LEVEL EVIDENCE

KAJIAN KRITIS HUBUNGAN KAUSAL

DR.dr. Bambang Udji Djoko Rianto, Sp.THT, M.Kes.

 The concepts of cause

something that brings about an effect or a result

cq. etiology, pathogenesis, or mechanisms
guiding for: prevention, diagnosis, & treatment
 Evidence that an association is cause & effect:

1. Temporality : cause precedes effect

2. Strength : large relative risk/ Odd ratio
3. Dose-response : larger exposure to cause associated
with higher rates of disease
4. Reversibility : reduction in exposure associated
with lower rates of disease
5. Consistency : repeatedly observed by different
persons, places, circumstances &
times
6. Biologic plausibility : makes sense, according to
biologic knowledge of the
time
7. Specificity : one cause leads to one effect
8. Analogy : cause-effect relationship
already established for a similar
exposure/ disease
 Types of evidence for cause-effect relationship:

Strength Design Finding

Strong Clinical trial Temporality

Cohort study Strength
Case control study Reversibility
Cross-sectional Dose-response
Aggregate risk Consistency
Case series Biologic plausibility
Weak Case report Specificity
Analogy
 Skenario klinis

kolega : - keamanan adrenergik agonis terhadap asma

- keraguan informasi: obat tersebut meningkatkan
risiko kematian

kolega lain: artikel hal tersebut terpublikasi secara luas

sering dalam praktek
bukti-bukti pada artikel
cari referensi laporkan pada kolega
 INTRODUCTION

klinisi menjumpai pasien terpapar:

- intervensi medis/ medical intervention
- environtmental agent

misal:
- apakah risiko abortus meningkat pada pekerja video
display terminals ?
- apakah vasectomi meningkatkan risiko Ca prostat ?
 jawaban klinisi harus mengevaluasi:

- validitas data
- kekuatan hubungan antara kausa dan outcome
- relevansi terhadap pasien
 Tabel 1. Users Guide for article about Harm

Are the result study valid ?

Primary guides:
Were there clearly identified comparison groups that were similar with respect to
important determinants of outcome, other than the one of interest ?
Were the outcomes and exposures measured in the same way in the groups being
compared ?
Was follow- up sufficiently long and complete ?
Secondary guides:
Is the temporal relationship correct ?
Is there a dose-response gradient ?

What are the resul ?

How strong is the association between exposure and outcoma ?
How precise is the estimate risk ?

Will the results help me in caring for my patients ?

Are the results applicable to my practice ?
What is the magnitude of the risk ?
Should I attempt to stop the exposure ?
 Tabel tersebut:

- mengevaluasi artikel causation

- menilai hubungan cause-effect dengan pertimbangan
informasi yang ada:

- systematic overviews ( meta analysis)

- kesimpulan terhadap bukti-bukti yang ada
 Are the results of the study valid ?
Primary guides:
Were there clearly identified comparison groups that were
similar with respect to important determinants of outcome,
other than the one of interest ?

pemilihan grup pembanding:

- berpengaruh terhadap kredibilitas hasil

dinilai berdasarkan al: design studi yang dipakai

Tabel 2. Directions of inquiry and key methodologic strengths and weakness
for different study design

Design Starting point Assessment Strength Weaknesses

RCT exposure status adverse event status internal validity feasibility,

generalizability

Cohort exposure status adverse event status feasibility when susceptibility to

randomization threats to interal
of exposure not validity
possible

Case adverse event exposure status overcomes tem- susceptibility to

control status poral delays, threats to inter-
may only require nal validity
small sample
size
1. RANDOMIZED CONTROLLED TRIAL (RCT)

experimental murni
pasien terbagi dengan cara sama ke tiap grup
causal agent/ no causal agent
follow-up
outcome: positif/ negatif
kekuatan: similaritas antar grup: +
dengan design baik, menunjukkan hubungan penting
antara agent dan outcome
jarang dipakai
 contoh: trial cardiac arrhytmia suppresion

hubungan antara obat anti aritmi:

- encainide
- flecainide mortalitas
- maricizine

klinisi membatasi penggunaan obat tersebut

 2. STUDI COHORT

bila tak fisibel/ tak etis untuk randomisasi

identifikasi: exposed & non exposed terhadap causal agent
follow-up
kejadian outcome
 contoh:

outcome perinatal pada anak dari pria terexposed

lead & larutan organik pada industri percetakan di
Norwegia:
- OT di kategorisasi terpapar terhadap 2 zat
- hasil: exposed group: 8 x terjadi partus pre term,
tapi tak signifikan

perdarahan tractus gastrointestinal (tgi.) pada

penggunaan NSAID:
- hasil: pada grup terexpose: 1,5 x non terexpose
per 1000 sampel
- jika menggunakan design RCT butuh 6.000 sampel
 pada studi cohort:

- subyek terseleksi sendiri bisa tidak similar

- hubungan NSAID & perdarahan tgi. usia di
hubungkan dengan exposure confounding
factor CF)
- jika CF tak terdistribusi rata teknik statistik
- kadang-kadang imbalance tersebut beda
prognostic outcome
 3. STUDI KONTROL KASUS (CCS)

bila outcome sangat jarang, studi cohort tak fisibel

CCS lebih fisibel:

- identifikasi kasus (misal: penyakit, hospitalisasi, kematian
- pilih kontrol: bukan outcome tetapi faktor-faktor yang simi-
lar dengan outcome, misal: - umur
- sex
- kondisi medis
- teliti secara retrospektif: frekuensi relatif exposure terhadap
faktor kausa pada kasus dan kontrol (pembanding)
 contoh:

Hubungan o.c. dietilbestrol pada wanita hamil & adeno-

karsinoma anak wanita beberapa tahun kemudian

Prospektif: butuh > 20 tahun & ratusan ribu sampel

CCS:
- 2 grup wanita muda:
- kasus adenokarsinoma vagina (n= 8)
- kontrol (n= 32)
- telusuri exposure rate terhadap obat
 4. CASE SERIES & CASE REPORT

tanpa grup pemdanding/kontrol

tak sesuai sebagai primary guide

Kesimpulan:
- RCT terbaik untuk causation
- terpenting: populasi kontrol yang sesuai
Were the exposures & outcomes measured in
the same way in the group being compared ?

- pada CCs exposure: terpenting

- blinding subyek & interviewer: minimisasi bias
- kesempatan exposure: sama
- pada RCT & Cohort, outcome: terpenting
Was follow-up sufficiently long & complete ?

Follow-up harus adekuat

Follow-up:
- hilang : validitas hasil menurun
- makin lama : sampel DO makin besar
 SECONDARY GUIDE
Is the temporal relationship correct ?

Exposure terhadap faktor kausal mendahului outcome

contoh:
- hubungan kasus bunuh diri dan obat antidepresi:
- bunuh diri pasca pemakaian obat ?
- menggunakan obat oleh karena gejala psikis
memburuk ?
 Is there a dose response gradient ?

Kuantitas/durasi exposure terhadap kausal tinggi:

risiko outcome meningkat

contoh:
- risiko kematian Ca paru pria perokok meningkat
- 50% : 14 batang/hari
- 132%: 15-24 batang/hari
- 220%: 25 batang/hari
 What are the result ?
How strong is the association between
exposure & outcome ?

1. Risiko relatif (: cohort study):

- risiko/insidensi efek pada grup exposed dibagi
risiko efek dalam grup non exposed
- nilai RR > 1: peningkatan risiko
- nilai RR < 1: penurunan risiko

contoh: 23/289 pria hipertensi (HT) meninggal

dibanding 3/185 non HT
RR pria HT: 4,9 dibanding non HT
2. Odds ratio (OR, pada CCS)
- odds kasus grup exposed dibagi
odds kontrol/ non exposed
- bila outcome jarang, RR=OR
 How precise is the estimate of the risk ?

- evaluasi ketepatan estimasi: confidence interval

- berdasar artikel-artikel tentang risiko
 What are the implications for my practice ?
Are the results applicable to my practice ?

Jika hasil valid extrapolasi: pasien/bidang kita

Pasien/sampel kita similar ?
Ada beda penting ?

Contoh: - peningkatan Ca uteri pada pemakai hormon

estrogen pasca menstruasi
 What is the magnitude of the risk ?

RR atau OR: efek terjadi > atau <

data RCT/ cohort: jumlah populasi yang harus
terexposed kausal outcome
 Should I attempt to stop the exposure ?

Aspek dasar clinical decission:

1. Kekuatan pengaruh
2. Seberapa besar risiko jika exposure
berlanjut ?
3. Konsekwensi bila mengurangi/ menghilangkan
exposure

misal: - bloker untuk HT resistensi jalan nafas ,

terutama pada asma (khronis)
- penggunaan obat alternatif dapat diterima
 Resolution of the scenario
Data: kematian asma pemakai adrenergik agonist
(OR: 2,6 ; 95% CI: 1,7 - 3,9)

Kesimpulan:
- terdapat peningkatan risiko kematian, tapi tak
dapat dipastikan apakah karena obat ataukah
keparahan penyakit

Saran: penggunaan obat secara intermittent

 Hal-hal terpenting:

- memilih kontrol yang cocok

- koreksi beda pengukuran
- exposure & outcome diukur dengan cara sama
- temporal relationship: benar
- terdapat dose-response gradient
- jika data population based, dapat digeneralisasi
- hubungan terkuat: desain RCT
TERIMA KASIH