Transcript www.indianchestsociety.in

Treating for COPD: today and
tomorrow
Dr. Parthasarathi Bhattacharyya
7/17/2015
napcon '13
1
Prescription is the written or printed
instruction of a doctor for evaluation and
medication to a patient with other
relevant information
7/17/2015
napcon '13
2
Dr P B
MD, ADCD
Regn no. 000000
Date: xx/yy/zz
Identification: age/sex
Clinical history
# (diagnosis)
Smoker : bidi-30 years (x 20/day)
SOB-8 years, now MRC III , worsened 2 days
expectoration ++, mucoid
Adv,
N diet
Findings
Stop smoking
Deriphylline R (300mg) 1 tab BDPC
Ventorlin Inhaler 2 puffs thrice daily
Nefindine R (20mg) 1 tab BDPC.
Follow up after one month
P-92 / min
BP= 120/84 mm
Occasional spasm +
Available investigations
Plan of evaluation
CxR (PA)
Hb, TC,DC, ESR
7/17/2015
Sugar (F) , Spirometry
napcon '13
signature
3
“Over 47 years ago, when the author graduated from
medical school, the only therapies for COPD were
antibiotics for pneumonia, potassium iodide used as a
mucus thinner, and combination products containing
ephedrine, a small amount of theophylline, and a minor
amount of sedative to deal with the side effects of
ephedrine. Inhaled isoproterenol began to be used in
the early 1960s. In that era, oxygen was considered
contraindicated, and exercise was prohibited for fear of
straining the right heart. Corticosteroids were almost
never used, even in cases of exacerbations of COPD.
Petty T L. The history of COPD. International Journal of COPD
7/17/2015
napcon '13
4
2006:1(1)
3–14
Milestones in understanding COPD
7/17/2015
napcon '13
5
Defining COPD
• The CIBA guest symposium of
physicians in 1959 : defining chronic
bronchitis and emphysema
• William Briscoe in 1965: first coined
the term COPD
7/17/2015
napcon '13
6
Smoking and annual decline in lung function
100
Non smoker
Non-susceptible
smoker
75
Susceptible
smoker
(10-20%)
50
Disability
25
Death
0
25
50
75
Age (years)
7/17/2015
Fletcher C, Peto R: BMJ 1977
napcon '13
7
The ‘GOLD’ initiative
• GOLD 1997
• Defining COPD with spirometric criteria and
classification according to the degree of
reduction of FEV1
• COPD: FEV1/FVC <70%
FEV1
Degree of obstruction: GOLD I
> 80 %
GOLD II > 50 %
GOLD III > 30 %
GOLD IV < 30 %
7/17/2015
napcon '13
8
Significant facts
• Understanding the genesis of symptoms
Air trapping and dynamic hyperinflation and that
(the degree of obstruction have no co-relationship with the symptomatology)
• Assessment of COPD needs
a) spirometric and lung functional
b) functional ability
c) health status and quality of life
doctor centric disease centric patient centric
7/17/2015
napcon '13
9
More facts: recognition of
• The importance of health status: CAT being
the most useful discovery
• The importance of COPD exacerbations in the
natural history of the disease
7/17/2015
napcon '13
10
Understanding the pathophysiology
Airway inflammation
+
Systemic inflammation
Renewed understanding of the clinical
spectrum
7/17/2015
napcon '13
11
Clinical spectrum renewed
Airway / lung related
Systemic
•
•
•
•
•
Shortness of breath
Cough
Mucus hypersecretion
Exacerbations
Complications
•
•
•
•
•




infection
respiratory failure
Pneumothorax
others
7/17/2015
Sarcopenia
Peptic ulcer
Osteoporosis
Peripheral neuropathy
Cardiovascular
problems
• Cancer (?)
• Depression
• Others
napcon '13
12
Understanding the molecular
mechanism of COPD
7/17/2015
Barnes P J. CHEST 2008; 134:1278–1286
napcon '13
13
Therapeutic advances:
•
•
•
•
•
•
Inhalation therapy
Role of long term oxygen
Pulmonary rehabilitation
Muscarinic antagonists
Role of steroid
Attention towards systemic complications and
co-morbidities The inclusion of co-morbidities
in the clinical work up and prescription (GOLD
2013 guideline)
7/17/2015
napcon '13
14
Understanding cardiovascular
involvement:
•
•
•
•
•
7/17/2015
CAD and Ischemic heart disease
LVDD
Heart failure
Atrial fibrillation
Pulmonary hypertension
napcon '13
15
7/17/2015
napcon '13
16
A diagnosis today: includes
• COPD,
• Predominant clinical phenotype (emphysema/ chronic
bronchitis), exacerbation phenotype
• Stable / exacerbation:
type of exacerbation (infective/ non infective)
degree of exacerbation (mild, moderate….)
• GOLD classification
• Health status (CAT score, SGRQ)
• Co-morbidities
• Complications
• Others
7/17/2015
napcon '13
17
A model diagnosis
Diagnosis of a rheumatic heart disease in 80s
• Rheumatic heart disease, severe MS- mild MR
and AR, normal sinus rhythm, no PH/
corpulmonale, no arrhythmia, no features of IE
Diagnosis of COPD today
• Stable COPD, GOLD III, Predominant emphysema,
with systemic features as ……., infrequent
exacerbations, no complications, having co
morbidities as ……… with a CAT score of 14
suggesting ……….
7/17/2015
napcon '13
18
Evolutions of a COPD prescription
7/17/2015
napcon '13
19
Dr. P B
MD, ADCD.
Regn no 00000
Mr SK R, 65M
7/17/2015
napcon '13
1985
20
Dr. P B
MD, ADCD.
Regn no 00000
1995
Mr SK R, 65M
Date:
Smoker 30 years
SOB, expectoration ++
# COPD
Adv,
N diet
Deriphylline R (300mg) 1 tab BDPC
Ventorlin Inhaler 2 puffs thrice daily
Nefindine R (20mg) 1 tab BDPC.
Follow up after one month
P-92 / min
BP= 120/84 mm
Occasional spasm +
CxR (PA)
Hb, TC,DC, ESR
Sugar (F)
7/17/2015
signature
napcon '13
21
2000
Mr S K R, 65M
Date:
Smoker : bidi-30 years (x 20/day)
# COPD: AE
SOB-8 years, now MRC III , worsened 2 days
expectoration ++, mucoid
Adv,
N diet
Stop smoking
P-92 / min
Deriphylline R (300mg) 1 tab BDPC
BP= 120/84 mm
Ventorlin Inhaler 2 puffs thrice daily
Occasional spasm +
Nefindine R (20mg) 1 tab BDPC.
No flaps
Follow up after one month
wysolone (10) one tab BD
Amoxycillin (500) 1 tab TDS
CxR (PA)
Bronchial Hygiene
Hb, TC,DC, ESR
Sugar (F)
Spirometry
sputum for C/S
signature
7/17/2015
napcon '13
22
Dr. P B
MD, ADCD.
Regn no 00000
2005
Mr S K R, 65M
Date:
Smoker : bidi-30 years (x 20/day)
# COPD with exacerbation, HTN
SOB-8 years, now MRC III , worsened 2 days
expectoration ++, mucoid
Adv,
N diet
Stop smoking
P-92 / min, SaO2 -95%
Deriphylline R (300mg) 1 tab BDPC
BP= 120/84 mm
Ventorlin Inhaler 2 puffs thrice daily
Occasional spasm +
Ipravent inhaler 2 puffs twice daily
seretide (250) evohaler : 2 puffs BD
Nefindine R (20mg) 1 tab BDPC.
No flaps
Follow up after one month
CxR (PA)
Hb, TC,DC, ESR
Sugar (F)
Spirometry
signature
Sputum for Gram’s stain and C/S
Plan:'13
Pulmonary rehabilitation
7/17/2015
napcon
23
Dr. P B
MD, ADCD.
Regn no 00000
2013
Mr S K R, 65M
Date:
Smoker : bidi-30 years (x 20/day)
# COPD- GOLD IV in AE (? non Infective),
SOB-8 years, now MRC III , worsened 2 days, poor QOL, exacerbation phenotype
expectoration ++, mucoid
Adv,
Co-morbiditiies: HTN, depression
N diet
Three exacerbations in last 6 months
Stop smoking
Azithromycin ………………
P-92 / min, SaO2 -95%
92 %
Deriphylline R (300mg) 1 tab BDPC
BP= 120/84 mm, BMI 19.2
Ventorlin Inhaler 2 puffs thrice daily
Acc muscles +,Occasional spasm +
Tiotropium inhaler 2 puffs once daily.
No flaps, P2
Amlodepine (5mg) 1 tab daily morning
CAT score 22
Follow up after one month
Ranitidine (150 mg) 1 tab before dinner
Bronchial hygiene
CxR (PA), ECG
Influenza and pneumococcal vaccine
Hb, TC,DC, ESR
Sugar (F)
Spirometry : FEV1% =61 FEV1 29 % (1.04 L)
signature
Sputum for Gram’s stain and C/S
7/17/2015
napcon
Echo
doppler , HRCT chest
Plan:'13
Pulmonary rehabilitation
24
Foundations for change in future
7/17/2015
napcon '13
25
New therapies
• Nicotine de-addiction
• Bronchodilatation
• Anti –inflammatory
a) anti oxidants
b) anti-protease
c) others
• Lung volume reduction
• Regenerative therapy
• Identification and treatment new associations of
COPD
7/17/2015
napcon '13
26
New therapies
• Nicotine de-addiction:
vaccine
• Bronchodilatation
• Anti –inflammatory
a) anti oxidants
b) anti-protease
c) others
• Lung volume reduction
• Regenerative therapy
• Identification and treatment new associations of COPD
7/17/2015
napcon '13
27
Nicotine de-addiction: vaccine
7/17/2015
napcon '13
28
7/17/2015
napcon '13
29
Improved smoking cessation:
nicotine vaccine
• Antibodies against the free nicotine circulating in
the blood
• Nicotine-Qbeta, CYT002-NicQb and NicVAX are
currently three such vaccines under
development. The combination of active and
passive immunization may also be a good
strategy. (1, 2)
1. Jacques Cornuz. A Vaccine against Nicotine for Smoking Cessation: A
Randomized Controlled Trial. PLoS ONE 3(6): e2547.
doi:10.1371/journal.pone.0002547
2. Carola Seifart and Claus Vogelmeier. Emerging drugs in chronic obstructive
pulmonary diseases. Expert Opinion. Emerging Drugs 2009;14:181-194
7/17/2015
napcon '13
30
7/17/2015
napcon '13
31
New bronchodilators
•
•
•
•
•
New antimuscarinic agents: Ultra LAMAs
New LABAs: ultra LABAs
Novel combinations
MABA
Antibody drug conjugate
7/17/2015
napcon '13
32
Ultra long acting anti-muscarinic
agents:
Potent and long acting
•
•
•
•
•
Aclidinium,
Glycopyrronium,
Darotropium,
TD-4208,
CHF5407, QAT-370, GSK-573719,
Dexpirronium and RBx 343E48F0
7/17/2015
napcon '13
33
“Aclidinium Bromide Improves Lung Function in a
Wide Range of Patients With Moderate to Severe
COPD: Pooled Subgroup Analysis of the ACCORD COPD
I and II and ATTAIN Trials”
‘These data show that ACL400 produces clinically and statistically
significant improvements in lung function from Week 1 through
Week 12. These improvements were seen regardless of sex, age,
smoking status, COPD severity, concomitant ICS, or bronchodilator
reversibility status. A larger improvement in lung function was seen
with ACL400 in patients with bronchodilator reversibility than
without.’
D'Urzo A, Jones P, Ferguson G, Rekeda L, Gil E G, Caracta C. Chest. 2013; 144
(4_MeetingAbstracts):746A. doi:10.1378/chest.1703098
7/17/2015
napcon '13
34
• Dose-Ranging Study of 2 Fixed-Dose Combinations
of Twice-Daily Aclidinium Bromide Plus Formoterol
in Patients With Moderate to Severe COPD
Improvement at day 14 in FEV1 over placebo
aclid.400µg + for 12µg :
aclid.400µg + for 6µg:
aclidinium 400µg,
formoterol 12µg
placebo,
200 ml
202
157
127
p <0.001
Kerwin E, Lapidus R, Leselbaum A, Ortiz S, Rowe P, Caracta C. Chest. 2013; 144
(4_MeetingAbstracts):747A. doi:10.1378/chest.1703061
7/17/2015
napcon '13
35
Ultra LABAs
• Carmoterol, indacaterol, milveterol, vilanterol,
olodaterol, LAS100977, PF610355,
JNJ39758979, Saligenin- or indolecontaining
β2-agonists, UK-503590 and Compound X and
others
•
•
•
Indacaterol may be better than salmeterol, formoterol and tiotropium in
increasing trough FEV1 in COPD with no evidence of tachyphylaxis.
Milveterol has been found to be safe and well-tolerated in asthma, with
efficacy comparable to salmeterol. Its role in COPD is yet unexplored.
Vilanterol has been found to be safe and effective in both asthma and COPD
patients.
7/17/2015
napcon '13
36
Novel combinations
LABA+LAMA+ steroids
• Aclidinium+formoterol±fluticasone/budesonide,
• Tiotropium+ formoterol ± Fluticasone /Budesonide,
• Glycopyronium+formoterol±mometasone,
• Indacaterol+ glycopyrronium (QVA-169),
• Olodaterol + tiotropium,
• Milveterol/vilanterol + darotropium,
• Carmoterol + tiotropium and formoterol +
dexpirronium.9-16
7/17/2015
napcon '13
37
Newer agents
MABA
• Dual-acting muscarinic antagonist- β2-agonist
(MABA) bronchodilators: GSK-961081,
Bicyclohept-7-ylamine derivatives, THRX200495, THRX-198321, LAS190792 and TD5959
Antibody drug conjugate
7/17/2015
napcon '13
38
Anti inflammatory agents
• Anti –inflammatory
a) PDE4 inhibitors
b) anti oxidants
b) anti-protease
c) others
7/17/2015
napcon '13
39
Roflumilast
• PDE4 inhibitor
• Small effects on COPD: 9 to 65 ml in FEV1
• Reduces moderate to severe exacerbation, not
hospitalization or mortality
• AEs are upto 2 % (GI, nervous system,
psychiatric, and sytemic) and discontinuation
for AEs 15 %
• SAE: AF and suicidality
7/17/2015
napcon '13
40
Antioxidants
7/17/2015
napcon '13
41
Kodgule R, Vaudya A, Salvi S. JAPI, 2012; 20: S8-13
Antioxidants
• NAC
• N-acestelyn (NAL): well tolerated in clinical
trials
• N-isobutyrylcysteine (NIC): less effective
• Erdosteine: reduces bacterial adhesiveness as
an additional property
• Procysteine: toxicities
• Carbocysteine
7/17/2015
napcon '13
42
N-acetyl cysteine
• Prospective randomized study: comparing high
dose NAC (1200 mg OD) with inhaled fluticasone
• 23 subjects of moderate to severe COPD
• 1200 mg per day for 4 weeks
• Significant reduction of exhaled carbon monoxide
(biomarker of oxidative stress)
• Increase in FEV1 by 112ml in NAC group against a
30ml reduction in the fluticasone group
7/17/2015
napcon '13
43
7/17/2015
napcon '13
44
Kodgule R, Vaudya A, Salvi S. JAPI, 2012; 20: S8-13
Antiprotease
7/17/2015
napcon '13
45
Molecular mechanism of COPD
MMPs
inhibitors
7/17/2015
napcon '13
46
Antiprotease
• Both human and animal studies suggests the
role of MMPs in COPD and MMPs inhibition
has been identifies as a prospective therapy
7/17/2015
napcon '13
47
Anti MMPs efforts
• (MMPs), a class of Zinc endopeptidase, has been found
to play an important role (1).
• They are found to be active and up-regulated in
emphysema induced by smoking (2,3,4).
• The pulmonary expressions of different MMPs are found
increased in several human observations in COPD (5, 6, 7).
1. Belvisi MG, Bottomley KM. Inflamm Res 2003; 52: 95–100.
2. Churg A, Zay K, Shay S, Xie C, et al. Am J Respir Cell Mol Biol 2002; 27: 368–374.
3. Churg A, Wang RD, Tai H, et al. Am J Respir Crit Care Med 2003; 167:1083–1089.
4. Houghton AM, Quintero PA, Perkins DL, et al. J Clin Invest 2006; 116:753–759.
5. Imai K., Dalal SS, Chen ES, et al. Am J Respir Crit Care Med 2001; 16: 3. 786-791
6. Finlay GA, Russell KJ, McMahon KJ, et al. Thorax 1997; 52(6): 502-506
7. Shapiro SD. Am J Respir Crit Care Med 1994; 150 (6 Pt 2): S160-S164
7/17/2015
napcon '13
48
Different anti MMPs in COPD
• Marimastat, a nonselective MMP inhibitors,
appeared to have major side effects in phase-III
human trials as (1)
• AZ11557272, a dual MMP-9/MMP-12 inhibitor,
has not passed the clinical developmental
procedure (2)
1. Hu J, Van Den Steen PE, Sang QX, et al. Matrix metalloproteinase inhibitors
as therapy for inflammatory and vascular diseases. Nat Rev Drug Discov 2007;
6: 480–498
2. Churg A, Wang R, Wang X, et al. Effect of an MMP-9/ MMP-12 inhibitor on
smoke-induced emphysema and airway remodelling in guinea pigs. Thorax
2007; 62: 706–713
7/17/2015
napcon '13
49
Anti MMPs therapy: doxycycline
• Acts by binding to the active zinc site and also
by inactivating calcium ion site leading to
conformational changes resulting in loss of
enzymatic activity (1)
• Available in the market with good safety
record with many documented long term uses
• Its anti MMPs use in periodontal disease has
been recognized by USFDA (2)
1. Kaito K, Urayama H, Watanabe G. Surg Today 2003; 33: 426-433
2. L.M.Gulab, H.M.Lee, M.E. Ryan, et al. Adv Dent Res 1998; 12:12-2.
7/17/2015
napcon '13
50
Long term doxycycline in COPD
Duration
Group 1 Group 2
Group 3
<100 days 100-400 d 400-800 d
A Number of patients n=8
n=26
n=11
Group 4
> 800 days
n=14
B Duration (mean)
83.0±11.83
234.65±90.75
590.27±133.74 734.93±425.56
C Age
64.38±6.78
60.77±10.82
61.82±6.69
65.43 ± 9.90
D Mean FEV1 (initial)
1.03±0.40
0.83±0.38
1.02±0.45
1.14 ± 0.39
1.11±0.47
(80 ml)
0.94±0.40
(110 ml)
1.11±0.45
(90 ml)
0.98 ± 0.42
(-160 ml)
0.252
0.000020
0.082
0.0734
E
F
Mean FEV1
(after add-on
doxycycline)
Significance in
difference (p value
7/17/2015
between D and E)
napcon '13
51
Unpublished data: source- IPCR, 2012
Long term doxycycline can improve
COPD: the initial interim results of an
open prospective randomized trial.
(CTRI No-CTRI/2011/07/001873) (P 213 NAPCON, ‘13)
7/17/2015
napcon '13
52
Randomized open prospective trial
Case
3 months
n=23
6 months
n=9
Before Rx
After Rx
p-value
Before Rx
After Rx
p-value
FEV1 %
(post BD)
51.69±13.02
55.11±14.76
0.00001
48.98±11.77
54.53±12.13
0.01
FEV1
(post BD)
1.10± 0.53 1.22±0.53
0.007
0.94± 0.38 1.05± 0.43 0.007
Control
3 months
n=20
6 months
n=11
FEV1 %
(post BD)
54.59±12.90
55.89±11.95
0.46
50.04±12.93
54.24±11.48
0.02
FEV1
(post BD)
1.10±0.28
1.01±0.35
0.45
0.92±0.25
0.89±0.30
0.46
7/17/2015
napcon '13
53
Comparison of standard therapy vs.
standard therapy + add-on doxycycline
Post BD FEV1 between standard therapy and
standard therapy + doxycycline on 3 months
3 month post BD
FEV1 (CASE)
1.5
3 month post BD
FEV1 (CONTROL)
1
Linear (3 month
post BD FEV1
(CASE))
0.5
0
0
10
20
n=23 (Case)
n=20 (Control
7/17/2015
30
Post BD FEV1 value
Post BD FEV1 value
2.5
2
Post BD FEV1 between standard therapy and
standard therapy + doxycycline on 6 months
1.8
Linear (3 month
post BD FEV1
(CONTROL))
napcon '13
1.6
1.4
6 months post BD
FEV1 (Case)
1.2
1
6 months post BD
FEV1 (Control)
0.8
0.6
Linear (6 months
post BD FEV1 (Case))
0.4
0.2
0
0
5
n= 9 (Case)
n= 11 (Control)
10
Linear (6 months
post BD FEV1
(Control))
54
Long term doxycycline can improve COPD: the initial
interim results of an open prospective randomized trial.
(CTRI No-CTRI/2011/07/001873)
Change in CAT score between standard therapy and
Standard therapy + add on doxycycline.
7/17/2015
napcon '13
55
Long term doxycycline can improve COPD: the initial interim
results of an open prospective randomized trial.
(CTRI No-CTRI/2011/07/001873)
Index
index
Exacerbation
index= no. exacerbations in anapcon
particular
period x100/ no. of visits in that period
7/17/2015
'13
56
What does it mean in real life ?
7/17/2015
napcon '13
57
7/17/2015
napcon '13
58
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. One
or more hospitalizations for COPD exacerbations
should be considered high risk.)
Patien
t
Characteristic
Spirometric
Classification
Exacerbations mMRC
per year
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
7/17/2015
napcon '13
© 2013 Global Initiative for Chronic Obstructive Lung Disease
≥ 10
59
ANNUAL DECLINE IN LUNG FUNCTION
100
Non smoker
Non-susceptible
smoker
75
Susceptible
smoker
(10-20%)
50
Disability
25
Death
0
25
50
75
Age (years)
7/17/2015
Fletcher C, Peto R: BMJ 1977
napcon '13
60
ANNUAL DECLINE IN LUNG FUNCTION
100
Non smoker
Non-susceptible
smoker
75
Susceptible
smoker
(10-20%)
50
Stopped smoking
aged 50 yr
Disability
25
Death
Stopped smoking
aged 60 yr
0
25
50
75
Age (years)
7/17/2015
Fletcher C, Peto R: BMJ 1977
napcon '13
61
ANNUAL DECLINE IN LUNG FUNCTION
100
Non smoker
Non-susceptible
smoker
75
Susceptible
smoker
(10-20%)
50
Stopped smoking
aged 50 yr (a)
Disability
25
Death
Stopped smoking
aged 60 yr (b)
0
25
50
65
70 75 80
Age (years)
7/17/2015
napcon '13
62
Fletcher C, Peto R: BMJ 1977 Disability by 15 years for ‘a’ and death by 8 years for ‘b’
ANNUAL DECLINE IN LUNG FUNCTION
100
Non smoker
Non-susceptible
smoker
75
Susceptible
smoker
(10-20%)
50
Disability
25
Death
Point of intervention
0
25
50
75
Age (years)
7/17/2015
Fletcher C, Peto R: BMJ 1977
napcon '13
Can we push the curve up 63
?
ANNUAL DECLINE IN LUNG FUNCTION
100
Non smoker
Non-susceptible
smoker
75
Susceptible
smoker
(10-20%)
50
Disability
25
Death
10
0
25
3
3
50
Age (years)
7/17/2015
Fletcher C, Peto R: BMJ 1977
napcon '13
20
12
75
64
Delaying disability by 12 years and death by over 10 years
Significance
•
•
•
•
Recovering apparently lost lung function
Adding quality to life
Adding years to life
Reducing exacerbations
7/17/2015
napcon '13
65
food special
Contains several nutriants as
• Diindolylmethane potent immunomodulator
• Selenium, vitamin C anti oxidants
• Glucoraphanin sulforaphane, an anti-cancer
compound,
• Indole-3-carbinol boosts DNA repair in cells and
appears to block the growth of cancer cells
7/17/2015
napcon '13
66
Lung volume reduction: BLRS
• Upper lobe predominant disease with poor
exercise capacity : shows both short and long
term survival advantage
Naumheim KS, Wood DE, Mohsenifar Z, et al. Ann Thorac Surg
2006;82, 431-443
7/17/2015
napcon '13
67
BLVR
Causing atelactasis of the affected areas
• VENT study: (endobronchial Vulve for
Emphysema Palliation Trial): significant
improvement in lung function and the exercise
tolerence
• Biological lung volume reduction: fibrogel
www.emphysemamedical.com/clinical information/vent study
7/17/2015
napcon '13
68
Umbrella valve
7/17/2015
napcon '13
69
One way valve
7/17/2015
napcon '13
70
Fenestrations
With stents
7/17/2015
napcon '13
71
Transbronchial decompression of
emphysematous bullae
7/17/2015
napcon '13
72
Regenerative therapy and Change in
delivery technology
• Stem cells
• Retinoic acids
• Anti aging therapy
•
•
•
Belloni P A etal.,Effects of All-Trans-Retinoic Acid in Promoting Alveolar
RepairCHEST. May 2000;117:5,235S-241S.
Frankenberger M, et al. All Trans-Retinoic Acid Selectively Down-Regulates Matrix
Metalloproteinase-9 (MMP-9) and Up-Regulates Tissue Inhibitor of
Metalloproteinase-1 (TIMP-1) in Human Bronchoalveolar Lavage Cells Molecular
Medicine 7(4): 263–270, 2001
Fujita M, Ye Q, Ouchi H, et al Retinoic acid fails to reverse emphysema in adult
mouse models. Thorax 2004;59:224–230.
7/17/2015
napcon '13
73
Identification and treatment of new
cardiovascular morbidities
• Pulmonary Hypertension
• LV diastolic dysfunction
• Infection
7/17/2015
napcon '13
74
Effect of sildenafil in COPD PH
Pre treatmnet
(n= 30)
post treatment
(n=30)
‘p’ value
Resting SaO2
93.14 ± 4.31
93.82 ± 3.39
0.56
Resting pulse rate
94.82 ± 14.51
86.95 ± 9.11
0.04
Exercise SaO2 drop
3.41 ± 1.22
2.77 ± 1.69
0.15
6MWT
1160 ± 192.87
1218 ± 204.85
0.65
CAT score
20.55 ± 5.75
12.55 ± 6.74
0.007
Unpublished data from the Institute of Pulmocare and Research, Kolkata, ‘12
7/17/2015
napcon '13
75
Significance of LVDD in COPD
• The frequency and the duration of hospitalization
are more in the presence of LVDD in COPD
• LVDD may manifest myocardial ischemia not
otherwise apparent the treatment of which may
be worthwhile
• LVDD can cause COPD exacerbation
• Treatment of LVDD leads to improved functional
ability
7/17/2015
napcon '13
76
Effect of treatment of LVDD on CAT score
Parameter
Visit 1
Visit 2
P value
FEV1
0.61 ± 0.14
0.68 ± 0.18
0.19
PR (rest)
89.56±14.92
45.67±15.66
0.36
SaO2
95.44 ± 1.59
95.44±1.33
0.84
CAT score
18.11 ± 5.09
13.56±4.39
0.0065
Bhattacharyya P, Chakraborty B , Bhattacharyya P. Lung India 2012; 29: 4, 302
7/17/2015
napcon '13
77
7/17/2015
napcon '13
78
Treatment of infection
• Infection according to ‘vicious cycle
hypothesis’ through smoking induced
reduction in the innate defense.
• Persistence of microbes leading to fibrotic or
destructive response
• Long term antibiotic therapy benefits them
7/17/2015
napcon '13
79
What will happen after five years or
next decade
• Practice of effective metabolomic, genomic, and
other markers
• Clear identifications of different subsets of
patients and customization of treatment
• Revolution in lung volume reduction technology
• Innovation of re-remodeling of airways
• Great reduction in mortality and morbidity with
improvement of the quality of life
7/17/2015
napcon '13
80
Imagining a future prescription:
7/17/2015
napcon '13
81
Proposed COPD diagnosis scheme
Grade
Diagnosis
Features
Evaluation of COPD in 2015
Status of obstruction
Symptom status
Exacerbation status
Status of inflammation
Status of dynamic hyperinflation
Cardiovascular and other co-morbidity status
Functional capacity
Quality of life
Other markers
7/17/2015
napcon '13
82
Proposed COPD assessment scheme
Tests
When ?
Clinical
Exacerbation status
Spirometry with reversibility
Sputum cells
Chest X-ray
ECG
Doppler echo
HRCT chest
Coronary perfusion status
Status of co-morbidities
Functional status
Quality of life
7/17/2015
Financial
and feasibility status
napcon '13
83
Proposed COPD analysis scheme
Tests
Scoring
Clinical
Exacerbation status
Spirometry with reversibility
Sputum cells
Chest X-ray
ECG
Doppler echo
HRCT chest
Coronary perfusion status
Status of co-morbidities
Functional status
Quality of life
7/17/2015
Financial
and feasibility status
napcon '13
84
Proposed COPD prescription scheme
Tests
Clinical, including SaO2
Exacerbation status
Spirometry with reversibility
Sputum cells
Chest X-ray
ECG
Doppler echo
HRCT chest
Coronary perfusion status
Status of co-morbidities
Functional status
Quality of life
Financial and feasibility status
Choices
LABA and ultra LABA
LAMA and ultra LAMA
MABAs and SOS-SABA
± ICS , Oral corticosteroids
Methyle xanthines
Antibiotics (short and long term)
Anti inflammatory and PDE4 inhibitors
Oxygen
Rehabilitation
Mucolytics
Antoxidants
Anti protease
New BLVR LVRS methods
Rx for PH / LVDD
Rx for CAD and other comorbidities
Vaccines
Active exacerbation / oxygenation
7/17/2015
Infection
/ sepsis / LVF/ others
Others / new agents
napcon '13
85
PUL. REHABILITATION
Proposed COPD prognostic scheme
Tests
When ?
Clinical a/b/c/d
Exacerbation status
Spirometry with reversibility
Sputum cells
Chest X-ray
ECG
Doppler echo
HRCT chest
Coronary perfusion status
Status of co-morbidities
Pre-morbid Functional status
Pre-morbid Quality of life
7/17/2015
Financial
and feasibility status
napcon '13
86
Proposed COPD genomic and metabolomic
score
Genomic
markers
Strength
Significance
GM –X 45 pro
GM –X 23-4-p 1
GM –X P 9-9 pro
GM –ZP1-V 15
GM –X 4-77 pro
GM –K 3-3 L
GM –Q 12-45 pro
Metabolomics
M1
M AVC 1296 s
7/17/2015
M Prc_ 234 K
napcon '13
87
Relative weight
Variables
0
1
2
3
4
5
6
7
6
12
napcon '13
12
5
12
4788
Symp A
Symp A
Symp A
Sign A
Sign B
Sign C
Radio A
CT A
Echo A
EcHO B
ECG A
Comor 1
Comor 2
CAT
……
7/17/2015
Role of scoring: score-clock and CDSS
 Assessment of severity
 Deciding management strategy
 Prognostic assessment
 Financial implications
 Others
Exacerbation score
Total score
7/17/2015
napcon '13
89
Future beyond next decade
• Stem cell therapy
• Spontaneous autologous lung replacement
7/17/2015
napcon '13
90
Thank you
[email protected]
7/17/2015
napcon '13
91