NAC in NEW PILLAR of EVIDENCE in COPD (Recent Clinical Research 2013 ) Pulmonary Update Padang 20

NAC IN NEW PILLAR OF EVIDENCE IN COPD (Recent clinical research 2013 )

Pulmonary Update Padang 2014

PATOGENESIS COPD Noxious particles and gases Host factors Antioxidants

Lung Inflamation

Oxidative stress

Antiproteinase

Proteinase

COPD pathology

Repair mechanisms

Vicious Circle COPD

( Chronic Obstructive Pulmonary Disease ) Initiating Factors (viral infection, smoking, etc)

Impaired mucociliary clearance Damaged to airways epithelium

Proggress of COPD

Altered elastase – anti-elastase balance

Bacterial Colonisation (Bacterial Adhesion)

Bacterial Product

LPS, Histamine, Protease

Increased Oxidative Stress (oxidant)

(consumption of antioxidant)

Increased elastolytic activity

Inflammatory Response

(Am. Rev. Resp. Dis 1992, 146:1067-83 modified after Cole & Wilson)

MANAJEMEN TERAPI

Tujuan • Mengurangi gejala • Memperbaiki toleransi olahraga • Memperbaiki status kesehatan

Mengurangi gejala

• Mencegah perburukan penyakit • Mencegah & mengobati eksaserbasi Menurunkan resiko • Menurunkan kematian Source: GOLD guideline 2014

Penatalaksanaan PPOK Stabil* Kelompo k

Pilihan Pertama yang direkomendasi

Pilihan Alternatif

Pengobatan lain yang dapat diberikan**

SAMA or SABA

LAMA or LABA or SABA and SAMA

Theophylline

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

Pasien A

B

*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. 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

GOLD 2014 Fulltext, halaman 26

PERBANDINGAN STRUKTUR KIMIA N-acetylcysteine & Carbocysteine Carbocysteine

HOOC CH S CH CH COOH 2

2

NH 2

Block Thiol (Gugus SH tidak bebas) Sumber: P.C. Braga and L. Allegra, Drugs in Bronchial Mucology,1989

N-acetylcysteine CH COOH

HS CH 2

NH COC H3

Free Thiol (Gugus SH bebas)

NAC sebagai satu-satunya TRUE MUKOLITIK 1. Direct mucolytic activity 2.Activation of mucociliary clearance

S S

NAC breaks disulfide chain, rendering the mucousless viscous and easier to expectorate

NAC improves the physiological transport of mucous, facilitating its removal 9

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 Lung function parameters for small airways

 FEF 25-75% = Forced Expiratory Flow 25% to 75%  FOT=Forced oscillation technique

Secondary outcome measures 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 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

Council (mMRC) dyspnea

HIACE Study 2013 : FORCED OSCILLATION TECHNIQUE (FOT)

Reactance (R)

Resistance (X)

p = 0.04*

p = 0.02*

P = 0.01*

p = 0.09

HIACE Study 2013 : LUNG FUNCTION PARAMETERS Changes at 16wk FEF25-75% (L/s)

NAC

+0.080+/0.03

Placebo +0.008+/0.02 FEV1 (L)

NAC

NAC

NAC

0.03*

0.2

0.047*

+0.05/-0.04

0.59

+0.06+/-0.06

0.42

+0.13+/-0.07 0.83

+0.49+/-0.08

Improvement of FEF25-75% in high-dose NAC group at 16wk and 52wk follow-up (p0.05)

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

3/58 = 5.2%

5/62 = 8.0%

Total

No major adverse effects reported No significant difference between NAC and placebo groups

HIACE Study 2013 : Kesimpulan • 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.. 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

Placebo-controlled study on efficAcy and safety of N-acetylcysTeine High dose in Exacerbations of chronic Obstructive pulmoNary

• The

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 Male (%) Age in years, mean (SD) BMI in kg/m2 , mean (SD) Ever smokers (%) % predicted post-FEV1 GOLD severity (%) GOLD II GOLD III GOLD Ⅳ

PANTHEON1 (n=1006) 81.91

PEACE2 (placebo, n=354) 79.7

TORCH3 (n=6112) 76

UPLIFT4 (n=5992) 74.6

66.27 ± 8.76 22.96 ± 3.64 76.2

64·95 ±8.58 74.0

65.0 ± 8.3 25.4 ± 5.2 100

64.5±8.5 26.0 ±5.1 100

48.95 ± 11.80

45·1 ± 15.23

44.3 ± 13.4

47.6 ± 2.7

45.73 52.78 1.49

50.0 39.6 11.4

35.3 49.4 15.3

46 44 9

40.75 ± 19.29 75.15 4.27 47.61 2.39 11.33 15.71 9.74 26.74

42.83 ±19.34 -

49.3 ± 17.1 -

45.9 ± 17.1 93.3 61.7 29.5 60.1 68.3 44.5 1.8 28.5

SGRQ score, mean (SD)

Total score Medications for COPD before study (%) ICS alone ICS plus LABA LABA SABA SAMA LAMA Theophylline (%)

15.25 17.23 10.17 26.84

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

Group A

NAC 1200mg（N-acetylcysteine)

600mg tablet, twice daily Group B

Placebo

One 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 p=0.137

*p=0.002

*p=0.001

22% reduction (risk ratio 0.78, 95% CI 0.67-0.90)

29% reduction

(risk ratio 0.71 (CI 0.58,0.88)

15% reduction

(risk ratio 0.85 (CI 0. 0.68,1.05)

2

Exacerbation rate (number/patient/year)

1.71 1.49 * 1.16

* 0.94

1

0

Placebo

NAC (1200 mg/d)

All patients

1.44

1.33

Placebo

NAC (1200 mg/d)

ICS naïve

Placebo

NAC (1200 mg/d)

ICS use

Zheng JP, et al. ERS Congress 2013. Poster P3394

PANTHEON: Karakteristik dasar dari tahap pasienPPOK dan status ICS - COPD GOLD stage and ICS status G O LD II G O LD III G O LD Ⅳ

2%

1%

46%

46% 53%

52%

NAC 1200mg (N=504)

GOLD Stages

Placebo (N=502)

IC S N aive IC S

44%

44%

56%

56%

ICS status NAC 1200mg (N=504)

Placebo (N=502)

PANTHEON: Penurunan angka eksaserbasi secara signifikan pada pasien tipe moderate menurut GOLD 2013 39% better than control

Time to first exacerbation – All patients Zheng JP, et al. ERS Congress 2013. Poster P3394

Time to first exacerbation – Gold moderate

PANTHEON: Reduction in AECOPD significant after 6 months of treatment

NAC 1200 mg

Placebo

2

AECOPD Rate

22% 19%

1.5

17%

** *

1

* 0.5

0

3 months

*p＜0.05 ; **p＜0.01 Zheng JP, et al. ERS Congress 2013. Poster P3394

6 months

9 months

12 months

PANTHEON: Summary of key results The largest (>1,000 patients) study of long-term (1 year) treatment with NAC in COPD conducted to date 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

ANTIOXIDANT

Idiopathic Pulmonary Fibrosis

I.C.U.

Activity MUCOLYTIC

I.V. INFUS.

600 mg x 3

3 Amp / hr

COPD with exacerbation

600 mg x 2

COPD

600 mg x 2

Chronic bronchitis

600 mg x 2

Acute bronchitis Influenza

600 mg 200 mg x 3 100 mg x 3

600 - 1800 mg

Activity

ORAL

NAC

NAC EFFECTIVENESS

Dosis / Hari

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.