Grazie per aver scelto di utilizzare a
scopo didattico questo materiale
delle Guidelines 2011 libra.
Le ricordiamo che questo materiale è
di proprietà dell’autore e fornito
come supporto didattico per uso
personale.
PHARMACOLOGICAL MANAGEMENT
OF COPD IN PATIENTS WITH
CHRONIC CO-MORBIDITIES
Professor Peter Calverley
University Hospital Aintree
Liverpool
UK
A RUMSFELD MOMENT!
 Does having COPD influence the choice of therapy
for a co-morbidity?
 Does taking a treatment for a co-morbidity improve
the outcome in COPD?
 Does taking a treatment for COPD affect the co-
morbidity?
BETA –BLOCKERS AND COPD
 Good data for the benefits of selective beta-
blockade in congestive heart failure, rate control of
AF
 Longstanding worry that beta-blockade might
precipitate bronchospasm
 So most people avoided beta-blockers in COPD
 Now we have evidence for safety and a reason
why this is the case
BETA-BLOCKERS, COPD AND
VASCULAR SURGERY
 1205 COPD patients, 462 receiving therapy with BB pre-
surgery
Van Gestel et al AJRCCM 2008
Why COPD is not asthma –bronchodilator testing is not
helpful
30
Percent
25
20
15
10
5
35
30
25
Percent
Smoker Controls
0
20
15
10
5
0
35
30
25
Percent
Non-smoker Contr
Subject Group
COPD Subjects
35
20
15
10
5
0
-0.65 -0.55 -0.45 -0.35 -0.25 -0.15 -0.05 0.05
0.15
0.25
0.35
0.45
0.55
0.65
0.75
0.85
Change in FEV1 (L), Post-bronchodilator
0.95
1.05
1.15
1.25
1.35
THE STATIN STORY
STATINS AND COPD OUTCOMES IN LOW RISK
PATIENTS
COPD/Low Risk
Hospitalization
0.87 (.76, 1.0),
0.78 (.64, .95),
0.65 (.55, .78),
for COPD
p = .0502
p = .015
p < .0001
Hospitalization for COPD
ACE Inhibitor
ARB
Statin
0.74 (.59, .92), p = .0062
Combination
Myocardial Infarction
0.97 (.63, 1.50)
0.96 (.53, 1.73)
0.87 (.51, 1.49)
0.87 (.49, 1.54)
Death
0.60 (.49,
0.52 (.38,
0.56 (.42,
0.38 (.27,
.73),
.72),
.74),
.54),
p
p
p
p
<
<
<
<
ACE Inhibitor
ARB
Statin
Combination
ACE Inhibitor
.0001
.0001
.0001
.0001
ARB
Statin
Combination
(.59,
(.49,
(.51,
(.36,
.85),
.84),
.83),
.66),
p
p
p
p
=
=
=
<
0.0
(.84,
(.78,
(.67,
(.62,
.99),
.96),
.81),
.80),
p
p
p
p
=
=
<
<
.0260
.0056
.0001
.0001
Myocardial Infarction
1.17 (.90, 1.52)
1.10 (.79, 1.54)
0.85 (.61, 1.18)
1.27 (.90, 1.78)
Death
0.73 (.65,
0.55 (.46,
0.51 (.43,
0.35 (.28,
.83),
.66),
.62),
.44),
p
p
p
p
<
<
<
<
.0001
.0001
.0001
.0001
Myocardial Infarction or Dea
Myocardial Infarction or Death
0.71
0.64
0.65
0.49
0.91
0.86
0.74
0.70
ACE Inhibitor
.0002
.0011
.0006
.0001
ARB
Statin
Combination
0.5
1.0
1.5
0.82
0.68
0.64
0.48
(.73,
(.58,
(.55,
(.40,
2.0
Risk Ratio
Mancini et al JACC 2006
.92),
.80),
.75),
.58),
p
p
p
p
=
<
<
<
0.0
.0008
.0001
.0001
.0001
STATINS AND EXACERBATIONS
Mortenson E et al Respir Res 2009
Angina
Acute coronary
syndromes
Systemic Effects of COPD:
Target Organs
Lung Infections
Lung Cancer
Weight loss
Muscle weakness
Diabetes
Metabolic syndrome
Osteoporosis
Peptic ulceration/reflux
Systemic
Inflammation
Oxidatitive Stress
From W MacNee
Depression
Depression
TREATMENT AND COMPLICATIONS
 Depression –common, often associated with
fatigue. Interaction with therapy more likely with
systemic treatment. Corticosteroids possibly –
roflumilast unproven
 Reflux – GI issues with theophyllines and PDEIV
inhibitors
 Metabolism and diabetes –ocs associated with
hyperglycaemia but this is a feature of acute
exacerbations. More data from roflumilast
 Muscles
Most frequently reported AEs
COPD safety pool
placebo
rof500
(N=5,491)
(N=5,766)
(%)
(%)
62.8
67.2
COPD exacerbations
23.1
19.8
Diarrhoea
2.6
10.1
Weight decreased
1.8
6.8
Nasopharyngitis
6.3
6.3
Nausea
1.4
5.2
Headache
2.0
4.6
Upper respiratory tract infection
4.3
3.8
Bronchitis
3.5
3.1
Back pain
2.1
3.1
Insomnia
0.9
2.6
Influenza
2.4
2.5
Dizziness
1.2
2.4
Decreased appetite
0.4
2.2
Pneumonia
2.0
1.8
All AEs
PHARMACOLOGICALLY PREDICTABLE
EFFECTS
Nausea
Events in the category
Events in the category (%)
Diarrhoea
<1 week ≥1 week ≥4 weeks ≥13 weeks ≥26 weeks
to <4
to <13
to <26
weeks
weeks
weeks
<1 week
placebo (n=5491)
rof 500 mcg (n=5766
ET=number of patient-years of exposure
≥1 week
to <4
weeks
≥4 weeks
to <13
weeks
≥13 weeks ≥26 weeks
to <26
weeks
Weight loss
 Noted as a self-reported finding more often with
roflumilast
 Not just confined to patients reporting GI
intolerance
 Monitored with regular weight measurement in
pivotal one year trials
 In one 6 month study bioimpedance data were
available
Body weight over time in the studies
with available data
4
placebo
roflumilast 500µg
2
= -2.17 kg
0
(CI –2.4;-1.9)
p < 0.0001
-2
-4
0
8
16
24
Weeks
Timecourse: Mean change in kg
Between Treatment Differences least-squares means from ANCOVA
32
40
48
Weight change by BMI
Percent weight change from baseline to end of treatment by BMI at baseline:
pivotal COPD studies pool (SAF)
Placebo
Mean Change (%)
Rof500
N=
127 134
Underweight
605 572
Normal
462 475
Overweight
316 317
Obese
Weight loss associated with
roflumilast was primarily fat mass
Tiotropium + placebo
(BMI)
Mass indices [kg/m2]
0
Tiotropium + placebo
(FFMI)
Tiotropium + Daxas®
(FFMI)
-0.5
Tiotropium + Daxas®
(BMI)
-1
0
4
8
12
16
20
24
Weeks
Wouters EFM, Teichmann P, Brose M, et al. Am J Respir Crit Care Med 2010;181:A4473.
FFMI: Fat Free Mass Index; BMI: Body Mass Index
MUSCLES
 Loss of muscle bulk vs weakness
 A marker for more health care expense and
mortality but the thresholds may vary
 A clear relationship of weakness to ocs use long
term –not seen with ics
 Anabolic steroids reverse this process but only in
people taking oral corticosteroids (Kreutzberg E et al)
BONES AND INHALED
CORTICSTEROIDS
 Database associations but confounded by disease
severity
TORCH - Time to First Fracture
Safety Population
Plc
N=1544
SAL
N=1542
FP
N=1552
SFC
N=1546
Non-Traumatic
20 (1.3%) 29 (1.9%) 21 (1.4%) 21 (1.4%)
Traumatic
39 (2.5%) 37 (2.4%) 45 (2.9%) 58 (3.8%)
KM Prob at 3 years
5.1%
5.1%
5.4%
6.3%
Hazard
Ratio
95% CI
p
SFC vs Placebo
1.22
(0.87, 1.72)
0.248
SFC vs SAL
SFC vs FP
1.23
1.16
(0.88, 1.72)
(0.83, 1.61)
0.229
0.382
SAL vs Placebo
FP vs Placebo
1.00
1.06
(0.69, 1.43)
(0.74, 1.51)
0.977
0.765
Prevalence of Osteoporosis &
Osteopenia at Baseline
% patients
50
40
30
20
10
0
Placebo
SALM 50
FP 500
SFC 50/500
T score < -1 and > -2.5 for hip or spine: osteopaenia
T score < -2.5 for hip or spine: osteoporosis
US Safety sub-study : percent
change in total hip BMD
Adjusted mean change BMD hip
1
0
–1
–2
–3
–4
Placebo
SAL
FP
SFC
–5
0
48
108
158
72
82
80
95
52
78
65
82
Time (weeks)
Number
of subjects
161
162
158
162
Vertical bars are standard errors
87
105
112
118
Ferguson et al Chest 2009
Time to First Pneumonia AE
Probability of Event (%)
12
11
10
9
8
7
6
5
4
3
2
1
Number 0
at Risk
Probability of event prior to wk 104
SFC 9.9%
TIO 5.5%
Treatment
TIO 18
SFC 50/500
656
664
550
543
511
497
491
468
470
4242
451
426
426
405
415
387
150
136
0
13
26
39
52
65
78
91
104
Time to Event (Weeks)
SFC vs TIO
Cox Hazard Ratio
1.94
95% CI
(1.19, 3.17)
p-value
0.008
SFC 50/500
TIO 18
TIME TO FIRST PNEUMONIA AE OR
SAE
Sin et al Lancet 2009
Cardiovascular Events with
Tiotropium
Composite Endpoint* Used by Singh et al applied to UPLIFT
Placebo
Tiotropium
Rate Ratio1 (95 % CI)
n
Rate2
n
Rate2
Composite endpoint
246
2.89
208
2.25
0.78 (0.65, 0.94)
Fatal composite
124
1.42
98
1.04
0.73 (0.56, 0.95)
UPLIFT
1
rate ratio tio vs. placebo; 2per 100 person-years of time at risk to tiotropium or placebo
*SOC cardiac (fatal), SOC vascular (fatal), MI (fatal+nonfatal), stroke (fatal+nonfatal),
sudden death, sudden cardiac death
All-cause mortality at 3 years
Probability of death (%)
18
16
14
12
10
8
6
4
Placebo
SALM
FP
SFC
2
0
0
12 24 36 48 60 72 84 96 108 120 132 144 156
Time to death (weeks)
Number 1524
alive
1533
1521
1534
Vertical bars are standard errors
1464
1487
1481
1487
1399
1426
1417
1409
1293
1339
1316
1288
Calverley et al. NEJM 2007
CARDIOVASCULAR EVENTS AND
THERAPY
Calverley et al Thorax 2010
CVS TREATED COPD AND THERAPY
Calverley et al Thorax 2010
Time to onset of first major adverse CV
event (MACE*)
Probability of event
0.04
roflumilast 500 mcg, od, p.o. + roflumilast 250 mcg, od p.o.
placebo, od, p.o.
0.03
0.02
0.01
0.00
0
30
60
90
120 150 180 210 240 270 300 330 360 390
Days post-randomisation
MACE : CV death, non-fatal MI, non-fatal stroke
CONCLUSIONS
 Beta–blockers and other cardiac drugs are safe in





COPD
Statins may improve COPD outcomes but proper
trial data are needed
Oral therapies produce more GI upset, oral
corticosteroids long term are hazardous
Inhaled corticosteroids do not seem to accelerate
osteoporosis but some may induce pneumonia
LAMA and LABA treatment is safe in COPD – antiinflammatory therapy may improve cardiac
outcomes
On balance our treatments are more friend than
foe