Why LAMA is Fundamental Treatment

for COPD?
dr. Sudarto SpPD – KP

GPM-SV-0004-ID
 Pathophysiology of COPD: Vagal Nerve System

Central
nervous
system

Vagus nerve
Airway smooth muscle
constriction ACh Parasympathetic
ganglion

ACh Submucosal
Inflammatory
ACh Cholinergic gland
cell mediators receptors

Airway epithelium

Irritants Mucus
(e.g. cigarette smoke, bacteria, viruses) Hypersecretion
Hansel TT and Barnes PJ. Drugs of Today. 2002; 38(9): 585-600
GOLD 2019 UPDATE
 Refined ABCD Assessment Grid
The ABCD assessment grid has been refined to utilize exclusively respiratory
symptoms and exacerbation history to assign categories

Spirometrically Assessment Assessment of

confirmed of airflow symptoms/risk
diagnosis limitation of exacerbations
Exacerbation
history
FEV ≥ 2 or ≥ 1
(% predicted) leading to
Post-bronchodilator GOLD 1 ≥ 80
hospital C D
admission
FEV1/FVC < 0.7 GOLD 2 50 – 79
0 or 1 (not
GOLD 3 30 – 49 leading to
hospital A B
GOLD 4 <30 admission)

mMRC 0-1 mMRC ≥ 2

CAT < 10 CAT ≥ 10
Symptoms
@2019 Global Initiative for Chronic Obstructive Lung Disease, all rights reserved. Use is by express license from the owner
 Management of Stable COPD

► Once COPD has been diagnosed, effective management should be

based on an individualized assessment to reduce both current
symptoms and future risks of exacerbations.

@2019 Global Initiative for Chronic Obstructive Lung Disease, all rights reserved. Use is by express license from the owner
 Treatment of Stable COPD

Definition of abbreviations: eos: blood eosinophil count in cells per microliter; mMRC: modified Medical Research Council dyspnea
questionnaire; CAT™: COPD Assessment Test™.

@2019 Global Initiative for Chronic Obstructive Lung Disease, all rights reserved. Use is by express license from the owner
 Treatment of Stable COPD
► Following implementation of therapy, patients should be reassessed for
attainment of treatment goals and identification of any barriers for
successful treatment (Figure 4.2).
► Following review of the patient response to treatment initiation,
adjustments in pharmacological treatment may be needed.

@2019 Global Initiative for Chronic Obstructive Lung Disease, all rights reserved. Use is by express license from the owner
 Treatment of Stable COPD
Follow-up pharmacological treatment

► A separate algorithm is provided for FOLLOW-UP treatment, where the

management is still based on symptoms and exacerbations, but the
recommendations do not depend on the patient’s GOLD group at diagnosis
(Figure 4.3).
► These follow-up recommendations are designed to facilitate management of
patients taking maintenance treatment(s), whether early after initial
treatment or after years of follow-up.
► These recommendations incorporate recent evidence from clinical trials and
the use of peripheral blood eosinophil counts as a biomarker to guide the
use of ICS therapy for exacerbation prevention.

@2019 Global Initiative for Chronic Obstructive Lung Disease, all rights reserved. Use is by express license from the owner
@2019 Global Initiative for Chronic Obstructive Lung Disease, all rights reserved. Use is by express license from the owner
 Treatment of Stable COPD
► Figure 4.3 suggests escalation and de-escalation strategies based
on available efficacy as well as safety data.
► The response to treatment escalation should always be reviewed,
and de-escalation should be considered if there is a lack of clinical
benefit and/or side effects occur.
► De-escalation may also be considered in COPD patients receiving
treatment who return with resolution of some symptoms that
subsequently may require less therapy.
► Patients, in whom treatment modification is considered, in
particular de-escalation, should be undertaken under close medical
supervision.
► We are fully aware that treatment escalation has not been
systematically tested; trials of de-escalation are also limited and
only include ICS.

@2019 Global Initiative for Chronic Obstructive Lung Disease, all rights reserved. Use is by express license from the owner
 COPD:
the added value of Tiotropium as well
as its wealth of data and experience
 Tiotropium Significantly Reduces Exacerbation Rate and Delays
Onset of First Exacerbation
Versus Patient Duration Exacerbation Patients with >1 Time to First
Number Number Exacerbation Exacerbation
Brusasco 2003 Placebo 1207 6 months -28% -18% P<0.01
P<0.025 P=0.06
Niewoehner 2005* Placebo 1829 6 months -19% -13% P=0.03
P=0.031 P=0.04
Casaburi 2002 Placebo 921 1 year -20% -14% P=0.01
P=0.045 P<0.05
Vincken 2002 Ipratropium 535 1 year -24% -11% P=0.008
P=0.006 P=0.01
Dusser 2006 Placebo 1010 1 year -35% -17% P<0.001
P<0.001 P<0.01

Powrie 2007 Placebo 142 1 year -52% -33% P=0.01

P=0.001 P=0.01
Freeman 2007 Placebo 395 12 weeks n/a -47% n/a
P=0.01
Chan 2007 Placebo 913 1 year -4% + 8% n/a
P=0.599 P=0.4

*Primary endpoint: exacerbation

1. Brusasco V et al. Thorax 2003; 58:399-404.; 2. Niewoehner DE et al. Ann Intern Med 2005;143:317-26.; 3. Casaburi R et al. Eur Respir J 2002; 12
19:217-224.; 4. Vincken W et al. Eur Respir J 2002; 19:209-216.; 5. Dusser D et al. Eur Respir J 2006; 27:547-555.; 6. Powrie DJ et al. Eur Respir J
2007; 30: 1–8.; 7. Freeman D et al. Respiratory Research 2007; 8:45-55.; 8. Chan CK et al. Can Respir J 2007;14:465-72.
UPLIFT : Maintenance Naïve Lung Function
Tiotropium Significantly Improved Lung Function vs Control
Tiotropium significantly improved lung function vs control for up to
4 years in patients new to maintenance therapy

Tiotropium
Control

Postbronchodilator FEV1
 = 96 mL

Prebronchodilator FEV1
 = 134 mL

FEV1, forced expiratory volume in 1 second

Troosters et al. Eur Respir J 2010

 “Two are not always Better than One”

Umeclidinium/
Competitor
vilanterol1,2
LAMA/ SPARK 2013 SHINE 2013 Decramer 2014
Glycopyrronium/
LABA FDC
Tiotropium - indacaterol3

unsurpassed in
the reduction of LABA/ICS FDC INSPIRE 2008 Salmeterol/ fluticasone
propionate4
moderate to
severe
exacerbations1-7 Competitor SPARK 2013 Glycopyrronium3
LAMA

LABA INVIGORATE 2013 POET 2012 Salmeterol MDI5

Indacaterol6

1. Decramer, M. et al. Lancet Respir Med 2014;2:427-486. 2. Anoro® Ellipta® Summary of Product Characteristics. GlaxoSmithKline. 3.
Wedzicha, JA. et al. Lancet Respir Med 2013;1:199-209. 4. Wedzicha, JA. et al. Am J Respir Crit Care Med 2008;177:19-26. 5. Vogelmeier. C.
14
et al. N Engl J Med 2011;264:1093-1103. 6. Decramer, ML. et al. Lancet Respir Med 2013;1:524-533. 7. Halpin, DMG. et al. Respir Med.
2016; doi:10.1016/j.rmed.2016.02.012.
INSPIRE : No Significant Difference in Exacerbation Rates between
Tiotropium vs. Salmeterol/Fluticasone
Estimated annual exacerbation rate
in patients with severe/very severe COPD
HCU* exacerbations mean number per year

2.0
Ratio of exacerbation rates = 0.97
p=0.656; 95% CI: 0.84, 1.12
p=not significant
1.5

1.32 1.28
1.0

0.5

n=658
n=665
0.0
Overall exacerbations
Tiotropium 18µg qd Salmeterol/fluticasone 50/500µg bid

*HCU: Health care utilization, defined as those that required treatment with oral corticosteroids and/or antibiotics or required hospitalization.

Wedzicha JA, et al. AJRCCM 2008; 177: 19-26

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

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

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

INVIGORATE : Tiotropium Significantly Better in Reducing First
Moderate or Severe Exacerbation vs. Indacaterol

Hazard Ratio 1.2 (p=0.0012)

Indacaterol (150 µg)

Tiotropium (18 µg)

Decramer ML et al. Lancet Respiratory Medicine 2013;1(7):524-533

 INVIGORATE: Tiotropium Significantly Better in Reducing
Moderate to Severe Exacerbation vs. Indacaterol

1 29% higher rate

exacerbation rate over 52 weeks

0.8 Indacaterol
demonstrated a
Moderate-severe

0.79 29% higher rate

0.6
of COPD
exacerbations vs
0.61
0.4 Tiotropium in a
1-year study
0.2

0
Tiotropium Indacaterol 150 µg
HandiHaler® 18 µg N=1675
N=1675

Decramer M, et al. Lancet Respir Med. 2013;1:524-33

 Consistently No Significant Difference between LAMA/LABA
(Umeclidinium/Vilanterol) vs. Tiotropium only in Reducing First
Exacerbation

Time to first COPD exacerbation CI, confidence interval;

Umeclidinium/vilanterol 62.5/25 µg vs. Tiotropium HandiHaler 18 µg COPD, chronic
obstructive pulmonary
disease; SHINE, A Study
to Assess the Efficacy,
Safety and Tolerability of
2.5 1.9 Once-daily QVA149 in
(95% CI: 1.0–3.6); In favour Patients With Moderate
P=0.06 to Severe Chronic
(Umeclidinium/vilanterol vs

of Tiotropium
2.0 1.2 Obstructive Pulmonary
(95% CI: 0.5–2.6); Disease
>1
Hazard ratio

Tiotropium)

P=0.71
1.5
<1

1.0
In favour
of umeclidinium
/ vilanterol FDC
0.5

0.0
Decramer Study 1 (n=203) Decramer Study 2 (n=215)

19

Decramer M, et al. Lancet Respir Med. 2014;2:472–486

SPARK: Dual Bronchodilators Combination is ONLY
COMPARABLE to Tiotropium Mono in Reducing Moderate to
Severe Exacerbations

QVA149 (N=729) Glycopyrronium (N=739) Tiotropium HandiHaler® 18 µg (N=737)

0.086 (0.78-0.94)
p=0.0017
4.5 Both the difference between the combination (QVA149)
0.85 (0.77-0.94)
and tiotropium in moderate or severe and
COPD exacerbations (annualised rate)

p=0.0012
4.0
0.084 (0.75-0.95) severe exacerbation were statistically not significant.
p=0.0052
3.5
0.85 (0.75-0.96)
3.0 p=0.0072

2.5
0.90 (0.79-1.02) 1.16 (0.84-1.61)
2.0
p=0.096 p=0.36
1.5 0.88 (0.77-0.99)

p=0.038
1.0 0.81 (0.60-1.10)

p=0.18
0.5
0
All Mild Moderate or Severe
exacerbations exacerbations severe exacerbations
exacerbations
“Mild drives all”
Values are rate reduction (95% CI; p-value)

20

Wedzicha JA, et al. Lancet Respir Med 2013;1:199-209.

 Take Home Message
• LAMA is fundamental treatment for COPD because cholinergic tone impacts
bronchoconstriction in COPD1-2
• GOLD 2019: LAMA is the initial treatment for stable COPD in all group
• Tiotropium shown consistent efficacy to reduce exacerbation:
– reduce exacerbation rate and delay time to first exacerbation  time to first
exacerbation means prevention 3-10
– significantly more effective vs LABA (salmeterol, indacaterol) in preventing
exacerbations and prevention of exacerbations by tiotropium alone appears to
be efficient 11, 12
– statistically comparable vs. combination LAMA/LABA
(Indacaterol/Glycopyrronium, Umeclidinium/Vilanterol) in reducing
exacerbations 12,15
• In patients with COPD, therapy with tiotropium was associated with
improvements in lung function, quality of life, and exacerbations during a 4-
year period but did not significantly reduce the rate of decline in FEV113
Reference:
1. Hansel TT and Barnes PJ. Drugs of Today. 2002; 38(9): 585-600; 2. @2019 Global Initiative for Chronic Obstructive Lung Disease, all rights reserved. Use is by express
license from the owner; 3. Brusasco V et al. Thorax 2003; 58:399-404.; 4. Niewoehner DE et al. Ann Intern Med 2005;143:317-26.; 5. Casaburi R et al. Eur Respir J 2002;
19:217-224.; 6. Vincken W et al. Eur Respir J 2002; 19:209-216.; 7. Dusser D et al. Eur Respir J 2006; 27:547-555.; 8. Powrie DJ et al. Eur Respir J 2007; 30: 1–8.; 9. Freeman
D et al. Respiratory Research 2007; 8:45-55.; 10. Chan CK et al. Can Respir J 2007;14:465-72. 11. Vogelmeier C et al. N Engl J Med 2011;364:1093-1103. 12. Wedzicha JA,
et al. Lancet Respir Med. 2013; 1: 199-209. 13. Troosters et al. Eur Respir J 2010; 14. Decramer ML et al. Lancet Respiratory Medicine 2013;1(7):524-533; 15. Decramer M,
et al. Lancet Respir Med. 2014;2:472–486
 Thank You

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