Terapia della fase stabile della BPCO: farmacoterapia

Dr. Claudio Micheletto – Legnago (VR)

…..

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

CLASSE FARMACO CARATTERISTICA

Anticolinergici a lunga durata d’azione (LAMA)

Tiotropio bromuroGlicopirronioAclidinium

Durata di azione 24 oreDurata di azione 24 oreDurata di azione 12 ore

Β2 agonisti a lunga durata d’azione (LABA)

SalmeteroloFormoteroloIndacaterolo

Durata di azione 12 oreDurata di azione 12 oreDurata di azione 24 ore

Combinazioni precostituite LABA + CSI

Salmeterolo-fluticasoneFormoterolo-budesonide

Durata di azione 12 ore

Inibitore delle fosfodiesterasi-4

Roflumilast Per os Durata di azione 24 ore

CLASSE FARMACO CARATTERISTICA

Β2 agonisti a breve durata d’azione (SABA)

SalbutamoloTerbutalinaFenoterolo

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 beta2 agonistLAMA: long acting muscarinic antagonist

SABA: short acting beta2 agonistSAMA: 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 FEV1/FVC

FEV1 % pred

At risk >0.7 80

Mild COPD 0.7 80Moderate COPD 0.7 50–80Severe COPD 0.7 30–50Very severe COPD 0.7 <30

Han AJRCC 2010

Han AJRCC 2010

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

The COPD dilemma

There is consensus that FEV1 by itself does not adequately describe the complexity of the disease and that FEV1 cannot be used in isolation for the optimal diagnosis, assessment, and management of the disease.

(C) (D)

(A) (B)

RIS

KE

xace

rbat

ion

hist

ory

RIS

KG

OLD

cla

ssifi

catio

n of

Airf

low

Lim

itatio

n

0

1

≥24

3

2

1

mMRC 0-1 mMRC ≥ 2 CAT < 10 CAT ≥ 10

Symptoms

Vestbo J, et al. AJRCCM 2013

Vestbo J, et al. AJRCCM 2013

GOLD 2013Manage Stable COPD: Pharmacologic Therapy

Patient RecommendedFirst choice

Alternative choice Other PossibleTreatments

ASAMA prn

or SABA prn

LAMA or

LABA or

SABA and SAMA

Theophylline

BLAMA

or LABA

LAMA and LABA SABA and/or SAMATheophylline

CICS + LABA

or LAMA

LAMA and LABA orLAMA and PDE4-inh. or

LABA and PDE4-inh. SABA and/or SAMA

Theophylline

DICS + LABA

and/or LAMA

ICS + LABA and LAMA or ICS+LABA and PDE4-inh. or

LAMA and LABA orLAMA and PDE4-inh.

CarbocysteineSABA 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 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 FEV1 ≥ 60% participating in the UPLIFT® Trial - SGRQ~40

Tashkin DP, et al J COPD 2012

Efficacy of Tiotropium in COPD Patients with FEV1 ≥ 60% participating in the UPLIFT® Trial

Tashkin DP, et al J COPD 2012

GOLD Stage II: ExacerbationsTiotropium

(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)†

<0.0001†

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)†

0.082†

*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: 1171-78

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

• 220• 200• 180• 160• 140• 120• 100• 80

• 60

• 40

• 20

• 0

• Tempo dopo la dose (min)• 5 • 15 • 30 • 60

• †††

• ***

• **

• †††

• ***

• †††

• ***

• ***

• †††

• ***

• ***

• ***

• †††

• ***

• ***

• ***

•FE

V1 (

ml)

• †††

• ***

• 50

• 120

• 130

• 90

• 150

• 160

• 110

• 140

• 180

• 120

• 160

• 190

• MCID

Vogelmeier et al. Respiratory Research 2010

1,201,40

1,95

2,272,13

2,412,382,58

Placebo Tiotropio 18 µg o.d.Indacaterolo 150 µg o.d. Indacaterolo 300 µg o.d.

******

†***

***

1 pu

nto

1 pu

nto

***3.0

2.0

1.0

0

TDI f

ocal

sco

re

Settimana 12 Settimana 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

51,0

47,0

43,0

39,0

35,0

MIGLIO

RAMEN

TO

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

*** ******

******

***

Aclidinium improves trough FEV1:

150

100

50

0

-50

-1004 2412 16

Treatment week2080

Placebo BIDAclidinium 400 µg BID

128 mL

Cha

nge

from

bas

elin

ein

tro

ugh

FEV 1

(mL)

Jones et al, Eur Respir J 2012***p0.001 vs placebo

Aclidinium reduces COPD exacerbation(any severity) rates (24 weeks)

Healthcare ResourceUtilization criteria

EXACTcriteria

0.4

0.8

1.2

1.6

0.0

0.60

0.40*

1.39

0.98*

CO

PD e

xace

rbat

ions

(/pt/y

ear)

Placebo BIDAclidinium 400 µg BID

29%

33%

Jones et al, CHEST 2012*p<0.05 vs placebo

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 FEV1 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 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

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 QVA149: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 FEV1 was significantly higher with QVA149 vs glycopyrronium and tiotropium at all assessments

0 4 12 26 38 52 640.60

0.70

0.80

0.90

1.00

1.10

1.20 QVA149 Glycopyrronium Tiotropium

Weeks

Trou

gh F

EV1(

L)

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 2013 1 (3): 199-209

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=0.0012.

Mild exacerbations Moderate/severe exacerbations

Severe exacerbations All exacerbations0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

QVA149 Glycopyrronium Tiotropium

CO

PD

Exa

cerb

atio

ns (a

nnua

lized

rate

)

0.84* (0.75, 0.95)

0.85† (0.75, 0.96)

0.88§

(0.77, 0.99)

0.90‡

(0.79, 1.02

1.16¶

(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 2013 1 (3): 199-209

FEV1 AUC0–12h at Week 26No riac per inclusione ; >80% moderati..

Values are least-squares mean ± standard error

1,56 1.701,4

1,5

1,6

1,7

1,8

∆=138 mL, p<0.0001

Fluticasone/salmeterol500/50 μg

QVA149110/50 μg

FEV

1 A

UC

0–12

h ( L

)

Vogelmeier CF, et al. Lancet Resp Med. 2012

Mean SGRQ-C total score Im

provement

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

GOLD 2013

In the TRISTAN study, FP/Salm combination reduced the number of severe exacerbations

* p< 0.001 vs PLA ** p = 0.003 vs PLA

0

0.5

1

1.5

PLA SAL50 FP500 SFC50/500

*** ** 0.97

1.051.04

1.30

num

ber/p

atie

nt/y

ear

Calverly et al, Lancet 2003

TORCH Study: additional effect of salmeterol/fluticasone vs both monotherapies

Calverley MD, et al. New Eng J Med 2007, Vol.356 (8): 775-210

FEV1≤60%

TORCH. SGRQ Total Score

–5–4–3–2–10123

0 24 48 72 96 120 156

Corrected mean change in SGRQ total score

Time (weeks)

Placebo

SALM*FP

†

*p = 0.057 vs placebo; †p < 0.001 vs placebo; ††p < 0.001 vs placebo, SALM and FP; vertical bars are standard errors

Number ofsubjects

1149114811551133

854906942941

781844848873

726807807814

675723751773

635701686731

569634629681

SALM/FP††

Calverley et al, NEJM 2007

Bud/Form: reduction of exacerbations

Numero medio di riacutizzazioni/paziente/anno1

Trattamento Szafranski CalverleyBUD/FORM 1,4* 1,4(*)BUD 1,6 1,6FORM 1,8 1,9PL 1,9 1,8

*p<0,05 vs BUD/FORM (*)p<0,05 vs BUD/FORM

0

0.20.4

0.6

0.81.0

1.2

1.4

1.61.82.0

BUD/FORM BUD FORM PL

1.41.6

1.81.9

0

0.20.4

0.6

0.81.0

1.2

1.4

1.61.8

2.0

BUD/FORM BUD FORM PL

1.41.6

1.81.9

N. m

edio

riac

utiz

zazi

oni/p

azie

nte/

anno

1. Szafranski W et al. Eur Respir J 2003; 21: 74-81; 2. Calverley PM et al. Eur Respir J 2003; 22: 912-919

** * *

0,80

1,09

0,0

0,2

0,4

0,6

0,8

1,0

1,2

BUD/FORM FLU/SAL

Exac

erba

tion

rate

(exa

cerb

ation

s/pa

tient

/yea

r)

Larsson et al. J Intern Med 2013; 273(6): 584–94.

Rate ratio (RR) = 0.74 (CI: 0.69, 0.79) p < 0.0001

0.4

0.3

0.2

0.1

0.00 15 30 45 60 75 90

Days since randomisation

Exa

cerb

atio

ns/p

atie

nt

Bud/form + TIOPBO + TIO

62% reduction in rate of exacerbation* Ratio: 0.38 (95% CI: 0.25–0.57)P < 0.001

Welte T, et al. Am J Respir Crit Care Med 2009;

COPD Exacerbations (Moderate or Severe)M2-124 & M2-125 pooled analysis

Mea

n ra

te o

f exa

cerb

a tio

ns p

er

patie

nt p

er y

ear

= - 17%(CI -25;-8)p = 0.0003

0

0.5

1

1.5

placebo roflumilast 500µg

1.374 1.142

Calverley PMA, Rabe, KF ,et al. Lancet 2009;374:685–94

RoflumilastPlacebo

1.3

1.4

1.5

1.6

466467

455463

410437

389419

374403

359384

0 8 244 12 18Weeks

Salmeterol + Placebo

Salmeterol+ Roflumilast

Pre

bd

FEV

1 [L]

Roflumilast as Add-On Therapy in COPDPre-bronchodilator FEV1

Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703

1.4

1.5

1.6

1.7

371372

364363

343352

325350

318347

310333

0 8 244 12 18Weeks

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 COPDPre-bronchodilator FEV1

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

Long acting bronchodilators

Inhaled corticosteroids

Mucolytics

PDE4 inhibitors

Macrolides

No exacerbator

Overlap COPD-asthma

Exacerbator with emphysema

Exacerbator with chronicbronchitis

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