LA CLINICA DELLA BPCO E IL RAZIONALE DI UNA NUOVA
OPZIONE TERAPEUTICA
Nicola Scichilone
Dipartimento Biomedico di Medicina Interna e Specialistica
_____________________________________
Clinical outcomes in chronic respiratory diseases
Life threat
Symptoms Emerge
Age
Diagnosis
Treatment
Intensity
Fenotipo enfisematoso
Tipo A o “pink puffer”
Fenotipo bronchitico
Tipo B o “blue bloater”
Le diverse “storie naturali” all’interno della BPCO:
“Cachessia polmonare”
Le diverse “storie naturali” all’interno della
BPCO
Airway inflammation
Mucus hypersecretion
Spirometric impairment
Hypoxemia
Remodeling
Persistence
of
symptoms
Soler-Cataluna JJ et al. Thorax 2005
*
*
*
10 20 30 40 50 60
Time (months)
0.2
0.4
0.6
0.8
1.0
Pro
ba
bility o
f su
rvivin
g
No exacerbation
1 - 2
>/= 3
Impact of COPD exacerbations on the natural
history of the disease
0.75
0.8
0.85
0.9
0.95
0 1 2 3 4
• < 2.92 Exacerbations/yr
• > 2.92 Exacerbations/yr
de
clin
e in
F
EV
1
Years
Donaldson et al, Thorax 2002
0 20 40 60 80 100
Percent
0 20 40 60 80 100 Percent
0 20 40 60 80 100 Percent
0 20 40 60 80 100 Percent
0 20 40 60 80 100
0 20 40 60 80 100
0 20 40 60 80 100
0 20 40 60 80 100
0 20 40 60 80 100
0 20 40 60 80 100
0 20 40 60 80 100
0 20 40 60 80 100
0 20 40 60 80 100
Percent
Year 1 Year 2 Year 3 23%
6% 2%
6% 3% 2%
2% 2% 1%
5% 3% 1%
3% 2% 2%
2% 2% 3%
2% 1% 1%
2% 2% 3%
1% 4% 12%
Patients with no
exacerbation
Patients with 1
exacerbation
Patients with ≥ 2
exacerbations
STABILITY OF THE FREQUENT-EXACERBATION PHENOTYPE
IN PATIENTS WITH COPD
Hurst J.R. et al., N Engl J Med 2010
Criticità delle definizioni
• COPD is a chronic disease with daily symptoms
especially during physical activity, and some have
acute severe worsenings
• Asthma is disease that vary in degree of obstruction
and symptoms during the day (nocturnal asthma),
the seasons and specific and non-specific exposures
Nella realtà…
• Asma e BPCO sono difficili da distinguere a causa
della variabilità dei sintomi e dell’ostruzione
bronchiale
• La BPCO può mostrare una significativa risposta al
broncodilatatore, e presenta spesso gradi variabili di
iperreattività bronchiale.
International Journal of COPD 2006:1(1) 49–60
© 2006 Dove Medical Press Limited. All rights reserved49
R E V I E W
Nicola Scichilone
Salvatore Battaglia
Alba La Sala
Vincenzo Bellia
Istituto di Medicina Generale e
Pneumologia, Cattedra di Malattie
dell’Apparato Respiratorio ,
Università di Palermo , Palermo, Italy
Correspondence: Nicola Scichilone
Istituto di Medicina Generale e
Pneumologia, Cattedra di Malattie
dell’Apparato Respiratorio, Università di
Palermo, via Trabucco 180, 90146
Palermo, Italy
Tel +39 091 680 2766
Fax +39 091 689 1857
Email [email protected]
Clinical implications of airway hyper-
responsiveness in COPD
Abstract: COPD represents one of the leading causes of mortality in the general population.
This study aimed at evaluating the relationship between airway hyperresponsiveness (AHR)
and COPD and its relevance for clinical practice. We performed a MEDLINE search that
yielded a total of 1919 articles. Eligible studies were defined as articles that addressed specific
aspects of AHR in COPD, such as prevalence, pathogenesis, or prognosis. AHR appears to be
present in at least one out of two individuals with COPD. The occurrence of AHR in COPD is
influenced by multiple mechanisms, among which impairment of factors that oppose airway
narrowing plays an important role. The main determinants of AHR are reduction in lung
function and smoking status. We envision a dual role of AHR: in suspected COPD, specific
determinants of AHR, such as reactivity and the plateau response, may help the physician to
discriminate COPD from asthma; in definite COPD, AHR may be relevant for the prognosis.
Indeed, AHR is an independent predictor of mortality in COPD patients. Smoking cessation
has been shown to reduce AHR. Further studies are needed to elucidate whether this functional
change is associated with improvement in lung function and respiratory symptoms.
Keywords: bronchial hyperreactivity, airway hyperresponsiveness, bronchial provocation
tests, COPD
IntroductionThe hyperresponsive state of the airways, defined as a condition in which the airways
narrow too easily or too much in response to a provoking stimulus, has been
historically associated with the asthmatic phenotype, and a body of evidence has
enabled definition of airway hyperresponsiveness (AHR) as one of the cardinal
features of asthma. However, other inflammatory respiratory diseases, such as cystic
fibrosis and COPD, may show an exaggerated airway response to spasmogens. The
significance of AHR in diseases other than asthma is yet to be elucidated and deserves
more attention. The so-called “Dutch hypothesis” postulates that asthma and COPD
are two different aspects of the same disease, and that AHR predisposes to the
development of both clinical conditions (Orie et al 1961). In this scenario, the increased
airway responsiveness could be envisaged as a contributing factor to the development
of COPD, rather than the consequence of this disease (Rijcken et al 1995), as proposed
by the international guidelines for COPD (NHLBI/WHO 2001; Celli and MacNee
2004). However, the mechanisms underlying the relationship between AHR and COPD
may not be the same as those between AHR and asthma.
COPD is characterized by progressive decline in lung function and impaired quality
of life. It represents one of the leading causes of mortality in the general population,
and its prevalence has increased dramatically in recent decades (Lopez and Murray
1998). Despite the impact of COPD in the healthcare system, the pathophysiological
components of the disease and the multiple clinical manifestations are not fully
understood. In this respect, some issues need to be addressed: first, the contribution
Price D et al. International Journal of COPD 2013
Sintomi della BPCO: impatto sugli stili di vita
2807 pazienti BPCO
Sintomatologia percepita dal paziente
Kinsman RA et al. Chest 1983
146 pazienti BPCO
Dispnea, l’importanza di indagare
Roche N et al. Presse Med, 2009
1991 soggetti affetti o a rischio di BPCO
Variabilità circadiana dei sintomi nella BPCO:
European and American survey
*p<0.001 vs all other times of day; †p<0.001 vs midday Partridge et al, Curr Med Res Opin 2009
% p
ati
en
ts
*
†
Disturbi del sonno nei pazienti anziani
con ostruzione bronchiale
Bellia et al. Sleep 2003
Presenza di sintomi notturni in funzione della
gravità di BPCO %
pati
en
ts b
oth
ere
d a
t n
igh
t b
y C
OP
D
Severity of COPD (most recent FEV1)
Price et al, World Asthma & COPD Forum 2011
COPD assessment test
Patient Characteristic Spirometric
Classification
Exacerbations
per year
mMRC CAT
A Low Risk
Less Symptoms GOLD 1-2 ≤ 1 0-1 < 10
B Low Risk
More Symptoms GOLD 1-2 ≤ 1 > 2 ≥ 10
C High Risk
Less Symptoms GOLD 3-4 > 2 0-1 < 10
D High Risk
More Symptoms GOLD 3-4 > 2 > 2
≥ 10
Global Strategy for Diagnosis, Management
and Prevention of COPD
Combined Assessment of
COPD
When assessing risk, choose the highest risk
according to GOLD grade or exacerbation history
COPD patients are at increased risk for:
• Cardiovascular diseases
• Osteoporosis
• Respiratory infections
• Anxiety and Depression
• Diabetes
• Lung cancer
These comorbid conditions may influence mortality and
hospitalizations and should be looked for routinely, and
treated appropriately.
Global Strategy for Diagnosis, Management and Prevention
of COPD - 2013
Assessment of comorbidities
Prevalence of cardiovascular diseases is
increased in COPD
Curkendall et al., Ann Epidemiol 2006
Storia naturale della BPCO nei pazienti con
malattia cardiovascolare associata
Mannino Eur Resp J 2008
CV disease
No CV disease
LA CLINICA DELLA BPCO:
IL RAZIONALE DI UNA NUOVA OPZIONE TERAPEUTICA
Somministrazione sistemica
Sangue
Alta dose
Escrezione
Organo
target
Effetti
sistemici
Sangue
Bassa dose
Effetti
sistemici
Razionale per la terapia inalatoria
Somministrazione locale
Organo
target
Escrezione
Global Strategy for Diagnosis, Management and Prevention of COPD
Manage Stable COPD: Pharmacologic Therapy
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
Ridurre i sintomi
Migliorare la tolleranza allo sforzo
Migliorare la qualità della vita
Prevenire l’ evoluzione della malattia
Prevenire e trattare le riacutizzazioni
Ridurre la mortalità
Ridurre i
sintomi
Ridurre il
rischio
Progetto strategico mondiale per la diagnosi, trattamento e
prevenzione della BPCO
Trattamento della BPCO stabile: obiettivi del
trattamento
©2014 Global Initiative for Chronic Obstructive Lung Disease
Air trapping
Hyperinflation
Airflow obstruction Exacerbations
Poor health-related quality of life
Activity
limitation
Dyspnea
Patient
Centered
Outcomes
Anxiety
Hypoxemia
Tachypnea
Ventilatory
requirement
Deconditioning
Bersagli del trattamento
COPD
Anzueto 2007 mod
Global Strategy for Diagnosis, Management and Prevention of COPD
Manage Stable COPD: Pharmacologic Therapy
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
Global Strategy for Diagnosis, Management and Prevention of COPD
Manage Stable COPD: Pharmacologic Therapy
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
Broncodilatatori approvati negli ultimi 5 anni e in
sviluppo per la terapia della BPCO
QD = once daily; BID = twice daily
Drug Class Route Development
stage
Glycopyrronium LAMA Inhaled, QD Approved
Aclidinium LAMA Inhaled, BID Approved
Vilanterol LABA Inhaled, QD Phase II
Olodaterol
LABA Inhaled, QD Phase III
Indacaterol LABA Inhaled, QD Approved
“Which treatments work best?”
Quanto la popolazione dei megatrial è
rappresentativa dei pazienti real-life?
Scichilone et al. Respiration 2013
IN MEDICINE:
Efficacy: how well a treatment works in clinical trials or
laboratory trials
Effectiveness: how well a treatment works in practice
Efficacia comparativa dei farmaci per la
BPCO
Recettori cardiaci
• I recettori M2 sono localizzati
sulle fibre nervose presinaptiche
e fungono da inibitori a feedback
di ACh. Recettori M2 sono anche
presenti a livello cardiaco dove si
ritiene siano implicati nella
modulazione di: attività
pacemaker, conduzione
atrioventricolare, forza
contrattile;
• Il blocco di questi recettori causa
un aumento del rilascio di Ach.
questo meccanismo spiega i
fenomeni di broncocostrizione
paradossa rilevati con ipratropio,
antimuscarinico non selettivo.
Gli antimuscarinici
Time after administration, h
Effetti dei broncodilatatori sulla funzione
respiratoria nella BPCO
Donohue et al., Chest 2002
Effetti dei broncodilatatori sulla qualità
di vita nella BPCO
Brusasco et al., Thorax 2003 Donohue et al., Chest 2002
Beier et al, COPD 2013
Effetti dell’aclidinio e del tiotropio sul FEV1
Preganglionic
nerve Parasympathetic
ganglion
Postganglionic
nerve
M3
Airway smooth muscle
Ach
Acl
Ach
Aclidinio:
antagonista selettivo dei recettori M3
• Aclidinium’s
affinity at
M3 receptors
results in
rapid onset
and long
duration of
action2
1Belmonte, Proc Am Thorac Soc 2005 .
2Gavaldà et al, J Pharmacol Exp Ther 2009
M2
Aclidinium
Aclidinium
Ach
Ach
Composto M2 (h)
M3 (h)
M3 / M2
Rapporto
[3H]Aclidinio 4,7 29,2 6,2
[3H]Tiotropio 15,1 62,2 4,1
[3H]Ipratropio 0,08 0,47 5,9
Il tempo di dissociazione dai recettori M3 risulta
approssimativamente
6 volte più prolungato di quello dai recettori M2
I dati riportati si riferiscono ai valori di T½ ,
emivita di residenza
Gavaldà A et al. JPET 2009
Aclidinium dissocia lentamente dai recettori M3
L’aclidinio è rapidamente idrolizzato nel plasma
120
60 48 36 24 12
% rim
an
en
te
d
i
co
mp
osto
Tempo (minuti)
0
20
40
60
80
100
0
Aclidinio
Ipratropio
Tiotropio
rapidità di idrolisi
dell'aclidinio 2,4
minuti
Sentellas S, et al, Eur J Pharm Sci 2010
AEs
Placebo
(n=273)
Aclidinium
200 µg BID
(n=277)
Aclidinium
400 µg BID
(n=269)
Any 156 (57.1) 151 (54.5) 144 (53.5)
Serious AEs 15 (5.5) 12 (4.3) 15 (5.6)
Fatal events 1 (0.4) 1 (0.4) 1 (0.4)
AEs occurring in >3% patients
COPD exacerbation 56 (20.5) 44 (15.9) 38 (14.1)
Headache 22 (8.1) 30 (10.8) 33 (12.3)
Nasopharyngitis 23 (8.4) 32 (11.6) 30 (11.2)
Rhinitis 7 (2.6) 4 (1.4) 9 (3.3)
Diarrhoea 3 (1.1) 5 (1.8) 8 (3.0)
Hypertension 9 (3.3) 5 (1.8) 7 (2.6)
Back pain 10 (3.7) 12 (4.3) 5 (1.9)
Data reported as n (%) of patients
Jones et al, Eur Respir J 2012
Profilo di tollerabilità dell’aclidinio:
ATTAIN
Studi sull’Aclidinio Bromuro
• ACCORD COPD I1 (LAS 33)
– Uno studio di Fase III della durata di 12 settimane, per valutare l’efficacia e la sicurezza dell’Aclidinio Bromuro 200 µg e 400 µg BID vs placebo (n=561)
• ACCORD COPD II2 (LAS 38)
– Uno studio di Fase III della durata di 12 settimane, per valutare l’efficacia e la sicurezza dell’Aclidinio Bromuro 200 µg e 400 µg BID vs placebo seguito da un’estensione di 9 mesi per valutare la sicurezza dell’Aclidinio Bromuro 400 µg (n=544)
• ATTAIN3 (LAS 34)
– Uno studio di Fase III della durata di 24 settimane, per valutare l’efficacia e la sicurezza dell’Aclidinio Bromuro 200 µg e 400 µg BID vs placebo (n=828)
• LAS 39 4
– Uno studio di Fase IIIb della durata di 6 settimane, per valutare l’efficacia e la sicurezza dell’Aclidinio Bromuro 400 µg BID in confronto al Tiotropio bromuro 22,5 µg QD (n=414)
Studi di Fase IIa • LAS 235
– Uno studio di Fase IIa della durata di 2 settimane per valutare l’efficacia e la sicurezza dell’Aclinidio Bromuro 400 µg BID in confronto al Tiotropio bromuro 22,5 µg QD (n=30)
1Kerwin EM et al, COPD 2012
2Almirall, dati in archivio
3Jones PW et al, Eur Respir J 2012
4Beier J et al, COPD 2012
5Fuhr R et al. Chest 2012
Studi di Fase III
ACCORD – ATTAIN Disegno degli studi
Studi controllati a bracci paralleli condotti, in condizioni di doppia cecità,
in pazienti con BPCO da moderata a grave
1Kerwin EM, D’Urzo AD, Gelb AF et al. COPD 2012;9(2):90-101;
2Jones PW, Singh D, Bateman ED et al. Eur Respir J 2012;40:830-836
Periodo di trattamento
Aclidinio 200 µg BID
Aclidinio 400 µg BID
Placebo BID
Run-in Follow-up
V1
-2 sett.
Screening
V2
Sett. 0
Randomizzazione/baseline
V3
Sett. 1
V4
Sett. 4
V5
Sett. 8
V6
Sett. 12
Endpoint
primario
V7
Sett. 14
Contatto
telefonico /
visita
561
Endpoint primario: variazione, dal basale a fine trattamento, del FEV1 pre-dose
Aclidinio 200 µg BID
Aclidinio 400 µg BID
Placebo BID
Run-in
V1
-2 sett.
Screening
V4
Sett.4
V8
Sett. 24
Endpoint
primario
V6
Sett. 12
Follow-up
V9
Contatto
telefonico /
visita
Periodo di trattamento
V2
Sett. 0
Randomizzazione/baseline
828
12
24
Numero pazienti Trattamento (settimane)
Studio ACCORD(1)
Studio ATTAIN(2)
*p<0.001 vs placebo
*
* * *
150
100
50
0
-50
-100
4 12
Settimane di trattamento
8 0
124
mL
Cam
biam
enti dal basale
del
FE
V1 pre
dose (m
L)
Miglioramento del FEV1 pre-dose
128
mL
* *
*
*
*
*
150
100
50
0
-50
-100
4 24 12 16
Settimane di trattamento
20 8 0
*p<0.001 vs placebo
Studio ACCORD(1)
Studio ATTAIN(2)
Cam
biam
enti dal basale
del
FE
V1 pre
dose (m
L)
Placebo BID
Aclidinio 400 µg BID
Aclidinio 200 µg BID
99 mL
86 mL
Placebo BID
Aclidinio 400 µg BID
Aclidinio 200 µg BID
1Kerwin EM, D’Urzo AD, Gelb AF et al. COPD 2012;9(2):90-101;
2Jones PW, Singh D, Bateman ED et al. Eur Respir J 2012;40:830-836
Studi randomizzati a bracci paralleli, controllati vs placebo in condizioni di doppia cecità.
Pazienti randomizzati: (1)= 561; (2)= 828, affetti da BPCO moderata-grave. Durata del trattamento: (1)= 12 settimane; (2)= 24 settimane
Effects of glycopirronium and tiotropium on FEV1
1.20
1.25
1.30
1.35
1.40
Week 12 Day 1 Week 26 Week 52
1.45
1.50
1.55
Primary endpoint
n=500 n=250 n=245 n=513 n=245 n=253 n=451 n=219 n=233 n=416 n=196 n=210
1.478
1.388
1.471
91 mL* 83 mL*
1.469
1.372
1.455
97 mL* 83 mL*
1.458
1.324
1.408
134 mL*† 84 mL*
1.412
1.303
1.392
108 mL* 89 mL*
NVA237 Placebo Tiotropium
Kerwin E et al. Eur Resp J 2012
*p<0.001 vs placebo
300
200
150
100
50
0
0
Cam
biam
enti dal basale
del
FE
V1 di picco (m
L)
250
* * * * *
Settimane di trattamento
192
mL
4 12 8
Miglioramento del FEV1 di picco
209
mL
*p<0.001 vs placebo
300
200
150
100
50
0
4 24 12 16
Settimane di trattamento
20 8 0
Ca
mb
ia
me
nti d
al b
asa
le
del
FE
V1
d
i p
ic
co
(m
L)
250
*
* *
*
*
Studio ACCORD(1)
Studio ATTAIN(2)
146 mL
Placebo BID
Aclidinio 400 µg BID
Aclidinio 200 µg BID
185 mL
Placebo BID
Aclidinio 400 µg BID
Aclidinio 200 µg BID
1Kerwin EM, D’Urzo AD, Gelb AF et al. COPD 2012;9(2):90-101;
2Jones PW, Singh D, Bateman ED et al. Eur Respir J 2012;40:830-836
Studi randomizzati a bracci paralleli, controllati vs placebo in condizioni di doppia cecità.
Pazienti randomizzati: (1)= 561; (2)= 828, affetti da BPCO moderata-grave. Durata del trattamento: (1)= 12 settimane; (2)= 24 settimane
Interventions to improve nocturnal
airflow limitation: tiotropium
Calverley et al, Thorax 2003
Tiotropium pm (n=35)
FE
V1 (
L)
at
the
en
d o
f W
ee
k 6
0.7
0.9
0.8
1.0
1.1
1.2
1.3
-3 3 6 9 12 15 18 21 24 0
3pm 9pm 3am 9am 9am
Time (hours)
Tiotropium am (n=37)
Placebo (n=33)
am, morning; FEV1, forced expiratory volume in 1 second; pm, evening
Interventions to improve nocturnal airflow
limitation: tiotropium and formoterol
1.5
1.4
1.3
1.2
1.1
1.0
0.9
-2 0 2 4 6 8 10 12 14 16 18 20 22 24
FE
V1 (
L)
at
the
en
d o
f
We
ek
2
9am 3pm 9pm 3am 9am
Time (hours)
Tiotropium q.d. + formoterol b.i.d.
Tiotropium q.d.
Tiotropium q.d. + formoterol q.d.
24 h baseline
van Noord et al, Chest 2006
Randomised, open-label, crossover study in patients (n=95)
with stable COPD
*
*
* *
* *
*p<0.05 for tiotropium q.d. + formoterol b.i.d. vs tiotropium q.d. + formoterol q.d.
b.i.d., twice daily; COPD, chronic obstructive pulmonary disease; q.d., once daily
Evening
dose
**
**
** *
* *
***
***
**
*
*
Ch
an
ge
fro
m b
ase
lin
e F
EV
1
(m
L)
Tiotropium 18 µg QD Aclidinium 400 µg BID Placebo
Time (h)
Aclidinio fornisce una broncodilatazione
persistente
9 am 9 pm 9 am
Fuhr et al, Chest 2012
*p<0.05, **p<0.01, ***p<0.001 aclidinium vs tiotropium
Aclidinio migliora i sintomi notturni
ACCORD COPD I
0.2
0.0
-0.6
Ch
an
ge
fro
m b
ase
lin
e
at W
eek
1
2
Aclidinium 400 µg BID
Placebo
-0.2
-0.4
Breathlessness Cough Sputum
production
Wheezing
**
*** ***
***
Kerwin et al, COPD 2012
0.0
-0.4 Aclidinium 400 µg
BID
Placebo
-0.1
-0.2
-0.3
Ch
an
ge
fro
m b
ase
lin
e at
We
ek
1
2
Severity for the first hour
on getting up in the
morning†
Impact on
morning activities‡
***
***
Aclidinio migliora i sintomi diurni:
ACCORD COPD I
Kerwin et al, COPD 2012
***p<0.001 vs placebo
0
-3
-4
-5
-6
Settimane di trattamento
0
2.5
Variazio
ne vs basale
(S
GR
Q) -2
4 12 8
MCID
-1
***
***
***
Miglioramento della QdV
**p<0.01, ***p<0.001 vs placebo
0
-2
-4
-6
-8
Settimane di trattamento
0
4.6
Differenza
clinicamente
significativa
Variazio
ne vs basale
(S
GR
Q)
24 12
MCID
**
***
***
20 8 16 4
Studio ACCORD(1)
Studio ATTAIN(2)
Placebo BID
Aclidinio 400 µg BID
Aclidinio 200 µg BID
Placebo BID
Aclidinio 400 µg BID
Aclidinio 200 µg BID
MCID, minimum clinically important difference
1Kerwin EM, D’Urzo AD, Gelb AF et al. COPD 2012;9(2):90-101;
2Jones PW, Singh D, Bateman ED et al. Eur Respir J 2012;40:830-836
Studi randomizzati a bracci paralleli, controllati vs placebo in condizioni di doppia cecità.
Pazienti randomizzati: (1)= 561; (2)= 828, affetti da BPCO moderata-grave. Durata del trattamento: (1)= 12 settimane; (2)= 24 settimane
Miglioramento della limitazione attività
Beier J et al. COPD 2013
Studio randomizzato a bracci paralleli, controllato vs placebo e tiotropio in condizioni di doppia cecità mediante la
tecnica del double-dummy.
Pazienti randomizzati: 414 affetti da BPCO moderata-grave.
Durata del trattamento: 6 settimane
**p<0.01 vs placebo, *p<0.05 vs tiotropio
NS= non significativo vs placebo
Aclidinio 400 µg BID
Tiotropio 18 µg UID
**
*
Limitazione attività
0.0
-0.3
Diffe
re
nza
d
al p
la
ceb
o
ne
lla
va
ria
zio
ne
vs b
asa
le
-0.1
-0.2
NS
Sesta settimana di
trattamento
Tiotropium Significantly Delayed Time to First
Exacerbation
Pro
bab
ilit
y o
f C
OP
D e
xacerb
ati
on
(%
)
Time to event (days)
0
50
0 30 60 90 120 150 180 210 240 270 300 330 360
Hazard ratio = 0.83*
(95% CI, 0.77, 0.90)
P<0.001 (log-rank test)
Tiotropium 3707 3369 3136 2955 2787 2647 2561 2455 2343 2242 2169 2107 1869
Salmeterol 3669 3328 3028 2802 2605 2457 2351 2251 2137 2050 1982 1915 1657
No. of patients at risk:
45
40
35
30
25
20
15
10
5
Tiotropium
Salmeterol
*Cox regression adjusted for (pooled) centre and treatment.
17%
Risk
difference
Vogelmeier C et al N Engl J Med 2011
Aclidinium riduce il tasso di riacutizzazioni
(24 settimane): ATTAIN
Healthcare Resource
Utilization criteria
EXACT
criteria
0.4
0.8
1.2
1.6
0.0
0.60
0.40*
1.39
0.98*
CO
PD
exa
cerb
ati
on
s
(/p
t/year)
Placebo Aclidinium 400 µg BID
29%
33%
Jones et al, CHEST 2012
*p<0.05 vs placebo
Fenotipi della BPCO: dalla clinica alla
terapia
Tinetti et al, American J Med 2004
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