Peran LAMA (Long Acting Anti

Muscarinic) pada PPOK

Budhi Antariksa. Sp.P(K), Ph.D

Dept Pulmonologi dan Ilmu Kedokteran
Respirasi
RSP - FKUI
 Global Strategy for Diagnosis, Management and Prevention of COPD

Definition of COPD
n COPD, a common preventable and treatable
disease, is characterized by persistent airflow
limitation that is usually progressive and
associated with an enhanced chronic
inflammatory response in the airways and the
lung to noxious particles or gases.
n Exacerbations and comorbidities contribute to
the overall severity in individual patients.
2015 Global Initiative for Chronic Obstructive Lung Disease
 Global Strategy for Diagnosis, Management and Prevention of COPD

Mechanisms Underlying Airflow

Limitation in COPD

Small Airways Disease Parenchymal Destruction

Airway inflammation Loss of alveolar attachments
Airway fibrosis, luminal plugs Decrease of elastic recoil
Increased airway resistance

AIRFLOW LIMITATION
2015 Global Initiative for Chronic Obstructive Lung Disease
 Global Strategy for Diagnosis, Management and Prevention of COPD

Burden of COPD
COPD is a leading cause of morbidity and
mortality worldwide.

The burden of COPD is projected to increase

in coming decades due to continued
exposure to COPD risk factors and the aging
of the worlds population.

COPD is associated with significant economic

burden.
2015 Global Initiative for Chronic Obstructive Lung Disease
 Chronic Respiratory Disease is a Leading Cause
of Chronic Disease Deaths Worldwide

The World Health Organization (WHO) projected that, in 2005, chronic respiratory disease
would be the third-leading cause of deaths from chronic disease worldwide

Adapted from: World Health Organization. Preventing chronic diseases: a vital investment. (2005) Available at:
http://www.who.int/chp/chronic_disease_report/contents/en/index.html (accessed June 2009).
Prevalence COPD in Asia-Pacific Region

Tan and NG Chest 2008; 133:517

Global Strategy for Diagnosis, Management and Prevention of COPD

Risk Factors for COPD

Genes

Infections

Socio-economic
status

Aging Populations
2015 Global Initiative for Chronic Obstructive Lung Disease
 Global Strategy for Diagnosis, Management and Prevention of COPD

Diagnosis of COPD

EXPOSURE TO RISK
SYMPTOMS FACTORS
shortness of breath
tobacco
chronic cough occupation
sputum indoor/outdoor pollution

SPIROMETRY: Required to establish

diagnosis
2015 Global Initiative for Chronic Obstructive Lung Disease
 Global Strategy for Diagnosis, Management and Prevention of COPD

Assessment of COPD

Assess symptoms
Assess degree of airflow
limitation using spirometry
Assess risk of exacerbations

Assess comorbidities
2015 Global Initiative for Chronic Obstructive Lung Disease
 Global Strategy for Diagnosis, Management and Prevention of COPD

Assessment of COPD
Assess symptoms
Assess degree of airflow limitation using spirometry
Assess risk
COPD of exacerbations
Assessment Test (CAT)
Assess comorbidities
or
Clinical COPD Questionnaire (CCQ)
or
mMRC Breathlessness scale
2015 Global Initiative for Chronic Obstructive Lung Disease
 Global Strategy for Diagnosis, Management and Prevention of COPD

Assessment of Symptoms

COPD Assessment Test (CAT): An 8-item

measure of health status impairment in COPD
(http://catestonline.org).

Clinical COPD Questionnaire (CCQ): Self-

administered questionnaire developed to
measure clinical control in patients with COPD
(http://www.ccq.nl).

2015 Global Initiative for Chronic Obstructive Lung Disease

Global Strategy for Diagnosis, Management and Prevention of COPD
Modified MRC (mMRC)Questionnaire

2015 Global Initiative for Chronic Obstructive Lung Disease

 Global Strategy for Diagnosis, Management and Prevention of COPD

Assessment of COPD
Assess symptoms
Assess degree of airflow limitation using
spirometry
Assess risk of exacerbations
Use spirometry for grading severity
Assess comorbidities
according to spirometry, using four
grades split at 80%, 50% and 30% of
predicted value

2015 Global Initiative for Chronic Obstructive Lung Disease

 Global Strategy for Diagnosis, Management and Prevention of COPD

Classification of Severity of Airflow

Limitation in COPD*
In patients with FEV1/FVC < 0.70:

GOLD 1: Mild FEV1 > 80% predicted

GOLD 2: Moderate 50% < FEV1 < 80% predicted

GOLD 3: Severe 30% < FEV1 < 50% predicted

GOLD 4: Very Severe FEV1 < 30% predicted

*Based on Post-Bronchodilator FEV1

2015 Global Initiative for Chronic Obstructive Lung Disease
 Global Strategy for Diagnosis, Management and Prevention of COPD

Assessment of COPD
Assess symptoms
Assess degree of airflow limitation using
spirometry
Assess risk of exacerbations
Assess comorbidities
Use history of exacerbations and spirometry.
Two exacerbations or more within the last year
or an FEV1 < 50 % of predicted value are
indicators of high risk. Hospitalization for a COPD
exacerbation associated with increased risk of death.
2015 Global Initiative for Chronic Obstructive Lung Disease
 Global Strategy for Diagnosis, Management and Prevention of COPD

Combined Assessment of COPD

Assess symptoms
Assess degree of airflow limitation using
spirometry
Assess risk of exacerbations

Combine these assessments for the

purpose of improving management of COPD
2015 Global Initiative for Chronic Obstructive Lung Disease
 Global Strategy for Diagnosis, Management and Prevention of COPD

Combined Assessment of COPD

2
(GOLD Classification of Airflow Limitation))

4 or
> 1 leading
(C) (D) to hospital

(Exacerbation history)
admission
3

Risk
1 (not leading
Risk

to hospital
2 admission)

(A) (B)
1
0
CAT < 10 CAT > 10
Symptoms
mMRC 01 mMRC > 2
Breathlessness
2015 Global Initiative for Chronic Obstructive Lung Disease
 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.)

Patient Characteristic Spirometric Exacerbations CAT mMRC

Classification per year
Low Risk
A GOLD 1-2 1 < 10 0-1
Less Symptoms
Low Risk
B GOLD 1-2 1 > 10 >2
More Symptoms
High Risk
C GOLD 3-4 >2 < 10 0-1
Less Symptoms
High Risk >2
D GOLD 3-4 >2 > 10
More Symptoms
2015 Global Initiative for Chronic Obstructive Lung Disease
 Global Strategy for Diagnosis, Management and Prevention of COPD

Manage Stable COPD: Goals of Therapy

Relieve symptoms
Improve exercise tolerance Reduce
symptoms
Improve health status

Prevent disease progression

Prevent and treat exacerbations Reduce
risk
Reduce mortality

2015 Global Initiative for Chronic Obstructive Lung Disease

 Global Strategy for Diagnosis, Management and Prevention of COPD
Manage Stable COPD: Non-pharmacologic

Patient Essential Recommended Depending on local

Group guidelines

Smoking cessation (can Flu vaccination

A include pharmacologic Physical activity Pneumococcal
treatment) vaccination

Smoking cessation (can

Flu vaccination
include pharmacologic
B, C, D Physical activity Pneumococcal
treatment)
vaccination
Pulmonary rehabilitation

2015 Global Initiative for Chronic Obstructive Lung Disease

 Global Strategy for Diagnosis, Management and Prevention of COPD
Manage Stable COPD: Pharmacologic Therapy
(Medications in each box are mentioned in alphabetical order, and therefore not
necessarily in order of preference.)

Patient RecommendedFirs Alternative choice Other Possible

t choice Treatments
LAMA
SAMA prn or
A or LABA Theophylline
SABA prn or
SABA and SAMA
LAMA
SABA and/or SAMA
B or LAMA and LABA
Theophylline
LABA
ICS + LABA LAMA and LABA or
or LAMA and PDE4-inh. or SABA and/or SAMA
C
LAMA LABA and PDE4-inh. Theophylline

ICS + LABA ICS + LABA and LAMA or Carbocysteine

and/or ICS+LABA and PDE4-inh. or N-acetylcysteine
D
LAMA LAMA and LABA or SABA and/or SAMA
LAMA and PDE4-inh. Theophylline
 Pathophysiology of COPD:
Vagal Nerve System
Central
nervous
system

Vagus nerve
Airway smooth muscle
constriction ACh Parasympathetic
ganglion

Submucosal
ACh
ACh Cholinergic gland
Inflammatory
receptors
cell mediators

Airway epithelium

Irritants Mucus
(e.g. cigarette smoke, bacteria, viruses) Hypersecretion
Adapted from: Hansel T/Barnes P. An Atlas of COPD. 2004
Cholinergic Receptor Subtypes in Airways
Pre-ganglionic
nerve
Nicotinic receptors (+)
Parasympathetic
ganglion M1 receptors (+)

Ideal anti
Post-ganglionic cholinergic
nerve

M2 receptors ()
ACh
M3 receptors (+)
Airway smooth
muscle

Hansel T / Barnes P. An Atlas of COPD. 2004

 FEV1 Model of Disease Progression in COPD
100% COPD
Stages
FEV1 (% of value at age 25)

75% Diagnosis
Moderate

50% Treatment
Severe

25%
Very
Severe
0%
25 50 75
Age (years)

Adapted from Fletcher C and Peto R, BMJ 1977; 1:1645-1648. Imagery courtesy ODonnell D
The Progression of COPD
Mild COPD Severe COPD
 UPLIFT : FEV1 Over 4-Year Trial Duration

Asian cohort1 Japanese cohort1 Total cohort2

rate of decline: rate of decline: rate of decline:
-2 mL/yr pre-BD (P=0.83) 11 mL/yr pre-BD (P=0.24) 0 mL/yr pre-BD (P=0.95)
Significant lung function improvement with
5 mL/yr post-BD (P=0.54) 13 mL/yr post-BD (P=0.16) 2 mL/yr post-BD (P=0.21)

1.50 tiotropium in total, Asian and Japanese cohort

Tiotropium Control 1.50 Tiotropium Control 1.50 Tiotropium Control
1.40 1.40 1.40 * * * * * Post-BD
1.30 1.30 1.30 * * * Tiotropium (n=2516)
* Control (n=2374)
1.20 1.20 1.20 * * * *
* Post-BD *
* * * * * Pre-BD
*
FEV1 (L)

1.10 * * * 1.10 * * * Tiotropium (n=46) 1.10 * Tiotropium (n=2494)

* * *
Post-BD Control (n=43)
Control (n=2363)
1.00 * * Tiotropium (n=156) 1.00 1.00
* * * Pre-BD
* * * Control (n=147) * * * * * * Tiotropium (n=45)
* *
0.90 * * * * Pre-BD 0.90 0.90
Control (n=43)
Tiotropium (n=152)
0.80 0.80 0.80
Control (n=145)
0.00 0.00 0.00
01 6 12 18 24 30 36 42 48 01 6 12 18 24 30 36 42 48 01 6 12 18 24 30 36 42 48
Month Month Month
Day 30 Day 30 Day 30

*P<0.05 vs control. Difference, tiotropium control.

BD, bronchodilator.
1Fukuchi Y, et al. Respirology 2011; 16: 825-835; 2Adapted from Tashkin DP, et al. N Engl J Med 2008;359:1543-1554.
 UPLIFT : SGRQ Total Score

Asian Cohort1 Japanese Cohort1 Total Cohort2

= 1.5-6.1 units = 1.1-6.2 units = 2.3-3.3 units
Significant SGRQ improvement with tiotropium
Tiotropium (n=184) Tiotropium (n=48) Tiotropium (n=2478)
Control (n=178) Control (n=43) Control (n=2337)
in total, Asian and Japanese cohort
50 50 50
Improvement
SGRQ Total Score (Units)

45 45 45

40
40 40
* * * *
*
* * * * * * * * *
35
35 * 35

0 6 12 18 24 30 36 42 48 0 6 12 18 24 30 36 42 48 0 6 12 18 24 30 36 42 48
Month Month Month

*P<0.05 vs. control.

Repeated measure ANOVA was used to estimate means. Estimated means are adjusted for baseline measurements. Patients
with 2 acceptable SGRQ Total Scores after Month 6 were included in the analysis.

1Fukuchi Y, et al. Respirology 2011; 16: 825-835; 2Adapted from Tashkin DP, et al. N Engl J Med 2008;359:1543-1554.
 The UPLIFT Lesson
Similar to the overall cohort, 4 years treatment with tiotropium
provided the following benefits in the subgroup of COPD
patients from Asia (Improved lung function, Improved HRQoL,
Reduced exacerbations)
These data indicate that tiotropium may be used in patients
from Asia in accordance with current international treatment
guidelines
Tiotropium is beneficial to COPD patients of various severities
(GOLD stages II to IV) and has clearly demonstrated benefit to
GOLD stage II patients

1Fukuchi Y, et al. Respirology 2011; 16: 825-835

 Clinical Course of COPD
COPD
Expiratory flow limitation
Exacerbations Air trapping
Hyperinflation

Breathlessness

Deconditioning Quality of Life Inactivity

Reduced exercise
capacity

Systemic Consequences
ie, muscle wasting, cardiovascular disease, weight change,
depression, osteoporosis, death
Decramer M et al. COPD 2008;5:235-256.
 What Is an Exacerbation and Why Are
They Important?

An exacerbation of COPD is:

an acute event characterized by a worsening
of the patients respiratory symptoms that is
beyond normal day-to-day variations and
leads to a change in medication.

GOLD Revision 2011

What Is an Exacerbation and Why Are
They Important?
750.000 hospitalizations annually in US1

Account for 70% of direct medical costs for COPD2

Acute mortality 10-15%3

Subsequent mortality as high as 40% in first year and 70% at 5

years4

1. Mannino DM, et al. Respir Care. 2003; 48(12): 1185-91; 2. Sullivan SD, et al. Chest. 2000; 117(suppl):S5-S9; 3.
www.goldcopd.com; 4. thorax.bmjjournals.com/content/vol59/suppl_1/
 Consequences Of COPD Exacerbations

Negative Impact on
impact on symptoms
quality of life and lung
function

EXACERBATIONS
Accelerated Increased
lung function economic
decline costs

Increased
Mortality
 Systemic inflammation increases during ECOPD potential mechanism to
explain the increased risk of vascular events
Plasma levels of the cardiac biomarkers NT-proBNP and troponin T were
abnormal in a significant number of ECOPD patients hospitalized both
markers predicted mortality
Patients with COPD had increased circulating platelete-monocyte
aggregates further increased during ECOPD

Fabbri LM, et al. Thorax. 2011; 66(9): 745-747

 POET-COPD: Tiotropium Significantly
Delayed Time to First Exacerbation
50
45 Tiotropium
Salmeterol 17%
Probability of COPD exacerbation (%)

40
Risk
35
difference
30
25
20
15 Hazard ratio = 0.83*
(95% CI, 0.77, 0.90)
10 P<0.001 (log-rank test)
5
0
0 30 60 90 120 150 180 210 240 270 300 330 360
Time to event (days)
No. of patients at risk:
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

*Cox regression adjusted for (pooled) centre and treatment. Vogelmeier C et al. N Engl J Med 2011;364:1093-1103.
POET-COPD: Tiotropium Reduced Number
of Exacerbations
RR 0.89*
(95% CI 0.83, 0.96)
Tiotropium
1
P=0.002 RR 0.93* Salmeterol
0.9 (95% CI 0.86, 1.00)
0.8 P=0.048
0.72
Adjusted yearly rate

0.7 0.64
0.59
0.6 0.54
0.5 RR 0.73*
(95% CI 0.66, 0.82)
0.4 P<0.001
0.3
0.2 0.13
0.09
0.1
0
All exacerbations Moderate Severe
exacerbations exacerbations
RR=rate ratio.
*Poisson regression correcting for overdispersion and adjusted for treatment exposure.

Vogelmeier C et al. N Engl J Med 2011;364:1093-1103.

POET-COPD : Post-hoc analysis of concomitant ICS
use during study treatment

Tiotropium Salmeterol Hazard Ratio p-value*

n/N n/N (95%CI)
Tio vs Sal
Concomitant ICS therapy during study
Continuous 614/1488 629/1444 0.91(0.82-1.02)
0.09
Never 554/2024 650/2022 0.81(0.72-0.91)

Cox regression adjusted for treatment, subgroup, and interaction between treatment and
subgroup
* for interaction between treatment and subgroup

Vogelmeier C et al. N Engl J Med 2011;364:1093-1103.

 POET-COPD: More Patients Receiving
Concomitant ICS Experienced Pneumonia
180 reported pneumonia cases
158 (87.8%) radiologically confirmed
70 in the tiotropium group
88 in the salmeterol group

Higher numbers of patients with 1 radiologically

confirmed pneumonia were receiving concomitant ICS
for 1 day on treatment
n=89, 2.7% (n=72 hospitalized) concomitant ICS
n=59, 1.5% (n=46 hospitalized) no concomitant ICS
Vogelmeier C et al. N Engl J Med 2011;364:1093-1103.
 The POET-COPD Lesson
Tiotropium was significantly more effective than salmeterol in
almost all assessed exacerbation endpoints and across all
major patient subgroups
Addition of ICS did not affect the outcome of exacerbation;
prevention of exacerbations by tiotropium alone appears to be
efficient
Adverse events seen in the POET-COPD trial were consistent
with the well-established, long-term safety profile of
tiotropium
Spiriva has already got its new indication from
Indonesian Local FDA

Spiriva BPOM Approved Document 2011

 Global Strategy for Diagnosis, Management and Prevention of COPD
Manage Stable COPD: Pharmacologic Therapy
Patient First choice Second choice Alternative Choices

LAMA
SAMA prn or
A or LABA Theophylline
SABA prn or
SABA and SAMA
LAMA
SABA and/or SAMA
B or LAMA and LABA
Theophylline
LABA
ICS + LABA
PDE4-inh.
or
C LAMA and LABA SABA and/or SAMA
LAMA
Theophylline

ICS and LAMA or

ICS + LABA
ICS + LABA and LAMA or Carbocysteine
or
D ICS+LABA and PDE4-inh. or SABA and/or SAMA
LAMA
LAMA and LABA or Theophylline
LAMA and PDE4-inh.
GOLD Revision 2011
Combination Therapy in Local and
International Guidelines

REVISED 2011

1. PPOK PDPI 2011; 2. GOLD 2011

 Take Home Messages

Cholinergic tone is the basic of COPD patophysiology

Early intervention impact disease progression
The UPLIFT and POET COPD trials of support
initiating tiotropium (Spiriva) as the preferred
foundation maintenance therapy as it improves
lung function, improves quality of life as well as
reduces the risk of COPD exacerbations
Thank You