NAC

IN NEW PILLAR OF EVIDENCE

IN COPD
(Recent clinical research 2013 )


Pulmonary Update Padang 2014

PATOGENESIS COPD
Noxious particles and
gases
Lung Inflamation
COPD pathology
Host factors
Antioxidants
Oxidative stress Proteinase
Repair
mechanisms
Antiproteinase
Vicious Circle COPD
( Chronic Obstructive Pulmonary Disease )
Impaired
mucociliary
clearance
Damaged to
airways
epithelium
Bacterial Product
LPS, Histamine, Protease
Proggress of
COPD
Inflammatory
Response
Increased Oxidative
Stress (oxidant)
(consumption of antioxidant)
Bacterial Colonisation
(Bacterial Adhesion)
Initiating Factors
(viral infection, smoking, etc)
(Am. Rev. Resp. Dis 1992,
146:1067-83 modified after Cole
& Wilson)
Increased elastolytic
activity
Altered elastase
anti-elastase
balance

MANAJEMEN
TERAPI
Tujuan
Mengurangi gejala
Memperbaiki toleransi olahraga
Memperbaiki status kesehatan

Mencegah perburukan penyakit
Mencegah & mengobati eksaserbasi
Menurunkan kematian
Mengurangi
gejala
Menurunkan
resiko
Source: GOLD guideline 2014
Penatalaksanaan PPOK Stabil*
GOLD 2014
*Medications in each box are mentioned in alphabetic order, and therefore not necessarily in order of preference
**Medications in this column can be used alone or in combination with other options in the Recommended First Choice and Alternative Choice columns.
Kelompo
k
Pasien
Pilihan Pertama
yang direkomendasi
Pilihan Alternatif Pengobatan lain
yang dapat
diberikan**

A
SAMA or SABA LAMA or
LABA or
SABA and SAMA
Theophylline

B
LAMA or LABA LAMA and LABA SABA and/or
SAMA
Theophylline

C
ICS+LABA or
LAMA
LAMA and LABA or
LAMA and PDE-4 inhibitor
or
LABA and PDE-4 inhibitor
SABA and/or
SAMA
Theophylline

D
ICS+LABA and/or
LAMA
ICS+LABA and LAMA or
ICS+LABA and PDE-4
inhibitor or
LAMA and LABA or
LAMA and PDE-4 inhibitor
N-acetylcysteine
SABA and/or
SAMA
Theophylline
COPD: Chronic Obstructive Pulomnary Disease; SAMA: short-acting muscarinic antagonist; SABA: short-acting 2-agonist;
LAMA: Long-acting muscarinic antagonist; LABA: Long-acting 2-agonist;; ICS: Inhaled corticosteroid; PDE-4: phophodiesterase-4
GOLD 2014 Fulltext, halaman 26
CH
2
HOOC S CH CH
2
NH
2
COOH
CH
2
HS CH
NH

COOH
COC
H
3
Carbocysteine
N-acetylcysteine
Block Thiol
(Gugus SH tidak
bebas)
Free Thiol
(Gugus SH
bebas)
PERBANDINGAN STRUKTUR KIMIA
N-acetylcysteine & Carbocysteine
Sumber: P.C. Braga and L. Allegra, Drugs in Bronchial Mucology,1989
9
S
S
1. Direct mucolytic activity
2.Activation of mucociliary clearance
NAC breaks disulfide chain,
rendering the mucousless viscous
and easier to expectorate
NAC improves the physiological
transport of mucous, facilitating
its removal
NAC sebagai satu-satunya TRUE MUKOLITIK
S
S
What really happen using Fluimucil
(NAC)
2. NAC sebagai antioksidan & precursor
glutathione (master oxidant)
Bukti-bukti klinis Terbaru
NAC dalam memenuhi sasaran
Pengobatan PPOK 2013

(New Pillar of Evidence in COPD)
HIACE Study
HIgh-Dose N-Acetylcysteine in Stable
Chronic Obstructive Pulmonary DisEase:
the 1-Year, Double-Blind, Randomized,
Placebo-Controlled HIACE Study

Published as Online First paper on CHEST journal (Official Publication of the American College of Chest
Physicians), January 2013.



HIACE Study 2013 : STUDY DESIGN
Primary outcome
measures
Secondary outcome
measures
Lung function parameters for small
airways

FEF
25-75% =
Forced
Expiratory Flow 25%
to 75%

FOT=Forced
oscillation technique

COPD exacerbation rate

Rate of hospitalization due to
COPD exacerbation

St. Georges Respiratory
Questionnaire (SGRQ) scores

Exercise tolerance: 6-min
walking distance (6MWD)
Symptoms: modified Medical Research
Council (mMRC) dyspnea
Tse HN et al. High-Dose N-Acetylcysteine in Stable COPD. The 1-year, Double-blind,
Randomized, Placebo-controlled HIACE Study.
Chest. 2013; 144(1):106118 DOI: 10.1378/chest.12-2357
HIACE Study 2013 : FORCED OSCI LLATI ON
TECHNI QUE (FOT)

p =0.04*
p = 0.09 P =0.01*

p =0.02*
Reactance
(R)
Resistance
(X)
HIACE Study 2013 : LUNG FUNCTION PARAMETERS
Changes
at 16wk
p
value
Changes
at 52wk
p value
FEF
25-75%
(L/s)
NAC +0.080+/-
0.03
+0.082+/-
0.03
Placebo +0.008+/-
0.02
0.03* -0.002+/-
0.03
0.047*
FEV1 (L) NAC +0.12+/-0.06 +0.07+/-0.33
Placebo +0.04+/-0.03 0.2 +0.05/-0.04 0.7
FVC (L) NAC +0.14+/-0.06 +0.13+/-0.05
Placebo +0.10+/-0.05 0.59 +0.06+/-0.06 0.42
IC (L) NAC -0.10+/-0.07 +0.13+/-0.07
Placebo -0.03+/-0.59 0.83 +0.49+/-0.08 0.73
Improvement of
FEF25-75% in
high-dose NAC
group at 16wk and
52wk follow-up
(p<0.05)
A tendency of
improvement over
FEV1, FVC and IC
in the NAC group
compared to
placebo
HIACE Study 2013:ACUTE EXACERBATION OF COPD

Significant reduction
of exacerbation
frequency in patients
receiving high dose
NAC compared to
placebo (P=0.019*)

(0.96 vs 1.71 episodes/ year )



HIACE Study 2013: FREQUENCY OF ADMISSIONS
DUE TO AECOPD
p=0.196 (NS)

p=0.08 (NS)
Patients on high dose NAC had a tendency of reduction of
admission and total day of hospitalization due to COPD (p>0.05)
HIACE Study 2013 : ADVERSE EFFECTS
High dose NAC group Placebo group
Major complications 0 0
GERD symptoms 1 3
Diarrhoea 1 0
Dry mouth 1* 1
Joint pain and muscle pain 1* 0
Increase in cough 0 1
Total 3/58 = 5.2% 5/62 = 8.0%
No major adverse effects reported
No significant difference between NAC and placebo groups
Selama 1 thn penelitian didapatkan peningkatan yang signifikan
dalam parameter pengukuran fungsi paru pada pasien PPOK

Terdapat kesimpulan bahwa kelompok yang menggunakan NAC
sebanyak 1200 mg/hari selama satu tahun dapat terhindar dari
derajat keparahan terjadinya air trapping, karena fungsi paru yang
membaik.

Ada juga penurunan yang signifikan dalam frekuensi eksaserbasi
COPD (0,96 VS 1,71 kali per tahun, p = 0,019 *)
serta kecenderungan penurunan tingkat penerimaan PPOK (0,5 VS
0,8 kali per tahun, p = 0,196) dengan NAC VS plasebo.

Tidak ada efek samping yang dilaporkan selama penelitian pada
pasien yang menerima NAC..
HIACE Study 2013 : Kesimpulan
Tse HN et al. High-Dose N-Acetylcysteine in Stable COPD. The 1-year, Double-blind, Randomized, Placebo-controlled HIACE Study. Chest. 2013; 144(1):106118 DOI:
10.1378/chest.12-2357
PANTHEON Study 2013
The Placebo-controlled study on efficAcy and
safety of N-acetylcysTeine High dose in
Exacerbations of chronic Obstructive pulmoNary
disease

By : Prof Jin-Ping Zheng et al , Published : ERS Barcelona 2013

PANTHEON Study Flowchart
PANTHEON: Komparasi dengan beberapa study
COPD yang melibatkan jumlah pasien yang besar
PANTHEON
1
(n=1006)
PEACE
2
(placebo, n=354)
TORCH
3
(n=6112)
UPLIFT
4
(n=5992)
Male (%) 81.91 79.7 76 74.6
Age in years, mean (SD) 66.27 8.76 6495 8.58 65.0 8.3 64.58.5
BMI in kg/m
2
, mean (SD) 22.96 3.64 - 25.4 5.2 26.0 5.1
Ever smokers (%) 76.2 74.0 100 100
% predicted post-FEV
1
48.95 11.80 451 15.23 44.3 13.4 47.6 2.7
GOLD severity (%)
GOLD II 45.73 50.0 35.3 46
GOLD III 52.78 39.6 49.4 44
GOLD 1.49 11.4 15.3 9
SGRQ score, mean (SD)
Total score 40.75 19.29 42.83 19.34 49.3 17.1 45.9 17.1
Medications for COPD before study (%) 75.15 - - 93.3
ICS alone 4.27
15.25
- 61.7
ICS plus LABA 47.61 - 29.5
LABA 2.39
17.23
- 60.1
SABA 11.33 - 68.3
SAMA 15.71
10.17
- 44.5
LAMA 9.74 - 1.8
Theophylline (%) 26.74 26.84 - 28.5
1. Zheng JP, et al. ERS Congress 2013. Poster P3394. 2. Zheng JP, et al. Lancet 2008;371:2013-8. 3. Calverley PM, et al. NEJM
2007;356:775-89. 4. Tashkin DP, et al. NEJM 2008;359:1543-54.

PANTHEON: STUDY DESIGN

Prospective, stratified, randomized, double-blind, placebo-controlled,
parallel groups, multi-centre



Stratify I: ICS naive (about 60% of the whole
subjects):
No use or irregular use of ICS during the last
3 months

Stratify II: ICS users (about 40% of the whole
subjects):
Regular daily use of ICS in the last 3 months
NAC 1200mgN-acetylcysteine)
Placebo
Group A
Group B
One tablet, twice daily
600mg tablet,
twice daily
Zheng JP, et al. High-Dose N-Acetylcysteine in the Prevention of COPD Exacerbations: Rationale and Design of the PANTHEON Study. COPD. 2013 Apr;10(2):164-71.
PANTHEON Primary endpoint:
Penurunan angka eksaserbasi
1.49
*
1.16
0
1
2
E
x
a
c
e
r
b
a
t
i
o
n

r
a
t
e


(
n
u
m
b
e
r
/
p
a
t
i
e
n
t
/
y
e
a
r
)

Placebo NAC
(1200 mg/d)
22% reduction
(risk ratio 0.78, 95% CI 0.67-0.90)
*p=0.001
All
patients
1.33
*
0.94
Placebo NAC
(1200 mg/d)
29% reduction
(risk ratio 0.71 (CI 0.58,0.88)

*p=0.002
ICS nave
1.71

1.44
Placebo NAC
(1200 mg/d)
15% reduction
(risk ratio 0.85 (CI 0. 0.68,1.05)

p=0.137
ICS use
Zheng JP, et al. ERS Congress 2013. Poster P3394
1%
53%
46%
G O LD II
G O LD III
G O LD
52%

46%
2%
GOLD Stages
PANTHEON: Karakteristik dasar dari tahap pasien-
PPOK dan status ICS
44%

56%
IC S N aive
IC S

44%

56%
NAC 1200mg (N=504) Placebo (N=502)
ICS status
- COPD GOLD stage and ICS status -
NAC 1200mg (N=504) Placebo (N=502)
Time to first exacerbation
All patients
Time to first exacerbation
Gold moderate
PANTHEON: Penurunan angka eksaserbasi secara
signifikan pada pasien tipe moderate menurut GOLD 2013
Zheng JP, et al. ERS Congress 2013. Poster P3394
39% better than control
PANTHEON: Reduction in AECOPD
significant after 6 months of treatment
0
1
2
A
E
C
O
P
D

R
a
t
e

1.5
0.5
3 months 6 months 9 months 12 months
NAC 1200 mg Placebo
17%
19%
22%
*
*
**
*p0.05 ; **p0.01
Zheng JP, et al. ERS Congress 2013. Poster P3394
PANTHEON: Summary of key results
Treatment for 1 year with NAC 1200 mg/d was effective
for patients with COPD
In terms of reduction in exacerbations (22% reduction)
Significant interaction between treatment and GOLD stage,
with greater improvement with NAC in the moderate GOLD
subgroup (39% reduction)
A possible greater benefit in ICS nave patients (29% reduction)
The prevention of exacerbations started at 6 months and increased
thereafter
Zheng JP, et al. ERS Congress 2013. Poster P3394
The largest (>1,000 patients) study of long-term (1 year) treatment with
NAC in COPD conducted to date
Activity
MUCOLYTIC
Activity
ANTIOXIDANT
Acute bronchitis
Influenza
Chronic bronchitis
COPD
COPD with exacerbation
ORAL I.V. INFUS.



600 mg
600 mg x 3
N
A
C



6
0
0

-


1
8
0
0

m
g

NAC EFFECTIVENESS
200 mg x 3
100 mg x 3
600 mg x 2
3 Amp / hr
600 mg x 2

Idiopathic Pulmonary Fibrosis

600 mg x 2
Dosis / Hari
I.C.U.
DOSIS NAC untuk PPOK
INFUS i.v. & AMPUL untuk pasien PPOK yang dirawat di rumah sakit





NAC 10% Ampoule 300 mg / 3ml :
Nebulisasi 1 ampul, ( 1 - 2 ) kali / hari selama 5-10 hari.
Tidak perlu dilarutkan dengan NACl untuk pemberian aerosol.
I.V. atau deep intra muscular: 1 ampul diberikan (1-2) kali/hari selama
5-10 hari.
Instilasi Endobronkhial: 1 ampul diberikan (1 2) kali /hari (permanent
catheter, bronchoscopy) selama 5-10 hari.