Terapia della fase stabile della BPCO farmacoterapia Dr

Terapia della fase stabile della BPCO: farmacoterapia Dr. Claudio Micheletto – Legnago (VR)

GOALS FOR TREATMENT OF STABLE COPD Reduce symptoms • Relieve symptoms • Improve exercise tolerance • Improve health status Reduce risk • Prevent disease progression • Prevent exacerbations • Reduce mortality Am J Resp Crit Care 2013

CLASSE FARMACO CARATTERISTICA Anticolinergici a lunga durata d’azione (LAMA) Tiotropio bromuro Glicopirronio Aclidinium Durata di azione 24 ore Durata di azione 12 ore Β 2 agonisti a lunga durata d’azione (LABA) Salmeterolo Formoterolo Indacaterolo Durata di azione 12 ore Durata di azione 24 ore Combinazioni precostituite Salmeterolo-fluticasone LABA + CSI Formoterolo-budesonide Durata di azione 12 ore Inibitore delle fosfodiesterasi-4 Per os Durata di azione 24 ore Roflumilast

CLASSE FARMACO CARATTERISTICA Β 2 agonisti a breve durata d’azione (SABA) Salbutamolo Terbutalina Fenoterolo Rapido esordio della broncodilatazione, durata di azione 4 -6 ore Anticolinergici a breve durata d’azione (SAMA) Ipratropio bromuro* Ossitropio bromuro* Esordio meno rapido, ma durata un po’ più lunga dei SABA (4 -6 ore) Metilxantine Teofilline orali a lento rilascio Finestra terapeutica ristretta. Farmaci aggiuntivi nei pazienti più gravi LABA: long acting beta 2 agonist LAMA: long acting muscarinic antagonist SABA: short acting beta 2 agonist SAMA: short acting muscarinic antagonist CSI: corticosteroidi inalatori * Disponibili solo per aerosol

La scelta terapeutica deve essere adeguata per la singola persona e guidata dalle caratteristiche e dalla gravità del quadro clinico considerato nel suo insieme di sintomi, funzione respiratoria, complicanze, comorbilità e delle peculiarità individuali (fenotipo) della persona che ne è affetta.

Am J Resp Crit Care Med 1995

The COPD dilemma COPD is defined by the presence of airflow limitation that is not fully reversible, and its treatment is mostly guided by the severity of this limitation. Severity Postbrochodilator FEV 1/FVC FEV 1 % pred At risk >0. 7 80 Mild COPD 0. 7 80 Moderate COPD 0. 7 50– 80 Severe COPD 0. 7 30– 50 Very severe COPD 0. 7 <30 Han AJRCC 2010

The COPD dilemma it is now widely recognized that COPD is a complex syndrome with pulmonary and extrapulmonary components. Importantly, significant heterogeneity exists with respect to clinical presentation, physiology, imaging, response to therapy, decline in lung function, and survival. Han AJRCC 2010

The COPD dilemma 4 (C) (D) ≥ 2 3 1 2 (A) (B) 1 0 RISK Exacerbation history RISK GOLD classification of Airflow Limitation There is consensus that FEV 1 by itself does not adequately describe the complexity of the disease and that FEV 1 cannot be used in isolation for the optimal diagnosis, assessment, and management of the disease. m. MRC 0 -1 m. MRC ≥ 2 CAT < 10 CAT ≥ 10 Symptoms Vestbo J, et al. AJRCCM 2013

Vestbo J, et al. AJRCCM 2013

GOLD 2013 Manage Stable COPD: Pharmacologic Therapy Patient Recommended First choice Alternative choice Other Possible Treatments 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 ICS + LABA or LAMA and PDE 4 -inh. or LABA and PDE 4 -inh. ICS + LABA and/or LAMA ICS + LABA and LAMA or ICS+LABA and PDE 4 -inh. or LAMA and LABA or LAMA and PDE 4 -inh. C D SABA and/or SAMA Theophylline Carbocysteine SABA and/or SAMA Theophylline SAMA: antimuscarinici a breve durata d’azione; SABA: β 2 -agonisti a breve durata d’azione; p. r. n. : all’occorrenza (pro re nata); LAMA: antimuscarinici a lunga durata d’azione; LABA: β 2 -agonisti a lunga durata d’azione; ICS: corticosteroidi per via inalatoria; PDE-4: fosfodiesterasi-4 Summary handout, Revised GOLD 2011 www. goldcopd. org/guidelines-gold-summary-2011. html

The identification and subsequent grouping of key elements of the COPD syndrome into clinically meaningful and useful subgroups (phenotypes) that can guide therapy more effectively is a potential solution of the dilemma Han KM, et al. Am J Respir Crit Care Med 2010; 182, 598 -564

Phenotypes – an operational definition ‘‘a single or combination of disease attributes that describe differences between individuals with COPD as they relate to clinically meaningful outcomes (symptoms, exacerbations, response to therapy, rate of disease progression, or death). ’’ Han KM, et al. Am J Respir Crit Care Med 2010; 182, 598 -564

GOLD 2013

Efficacy of Tiotropium in COPD Patients with FEV 1 ≥ 60% participating in the UPLIFT® Trial - SGRQ~40 Tashkin DP, et al J COPD 2012

Efficacy of Tiotropium in COPD Patients with FEV 1 ≥ 60% participating in the UPLIFT® Trial Tashkin DP, et al J COPD 2012

GOLD Stage II: Exacerbations Tiotropium (n=1384) Control (n=1355) Ratio (95% CI) P-value Time to first exacerbation (month) 23. 1 (21. 0, 26. 3) 17. 5 (15. 9, 19. 7) 0. 82 (0. 75, 0. 90)* <0. 0001* Mean number of exacerbations/pt yr (95% CI) Mean number of hospitalizations for exacerbations/ pt yr (95% CI) 0. 56 (0. 52, 0. 60) 0. 70 (0. 65, 0. 75) 0. 80 (0. 72, 0. 88)† <0. 0001† 0. 08 (0. 07, 0. 09) 0. 10 (0. 08, 0. 12) 0. 80 (0. 63, 1. 03)† 0. 082† †Rate *Hazard ratio (control vs. tiotropium) and P-value were estimated using Cox regression. ratio (tiotropium/control) and P-value were estimated using the Poisson with Pearson overdispersion model adjusting for treatment exposure. Decramer et al. Lancet 2009; 374: 1171 -78

Indacaterolo 300 µg Indacaterolo µg 150 Tiotropio • ††† • 220 • 200 • ††† • 180 • ††† • 160 • FEV 1 (ml) • • 150 *** • ††† • • 120 *** • 140 • • 130 *** • • 190 *** • • 180 • ††† • • 160 *** • 160 • *** • 140 • • 110 *** • 120 • MCID • 90 • 100 • 80 • • 50 ** • 60 • 40 • 20 • 0 • 5 • 15 • 30 • 60 • Tempo dopo la dose (min) **p<0, 01; ***p<0, 001 vs placebo. †††p<0, 05 vs tiotropio Aumenti rispetto al basale a 5 min post-dose: 60 ml (4, 4%) con tiotropio, 130 ml (9, 7%) con indacaterolo 150 µg e 140 ml (10, 2%) con indacaterolo 300 µg. Vogelmeier et al. Respiratory Research 2010

3. 0 † *** 2. 0 *** 1 punto TDI focal score *** 1. 0 0 Settimana 12 Settimana 26 • Media dei minimi quadrati (LSM). . ***p<0. 001 vs placebo; +p<0. 05 vs tiotropio BRACCIO IN APERTO • Differenza ≥ 1 = miglioramento clinicamente significativo del TDI score Donohue et al. Am J Respir Crit Care Med 2010

Punteggio totale SGRQ 51, 0 MIGLIORAMENTO Differenza -2, 1 (p<0, 001) 47, 0 43, 0 Pazienti (%) con variazione clinicamente importante del punteggio totale SGRQ Odds ratio 1, 43 (p<0, 001) 39, 0 35, 0 SGRQ = St. George’s Respiratory Questionnaire (questionario respiratorio St. George) L. J Dunn , R Buhl et al. Studio Intensity

Aclidinium improves trough FEV 1: 150 Placebo BID Aclidinium 400 µg BID Change from baseline in trough FEV 1 (m. L) 100 *** *** *** 50 128 m. L 0 -50 -100 0 4 8 12 16 20 24 Treatment week ***p 0. 001 vs placebo Jones et al, Eur Respir J 2012

Aclidinium reduces COPD exacerbation (any severity) rates (24 weeks) COPD exacerbations (/pt/year) 1. 6 Placebo BID Aclidinium 400 µg BID 1. 39 1. 2 29% 0. 98* 0. 8 0. 60 0. 4 0. 0 *p<0. 05 vs placebo 0. 40* 33% Healthcare Resource Utilization criteria EXACT criteria Jones et al, CHEST 2012

Nelle persone in regolare trattamento farmacologico, valutare ad ogni visita programmata: • la corretta e regolare assunzione della terapia • la valutazione dei sintomi ed in particolare, la tolleranza all’esercizio fisico e la dispnea da sforzo

• le modificazioni della funzione polmonare non solo in termini di FEV 1 ma anche di altri parametri come i volumi polmonari e la DLCO • la frequenza con la quale la persona ricorre a broncodilatatori a breve durata d’azione come supporto occasionale

• la frequenza e riacutizzazione gravità degli episodi di • la frequenza e la durata degli episodi di ospedalizzazione • la frequenza e la gravità collaterali e/o avversi di eventuali eventi

GOLD 2013

Kaplan–Meier Curves for the Primary and Selected Secondary Outcomes. • Vogelmeier C et al. N Engl J Med 2011; 364: 1093 -1103 These results show that, in patients with moderate-to-very-severe COPD, tiotropium is more effective than salmeterol in preventing exacerbations.

GOLD 2013

JA van Noord, et al. Eur Resp J 2005; 26: 214 -22.

Dual bronchodilation with QVA 149: the SHINE study 2/3 moderati; quasi 80% no riac. Sintomatici per entry. SGRQ >40 Bateman et al Eur Respir J. 2013

Pre-dose trough FEV 1 was significantly higher with QVA 149 vs glycopyrronium and tiotropium at all assessments 1. 20 QVA 149 Glycopyrronium Tiotropium Trough FEV 1(L) 1. 10 1. 00 0. 90 0. 80 0. 70 0. 60 0 0 4 12 26 38 52 64 Weeks Differences between QVA 149 and glycopyrronium and tiotropium were statistically significant (p<0. 0001) at each assessment during the treatment period. Data are least squares means ±SE Wedzicha JA, et al. Lancet Resp Med 2013 1 (3): 199 -209

Rate reduction of COPD exacerbations QVA 149 COPD Exacerbations (annualized rate) 5 4 3. 5 Glycopyrronium Tiotropium 0. 84* (0. 75, 0. 95) 0. 86** (0. 78, 0. 94) 0. 85†† (0. 77, 0. 94) 0. 85† (0. 75, 0. 96) 3 0. 90‡ (0. 79, 1. 02 2. 5 2 0. 88§ (0. 77, 0. 99) 1. 5 1. 16¶ (0. 84, 1. 61) 0. 81|| (0. 60, 1. 10) 1 0. 5 0 Mild exacerbations Moderate/severe exacerbations Severe exacerbations All exacerbations Values are rate reduction (95% CI); n numbers per treatment group: QVA 149 n=729; glycopyrronium n=739; tiotropium n=737. *p=0. 0052, †p=0. 0072, ‡p=0. 096, §p=0. 038, ¶p=0. 36, ||p=0. 18, **p=0. 0017, ††p=0. 0012. Wedzicha JA, et al. Lancet Resp Med 2013 1 (3): 199 -209

FEV 1 AUC 0– 12 h at Week 26 No riac per inclusione ; >80% moderati. . FEV 1 AUC 0– 12 h ( L) ∆=138 m. L, p<0. 0001 Fluticasone/salmeterol 500/50 μg Values are least-squares mean ± standard error QVA 149 110/50 μg Vogelmeier CF, et al. Lancet Resp Med. 2012

Mean SGRQ-C total score Improvement Data are LSM (SE); Mean difference in SGRQ-C total score for QVA 149 versus SFC at Week 26 was – 1· 24 (p=0· 245); SGRQ=St George’s Respiratory Questionnaire; LSM=least squares mean; SE=standard error; SFC=salmeterol/fluticasone Vogelmeier CF, et al. Lancet Resp Med. 2012

GOLD 2013

number/patient/year In the TRISTAN study, FP/Salm combination reduced the number of severe exacerbations 1. 5 1. 30 1. 04 ** 1. 05 ** 1 0. 97 * 0. 5 0 PLA * p< 0. 001 vs PLA SAL 50 FP 500 ** p = 0. 003 vs PLA SFC 50/500 Calverly et al, Lancet 2003

TORCH Study: additional effect of salmeterol/fluticasone vs both monotherapies FEV 1≤ 60% Calverley MD, et al. New Eng J Med 2007, Vol. 356 (8): 775 -210

TORCH. SGRQ Total Score Corrected mean change in SGRQ total score 3 Placebo 2 1 SALM * 0 – 1 † FP †† SALM/FP – 2 – 3 – 4 – 5 0 Number of 1149 1148 subjects 1155 1133 24 48 854 906 942 941 781 844 848 873 72 96 Time (weeks) *p = 0. 057 vs placebo; †p < 0. 001 vs placebo; 726 807 814 ††p 675 723 751 773 120 156 635 701 686 731 569 634 629 681 < 0. 001 vs placebo, SALM and FP; vertical bars are standard errors Calverley et al, NEJM 2007

N. medio riacutizzazioni/paziente/anno Bud/Form: reduction of exacerbations * 1. 8 2. 0 1. 8 1. 6 * 1. 9 1. 6 1. 4 1. 2 1. 0 0. 8 0. 6 0. 4 0. 2 0 BUD/FORM BUD FORM 1. 9 1. 8 1. 6 1. 4 * 2. 0 PL Szafranski Calverley BUD/FORM 1, 4* 1, 4(*) BUD 1, 6 FORM 1, 8 1, 9 PL 1, 9 1, 8 1. Szafranski W et al. Eur Respir J 2003; 21: 74 -81; 2. Calverley PM et al. Eur Respir J 2003; 22: 912 -919 1. 8 1. 6 1. 4 0 BUD/FORM BUD FORM Numero medio di riacutizzazioni/paziente/anno 1 Trattamento * *p<0, 05 vs BUD/FORM (*)p<0, 05 vs BUD/FORM PL

Rate ratio (RR) = 0. 74 (CI: 0. 69, 0. 79) p < 0. 0001 Larsson et al. J Intern Med 2013; 273(6): 584– 94.

0. 4 62% reduction in rate of exacerbation* Ratio: 0. 38 (95% CI: 0. 25– 0. 57) P < 0. 001 Bud/form + TIO PBO + TIO Exacerbations/patient 0. 3 0. 2 0. 1 0. 0 0 15 30 45 60 75 90 Days since randomisation Welte T, et al. Am J Respir Crit Care Med 2009;

COPD Exacerbations (Moderate or Severe) Mean rate of exacerbations per patient per year M 2 -124 & M 2 -125 pooled analysis = - 17% (CI -25; -8) p = 0. 0003 1. 5 1 0. 5 1. 374 1. 142 0 placebo roflumilast 500µg Calverley PMA, Rabe, KF , et al. Lancet 2009; 374: 685– 94

Roflumilast as Add-On Therapy in COPD Pre-bronchodilator FEV 1 1. 6 Salmeterol+ Roflumilast Pre bd FEV 1 [L] 1. 5 1. 4 1. 3 Salmeterol + Placebo 466 467 455 463 410 437 0 4 8 389 419 12 Weeks 374 403 359 384 18 24 Roflumilast Placebo Fabbri LM, Calverley PMA et al. Lancet 2009; 374: 695– 703

Roflumilast as Add-On Therapy in COPD Pre-bronchodilator FEV 1 1. 7 Tiotropium+ Roflumilast Pre bd FEV 1 [L] 1. 6 1. 5 Tiotropium + Placebo 1. 4 371 372 364 363 343 352 0 4 8 325 350 12 Weeks 318 347 310 333 18 24 Roflumilast Placebo Fabbri LM, Calverley PMA et al. Lancet 2009; 374: 695– 703

Phenotypes – an operational definition ‘‘a single or combination of disease attributes that describe differences between individuals with COPD as they relate to clinically meaningful outcomes (symptoms, exacerbations, response to therapy, rate of disease progression, or death). ’’ Han KM, et al. Am J Respir Crit Care Med 2010; 182, 598 -564

No exacerbator Overlap COPD -asthma Exacerbator with emphysema Exacerbator with chronic bronchitis Long acting bronchodilators Inhaled corticosteroids Mucolytics PDE 4 inhibitors Macrolides M Miravitlles, et al. Eur Resp J 2013

• Cessazione dal fumo : riduzione del declino funzionale • Vaccinazione antiinfluenzale : riduzione del 39% delle ospedalizzazioni e 50% della mortalità • Vaccinazione antipneumococcica: non chiara diminuzione delle riacutizzazioni; diminuzione delle polmoniti • Educazione all’autogestione con piano scritto • Terapia farmacologica • Non vi sono evidenze sull’utilizzo profilattico degli antibiotici • La riabilitazione respiratoria è associata ad un minor numero di riacutizzazioni