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 β2-agonist;

LAMA: Long-acting muscarinic antagonist; LABA: Long-acting β2-agonist;; ICS: Inhaled corticosteroid; PDE-4: phophodiesterase-4

GOLD 2014 Fulltext, halaman 26

CH2

HOOC S CH CH2

NH2

COOH CH2

HS CH

NH

COOH

COC

H3

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. George’s 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):106–118 DOI: 10.1378/chest.12-2357

HIACE Study 2013 : FORCED OSCILLATION

TECHNIQUE (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

FEF25-75%

(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):106–118 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

PANTHEON1

(n=1006) PEACE2

(placebo, n=354) TORCH3

(n=6112) UPLIFT4

(n=5992)

Male (%) 81.91 79.7 76 74.6

Age in years, mean (SD) 66.27 ± 8.76 64·95 ±8.58 65.0 ± 8.3 64.5±8.5

BMI in kg/m2 , mean (SD) 22.96 ± 3.64 - 25.4 ± 5.2 26.0 ±5.1

Ever smokers (%) 76.2 74.0 100 100

% predicted post-FEV1 48.95 ± 11.80 45·1 ± 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 Ⅳ 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 1200mg（N-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

Exa

ce

rba

tio

n r

ate

(n

um

be

r/p

atie

nt/

ye

ar)

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 naïve

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 Ⅳ

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

AE

CO

PD

Rate

1.5

0.5

3 months 6 months 9 months 12 months

NAC 1200 mg Placebo

17%

19%

22%

*

*

**

*p＜0.05 ; **p＜0.01

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 naïve 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

NA

C 6

00

- 1

80

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.