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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 80
Moderate COPD 0.7 50–80
Severe COPD 0.7 30–50
Very 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
rba
tion
his
tory
RIS
KG
OL
D c
lass
ifica
tion
of A
irflo
w L
imita
tion
0
1
≥2
4
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 LABASABA and/or SAMA
Theophylline
C
ICS + LABAor
LAMA
LAMA and LABA orLAMA and PDE4-inh. or
LABA and PDE4-inh. SABA and/or SAMA
Theophylline
D
ICS + LABAand/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
• †††
• ***
• **
• †††
• ***
• †††
• ***
• ***
• †††
• ***
• ***
• ***
• †††
• ***
• ***
• ***
•F
EV
1 (
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
2,27
2,13
2,412,382,58
Placebo Tiotropio 18 µg o.d.
Indacaterolo 150 µg o.d. Indacaterolo 300 µg o.d.
******
†
******
1 p
un
to
1 p
un
to
***3.0
2.0
1.0
0
TD
I fo
cal s
core
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
MIG
LIORAM
ENTO
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
-100
4 2412 16
Treatment week
2080
Placebo BIDAclidinium 400 µg BID
128 mL
Ch
ang
e fr
om
bas
elin
ein
tro
ug
h F
EV
1 (m
L)
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
exa
cerb
atio
ns
(/p
t/ye
ar)
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
Tro
ug
h F
EV
1(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
(an
nu
aliz
ed
ra
te)
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
FE
V1
AU
C 0
–1
2h (
L)
Vogelmeier CF, et al. Lancet Resp Med. 2012
Mean SGRQ-C total score
Improvem
ent
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
/pat
ient
/ye
ar
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
–1
0
1
2
3
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 Calverley
BUD/FORM 1,4* 1,4(*)
BUD 1,6 1,6
FORM 1,8 1,9
PL 1,9 1,8*p<0,05 vs BUD/FORM (*)p<0,05 vs BUD/FORM
0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
BUD/FORM BUD FORM PL
1.4
1.6
1.81.9
0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
BUD/FORM BUD FORM PL
1.41.6
1.81.9
N.
me
dio
ria
cutiz
zazi
on
i/pa
zie
nte
/an
no
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/
patie
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 M
e an
rate
of
exac
erba
ti on s
pe r
p a
t ien t
pe r
ye a
r
= - 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
FE
V1 [ 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 18
Weeks
RoflumilastPlacebo
Pre
bd
FE
V1
[ 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