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COPD
2014
Alejandro C. Arroliga, M.D.
Chairman and Professor
Dr. A. Ford Wolf and
Brooksie Nell Boyd Wolf
Centennial Chair of Medicine
Organization of the talk
• A.- Inflammation
• B.- Brief review of therapy including for exacerbation
(recent papers in red)
• COPD is a systemic disease
2
PLATINO: COPD in
LatinAmerica
Mexico (Mexico
city)
12,1%!!!
Venezuela
(Caracas)
Brazil (São
Paulo)
Chile
(Santiago)
Uruguay
(Montevideo)
Menezes A, et al. Lancet 2005
COPD is a progressive
disease with inflammation
as a key process
Understanding inflammation
• Airway inflammation negatively affects health
status of COPD patients1
• Higher levels of certain inflammatory markers are
associated with a decline in lung function and
subsequent disease progression2
1. Snoeck-Stroband JB et al. Respir Res 2006; 7: 140. 2. Parr DG et al. Respir Research 2006; 7: 136 (online journal).
Inflammation is present even in the
early stages of COPD
• Airway inflammation is characterised by increased
numbers of neutrophils, macrophages and CD8+
lymphocytes1,2
• Infiltration of inflammatory cells into the airways occurs in
both early and late stages of COPD3
• As the disease progresses, the small airways fill with
inflammatory mucus exudates3
• The presence of inflammation in the airways provides a
rationale for using inhaled corticosteroids and long-acting
beta2-agonists to treat the disease
1. Gold Guideline http://goldcopd.com 2007. 2. Barnes NC et al. Am J Respir Crit Care Med 2006; 173: 736–743. 3. Hogg JC et al. New Eng J Med 2004;
350: 2645–2653.
CD8
p=0.001
CD68
p=0.288
CD45
p=0.001
30
20
CD4
p=0.002
Mast cells
p=0.022
TNF-
p=0.007
IFN-
p=0.055
Change favours
placebo
Percentage change from baseline
in biopsy and sputum endpoints
10
0
-20
-30
-40
-50
-60
-70
-80
1. Barnes NC et al. Am J Respir Crit Care Med 2006; 173: 736–743.
Change favours
SFC
SFC 50/500 – placebo (%)
-10
The Anti-inflammatory Effect Is
Associated With A Reduced Rate In
The FEV1 Decline
Ann Intern Med. 2009;151:517-527.
Synergistic effects of SFC
• Bourbeau et al suggest that combination therapy has anti-inflammatory
effects, not seen with inhaled corticosteroids alone1
• Compared with monotherapy, enhanced effects for combination are
consistent not only with clinical data but also with in vitro data2–5
• Bourbeau et al propose that the anti-inflammatory activity seen with SFC
but not FP may be due to additive or synergistic effects at the receptor
level1
• Corticosteroids may regulate 2 receptor function by increasing
expression of the receptor, and inhibiting 2 receptor down-regulation6,7
1. Bourbeau J et al. Thorax 2007; 62: 938–943. 2. Kardos P et al. Am J Respir Crit Care Med 2007; 175:144–149. 3. Mahler DA et al. Am J
Respir Crit Care Med 2002 166: 1084–1091; 4. Calverley PMA et al. Lancet 2003; 361: 449–456. 5. Calverley PMA et al. New Eng J Med 2007;
356: 775–789. 6. Johnson M. Proc Am Thor Soc 2004; 1: 200–206 7. Adcock IM. J Allergy Clin Immunol 2002; 110(6 Suppl): s261–s268.
COPD 2013
• “patients who benefit the most from inhaled
bronchodilators seem to be those who have respiratory
symptoms and airflow obstruction with an FEV1 less than
60% predicted”
• “monotherapy using either long acting inhaled
anticholinergics or long acting beta agonists(but not
inhaled steroids as monotherapy) for symptomatic
patients with an FEV1 of less than 60% predicted is
recommended
Courtesy of Frank Perez-Guerra, M.D.
Summary of data of different therapeutic
studied in patients with COPD
• UPLIFT (Tiotropium achieves improvement in lung
function over time, although rate of decline not reduced;
reduction in frequency of exacerbations and in
hospitalizations; no difference in mortality between
tiotropium and placebo
• TORCH- reduction in the rate of decline in airflow
limitation in the salmeterol/fluticasone arm compared to
placebo
• INSPIRE – comparison of SFC versus tiotropium in
severe COPD – no difference in exacerbation frequency
between the two treatments. Question of better quality of
life and reduced mortality risk with SFC.
Summary of data of different therapeutic
studied in patients with COPD
• Tiotropium/formoterol (Foradil) vs salmeterol(Serevent)/fluticasone in
moderate COPD – TF superior in lung function over the day
compared to SF (this study appeals to me, Chest 2008;134:255)
• OPTIMAL (Tiotopium/placebo, T plus salmeterol, T plus
salmeterol/fluticasone) – patients treated with T/F/S had significantly
better disease specific quality of life and fewer hospitalizations
compared to T/placebo, however these improvements in health
outcomes were associated with increased costs. Monotherapy with T
most economically attractive. Exacerbation rate did not differ
Others therapy
• Immunizations – both Pneumovax and influenza (this is an
“accepted” recommendation)
• Testing for alpha-one-anti-trypsin deficiency –
• Lung volume reduction surgery (or “medical treatment utilizing
valves”) - not a common procedure, but may be considered in very
symptomatic patients with well documented predominant upper lobe
emphysema with an FEV1 and DlCO of more than 20% of predicted
• Transplantation - LVRS may be a bridge to this. When to refer –
BODE index of over 5, post dilator FEV1 of less than 20% predicted,
resting hypoxemia, hypercapnia, secondary PH, accelerated decline
in FEV1 – but…is there a survival benefit?
Global Strategy for Diagnosis, Management and Prevention of COPD
Manage Stable COPD: Non-pharmacologic
Patient
Group
Essential
A
Smoking cessation (can
include pharmacologic
treatment)
B, C, D
Smoking cessation (can
include pharmacologic
treatment)
Pulmonary rehabilitation
Recommended
Depending on local
guidelines
Physical activity
Flu vaccination
Pneumococcal
vaccination
Physical activity
Flu vaccination
Pneumococcal
vaccination
Courtesy of Shirley Jones, M.D.
© 2013 Global Initiative for Chronic Obstructive Lung Disease
COPD 2013
• Roflumilast – this is a PDE-4 inhibitor (PDE-4
inhibition decreases inflammation and promotes
airway smooth muscle relaxation)
• Approved for COPD patients with a history of
exacerbations – the experience is limited, but this agent
may be useful perhaps not only in COPD, but in asthma,
bronchiectasis, etc – time will tell
• Mucoactive agents- the jury is out, but some
patients may improve, some even think that they
are better than the inhaled medications (but this
is doubtful)
GOLD
Assessment
Frequent
exacerbations
C
D
Severe Obstruction
Minimal Symptoms
++ Exacerbations
Severe Obstruction
Severe Symptoms
++ Exacerbations
A
B
Mild-Mod Obstruction Mild-Mod Obstruction
Severe Symptoms
Minimal Symptoms
Few Exacerbations
Few Exacerbations
Symptoms
GOLD Website. http://www.goldcopd.com. Updated December 2011
Exacerbations
Severity of Airflow
Obstruction
Worse
obstruction
More
severe
Survival shown as Kaplan-Meier curves
Groups C and D experienced a higher incidence of exacerbations in the
following year and a higher average number of exacerbations per year than
groups A and B.
Lange et al AJRCCM 2012; 186: 975–981
COPD: Pharmacologic Therapy
(FIRST CHOICE)
C
ICS + LABA
or
LAMA
ICS + LABA
or
LAMA
A
GOLD 2
or
GOLD 1
Risk
D
>2
B
SAMA prn
or
SABA prn
mMRC 0-1
CAT < 10
1
LABA
or
LAMA
mMRC > 2
CAT > 10
Symptoms
0
•
Exacerbations per year
Risk
FEV1
GOLD 4
or
GOLD 3
In alphabetical order
Exacerbations Are Not Random Events
Risks of COPD Exacerbations
Strongest predictor of an
AECOPD in a given year
was the presence of an
exacerbation in the previous
year
Gold Stage
AECOPD Rate in
Yr 1
II
0.85
III
1.34
IV
2.00
Hurst JR et al. N Engl J Med 2010; 363:1128-1138
Agusti
A, et al. Eur Respir J 2013; 42: 636
22
PA:A ratio of more than 1 at baseline was
associated with future exacerbations of COPD,
particularly those requiring hospitalization
The PA:A ratio also appears to outperform many established risk factors for
exacerbation including GERD, SGRQ score, breathlessness, chronic bronchitis,
and FEV1,as well as recently identified CT predictors.
23
Annualised exacerbation rate
SFC significantly reduces exacerbations
and severity of exacerbations over 3 years
(TORCH)
25% (p<0.001)
1.2
1
1.13
0.97
0.8
0.93
0.85
0.6
0.4
0.2
0
Placebo
SFC vs placebo
SFC vs sal
SFC vs FP
1. Calverley PMA et al. New Eng J Med 2007; 356: 775–789.
Sal
FP
SFC
Treatment effect
p-value
25%
12%
9%
<0.001
0.002
0.02
Treatment of ambulatory exacerbations of mildmoderate COPD is more effective with antibiotic vs.
placebo
Primary and Secondary
Outcomes
AMX (500/125
mg/8 hrs)
%
N=158
PBO
%
N= 152
P value
Clinical cure days 9-11*
74
59
0.016
Clinical cure at day 20
81
67
0.006
Days until exacerbation,
median
233 (110-365)
160 (66-365)
0.015
38
0.039
Peak expiratory flow from
52
basal , L/min
The NNT is seven
Llor C, et al Am J Respir Crit Care Med 2012; 186:
716 25
In patients presenting to the ER with acute
exacerbation, 5-day treatment of prednisone (40mg
daily) was noninferior to 14-day treatment
• Non inferiority was defined as a 15% absolute difference
in % of patients with a re-exacerbation (6 months)
• Average FEV1 was 31% and 87% were GOLD 3 or 4
End point
Conventional
treatment
(n=155)
Short- term
(n= 156)
Comparison
measure (95%CI)
P
value
Reexacerbations
(ITT)
36%
35%
HR 0.95 (0.70-1.29)
0.006
Deaths follow up
8%
7%
HR 0.93 (0.40-2.20)
.87
Need for MV
13%
11%
OR 0.78 (0.37-1.63) .49
Cumulative dose, 560 (560-773)
median, mg
Leuppi
JD, et al. JAMA 2013; 309: 2223-2231
26
200 (200310)
<0.001
COPD affects more
than the lungs!
TORCH overall causes of death as
adjudicated by the Clinical Endpoint
Committee
Other
10%
Unknown
7%
Cancer
21%
1. Calverley PMA et al. New Eng J Med 2007; 356: 775–789.
Respiratory
35%
Cardiac
27%
84% of COPD patients in TORCH study had
comorbidities in at least one body system
% total population
53
n=6112
34
25
21
18
18
17
14
14
12
11
10
10
9
4
4
Clinical consequences of
osteoporosis
• Acute and chronic
• Bulging abdomen, reflux and other GI
pain
• Kyphosis
symptoms
• Breathing difficulties
• Loss of height
• Loss of mobility
• Depression
• Loss of independence
Courtesy of Tony Anzueto, M.D.
REDUCED QUALITY OF LIFE
What Do COPD Patients Die From?
COPD
ASCVD
Lung Cancer
Pneum/Inf
Other
No COPD
GOLD Stage 0
Moderate COPD
GOLD Stage II
Severe COPD
GOLD Stage III
0
20
40
60
Patients (%)
Courtesy of Tony Anzueto, M.D.
Mannino et al. Thorax. 2003;58:388-393.
80
100
Prevalence of CVD in COPD
Odds ratio
8
7
6
5
4
3
2
1
0
Arrhythmia Angina
Courtesy of Tony Anzueto, M.D.
Curkendall et al, AEP 2006
Congestiv Stroke
Acute
Myocardial e Heart
Infarction Failure
Pulmonary
Embolism
Other
Cardiovascular
Disease
β-blockers can be used in patients with
COPD and heart failure
• To explore the interaction of β-blocker selectivity and
outcomes the authors queried the OPTIMIZE-HF registry
Mentz
RJ, Am J Cardiol 2013; 111: 582-87
33
β-blockers can be used in patients
with COPD and heart failure
Mentz RJ, Am J Cardiol 2013; 111: 582-87
34
Mentz RJ, Am J Cardiol 2013; 111: 582-87
35
Conclusions
The burden of COPD is high and is rising1
• COPD is a multicomponent disease with inflammation at
its core2
•
• It is important to treat the underlying inflammation, which
is present even in the early stages of the disease3,4
• Patients on SFC have significantly improved lung
function and quality of life, and a significant reduction in
exacerbations compared with components or placebo5
1. Murray CJL et al. Lancet 1997; 349:1498–1504. 2. Agusti AGN et al. Eur Respir J 2005; 99: 670–682. 3. Hogg JC et al. New Eng J Med 2004; 350: 2645–
2653. 4. Barnes NC et al. Am J Respir Crit Care Med 2006; 173: 736–743. 5. Calverley PMA et al. New Eng J Med 2007; 356: 775–789.
Conclusions
• Exacerbations are common. Patients with previous
exacerbations are more likely to have more. Presence of
cough and sputum production are associated with more
exacerbations
• Antibiotics are useful to treat exacerbations in patients
with mild to moderate COPD
• Prednisone 40 mg daily for 5 days is enough
• Use of β-blockers in patients with HF, even non selective
are well tolerated and may be associated with improve
survival
38
COPD : a vision for the next 10 years
Understanding
Improved
New
airway obstruction
drug delivery
LABAs and LAMAs
Combinations
LAMA + LABA
Ultra long-acting β2 agonists under
development
Vilanterol
Olodaterol
Abediterol (LAS-100977)
AZD3199
PF-610355 (?)
NEW LABAs

Cazzola M, et al. Respir Med 2013
Disease Severity: BDs +/- ICS

Decramer M, et al. Respir Med 2013
New LABA’s
n=35
FEV1: 37 ± 9%
TBD: 21 ± 8%
Respimat

van Noord JA, et al. Pulm Pharmacol Ther 2011
Long-acting antimuscarinic
agents
Glycopyrronium (NVA-237)
Umeclidinium (GSK-573719)
Aclidinium
TD-4208
CHF 5407
QAT370
BEA-2180BR
Trospium
Dexpirronium
AZD8683
PF-3715455 or PF-3635659
New LABA - NAV 237
n=1066
FEV1: 55,7 ± 13%
TBD: 16 ± 15%
Breezhaler

Kerwin E, et al; GLOW2. Eur Respir J 2012
New LAMA’s
n=828
FEV1: 53 ± 14%
TBD: –
Genuair
Jones PW, et al; ATTAIN. Eur Respir J 2012
COPD : a vision for the next 10 years
Understanding
Improved
New
airway obstruction
drug delivery
LABAs and LAMAs
Combinations
LAMA + LABA
The present and future
LAMAs
•
•
•
•
LABAs
• Oledanterol
Tiotropium Fixed - Combinations
- Olodaterol/ tiotropium
•
Indacaterol
Glycopyrronium
(NVA237)
-Umeclidinium/ vilanterol
• Vilanterol
-- Indacaterol/
Umeclidinium
bromide glycopyrronium
- Formoterol/aclidinium
-Formoterol/glycopyrrolate
Aclidinium bromide
•
•
•
Carmoterol
Formoterol
Salmeterol
Rationale for combining long-acting
bronchodilators
•
Inhaled bronchodilators are the foundation
of COPD treatment
•
Most patients with COPD improve with
bronchodilation
•
Maximal bronchodilation is not achieved
using clinically approved doses of 1 class of
bronchodilator alone
•
There could be synergistic interactions
Cazzola M, Molimard M. Pulm Pharmacol Ther 2010;23:257-67
between 2-agonists and anticholinergics
Combination short acting therapy
100
Albuterol
Ipratropium + Albuterol
Ipratropium
% Responding
90
80
70
60
50
40
0
15
30
45
60
75
90
105
Minutes post-drug administration
Dorinsky PM, et al. Chest. 1999;115:966–971.
120
Combining tiotropium and formoterol (dosed
once or twice daily): FEV1
Tiotropium qd + formoterol qd
Tiotropium qd + formoterol bid
Tiotropium qd + placebo bid
24-hour base
1.5
FEV1 (L)
1.4
1.3
1.2
1.1
1.0
0.9
0 2
9 AM
4
6 8
3 PM
10 12 14 16 18 20 22 24
9 PM
3 AM
9 AM
Time (hours)
van Noord JA et al. Chest 2006;129:509-17
Effects of tiotropium and formoterol on
dynamic hyperinflation and exercise
endurance in COPD
time to exercise intolerance
FEV1
Berton et al. Respiratory Medicine 2010; 104: 1288-96
Combination: LABA + LAMA
Tiotropio
(Boehringer)
Glicopirronio Aclidinio Umeclidinio
(Novartis)
(Almirall)
(GSK)
Salmeterol
(GSK)
Yes
Formoterol
(AstraZeneca)
Yes
Yes
INTRUST
QVA149
Indacaterol
(Novartis)
Vilanterol
(GSK)
Carmoterol
(Tanabe)
Yes
Yes
Yes
Olodaterol
(Boehringer)
Yes
Darotropio
(GSK)
2
Nuevas evidencias en LABA-LAMA
LS mean of FEV1(L)
QVA149
Indacaterol
Glycopyrronium
Open-label tiotropium
Placebo
1.60
1.55
1.55
1.45
1.40
1.35
1.30
1.25
1.20
1.15
1.10
1.05
1.00
5m 1h 2h
4h
8h
12h
16h
22h 24\9
Time
54/46
Bateman E, et al; SHINE. ERS Congress 2012
LABA + LAMA vs ICS/LABA

Vogelmeier CF, et al; ILLUMINATE. Lancet 2012
Four weeks once daily treatment with tiotropium +
olodaterol fixed dose combination compared with
tiotropium in COPD patients
450
*
400
*
350
*
300
250
Peak FEV1 response (mL)
200
*
Trough FEV1 response (mL)
150
100
50
0
T 5μg
T+O 5/2μg
T+O 5/5μg
T+O 5/10μg
Maltais et al, ERS Congress 2010
FEV1 after 4 weeks of treatment
1.60
FEV1 (L)a
1.50
1.40
T+O (5 / 10 µg)
T+O (5 / 5 µg)
T+O (5 / 2 µg)
T (5 µg)
1.30
1.20
-1
aMean
0
values adjusted for baseline, treatment and centre
1
2
3
Time (hours)
4
5
6
Maltais F et al. P5557 presented at ERS 2010
28-day safety and tolerability of umeclidinium in
combination with vilanterol in COPD
Change from baseline in 0–6 h weighted mean pulse rate
Feldman et al, Pulm Pharmacol Ther 2012
(Ultra) LABA/ICS combinations in clinical
development
Formoterol + mometasone (MFF258)
Formoterol + fluticasone propionate
Formoterol + ciclesonide
Indacaterol + mometasone (QMF-149)
Indacaterol + QAE-397
Vilanterol + fluticasone furoate
GS-424020 (novel mutual prodrug of salmeterol and
desisobutrylciclesonide)
Triple combination therapies in Phase I and
II clinical trials
Cazzola et al, Expert Opin Pharmacother 2012
COPD: Drug Combinations
Patient
First choice
Second choice
(in alphabetical order)
Alternative Choices
LAMA
SAMA prn
A
or
SABA prn
or
LABA
or
Theophylline
SABA and SAMA
LAMA
B
or
LAMA and LABA
SABA and/or SAMA
Theophylline
LAMA and LABA
PDE4-inh.
SABA and/or SAMA
Theophylline
LABA
ICS + LABA
C
or
LAMA
ICS + LABA
D
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
MABA: LABAS + LAMA
LABA
Long-acting beta agonist
LAMA
Long-acting muscarinic antagonist
MABA
Muscarinic antagonist and beta agonist

Hughes AD, et al. Prog Med Chem 2012
Astra Zeneca – PATHOS Study
• Objectives:
– To investigate exacerbation rates in primary care patients with COPD
treated with BF vs FS.
• Methods:
– Data from primary care medical records.
– Pairwise (1:1) propensity score matching.
• Results
– Matching of 9893 patients (7155 BF; 2738 FS yielded two cohorts of
2734 patients), comprising 19,170 patient-years.
– The exacerbation rates were 0.80 and 1.09 per patient-year BF and FS
– Yearly rates for COPD-related hospitalizations were 0.15 and 0.21,
respectively
• Conclusions
– Long-term treatment with fixed-combination BF was associated with
fewer exacerbations than FS in patients with moderate and severe
COPD.
Journal of Internal Medicine 2013 in press.
New ICS-LABAS combination
Martinez F et al Respiratory Medicine 2013; 107: 550
Inhibition of release of
inflammatory mediators by p38 inhibitors
- Signalling through p38 mitogen-activated protein kinase (p38MAPK) is required for the expression of a range of inflammatory
mediators associated with COPD such as tumor necrosis factor α,
interleukin-1 (IL-1), IL-6 and IL-8.
- PH-797804 is a potent, selective p38-MAPK
MacNee W, et al. Thorax 2013
Novel classes of bronchodilators
• Selective phosphodiesterase inhibitors
• K+ channel openers
• Vasoactive intestinal peptide analogs
• Rho kinase inhibitors
• Brain natriuretic peptide and analogs
• Nitrix oxide donors
• E-prostanoid receptor 4 agonists
• Bitter taste receptor agonists
Cazzola et al, Pharmacol Rev 2012
COPD : a vision for the next 10 years
• Further understanding of the impact of long acting
bronchodilators.
• Demonstrate the efficacy of intervention in milder
disease.
• New delivery systems
• Provide maximum bronchodilation - combination therapy
– LABA-LAMA
• New molecules