Bedah Makalah 1

IMPROVEMENT IN INNER RETINAL FUNCTION IN

GLAUCOMA WITH NICOTINAMIDE (VITAMIN B3)
SUPPLEMENTATION: A CROSSOVER RANDOMIZED CLINICAL
TRIAL

Hui F, Tang J, Williams PA, et al

Clin Experiment Ophthalmol. 2020;1-12.

ANNISA NINDIANA PERTIWI

DIVISI GLAUKOMA
DEPARTEMEN ILMU KESEHATAN MATA – FKUI-RSCM KIRANA
 PENDAHULUAN

karakteristik klinis
Glaukoma Ekskavasi (cupping) diskus optikus
Lee et al2 , Osborne et al 3 :
masih menjadi penyebab
Kematian retinal ganglion cell (RGC) kematian RGC berhubungan
utama kebutaan permanen
dengan stres oksidatif dan
di seluruh dunia 1 Penurunan lapang pandang disfungsi mitokondria
+/- Peningkatan tekanan intraokular

Strategi neuroprotektif
Strategi pengobatan : menurunkan TIO - Target langsung : kesehatan RGC
- Menurunkan kerentanan terhadap
Obat-obatan Pembedahan stressor seluler terkait-glaukoma
1. Tham YC, Li X, Wong TY, Quigley HA, Aung T, Cheng CY. Global prevalence of
glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-
analysis. Ophthalmology. 2014;121:2081-2090.
2. Lee S, Sheck L, Crowston JG, et al. Impaired complex-I-linked respiration and ATP
synthesis in primary open-angle glaucoma patient lymphoblasts. Invest Ophthalmol Vis Sci.
2012;53:2431- 2437.
Banyak pasien refrakter terhadap penurun TIO, atau
3. Osborne NN, del Olmo-Aguado S. Maintenance of retinal ganglion cell mitochondrial
functions as a neuroprotective strategy in glaucoma. Curr Opin Pharmacol. 2013;13:16-22 tetap berkembang menjadi kebutaan meskipun TIO turun
 PENDAHULUAN (2)

NAD+ (Nicotinamide adenine dinucleotide)

Kofaktor esensial Potensi terapeutik dalam :
untuk pembuatan
ATP di mitokondria Ageing Penyakit
neurodegeneratif

prekursor NAD+ =
Nikotinamid (NAM)
= vitamin B3

Kouassi et al 1 Williams et al 2
Kadar NAM serum Peningkatan kadar NAD+ dengan diet NAM
rendah pada POAG menghasilkan neuroproteksi jangka panjang
terhadap RGC
1. Kouassi Nzoughet J, de la Chao Barca JM, Guehlouz K, et al. Nicotinamide deficiency in primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 2019;60:2509-2514.
2. Williams PA, Harder JM, Foxworth NE, et al. Vitamin B3 mod-ulates mitochondrial vulnerability and prevents glaucoma in aged mice. Science. 2017;355:756-760.
PENDAHULUAN (3)

Hipotesis : suplementasi nikotinamid memiliki potensi terapeutik

Studi-studi sebelumnya telah menggunakan nikotinamid  efek samping minimal1,2

Pertanyaan Penelitian :
• Apakah perbaikan fungsi visual yang diamati pada suplementasi NAM pada tikus dapat
direkapitulasi pada manusia dengan glaukoma (studi intervensi, luaran utama: PhNR ERG dan
lapang pandang)?
• Apakah NAM sebagai neuroprotektan potensial dengan target insufisiensi bioenergetik pada
glaukoma, dapat menyebabkan perbaikan fungsi retina dalam?

1. Chen AC, Martin AJ, Choy B, et al. A phase 3 randomized trial of nicotinamide for skin-cancer chemoprevention. N Engl J Med. 2015;373:1618-1626.
2. Knip M, Douek IF, Moore WP, et al. European nicotinamide diabetes intervention trial G. safety of high-dose nicotinamide: a review. Diabetologia. 2000;43:1337-1345.
TELAAH JURNAL
DESAIN PENELITIAN

Desain studi
• Uji klinis acak, tersamar ganda, desain menyilang

Tempat dan waktu penelitian

• Centre for Eye Research Australia, Oktober 2017 – Januari 2019

Partisipan
• Direkrut dari dua pelayanan kesehatan tersier: Australia Royal Victorian Eye and Ear Hospital,
Melbourne Eye Specialists
• Sebanyak 57 subjek, didiagnosis dan diterapi sebagai glaukoma oleh dokter mata subspesialis
SUBJEK PENELITIAN

Kriteria Inklusi Kriteria Eksklusi

Peserta dewasa yang didiagnosis dan diobati karena Hamil / menyusui
glaukoma awal-sedang (simpang rerata VF >= -10 dB)
oleh dokter mata sub-spesialis.
Alergi terhadap NAM/niacin
Tajam penglihatan minimal 6/18
Riwayat kanker dalam 5 tahun terakhir
Telah menjalani pemeriksaan lapang pandang yang
dapat dipercaya dalam 6 bulan terakhir Riwayat penyakit hati dan ulkus lambung
Jika kedua mata dapat dipilih, mata dengan lapang Riwayat pembedahan intraokular dalam 6 bulan terakhir dan
penyakit yang mempengaruhi fungsi retina (contoh: ARMD,
pandang lebih baik yang dipilih
DR)
METODE PENELITIAN
Pemeriksaan klinis
(dikerjakan setiap visit)

Tekanan
Tajam Tekanan
intraokular
Penglihatan darah
(Icare)

Elektroretinogram
Slit lamp Perimetri
(ERG)
 METODE PENELITIAN
Serial respon luminans ERG
Parameter ERG

Vmax = saturating amplitude

N = slope
K = semi-saturating constant
METODE ANALISIS
METODE ANALISIS (2)

LUARAN METODE STATISTIK

Perubahan
• Amplitudo PhNR tersaturasi = Vmax (uV)
pada fungsi • Rasio amplitudo PhNR/gelombang-B = Vmax Stata Perubahan dari nilai dasar
lapisan retina ratio (Versi SE (baseline) selama terapi
15.1, placebo vs terapi NAM
dalam Texas)
dibandingkan antara
kelompok perlakuaan
• Konversi skala linear  dB = [Uji T dua sampel]
Lapang 10.Log(1/lambert)
pandang • Proporsi partisipan dengan perubahan >= 1dB
kelompok NAM vs placebo Uji Fischer
Efek periode : selisih
NAM-PL pada Per protokol
partisipan relatif
dibandingkan antara terhadap baseline (%)
kelompok perlakuaan
[regresi linier]
HASIL - KARAKTERISTIK BASELINE
HASIL - FOLLOW UP DAN ANGKA KEPATUHAN
 (E dan F) Tidak ada perubahan
signifikan dalam amplitudo
HASIL – FUNGSI RETINAL GANGLION CELL gelombang-a dan waktu implisit
(fotoreseptor) setelah intervensi

(A) Perbedaan signifikan rasio (B) Perbedaan signifikan Vmax

Vmax setelah 12 minggu
(NAM-PL: 0.02 [0.002,
0.025], P = 0.02)
PhNR setelah12 minggu
(NAM-PL: 1.35 uV [0.159,
2.551], P = 0.03)
(G dan H) Tidak ada perbedaan
signifikan dalam amplitudo
gelombang-b dan waktu implisit
(sel bipolar) setelah intervensi

(C) Peningkatan signifikan rasio(D) Vmax

Peningkatan signifikan Vmax
relatif terhadap baseline setelah
PhNR relatif terhadap baseline setelah
intervensi NAM 12 minggu (12.6% vs intervensi NAM 12 minggu
12 minggu
3.6%, P = 0.002, paired T-test) (14.8% vs 5.2%, P = 0.02)
 (E) Korelasi positif(F) Korelasi
sedang positif sedang antara
antara
perubahan Vmax PhNR perubahan
dan VFVmax PhNR dan VF
MDplasebo
MD setelah intervensi setelah intervensi
12 NAM 12
HASIL – LAPANG PANDANG minggu (Pearson's minggu
r = 0.34,(Pearson's
P = .02) r = 0.50, P = .
0006).

(C) Proporsi partisipan (%) yang

menunjukkan perbaikan dari baseline lebih
banyak pada kelompok NAM dibandingkan
dengan plasebo (27% vs 16% (D) Proporsi partisipan (%) yang (H) Korelasi positif sedang antara
Perburukan dari baseline lebih sedikit padamenunjukkan perbaikan dan perburukan(G) Korelasi positif sedang antara
VF MLS dan Vmax PhNR setelah
kelompok NAM dibandingkan dengan placeboVF PSD sebesar ≥1 dB hampir samaVF MLS dan Vmax PhNR setelah
intervensi NAM 12 minggu
(4% vs 12%, Fisher's exact test P = .02) pada kedua kelompok (P = 0.61) intervensi plasebo 12 minggu
(Pearson's r = 0.37, P(Pearson's
= .01). r = 0.54, P = .0002).
HASIL – TIO, RNFL, DAN EFEK SAMPING

TIO dan RNFL Efek Samping

  Tidak terdapat perbedaan TIO, MAP, atau visus yang bermakna  NAM dosis tinggi ditoleransi dengan baik
antar kelompok setelah pemberian NAM dan setelah pemberian  Efek samping paling sering
placebo.
 gastrointestinal (konstipasi atau diare; 10.5%)
 TIO setelah pemberian NAM dibandingkan placebo = 13.8 +/-
 mual (5.3%)
4.1 vs 13.4 +/- 2.4 mmHg (mean adjusted NAM-PL: 0.2 mmHg
[-0.58, 1.003], p = 0.59)  sakit kepala (3.5%)

 Ketebalan retinal nerve fiber layer (RNFL) dibandingkan

baseline setelah terapi NAM: -0.3 +/- 2.9 m vs Plasebo: 0.4 +/-
2.4 m (P= 0.11)
DISKUSI

 Nikotinamid dapat menyebabkan perbaikan dini pada fungsi retina dalam pada
sebagian besar pasien glaukomayang diobati, setelah 12 minggu suplementasi.
 Mayoritas pada individu yang mengalami perbaikan PhNR, VF MD juga membaik
 Angka kepatuhan >94%  tolerabilitas baik
 Suplementasi nikotinamid dapat menjadi terapi yang mudah, aman, dan hemat biaya
bersama dengan terapi penurun TIO
 DISKUSI (2)

Penelitian Sebelumnya Penelitian Ini

Gandolfi et al Caprioli et al  Dalam studi jangka pendek, setelah suplementasi
(2005)1 (2016) 2 NAM selama 12 minggu
 Lebih banyak partisipan (27%) menunjukkan
perbaikan signifikan pada perbaikan jangka panjang
sensitivitas kontras 3-9 sensitivitas 44% lokasi perbaikan VF MD
bulan setelah lapang pandang, 5 tahun
 Lebih sedikit (4%) mengalami penurunan VF MD
trabekulektomi, bertahan setelah trabekulektomi
s/d 3 tahun  Studi jangka panjang direncanakan untuk
menentukan apakah perbaikan fungsional ini
bertahan dan dapat menunda progresi glaukoma

1. Gandolfi SA, Cimino L, Sangermani C, Ungaro N, Mora P, Tardini MG. Improvement of spatial contrast sensitivity thresh- old after surgical reduction of
intraocular pressure in unilateral high-tension glaucoma. Invest Ophthalmol Vis Sci. 2005;46: 197-201.
2. Caprioli J, de Leon JM, Azarbod P, et al. Trabeculectomy can improve long-term visual function in glaucoma. Ophthalmol- ogy. 2016;123:117-128.
 DISKUSI (3)

Penelitian Sebelumnya Penelitian Ini

Sehi et al Ventura et al Niyadurupola  Suplementasi NAM oral berhubungan dengan:
(2010) 1 (2005) 2 et al (2013) 3  perbaikan amplitudo Vmax PhNR sebanyak
peningkata 14.8% (2.8%, 26.9%)
perbaikan perbaikan ERG
electroretinogram setelah terapi n amplitudo  perbaikan rasio Vmax 12.6% (5%, 20,2%)
(ERG) 3 bulan acetazolamide PhNR
setelah oral setelah  Efek yang diberikan tidak bergantung pada
trabekulektomi penurunan
TIO >25% 3 TIO

1. Sehi M, Grewal DS, Goodkin ML, Greenfield DS. Reversal of retinal ganglion cell dysfunction after surgical reduction of intraocular pressure. Ophthalmology. 2010;117:2329-2336.
2. Ventura LM, Porciatti V. Restoration of retinal ganglion cell function in early glaucoma after intraocular pressure reduc- tion: a pilot study. Ophthalmology. 2005;112:20-27.
3. Niyadurupola N, Luu CD, Nguyen DQ, et al. Intraocular pressure lowering is associated with an increase in the photopic negative response (PhNR) amplitude in glaucoma and ocular
hypertensive eyes. Invest Ophthalmol Vis Sci. 2013;54:1913-1919.
DISKUSI (4)

Pada penelitian ini: partisipan tetap

Deplesi NAD+ jaringan Kadar NAM serum rendah diberikan terapi glaukoma, TIO
seiring penuaan pada pasien POAG
terkontrol
TIO tidak berubah selama terapi NAM
 pengaruh NAM terhadap fungsi retina
Mekanisme bagaimana NAD+ dapat meningkatkan fungsi
RGC belum diketahui, namun dari studi pada hewan tidak dimediasi oleh perubahan TIO
dikaitkan dengan integritas dan fungsi mitokondria
HIPOTESIS

Suplementasi NAM dapat memberikan keuntungan pada mata

dengan TIO tinggi (berhubungan dengan peningkatan stres dan
disfungsi metabolik RGC)
KELEMAHAN PENELITIAN

 Dosis NAM yang digunakan dalam penelitian mungkin sub optimal; dosis tunggal
tidak ideal untuk semua orang (farmakokinetik dan farmakodinamik setiap orang
berbeda)
 Tidak menggunakan periode washout
 Belum dapat menyimpulkan apa dampak suplementasi NAM pada kualitas hidup
pasien dengan glaukoma
KESIMPULAN

Suplementasi nikotinamid dapat memperbaiki fungsi retina dalam

pada glaukoma.
Studi lanjutan dibutuhkan untuk melihat efek suplementasi
nikotinamid jangka panjang
TELAAH PENULISAN
PEDOMAN CONSORT 2010 (RCT)
 JUDUL

Section / Reported on
Topic Checklist item page #
Title and abstract Identification as a randomised trial in the title 1
ABSTRAK

Latar
Jelas
Belakang

Desain Jelas

Metode Jelas
ABSTRAK (2)
Section / Reported on
Topic Checklist item page #
Structured summary of trial design, methods,
Title and abstract 1-2
results, and conclusions

Hasil Jelas

Simpulan Jelas

Keyword Disebutkan
PENDAHULUAN (LATAR BELAKANG)

Section / Reported on
Topic Checklist item page #
Introduction Scientific background and explanation of rationale 2-3

Specific objectives or hypotheses 3

METODE
Reported
Section / Topic Checklist item on page #
Description of trial design (such as parallel, factorial) including
Trial design allocation ratio
4
Important changes to methods after trial commencement (such as
eligibility criteria), with reasons
Participants Eligibility criteria for participants 4
Settings and locations where the data were collected 4
The interventions for each group with sufficient details to allow
Interventions replication, including how and when they were actually 4
administered
Completely defined pre-specified primary and secondary outcome
Outcomes measures, including how and when they were assessed
4-5
Any changes to trial outcomes after the trial commenced, with
reasons
METODE (2)
Reported
Section / Topic Checklist item on page #
Sample size How sample size was determined 6
When applicable, explanation of any interim analyses and stopping
guidelines
Randomisation
 Sequence
1. Method used to generate the random allocation sequence 4
Type of randomisation; details of any restriction (such as blocking and block
generation size)
4

Allocation Mechanism used to implement the random allocation sequence (such as

concealment sequentially numbered containers), describing any steps taken to conceal the 4
mechanism sequence until interventions were assigned
Who generated the random allocation sequence, who enrolled participants,
Implementation and who assigned participants to interventions
4
METODE (3)
Reported
Section / Topic Checklist item on page #
If done, who was blinded after assignment to interventions (for example,
Blinding participants, care providers, those assessing outcomes) and how
4

If relevant, description of the similarity of interventions 4

 Statistical
1. Statistical methods used to compare groups for primary and secondary
6
methods outcomes
Methods for additional analyses, such as subgroup analyses and adjusted
analyses
6-7
 HASIL
Reported
Section / Topic Checklist item on page #
Participant flow For each group, the numbers of participants who were randomly assigned, 5 (Fig. 2);
(a diagram is strongly received intended treatment, and were analysed for the primary outcome 7
recommended)
For each group, losses and exclusions after randomisation, together with 5 (Fig. 2);
reasons 7
 1.
Recruitment Dates defining the periods of recruitment and follow-up 7 (Table 2)
Why the trial ended or was stopped
A table showing baseline demographic and clinical characteristics for each
Baseline data group
6
HASIL (2)
Reported
Section / Topic Checklist item on page #
Number For each group, number of participants (denominator) included in each
7
analysed analysis and whether the analysis was by original assigned groups
For each group, losses and exclusions after randomisation, together with
reasons
5
Outcomes and For each primary and secondary outcome, results for each group, and
7
 1.
estimation estimated effect size and its precision (such as 95% confidence interval)
For binary outcomes, presentation of both absolute and relative effect sizes is
recommended
Ancilary Results of any other analyses performed, including subgroup analyses and
analyses adjusted analyses, distinguishing pre-specified from exploratory
All important harms or unintended effects in each group (for specific guidance
Harms see CONSORT for harms)
9
DISKUSI

Reported
Section / Topic Checklist item on page #
Trial limitations, addressing sources of potential bias, imprecision, and,
Limitations if relevant, multiplicity of analyses
9-10
Generalisability Generalisability (external validity, applicability) of the trial findings 10
Interpretation consistent with results, balancing benefits and harms, and
Interpretation considering other relevant evidence
10
INFORMASI LAINNYA

Reported
Section / Topic Checklist item on page #
Registration Registration number and name of trial registry 3
Protocol Where the full trial protocol can be accessed, if available 12
Sources of funding and other support (such as supply of drugs), role of 1; 10
Funding funders
TELAAH KRITIS
CEBM : RANDOMISED CONTROLLED TRIALS (RCT) CRITICAL APPRAISAL SHEET
P-I-C-O

Population • Pasien dewasa dengan glaukoma awal-sedang (didiagnosa dan

diterapi oleh dokter mata subspesialis)

Intervention • Nikotinamid oral 1.5 gram/hari (6 minggu) kemudian 3 gram/hari (6

minggu)

Comparison • Plasebo oral (12 minggu)

Outcome • Perubahan parameter Vmax photopic negative response (PhNR),

rasio Vmax; lapang padang
 VALIDITY
Q A
Was the assignments of patients to treatments randomised?
Were the group similar at the start of the trial?
Aside from the allocated treatment, were groups treated equally?
Were all patients who entered the trial accounted for? And were they
analysed in the groups to which they were randomised?
Were measure objective or were the patients and clinicians kept “blind”
to which treatment was being received?
Notes
YES “Participants were randomized 1:1 with randomly selected
block sizes of 4, 6 and 8 using a computer- generated list to the
intervention in either the first or second study period.” (page 4)
YES “Inclusion criteria included adult participants diagnosed and
treated for early-moderate glaucoma (VF mean devi- ation
(MD) ≥−10 dB) by a sub-specialist ophthalmologist, and with
visual acuity of at least 6/18. “ (page 4)
YES “Treatment was taken in conjunction with any glaucoma
therapies participants were using.” (page 4)
YES Data from one eye per participant were included in the
analyses. Placebo and NAM treatments were randomly
assigned a label of “treatment A" or “treatment B.” (page 6)
YES “Participants, treating physicians, certified assessors and
biostatisticians were masked to treatment allocation.” (page 4)
IMPORTANCE

 How large was the treatment effect?

 How precise was the estimate of the treatment effect?
 IMPORTANCE

 How large was the treatment effect?

 How precise was the estimate of the treatment effect?
 * 95% confidence interval (CI) on an NNT = 1/(limits on the CI of its ARR) =

Placebo Nicotinamide Absolute Risk Number Needed

(12 weeks) (12 weeks) Reduction to Treat (NNT)
(ARR)
Improved 14% (-1% to
9% 23% 8 pts
PhNR Vmax 29%)
Improved
14% 21% 7% (-9% to 23%) 15 pts
Vmax ratio
Improved
16% 27 % 11% (-6% to 28%) 10 pts
VF MD
APPLICABILITY

Q A
Is my patient so different to those in the study
NO
that the results cannot apply?
Is the treatment feasible in my setting? YES
Will the potential benefit of treatment
outweigh the potential harms of treatment for YES
my patient?
 TERIMA KASIH

TERIMA KASIH