Why LAMA is Fundamental Treatment

for COPD?

For Healthcare Professionals Only

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

Vagus nerve
Airway smooth
muscle ACh Parasympathetic
constriction 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 leading to
30 – 49
hospital A B
GOLD 4 admission)
<30

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
 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
 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
 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
 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
@2019 Global Initiative for Chronic Obstructive Lung Disease, all rights reserved. Use is by express license from the
 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
 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 Exacerbatio Patients with Time to First

Number n >1 Exacerbation
Brusasco 2003 Placebo 1207 6 months Number
-28% Exacerbation
-18% P<0.01
P<0.025 P=0.06
Niewoehner Placebo 1829 6 months -19% -13% P=0.03
2005* 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 12
2002;
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/
Competito r
vilanterol1,2
LAMA/ SPARK 2013 SHINE 2013 Decramer 2014
Glycopyrronium/
LABA FDC
Tiotropium - indacaterol3

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

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 Salmeterol/fluticasone 50/500µg
qd 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
40 Risk
difference
Probability of COPD exacerbation

35
30
25
20
HR 0.83 (95% CI, 0.77,
15 0.90)
P<0.001
10
5
(%)

0
0 30 60 90 120 150 180 210 240 300 330 360
No. of patients at risk:
270
Tiotropium 3707 3369 3136
Time to 2647
2955 2787
event (days)
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;
COPD, chronic
Umeclidinium/vilanterol 62.5/25 µg vs. Tiotropium HandiHaler 18 µg
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
Tiotropium)

P=0.71
Hazard ratio

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
0.85 (0.77-0.94)
(QVA149)
COPD exacerbations (annualised rate)

p=0.0012
4.0
0.084 (0.75-0.95) and tiotropium in moderate or severe
3.5 p=0.0052
and
0.85 (0.75-0.96)
3.0 p=0.0072 severe exacerbation were statistically not
significant.
2.5
0.90 (0.79-1.02) 1.16 (0.84-
1.61)
2.0
1.5
p=0.096 p=0.36
0.88 (0.77-0.99)
1.0 p=0.038
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- 13

year period but did not significantly reduce the rate of decline in FEV1
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
 Thank You

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