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

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Presentazione sul tema: "Terapia della fase stabile della BPCO: farmacoterapia Dr. Claudio Micheletto – Legnago (VR)"— Transcript della presentazione:

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

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7 Am J Resp Crit Care 2013 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

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9 CLASSEFARMACOCARATTERISTICA 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 LABA + CSI Salmeterolo-fluticasone Formoterolo-budesonide Durata di azione 12 ore Inibitore delle fosfodiesterasi-4 RoflumilastPer os Durata di azione 24 ore

10 CLASSEFARMACOCARATTERISTICA 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) MetilxantineTeofilline orali a lento rilascio Finestra terapeutica ristretta. Farmaci aggiuntivi nei pazienti più gravi LABA: long acting beta2 agonist LAMA: long acting muscarinic antagonist SABA: short acting beta2 agonist SAMA: short acting muscarinic antagonist CSI: corticosteroidi inalatori * Disponibili solo per aerosol

11 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.

12 Am J Resp Crit Care Med 1995

13 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. SeverityPostbrochodilator FEV 1 /FVC FEV 1 % pred At risk >0.7  80 Mild COPD  0.7  80 Moderate COPD  –80 Severe COPD  –50 Very severe COPD  0.7 <30 Han AJRCC 2010

14 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. The COPD dilemma

15 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. (C) (D) (A) (B) RISK Exacerbation history RISK GOLD classification of Airflow Limitation 0 1 ≥ mMRC 0-1 mMRC ≥ 2 CAT < 10 CAT ≥ 10 Symptoms Vestbo J, et al. AJRCCM 2013

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17 GOLD 2013 Manage Stable COPD: Pharmacologic Therapy PatientRecommended First choice Alternative choiceOther 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 C ICS + LABA or LAMA LAMA and LABA or LAMA and PDE4-inh. or LABA and PDE4-inh. SABA and/or SAMA Theophylline D ICS + LABA and/or LAMA 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 SAMA: antimuscarinici a breve durata d’azione; SABA: β2-agonisti a breve durata d’azione; p.r.n.: all’occorrenza (pro re nata); LAMA: antimuscarinici a lunga durata d’azione; LABA: β2-agonisti a lunga durata d’azione; ICS: corticosteroidi per via inalatoria; PDE-4: fosfodiesterasi-4 Summary handout, Revised GOLD 2011

18 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,

19 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,

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21 GOLD 2013

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

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

25 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) 0.56 (0.52, 0.60) 0.70 (0.65, 0.75) 0.80 (0.72, 0.88) † < † Mean number of hospitalizations for exacerbations/ pt yr (95% CI) 0.08 (0.07, 0.09) 0.10 (0.08, 0.12) 0.80 (0.63, 1.03) † † *Hazard ratio (control vs. tiotropium) and P-value were estimated using Cox regression. † Rate 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:

26 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. **p<0,01; ***p<0,001 vs placebo. ††† p<0,05 vs tiotropio Indacaterolo µg 150Indacaterolo 300 µg Tiotropio Tempo dopo la dose (min) ††† *** ** ††† *** ††† *** ††† *** ††† *** FEV 1 (ml) ††† *** MCID Vogelmeier et al. Respiratory Research 2010

27 *** † 1 punto *** TDI focal score Settimana 12Settimana 26 *** Donohue et al. Am J Respir Crit Care Med 2010 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

28 51,0 47,0 43,0 39,0 35,0 MIGLIORAMENTO Odds ratio 1,43 (p<0,001) Punteggio totale SGRQ Pazienti (%) con variazione clinicamente importante del punteggio totale SGRQ SGRQ = St. George’s Respiratory Questionnaire (questionario respiratorio St. George) Differenza -2,1 (p<0,001) L.J Dunn, R Buhl et al. Studio Intensity

29 *** Aclidinium improves trough FEV 1 : Treatment week 2080 Placebo BID Aclidinium 400 µg BID 128 mL Change from baseline in trough FEV 1 (mL) Jones et al, Eur Respir J 2012 ***p  vs placebo

30 Aclidinium reduces COPD exacerbation (any severity) rates (24 weeks) Healthcare Resource Utilization criteria EXACT criteria * * COPD exacerbations (/pt/year) Placebo BID Aclidinium 400 µg BID 29% 33% Jones et al, CHEST 2012 *p<0.05 vs placebo

31 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

32 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

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

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36 GOLD 2013

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

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39 GOLD 2013

40 JA van Noord, et al. Eur Resp J 2005; 26:

41 Dual bronchodilation with QVA149: the SHINE study 2/3 moderati; quasi 80% no riac. Sintomatici per entry. SGRQ >40 Bateman et al Eur Respir J. 2013

42 Pre-dose trough FEV 1 was significantly higher with QVA149 vs glycopyrronium and tiotropium at all assessments Differences between QVA149 and glycopyrronium and tiotropium were statistically significant (p<0.0001) at each assessment during the treatment period. Data are least squares means ±SE 0 Wedzicha JA, et al. Lancet Resp Med (3):

43 Rate reduction of COPD exacerbations Values are rate reduction (95% CI); n numbers per treatment group: QVA149 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= * (0.75, 0.95) 0.85 † (0.75, 0.96) 0.88 § (0.77, 0.99) 0.90 ‡ (0.79, ¶ (0.84, 1.61) 0.81 || (0.60, 1.10 ) 0.85 †† (0.77, 0.94 ) 0.86 ** (0.78, 0.94 ) Wedzicha JA, et al. Lancet Resp Med (3):

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

45 Mean SGRQ-C total score Improvement Data are LSM (SE); Mean difference in SGRQ-C total score for QVA149 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

46 GOLD 2013

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49 In the TRISTAN study, FP/Salm combination reduced the number of severe exacerbations * p< vs PLA ** p = vs PLA PLASAL50FP500SFC50/500 * ** number/patient/year Calverly et al, Lancet 2003

50 TORCH Study: additional effect of salmeterol/fluticasone vs both monotherapies Calverley MD, et al. New Eng J Med 2007, Vol.356 (8): FEV1≤60%

51 TORCH. SGRQ Total Score –5 –4 –3 –2 – Corrected mean change in SGRQ total score Time (weeks) Placebo SALM * FP † *p = vs placebo; † p < vs placebo; †† p < vs placebo, SALM and FP; vertical bars are standard errors Number of subjects SALM/FP †† Calverley et al, NEJM 2007

52 Bud/Form: reduction of exacerbations Numero medio di riacutizzazioni/paziente/anno 1 TrattamentoSzafranskiCalverley BUD/FORM1,4*1,4(*) BUD1,6 FORM1,81,9 PL1,91,8 *p<0,05 vs BUD/FORM ( * ) p<0,05 vs BUD/FORM BUD/FORMBUDFORMPL BUD/FORMBUDFORMPL N. medio riacutizzazioni/paziente/anno 1. Szafranski W et al. Eur Respir J 2003; 21: 74-81; 2. Calverley PM et al. Eur Respir J 2003; 22: * * **

53 Larsson et al. J Intern Med 2013; 273(6): 584–94. Rate ratio (RR) = 0.74 (CI: 0.69, 0.79) p <

54 Days since randomisation Exacerbations/patient Bud/form + TIO PBO + TIO 62% reduction in rate of exacerbation* Ratio: 0.38 (95% CI: 0.25–0.57) P < Welte T, et al. Am J Respir Crit Care Med 2009;

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56 COPD Exacerbations (Moderate or Severe) M2-124 & M2-125 pooled analysis Mean rate of exacerbations per patient per year  = - 17% (CI -25;-8) p = placeboroflumilast 500µg Calverley PMA, Rabe, KF,et al. Lancet 2009;374:685–94

57 Roflumilast Placebo Weeks Salmeterol + Placebo Salmeterol+ Roflumilast Pre bd FEV 1 [L] Roflumilast as Add-On Therapy in COPD Pre-bronchodilator FEV 1 Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703

58 Weeks RoflumilastPlacebo Pre bd FEV 1 [L] Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703 Tiotropium + Placebo Tiotropium+ Roflumilast Roflumilast as Add-On Therapy in COPD Pre-bronchodilator FEV 1

59 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,

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

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62 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


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