NAC IN NEW PILLAR OF EVIDENCE IN COPD (Recent clinical research 2013 ) Pulmonary Update Padang 2014

(1)

NAC

IN NEW PILLAR OF EVIDENCE

IN COPD

(Recent clinical research 2013 )

(2)

PATOGENESIS COPD

Noxious particles and

gases

Lung Inflamation

COPD pathology

Host factors

Antioxidants

Oxidative stress

Proteinase

Repair

mechanisms

Antiproteinase

(3)

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

(4)

MANAJEMEN

(5)

Tujuan

• Mengurangi gejala

• Memperbaiki toleransi olahraga

• Memperbaiki status kesehatan

• Mencegah perburukan penyakit

• Mencegah & mengobati eksaserbasi

• Menurunkan kematian

Mengurangi

gejala

Menurunkan

resiko

(6)

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

(7)

(8)

CH

2

HOOC

S

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

(9)

9

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

(10)

What really happen using Fluimucil

(NAC)

(11)

2. NAC sebagai antioksidan & precursor

glutathione (master oxidant)

(12)

Bukti-bukti klinis Terbaru

NAC dalam memenuhi sasaran

Pengobatan PPOK 2013

(13)

HIACE Study

“

HI

gh-Dose N-

A

cetylcysteine in Stable

C

hronic Obstructive Pulmonary Dis

E

ase:

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.

(14)

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.

(15)

HIACE Study 2013 : FORCED OSCILLATION

TECHNIQUE (FOT)

p = 0.04* p = 0.09 P = 0.01* p = 0.02*

Reactance

(R)

Resistance

(X)

(16)

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

(17)

HIACE Study 2013:ACUTE EXACERBATION OF COPD

Significant reduction of exacerbation frequency in patients

receiving high dose NAC compared to

placebo (P=0.019*)

(18)

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

(19)

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

(20)

• 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

(21)

PANTHEON Study 2013

• The

P

lacebo-controlled study on effic

A

cy and

safety of

N

-acetylcys

T

eine

H

igh dose in

E

xacerbations of chronic

O

bstructive pulmo

N

ary

disease

(22)

(23)

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.

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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

(25)

PANTHEON Primary endpoint:

Penurunan angka eksaserbasi

1.49 * 1.16 0 1 2 Ex acer ba tion rate (numb e r/pat ie n t/y e 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

(26)

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 -

(27)

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

(28)

PANTHEON: Reduction in AECOPD

significant after 6 months of treatment

0 1 2 AEC OP D 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

(29)

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

(30)

Activity MUCOLYTIC Activity ANTIOXIDANT Acute bronchitis Influenza

Chronic

bronchitis

COPD

with exacerbation

ORAL I.V. INFUS.

600 mg 600 mg x 3

NAC

600 - 1800 mg

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

(31)

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.

(32)