Bronchodilators in COPD

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Lecture presented by Dr.Ronald Dahl at Allergy Alex , February 2014 held at Alexandria, Egypt.
Allergy Alex is the leading medical event and exhibition for Allergy, Asthma and COPD in Egypt. www.allergyalex.com

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Bronchodilators in COPD

  1. 1. 2/21/2014 1 Bronchodilators in COPD Ronald Dahl Odense University Hospital Dahl Denmark Odense Research Center for Anaphylaxis Center for Eosinofilsygdom
  2. 2. 2/21/2014 2 Ronald Dahl: Disclosures • Consulting, given lectures for : Boehringer-Ingelheim, Novartis, TEVA, MEDA, Pfizer, ALK-Abello, Vectura, AZ, GSK, CIPLA COPD: Drug Combinations in alphabetical order Patient First choice Second choice Alternative Choices A SAMA prn or SABA prn LAMA or LABA or SABA and SAMA Theophylline B LAMA or LABA LAMA and LABA SABA and/or SAMA Theophylline C ICS + LABA or LAMA LAMA and LABA PDE4-inh. SABA and/or SAMA Theophylline D ICS + LABA or LAMA ICS and LAMA or ICS + LABA and LAMA or ICS+LABA and PDE4-inh. or LAMA and LABA or LAMA and PDE4-inh. Carbocysteine SABA and/or SAMA Theophylline GOLD 2013
  3. 3. 2/21/2014 3 Modified from Cooper CB, Tashkin DP. BMJ 2005;330;640-44 A clinical algorithm for the treatment of COPD Pharmacotherapy 0 1 2 LABALAMA 3 LAMA + LABA 4 LAMA + LABA + roflumilast Non-pharmacological therapy Smoking cessation Avoidance of exposure Vaccination (influenza, pneumococcal) Pulmonary rehabilitation (Exercise prescription) Supplemental oxygen Lung volume reduction surgery Lung transplantation SAMA, SABA or SAMA + SABA GOLD Spirometric Stage (approximate) Clinical stage At risk Intermittent symptoms Persistent symptoms‡ Frequent exacerbations Respiratory failure LAMA + LABA + ICS* LAMA + LABA + azithromycin *Clinical benefit of adding ICS to LABA+LAMA has not yet been demonstrated or COPD and the pathologic changes in lung tissue and airways Juni 2009 6
  4. 4. 2/21/2014 4 Mechanisms of airflow obstruction in COPD: small airways remodeling Kim et al. Proc Am Thorac Soc 2008 Emphysema causes loss of alveolar attachments to the airway wall, predisposing it to expiratory collapse Epithelial thickening (E), smooth muscle hypertrophy (SM), and chronic airway inflammation (I) E SM I Mechanisms of airflow obstruction in COPD: small airways remodeling Kim et al. Proc Am Thorac Soc 2008 Emphysema causes loss of alveolar attachments to the airway wall, predisposing it to expiratory collapse Epithelial thickening (E), smooth muscle hypertrophy (SM), and chronic airway inflammation (I) E SM I The time required to empty the different parts of the lung is determined by the product of 1. An airway component: The airway resistance (cm H2O/L/s) and 2. A lung tissue component The elastic recoil force (compliance) available to drive air out of the lung (L/cm H2O).
  5. 5. 2/21/2014 5 Airway smooth muscle contractility and lung function in smokers Opazo Saez et al. Am J Respir Crit Care Med 2000 0 20 8040 10060 120 0.0 0.5 1.5 2.5 3.5 1.0 2.0 3.0 Maximalisometricforce(g) FEV1 (% predicted) FEV1/FVC (%) 0 20 8040 10060 120 0.0 0.5 1.5 2.5 3.5 1.0 2.0 3.0 Maximalisometricforce(g) r = –0.579, p<0.004 r = –0.720, p<0.003 Effect of bronchodilator on airway distensibility and emphysema extent Baldi et al. J Appl Physiol 2010 1.4 1.0 0.6 0.2 −0.2 0 10 20 30 40 50 Baseline LAA (%) DGrs/DVL(cmH2O–1•s–1) After 400 µg albuterol Before 400 µg albuterol Linear regression lines before (dashed) and after (continuous) albuterol are shown Grs = respiratory conductance; LAA = low attenuation area; VL = lung volume
  6. 6. 2/21/2014 6 Hypotetisk model af lungedeflation med øget luftvejskaliber As airway patency over time increases with longer duration of bronchodilator action, emptying of peripheral airways with trapped air is facilitated, thus reducing hyperinflation and improving breathing mechanics (“pharmacological lung volume reduction”). A= korttidsvirkende; B=2-gange dagligt; C=1–gang dagligt Air trapping/hyperinflation – –– ––– + ++ +++ Perifer luftvej net diameter A B C Beeh KM & Beier J Adv Ther (2010) 27(3):1-10 COPD and the consequenses for respiratory physiology Juni 2009 12
  7. 7. 2/21/2014 7 In COPD FEV-1/FVC ≤ 70%FEV-1% predicted 80 50 30 Mild Moderate Severe Very severe Expected normal Mild obstruction Moderate obstruction Severe obstruction Spirometry in a 50 year old male witth different degrees of obstruction Flow-volume trace with time points in health and COPD NOLAN D , and WHITE P Thorax 1999;54:468-468
  8. 8. 2/21/2014 8 Hyperinflation VT IRVERV IC RV Normal Years - Decades Disease Progression Rest Static Hyperinflation Air Trapping at Rest Seconds - Minutes Exercise Dynamic Hyperinflation Additional Air Trapping During Exercise What is the main reasons for bronchodilators efficacy in COPD?
  9. 9. 2/21/2014 9 Bronchodilation increases IC/TLC 0 1 2 3 4 5 6 7 8 Pre Post BD Liters IC EELV IC, inspiratory capacity; TLC, total lung capacity TLC FVC FEV1 IC EELV SVC Changes in lung volumes after bronchodilation ml Celli. Chest 2003; 124:1743-1748 -1000 -800 -600 -400 -200 0 200 400 600 Tiotropium (n=37) Placebo (n=38)
  10. 10. 2/21/2014 10 FVC FEV1 IC EELV SVC ml Celli. Chest 2003; 124:1743-1748 -1000 -800 -600 -400 -200 0 200 400 600 Tiotropium (n=37) Placebo (n=38) Easier to breathe Changes in lung volumes after bronchodilation FVC FEV1 IC EELV SVC ml Celli. Chest 2003; 124:1743-1748 -1000 -800 -600 -400 -200 0 200 400 600 Tiotropium (n=37) Placebo (n=38) More air available for use Changes in lung volumes after bronchodilation
  11. 11. 2/21/2014 11 FVC FEV1 IC EELV SVC ml Celli. Chest 2003; 124:1743-1748 -1000 -800 -600 -400 -200 0 200 400 600 Tiotropium (n=37) Placebo (n=38) The air can be moved faster Changes in lung volumes after bronchodilation Constant-load 5% Wmax TLC TLC IC VT IRV The mechanical “threshold” in COPD O’Donnell and Laveneziana COPD 2007 0 1 2 3 4 5 6 7 0.00.51.01.52.0 IRV (L) Dyspnea(Borg) 0.0 0.5 1.0 1.5 2.0 2.5 0 1 2 3 4 5 6 7 8 9 10 Exercise time (min) Lungvolume(L)
  12. 12. 2/21/2014 12 Baseline Tiotropium Reduction in operational lung volume improves exercise tolerance in COPD O’Donnell et al. Eur Respir J 2004 TLC TLC EELV EILV VT IRV IC IRV 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 0 2 4 6 8 10 12 Exercise time (min) Lungvolume(L) 1.98 1.94 2.17 2.22 1.5 1.7 1.9 2.1 2.3 2.5 Day 1 After 3 weeks Placebo Indacaterol 300 µg Effects of indacaterol on inspiratory capacity and exercise tolerance in COPD Data are least squares means and standard error *p=0.04; **p=0.002 O’Donnell et al. Respir Med 2011 190 mL* 280 mL** 101 s*** 111 s* Data are least squares means and standard error *p=0.011; ***p<0.001 End-exerciseIC(L) Time(s) 484 475 585 586 0 100 200 300 400 500 600 700 Day 1 After 3 weeks 101 s*** 111 s*
  13. 13. 2/21/2014 13 Bronchodilator response in COPD Cerveri et al. J Appl Physiol 2000 Before salbutamol After salbutamol 1 2 3 4 –1 0 1 2 3 4 Volume (L) Flow(L/s) FEV1 and FVC responder 1 2 3 4 –1 0 1 2 3 4 Volume (L) Flow(L/s) FVC responder 1 2 3 4 –1 0 1 2 3 4 Volume (L) Flow(L/s) FEV1 and FVC responder Bronchodilator response in COPD • In some patients, FVC increases without an increase in FEV1 Cerveri et al. J Appl Physiol 2000 Before salbutamol After salbutamol
  14. 14. 2/21/2014 14 FVC responders FVC and FEV1 responders Emphysema extent (%) ΔFEV1(%predicted) 0 12 24 20 30 40 50 60 Bronchodilator response in COPD • Isolated volume response is associated with prevelant emphysema Cerveri et al. J Appl Physiol 2000 r = –0.89; p<0.001 The central role of airflow limitation leading to symptoms in COPD Disability Disease progression Death Air trapping Expiratory flow limitation Hyperinflation Deconditioning Inactivity Reduced exercise capacity Exacerbations COPD Breathlessness Quality of life Exercise Adapted from Cooper. Respir Med 2009
  15. 15. 2/21/2014 15 Disability Disease progression Death Air trapping Expiratory flow limitation Hyperinflation Deconditioning Inactivity Reduced exercise capacity Exacerbations COPD Breathlessness Quality of life Exercise The central role of airflow limitation leading to symptoms in COPD Bronchodilators reduce airflow limitation, air trapping and hyperinflation Adapted from Cooper. Respir Med 2009 Disability Disease progression Death Air trapping Expiratory flow limitation Hyperinflation Deconditioning Inactivity Reduced exercise capacity Exacerbations COPD Breathlessness Quality of life Exercise The central role of airflow limitation leading to symptoms in COPD This leads to fewer symptoms, improved health status, reduced exacerbation rate and possible improved survival Adapted from Cooper. Respir Med 2009
  16. 16. 2/21/2014 16 As new bronchodilators are introduced there have been more consistent improvements in outcomes for patients with COPD †≥12Formoterol (‡)≥12Salmeterol (‡)(‡)24Tiotropium Improvement in outcome 6–8 Ipratropium bromide NANA4–6Albuterol Exacerbations1–3,5,7–14 Quality of life1–14 Exercise endurance*1,2Breathlessness2–8 Lung function2–8 Duration of action (hours)1 *Outcome demonstrated by all bronchodilators, lack of evidence of significant differences between them †Equivocal evidence depending on formulation;5,10,11 ‡Evidence of numerical improvements over shorter acting comparator4,8 NA = evidence not available 1. GOLD 2009; 2. Celli et al. ERJ 2004; 3. Mahler et al. Chest 1999; 4. Rennard et al. AJRCCM 2001 5. Dahl et al. AJRCCM 2001; 6. Wadbo et al. ERJ 2002; 7. Vincken et al. ERJ 2002; 8. Brusasco et al. Thorax 2003 9. Rutten van-Molken et al. Eur J Health Econ 2007; 10. Szafranski et al. ERJ 2003; 11. Calverley et al. ERJ 2003 12. Calverley et al. NEJM 2007; 13. Niewoehner et al. Ann Intern Med 2005; 14. Tashkin et al. NEJM 2008 evidence of effectiveness; evidence of effectiveness over SABA or SAMA; evidence of effectiveness over LABA Time (h) 0 126 FEV1 4 x / day = SABA or SAMA 2418 Progress in maximizing bronchodilation in COPD 4 x / day = SABA + SAMA Trough FEV1 Trough FEV1 Trough FEV1 Trough FEV1 Beeh KM & Beier JK. Adv Ther 2010; 27:150-159
  17. 17. 2/21/2014 17 Time (h) 0 126 FEV1 4 x / day = SABA or SAMA 2418 Progress in maximizing bronchodilation in COPD 4 x / day = SABA + SAMA Beeh KM & Beier JK. Adv Ther 2010; 27:150-159 Trough FEV1 Trough FEV1 2 x / day = Long-acting e.g. LABA Time (h) 0 126 FEV1 4 x / day = SABA or SAMA 2418 Progress in maximizing bronchodilation in COPD 4 x / day = SABA + SAMA Beeh KM & Beier JK. Adv Ther 2010; 27:150-159 2 x / day = Long-acting e.g. LABA Trough FEV1 1 x / day = Ultra-long-acting (tiotropium)
  18. 18. 2/21/2014 18 Time (h) 0 126 FEV1 2418 Progress in maximizing bronchodilation in COPD Beeh KM & Beier JK. Adv Ther 2010; 27:150-159 2 x / day = Long-acting e.g. LABA Trough FEV1 1 x / day = Ultra-long-acting (tiotropium) Onset of action 1 x / day = Ultra-long-acting (LABA/LAMA or MABA) Short- vs long- vs ultralong – acting bronchodilators Type Generic name Onset of action Duration of action β-agonists Salbutamol 3–5 min <6 hours Salmeterol 20–30 min <12 hours Formoterol 3–10 min <12 hours Indacaterol 3–10 min >24 hours Anticholinergics Ipratropium 30–45 min 4–6 hours Oxitropium 30–45 min 6–8 hours Tiotropium 30–60 min 24 hours Glycopyrronium 5–15 min 24 hours Aclidinium 30–60 min >12 hours
  19. 19. 2/21/2014 19 Dose response: indacaterol and comparators F12 = formoterol 12 µg b.i.d.; S50 = salmeterol 50 µg b.i.d.; T18 = tiotropium 18 µg b.i.d. = twice-daily 250 200 150 100 50 0 TroughFEV1–differencefromplacebo(mL) 18.75 75 150 300 600 F12 S50 T18 Renard et al. Respir Res 2011 MCID 95% confidence interval 95% prediction interval Indacaterol Dose (µg) Comparators 38 Lack of Tachyphylaxis over 52 Weeks Study B2335S/SE 0 50 100 150 200 250 TroughFEV1– differencefromplacebo(mL) 75 µg 150 µg 300 µg All p<0.001 vs placebo Dotted line shows prespecified 120 mL level of clinically important difference Trough FEV1 = mean of measurements at 23 h 10 min and 23 h 45 min post-dose After 1 day Day 15 Week 12 Week 26 Week 52
  20. 20. 2/21/2014 20 39 INSURE: Indacaterol onset of action B2307 study design Phase III, randomized, double-blind, triple-dummy, placebo controlled, multicenter, 5-period, single-dose, complete block, crossover study Indacaterol 150 μg Indacaterol 300 μg Placebo Salbutamol 200 μg Salmeterol/fluticasone 50/500 μg Period II Period III Period IVPeriod I *Screening (–14 days) Washout (4–7 days) Period V Washout (4–7 days) Washout (4–7 days) Washout (4–7 days) NB: doses of indacaterol approved in Europe are 150 and 300 μg via SDDPI Balint et al. Int J COPD 2010 (Study B2307) 40 INSURE: Indacaterol demonstrates fast onset of bronchodilator effect at 5 minutes post-dose 1,2 1,3 1,4 1,5 1,6 Placebo (n=88) Salmeterol/ fluticasone (n=88) Salbutamol (n=86) Indacaterol 150 µg (n=85) Indacaterol 300 µg (n=87) LSmeanofFEV1(L) ***p<0.001, **p<0.01 versus placebo Data are least squares mean (LSM) with standard errors of the mean at 5 minutes post-dose Numbers on bars represent the difference from placebo (mL) ** *** *** *** NB: doses of indacaterol approved in Europe are 150 and 300 μg via SDDPI + 50 mL + 90 mL + 100 mL + 120 mL Balint et al. Int J COPD 2010 (Study B2307)
  21. 21. 2/21/2014 21 41 INSURE: Significantly higher proportion of patients achieving improvements of ≥12% and 200 mL in FEV1 at 5 minutes post-dose with indacaterol versus placebo and salmeterol/fluticasone 0 5 10 15 20 25 30 Placebo Salmeterol/fluticasone Salbutamol Indacaterol 150 µg Indacaterol 300 µg Patients(%)withatleast12%and200mL improvementinFEV1at5minutespost-dose * *** ††† *** ††† *** †† *p<0.05, ***p<0.001 versus placebo; ††p≤0.01, †††p≤0.001 versus salmeterol/fluticasone for odds ratios (likelihood of achieving this improvement) NB: doses of indacaterol approved in Europe are 150 and 300 μg via SDDPI Balint et al. Int J COPD 2010 (Study B2307) 42 Key findings  Indacaterol has a fast onset of bronchodilation effect 5 mins post-dose  The bronchodilator effect at 5 min post dose was similar to salbutamol but significantly superior to salmeterol/fluticasone  Indacaterol significantly increased the proportion of patients achieving improvements of ≥12% and 200 mL in FEV1 at 5 mins post-dose compared with placebo and salmeterol/fluticasone  Indacaterol shows significant improvement in bronchodilation over salbutamol and salmeterol/fluticasone at 2 hours
  22. 22. 2/21/2014 22 43 B2335S: Efficacy and safety of indacaterol once daily versus placebo and open-label tiotropium over 6 months (INHANCE) Patients Male or female, age ≥40 years, moderate-to-severe COPD FEV1 <80% and ≥30% predicted; FEV1/FVC <70% (post-bronchodilator) Number 2,059 patients involved in Stages 1 and 2; 1,683 received selected doses/comparators in Stage 2 Device Single-dose dry-powder inhaler (SDDPI) Indacaterol dose 150 and 300 µg o.d. Comparators Placebo; open-label tiotropium Main objective Efficacy of indacaterol versus placebo (FEV1 24 hours post-dose) at Week 12 Donohue et al. AJRCCM 2010 44 Stage 1 Indacaterol 75 µg o.d. (n=115) Indacaterol 150 µg o.d. (n=111) Indacaterol 300 µg o.d. (n=114) Indacaterol 600 µg o.d. (n=111) Placebo (n=119) Formoterol 12 μg b.i.d. (n=112) Tiotropium* 18 μg o.d. (n=119) Indacaterol 150 µg o.d. (n=420) Indacaterol 300 µg o.d. (n=418) Placebo (n=425) Tiotropium* 18 μg o.d. (n=420) Dose ranging 2 weeks Efficacy and safety 26 weeks Stage 2 Dose selection INHANCE: 26-week efficacy and safety B2335S study design *Open-label All drugs were delivered via proprietary single-dose dry powder inhalers NB: doses of indacaterol approved in Europe are 150 and 300 μg via SDDPI Donohue et al. AJRCCM 2010
  23. 23. 2/21/2014 23 45 INHANCE: Bronchodilation achieved by all doses of indacaterol exceeded pre-set efficacy criterion for trough FEV1 75 µg (n=115) 150 µg (n=111) 300 µg (n=114) 600 µg (n=111) Indacaterol once daily Formoterol 12 μg b.i.d. (n=112) Tiotropium 18 μg o.d. (n=119) 0 50 100 150 200 250 300 DifferenceintroughFEV1versusplacebo(mL) Data are LSM and 95% confidence intervals Barnes et al. PPT 2010 Day 15 NB: doses of indacaterol approved in Europe are 150 and 300 μg via SDDPI Pre-set efficacy criterion = highest value of: a) tiotropium vs placebo b) formoterol vs placebo c) 120 mL vs placebo 46 INHANCE: Indacaterol doses of 150, 300 and 600 µg exceeded the pre-set criterion for FEV1 AUC 75 µg (n=115) 150 µg (n=111) 300 µg (n=114) 600 µg (n=111) Indacaterol once daily 0 50 100 150 200 250 300 400 350 DifferenceinFEV1AUC1–4hversusplacebo(mL) Lowest two effective doses selected to move forward into Stage 2 of the study Data are LSM and 95% confidence intervals Barnes et al. PPT 2010 Day 14 Formoterol 12 μg b.i.d. (n=112) Tiotropium 18 μg o.d. (n=119) NB: doses of indacaterol approved in Europe are 150 and 300 μg via SDDPI Pre-set efficacy criterion (highest value among formoterol and tiotropium)
  24. 24. 2/21/2014 24 47 INVOLVE: 52-week efficacy and safety 52 weeks2 weeks Indacaterol 300 μg o.d. (n=437) Indacaterol 600 μg o.d. (n=428) Placebo (n=432) Formoterol 12 μg b.i.d. (n=435) Double-blind, randomized, placebo-controlled, parallel-group study Baseline Screening period N.B. Indacaterol 150 μg and 300 μg once-daily are registered doses The recommended dose strength is 150 μg once-daily, to be increased only on medical advice INVOLVE Dahl et al. Thorax 2010 48 1.38 Indacaterol 300 µg provided significant improvement in trough FEV1 over 52 weeks, superior to formoterol *p<0.05, ***p<0.001 vs placebo; †p<0.05, †††p<0.001 vs formoterol Data are LSM in the modified intent-to-treat population Trough = average of 23 h 10 min and 23 h 45 min post-dose values Placebo Formoterol 12 µg b.i.d. Indacaterol 300 µg o.d. *** 1.43 1.45 1.31 1.32 1.28 1.48 1.31 1.38 1.55 1.50 1.45 1.40 1.35 1.30 1.25 1.20 1.15 TroughFEV1(L) *** *** * 1.43 Day 2 Week 12 Week 52 Primary endpoint *** ††† *** ††† † Dahl et al. Thorax 2010 INVOLVE
  25. 25. 2/21/2014 25 49 Pooled efficacy data 50 *** *** *** *** *** *** 0 50 100 150 200 250 300 >12% Prespecified level of clinically relevant effect1 DifferenceintroughFEV1versusplacebo(mL) *** *** *** ≤12% ≤5% INHANCE ***p<0.001 vs placebo Data are LSM with 95% CI MCID = minimal clinically important difference Open-label tiotropium Indacaterol 150 µg Indacaterol 300 µg Baseline SABA reversibility at screening Indacaterol provides clinically significant bronchodilation at Week 12 compared with placebo regardless of SABA reversibility 1. Kleerup et al. ERS 2010; 2. Donohue et al. 2005 Published threshold of MCID1
  26. 26. 2/21/2014 26 51 1. Kleerup et al. ERS 2010; 2. Donohue et al. 2005 *** *** *** *** *** *** 0 50 100 150 200 250 300 >12% Prespecified level of clinically relevant effect1 *p<0.05, **p<0.01, ***p<0.001 vs placebo Data are LSM with 95% CIs MCID = minimal clinically important difference DifferenceintroughFEV1versusplacebo(mL) * **** ≤12% ≤5% Baseline SAMA reversibility at screening Published threshold of MCID2 Open-label tiotropium Indacaterol 150 µg Indacaterol 300 µg Indacaterol provides clinically significant bronchodilation at Week 12 compared with placebo regardless of SAMA reversibility INHANCE 52 Indacaterol provides clinically significant bronchodilation regardless of ICS use Donohue et al. (ATS poster) 2010 0 20 40 60 80 100 120 140 160 180 200 ICS non-users ICS users Data are unadjusted means and standard errors ChangeintroughFEV1frombaseline(mL) Tiotropium Formoterol Prespecified level of clinically relevant effect Indacaterol 150 µg Indacaterol 300 µgPlacebo †† ‡‡ †p<0.05, ††p=0.001 vs formoterol; ‡‡p=0.015 vs tiotropium ‡ NB: doses of indacaterol approved in Europe are 150 and 300 μg via SDDPI
  27. 27. 2/21/2014 27 53 Indacaterol provides clinically significant bronchodilation on regardless of age 0 20 40 60 80 100 120 140 160 180 200 Data are unadjusted means and standard errors ChangeintroughFEV1frombaseline(mL) Tiotropium Formoterol Indacaterol 150 µg Indacaterol 300 µgPlacebo Mahler et al. (ATS poster) 2010NB: doses of indacaterol approved in Europe are 150 and 300 μg via SDDPI Prespecified level of clinically relevant effect Age <65 years Age ≥65 years 54 1.25 1.30 1.35 1.40 1.45 1.50 1.55 1.60 Bronchodilation and baseline smoking status NB: doses of indacaterol approved in Europe are 150 and 300 μg via SDDPI Data are least squares means and standard errors **p<0.01, ***p<0.001 vs placebo; †p<0.05, ††p<0.01, †††p<0.001 vs formoterol; ‡p<0.05 vs tiotropium TroughFEV1(L) *** *** *** ††† *** † *** *** ††† ‡ *** ††† Ex-smokers Current smokers *** †† Patients evaluated: 515 220 293 440 315 422 173 202 338 275 Novartis, data on file 2008 Open-label Tiotropium Formoterol Indacaterol 150 µg Indacaterol 300 µgPlacebo
  28. 28. 2/21/2014 28 55 Kleerup et al. ATS 2010 0 70 20 30 40 50 60 Plotted data are unadjusted means. *p<0.05 vs placebo for odds ratio (OR) Difference of ≥1 = clinically important improvement in the TDI total score TDI = Transition Dyspnea Index. Patientswithclinicallyrelevant increaseinTDIscorefrombaseline (%) 45.3 57.8 54.1 60.5 65.9 Open-label Tiotropium Formoterol Indacaterol 150 µg o.d. Indacaterol 300 µg o.d. Placebo 54.3 Salmeterol OR vs placebo: 1.49* 2.02* 1.79* 1.91* 2.69* 20 60 Indacaterol provided significant and clinically relevant improvements in breathlessness over 6 months (pooled analysis) 56 Change from baseline in percentage of days with no rescue use NB: doses of indacaterol approved in Europe are 150 and 300 μg via SDDPI Siler et al. (ATS poster) 2010 0 30 5 10 15 20 25 Data are unadjusted means * p<0.05, *** p<0.001 vs placebo; ††† p<0.001 vs tiotropium Changefrombaselineinpercentage ofdayswithnorescueuse 6.8 12.0 22.0 21.6 25.4 Tiotropium Formoterol Indacaterol 150 µg Indacaterol 300 µg Placebo * *** ††† *** ††† *** †††
  29. 29. 2/21/2014 29 Indacaterol and COPD exacerbation 58 Indacaterol significantly reduces the risk of COPD exacerbations in non-ICS users over 12 weeks compared with placebo * *** * 0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 ICS non-users ICS users *p<0.05, ***p<0.001 vs placebo Data are hazard ratios and 95% confidence intervals ICS = inhaled corticosteroid Hazardratioforexacerbationsvsplacebo Open-label Tiotropium Formoterol Indacaterol 150 µg o.d. Indacaterol 300 µg o.d. Decramer et al. ERS 2010 POOLED ANALYSIS
  30. 30. 2/21/2014 30 Time to first moderate or severe COPD exacerbation Invigorate study Lacet Respiratory 2013 LABA – indacaterol improve symptoms more LAMA – tiotropium, glycopyrronium etc reduce more exacerbations GOLD 2006 revision (+ annual updates) GOLD 2011 revision GOLD 2006 vs 2011: first-line treatment I: Mild II: Moderate III: Severe IV: Very severe • FEV1/FVC <0.70 • FEV1 80% predicted • FEV1/FVC <0.70 • 50% FEV1 <80% predicted • FEV1/FVC <0.70 • 30% FEV1 <50% predicted • FEV1/FVC <0.70 • FEV1 <30% predicted or FEV1 <50% predicted plus chronic respiratory failure Active reduction of risk factor(s); influenza vaccination Add short-acting bronchodilator (when needed) Add regular treatment with one or more long-acting bronchodilators (when needed); add rehabilitation Add inhaled glucocorticosteroids if repeated exacerbations Add long-term oxygen if chronic respiratory failure Consider surgical treatments Risk GOLDclassificationofairflowlimitation Risk Exacerbationhistory Symptoms (mMRC or CAT score) (C) (D) (A) (B) 1 2 3 4 0 1 2 mMRC 2 CAT 10 mMRC 0–1 CAT <10
  31. 31. 2/21/2014 31 Indacaterol in COPD treatment which patients? • In clinical practice indacaterol is of benefit in all cases of COPD that come to the doctor. • Especially those patients with more breathlessness and many symptoms Indacaterol in COPD treatment which dose? • 150 µg of clinical value in all cases • 300 µg considered in the more symptomatic, • Both dosages are without side effects and adverse effectsh
  32. 32. 2/21/2014 32 Patients (%) with notable values for laboratory variables, vital signs and QTc interval Indacaterol Tiotropium Plasma potassium <3.0 mmol/L 0 0 Blood glucose >9.99 mmol/L 3.3 2.6 Pulse rate – high† 0.3 0 Systolic blood pressure – high‡ 0.9 0.6 Diastolic blood pressure – high§ 0.8 1.6 QTc interval (Fridericia’s) Absolute value >450/470 ms (males/females) 2.9 3.1 Absolute value >500 ms 0 0.1 Increase from baseline 30–60 ms 4.6 6.0 Increase from baseline >60 ms 0.3 0 †>130 bpm, or ≥120 bpm and ≥15 bpm increase from baseline; ‡>200 mmHg, or ≥180 mmHg and ≥20 mmHg increase from baseline; §>115 mmHg, or ≥105 mmHg and ≥15 mmHg increase from baseline NB: doses of indacaterol approved in Europe are 150 and 300 μg via SDDPI Buhl et al. Eur Respir J 2011 Indacaterol 150 µg o.d. (N=144) n (%) Indacaterol 300 µg o.d. (N=146) n (%) Placebo (N=124) n (%) Pulse rate – higha 0 1 (0.7) 0 Systolic blood pressure – highb 1 (0.7) 2 (1.4) 2 (1.6) Diastolic blood pressure – highc 1 (0.7) 0 2 (1.6) QTc >450/470 ms (males/females)d 10 (6.9) 9 (6.2) 11 (8.9) Increase 30–60 ms 28 (19.4) 30 (20.5) 30 (24.4) Increase >60 ms 1 (0.7) 1 (0.7) 1 (0.8) a>130 bpm, or ≥120 bpm and ≥15 bpm increase; b>200 mmHg, or ≥180 mmHg and ≥20 mmHg increase; c>115 mmHg, or ≥105 mmHg and ≥15 mmHg increase dNo patient had value >500 ms Cardiovascular safety profile of indacaterol: 52-week safety study Chapman et al. Chest 2011 () INDORSE
  33. 33. 2/21/2014 33 Safety: Indacaterol is not associated with increased risk of CCV adverse events or serious adverse events Indacaterol 150 µg Indacaterol 300 µg Indacaterol 600 µg Indacaterol doses combined Formoterol Salmeterol Open-label Tiotropium Placebo N 746 853 547 2146 556 333 415 1,185 Total patient years 331.04 379.31 222.25 932.87 227.49 149.79 180.23 487.41 No of CCV AEs 46 56 24 126 28 19 33 54 Patients with CCV AEs, n (%) 39 (5.2) 43 (5.0) 18 (3.3) 100 (4.7) 22 (4.0) 16 (4.8) 24 (5.8) 41 (3.5) Relative risk versus placebo of experiencing ≥ one CCV AE (95% CI) 1.51 (0.98, 2.32) 1.46 (0.96, 2.22) 0.95 (0.55, 1.64) 1.35 (0.94, 1.92) 1.14 (0.69, 1.90) 1.39 (0.79, 2.44) 1.67 (1.02, 2.73) p-value 0.061 0.090 1.000 0.106 0.585 0.255 0.044 No. of CCV SAEs 15 15 9 39 5 7 12 16 Patients with CCV SAEs, n (%) 15 (2.0) 12 (1.4) 7 (1.3) 34 (1.6) 3 (0.5) 5 (1.5) 9 (2.2) 15 (1.27) Relative risk vs placebo of experiencing ≥ one CCV SAE (95% CI) 1.59 (0.78, 3.23) 1.11 (0.52, 2.36) 1.01 (0.42, 2.47) 1.25 (069, 2.29) 0.43 (0.12, 1.47) 1.19 (0.43, 3.24) 1.71 (0.76, 3.89) p-value 0.256 0.845 1.000 0.549 0.208 0.785 0.238 Worth et al. Resp Med 2011 N.B. Registered doses of indacaterol are 150 and 300 μg once daily via Onbrez® Breezhaler®. The 600 µg dose is not registered. Safety: Rate of CCV adverse events is similar across treatments Indacatero l150 µg Indacatero l300 µg Indacaterol 600 µg Formoterol 12 µg Salmeterol 50 µg Open-label Tiotropium 18 µg Placebo N 746 853 547 556 333 415 1,185 CCV AEs†, n (%) Arrhythmia SMQ 22 (2.9) 24 (2.8) 12 (2.2) 11 (2.0) 9 (2.7) 17 (4.1) 26 (2.2) Cardiac failure SMQ 3 (0.4) 4 (0.5) 3 (0.5) 7 (1.3) 2 (0.6) 2 (0.5) 4 (0.3) Ischemic heart disease SMQ 10 (1.3) 12 (1.4) 5 (0.9) 4 (0.7) 6 (1.8) 7 (1.7) 6 (0.5) Cerebrovascular disorders SMQ 4 (0.5) 3 (0.4) 0 1 (0.2) 0 2 (0.5) 7 (0.6) CCV SAEs†, n (%) Arrhythmia SMQ 5 (0.7) 1 (0.1) 2 (0.4) 1 (0.2) 2 (0.6) 4 (1.0) 4 (0.3) Cardiac failure SMQ 0 2 (0.2) 1 (0.2) 1 (0.2) 0 0 2 (0.2) Ischemic heart disease SMQ 7 (0.9) 6 (0.7) 5 (0.9) 1 (0.2) 4 (1.2) 4 (1.0) 5 (0.4) Cerebrovascular disorders SMQ 3 (0.4) 3 (0.4) 0 0 0 1 (0.2) 4 (0.3) Worth et al. Resp Med 2011 †Patients may be counted more than once across different SMQ groupings. N.B. Registered doses of indacaterol are 150 and 300 μg once daily via Onbrez® Breezhaler®. The 600 µg dose is not registered.
  34. 34. 2/21/2014 34 Summary: Safety • Once-daily indacaterol was shown to have an acceptable safety profile • The overall incidence and pattern of adverse events and serious adverse events were similar to placebo and the active comparators tiotropium, salmeterol and formoterol in patients with moderate-to-severe COPD LABA is established in COPD and improves a range of clinical outcomes • Lung function • Inspiratory capacity • Exercise capacity • Effectiveness of pulmonary rehabilitation • Dyspnea • Health status • Exacerbations
  35. 35. 2/21/2014 35 COPD: Drug Combinations in alphabetical order Patient First choice Second choice Alternative Choices A SAMA prn or SABA prn LAMA or LABA or SABA and SAMA Theophylline B LAMA or LABA LAMA and LABA SABA and/or SAMA Theophylline C ICS + LABA or LAMA LAMA and LABA PDE4-inh. SABA and/or SAMA Theophylline D ICS + LABA or LAMA ICS and LAMA or ICS + LABA and LAMA or ICS+LABA and PDE4-inh. or LAMA and LABA or LAMA and PDE4-inh. Carbocysteine SABA and/or SAMA Theophylline GOLD 2013 Modified from Cooper CB, Tashkin DP. BMJ 2005;330;640-44 A clinical algorithm for the treatment of COPD Pharmacotherapy 0 1 2 LABALAMA 3 LAMA + LABA 4 LAMA + LABA + roflumilast Non-pharmacological therapy Smoking cessation Avoidance of exposure Vaccination (influenza, pneumococcal) Pulmonary rehabilitation (Exercise prescription) Supplemental oxygen Lung volume reduction surgery Lung transplantation SAMA, SABA or SAMA + SABA GOLD Spirometric Stage (approximate) Clinical stage At risk Intermittent symptoms Persistent symptoms‡ Frequent exacerbations Respiratory failure LAMA + LABA + ICS* LAMA + LABA + azithromycin *Clinical benefit of adding ICS to LABA+LAMA has not yet been demonstrated or
  36. 36. 2/21/2014 36 GOLD 2013: treatment goals for stable COPD  Relieve symptoms  Improve exercise endurance  Improve health status REDUCE SYMPTOMS AND  Prevent disease progression  Prevent and treat exacerbations  Reduce mortality REDUCE RISK COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease. GOLD 2013 GOLD 2013: treatment goals for stable COPD  Relieve symptoms  Improve exercise endurance  Improve health status REDUCE SYMPTOMS AND  Prevent disease progression  Prevent and treat exacerbations  Reduce mortality REDUCE RISK COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease. GOLD 2013 yes yes yes yes
  37. 37. 2/21/2014 37 Thank you for your attention

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