax 2005 * -0.10 -0.05 0.00 0.05 0.10 0.15 0.20 Leastto most eosinophilic tertile Leastto most eosinophilic tertile -0.3 -0.2 -0.1 0 0.1 0.2 0.3 1 0 ‒0.05 ‒0.10 ‒0.1 ΔtotalCRQ ‒0.2 ‒0.3 Δpost-BDFEV1(L) 0.05 0.10 0.15 0.20 0 0.1 0.2 0.3
  24. 24. April 2015_GMCC_NP4_GLRESP/COPD/0012o Risks associated with ICS use in COPD
  25. 25. Risks associated with ICS use in COPD  Previous data have indicated an increased risk of pneumonia among patients with COPD receiving ICS1  Evidence for an association between ICS use and pneumonia in patients with COPD has grown in recent years:2,3 COPD = chronic obstructive pulmonary disease CI = confidence interval; ICS = inhaled corticosteroid 1. Crim et al. Eur Respir J 2009; 2. Yawn et al. Int J Chron Obstruct Pulmon Dis 2013; 3. Suissa et al. Thorax 2013 Evidence for sustained elevatedrisk with long-term use3 2.0 1.8 1.6 1.4 1.2 1.0 0 10 20 30 40 50 60 Rateratio Duration of ICS use in months Rate ratio for ICS use vs non-ICS use represented by solid line; dashed lines represent 95% CI Evidence for a dose-response relationship2 Hazard ratio (95% CI) Increased risk (compared with no ICS)Decreased risk High ICS dose Moderate ICS dose No ICS (reference) 1.38 (1.27, 1.49) p<0.001 1.69 (1.52, 1.88) p<0.001 2.57 (1.98, 3.33) p<0.001 Hazard ratio (95% CI) (vs no ICS use) Low ICS dose 0 1 2 3 4
  26. 26. 25Probabilityofpneumonia(%) 0 24 48 72 96 120 156 1,544 1,117 947 587 1,552 1,189 992 574 1,542 1,214 1,024 645 1,546 1,231 1,034 631 Numberat risk Placebo Fluticasone Salmeterol SFC Time to pneumonia (weeks) HR (SFC vs placebo)1.64 (95% CI 1.33, 2.02) 20 15 10 5 0 TORCH study: SFC combination and risk of pneumonia b.i.d. = twice daily; CI = confidence interval; SFC = salmeterol/fluticasone propionate HR = hazard ratio TORCH = Towards a Revolution in COPD Health Crim et al. Eur Respir J 2009 Salmeterol 50 μg b.i.d. Fluticasone500 μg b.i.d. Placebo SFC 50/500 μg b.i.d.
  27. 27. Hazard ratio (95% CI) Increased risk (compared with no ICS)Decreased risk High ICS dose Moderate ICS dose No ICS (reference) 1.38 (1.27, 1.49) p<0.001 1.69 (1.52, 1.88) p<0.001 2.57 (1.98, 3.33) p<0.001 Hazard ratio (95% CI) (vs no ICS use) Use of ICS and risk of pneumonia: dose-response relationship CI = confidence interval; ICS = inhaled corticosteroid Yawn et al. Int J Chron Obstruct Pulmon Dis 2013 Low ICS dose 0 1 2 3 4
  28. 28. ICS use and risk of bone fractures in COPD patients Meta-analysis of inhaled corticosteroids versus controls for fractures in observational studies; Odds ratio (OR) represented by solid line; dashed lines represent 95% confidence intervals; COPD = chronic obstructive pulmonary disease; ICS = inhaled corticosteroid Loke et al. Thorax 2011 0 500 1000 1500 2000 2500 Beclomethasone equivalentdose (µg) 0.4 0.2 0 –0.2 Log(adjustedOR) 0.6 Log (adjusted OR) 95% upperbound:log OR 95% lower bound:log OR Prediction
  29. 29. Diabetes risk may be increased with ICS use in patients with COPD  In an observational cohort study (n=388,584), the risk of diabetes associated with ICS use was investigated  In total, 30,167 patients had diabetes onset during the 5.5-year follow-up  The onset and progression of diabetes increased in patients with COPD receiving ICS1 • Increased risk of diabetes: RR 1.34 (95% CI 1.29,1.39) • Rate of diabetes progression: RR 1.34 (95% CI 1.17,1.53) • Risk of diabetes increasedwith highestdoses of ICS CI = confidence interval; COPD = chronic obstructive pulmonary disease ICS = inhaled corticosteroid; RR = rate ratio Suissa et al. Am J Med 2010
  30. 30. ICS use and diabetes risk in patients with COPD: effect of dose Suissa et al. Am J Med 2010 3.0 2.5 2.0 1.5 1.0 0.5 0 250 500 750 1000 1250 1500 1750 2000 Daily dose in fluticasone equivalents(µg) Rateratio 3.5 Adjusted rate ratio of diabetes incidence associated with ICS use; Rate ratio represented by solid line; dashed lines represent 95% confidence intervals. COPD = chronic obstructive pulmonary disease; ICS = inhaled corticosteroid
  31. 31. April 2015_GMCC_NP4_GLRESP/COPD/0012o Correct diagnosis is key to deciding the treatment strategy, which differs between asthma and COPD.
  32. 32. There are now good scientific reasons why even high doses of ICS fail to reduce inflammation in COPD patients.  This corticosteroid-resistance has been demonstrated by the failure of high doses of ICS to reduce inflammatory markers in sputum or bronchial biopsies of COPD patients. Peter J. Barnes Respiration 2010;80:89–95
  33. 33. Possible reasons for corticosteroid resistance  The reason for the extreme corticosteroid resistance in COPD may be due to a marked reduction in the nuclear enzyme histone deacetylase-2 (HDAC2), which is required for corticosteroids to switch off activated inflammatory genes that are associated with histone acetylation Peter J. Barnes Respiration 2010;80:89–95
  34. 34. Possible mechanisms for decreased HDAC-2 activity in smokers with asthma and COPD. Respiratory Medicine (2012) 106, 319-328 Inactivation of HDAC-2 results in increasedinflammatorygene expressionand reduced response to anti-inflammatoryactions of corticosteroids.
  35. 35. Glucocorticoids have been reported not to reduce, but even to increase, neutrophils numbers in induced sputum  Corticosteroids inhibit neutrophils apoptosis at clinically relevant drug concentrations and the effect seems to be mediated through glucocorticoid receptors.  Accordingly, oral and inhaled corticosteroids have been reported to increase neutrophils numbers in the lung tissue. European Journal of Pharmacology 431(2001)365–371 Journal of Chronic Obstructive Pulmonary Disease, 5:163–169
  36. 36. April 2015_GMCC_NP4_GLRESP/COPD/0012o Can ICS be withdrawn safely?
  37. 37. INSTEAD study design b.i.d. = twice daily; FEV1 = forced expiratory volume in 1 second TDI = transition dyspnea index; SGRQ = St George’s Respiratory Questionnaire; q.d. = once daily; SFC = salmeterol/fluticasone propionate Rossi et al. Eur Respir J 2014 SFC 50/500 µg b.i.d. Indacaterol 150 µg q.d. Randomization (1:1) Continue on SFC or switch to indacaterol SFC 50/500 µg b.i.d. Run-in/screening SFC 50/500 µg b.i.d. 2 weeks≥3 months Visits: Weeks 4, 8 Primary endpoint • Trough FEV1 at Week 12 (non-inferiority) Secondary endpoints include: • Lung function • Breathlessness (TDI) • Health status (SGRQ) 26-week blinded treatment
  38. 38. INSTEAD: switch from SFC 50/500 µg b.i.d. to indacaterol 150 µg q.d. had no clinically relevant effect on lung function PPS (all patients in FAS without major protocol deviations) was used for primary efficacy analysis. FAS included all randomised patients who received at least one dose of study drug, and was used for all secondary analyses. Non-inferiority demonstrated if 95% CI for difference between indacaterol and SFC was above –0.06 (i.e. to right of dashed rule) b.i.d. = twice daily; CI = confidence interval; FAS = full analysis set; LSM = least-squares mean q.d. = once daily; FEV1 = forced expiratory; volume in 1 second; PPS = per-protocol set (primary analysis); SFC = salmeterol/fluticasone propionate Rossi et al. Eur Respir J 2014 LSM treatment difference in trough FEV1 after 12 weeks Indacaterol 150 µg q.d. versus SFC 50/500µg b.i.d. treatmentdifference(L) Trough FEV1 Primary analysis (PPS) Secondary analysis (FAS) Difference (95% Cl) –0.009 (–0.045,0.026) –0.014 (–0.046,0.019) –0.09 –0.06 –0.03 0.00 0.03
  39. 39. Time to first moderate or severe COPD exacerbation to Week 26 Hazard ratio: 0.80, p=0.258 Indacaterol 150 µg q.d. SFC 50/500 µg b.i.d. 100 80 60 40 20 0 1 2 3 4 5 Time to first exacerbation(months) Patientsexacerbation-free(%) 6 INSTEAD: switch from SFC to indacaterol did not increase risk of moderate-to-severe exacerbations b.i.d. = twice daily; q.d. = once daily SFC = salmeterol/fluticasone propionate Rossi et al. Eur Respir J 2014 0
  40. 40. WISDOM study design b.i.d. = twice daily; ICS = inhaled corticosteroid q.d. = once daily Magnussen et al. N Engl J Med 2014 Salmeterol 50 µg b.i.d. + fluticasone 500 µg b.i.d. Tiotropium 18 µg q.d. + salmeterol 50 µg b.i.d. Randomization (1:1) Continue on triple or withdraw ICS in a stepwise manner Run-in/screening Tiotropium 18 ug q.d. + salmeterol 50 ug b.i.d. + fluticasone 500 µg b.i.d. 6 weeks 52-week blinded treatment Reduced to 500 µg Reduced to 200 µg Reduced to 0 µg (placebo) Daily fluticasone dosein ICS withdrawalgroup 0‒6 6–12 12–52 weeks
  41. 41. Daily fluticasone dosein ICS withdrawalgroup Reduced to 500 µg Reduced to 200 µg Reduced to 0 µg (placebo) ICS continuation ICS withdrawal 0 –20 –40 –60 –80 0 6 12 18 52 p<0.001 p=0.001 Adjustedmeanchange inFEV1(mL) Week Number at risk: ICS continuation 1,223 1,135 1,114 1,077 970 ICS withdrawal 1,218 1,135 1,092 1,058 935 WISDOM: ICS withdrawal led to a small but significant reduction in FEV1 versus ICS continuation in patients with severe COPD b.i.d. = twice daily; COPD = chronic obstructive pulmonary disease FEV1 = forced expiratory volume in 1 second ICS = inhaled corticosteroid; q.d. = once daily Magnussen et al. N Engl J Med 2014
  42. 42. Number at risk: ICS continuation 1,243 1,059 927 827 763 694 646 615 581 14 ICS withdrawal 1,242 1,090 965 825 740 688 646 607 570 19 WISDOM: withdrawal of ICS did not increase the risk of moderate or severe exacerbations in patients with severe COPD b.i.d. = twice daily; CI = confidence interval; COPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory volume in 1 second; ICS = inhaled corticosteroid Magnussen et al. N Engl J Med 2014 Moderate or severe COPD exacerbation Hazard ratio, 1.06 (95% CI 0.94, 1.19) p=0.35 by Wald’s chi-squaretest ICS continuation ICS withdrawal 1.0 0 0 Estimatedprobability Weeks to event 0.2 0.4 0.6 0.8 6 12 18 24 30 36 42 48 54
  43. 43. OPTIMO study design  Prospective, real-life study: physicians prescribed treatment as they saw fit • Aim: to investigate whether withdrawal of ICS in COPD patients at low risk of exacerbation is linked to a deterioration in lung function and symptoms and to a higher frequency of exacerbations. COPD = chronic obstructive pulmonary disease ICS = inhaled corticosteroid; LABA = long-acting β2- agonist Rossi et al. Respir Res 2014 914 patients on LABA+ ICS Remained on ICS: n=482 (59.1%) No ICS n=334 (40.9%) Remained on ICS: n=546 (59.7%) Changed to no ICS n=368 (40.3%) Treatmentdecision at initial visit Treatmentreceived at Month 6 visit Tiotropium (27%) Indacaterol (29%) Formoterol or salmeterol (15%) Tiotropium/indacaterol (20%) Other (9%)
  44. 44. OPTIMO: lung function was similar for a bronchodilator-only regimen versus remaining on LABA/ICS therapy at 6 months  914 patients at low risk of an exacerbation treated with a LABA/ICS • Of these, 59.7% of patients continued with LABA/ICS; the remaining 40.3% had their ICS withdrawn and treatment with bronchodilator monotherapy or dual therapy was instituted* *LABA; LAMA; LABA/LAMA; short-acting bronchodilators and/or theophylline FEV1 = forced expiratory volume in 1 second ICS = inhaled corticosteroid; LABA = long-acting β2-agonist LAMA = long-acting muscarinic antagonist Rossi et al. Respir Res 2014 p=0.752 100 0 No ICS FEV1%predicted 80 60 40 20 ICS 72.5 72.1
  45. 45. OPTIMO: withdrawal of ICS in COPD did not increase risk of exacerbations versus a bronchodilator-only regimen *Patients with moderate airflow limitation (forced expiratory volume in 1 second >50% predicted); †LABA; LAMA; LABA/LAMA; short-acting bronchodilators and/or theophylline ICS = inhaled corticosteroid; LABA = long-acting β2-agonist LAMA = long-acting muscarinic antagonist Rossi et al. Respir Res 2014 Withdrawal of ICS can be safe in COPD patients at low risk of exacerbation*, provided maintenance treatment with bronchodilators† is continued p=0.347 100 0 No ICS Patientsexacerbation-freeafter 6months(%) 80 60 40 20 ICS 74.0 71.0
  46. 46. Inhaled corticosteroids in COPD: the clinical evidence:Pierre Ernst, Nathalie Saad, Samy Suissa ERS J Published 1 February 2015 In this article, we focus on the scientific evidence from randomised trials supporting treatment with inhaled corticosteroids (ICS) in chronic obstructive pulmonary disease (COPD), including treatment with combinations of long-acting β-agonist (LABA) bronchodilators and ICS. Our emphasis is on the methodological strengths and limitations that guide the conclusions that may be drawn.
  47. 47. Inhaled corticosteroids in COPD: the clinical evidence:Pierre Ernst, Nathalie Saad, Samy Suissa ERS J Published 1 February 2015 The evidence of benefit of ICS and, therefore, of the LABA/ICS combinations in COPD is limited by major methodological problems. From the data reviewed herein, we conclude that there is no survival benefit independent of the effect of long-acting bronchodilation and no effect on FEV1 decline, and that the possible benefit on reducing severe exacerbations is unclear. Our interpretation of the data is that there are substantial adverse effects from the use of ICS in patients with COPD, most notably severe pneumonia resulting in excess deaths.
  48. 48. Inhaled corticosteroids in COPD: the clinical evidence: Pierre Ernst, Nathalie Saad, Samy Suissa ERS J Published 1 February 2015 Currently, the most reliable predictor of response to ICS in COPD is the presence of eosinophilic inflammation in the sputum. There is an urgent need for better markers of benefit and risk that can be tested in randomised trials for use in routine specialist practice. Given the overall safety and effectiveness of long-acting bronchodilators in subjects without an asthma component to their COPD, we believe use of such agents without an associated ICS should be favoured.
  49. 49. April 2015_GMCC_NP4_GLRESP/COPD/0012o Clinical efficacy of IND/GLY in COPD
  50. 50. What is QVA 149 ?  ULTIBRO is an inhaled once-daily fixed-dose combination of a LABA (indacaterol) and a LAMA (glycopyrronium bromide) in a single inhaler, developed for use in COPD.  The dry-powder formulation of ULTIBRO is suitable for once-daily dosing via the Breezhaler® device.  ULTIBRO has been approved for the management of COPD in the EU and in a number of countries worldwide, including Australia, Japan, Canada and Singapore.
  51. 51. April 2015_GMCC_NP4_GLRESP/COPD/0012o Effect of IND/GLY on COPD Exacerbations
  52. 52. IND/GLY significantly improved important patient outcomes vs monotherapies and LABA/ICS 1. Wedzicha et al. Lancet Respir Med 2013 2. Bateman et al. Eur Respir J 2012 3. Vogelmeier et al. Lancet Respir Med 2013 4. Mahler et al. ATS 2013 Abstract Dyspnea Quality of Life(SGRQ) Rescue medication Exacerbations Lung Function
  53. 53. LANTERN Study design Before the run-in period,patients discontinued LAMAs and the LABAindacaterolforat least7 days and all otherLABAs and LABA/inhaledcorticosteroid combinations for 48 hours.o.d., once-daily 26-week,multicenter,randomized,double-blind,double-dummy,parallel-group,active controlled study Pre-randomization period Pre-screening Run-in period Day -21 to Day -15 Day -14 to Day -1 Treatment Period IND/GLY110/50 μg o.d. via the Breezhaler® Device Day 1 to Day 184 Randomization (1:1) Salmeterol/Futicasone 50/500 μg b.i.d. via the Accuhaler® Device 30 Days Post-treatment follow-up 1. NanshanZhong,ChangzhengWang,XiangdongZhou.LANTERN:a randomizedstudyof ULTIBRO versus salmeterol/fluticasone combinationin patients with COPD.InternationalJournalof COPD 2015:101015–1026
  54. 54. IND/GLY significantly lowered moderate or severe COPD exacerbations versus SFC, with a risk reduction of 31% Moderate or severe COPD exacerbations IND/GLY (n=372) SFC (n=369) Number of exacerbations per patient ( n [%]) 0 328 (88.2) 301 (81.6) 1 35 (9.4) 55 (14.9) 2 9 (2.4) 13 (3.5) 3 0 0 ≥4 0 0 Total number of exacerbations 53 81 Total number of treatment years 179.2 174.9 Rate of exacerbations per year 0.30 0.46 Treatment comparison vs. SFC Ratio of rate (95 % CI) 0.69 (0.48, 1.00)* *p<0.05 1. NanshanZhong,ChangzhengWang,XiangdongZhou.LANTERN:a randomizedstudyof ULTIBRO versus salmeterol/fluticasone combinationin patients with COPD.InternationalJournalof COPD 2015:101015–1026
  55. 55. IND/GLY significantly prolonged the time to first moderate or severe exacerbation by 35% compared with SFC  Kaplan-Meier plots of the time to first moderate or severe COPD exacerbation over 26 weeks of treatment (full analysis set) IND/GLY IND/GLY NanshanZhong,Changzheng Wang,Xiangdong Zhou.LANTERN:a randomized study of QVA149 versus salmeterol/fluticasone combination in patients with COPD. InternationalJournalof COPD 2015:101015–1026
  56. 56. IND/GLY reduced rate of moderate or severe exacerbation, irrespective of baseline exacerbation history Treatment Annualized rate (95% CI) Comparison Rate ratio 95% CI p-value With COPD exacerbationhistoryat baseline IND/GLY (n=61) 0.49 (0.29, 0.82) IND/GLY - SFC 0.60 (0.33, 1.08) 0.086 SFC (n=93) 0.81 (0.56, 1.19) WithoutCOPD exacerbationhistoryat baseline IND/GLY (n=311) 0.23 (0.16, 0.33) IND/GLY - SFC 0.76 (0.46, 1.24) 0.266 SFC (n=276) 0.30 (0.21, 0.43) Rate ratio, its 95% CI, and p-value are from a negative binomial regression model: log (exacerbation rate)=treatment+baseline ICS use (yes/no)+baseline total symptom score+FEV1 reversibility components. Log (length of time in the study) is included in the model as an offset term. CI, confidence interval. NanshanZhong,Changzheng Wang,Xiangdong Zhou.LANTERN:a randomized study of QVA149 versus salmeterol/fluticasone combination in patients with COPD. InternationalJournalof COPD 2015:101015–1026
  57. 57. IND/GLY SIGNIFICANTLY REDUCED THE RATE OF MODERATE OR SEVERE EXACERBATIONS SIGNIFICANT RISK REDUCTION OF 31% Annualized rate of moderate or severe exacerbations IND/GLY (n=372) vs. fluticasone/salmeterol (n=369) MODERATE OR SEVERE EXACERBATIONS vs.fluticasone/salmeterol6 BENEFITS vs. fluticasone/salmeterol IND/GLY significantly prolonged the time to first moderate or severe exacerbation and reduced the hazard of having such exacerbations by 35% vs. fluticasone/salmeterol (P=0.028) 6 P=0.048
  58. 58. IND/GLY SIGNIFICANTLY REDUCED THE RATE OF MODERATE OR SEVERE EXACERBATIONS SIGNIFICANT REDUCTION OF 69%SEVERE EXACERBATIONS vs.fluticasone/salmeterol 6 P=0.023 Annualized rate of severe exacerbations BENEFITS vs. fluticasone/salmeterol IND/GLY (n=372)vs fluticasone/salmeterol(n=369) IND/GLY reduces the rate of severe exacerbations vs. fluticasone/salmeterol6 * In a post-hocanalysis
  59. 59. Where does dual bronchodilation fit?  For patients in GOLD Groups B, C, and D, a LABA/LAMA combination is included as an alternative choice option1 Which patientswill benefit from dual bronchodilation?  The IGNITE Phase III clinical program showed superior efficacy on a variety of outcomes (including lung function, dyspnea, health status) to placebo and active comparators in patients in Groups A, B, and D2–7 • In particular, ILLUMINATE highlighted the potential of LAMA/LABA therapy to replace and provide superior efficacy to ICS/LABA in GOLD Group B patients2 1. GOLD 2013; 2. Vogelmeier et al. Lancet Respir Med 2013 3. Bateman et al. Eur Respir J 2013; 4. Wedzicha et al. Lancet Respir Med 2013 5. Beeh et al. BTS 2012 Abstract; 6. Mahler et al. ATS 2013 Abstract; 7. Dahl et al. Respir Med 2013; 8. Adelphi DSP 2011 Importance of Dual Bronchodilation In Conclusion.....
  60. 60. When should physicians consider stepping up or switching to dual bronchodilation?  Physicians recognize symptomatic patients who require treatment change and also for ‘not well controlled’ and ‘symptomatic’ patients8  The GOLD 2013 strategy advocates more focus on symptoms that may improve patient outcomes, if adhered to1 Importance of Dual Bronchodilation In Conclusion.....
  61. 61. Summary  ICS use is associated with benefits in lung function, HRQoL and exacerbation risk  However, ICS use was found to be associated with increased risk pneumonia, bone fracture and diabetes  Real-world prescription data indicate that ICS are prescribed to patients with all severities of COPD, contrary to GOLD recommendations  Withdrawal of ICS may be warranted and appropriate in some patients • Studies have shown no increased risk of moderate-to-severe exacerbations following ICS withdrawal in patients with moderate COPD and no exacerbation history if appropriate bronchodilator therapy is in place COPD = chronic obstructive pulmonary disease GOLD = Global initiative for chronic Obstructive Lung Disease HRQoL = health-related quality of life ICS = inhaled corticosteroid
  62. 62. Dual bronchodilation : summary  The GOLD 2015 strategy document recommends combining bronchodilators in Groups B−D in order to optimize symptom benefits  β2-agonists and muscarinic antagonists target different sites and modes of action  Several studies have shown that LAMA/LABA free combinations provide greater bronchodilation than LAMA or LABA monotherapy, which translated in greater improvements in important clinical outcomes  QVA149 is an inhaled fixed-dose combination indacaterol and glycopyrronium approved for the treatment of COPD COPD = chronic obstructive pulmonary disease LABA= long-acting β2-agonist; LAMA = long-acting muscarinic antagonist
  63. 63. -THANK YOU- 64

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