Evidence-Based Medicine,

tuntutan baru dalam profesionalisme

pengobatan seorang penderita

Iwan Darmansjah
Pusat Uji KLinik Obat, FKUI
Dutch Foundation Seminar: Boerhaavse Kursus, FKUI 22-23 Apr.2002

Evidence Based Medicine (EBM)

Menggunakan segala pertimbangan
bukti ilmiah (evidence) yang sahih yang
diketahui hingga kini untuk menentukan
pengobatan pada penderita yang
sedang kita hadapi.
Merupakan penjabaran bukti ilmiah
lebih lanjut setelah obat dipasarkan dan
seiring dengan pengobatan rasional.

What is the level (L)

of evidence ? (TGA)

L1a. Randomized controlled trial (best evidence)

L1b. Meta-analysis (pros and cons)
L2. Retrospective analysis (case-control studies)
L2. Prospective follow-up (cohort studies)
Cross-sectional population (prevalence studies)
Previous reviews (position statements)
Clinical interventions (non-randomized)

A comprehensive evaluation of all data is the best approach!

Safety data (important element !)

How is LoE implemented in

Recommendation Guidelines? (1)
Levels of Evidence for Heart Failure:
A. Data derived from multiple RCTs.
B. Data derived from a single randomized trial or
non-randomized studies.
C. Consensus opinion of experts was the primary
source of recommendation.

www.guidelines.gov/

How is LoE implemented in

Recommendation Guidelines? (2)
Strength of Recommendation:
Class I:

Conditions for which there is evidence/general agreement

that a given procedure/therapy is useful and effective.

Class II:

Condition for which there is conflicting evidence or

divergence of opinion about the usefulness /efficacy of performing the
procedure /therapy.

Class IIa: in favor of usefulness

Class IIb: usefulness is less well established

Class III:Condition for which there is evidence/general agreement

that a procedure/therapy is not useful/effective and may be harmful.

www.guidelines.gov/

How is LoE implemented in

Recommendation Guidelines? (3)
The strength of evidence does not necessarily
reflect the strength of recommendation. A
treatment may be considered controversial
although it has been evaluated in CTs;
conversely, a strong recommendation may be
based on years of clinical experience and be
supported only by historical data or by no data
at all.
Disini conflict of interest dari penilai dijaga ketat!!

www.guidelines.gov/

Drug Safety in increased focus

around the world
Increasing number of drug withdrawals
because of harmful effects (recently: Prepulsid,
Posicor, Hismanal, Rezulin, Lipobay, etc).

Scientific report on epidemic proportions of

serious ADRs in hospitalized patients.
(Lazarou, JAMA 1998)

Medical mistakes (45.000 deaths/annually)

and medication errors (28%) are reported,
including under-utilization of proven drug
therapies. (US Institute of Medicine, 2001)

Inhaled Steroids Can Cause Bone Loss in Young Asthmatic Women

Effects of Inhaled Glucocorticoids on Bone Density in Premenopausal Women,

by Elliot Israel, M.D., Taruna R., Banerjee, M.P.H., Garrett M. Fitzmaurice, Sc.D., Tania V. Kotlov,
M.S., Karen LaHive, M.D., and Meryl S. LeBoff, M.D.;
The New England Journal of Medicine, September 27, 2001.

Background

Here is the important background information that the authors give us:
-consensus reports recommend increased use of inhaled corticosteroids
(also referred to as glucocorticoids) for patients with asthma,
-it is known that oral corticosteroids accelerate bone loss, and that
fractures occur in 30 to 50% of patients on oral corticoids,

-it is not clear, however, whether inhaled corticosteroids accelerate bone

loss.

ES obat kronis dapat

diperkirakan dari parameter
Chronicity Index

CHRONICITY INDEX is
a measure of chronic toxicity:
LD50
Endrin :

7
=

LD50
(90 hari)

= CI = 7
1

120
Deksametason :

= 1714
0.07

EBM sebenarnya merupakan cara yg

biasa dilakukan dalam proses penilaian
suatu obat baru yg akan dipasarkan.
Disini malah diperlukan juga penilaian
animal dan in-vitro studies.
Perbedaannya:
* Penilaian obat pra-pemasaran
mempertimbangkan seluruh masyarakat,
* EBM menimbang untuk satu pasien.

EBM in terms of
Benefit-Risk Ratio
The seriousness of the problem to be treated
The efficacy of the drug you intend to use
The seriousness and frequency of possible
adverse effects
The efficacy of other drugs which might be
used instead
The safety of other drugs which might be
used instead.

Bagaimana dokter bisa mengerti

EBM ?
Evidence perlu diterapkan pada penderita
dg segala penyakit/komplikasi-nya.
Evidence berubah menurut perkembangan ilmu.
Perlu CME model baru untuk mensosialisasikan pengetahuan baru ini.
Forum seminar biasa tidak lagi adekuat.
Pengobatan profesional membutuhkan
paradigma baru dalam CME.

Primary literature
How much is
incorrect?

Correction
of errors

Much of it is correct

The Knowledge Filter

(H.H. Bauer, 1995)

(adapted)

Untuk menunjang EBM, FDA telah

melakukan perubahan label indikasi
obat sewaktu ijin pemasaran melalui
undang-undang.
Misalnya: Indikasi antibiotik yang luas,
seperti untuk
upper respiratory tract infection,
terdiri dari banyak lokasi yang kuman
penyebab maupun antibiotiknya berbeda.

Respiratory Tract Infections

(FDA Points to Consider doc.)
The terms of URTI and LRTI are being
refined by more specific infections:
5. Community-acquired pneumonia (CAP)

6. Nosocomial pneumonia
7. Acute bacterial exacerbations of chronic bronchitis
8. Secondary bacterial infections of acute bronchitis
9. Acute otitis media
10. Acute sinusitis
11. Streptococcal pharyngitis
(More indications may follow in response to industrys marketing
application of claims)

Community acquired pneumonia (1):

(FDA Points to Consider doc.)

Differentiation of CAP acc. to Label Claim:

Atypical pneumonia
Viral peumonia
Acute bacterial pneumonia
Aspiration pneumonia
Ventilator-associated pneumonia
Pneumonia in an immuno-compromised
and/or neutropenic host.

Community acquired pneumonia (2):

(FDA Points to Consider doc.)

Differentiation made for bacterial

pneumonia:
Pediatric patients:
no sputum for culture
infants (3-24 mo) higher baseline value for fever
WBC count >15.000 usually assoc. with severe
infection.
Radiographic findings different, etc

Geriatric patients: ..

Susceptibility of S.pneumoniae to commonly

used ABs, stratified by susceptibility to penicillin
Susceptibility to indicated agent,

per penicillin MIC category

Agent

< 0.1 g/mL

0.1-1.0 g/mL

> 2 g/mL

Amoxicillin ..

+++

+++

Doxycycline

+++

+/-

Ery, Clari, Azi-

+++

+/-

Clindamycin

+++

++

TMP-SMZ .

++

Cefuroxime

+++

Cefotaxime

+++

+++

Levo, Grepa, Trova-

+++

+++

+++

Imipenem

+++

+++

Vancomycin ..

+++

+++

+++

+++ : > 90%

++ : > 75%

+ : > 50%

+/- : > 40%

- : < 40%

Bagaimana dg penisilin G
untuk CAP tanpa penyulit?
Intravenous crystalline Pen G, 3 - 5 juta Unit,
setiap 3 jam menghasilkan Cmax rata-rata
+ 20 45 g/ml*, yaitu 10 22 kali > MIC
S. pneumoniae yg resisten, tapi tidak disebut
dalam informasi tabel tadi.
Rasio Cmax / MIC yang besar merupakan faktor
daya bunuh kuman (conc.dependant) yg
ampuh.
CAP tanpa penyulit juga dianjurkan diobati di
rumah untuk menghindari nosocomial infection.
*(Kucers & Bennett, 4 ed. 1987, pg 23)
th

Bagaimana interpretasi hasil Lab

yg tidak pas?
Nilai Widal yg dipakai untuk diagnosis tifus.
SGPT yg merupakan surrogate endpoint.
Hasil antibiogram yg mengikutsertakan AB yg
tidak semestinya:
gentamicin (tidak pas) untuk kuman tifus,
tidak mengikutsertakan AB terpilih seperti
flukloksasilin, dikloksasilin atau penisilin G untuk
Staph. aureus atau stretokokkus, tapi
menyertakan berbagai sefalosporin,... dsb.

Lalu, bagaimana dg evidence

pengobatan empirik yg tidak ada uji
klinik formal, tetapi sangat berguna?
Varisella: cukup mandi teratur, tidak perlu AB
rutin
Parotitis epidemika: cukup permen karet.
Dikloksasilin atau flukloksasilin untuk staph.
resisten, juga penisilin prokain tidak dipakai lagi.
Probenesid (dosis kecil) telah dilupakan untk
gout, walaupun 65% merupakan masalah
ekskresi asam urat (alopurinol di-indikasikan
untk masalah pembentukan urat {35%}).

Case: Yn. 18 yrs with Grand Mal

for 14 years since 4 yrs old.
2-4 convulsions a day with coma now
and then, but now controlled. Evidence?
Anticonvulsant blood levels were:
daily dose blood l. norm. range
(mcg/ml)

- Dilantin 400 mg
1.57
- Luminal 200 mg
30.19
- Carbzepine 200 mg 1.97

/10-20/
/15-40/
/4-10/

FDA

Masalah

Industri

terbesar ialah

Dokter

bahwa

Spesialis

evidence

Farmasis

dapat diartikan

Herbalis

berbeda-beda

Naturo-

menurut

patis
Awam
dsb.

setiap orang

atau profesi.

Number Needed to Treat (NNT)

sebagai petunjuk statistik & klinis EBM
RCT, karena keterbatasannya sendiri, kadang-kadang
tidak memberi petunjuk jelas akan manfaat suatu
pengobatan untk penderita yg akan diobati (EBM).
NNT mungkin dapat memberi pegangan yg lebih mudah
diartikan dalam keputusan memberi (obat) atau tidak.
NNT= the number of patients who must be treated for a
given period to prevent a clinical outcome (e.g. stroke).
NNT= 100/absolute risk reduction.
Absolute risk reduction (stroke) =
Stroke Pla (20%) - Stroke Aktif (12%) = 0.20 - 0.12 = 0.08.

NNT untuk mengobati hipertensi

mencegah stroke
Stroke in 5 yrs
Hypertension

Control
group

Active
group

RRR

Absolute RR

(PC - PA)/PC

PC - PA

NNT
1/(PC - PA)

Mod. hypertension (diast. < 115 mm Hg)

Event rate (P)
Tot. N patients

0.20
16 778

0.12

0.40

0.08

13

0.40

0.006

167

16 898

Mild hypertension (diast. < 110 mm Hg)

Event rate (P)
Tot. N patients

0. 015
15 165

0.009
15 238

(BMJ 1995;310:452-4)

LIPID study: 9014 pats, 6.1 yrs follow-up,

secondary prevention of fatal & non-fatal
myocardial infarction by pravastatin
Placebo

Pravastatin

CHD death &

MI non-fatal

15.9%

12.3%

RR (relative risk)

0.76 (0.68-0.85)

Absolute risk
reduction

3.6%

Relative reduction

24%

Number Needed to Treat: Diperlukan mengobati 28 orang dgn

pravastatin selama 6 tahun untuk mencegah 1 event (koroner)

What is the status of

clopidogrel ?

Clopidogrel in addition to aspirin in unstable angina (source of Figure: Chris Cates , from
internet) original article: NEJM 2001;345(7):494-502)

Slide sebelumnya sangat jelas menggambarkan risiko kematian, MI, atau

stroke bila pakai aspirin saja atau ditambah dg clopidogrel.
Data ini sebelumnya dilaporkan dalam berbagai media kedokteran dengan
mengatakan RRR (relative risk reduction) adalah 20%. Tanpa
memperhitungkan absolute risk angka ini tidak cukup jelas artinya dan
seolah-olah besar.
Namun dg analisis NNT, terlihat secara visual (Visual Rx) jelas sekali,
karena 20% tadi berarti perbedaan antara 11,4% (11 dari 100 orang)
kematian dalam group aspirin saja (active plasebo) vs 9.3% (9 orang)
dalam group clopidogrel.
Dengan lain kata: bila kita mengobati 100 orang dg clopidogrel dan aspirin
selama 9 bulan, akan mencegah 2 kematian, MI, atau stroke.
NNT = 48: karena dalam praktek kita tidak bisa mengetahui 2 pasien yg
mana yg akan tertolong, semua 100 pasien harus diobati dg clopidogrel.
Data ini ialah untuk unstable angina. In practice: dipakai untuk kasus lain
dengan indikasi yg berbeda. Apakah ini evidence -based atau extended
evidence?

EBM menjembatani
Ilmu Kedokteran dan Hukum ?
EBM mulai dibutuhkan juga oleh seorang
hakim menentukan apakah suatu
pengobatan tertentu sudah benar dalam
persidangan. Diperlukan ilmu (evidence)
di belakang pertimbangan suatu testimoni
seorang saksi ahli. (JAMA Vol. 283 No.21, June 2000)
Juga, EBM menentukan harga saham
pabrik obat, yang disebarkan mass media
ekonomi.

 Namun, masih akan dijumpai

berbagai kendala, karena ilmu
pengobatan dan EBM sendiri
tidak sesederhana itu.

New Pediatric Studies

will change current State of the Art
Pediatric studies are rare, although FDA
had recommended since 1962.
There will be more pediatric clinical trials in
the future to support claim.
FDA Modernization Act (FDAMA 1993) and
the Pediatric Exclusivity Right Act (1998)
will make the above an incentive for the
industry to do pediatric clinical trials.

FDAs Approved Drugs under

Pediatric Exclusivity Rights Act (1998)
(36/37 active moieties)
Abacavir
Ammon. lactate
Azelastine
Bisoprolol
Buspirone
Calcitriol
Cromolyn
Didanosine
Enalapril
Etodolac
Famotidine
Felodipine
Fluoxetine
Flufoxamine
Gabapentin
Ibuprofen
Insulin glargine
isotretinoin

Glaxo
Westwod-Squibb
Asta Medica
Wyeth Ayerst
BMS
Abbott
Pharmacia-Upjohn
BMS
Merck
Wyeth-Ayerst
Merck
Astra Zeneca
Lilly
Solvay
Parke-Davis
2 companies
Aventis
Roche

(FDA data: Sept. 2001)

Ketorolac
Lamivudine
Loratadine
Lovastatin
Metformin
Midazolam
Nabumetone
Omeprazole
Oxaprozin
Pemiroplast
Propofol
Ranitidine
Remifentanil
Ribavirin/Intron A
Sevoflurane
Sotalol
Stavudine
Tramadol

Allergan
Glaxo
Schering Corp.
Merck
BMS
Roche
SmithKline
Astra Zeneca
Glaxo
Santen
Zeneca
Glaxo
Abbott
Schering Corp.
Abbott
Berlex
BMS
Johnson

EBM is challenged by the very

presence of neutraceuticals
While orthodox medicine is requiring
stricter use of drugs by scientific evidence,
unrestricted availability of alternative
methods and medicines are worldwide most without even any evidence of efficacy
and safety - at a price that surpass new
pharmaceuticals.

(1) Sepuluh Pedoman Pengobatan Rasional :

1. Timbanglah manfaat-risiko dgn memperhitungkan
prinsip Primum non nocere.
2. Gunakanlah pertama-tama obat yg paling
established, dan kenalilah obat pilihan ini untuk
setiap indikasi.
3. Gunakanlah obat pilihan yg anda ketahui paling
baik efeknya.
4. Batasilah pemberian jenis obat seminimal mungkin
5. Sesuaikanlah dosis obat untuk setiap penderita.

(2) Sepuluh Pedoman Pengobatan Rasional :

6. Gunakanlah dosis efektif terkecil.
7. Pilihlah cara pemberian obat yg paling aman,
tanpa mengurangi efektivitas.
8. Jangan memilih preparat terbaru, karena
barunya.
9. Janganlah ketinggalan menggunakan obat baru
yang (lebih) baik.
10. Cocokkanlah kebenaran data promosi pabrik
obat.
(Darmansjah, 1979)

EBM is perhaps not always

applicable for many reasons:
Some times we cannot treat just the numbers.
Other times we cannot use statistics to treat a specific patient.
Large outcome studies includes patients with uncontrollable
variables.
Controlled clinical trials are not always flawless.
Pediatric CTs have not been required until 1998, although
compulsory for adults since 1962.
Dose-finding studies are rare, not the least in pediatrics.
Ultimately: ask 3 specialists and you will get 2-3 different
answers. Equipoise of opinions should perhaps be set at
around 70 : 30, or more.

Conclusion
Proper drug use should be promoted nationally.
Education on drugs and EBM must take a
different approach (not education by coercive,
pharmaceutical marketing needs).
The cause of irrationalism is linked with a
perpetuating error in a larger (health) system.
Health and DrugUsePolicy must be established.
If the Health Department is failing, universities
and the profession should - morally - take
initiative.

<puko98@indosat.net.id>
<puko@makara.cso.ui.ac.id>
http://www.geocities.com/iwandarmansjah

Terima Kasih !