Artikel Jurnal DR Theo

i
dr. Theodorus, MMedSc

Staf Bagian Farmakologi FK UNSRI
Alasan pentingnya penelitian (Why

this study is important)
1. Belum ada data ( No, few, atau scarce data)
2. Melengkapi data ( dari retrospektif ke prospektif
atau dari in vitro ke invivo)
3. Kontroversi data (hasil dari 1 senter berbeda dengan
senter lain)
4. Spesifik lokal area ( terutama pada daerah endemis )
5.Indikasi baru( terutama uji klinik; misal rosiglitazon
sbg anti asma atau tilmisartan sbg antiinflamasi)
1
WHY THIS STUDY IS IMPORTANT?
Judul 1: (background, akhir kalimat paragraf 2)
No data: the evidence from both these resources cannot be
assumed between the two dose regimen
Judul 2: (Introdution, akhir kalimat paragraf 1)
No data: the relation cannot yet be considered secure
Judul 3: (Introduction, akhir kalimat paragraf 4)
No data; However, no clinical study comparing tamsulosin with
non selective 1 adrenoceptor antagonist has yet been published
Judul 4: (Intoduction, awal kalimat paragraf 3)
Kontroversi data; the controversy about the number of fatal
peptic ulcer complications that can be attributed to NSAID need
to be settled
WHY THIS STUDY IS IMPORTANT?

Judul 5: (backgroud, awal kalimat paragraf 3)
Only two studies (few data), however, have focused on
the potential use of mifepristone and misoprostol for
medical abortion in developing countries, and only
one of these measured the methods acceptability to
clients.
Judul 6: (Introduction, awal kalimat, paragraf 7)
No data: Although global epidemiological data
regarding NSAID induced complications are available,
we planned to evaluate the prevalence of GI, cardiac
and renal complication in India.
2
1. What is the research question or
hypothesis? (aim, purpose, objective
or goal)
RESEARCH QUESTION: the essensial question the
study is set up to answer
menilai berapa besar masalah kesehatan
menilai hubungan 1/kelompok faktor risiko dng
penyakit/hasil yang akan diteliti
nenilai perjalanan penyakit
menilai efektifitas intervensi: obat, tindakan
operasi
1. What is the research question or

hypothesis? (aim, purpose,
objective or goal)
HIPOTESA
This is a proportion about the relation among two or
more factors or variables
May not be stated, but it is implicit
Are often stated in null form
Debateable or refuteable
3
1. What is the research question or hypothesis?
(aim, purpose, objective or goal)
Judul 1: (background, awal kalimat paragraf 3)
To evaluate the biological efficacy of low dose aspirin
and to compare it against a medium dose preparation
Judul 2: (introduction; kalimat akhir paragraf 2)
To assess the association between regular use of
analgesics containing aspirin and the incidence of
several chronic disease including cardiovascular and
cancer
1.What is the research question or hypothesis

(aim, purpose, objective or goal)
Judul 3: ( introduction; awal kalimat paragraf 5)
To compare the efficacy and safety of tamsulosin and
terazosin in the treatment of urinary outflow
obstruction associated with BPH in Korean patients
Judul 4: (introduction, kalimat ke2 paragraf 3)
To determine whether their use was associated with
an increase case fatality rate from peptic ulcer
complication in patients admitted to Hospital in
Newcastle.
4
1. What is the research question or hypothesis
(aim, purpose, objective or goal)?
Judul 5: (introduction; kalimat ke2, paragraf 7)
We address three important question: First, is medical
abortion as effective as surgical abortion for women who
choose the method? Second, how do the safety, risk and
side effects of medical abortion compare with those of
surgical abortion? Third, do women who choose
mifepristone-misoprostol abortion find the method
acceptable?
Judul 6 (introduction; kalimat ke 2, paragraf 7)
The primary of the study was to assess the point prevalence
of GI, cardiac, renal complications associated with the use
of NSAID as a standard of care in patients across India for
the first time?
2. What is the study type?

Hierarchy of Study Types??
Descriptive Analytic
Case report
Case series
Survey
Diagnostic Test
Observational
Experimental
Cross sectional
In vitro in vivo
Case-control
Ranzomized
Cohort studies
controlled trials
Strength of evidence for causality between a risk factor and outcome
5
Comparison of Intervension
VAR Treated Controlled
Before / After / P* Before/ After / P* P**
baseline Endpoint baseline Endpoint
EC 50
Agree-
gation
Dependent* / Independent** T Test ; P ( 0,01, 0,05, atau 0,1)
Note : Controlled Positive = drug of choice

Controlled Negative = placebo

Comparison of Intervension
VAR Treated Controlled
Before / After / P* Before/ After / P* P**
baseline Endpoint baseline Endpoint
EC 50
Agree-
gation
Simpulan :
1. Treated sama efektif dengan controlled
2. Treated lebih efektif dari controlled
3. Controlled lebih efektif dari treated
4. Treated dan controlled sama-sama tidak efektif
6
Measures of association ( Relationship)
Disease / Outcome
Yes No RR/OR
Ye A B
Risk
s
Or
Exposure
No C D
Chi Square Test, P = ( 0,01, 0,05, atau 0,1)
2.What is the study type?

Measures of association ( Relationship)
Disease / Outcome
Yes No RR/OR
Yes A B
Risk
Or
Exposure
No C D
Simpulan :
1. Berhubungan (RR/OR 1,5) dan bermakna (p < 0,01, < 0,05, atau < 0,1)
2. Berhubungan (RR/OR 1,5), dan tidak bermakna (p > 0,01, > 0,05, atau >
0,1)
3. Tidak berhubungan (RR/OR 1) dan bermakna (p < 0,01, < 0,05, atau <
0,1)
4. Tidak berhunngan (RR/OR 1) dan tidak bermakna (p > 0,01, > 0,05, atau
> 0,1)
7
Judul 1: (introduction; akhir kalimat paragraf 3)
Randomised controlled trials, double blind
Judul 2: (methods; awal kalimat paragraf 4)
Studi Kohort: The members of cohort were followed
up to the time of the event of interest (admission to
hospital) or death or to 1 January 1988, whichever came
first

Judul 3: (Patients and Methods; awal kalimat paragraf
1)
Randomised Controlled trials, single blind
Judul 4: ( introduction; kalimat ke 2 paragraf 3)
We therefore conducted a case-control study to
determine whether their use was associated with an
increased case fatality rate from peptic ulcer
complication in patients admitted to hospital in
Newcastle, NSW
8
Judul 5: (methods, kalimat ke 2, paragraf 1)
Randomised Clinical trials, no blind
Judul 6 ( Materials and methods, awal kalimat
paragraf 1)
A cross sectional study, multicentre
3. WHAT IS SAMPLING METHOD

a. Non-random (probability) sampling :
- Voluntary samples
- Purposive (judgemental) samples
- Convenience (concecutive) samples
- Snowball samples
- Quota sampling
- Haphazardous (self selecting) samples
9
b. Random (probability) sampling :
- Simple random sampling
- Systematic sampling
- Block sampling
- Cluster sampling
- Stratified sampling
- Multistage random sampling
c. Matching

Judul 1: (intervention and randomisation; kalimat ke 2)
Randomisation into allocation blocks of 6 (six)
Judul 2: (methods, awal kalimat paragraf 1)
Total sampling; all residents of Leisure World
Judul 3: (patients and methods; awal kalimat paragraf 2)
Simple randomisation
Judul 4: (subjects and methods, paragraf 1)
Controls were matched with cases for age, sex, site of ulcer
and the nature of the complication
10
3. What is sampling method?
Judul 5: (methods,, kalimat ke 7 dan 8 paragraf 4)
After hearing about medical and surgical abortion
methods, women choose between them. Any women
who could not decide would have been randomised to
a method, but no participants were undecided.
Judul 6: (sample size; kalimat ke 3 paragraf 1)
The subjects were enrolled for the study by designated
members of the investigators team after visiting
indoor or OPD (outpatient department) clinics of
respective departments.
a. Sample size
Judul 1: (sample size): rencananya 108 orang dibagi 3
kelompok; yang dianalisa terakhir menjadi hanya 2
kelompok dengan total sampel 69; dan 1 kelompok
tidak diikut sertakan untuk dianalisa (lihat figure 1)
Apakah ada bias seleksi atau bias indikasi dalam
pemilihan sampel?
Judul 2: (results, awal kalimat)
13.987 dari total residents 22.781 (61% respon rate)
Apakah ada bias respon dalam penelitian ini, karena
kurang dari 80%?
11
Sample size
Judul 3: (patients and methods, paragraf 1)
Total 98 patients dan 26 diantaranya tidak dianalisa
atau withdrawn
Apakah ada bias seleksi atau bias respon?
Total 240: dimana kasus ada 80 dan kontrolnya 160
Apakah ada bias seleksi atau bias riskfactor dalam
penelitian ini?
Sample Size
Judul 5: (results; sample characteristics, paragraf 1)
The sample consist of 393 women- 221 in Hanoi and
172 in Ho Chi Minh City. Overall, 260 women choose
medical abortion and and 133 opted for surgical
procedure.
Judul 6: (sample size; kalimat ke 4 paragraf 1)
A total of 3600 subjects were planned to be recruited
from each investigational site (1200 subjects each for
GI, cardiac and renal complications).
12
b. Sample
HIERARCHY OF SAMPLING
REFERENCE POPULATION
SOURCE POPULATION
SAMPLING FRAME
UNITA SAMPLING/SAMPLE
SAMPLE/STUDY SUBJEKS
3. HIERARCHY OF SAMPLING
Referance Population : Pelajar SD di Indonesia

Source Population : Pelajar SD di Palembang
Sampling Frame : Daftar sekolah di Palembang
Unit Sampling : 10-25% SD di Palembang
Sample : Pelajar yang ikut
13
b. Sample
Judul 1: (methods, kalimat ke 2)
Inclusion criteria: all patients undergoing elective
primary coronary artery bypass surgery were invite to
participate and informed consent was obtained
Exclusion criteria: if the patients did not stop
antiplatelet therapy a week prior to surgery, had
contraindication to aspirin or other medication
Judul 2: (methods, awal kalimat paragraf 1)
All residents of Leisure World
Sample
Judul 3: (patients and methods, paragraf 1)
Inclusion criteria: patients with moderate to severe symptomatic
BPH
Exclusion criteria: if the patients had prostatic cancer, a serum
PSA level > 10ng/ml, prostatitid etc
Inclusion criteria for cases: all patients who had died during
their hospital admission and whose record contained any
mention of peptic ulcer complication in the discharge
diagnoses were reviewed and matched by two controls
Inclusion criteria for controls: who were patients who had
survived a bleeding or perforated ulcers within 2 years of the case
and matched by age, sex etc
14
Sample
Judul 5: (methods; Kalimat ke 2 paragraf 3)
Inclusion criteria: if bimanual examination showed that they were no
more than eight weeks pregnant (or if it had been no more than 56
days since their last menstrual periode), they had no contraindication
to medical abortion, they lived within one hour of the clinic , willing
return to follow up, and aged < 35.
Judul 6 (Eligibility criteria, paragraf 1)
Men or women ( 18 years) from outpatient department or those
admitted to the hospital for the following reason were included in the
study; admitted to gastroenterology department for upper GI
endoscopy within 4 weeks prior to the study, admitted to cardiology
department for one or more investigations amongst ECG, treadmill test
and ECG within 3 months prior to study and admitted to nephrology
department for one or more investigation; serum urea, serum
creatinine and creatinine clearance withnin 6 months prior to study
4. How were subjects assigned to group and

were blind? Has bias been introduced?
Blinding (masking) : hanya berlaku untuk study
eksperimental (randomized controlled trials). Ada 4
jenis blind yang dikenal ,
- No blind (open label) dimana peneliti dan sample
tahu perlakuan (obat) yang diberikan
- Single blind : peneliti tahu perlakuan (obat) yang
diberikan
- Double blind : peneliti dan sample tidak tahu
perlakuan (obat) yang diberikan
- Triple blind : peneliti, sample dan penganalisa tidak
tahu
15
4. How were subjects assigned to group and
were blind? Has bias been introduced?
Bias is any effect at any stage of investigation (or
inference) tending to produce result that depart
systematically from the truth.
Ada beberapa bias yang dikenal diantaranya yaitu bias
seleksi, bias respon, bias pengukuran, bias indikasi,
bias peneliti, recalling bias, journal bias, risk factor
bias, outcome bias, interviewer bias
Cara mengatasi bias yaitu dengan Randomisasi
pengecualian untuk bias peneliti pada study
eksperimental (randomized controlled trials) diatasi
dengan blinding.
4. How were subjects assigned to group and were

blind? Has bias been introduced?
Judul 1: (intervention and randomisation, kalimat ke
2)
Randomisation was undertaken by pharmacy into
treaament allocation blocks of 6 .
Hanya 69 dari 2 kelompok yang mencapai akhir dari
rencana total sampel 108 dari seharusnya 3 kelompok
Apakah ada bias seleksi atau respon?
Blinding: Participants, researchers and statisticians
were blind to the treatment allocation (triple blind)
16
Aspirin 100 Mg (36) 35
Low Dose
Sampel
Randomization
Aspirin 325 Mg (36) 34

Medium Dose
Clopidogrel (36) 18 Terminated
4.How were subjects assigned to group and were

Judul 2: (methods, awal kalimat, paragraf 1)
Total sampling 22 781 residents, dan tidak dijelaskan
berapa banyak yang menjadi kelompok risiko dan
kelompok non risiko; dan hanya 61% response rate
(13.987 yang mengembalikan kuesionair)
Apakah ada bias seleksi, bias respon atau interviewer
bias dalam penelitian ini?
17
Aspirin Users Cardiovascular

Questionnaire
13987 Follow Up
1981 - 1988
Non Users Cancer
Populasi
22781

Judul 3: (patients and methods, awal kalimat paragraf
2)
The patients were randomised into two group of 49
each
Dari rencana total 98 pasien, hanya 72 pasien yang
dianalisa. Dari 26 yang tidak dianalisa, 16 pasien lost
follow up, 5 protocol violation and 2 karena adverse
reaction dan 3 tidak dijelaskan.
Single blind (patients and methods, awal kalimat
paragraf 1)
Apakah ada bias peneliti dalam penelitian ini
18
Tamsulosin (49) 39
Sampel -IPSS
Randomization - Qmax
- PVR
Terasosin (49) 33

By matching: Each fatal case were matched with two
controls , who were patients who had survived a
bleeding or perforated ulcers within two years of the
case. Controls were matched with cases for age (to
within five years), sex, site of ulcers (gastric or
duodenal), and the nature of the complication
(hemorrhage or perforation) .
19
NSAID DEATH
(80)
Aspirin Medical
Retrospective Record
1980 - 1986
Matching
Cortico Streoid SURVIVED
(160) Kriteria Inklusi
Kriteria Eksklusi
4. How were subjects assigned to

groups and were blind?
Judul 5 (methods, kalimat ke 7 paragraf 4)
After hearing about medical and surgical methods,
women choose between them. Any women who could
not decide would have been randomised to a method,
but no participants were undecided
No randomization and no blind
Apakah ada bias seleksi atau bias peneliti?
20
Medical(260) 258 (96,1%)

Abortion
Sampel
Choosing Success
Failed
No randomization 131 (99,2%)

Surgical (133)
Abortion
4. How were subject assigned to

groups and were blind?
Judul 6: (patient recrutment, paragraf 2)
All patients with investigational reports of erosion/
ulcers/gastritis in upper GI endoscopy investigational
reports suggestive recent or old AMI, systolic or diastolic
cardiac dysfunction failure or ACS, or subjects who have
raised serum creatinine, serum urea, or low calculated
creatinine clearance values suggestive of diagnosis of renal
failure (acute or chronic) are considered as cases while
those without above considered as control. The case:
control ratio is 3: 1
Tidak dijelaskan cara pengambilan sampel baik non
random ataukah randomisasi
21
1300 GI 724
Interim
analysis
Sampel Admitted
1300 Cardiac 690
July 7
2014
1300 Renal 726
Aspirin
users / not
Note : Periode penelitian August 15, 2013 January 2015, Total pasien
yang dianalisa 2140 (interim analysis) out of 3600
5. What are the study factors and

how are they measured?
Judul 1: (laboratory methods, kalimat 3 dan 6)
Platelet aggregation was determined turbidimetrically
using the Platelet Aggregation Profiler PAP-4
Platelet aggregometry reading for each agonist were
converted to EC50 using curve fit software
Judul 2: (methods; kalimat 2 paragraf 2)
The use of analgesics was ascertained from the
questions Which of the following best describes your
use of non prescription pain medication? And When
you take non-prescription pain medication? etc
22
5.What are the study factors and
Judul 3: (patients and methods; kalimat 5 paragraf 1
dan awal kalimat paragraf 3)
IPSS question (max 35 point; the obstructive
question 1,3,5 and 6 (point 20) and irritative question
2,4 and 7)
A maximum urinary flow rate ( Q max) by using
Urinary flowmetry
The PVR by using ultrasonography
5. What are the study factors and

Judul 4: (subjects and methods; kalimat 5)
The notes of all patients who had died during their
hospital admission and whose records contained any
mention of peptic ulcer complications in the discharge
diagnosis were reviewed. Eighty one patients had died
after admission to hospital with a primary diagnosis of
complicated peptic ulcer. Each fatal case were matched
with two controls who were patients who had survived
a bleeding or perforated ulcers within two years of the
case
23
5. What are the stury factors and
Judul 5 ( Awal kalimat, paragraf 6 dan akhir kalimat
paragraf 7)
Generally, if the abortion by medical was not complete at
the follow up visit, surgical abortion was performed as a
backup. And for surgical abortion, patients returned to
clinic after first visit (14 days later) for a check up.
Judul 6: (data collection, awal kalimat paragraf 1)
History of NSAID intake including name of the
medications, fraquency of intake, indication of use,
duration of use, whether prescribed or taken over the
counter and history of concomitant medications.
6. What are the outcome factors

and how are they measured?
Judul 1: (background; awal kalimat paragraf 3)
To evaluate the biological efficacy of low dose aspirin to
compare against a medium dose preparation.
Primary outcomes: reduction percentage of aggregation
Secondary outcome: increase mean of EC50 concentration
Judul 2: (methods; awal kalimat, paragraf 4)
The members of the cohort were followed up to the time of
the events of interest (admission hospital), or death or to 1
January 1988, whichever came first.
24
Judul 3: (introduction; awal kalimat paragraf 5 dan
patients and methods; awal kalimat serta kalimat 3
paragraf 3)
terazosin in the treatment of urinary outflow
obstruction associated with BPH in Korean patients
Primary outcomes for assessing efficacy were changes
in Qmax and total IPSS; and also the PVR
Secondary outcome: adverse reactions

Judul 4: (subjects and methods; kalimat 9)
The clinical notes from all cases and controls were
examined to identify all drugs (Non steroidal
antiinflamation, corticosteroid and aspirin) which had
been taken during the week before admission to
hospital.
25
6 What are the outcome factors
and how they are measured?
Judul 5: ( methods: awal kalimat paragraf 5 dan 7)
Women who choose medical abortion received 600 mg
of mifepristone at their admission visit and remained
under observation for 30 minutes. At second visit, two
days later, they received 400mcg of misoprostol orally
and were monitored at the clinic for at least four
hours.
Patients who choose surgical abortion had the
procedure on their first visit in accordance with the
clinics regular practices.

and how they are measured?
Judul 6: (patient recruitment; awal kalimat paragraf ke
2)
All patients with investigational reports of
erosion/ulcers/gastritis in upper GI endoscopy,
investigational reports suggestive of recent or old AMI,
systolic or diastolic cardiac dysfunction failure or ACS
or subjects who have raised serum creatinine, serum
urea or low calculated creatinine clearance values
suggestive of diagnostis of renal failure (acute or
chronic).
26
7. What important potential
confounders are considered?
* CONFOUNDER (Faktor pengganggu): is a
factor that distort the apparent magnitude of the
study factor on the outcome factor
AINS
Perdarahan
Saluran cerna
> 65 TAHUN

Cara mengatasi confounders (faktor pengganggu) :
1. Stratified random sampling
2. Matching
27
7. What important potential confounders
are considered?
Judul 1: (Primary outcome, awal kalimat)
The patients were well matched for baseline
characteristics (lihat tabel 1)
Judul 2: (results; kalimat ke 2)
The distribution of sex was comparable in
respondent and non respondent, but non respondent
were slightly older ; overall mortality was greater in
non-respondent in the first few years of follow up and
then became identical with that in the respondent

Judul 3: (results; kalimat ke 3)
There were no differences in patients background
between the groups for any comparison (lihat tabel 2)
Judul 4: (subjects and methods; kalimat ke 8 dan 9)
Each fatal case were matched with two controls , who
were patients who had survived a bleeding or
perforated ulcer within two years of the case. Controls
were matched with case for age (to within five years),
sex, site of ulcer (gastric or duodenal), and the nature
of complication (haemorrhage or perforation).
28
confournders are considered?
Judul 5: (tabel 1)
Women who selected the medical method were
younger than those who decided on surgical abortion
(26.4 vs 27.9 years); and the number of who had had
previous abortion on the medical abortion are higher
than those on surgical abortion (48.5 vs 43.6)
Seharusnya karakteristik sampel untuk kedua
kelompok homogen.
7. What important confounders are

considered?
Judul 6: (tabel 1)
Dari demographis profile dapat diketahui bahwa pada
kelompok cardiac complication lebih tua (51.5 13.4)
dibandingkan dengan kelompok renal complication
(45.3 16.1) dan GI complication (44.3 14.7), dan
perbandingan cases: controls= 3 : 1 pada semua
kelompok tidak sesuai dengan rencana penelitian
(cases: control GI complication: 73.8 vs 26.2; diikuti
Cardiac complication: 72.7 vs 27.3; serta renal
complication 73.6 vs 26.4)
29
8. Are statistical tests considered?
Judul 1: (statisitcal methods; dan tabel 2)
Analysis were performed using Stata 8.2 (Stata Corp, Texas, USA)
Tabel 2: hanya menggunakan dependent T test yaitu hanya
membandingkan efektifitas (-37 vs -36) dalam kelompok tetapi
tidak membandingkan hasil final antar kelompok
Judul 2: (methods; kalimat akhir paragraf 4)
The generalised linear interactive modelling (GLIM), software
package programs was used to make these calculations. All
reported p values are two sided
Lihat tabel 1 dan 2: RR untuk laki-laki pengguna aspirin daily
yaitu 6.28 terhadap kejadian kanker ginjal dan RR baik laki-laki
(1.86) dan perempuan (1.72) pengguna aspirin daily terhadap
kejadian ischaemic heart disease
8.Are statistical tests considered?

Judul 3: (patients and methods; paragraf 4)
The patients demographisc differences and any differences in
subjective and objective changes between the baseline and
treatment periods were assessed using Student t-Test
Tabel 2: menunjukkan bahwa kedua kelompok homogen
Tabel 3: Tamsulosin and terasozin efektif secara bermakna
terhadap Total IPSS (baik irritative dan obstructive) dan Qmax;
tetapi tidak terdapat analisa terhadap PVR. Sayangnya tidak
dilakukan analisa antar kelompok terhadap masing-masing
endpoint, untuk menyatakan kelompok mana yang lebih efektif,
misal Changes total IPSS pada kelompok tamsulosin= -6.4
sedangkan pada kelompok terazosin= -8.0
30
8. Are statistical tests considered?
Judul 4: (subjects and methods; awal kalimat paragraf
2)
The measure of association between exposure to the
drugs of interest and mortality from ulcer
complications was the odd ratio with in 95%
confidence interval calculated for matched triplets by
methods Miettinen.
Lihat tabel 1: only the use of Corticosteroid was
associated with a roughly fourfold (OR= 4,2) increase
in the risk of death
8. Are statistical test considered?

Judul 5: (methods; kalimat ke 2 paragraf 10)
All means testing used t-test with Levenes tests conducted to
determine whether pooled or separate variance estimates were
appropriate. Chi-square tests were used to analyse categorical
data.
Judul 6: (statistical analysis, awal kalimat)
Continous variables (age, weight) were presented using mean
and standard deviation. Categorical variables (gender, presence
of risk factors) were presented using frequency and percentage.
Age and, history of GI complication, dosage, concurent
administration of known GI toxic drugs, concurent use of
NSAIDS and history of comorbidities were the risk factors and
were considered for the analysis. A subgroup analysis was
conducted based on the above specified risk factors to analyze
the prevalence of NSAID-induced complications
31
9. Are the results clinically/socially
important?
Judul 1: (conclusion; awal kalimat)
Low dose aspirin is effective and medium dose aspirin did
not prove superior as an inhibitor pf platelet aggregation in
vitro after coronary surgery.
69 dari 72 pasien yang menyelesaikan penelitian
Judul 2: ( discussion; akhir kalimat paragraf 1 dan akhir
kalimat paragraf 5)
Our current results are compatible with these published
(the data on renal cell carcinomas are scanty and
inconclusive) findings for cancer of the renal pelvis and
suggest that an even stronger association may exist
betweeen the regular use of aspirin and the development
of renal cell carcinoma

important?
In fact, our study found a significantly increased
incidence of ischaemic heart disease in regular use
aspirin users of both sexes and an increased incidence
of other heart disease, which was significant in men
13987 dari 24781 residents (hanya 61%) yang
mengembalikan kuesionair; 8881 diantaranya wanita
dan sisanya 5106 adalah laki-laki
Judul 3: (conlcusion pada abstract}
Tamsulosin was as effective as terazosin in treating
urinary outflow obstruction associated with BPH but
had a markedly better safety profile
32
important?
Hanya 72 dari 98 pasien yang dianalisa dimana 16 pasien
lost follow up dan protocol violation ada 5 pasien ; 39 pada
kelompok tamsulosin dan 33 pada kelompok terazosin.
Judul 4: (discussion, kalimat ke 4 paragraf 3)
Thus, the main thrust of attempts to reduce morbidity and
mortality from non-steroidal anti-inflamatory drugs in the
community should be to limit their use rather than to
attempt to lower relative risk further by widespread
coprescription of agents design to protect the
gastrointestinal mucosa such as prostaglandine, sucralfate
or histamine H2 antagonist

important?
(subjects and methods; kalimat ke 2 paragraf 2)
With 80 cases and 160 controls and predicted
prevalence of use of non steroidal anti-inflamatory
drugs of about 40% the study had a power of
approximately 0,7 to detect as significant (alpha=0,05)
a relative risk of 2.0. This was considered sufficient to
discriminate between the extremes of the published
estimates of attributable mortality.
33
9. Are the result clinically/socially
important?
Judul 5 :
This study result showed (discussion, awal kalimat):
That mifepristone-misoprostol medical abortion is a safe,
effective, and desireable alternative to surgical abortion in
Vietnam. Moreover, while the medical abortion failure rate
in our study exceeds that of surgical method, many
Vietnamese women apparently are willing to accept an
increased risk of failure, since most said they would choose
medical abortion again and would recommend it to their
friends

important ?
Judul 6: ( discussion, awal kalimat paragraf 1 dan
kalimat paragraf 7))
The result of primary objective has shown that the
point prevalence of GI (30,08%), cardiac (42,7%) and
renal complications (27,88%) with the use of NSAIDs
in India. These results show that there is a need to
channelize and standardize appropriate usage of
NSAIDs among patients.
However, there is no result found for second or other
study objective in this study
34
10. What conclusion did the authors reach about the
research question? Did they generate new hypotheses?
Do you agree with with the conclusions?
Judul 1 ( Research Question; background, awal kalimat
paragraf 3)
To evaluate the biological efficacy of low dose aspirin and
to compare it against a medium dose preparation?
(conclusion, awal kalimat)
Low dose aspirin is effective and medium dose aspirin did
not prove superior as an inhibitor pletelet aggregation in
vitro after coronary surgery.
The clopidogrel arm was terminated in accordance to pre-
planned criterion owing to concerns for participant safety
(results, kalimat ke 3 paragraf 1): tidak dijelaskan apakah
ada persetujuan ulang dari Local Research Ethics
Committee Huntingdon.

research question ? Did they generate new
hyphotheses? Do you agree with the conclusion?
Judul 2: (Research Question; introduction, akhir kalimat
paragraf 2)
To assess the association between regular use of analgesics
containg aspirin and the incidence of several chronic
disease, including cardiovascular disease and cancer?
Our result suggest that an even stronger association (RR=
6.28) may exist between regular use of aspirin and the
development of renal cancer carcinoma (discussion, akhir
kalimat paragraf 1) and a significant increased incidence of
ischaemic heart disease (RR for men; 1,86 and RR for
women: 1,72) in regular users both sexes (akhir kalimat
paragraf 5)
Hanya 61% yang berpartisipasi
35
research question? Did they generate new hyphotheses?
Do you agree with the conclusion?
Judul 3: (Research Question; introduction; awal kalimat
paragraf 5)
terazosin in the treatment of urinary outflow obstruction
associated with BPH In korean patients
This study suggest that both selective and non selective 1
A_adrenoreceptors antagonists has qualitatively similar
efficacy in subjective and objective symptoms of urinary
outflow obstruction with BPH; and also suggest that better
safety with tamsulosin over terasozin ( awal kalimat
paragraf 2 dan 3)
Hanya 72 pasien yang dianalisa dari rencana total 98 pasien

research question? Did they generate new hyphotheses?
Judul 4: (Research Question; introduction, kalimat 2
paragraf 3)
To determine whether their use was associated with an
increased fatality rate from peptic ulcer complications
in patients admitted to hospital in Newcastle, NSW.
In contrast, the use of corticosteroids was associated
with a roughly fourfold (OR: 4,2) increase in the risk of
death (results, awal kalimat paragraf 3)
36
research question ? Did they generate new hypotheses?
Judul 5: (introduction, kalimat ke 2 paragraf 7)
We address three important questions. First, is medical abortion
as effective as surgical abortion for women who choose the
method? Second, how do the safety risk and side effects of
medical abortion compare with those of surgical abortion?
Third, do women who choose mifepristone-misoprostol abortion
find the method acceptable?
(Discussion, awal kalimat dan kalimat ke 3): Our findings
suggest that mifepristone-misoprostol medical abortion is a safe,
effective and desirable alternative to surgical abortion in
Vietnam Moreover, while the medical abortion failure rate in
our study exceeds that of surgical method, many Vietnamese
women apparently are willing to accept an increased risk of
failure since most said they would choose medical abortion again
and would recommend it to their friends
5. What conclusion did authors reach about the research

question? Did they generate new hypotheses? Do you agree
with the conclusion?
Judul 6: (introduction, kalimat ke 2 paragraf 7)
This primary objective of the study was to assess the point
prevalence of GI, cardiac, and renal complications associated
with the use of NSAIDs as standard of care in patients across
India for the first time. The other study objectives were to
evaluate the association between the risk factors and GI, cardiac,
and renal complication in patients using NSAID
(Discussion; awal kalimat paragraf 1 dan kalimat 2 paragraf 7).
The result of this interim analysis has shown the point
prevalence of GI (30,08%), cardiac (42,77%) and renal
complications (27,88%) with the use of NSAIDs in India. This
result also shown that there is a need to channelize and
standardize appropriate usage of NSAIDs among patients
There is no result finding for other or second objective of this
study
37
Thank you
38
BMC Medicine BioMed Central
Open Access
Research article
Biological efficacy of low versus medium dose aspirin after
coronary surgery: results from a randomized trial [NCT00262275]
1 1 1 1
Eric Lim* , Jacqueline Cornelissen , Tom Routledge , Ayyaz Ali ,
Stephen Kirtland1, Linda Sharples2, Kate Sheridan1, Sarah Bellm1,
1 1
Helen Munday and Stephen Large
Address: 1Departments of Cardiothoracic Surgery and Clinical Pharmacology, Papworth Hospital, Cambridge, CB3 8RE, UK and 2Medical
Research Council Biostatistics Unit, Cambridge, UK
Email: Eric Lim* - eric.lim@cvsnet.org; Jacqueline Cornelissen - Jacqueline.Cornelissen@papworth.nhs.uk;
Tom Routledge - Tom.Routledge@papworth.nhs.uk; Ayyaz Ali - Ayyaz.Ali@papworth.nhs.uk;
Stephen Kirtland - Stephen.Kirtland@papworth.nhs.uk; Linda Sharples - Linda.Sharples@papworth.nhs.uk;
Kate Sheridan - Kate.Sheridan@papworth.nhs.uk; Sarah Bellm - Sarah.Bellm@papworth.nhs.uk;
Helen Munday - Helen.Munday@papworth.nhs.uk; Stephen Large - Stephen.Large@papworth.nhs.uk
* Corresponding author
Published: 22 May 2006 Received: 27 November 2005

Accepted: 22 May 2006
BMC Medicine 2006, 4:12 doi:10.1186/1741-7015-4-12
This article is available from: http://www.biomedcentral.com/1741-7015/4/12
2006 Lim et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Background: The beneficial effect of aspirin after coronary surgery is established; however,
a recent study reported the inability of low doses (100 mg) to inhibit postoperative platelet
function. We conducted a double-blind randomised trial to establish the efficacy of low dose
aspirin and to compare it against medium dose aspirin.
Methods: Patients undergoing coronary surgery were invited to participate and consenting
patients were randomised to 100 mg or 325 mg of aspirin daily for 5 days. Our primary
outcome was the difference in platelet aggregation (day 5 baseline) using 1 g/ml of
collagen. Secondary outcomes were differences in EC50 of collagen, ADP and epinephrine
(assessed using the technique of Born).
Results: From September 2002 to April 2004, 72 patients were randomised; 3 patients
discontinued, leaving 35 and 34 in the low and medium dose aspirin arms respectively. The
mean aggregation (using 1.1 g/ml of collagen) was reduced in both the medium and low dose
aspirin arms by 37% and 36% respectively. The baseline adjusted difference (low medium)
was 6% (95% CI -3 to 14; p = 0.19). The directions of the results for the differences in EC50 (low
medium) were consistent for collagen, ADP and epinephrine at -0.07 (-0.53 to 0.40), -0.08 (-
0.28 to 0.11) and -4.41 (-10.56 to 1.72) respectively, but none were statistically significant.
Conclusion: Contrary to recent findings, low dose aspirin is effective and medium dose
aspirin did not prove superior for inhibiting platelet aggregation after coronary surgery.
Page 1 of 6
(page number not for citation purposes)
39
BMC Medicine 2006, 4:12 http://www.biomedcentral.com/1741-7015/4/12
Background expressed as percentage of baseline, using 1.1 g/ml colla-gen

Normal platelet physiology cannot be assumed to prevail in as an agonist. Assessment of platelet aggregation was
conditions of severe physiological stress such as major surgery. undertaken using the technique of Born [5]. Secondary
However, the impact of antiplatelet therapy is critical in the outcome measures were the effective concentrations of Horm
early postoperative period after coronary surgery as it confers collagen, adenosine diphosphate (ADP) and epine-phrine on
lower in-hospital mortality [1] and morbidity and improves day 5 required to produce 50% aggregation (EC50) compared
graft patency [2]. to baseline.
The motivation for the present study was a report that low dose Laboratory methods
aspirin (100 mg) did not inhibit collagen-induced platelet Venous blood (30 ml) was collected into 3.8% trisodium
aggregation after cardiac surgery [3]. Moreover, our systematic citrate monovettes (Sarstedt) and gently inverted to ensure
review and indirect comparison meta-anal-ysis suggested that mixing. Within 30 minutes of venepuncture, sam-ples were
trials using medium dose aspirin regi-mens (325 mg) after centrifuged at 1000 r.p.m for 15 minutes to obtain platelet rich
coronary surgery could have better graft patency rates than plasma (PRP). Platelet poor plasma (PPP) was prepared by
trials using low dose aspirin (75 to 150 mg) [4]. The evidence centrifuging 1 ml of PRP at 6000 r.p.m. for 1 minute. Platelet
from both these sources sug-gests that equivalence cannot be aggregation was determined turbidimetrically using the
assumed between the two dosing regimens. Platelet Aggregation Profiler PAP-4 (BioData Corporation,
PA, USA), with baseline optical density set with PPP. PRP
samples (225 l) were pre-warmed to 37C for 30 seconds
To evaluate the biological efficacy of low dose aspirin and to before the addition of agonist (25 l), with the stir bar rate set
compare it against a medium dose preparation, we con-ducted at 1000 r.p.m. PRP samples were stimulated for 4.5 minutes
a double-blind randomized trial of low against medium dose with freshly pre-pared adenosine 5'-diphosphate (ADP, Sigma;
aspirin after coronary artery bypass surgery. final con-centration range of 0.255.0 mol/l), Horm collagen
(Axis-Shield Diagnostics; range 0.114.4 g/ml) and
Methods epinephrine (Sigma; range 0.1255.0 mol/l). Stock saline
Participants solutions of epinephrine and ADP were stored at - 80C, with
We conducted a Local Research Ethics Committee appropriate precautions taken to prevent the light-dependent
(Huntingdon Local Ethics Research Committee) approved degradation of epinephrine. Platelet aggregometry readings for
prospective randomised trial. All patients undergoing elective each agonist were converted to EC50 using curve fit software.
primary coronary artery bypass sur-gery were invited to The EC50 represents the concentration of agonist required to
participate, and informed consent was obtained. We excluded cause 50% of maxi-mal aggregation.
patients if they did not stop antiplatelet therapy a week prior to
surgery, had contrain-dications to aspirin or were on other
medications that interact with aspirin, if surgery was
performed without cardiopulmonary bypass, if platelet Sample size
transfusion was administered intra-operatively or within the The original trial started as a three arm study (low dose aspirin,
first 24 hours and if extubation was not achieved in the first 24 medium dose aspirin and clopidogrel) intending to recruit 108
hours (to ensure all patients had 5 full days of oral antiplatelet patients with 36 participants in each arm. We aimed to be able
ther-apy). to detect a difference of 30% in post-operative platelet
aggregation at day 5, expressed as a per-centage of pre-
operative values between any two arms.
Intervention and randomisation
On the first postoperative morning, patients were ran-domised An interim analysis of 54 patients (18 in each arm) was
to receive one of the following identically encap-sulated planned with the stopping criterion of a significant differ-ence
treatments: aspirin 100 mg or aspirin 325 mg for 5 days. at 2% level. At that stage, there would be at least 90% power
Randomisation was undertaken by pharmacy into treatment to detect a difference of at least 1.5 standard devia-tions, and
allocation blocks of 6 and medications were stored in the inferior arm would be terminated.
numbered containers. Participants, researchers and statisticians
were blind to the treatment allocations. All patients routinely Statistical methods
received low molecular weight heparin postoperatively. Patients were grouped according to treatment allocation.
Categorical data are presented as frequency (%) and con-
tinuous data as mean with standard deviation (SD) or median
Outcome measures with interquartile range (IQR). Comparisons of categorical
Our primary outcome measure was percentage aggrega-tion on data between groups were made using Fisher's exact test or
day 5 (2 hours after drug administration,) Pearson's Chi Squared test. Continuous data
Page 2 of 6
40
Table 1: Baseline characteristics of patients randomised As the results for patients in the clopidogrel arm have been
to aspirin published [6], we report the results of the patients in the two
Medium dose Low dose aspirin arms.
Sample size 36 36 Primary outcome

Mean age, years (SD) 66 (6) 66 (8) The patients were well matched for baseline characteristics
Mean height, m (SD) 1.75 (0.08) 1.73 (0.07) (Table 1). Mean platelet aggregation (using 1.1 g/ml of
Mean weight, kg (SD) 83.1 (2.4) 85.3 (2.6) collagen) was reduced in both medium and low dose aspi-rin
Male sex, n (%) 33 (92) 33 (92)
arms by 37% and 36% respectively (table 2). The base-line
Mean platelet count, 109 (SD) 229 (59) 211 (66) adjusted difference comparing low to medium dose (low
Diabetes, n (%) 4 (11) 10 (28) medium dose) was 6% (95% CI -3 to 14; p = 0.19) in favour of
Hypercholesterolaemia, n (%) 33 (92) 32 (89) medium dose but not statistically significant.
Hypertension, n (%) 21 (58) 24 (67)
Current smokers, n (%) 3 (8) 0 (0) Secondary outcomes
The directions of the results for the differences in EC50
Median number of grafts, n (IQR) 4 (3 to 4) 3.5 (3 to 4)
concentrations were consistent for all three agonists in favour
Median bypass time, min (IQR) 73 (60 to 86) 70 (54 to 87)
of medium dose, although none were statistically significant.
The baseline adjusted EC50 concentrations (low medium
dose) for collagen, ADP and epinephrine were -0.07 g/ml (-
were compared using Student's t-test or Wilcoxon rank sum as 0.53 to 0.40), -0.08 mol/l (-0.28 to 0.11) and -4.41 mol/l (-
appropriate. Primary outcome was compared using regression 10.56 to 1.72) respectively.
analysis (ANCOVA) with robust standard errors to adjust for
baseline values of platelet aggregation and EC50 Discussion
concentrations. Analyses were performed using Stata 8.2 The results of our study confirm that both aspirin doses (325
(StataCorp, Texas, USA). mg and 100 mg) were effective in the inhibition of platelet
aggregation after cardiac surgery. The mean reduc-tions by day
Results 5 compared to baseline were 37% and 36% for the medium
From September 2002 to April 2004, patients were con- and low dose aspirin regimens respec-tively.
secutively screened for eligibility and 200 participants were
invited to participate, of whom 116 consented. A fur-ther 26
did not meet the inclusion criteria, leaving 90 patients suitable Efficacy of low dose regimen
for randomization. At interim analysis, after 54 were Our results contradict the findings of the observational study
randomized (18 in each arm), and the clopi-dogrel arm was by Zimmerman [3], who reported that 100 mg of aspirin was
terminated in accordance to pre-planned criterion owing to insufficient to inhibit platelet aggregation after coronary
concerns for participant safety [6]. surgery, with a mean aggregation of 103% of the baseline
value in his series. It is not possible to determine why the
Of the 90 patients, a total of 36 were randomized to medium results for low dose aspirin from our centre in Cambridge were
dose aspirin, 36 to low dose aspirin and 18 to clopidogrel. One so different from those of Zim-merman in Dsseldorf. The
patient did not receive allocated medica-tion and another baseline characteristics of our patients were comparable, and
withdrew consent to the study in the low dose aspirin arm. One our laboratory methods were similar. However, unmeasured
patient did not receive the allo-cated medication and 2 were differences can exist. A potential difference could be in the
withdrawn (abdominal pain, re-operation) in the medium dose genetic makeup with respect to aspirin resistance. The
aspirin arm. We analyzed the results from 35 and 34 patients in prevalence of PlA2 polymorphism (linked to aspirin resistance)
the low and medium dose arms respectively by intention-to- has been estimated at 39% in patients with ischaemic heart
treat. disease
Table 2: Effects of aspirin on collagen induced platelet aggregation and EC50 concentrations postoperatively (final baseline)
Baseline (SD) Final (SD) Difference (95% CI) P value
Percentage aggregation (using 1.1 g/ml collagen)

Medium dose 70 (28) 32 (15) -37 (-46 to -28) <0.001
Low dose 76 (21) 39 (21) -36 (-46 to -27) <0.001
Mean EC50 concentration (using 0.11 4.4 g/ml collagen)
Medium dose 0.53 (0.58) 1.79 (0.91) 1.23 (0.95 to 1.52) <0.001
Low dose 0.48 (0.51) 1.69 (1.10) 1.20 (0.80 to 1.59) <0.001
Page 3 of 6
41
Figure 1
Trial flow diagram. Footnote: numbers that were analyzed were more than expected, taking into account patients who
discontinued or did not receive allocated medication owing to intention-to-treat analysis.
[7], and has greater potential to influence the results of studies Clinical implications
with smaller sample sizes. The total number of participants in Throughout, we have used platelet aggregation as a surro-gate
the observational series by Zimmerman was 24. for clinical outcome, as clinical efficacy cannot be assumed
without evidence of inhibition. Our previous
Page 4 of 6
42
Table 3: Adjusted outcome measures comparing low to to report the results of platelet inhibition to facilitate com-
medium dose aspirin (low medium) parisons among different centres.
Baseline adjusted difference (95% CI) P value
Competing interests
Change in percentage aggregation * The author(s) declare that they have no competing inter-ests.
Collagen 1 g/ml 6 (-3 to 14) 0.19
ADP 5 mol/l 6 (0 to 13) 0.07
Epinephrine 10 mol/l 3 (-5 to 11) 0.44
Authors' contributions
Change in EC50 concentration **
EL conceived and designed the study, performed the sta-
Collagen g/ml -0.07 (-0.53 to 0.40) 0.77 tistical analysis and drafted the initial and final manu-script; JC
ADP mol/l -0.08 (-0.28 to 0.11) 0.40 was involved in designing the study, performed the
Epinephrine mol/l -4.41 (-10.56 to 1.72) aggregometry, coordinated the clinical trials and approved the
final manuscript; TR and AA were involved in coordinating
* Positive results favour greater treatment effect for medium the clinical trials and data collection and helped draft the initial
dose aspirin
** Negative results favour greater treatment effect for medium
manuscript; SK was involved in designing the study and
dose aspirin approved the final manuscript; LS helped design the study,
performed the statistical analyses and approved the final
indirect comparison meta-analysis suggested that the effi-cacy manuscript; KS and SB performed aggregometry, helped in
of low dose aspirin cannot be assumed to be equiva-lent to data collection and approved the final manuscript; HM was
superior results with medium dose regimens in the involved in coordinating the clinical trials and approved the
preservation of graft patency [4]. In vitro, however, medium final manuscript; SL was the overall study supervisor, who
dose aspirin did not prove superior in the inhibi-tion of platelet participated in the design, conduct and management of the
aggregation. The upper limit of the 95% confidence interval project and approved the final manuscript.
was 14% for the primary outcome measure in favour of
medium dose aspirin, and it is diffi-cult on the limited
information available to be certain if this excludes a clinically Acknowledgements
meaningful or important differ-ence. Unfortunately (as in most This study was funded by Papworth Hospital NHS Trust and the
research) we have gener-ated more questions rather than Papworth Hospital Surgeons Research Fund. Dr Lim was also
clarifying answers. Further translational research evaluating (in supported by the Med-ical Research Council, UK. The authors gratefully
acknowledge Emma Kadri and Elizabeth Bligh from the Hospital
part) the effects of platelet aggregation on clinical outcomes
Pharmacy for their assistance, Pap-worth Hospital Research and
would be invaluable. Development department for project man-agement, and the nurses of
the Surgical Unit in Papworth hospital. We especially acknowledge the
contribution of the late Andrew Trull for project team assistance.
Standardization of platelet aggregation
A difficulty that we encountered in comparing our results with References
those from other centres was the lack of standardiza-tion in 1. Mangano DT: Aspirin and mortality from coronary bypass
sur-gery. N Engl J Med 2002, 347:1309-1317.
measuring platelet aggregation. The most common method is 2. Goldman S, Copeland J, Moritz T, Henderson W, Zadina K, Ovitt T,
to use a fixed concentration of agonist to com-pare percentage Doherty J, Read R, Chesler E, Sako Y: Saphenous vein graft pat-
aggregation to baseline. However, the drawbacks of this ency 1 year after coronary artery bypass surgery and effects of
antiplatelet therapy. Results of a Veterans Administration
technique is that some samples do not aggregate with a low Cooperative Study. Circulation 1989, 80:1190-1197.
dose of agonist or aggregate com-pletely when a high dose is 3. Zimmermann N, Kienzle P, Weber AA, Winter J, Gams E, Schror K,
selected. Moreover, as differ-ent fixed concentrations are used, Hohlfeld T: Aspirin resistance after coronary artery bypass
grafting. J Thorac Cardiovasc Surg 2001, 121:982-984.
it is not possible to compare the results between centres. A 4. Lim E, Ali Z, Ali A, Routledge T, Edmonds L, Altman DG, Large S:
solution is to report EC50s, the concentrations of agonist that Indirect comparison meta-analysis of aspirin therapy after
coronary surgery. BMJ 2003, 327:1309.
produce 50% aggregation. In this way, it is possible to avoid 5. Born GVR: Aggregation of blood platelets by adenosine
the arbitrary selection of a fixed dose of agonist and also to diphosphate and its reversal. Nature 1962, 164:927-929.
allow results from different studies to be compared. 6. Lim E, Cornelissen J, Routledge T, Kirtland S, Charman SC, Bellm
S, Munday H, Khan O, Masood I, Large S: Clopidogrel did not
inhibit platelet function early after coronary bypass surgery: A
pro-spective randomized trial. J Thorac Cardiovasc Surg 2004,
128:432-435.
Conclusion 7. Weiss EJ, Bray PF, Tayback M, Schulman SP, Kickler TS, Becker LC,
Low dose aspirin is effective and medium dose aspirin did not Weiss JL, Gerstenblith G, Goldschmidt-Clermont PJ: A polymor-phism
prove superior as an inhibitor of platelet aggregation in vitro of a platelet glycoprotein receptor as an inherited risk factor for
coronary thrombosis. N Engl J Med 1996,
after coronary surgery. Further studies are required to compare 334:1090-1094.
clinical outcomes with platelet aggregation results, and
researchers should consider the use of EC50
Page 5 of 6
43
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Page 6 of 6
(page number not for citation purposes
44
45
46
47
48
British Journal of Urology (1997), 80, 606611
Clinical comparison of selective and non-selective a1A-

adrenoreceptor antagonists in benign prostatic hyperplasia:
studies on tamsulosin in a xed dose and terazosin in
increasing doses
E . L EE and C. L EE
Department of Urology, Seoul National University College of Medicine, Seoul, Korea
Objective To compare the e cacy and safety of a xed dose Qmax or >20% decrease in total IPSS. Adverse reac-
(0.2 mg) of tamsulosin, a selective a1A-adrenore-ceptor tions possibly or probably related to study medication
antagonist, with an increasing dose (15 mg) of were recorded throughout the treatment period.
terazosin, a non-selective antagonist, in the treat-ment of Results Both tamsulosin and terazosin produced similar
urinary outow obstruction associated with benign signicant improvements in subjective and objective
prostatic hyperplasia (BPH) in Korean patients. symptoms of urinary outow obstruction (P>0.05).
Patients and methods The study comprised a single-blind Systolic and diastolic (standing) blood pressures
and randomized design with tamsulosin or tera-zosin decreased signicantly in patients treated with terazo-sin
taken once daily for 8 weeks. A total of 98 patients was (P<0.05). The adverse reactions, most frequently dry
enrolled, with 72 patients included in the analyses after 4 mouth and dizziness which were usually mild and
and 8 weeks. The primary vari-ables assessed were transient, were signicantly higher in patients on
changes in the maximum urinary ow rate (Qmax ) and terazosin (18 patients, versus one on tamsulosin,
the total International Prostate Symptom Score (IPSS), P<0.001). The changes led to discontinuation of therapy
with the post-void residual urine volume, òbstructive' in two patients on terazosin.
and ìrritative' questions in the IPSS, and the Conclusion Tamsulosin was as e ective as terazosin in
investigators' global assessment of e cacy also treating urinary outow obstruction associated with BPH,
determined. The number of patients with a clinically but had a markedly better safety prole.
signicant response to treatment with tamsulosin or Keywords Benign prostatic hyperplasia, selective and non-
terazosin was determined and dened as those with >20% selective a1A-adrenoreceptor antagonist, tamsu-losin,
improvement from the baseline terazosin, lower urinary tract symptoms
smooth muscles of the bladder neck and prostate, decrease

Introduction
bladder outlet resistance and facilitate urinary ow without
BPH is a major cause of morbidity among elderly men [1]; a ecting detrusor smooth muscle contrac-tility. These e ects
primarily, it produces bothersome urinary symptoms which result from the distribution of recep-tors, which are
decrease the quality of life of these patients and this aspect abundant in the bladder neck, prostatic capsule and stroma,
has become the major focus in the manage-ment of this and scarce in the main bladder [811]. a1-adrenoreceptor
condition. The standard treatment for symptomatic BPH antagonists such as prazosin [2], terazosin [35], doxazosin
remains TURP. However, drug therapy represents an [6], and alfuzosin [7] have been used to treat BPH and
important alternative to TURP for patients with mild-to- increase urinary outow and improve symptoms. However,
moderate symptoms or for those who are unable or their use is associated with adverse reactions such as
unwilling to undergo surgery because of the risk of both postural hypo-tension, dizziness and dry mouth. To reduce
morbidity and mortality, coupled with increased public these adverse reactions, dose titration is common in clinical
awareness of non-surgical alternatives. practice, but about 10% of patients discontinue medi-cation
The use of a1-adrenoreceptor antagonists is a reason-ably because of adverse reactions [5].
well established treatment modality for symptomatic BPH
[27]. a1-adrenoreceptor antagonists relax the Recent pharmacological studies of the a1-adrenorecep-tor
have revealed two subtypes, a1A and a1B [12,13]. The a1A-
Accepted for publication 10 June 1997 adrenoreceptor subtype is present in the greatest
606 1997 British Journal of Urology
49
TAM SU LO S IN A ND T ER AZ OS IN IN BPH 607
concentration in human prostate and is responsible for b-adrenoreceptor antagonists for at least 1 week before the
prostate smooth muscle contraction [1419]. By con-trast, study.
The patients were randomized into two groups of 49
the a1B-adrenoreceptor subtype is involved in smooth
each, one receiving tamsulosin at a dose of 0.2 mg and the
muscle contraction of large human arteries [20]. Therefore,
other terazosin at doses of 1 mg on day 1, increasing to 2
a drug with a relatively high a nity particu-larly for the mg for the next 6 days and 5 mg thereafter. After a 1 week
a1A-adrenoreceptor could be prostate-specic. pretreatment stage, all patients were given the test drug
Tamsulosin is a new selective a1A-adrenoreceptor once daily after a meal (tamsulosin) or before bedtime
subtype antagonist; it has been reported that the a nity of (terazosin) for 8 weeks. During the whole study period of 9
tamsulosin for a1A-receptors is seven to 38 times greater weeks, the medical history of the patient, subjective
than that for a1B-receptors [1520]. In studies in Japan symptoms as assessed from the IPSS, and objective
[21,22], Europe [2325] and the USA [26], tamsulosin, at a examinations (e.g. urinary ow rate, PVR, blood pressure
dose of 0.20.4 mg once daily, produced symptomatic and pulse rate in the supine and standing positions,
complete blood cell count, serum biochemistry and routine
improvement without a ecting blood press-ure and pulse
urine analysis) were performed according to the schedule
rate in patients with BPH. Further, patients treated with
in Table 1. The e cacy and safety was evaluated at the end
tamsulosin rarely experienced adverse reac-tions such as of 4 and 8 weeks for all analysable patients in both groups.
postural hypotension, dizziness and dry mouth. However,
no clinical study comparing tamsulosin with non-selective The primary variables for assessing e cacy were changes
a1-adrenoreceptor antagonists has yet been published. in Qmax and total IPSS (maximum 35 points) and other
The aims of the present study were to compare the e variables examined were the PVR, the òbstructive'
cacy and safety of tamsulosin and terazosin in the (questions 1, 3, 5 and 6 in the IPSS, total 20 points) and
treatment of urinary outow obstruction associated with ìrritative' symptoms (questions 2, 4 and 7 in the IPSS,
BPH in Korean patients. Tamsulosin was administered in a total 15 points), and the investigators' global assessment of
xed dose of 0.2 mg and terazosin in escalating doses of 1, e cacy. In addition, the number of patients with a clinically
2 and 5 mg to avoid the side-e ects of accompanying
signicant response to tamsulo-sin or terazosin treatment
hypotension.
was determined, dened as patients with >20%
improvement from the baseline Qmax or >20% decrease
Patients and methods in total IPSS [28]. Adverse reactions considered to be
possibly or probably related to the study medication were
The 9-week, randomized, single-blind study was author-
recorded throughout the treatment period.
ized by the ethics committee of Seoul National University
Hospital. The doctors informed their patients of the details The patients' demographic di erences and any di er-ences
of the study and obtained their consent before it in subjective and objective changes between the
commenced. Patients with moderate to severe sympto-
matic BPH were selected. BPH was diagnosed from the Table 1 The observation and assessment schedule
history, symptoms, a DRE and TRUS. The Korean version
of the IPSS was used to assess symptoms [27]. The post- Before treatment Treatment
void residual urine volume (PVR) was measured by
ultrasonography. In total, 98 patients with symptomatic Week 1 to 0 2 4 8
BPH (aged 5180 years), with a total IPSS of 8 [28], a
Selection of patient
maximum urinary ow rate (Qmax ) of 515 mL/s and a
Diagnosis *
PVR of <150 mL, were enrolled. Patients were excluded if DRE *
they had prostatic cancer, a serum PSA level >10 ng/mL, TRUS *
prostatitis, a neurogenic bladder, bladder cancer, bladder PSA test *
stones, urethral strictures and neurolog-ical conditions that E cacy evaluation
might interfere with normal voiding; also excluded were IPSS ** * *
patients with BPH who had under-gone transurethral Urinary owmetry * * *
PVR by ultrasonography * * *
resection or had experienced urinary retention, and patients
Adverse reaction evaluation
with marked cardiac, renal or hepatic insu ciency. Patients Blood pressure ** * * *
were not permitted to take concomitant drugs which could Pulse rate * * * *
inuence the outcome of the study, e.g. antiandrogenic Adverse reaction * * * *
hormones and 5a-reductase inhibitors, for at least 4 weeks Laboratory test * * * *
and a- and
1997 British Journal of Urology 80, 606611
50
608 E. L EE and C. L E E
baseline and treatment periods were assessed using at 4 and 8 weeks after treatment were 11.0 (3.7) and 11.6
Student's t-test. An ANOVA with Duncan's multiple-range (3.6), and 11.7 (5.0) and 10.9 (4.1) mL/s in the tamsulosin
test was used to assess inter- and intra-group di erences. and terazosin groups, respectively. The Qmax was
The appearance rate of adverse reactions between the signicantly better than baseline at 4 and 8 weeks after
groups was analysed using Fisher's exact test. Statistical di treatment in both groups (P<0.05, ANOVA with Duncan's
erences were tested at a signicance level of 0.05. multiple-range test). The mean increase in Qmax from
baseline to endpoint was about 20% in both groups (Table
3), the di erences before and after treat-ment being
signicant in both (P<0.05). There were no signicant di
Results
erences in Qmax between the groups at 4 and 8 weeks
Of the 98 patients, 26 patients (10 in the tamsulosin and 16 after treatment (P>0.05).
in the terazosin group) were excluded from analysis or Five patients in the tamsulosin group and eight in the
were withdrawn, allowing a nal evaluation in 72 patients terazosin group showed abnormal PVRs (>50 mL) at
(39 in the tamsulosin and 33 in the terazosin group). The baseline; the mean (range) reduction in PVR after treat-
main reasons for exclusion and withdrawal were failure to ment was 44% (2754) with tamsulosin and 62% (995)
return to follow-up (16 patients), protocol violation (ve with terazosin, again with no di erence in the improvement
patients) and adverse reaction in the terazosin group (two between the groups (P>0.05).
patients). The patients' baseline characteristics, prostate At the endpoint, 20 (51%) and 29 patients (74%) in the
volume and PSA level are shown in Table 2. There were no tamsulosin group and 15 (45%) and 26 patients (79%) in
di er-ences in patient background between the groups for the terazosin group were considered to have a clinically
any comparison (P>0.05). signicant improvement in Qmax (>20% increase) and
IPSS (>20% decrease), respectively. In the investigators'
global assessment of e cacy, 72% of patients in tamsulosin
and 67% in terazosin group were considered to be
E cacy
moderately or much improved. The distribution of those
The mean (sd) IPSS in the tamsulosin and terazosin groups responding in Qmax and IPSS and moderately to much-
during the pre-treatment period is shown in Table 3. The improved patients in global assess-ment was not di erent
mean (sd) scores at 4 and 8 weeks after treatment were between the groups (P>0.05).
12.7 (7.2) and 11.4 (7.2), and 14.7 (8.0) and 13.4 (7.2) in
the tamsulosin and terazosin groups, respectively. The total
Safety
IPSS was signicantly better than baseline at 4 and 8
weeks after treatment in both groups (P<0.01, ANOVA Tamsulosin was very well tolerated, with one patient
with Duncan's multiple-range test). There was a signicant experiencing headache (Table 4). In contrast, 18 patients in
reduction in the total IPSS from baseline to endpoint with the terazosin group experienced 27 adverse reactions
tamsulosin and terazosin (Table 3), these values being (Table 4), although these adverse reactions were gener-ally
similar (P>0.05). Like the total IPSS, the òbstructive' and mild. Two patients in the terazosin group withdrew from
ìrritative' symptom scores improved signicantly in both the study due to dry mouth and dizziness (one patient each).
groups (P<0.05), with no di erence between them (P>0.05, The di erence in adverse reaction prole between the
Table 3). groups was signicant (P<0.001, Table 4). Six patients had
The mean (sd) Qmax measured before treatment was abnormal laboratory test values but these changes were not
similar in both groups (Table 2) and the respective values considered to be related to the treatment.
Table 2 Baseline characteristics of the patients included in the study Standing and supine systolic and diastolic blood press-
ures tended to decrease in both treatment groups and the di
Mean (sd) Tamsulosin Terazosin erence was statistically signicant in the terazosin-treated
patients for systolic and diastolic blood pressure when
Age (years) 68.1 (7.6) 66.1 (9.4) standing, and for diastolic blood pressure when supine. The
Weight (kg) 61.6 (7.7) 61.7 (8.7)
pulse rate did not change signicantly in either position in
Height (cm) 165.1 (3.7) 167.2 (4.6)
Prostate volume (mL)* 30.8 (12.0) 27.1 (7.2) both groups (Table 3).
PSA level (ng/mL) 3.0 (2.2) 2.8 (2.6)
Qmax (mL/s) 9.5 (2.9) 9.2 (2.7) Discussion
Di erences not signicant for any comparison (Student's t-test). Compared with baseline values, tamsulosin and terazosin
*Estimated by TRUS. improved the subjective and objective symptoms of
51
Table 3 The mean (sd) change in total,

ìrritative' and òbstructive' symptom P
scores, Qmax , blood pressures and Baseline Endpoint Change (%) paired t-test
pulse rates, from baseline to endpoint
Tamsulosin (n=39)
Total IPSS 17.8 (6.8) 11.4 (7.2) 6.4 (36) <0.01
Irritative 7.4 (3.9) 4.8 (3.5) 2.6 (35) <0.05
Obstructive 10.4 (4.6) 6.6 (4.7) 3.8 (37) <0.01
Terazosin (n=33)
Total IPSS 21.4 (7.2) 13.4 (7.2) 8.0 (37) <0.01
Irritative 9.1 (3.9) 5.9 (3.1) 3.2 (35) <0.01
Obstructive 12.3 (4.5) 7.5 (4.7) 4.8 (39) <0.01
Qmax (mL/s)
Tamsulosin 9.5 (2.9) 11.6 (3.6) +2.1 (22) <0.05
Terazosin 9.2 (2.7) 10.9 (4.1) +1.7 (19) <0.05
Blood pressure (mmHg) (systolic/diastolic)
Tamsulosin
Supine 146.8 (26.2) 142.6 (26.7) 4.2 (3) NS
89.4 (15.4) 82.8 (13.7) 6.6 (7) NS
Standing 140.7 (26.3) 131.3 (19.6) 9.4 (7) NS
87.7 (17.8) 82.3 (14.8) 5.4 (6) NS
Terazosin
Supine 142.4 (26.7) 132.4 (19.8) 10.0 (7) NS
90.3 (15.7) 78.2 (9.5) 12.1 (13) <0.01
Standing 138.7 (24.8) 122.6 (24.1) 16.1 (12) <0.01
88.3 (16.9) 76.9 (11.9) 11.4 (13) <0.05
Pulse rate (bpm) (supine/standing)
Tamsulosin 78.2/80.5 75.3/83.7 2.9/3.2 NS
Terazosin 77.4/85.9 72.4/83.9 5.0/2.0 NS
Table 4 The incidence of adverse reactions related to study medication whereas 18 patients in the terazosin group experienced a
total of 27 adverse reactions considered to be possibly or
Tamsulosin Terazosin probably related to study medication and generally
attributable to an a1-adrenoreceptor antagonist. While
Total number of patients enrolled 49 49 there were no signicant di erences in the cardiovascular
Adverse reactions* variables before and after treatment in the tamsulosin group,
Dry mouth 0 8 (16.3) there was a signicant decrease in blood pressure in the
Dizziness 0 6 (12.2) terazosin group. The incidence of adverse events such as
Headache 1 4 (8.2) dizziness associated with blood pressure reduction was
Dyspepsia 0 4 (8.2)
12.2% with terazosin, whereas there were no such changes
Constipation 0 4 (8.2)
in the tamsulosin group. Two patients in the terazosin
Skin rash 0 1 (2.0)
Discontinuations due to adverse 0 2 (4.1) group who experienced dry mouth and dizziness were
reactions withdrawn from treatment. The e cacy prole of
Total number of adverse reactions 1 27 tamsulosin in this study is in agreement with that reported
Total number of patients showing 1 18 by others [2126]. The safety prole as determined from
adverse reactions the incidence of adverse reactions and e ect on blood
pressure and pulse rate was similar to that in a Japanese
*As reported by patient. Incidence of adverse reactions (%): number study reported by Kawabe et al. [21,22], but lower than
of patients showing adverse reactions/ total number of patients that in European studies reported by Abrams et al. [23] and
analysed. P<0.001, signicantly di erent from the values in terazosin
Schulman et al. [24]. This di erent incidence of adverse
group (Fisher's exact test).
reactions may be related to the di erent dosage of
tamsulosin in this and Japanese studies (0.2 mg) and
urinary outow obstruction associated with BPH in 4 and 8 European studies (0.4 mg). Patients with BPH in Oriental
weeks after treatment. The improvements with tamsu-losin countries seem to require lower doses than those in
were similar to those with terazosin. Only one patient in Western countries. Thus the present study used tamsulosin
the tamsulosin group had an adverse event, and terazosin in doses of 0.2 mg
52
610 E. L EE and C. L E E
and 15 mg, respectively, as is normal clinical practice in prostatic obstruction: a placebo-control study. Br J Urol 1987;
patients in Oriental countries; patients in Western countries 60: 13642
are given doses of 0.4 and 110 mg, respect-ively. The e 3 Lepor H, Auerbach S, Puras-Baez A et al. A randomized,
cacy and safety proles of terazosin were similar to those placebo-controlled multicenter study of the e cacy and safety
of terazosin in the treatment of benign prostatic hyperplasia. J
in previous studies [35], even though terazosin in
Urol 1992; 148: 146774
escalating doses of 1, 2 and 5 mg (the usual dose in Korea)
4 Brawer MK, Adams G, Epstein H, the Terazosin Benign
were administered to avoid the adverse reactions Prostatic Hyperplasia Study Group. Terazosin in the treatment
accompanying hypotension. of benign prostatic hyperplasia. Arch Fam Med 1993; 2:
In the present study, there was no signicant di erence 92935
in e cacy between tamsulosin (0.2 mg/day) and terazo-sin 5 Roehrborn CG, Oesterling JE, Arbor A et al. Hytrin
at an increasing dose (15 mg/day), suggesting that both Community Assessment Trial (HYCAT): evaluation of the
selective and non-selective a1A-adrenoreceptor clinical e ectiveness of terazosin versus placebo in the
antagonists have qualitatively similar e cacy in subjec-tive treatment of patients with symptomatic benign prostatic
and objective symptoms of urinary outow obstruc-tion hyperplasia. J Urol 1995; 153 (suppl): 272 abstr 175
associated with BPH. However, tamsulosin had a better 6 Chapple CR, Carter P, Christmas TJ et al. A three month
double-blind placebo controlled study of doxazosin as
adverse reaction prole than terazosin, even when the
treatment for benign prostatic bladder outow obstruction. Br
latter was given in an escalating dose. The superior safety J Urol 1994; 74: 506
of tamsulosin to terazosin may arise from the selective and 7 Jardin A, Bensadoun H, Delauche-Cavallier MC et al. Long-
strong a nity of tamsulosin for the a1A-adrenoreceptor term treatment of benign prostatic hyperplasia with
subtype, which is present in the greatest density in human alfuzosin: a 2430 month survey. Br J Urol 1994;
prostate and is responsible for prostate smooth muscle 74: 57984
contraction; it thus plays an important role in the dynamic 8 Kunisawa Y, Kawabe K, Niijima T, Honda K, Takenaka T. A
component of bladder outlet obstruc-tion in symptomatic pharmacological study of alpha adrenergic receptor subtypes
BPH. in smooth muscle of human urinary bladder and prostatic
urethra. J Urol 1985; 134: 3968
Although a comparative major clinical study between
9 Yamada S, Tanaka C, Kimura R, Kawabe K. Alpha-1
selective and non-selective a1A-adrenoreceptor subtype adrenoreceptors in human prostate: Characterization and
antagonists in symptomatic patients with BPH has not been binding characteristics of alpha-1-antagonists. Life Sci 1994;
published, the results of the present study suggest better 54: 184554
safety with tamsulosin over the non-selective-subtype 10 Lepor H. Role of alpha-adrenergic blockers in the treatment of
antagonist terazosin in patients with sympto-matic BPH, benign prostatic hyperplasia. Prostate 1990; 3 (Suppl): 7584
even when an increasing dose of terazosin was
11 Hieble JP, Caine M, Zalaznik E. In vitro characterization of
administered. If more extensive comparisons of tamsulosin
the alpha-adrenoreceptors in human prostate. Eur J Pharmacol
against other non-selective a1-adrenoreceptor antagonists 1985; 107: 1117
conrm the better tolerance and e cacy prole for the 12 Ford APDW, Williams TJ, Blue DR, Clarke DE. a1-
selective a1-adrenoreceptor antagonist, these agents will be adrenoreceptor classication: sharpening Occam's razor.
ideally placed to provide an import-ant alternative in the Trends Pharmacol Sci 1994; 15: 16770
treatment of patients with mild to moderate symptomatic 13 Hieble JP, Bylund DB, Clarke DE et al. International Union
of Pharmacology. X Recommendation for nomenclature of
BPH and in those awaiting or unable to undergo surgery.
a1-adrenoreceptor: Consensus Update. Pharmacol Rev 1995;
47: 26770
Acknowledgement 14 Price DT, Schwinn DA, Lomasney UW et al. Identication,
quantication and localization of mRNA for three distinct
We thank Dr Keun-Young Yoo, Department of Preventive alpha 1 adrenergic receptor subtypes in human prostate. J Urol
Medicine, Seoul National University College of Medicine, 1993; 150: 54651
for his statistical consultation, and all those who willingly 15 Yamada S, Suzuki M, Tanaka C et al. Comparative study on
participated in this study. a1-adrenoreceptor antagonist binding in human prostate and
aorta. Clin Exp Pharmacol Physiol 1994; 21: 40511
16 Garcia-Sainz JA, Romero-Avila MT, Villalobos-Molina R et
al. a1-adrenoreceptor subtype selectivity of tamsulosin:
References studies using livers from di erent species. Eur J Pharmacol
1 Garraway WM, Collins GN, Lee RJ. High prevalence of Mol Pharmacol 1995; 289: 17
benign prostatic hypertrophy in the community. Lancet 1991; 17 Michel MC, Buscher R, Kerker J et al. a1-adrenoreceptor
338: 46971 subtype a nities of drugs for the treatment of prostatic
2 Kirby RS, Coppinger SWC, Corcoran MO, Chapple CR, hypertrophy. Arch Pharmacol 1993; 348: 38595
Flannagan M, Milroy EJG. Prazosin in the treatment of 18 Yamada S, Tanaka C, Ohkura T et al. High-a nity specic
53
[3H] tamsulosin binding to a1-adrenoreceptors in human assessing the long-term e cacy and safety in patients with
prostates with benign prostatic hypertrophy. Urol Res 1994; benign prostatic obstruction(symptomatic BPH). Eur Urol
22: 2728 1996; 29: 14554
19 Foglar R, Shibata K, Horie K et al. Use of recombinant a 1- 25 Chapple CR. Selective a1-adrenoreceptor antagonists in
adrenoreceptors to characterize subtype selectivity of drugs benign prostatic hyperplasia: rationale and clinical experi-
for the treatment of prostatic hypertrophy. Eur J Pharmacol ence. Eur Urol 1996; 29: 12944
Mol Pharmacol 1995; 288: 2017 26 Lepor H, the Tamsulosin Investigator Group. Clinical
20 Hatano A, Takahashi, H, Tamaki M et al. Pharmacological evaluation of tamsulosin, a prostate selective alpha-1c-
evidence of distinct a1-adrenoreceptor subtypes mediating the antagonist. J Urol 1995; 153 (Suppl): 274, abstr 182
contraction of human prostatic urethra and peripheral artery. 27 Lee E, Lee C, Kim Y, Shin Y. Estimation of benign prostatic
Br J Pharmacol 1994; 113: 7238 hyperplasia prevalence in Korea: an epidemiological study
21 Kawabe K, Ueno A, Takimoto Y, Aso Y, Kato H. Use of an using International Prostatic Symptom Score (IPSS) in
a1-blocker, YM617, in the treatment of benign prostatic Yonchon County. Korean J Urol 1995; 36: 134552
hypertrophy. J Urol 1990; 144: 90812 28 Homma Y, Imajo C, Kawabe K et al. Response criteria of
22 Kawabe K. E cacy and safety of tamsulosin in the treatment of treatments for benign prostatic hyperplasia. Int J Urol 1995; 2:
benign prostatic hyperplasia. Br J Urol 1995; 76 (Suppl 1): 338
637
23 Abrams P, Schulman CC, Vaage S, European Tamsulosin
Study Group. Tamsulosin, a selective a1c-adrenoreceptor
Authors
antagonist: a randomized, controlled trial in patients with
benign prostatic òbstruction' (symptomatic BPH). Br J Urol E. Lee, MD, Assistant Professor.
1995; 76: 32536 C. Lee, MD, Professor.
24 Schulman CC, Cortvriend J, Jonas U et al. Tamsulosin, the Correspondence: Dr E. Lee, Department of Urology, Seoul
rst prostate selective a1A-adrenoreceptor antagonist: National University Hospital, 28 Yongon-Dong, Chongno-Ku,
analysis of a multinational, multicenter, open-label study Seoul 110744, Korea.
54
55
56
57
Safety, Efficacy and Acceptability of Mifepristone-
Misoprostol Medical Abortion in Vietnam
By Nguyen Thi Nhu Ngoc, Beverly Winikoff, Shelley Clark, Charlotte Ellertson, Khong Ngoc Am, Do Trong Hieu and Batya Elul
is inadequate in some clinics, and man-

Context: In developing countries where the demand for abortion services is high, such as Viet- agement of pain requires improvement.
nam, the need for safe and effective alternatives to surgical abortion is great. Medical abortion Indeed, while some women receive no pain
using mifepristone and misoprostol may be an appropriate option in some of these countries. medication, others are medicated be-yond
Methods: In a comparative study of the safety, efficacy and acceptability of medical and the point of conscious sedation and are
surgi-cal abortion, 393 women at two urban clinics chose between a mifepristone- consequently unable to respond to physical
misoprostol med-ical regimen and the standard surgical procedure offered in each clinic. or verbal stimuli.
Results: Success rates for both methods were extremely high (96% for medical abortion Vietnamese officials have responded to
and 99% for surgical abortion). Medical abortion patients reported many more side effects this situation by committing themselves to
than women obtaining surgical procedures (most commonly, cramping, prolonged bleeding offering a broader range of contracep-tives.
and nausea), but none of these side effects represented a serious medical risk. Nearly all They have also increased efforts to improve
women, regardless of the method they chose, were satisfied with their abortion experience. the quality of abortion services, including
Additionally, among women who had previously undergone surgical abortion, those who investigating the addition of al-ternatives to
selected medical abortion were more likely than those who chose surgery to say that their surgical abortion.
study abortion was more satisfacto-ry than their earlier one (32% vs. 4%). In this article, we describe a study ex-
Conclusions: Mifepristone-misoprostol abortion is safe, effective and acceptable for urban ploring the safety, efficacy and accept-
Viet-namese women who are given a choice of methods. If similar results are observed for ability of mifepristone-misoprostol med-
rural areas, the regimen could help meet the need for abortion services nationwide. ical abortion among women attending two
International Family Planning Perspectives 1999, 25(1):1014 & 33 clinics in Vietnam. We address three
important questions: First, is medical
abortion as effective as surgical abortion
Only two studies, however, have focused for women who choose the method? Sec-
on the potential use of mifepristone and ond, how do the safety, risks and side ef-
I n the past decade, several nonsurgical

options have been developed for women
misoprostol for medical abortion in de-
veloping countries,4 and only one of these
measured the methods acceptability to
fects of medical abortion compare with
those of surgical abortion? Third, do
women who choose mifepristone-miso-
seeking to terminate pregnan-cies. To date, prostol abortion find the method accept-
however, medical methods of abortion have clients.5 Given the potential of medical
been officially approved only in several abortion to improve conditions for women able? Answers to these questions can help
European countries and China. Although policymakers and providers in Vietnam, as
women in developed countries benefit from in developing countries, these womens
these new options, women in the developing perceptions of the method in general and of well as in other developing countries,
world have a greater need for safe and the mifepristone-misoprostol regimen in determine if medical abortion is a feasi-ble
effective alternatives to surgi-cal abortion: and desirable alternative method of
Nearly all of the estimated 70,000 deaths each particular is critical to its acceptability.
year due to unsafe abor- Patients attitudes, expectations and toler- pregnancy termination.
tion occur in developing countries.1 ance of side effects influence surgical in-
The administration of mifepristone, a tervention rates; ultimately, for the method Methods
powerful antiprogestin, coupled with a to work successfully, women must com- Study design plays a paramount role in the
prostaglandin is a highly effective med-ical plete the regimen and wait while the treat- reliability and validity of acceptabili-ty data.
method of terminating pregnancy.2 Of the ment takes its course. In randomized clinical trials, which are
most widely used prostaglandins, In Vietnam, the number of pregnancy designed primarily to collect safety and
gemeprost and misoprostol, the latter shows terminations has risen steadily over the past efficacy data, women are as-signed to use a
the greater promise for use in de-veloping 15 years and is now estimated at more than particular method. In our study, which was
countries. Misoprostol can be ad-ministered one million per year;6 since the early 1990s, modeled on research conducted in China,
orally and is inexpensive, sta-ble at ambient the annual number of abortions has Cuba and India,11
temperatures and widely available. By exceeded the annual number of births.7 A
contrast, gemeprost is ex-pensive, not 1994 nationwide survey found that 13% of Nguyen Thi Nhu Ngoc is vice director, Hung Vuong Hos-
pital, Ho Chi Minh City, Vietnam; Khong Ngoc Am is re-
widely available and pro-vided in a vaginal women have had at least one abortion.8 tired director, Maternal and Child Health and Family
suppository that re-quires refrigeration. In Moreover, in 1992, the total abortion rate Planning, Hanoi Obstetric and Gynecology Hospital, Hanoi,
1993, a large French trial confirmed the was estimated as 2.5 lifetime abortions per Vietnam; and Do Trong Hieu is chief, Maternal and Child
safety and efficacy of a regimen consisting woman, the highest in Asia and the third- Health Department, Ministry of Health, Hanoi. Beverly
of mifepristone and oral misoprostol.3 This highest in the world.9 Winikoff is director, Reproductive Health; Shel-ley Clark is
consultant; Charlotte Ellertson is program associate; and
regimen, with a success rate of 96%, has Additionally, the surgical abortion ser- Batya Elul is staff program associateall with the
been used exten-sively in France and may vices available in Vietnam are marked by a Population Council, New York. This study was funded by
be available in the United States by the end number of safety and quality problems.10 an anonymous donor. The authors thank Kurus Coyaji and
of 1999. For example, sterilization of instruments Andrea Eschen for their assistance.
10 International Family Planning Perspectives
58
women were allowed to choose their abor- two days later, they received 400 mcg of
Table 1. Selected characteristics of women
tion method. This design reflects more misoprostol orally and were monitored at ob-taining abortions, by method, Hanoi and
closely the situation under which the the clinic for at least four hours. Partici- Ho Chi Minh City, Vietnam, 19951996
method will be used when offered in a pants were instructed to return for a fol-
clinic. Thus, a sample of women who have low-up exam and an exit interview 14 days Characteristic Medical
(N=260)
Surgical
(N=133)
chosen between medical and surgical later, and were told to come to the clinic at
abortion constitute the correct population any time before then if they were worried Mean age
Mean weight (kg)
26.4
46.4
27.9**
46.6
from which to generalize about the ac- or if they changed their mind about the Mean height (cm) 155.8 154.5**
ceptability of both methods. A drawback, method. The women were not given any Mean education (yrs.) 11.6 10.6**
Mean gestational
however, is that safety and efficacy data medication to control pain, since such age (wks.) 5.9 6.1*
can be generalized only to women who medications are easily available over the % with first pregnancy 35.4 30.1
% married/in union 73.1 84.2*
choose between methods. counter in Vietnam. % who had used
The study was conducted from January Generally, if the abortion was not com- contraceptives 37.7 58.6***
1995 to April 1996 in the two largest urban plete at the follow-up visit, surgical abor- %previous
who had had
abortion 48.5 43.6
centers in Vietnam, Hanoi and Ho Chi tion was performed as a backup. Among the
Minh City; one clinic in each city partici- 10 women who had backup proce-dures, *Difference between medical and surgical abortion patients is sig-
nificant at p.05. **Difference between medical and surgical abor-
pated. Both facilities had legal, established five underwent vacuum aspiration and three tion patients is significant at p.01. ***Difference between med-ical
surgical abortion services. Although abor- had sharp curettage; the method was and surgical abortion patients is significant at p.001. Note: While
the number of medical patients was roughly equally dis-tributed by
tion services in Vietnam generally are of unknown for the other two. Three women site (48% from Hanoi, 52% from Ho Chi Minh City), the distribution
rather poor quality, these clinics had among whose abortions were incomplete at the of surgical patients was quite uneven (72% from Hanoi, 28% from
the best services. follow-up visit were permitted to keep Ho Chi Minh City). Thus, the background data present-ed for
surgical clients are more heavily weighted toward Hanoi.
Both sites followed a uniform study pro- waiting rather than receiving surgi-cal
tocol. Women seeking abortions could par- abortions. They returned later for ad-
ticipate if bimanual examination showed ditional follow-up. may have been influenced by their earli-er
that they were no more than eight weeks Patients who chose surgical abortion had experiences, these women were asked to
pregnant (or if it had been no more than 56 the procedure on their first visit, in ac- compare their study abortion and their prior
days since their last menstrual period), they cordance with the clinics regular prac-tices. abortion.
had no contraindications to medical or Nearly all of these women (98%) re-ceived Data entry and analysis were per-formed
surgical abortion, they lived within one vacuum aspiration without dilation. (Two using standard statistical software (SPSS)
hour of the clinic and they were willing to women had vacuum aspi-ration with and procedures. All means testing used t-
return for follow-up visits. Women aged 35 dilation, and one woman un-derwent sharp tests, with Levenes tests conduct-ed to
or older were ineligible if they smoked 10 curettage.) In Ho Chi Minh City, all determine whether pooled or sepa-rate
or more cigarettes per day. surgical abortion patients received local variance estimates were appropriate. Chi-
If a woman met the study criteria and anesthesia, while in Hanoi, most did not square tests were used to analyze cat-
wished to participate, a trained provider receive any anesthesia. Fourteen days after egorical data. All tests were two-tailed.
explained both abortion methods. All the procedure, patients returned to the clinic
women received standardized counseling for a checkup and exit interview. Results
about both procedures and their most Clinic physicians were already trained in Sample Characteristics
common side effects. For example, women providing surgical abortions and received The sample consisted of 393 women221
were told that medical abortion is a rela- additional training in medical abortion for in Hanoi and 172 in Ho Chi Minh City.
tively new method, that it requires taking the study. They provided all of the surgical Overall, 260 women chose medical abor-
two sets of pills orally and that after the procedures, administered about half of the tion and 133 opted for a surgical proce-dure
second set of pills, most women experi- medical abortions and supervised the nurses (Table 1).
ence cramping for several hours and who administered the other half. The in- Women who selected the medical
bleeding for several days.* Moreover, they country principal investigators closely method were slightly younger than those
were informed that in French studies, this monitored the study to ensure standardized who decided on surgical abortion (26.4 vs.
medical abortion regimen was about 95% treatment. Before the main study began, 27.9 years) and had had more years of
effective. The provider also explained the each site conduct-ed a pilot study of 10 schooling (11.6 vs. 10.6). Both groups
types of surgical abortion available at the medical patients. Data on these women are sought to terminate their pregnancies quite
clinic and that this method was nearly 100% included in our analyses, since no early, but the mean gestational age was
effective. Explicit comparisons be-tween significant changes were made to the somewhat lower among women who chose
medical and surgical abortion were avoided, protocol following re-view of their the medical method (5.9 weeks) than
however, so as not to bias womens experiences. among those who opted for surgery (6.1
selection. After hearing about both methods, Providers collected clinical and experi- weeks). Women undergoing medical abor-
women chose between them. Any women ential data from each patient. Questions
who could not decide would have been covered procedures, medications, side ef- *If a woman asked how long a medical abortion takes, she
randomized to a method, but no participants fects or problems, and the womans reac- was informed that while the majority of women ex-perience
a complete abortion within several hours of tak-ing the
were unde-cided. All women gave informed tion to the abortion experience. Addi- second set of pills, some wait up to two weeks to have a
consent. tionally, women completed a daily diary of complete expulsion.
Women who chose medical abortion re- all side effects during the weeks of the
This ratio is not meaningful, because many women who
ceived 600 mg of mifepristone at their ad- study and indicated when they thought their preferred surgical abortion (particularly in Ho Chi Minh
mission visit and remained under obser- abortion had occurred. Finally, since City) saw no reason to enroll in the study rather than sim-
vation for 30 minutes. At a second visit, women who had had previous abortions ply to undergo the standard procedure.
Volume 25, Number 1, March 1999 11
59
Mifepristone-Misoprostol Medical Abortion in Vietnam
because it entailed fewer

Table 2. Percentage of abortion patients Table 4. Percentage of medical abortion patients experiencing
citing various reasons for selecting their visits (28%) or was con- various side effects, by segment of the regimen
method, by method venient (26%). Fear of
side effects was not a Side effect After mifepri- During obser- After obser-
Reason Medical Surgical stone, before vation after vation, until
(N=258) (N=131) major concern to women misoprostol misoprostol exit
in either group when (N=258) (N=259) (N=257)
Effective 5.4 64.1
Simpler and faster 67.9 they selected their
Nausea 37.6 6.9 6.2
Less pain 58.9 method. Vomiting 15.9 0.8 2.3
Safer 40.4 47.3
Avoids surgery/anesthesia 43.4
Only three medical Cramping/abdominal pain 38.8 93.8 37.7
Easier emotionally 30.2 abortion patients did not Diarrhea 1.2 3.1 2.7
Fewer visits 27.5 Prolonged bleeding 0.0 0.0 80.5
Convenient 7.8 26.0
complete the protocol. Profuse bleeding 2.7 4.2 2.3
Less bleeding 7.6 One woman, feeling Increased bleeding 0.0 94.6 0.0
More natural 6.2 worried and fatigued,
Private 5.8 Note: The observation period after administration of misoprostol was at least four hours.
went to another clinic be-
Fewer side effects 3.8
fore taking misoprostol
Cited by one woman or no women. Note: Women could cite
up to three reasons. and obtained a surgical abortion. Another surgical patients (7%) and three medical
woman did not return to the clinic in time abortion patients (1%) were lost to follow-
to receive misoprostol and had a surgical up. All available data from these 12
tion were less likely than those having sur- intervention. The third woman requested women are included in our analysis.
gical procedures to be married (73% vs. a surgical abortion at another clinic after Side effectsnausea, vomiting, cramp-
84%) and to have been using a contracep- taking misoprostol because she had expe- ing, pain, diarrhea and bleedingwere far
tive (38% vs. 59%). The differences in age rienced only spotting and not heavy bleed- more common among the medical abor-
and length of gestation, however, were no ing. All three are included in the analysis. tion clients than among the women who
longer statistically significant once we con- chose surgery (Table 3). However, al-
trolled for study site (not shown). Efficacy and Safety though we have included cramping and
Since medical abortion clients selected bleeding as side effects, they may be
Method Choice and Adherence to Protocol their method to avoid surgery, we con- symptoms of a medical abortion; indeed,
Upon enrollment in the study, women were sidered any of these women who under- if they do not occur, the woman is unlikely
asked to name up to three reasons for their went a surgical procedure for any reason to have a successful medical abortion.
method selection. Among women who se- to represent a treatment failure.12 All sur- Furthermore, medical abortion patients
lected the medical method, 59% did so to gical abortion patients who had more than were observed on more occasions (at least
avoid pain (Table 2). Substantial proportions one surgical procedure were also deemed three visits vs. at least two) and for a
also chose the medical method to avoid to represent treatment failures. longer period of time (17 vs. 15 days) than
surgery or anesthesia (43%), or because they Three types of failures can occur among were surgical abortion patients. More im-
believed that it was the safer option (40%) or medical patients: user choice, provider portant, even for medical clients, none of
that it would be less traumatic (30%). choice (or error) and true drug failures. the observed side effects represented a se-
In contrast, women choosing surgical User choice failure occurs when a woman rious medical risk.
abortion did so mainly because they per- asks for surgical intervention prior to the Side effects of medical abortion varied
ceived it to be simpler and faster (68%) or end of the study or is unable or chooses at different stages of the procedure (Table
more effective (64%) than medical abortion. not to take the complete medical treat- 4). Women were more likely to report nau-
As with the medical patients, safety con-cerns ment. Provider choice failure occurs when sea and vomiting after taking mifepristone
loomed large in the minds of surgi-cal patients a provider performs or recommends med- than later in the abortion process, but this
(47%). Large proportions of women also ically unwarranted surgical interventions may reflect symptoms of pregnancy. (In-
decided to undergo surgery (either out of impatience or in reaction to deed, upon enrollment in the study, 43%
a concern with no clear medical basis). of all women reported nausea42% who
Table 3. Percentage distribution of abortion True drug failure occurs when an adverse chose medical abortion and 46% who
patients, by outcome, and percentage of pa- event requires surgical intervention dur- opted for surgicaland 6% reported vom-
tients citing various side effects, by method
ing the study period or when an abortion iting.) Cramping and abdominal pain in-
Measure Medical Surgical is not complete by the end of the study. creased sharply during the four-hour ob-
(N=257) (N=124) Failure rates for both abortion methods servation period immediately after
Outcome were extremely low (Table 3). Only one administration of misoprostol, but sub-
Successful abortion 96.1 99.2 surgical patient (1%) required a backup in- sided later. Profuse bleeding, although
Failure 3.9 0.8
Total 100.0 100.0 tervention. Among medical patients, there never experienced by more than 5% of the
were 10 failures (for a rate of 4%): six user medical abortion clients, was also most
Side effects
Nausea 39.3 0.8***
choice, one provider choice and three true likely during these four hours.
Vomiting 17.1 2.4*** drug failures.*
Cramping/abdominal pain 96.1 37.1*** Diligent efforts were made to minimize *At the follow-up visit, three medical abortion patients
Diarrhea 5.8 0.0** had had incomplete abortions and were permitted to
Profuse bleeding 8.9 4.8
loss to follow-up. All women who did not
keep waiting for their abortions to become complete. Two
Prolonged bleeding 80.5 25.8*** report for a scheduled appointment were
of these women had complete abortions confirmed when
**Difference between medical and surgical abortion patients is
sent up to three reminder letters. Only after they returned for an additional follow-up visit, a few days
significant at p.01. ***Difference between medical and providers made home visits in an effort to to one month after the first; the third woman received a
surgical abortion patients is significant at p.001. Note:
Patients who were lost to follow-up are excluded.
trace these patients were the women des- surgical intervention, because her abortion still was not
ignated as lost to follow-up. In total, nine complete three days after her initial follow-up visit.
60
Among the most serious risks of abor- medically induced abortions took place on
Table 6. Percentage distribution of abortion
tion, regardless of the method used, is ex- the day the women received misoprostol, patients, by measure of satisfaction with
cessive blood loss during and following the and 8% took place throughout the next two their method, according to method
procedure. On average, the women in both weeks. However, medical abortion early in
Measure Medical Surgical
groups experienced minimal blood loss gestation can escape detection; 10% of
(Table 5). Only 2% of women who had medical abortion patients did not recog-nize Satisfaction (N=257) (N=124)
Highly satisfied 5.4 2.4
medical abortions and 1% of their coun- when their abortions occurred. Satisfied 91.8 92.7
terparts who had surgical procedures ex- Most medical patients could identify Not satisfied 2.7 4.8
perienced a reduction in their hemoglo-bin where they were when the abortion oc- Would choose
levels of greater than 2 g per deciliter curred (even if they could not pinpoint the method again*** (N=256) (N=123)
(which is considered clinically meaning-ful time of the abortion). Nearly three-quarters Yes 95.7 51.6
No 4.3 48.4
blood loss), and none required a trans- (72%) reported that their abortions occurred
fusion (not shown). at the clinic, but many (20%) said theirs oc- Would recommend
method*** (N=251) (N=124)
Analysis of participants diaries showed curred at home. About 1% reported other Medical 95.2 37.1
that medical abortion clients reported more locations, and the rest were unsure. Surgical 2.0 28.2
Either 2.8 34.7
blood loss than did surgical abortion At the exit visit, all but one patient (who
patients. The mean number of days of had had a surgical procedure) stated that the Comparison with previous
bleeding (i.e., heavy, normal or light) was explanation they had received about their abortion*** (N=121) (N=57)
More satisfactory 32.2 3.5
significantly greater for women who had method adequately prepared them for the As satisfactory 64.5 86.0
medical abortions than for those who had abortion experience. The remain-ing Less satisfactory 3.3 10.5
surgical abortions.* For both groups, how- woman reported that the experience was Total 100.0 100.0
ever, heavy bleeding accounted for only a worse than she had expected it to be.
***Difference in distributions between medical and surgical
small number of total bleeding days. The vast majority of women were satis- abor-tion patients is significant at p.001.
Expectations about both the amount and fied with their abortion experience97%
the duration of bleeding also differed of those who had medical procedures and
between the medical and surgical groups. 95% who had surgical abortions (Table 6). surgical abortion clients believed that the
Medical abortion patients were more like-ly Of the 13 women who were not satisfied alternative procedure was preferable to the
than surgical patients to have bled more and with the experience, five had had method one they had chosen, perhaps because of
longer than they had expected to. failures. Nevertheless, about half of women discussions they had with women who ob-
who had failures remained satisfied with tained the other procedure.
Acceptability their abortions. A patient who had under- At their final visit, women were asked to
Where and when an abortion occurs after a gone a surgical intervention after the med- describe the best and worst aspects of their
medical procedure may significantly in- ical procedure failed concluded that there abortion method (Table 7, page 14). Each
fluence the methods acceptability. Ac- was nothing wrong with the medical was permitted up to three answers. For
cording to participants diaries, 82% of method, but that she was simply unlucky. medical abortion, the features most
In all, 178 women had had a previous frequently cited by patients were that the
Table 5. Measures of bleeding experienced surgical abortion60% vacuum aspira-tion, method is less painful than surgical abor-
by abortion patients, by method 37% dilation and curettage, and 3% some tion (35%), is safer (30%), does not involve
Measure Medical Surgical
other surgical procedure. When asked how surgery (20%) and is effective (14%). The
their experience during the study compared emphasis on less pain is not surprising,
MEANS given that surgical abortion is delivered
Hemoglobin level (g/dl) (N=253) (N=123)
with their previous abor-tion experience,
At entry 11.8 11.6 women who had medical abortions were with minimal anesthesia in Vietnam.
At exit 11.7 11.6 significantly more likely than those who Prolonged heavy bleeding was most
Change 0.1 0.1
had surgical procedures to say that their commonly reported as the worst feature of
Days of bleeding*** (N=257) (N=124) study experience was more satisfactory (32% medical abortion (mentioned by 39% of
Heavier than usual menses 1.3 (2.2) 0.4 (0.8) vs. 4%). Medical clients were less likely women). A substantial proportion of med-
Like normal menses 3.1 (2.7) 2.2 (1.2)
Lighter than usual menses 6.2 (3.5) 3.1 (1.7)
than surgical clients to report that the study ical clients (17%) also reported that the
abortion was not as satisfactory as their method involved too many visits and too
PERCENTAGE DISTRIBUTIONS previous abortion (3% vs. 11%). lengthy a follow-up. Some 30% of women
Amount of bleeding* (N=257) (N=124)
More than expected 25.3 16.9 Women who had medical abortions were who had medical abortions, however, were
As much as expected 57.2 65.3 significantly more likely to say they would unable to offer any negative features of the
Less than expected 16.0 11.3 select the same method again than were method.
Not sure/do not know 1.6 6.5
those who selected surgical abortion (96% Women who chose surgical abortion
Duration of bleeding*** (N=257) (N=124) vs. 52%). Nearly all (95%) medical clearly appreciated the methods effec-
Longer than expected 49.0 24.2
As long as expected 34.2 58.1
abortion clients would recommend their tiveness (46%), as well as the ease and sim-
Shorter than expected 14.8 11.3 method, compared with only 28% of sur- plicity of the procedure (23%). Yet 23%
Not sure/do not know 1.9 6.5 gical abortion clients.
Additionally, 37% of surgical abortion *Analysis of the mean number of days of bleeding, how-
Total 100.0 100.0 ever, overestimates the total number of days of bleed-ing,
clients would recommend medical abortion
*Difference in distribution between medical and surgical since diary entries recording different types of bleed-ing on
abortion patients is significant at p.05. ***Difference in
to friends, while only 2% of medical abor- a single day were counted as separate days of bleeding.
distribution be-tween medical and surgical abortion patients is tion clients would recommend surgical Thus, for example, if a woman recorded both normal and
significant at p.001. Notes: For days of bleeding, numbers in
parentheses are standard deviations. abortion. Thus, in hindsight, some of the heavy bleeding one day, she was counted as having had a
full day of each.
Volume 25, Number 1, March 1999 13
61
Mifepristone-Misoprostol Medical Abortion in Vietnam
ployed and suggests that the date of the 25(6, part 1):342352.
Table 7. Percentage of abortion patients
cit-ing various features as their methods follow-up visit can be successfully delayed 8 Johansson A et al., Abortion in context: womens ex-
best and worst characteristic, by method beyond the current standard of two weeks, perience in two villages in Thai Binh Province, Vietnam,
which has been adopted from the surgical International Family Planning Perspectives, 1996, 22(3):
Feature Medical Surgical 103107.
(N=257) (N=124)
regimen.
Side effects were more common among 9 Statistical Publishing House, Vietnam Intercensal De-
Best mographic Survey, 1994: Major Findings, Hanoi, Vietnam:
Effective 14.4 46.0
medical abortion clients than among sur-
Statistical Publishing House, 1995.
Less pain 34.6 gical clients, but they did not jeopardize the
Safer/less risk safety of the medical regimen and were 10 Goodkind D, 1994, op. cit. (see reference 6).
of complication 30.4 7.3
Faster/easier/simpler 5.1 23.4 tolerable for the vast majority of women 11 Vietnamese Ministry of Health, A strategic assessment
None/not sure 8.2 22.6 who chose that method. Howev-er, women of policy, programme and research issues relating to abor-
Avoids surgery 19.8 who had medical abortions re-ported tion in Vietnam: a draft report, Hanoi, Vietnam, 1997.
Less mental stress/
healthier 7.4 bleeding more and longer than they had 12 Winikoff B et al., The acceptability of medical abor-
Convenient/compatible expected and more frequently than women tion in China, Cuba and India, International Family Plan-
with duties 6.6 4.0 ning Perspectives, 1997, 23(2):7378 & 89; and Winikoff
who obtained surgical pro-cedures. Since B et al., 1997, op cit. (see reference 4).
Worst womens expectations may significantly
12. Winikoff B et al., Analysis of failure in medical abor-
Pain 57.3 affect their comfort and sat-isfaction with a
Prolonged heavy tion, Contraception, 1996, 54(6):323327.
bleeding 38.9 22.6
method, medical abortion patients must
receive appropriate advance information to 12 Winikoff B et al., 1997, op. cit. (see reference 11); and
None/not sure 30.0 18.5
Winikoff B et al., 1997, op. cit. (see reference 4).
Too many visits/lengthy prepare them for the methods potential
follow-up 16.7 13 Winikoff B et al., 1997, op. cit. (see reference 4); Pey-
Fear of surgery 10.5
side effects.
ron R et al., 1993, op. cit. (see reference 3); and Aubny E
More mental stress 8.9 This trial was conducted in major clin-ics et al., Termination of early pregnancy (up to and after
Long waiting time until in large urban areas, where backup fa-
abortion 7.8 19 days of amenorrhea) with mifepristone (RU 486) and
Fatigue/dizziness 5.1 cilities are easily accessible and of rea- increasing doses of misoprostol, International Journal of
sonably high quality. Studies in rural areas Fertility, 1995, 40(Suppl. 2):8591.
Cited by one woman or no women. Note: Women could cite
up to three reasons. with more basic facilities are needed be-
fore the methods safety, effectiveness and Resumen
acceptability for women throughout the Contexto: En los pases en desarrollo donde es
were unable to name any good charac- country can be judged. Additionally, since elevada la demanda de servicios de aborto, tales
teristics of the method. Although surgi-cal many medical abortion clients reported that como Vietnam, es enorme la necesidad que
abortion clients reported far less pain the regimen involved too many vis-its and existe de contar con alternativas seguras y efi-
during the study than did medical clients, many surgical clients chose their method caces para evitar la intervencin quirrgica.
57% considered pain the methods worst because it entailed fewer visits, research Una buena opcin en algunos de estos pases
feature. Surgical clients also included fear into a simplified protocol in-volving fewer puede ser el aborto mdico realizado median-te
of surgery and mental stress among the clinic visits is important. Nevertheless, our el uso del mifepristone y el misoprostol.
worst features of their method. results indicate that mifepristone- Mtodos: En un estudio comparativo realiza-do
misoprostol medical abor-tion can sobre la seguridad, la eficacia y la aceptabili-
Discussion complement available surgical services and dad de los abortos mdico y quirrgico, 393 mu-
Our findings suggest that mifepristone- help meet the pressing need for safe, jeres de dos clnicas urbanas eligieron entre el
misoprostol medical abortion is a safe, ef- effective and acceptable abortion services mtodo mdico en base a mifepristone y miso-
fective and desirable alternative to surgical in Vietnam. prostol y el procedimiento quirrgico estndar.
abortion in Vietnam. The methods success Resultados: Las tasas de xito para ambos
rate in our study (96%) is the highest docu- References mtodos resultaron extremadamente elevadas
13 1. World Health Organization, Abortion: A Tabulation of (96% para el aborto mdico y 99% para el abor-
mented in a developing country and is
Available Data on the Frequency and Mortality of Unsafe
comparable to the rate found in developed to quirrgico). Las pacientes del aborto mdi-co
Abor-tion, second ed., Geneva: World Health Organization,
14 indicaron un nmero mucho mayor de efec-tos
countries. Moreover, while the medical 1994.
abortion failure rate in our study exceeds that secundarios que las que se sometieron a
2. Bygdeman M et al., Progesterone receptor blockage:
of the surgical method, many Vietnamese effect on uterine contractility and early pregnancy, Con-
procedimientos quirrgicos (ms comnmente
women apparently are willing to accept an traception, 1985, 32(1):4551. dolores, sangrado prolongado y nuseas), aun-
increased risk of failure, since most said they 3. Peyron R et al., Early termination of pregnancy with
que ninguno de estos efectos secundarios re-
would choose medical abortion again and mifepristone (RU 486) and the orally active prostaglandin present un riesgo mdico serio. Casi todas las
would recommend it to their friends. misoprostol, New England Journal of Medicine, 1993, mujeres, fuere cual fuere el mtodo escogido, se
Three women whose pregnancies had not 328(21):15091513. mostraron satisfechas con su experiencia.
yet terminated as of their exit visits were 4. He C et al., Study on safety and efficacy of mifepris- Adems, entre las mujeres que previamente se
advised to return for additional fol-low-up tone plus misoprostol for termination of early pregnan-cy, haban sometido a un aborto quirrgico, aque-
Reproduction and Contraception, 1992, 3:110; and llas que escogieron un aborto mdico eran ms
rather than receive surgical inter-vention. Winikoff B et al., Safety, efficacy, and acceptability of
Two had had complete abortions by the med-ical abortion in China, Cuba, and India: a comparative
proclives que las que dicidieron de someterse a
time they returned and thus re-quired no trial of mifepristone-misoprostol versus surgical abor-tion, un aborto quirrgico a indicar que su abor-to
backup procedure, while the third American Journal of Obstetrics and Gynecology, 1997, actual era ms satisfactorio que el anterior (32%
176(2):431437. contra 4%).
eventually received sharp curettage to
complete her abortion. This experience 5. Winikoff B et al., 1997, op. cit. (see reference 4). Conclusiones: El aborto mdico en base a
confirms that the methods failure rate is 6. Goodkind D, Abortion in Vietnam: measurements, mi-fepristone y misoprostol es seguro, eficaz y
largely a function of the protocol em- puzzles, and concerns, Studies in Family Planning, 1994, (continued on page 33)
62
Medical Abortion in Vietnam... option viable dans certains de ces pays. ment de la mthode choisie, presque toutes les
(continued from page 14) Mthodes: Dans une tude comparative de la femmes se sont dclares satisfaites de leur ex-
scurit, de lefficacit et de lacceptabilit de prience. De celles qui avaient subi un avor-
aceptable para las mujeres vietnamitas de zonas lavortement mdical et chirurgical, 393 femmes tement chirurgical prcdent, celles ayant choi-
urbanas que tienen la opcin de escoger un rencontres dans deux cliniques ur-baines ont si la procdure mdicale se sont du reste
mtodo. Si se observan resultados simila-res en choisi entre un rgime mdical base de rvles plus susceptibles, par rapport leurs
las zonas rurales, este sistema podra sa-tisfacer mifepristone-misoprostol et la procdure chi- homologues qui avaient de nouveau choisi la
la necesidad insatisfecha de servicios de aborto rurgicale ordinaire offerte dans chaque clinique. mthode chirurgicale, de qualifier la procdu-re
que existe a nivel nacional en el pas. Rsultats: Les taux de succs des deux m- incluse dans ltude de plus satisfaisante que la
thodes se sont avrs extrmement levs (96% prcdente (32% par rapport 4%).
Rsum pour lavortement mdical et 99% pour la m- Conclusions: Lavortement provoqu par mi-
Contexte: Dans les pays en voie de dvelop- thode chirurgicale). Les patientes ayant choi-si fepristone-misoprostol offre une mthode sre,
pement qui prsentent une demande de services la procdure mdicale ont signal beaucoup plus efficace et acceptable aux yeux des Vietna-
davortement leve (le Viet Nam, par exemple), deffets secondaires que celles qui avaient miennes auxquelles un choix de mthode est
il existe un besoin important de solutions sres demand lintervention chirurgicale (douleurs offert. Si des rsultats comparables taient ob-
et efficaces autres que les procdures chirurgi- abdominales, saignements prolongs et nau-ses, servs dans les milieux ruraux, le rgime pour-
cales. Lavortement mdical base de mife- surtout), mais aucun de ces effets ne pr-sentait rait aider rpondre au besoin de services
pristone et de misoprostol pourrait offrir une de risque mdical grave. Indpendam- davortement lchelle nationa
Volume 25, Number 1, March 1999
63
Elmer ress
Gastroenterol Res. 2015;8(3-4):216-221
Original Article
Cross-Sectional Study for Prevalence of Non-Steroidal Anti-

Inflammatory Drug-Induced Gastrointestinal, Cardiac and
Renal Complications in India: Interim Report
Suparna Chatterjeea, d, Gur Prasad Durejab, Ganesh Kadhec, Amey Manec, Abhay A. Phansalkarc,
Sandesh Sawantc, Vaibhavi Kapatkarc
Abstract Keywords: NSAIDs; Gastrointestinal; Renal; Cardiac; Complica-

tions; Pain management; Risk factors; Prevalence
Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are
the most common therapeutic products used for the management of
inflammation and pain. However, their use is associated with gas-
trointestinal (GI), cardiovascular and renal complications. Although Introduction
prevalence data regarding NSAID-induced complications are avail-
able worldwide, but none of the study has assessed the prevalence of Non-steroidal anti-inflammatory drugs (NSAIDs) are mainly
GI, cardiac and renal complications in India. This study aimed to used for the management of inflammation and pain. Most pa-
assess the point prevalence of GI, cardiac and renal complications tients with different etiologies of pain are treated with NSAIDs
associated with the use of NSAIDs in India. The study also aimed to (up to 71.6% patients with cancer pain) as compared with other
evaluate the association between the risk factors and GI, renal and classes of drugs [1]. These agents act by inhibiting cyclooxy-
cardiac complications in patients using NSAIDs. genase (COX) enzyme which regulates the synthesis of pros-
taglandins (PGs) [2]. Inhibition of COX enzyme by NSAIDs
Methods: This prospective, cross-sectional, multi-centric study was
results in their analgesic, anti-inflammatory and anti-pyretic
conducted in eight medical colleges across India (North, East, West,
action [3]. Although NSAIDs are the most widely used thera-
South and Central India). Data related to GI complications includ-
peutic agents in the management of pain, their use is associated
ing gastric, duodenal and gastroduodenal erosions/ulcers/gastritis,
with gastrointestinal (GI), cardiovascular, and renal adverse
renal complications including acute and chronic renal failure or car- events (AEs) [4]. A meta-analysis by Coxib and traditional
diac complications including acute coronary syndrome (ACS), acute NSAID trialists (CNT) collaboration reported that the use of
myocardial infarction (AMI) and cardiac failure, were collected NSAIDs increased the risk of major vascular events by 40% [5].
from patients. Another meta-analysis conducted by Scheiman reported that the
risk of gastric ulcers (RR: 0.39; 95% CI: 0.31 - 0.50) and
Results: The cut-off date for interim data analysis was July 7, 2014.
duodenal ulcers (RR: 0.20; 95% CI: 0.10 - 0.39) reduced to a
A total of 2,140 patients out of 3,600 were enrolled from eight
significant extent, when NSAIDs were used in combina-tion with
centers at the time of interim analysis. The NSAID-associated point
proton pump inhibitors (PPIs) [6, 7].
prevalence of GI complications was 30.08%; cardiac complication
The duration of NSAID use and the dose administered
was 42.77%; and renal complication was 27.88%. decide the severity of complications [3]. Lim et al in a re-view
Conclusions: Results of the present interim analysis show that the showed that the use of NSAIDs increased the risk of GI
prevalence of GI, cardiac and renal complications among patients is complications in 55-75% healthy volunteers [8]. The use of
NSAIDs is inappropriate in patients with a previous his-tory of
high due to exaggerated usage; however, the final analysis would
GI events, as these agents may increase the risk of GI
pro-vide the overall prevalence of these complications.
complications by 2.5- to 5-fold in them as compared with
patients not receiving NSAIDs [9]. Traditional NSAIDs with
structural components of arylacetic acids (indomethacin), ar-
Manuscript accepted for publication May 13, 2015 ylpropionic acids (ibuprofen, ketoprofen and flurbiprofen) and
a
anthranilates (meclofenamic acid and analogues) inhibit both
Department of Pharmacology, IPGMER, Kolkata, India isoforms of COX (COX-1 and COX-2) enzyme responsible for
b
Department of Pain Medicine, New Delhi Pain Management Center, New the synthesis of gastro-protective PGs resulting in severe GI
Delhi, India
c
Medical Affairs, Wockhardt Limited, Mumbai, India toxicities [10]. Pareek and Chandurkar reported that the number
d
Corresponding Author: Suparna Chatterjee, Department of Pharmacology,
of GI-related AEs induced by NSAIDs increased with the
IPGMER, Kolkata, India. Email: drsupchat@gmail.com prolonged use of NSAIDs and a significantly higher (P = 0.053)
number of GI-related AEs were observed among the patients
doi: http://dx.doi.org/10.14740/gr658w using diclofenac as compared with aceclofenac [11]
Articles The authors | Journal compilation Gastroenterol Res and Elmer Press Inc | www.gastrores.org
216 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distr ibution, and reproduction
in any medium, provided the original work is properly cited
64
Chatterjee et al Gastroenterol Res. 2015;8(3-4):216-221
In elderly, use of NSAIDs, including the COX-2 inhibitors, College, Mumbai; Grant Medical College, Mumbai; Govern-
significantly increases the risk of GI bleeding. This has led ment Medical College, Nagpur; Byramjee Jeejeebhoy Medi-cal
American Geriatric Society (AGS) to publish a new pain College, Pune; Nizams Institute of Medical Sciences,
man-agement guideline stating that the use of non-selective Hyderabad; Institute of Post Graduate Medical Education and
NSAID and COX-2 inhibitors should generally not be Research, Kolkata; Sawai Man Singh Medical College, Jaipur
prescribed for elderly for longer duration [12]. Co- and M. S. Ramaiah Institute of Technology, Bangalore) across
administration of PPIs has shown a reduction in the risk of India (North, East, West, South and Central India). Physicians
several GI complications [11, 13]. from the departments of gastroenterology, cardiology, neph-
Even short-term use of NSAIDs (less than 90 days) such rology and pharmacology participated in the present study (as
as ibuprofen (incidence rate ratio (IRR): 1.67; 95% CI: 1.09 - investigators). The study was initiated on August 16, 2013 and is
2.57), diclofenac (IRR: 1.86; 95% CI: 1.18 - 2.92), and ro- presently ongoing. Written informed consent was ob-tained from
fecoxib (IRR: 1.46; 95% CI: 1.03 - 2.07) was associated with all patients whose data were used in the study.
increased risk of serious coronary heart disease [14]. Johnson The study protocol, informed consent form, case report form
et al demonstrated that NSAIDs increase blood pressure by (CRF), were reviewed and approved by Institutional Ethics
up to 5 mm Hg and also antagonize the effect of antihyperten- Committee (IEC) of respective medical colleges. The study
sive medications such as -blockers [15]. An increased risk of was conducted in accordance to Good Clinical Practice (GCP)
cardiac complications with concomitant use of NSAIDs has as required by the International Conference on Harmonization
been observed among the elderly with a previous history of (ICH) guidelines, Ethical Guidelines for Biomedical Research
myocardial infarction and other cardiovascular disorders on Human Subjects (ICMR, 2006) and Declaration of
[16]. Helsinki [22].
Aronoff in a review reported renal complications such as
acute renal failure as a result of compromised renal blood flow
and unopposed renal vasoconstriction among patients taking Patient recruitment
NSAIDs. These renal effects may occur as a result of unop-posed
vasoconstriction or acute interstitial nephritis due to All data of patients were collected on a CRF by the investiga-
NSAID use [17]. NSAIDs selectively inhibit renal PGs which tors (see supplemental data for CRF). All patients in the study
result in renal ischemia. Elderly patients are at a higher risk of are being assigned a unique five-digit number by the study
renal complications with the use of NSAIDs [18]. Kristensen et per-sonnel of the pharmacology department. The first two
al showed that 36.1% of the patients who were on chronic renal digits of the patient identification number will represent the
replacement therapy had received NSAIDs within 3 years of site code (01: site 1, 02: site 2), followed by the code for
therapy initiation [19]. Nderitu et al in a review reported that complication (GAST: patients with GI complications, CARD:
chronic renal failure progression may result from the use of high patients with cardiac complications, and REN: patients with
dose NSAIDs; however, a standardized guideline for cal-culating renal complica-tions) and the remaining three digits will be a
the optimum dose has not been defined [20].
sequential num-ber (001, 002, 003 and so on).
Several studies conducted in the past have highlighted a All patients with investigational reports of erosion/ulcer/
higher risk of GI, cardiac and renal complications with the use of
gastritis in upper GI endoscopy; investigational reports
NSAIDs [10, 17, 21]. A higher risk of these complications has
sugges-tive of recent or old AMI, systolic or diastolic cardiac
been reported among patients who are above 65 years of age,
dysfunc-tion/failure or ACS; or subjects who have raised
patients with a previous history of a GI and cardiac events. Also,
the risk of NSAIDs-associated GI complications can be reduced
serum creati-nine, serum urea or low calculated creatinine
with the co-administration of PPIs [9]. clearance values suggestive of a diagnosis of renal failure
Although global epidemiological data regarding NSAID- (acute or chronic) are considered as cases while those
induced complications are available, we planned to evaluate the without the above findings confirming these complications
prevalence of GI, cardiac and renal complications in India. This are considered as controls. The case/control ratio for
primary objective of the study was to assess the point prevalence patients with GI, cardiac and renal complications is 3:1.
of GI, cardiac and renal complications associated with the use of
NSAIDs as a standard of care in patients across India for the first Eligibility criteria
time. The other study objectives were to eval-uate the association
between the risk factors and GI, cardiac and renal complications
Men or women ( 18 years) from outpatient department
in patients using NSAIDs.
(OPD) or those admitted to the hospital for the following
reasons were included in the study: admitted to
Materials and Methods gastroenterology department for upper GI endoscopy within 4
weeks prior to the study; ad-mitted to cardiology department
for one or more investigations amongst electrocardiography
Study characteristics
(ECG), tread mill test (TMT) and ECG within 3 months prior
to study; and admitted to neph-rology department for one or
This cross-sectional, multi-centric study was conducted in more investigations serum urea, serum creatinine and
eight medical colleges (Lokmanya Tilak Municipal Medical creatinine clearance within 6 months prior to study.
Articles The authors | Journal compilation Gastroenterol Res and Elmer Press Inc | www.gastrores.org 217
65
NSAIDs-Induced Complications Gastroenterol Res. 2015;8(3-4):216-221
Figure 1. Study activity flow chart.
Data collection Statistical analysis
The demographic data, medical history including prior addic- Continuous variables (age, weight) were presented using
tions to smoking, alcohol, history of NSAIDs intake includ- mean and standard deviation (SD). Categorical variables
ing name of the medications, frequency of intake, indications (gender, presence of risk factors) were presented using fre-
of use, duration of use, whether prescribed or taken over the quency and percentage. Age, history of GI complications,
counter, and history of concomitant medications were collect- dosage, concurrent administration of known GI toxic drugs,
ed from all patients. concurrent use of NSAIDs and history of comorbidities were
Data related to GI complications including gastric, duode- the risk factors and were considered for the analysis. A
nal and gastroduodenal erosions/ulcers/gastritis, cardiac com- subgroup analysis was conducted based on the above speci-
plications including acute coronary syndrome (ACS), acute fied risk factors to analyze the prevalence of NSAID-induced
myocardial infarction (AMI) and cardiac failure, and renal complications.
complications including acute and chronic renal failure, were
collected from patients. The information on safety was also
collected under the responsibility of the principal investigator. Results
Sample size Study patients
The expected proportion of patients with NSAID-induced GI/ The proposed number of patients for the entire study is 3,600.
cardiac/renal complications was assumed to be 0.25 (25%). The cut-off date for the interim analysis of the present study
An error margin of 0.025 (2.5%) and a level of confidence as was July 7, 2014. Overall, 2,140 patients were enrolled up to
95% results in a sample size of 1,153 patients for each this time and were included in this interim analysis. A total of
complication (GI, cardiac and renal). The study personnel seven investigational sites recruited 724 patients with GI
from pharmacol-ogy department screened the medical records complications, six investigational sites recruited 690 patients
of gastroenter-ology, cardiology and nephrology departments with cardiac complications, and seven investigational sites re-
and collecting relevant data on weekly OPD days. The cruited 726 patients with renal complications. The study
subjects were enrolled for the study by designated members activ-ity is presented in Figure 1.
of the investigators team after visiting indoor or OPD clinics The mean age of the patients enrolled with GI complica-
of respective departments. A total of 360 subjects were tions was 44.3 14.7 years; for cardiac complications was
planned to be recruited from each investigational site (120 51.5 13.4 years; and for renal complications was 45.3
subjects each for GI, cardiac and renal complications). The 16.1 years. Most of the patients enrolled in the present study
total sample size will be 3,600 with case/ control ratio of 3:1. were male (GI: 67.6%; cardiac: 71%; and renal: 65.8%).
218 Articles The authors | Journal compilation Gastroenterol Res and Elmer Press Inc | www.gastrores.org
66
Table 1. Demographic Profile of Study Subjects
Complication Gastrointestinal Cardiac Renal

Age (years), mean SD 44.3 14.7 51.5 13.4 45.3 16.1
Gender
Male, n (%) 483 (67.6) 486 (71) 469 (65.8)
Female, n (%) 231 (32.3) 198 (28.9) 244 (34.2)
Status
Cases, n (%) 530 (73.8) 493 (72.7) 504 (73.6)
Controls, n (%) 188 (26.2) 185 (27.3) 181 (26.4)
There were 530 cases (73.8%) and 188 controls (26.9%) for (8.03%) (Fig. 3).
GI complications; 493 cases (72.7%) and 185 controls
(27.3%) for cardiac complications; and 504 cases (73.6%)
and 181 controls (26.4%) for renal complications. The de-
Discussion
mographics of all the patients with all complications are pre-
sented in Table 1. The result of this interim analysis has shown the point preva-
lence of GI (30.08%), cardiac (42.77%) and renal complica-tions
(27.88%) with the use of NSAIDs in India. The results of this
Point prevalence of NSAIDs-associated complications interim analysis have shown a trend of NSAIDs being used in
patients with GI, cardiac and renal complications. The use of
Of the 724 patients enrolled in the present study with GI NSAIDs is exaggerated among the patient population in India.
complications, the point prevalence of NSAID- associated GI Although several other classes of analgesics are avail-able, most
complications was 30.08% (216 patients) (Fig. 2). The num-ber patients are either prescribed NSAIDs or consume NSAIDs
of cases and controls among the patients taking NSAIDs was 216 without the consent of their physician (OTC route).
(30.08%) and 69 (9.61%), respectively (Fig. 3). Of the 690 Our previous study demonstrated that up to 55% of the
patients enrolled with cardiac complications, the point patients with chronic pain received NSAIDs for pain control.
prevalence of NSAID-associated cardiac complications was Although elderly patients are at a higher risk of developing
42.77% (290 patients) (Fig. 2). The number of cases among the complications with the use of NSAIDs, a higher proportion of
patients taking NSAIDs was 290 (42.77%), and the num-ber of elderly (61%) have demonstrated the use of NSAIDs for pain
controls was 98 (14.45%) (Fig. 3). Of the 726 patients enrolled control as per the results of our previous study [23]. Analysis
with renal complications, the point prevalence of of the GI, cardiac and renal complications which may result
NSAID-associated renal complications was 27.88% (191 pa- from the usage of NSAIDs is extremely important for appro-
tients) (Fig. 2). The number of cases among the patients taking priate use of NSAIDs and to standardize patient care.
NSAIDs was 191 (27.88%) and the number of controls was 55 Several studies conducted in the past have reported that
Figure 2. Point prevalence of NSAID-associated complications (interim analysis).
Articles The authors | Journal compilation Gastroenterol Res and Elmer Press Inc | www.gastrores.org 219
67
NSAIDs-Induced Complications Gastroenterol Res. 2015;8(3-4):216-221
Figure 3. Proportion of cases and controls in GI/cardiac/renal complications (interim analysis).
the use of NSAIDs is associated with varying degree of com- professionals and the patients about the proper use of
plications among patients. Long-term use of NSAIDs may re-sult NSAIDs. The study would also highlight the need for
in severe GI complications [24]. In addition, the risk of appropriate pain management solutions.
complications with the use of NSAIDs is higher among the el- In conclusion, the result of this interim analysis has
derly [25] and in patients with a history of GI [26], cardiac [14] shown a trend of NSAIDs being associated with most
and renal disorders [16]. The AGS advises that use of NSAIDs GI/cardiac/ renal complications among patients. These results
should be avoided in patients with abnormal renal function, a show that there is a need to channelize and standardize
history of peptic ulcer disease or a bleeding diathesis. Further, appropriate usage of NSAIDs among patients. Increasing
patients should not use more than one NSAID at a time [12]. prevalence of NSAIDs-associated GI/cardiac/renal
Interestingly, Simon reported that exposure to NSAIDs complications may be attributed to the exaggerated use of
with a longer half life is associated with an increased risk of NSAIDs among Indian population. However; the final results
AEs. However; concomitant use of PPIs, H2 receptor antago- of this study (to be published after completion of the study in
nists and prostaglandin analogues may prove effective in re- January 2015) will provide clearer evidence regarding the
ducing the risk of several GI complications [26]. However, association of NSAIDs with GI/car-diac/renal complications.
the use of drugs such as PPIs along with NSAIDs for a longer Although most studies conducted in the past have shown the
du-ration is still not recommended [3]. A few studies suggest efficacy of NSAIDs in relieving pain, their appropriate use is
co-administration of gastro-protective agents along with the need of hour to minimize the in-creasing prevalence of
NSAIDs to minimize GI-related AEs. A study conducted to NSAID-related complications among patient population.
evaluate the prevalence of gastroduodenal ulcers among
NSAID users observed gastroduodenal mucosal injuries in
63.5% of the pa-tients [13]. Conflict of Interest
According to the current treatment guidelines with
NSAIDs, use of lowest effective dose for a shorter time Gur Prasad Dureja declares no current conflict of interest. Su-
period is recommended. The American College of parna Chatterjee received research funding for the conduct of
Gastroenterology, the European League Against Rheumatism, this trial from Wockhardt Ltd, Mumbai. Ganesh Kadhe, Amey
and the First Inter-national Working Party on Gastrointestinal Mane, Abhay A. Phansalkar, Sandesh Sawant, Vaibhavi K. Ka-
and Cardiovascu-lar Effects of NSAIDs and Anti-Platelet patkar are employees and stakeholders by means of salary at
Drugs recommend the co-administration of misoprostol or Wockhardt Ltd, which sponsored the study.
gastro-protective agents such as PPls [6].
A lack of awareness regarding the prevalence rate of
NSAID-induced complications among healthcare profession-als References
and limited access to facilities are resulting in an indiscrim-inate
use of NSAIDs for pain relief [27]. There is no specially 1. Bekkering GE, Bala MM, Reid K, Kellen E, Harker J,
designed study conducted across India to get relevant data about Riemsma R, Huygen FJ, et al. Epidemiology of chronic
toxicities related to the use of NSAIDs. The proposed study aims pain and its treatment in The Netherlands. Neth J Med.
to fulfill this lacuna and help educate healthcare 2011;69(3):141-153.
220 Articles The authors | Journal compilation Gastroenterol Res and Elmer Press Inc | www.gastrores.org
68
7. Thomas MA. Pain management - the challenge. Ochsner sis. Ann Intern Med. 1994;121(4):289-300.
J. 2003;5(2):15-21. 13 Harirforoosh S, Asghar W, Jamali F. Adverse effects of
8. Day RO, Graham GG. Non-steroidal anti-inflammatory nonsteroidal antiinflammatory drugs: an update of gas-
drugs (NSAIDs). BMJ. 2013;346:f3195. trointestinal, cardiovascular and renal complications. J
9. Balmaceda CM. Evolving guidelines in the use of topical Pharm Pharm Sci. 2013;16(5):821-847.
nonsteroidal anti-inflammatory drugs in the treatment of 14 Aronoff GR. Nonsteroidal anti-inflammatory drug induced
osteoarthritis. BMC Musculoskelet Disord. 2014;15:27. renal syndromes. J Ky Med Assoc. 1992;90(7):336-339.
10. Bhala N, Emberson J, Merhi A, Abramson S, Arber N, 15 Dhanvijay P, Misra AK, Varma SK. Diclofenac induced
Baron JA, Bombardier C, et al. Vascular and upper gas- acute renal failure in a decompensated elderly patient. J
trointestinal effects of non-steroidal anti-inflammatory Pharmacol Pharmacother. 2013;4(2):155-157.
drugs: meta-analyses of individual participant data from 16 Kristensen SL, Fosbol EL, Kamper AL, Kober L, Hom-
randomised trials. Lancet. 2013;382(9894):769-779. mel K, Lamberts M, Abildstrom SZ, et al. Use of non-
11. Scheiman JM. The use of proton pump inhibitors in steroidal anti-inflammatory drugs prior to chronic renal
treat-ing and preventing NSAID-induced mucosal replacement therapy initiation: a nationwide study. Phar-
damage. Ar-thritis Res Ther. 2013;15(Suppl 3):S5. macoepidemiol Drug Saf. 2012;21(4):428-434.
12. Hawkey CJ. NSAID toxicity: where are we and how do 17 Nderitu P, Doos L, Jones PW, Davies SJ, Kadam UT.
we go forward? J Rheumatol. 2002;29(4):650-652. Non-steroidal anti-inflammatory drugs and chronic kid-
13. Lim YJ, Yang CH. Non-steroidal anti-inflammatory drug- ney disease progression: a systematic review. Fam Pract.
induced enteropathy. Clin Endosc. 2012;45(2):138-144. 2013;30(3):247-255.
14. Dubois RW, Melmed GY, Henning JM, Laine L. Guide- 18 Fanelli A, Romualdi P, Vigano R, Lora Aprile P,
lines for the appropriate use of non-steroidal anti-in- Gensini G, Fanelli G. Non-selective non-steroidal anti-
flammatory drugs, cyclo-oxygenase-2-specific inhibitors inflamma-tory drugs (NSAIDs) and cardiovascular risk.
and proton pump inhibitors in patients requiring chronic Acta Bi-omed. 2013;84(1):5-11.
anti-inflammatory therapy. Aliment Pharmacol Ther. 19 Hurst SA. Declaration of Helsinki and protection for vul-
2004;19(2):197-208. nerable research participants. JAMA. 2014;311(12):1252.
15. Narsinghani T, Sharma R. Lead optimization on conven- 20 Dureja GP, Jain PN, Shetty N, Mandal SP, Prabhoo R,
tional non-steroidal anti-inflammatory drugs: an Joshi M, Goswami S, et al. Prevalence of chronic pain,
approach to reduce gastrointestinal toxicity. Chem Biol impact on daily life, and treatment practices in India.
Drug Des. 2014;84(1):1-23. Pain Pract. 2014;14(2):E51-62.
16. Pareek A, Chandurkar N. Comparison of gastrointes- 21 Sinha M, Gautam L, Shukla PK, Kaur P, Sharma S,
tinal safety and tolerability of aceclofenac with di- Singh TP. Current perspectives in NSAID-induced
clofenac: a multicenter, randomized, double-blind study gastropathy. Mediators Inflamm. 2013;2013:258209.
in patients with knee osteoarthritis. Curr Med Res Opin. 22 Oka Y, Okamoto K, Kawashita N, Shirakuni Y, Takagi T.
2013;29(7):849-859. Meta-analysis of the risk of upper gastrointestinal hem-
17. Rose VL. Guidelines from the American Geriatric Soci- orrhage with combination therapy of selective serotonin
ety target management of chronic pain in older persons. reuptake inhibitors and non-steroidal anti-inflammatory
Am Fam Physician. 1998;58(5):1213-1214, 1217. drugs. Biol Pharm Bull. 2014;37(6):947-953.
18. Thongbai T. The prevalence of gastroduodenal mu-cosal 23 Simon LS. Nonsteroidal anti-inflammatory drugs and
injuries in aspirin users. J Med Assoc Thai. their risk: a story still in development. Arthritis Res Ther.
2013;96(11):1423-1427. 2013;15(Suppl 3):S1.
19. Pawlosky N. Cardiovascular risk: Are all NSAIDs alike? 24 Bond M. Pain education issues in developing countries
Can Pharm J (Ott). 2013;146(2):80-83. and responses to them by the International Association
20. Johnson AG, Nguyen TV, Day RO. Do nonsteroidal anti- for the Study of Pain. Pain Res Manag. 2011;16(6):404
inflammatory drugs affect blood pressure? A meta-analy-
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Alasan pentingnya penelitian (Why

WHY THIS STUDY IS IMPORTANT?

1. What is the research question or

1.What is the research question or hypothesis

2. What is the study type?

Strength of evidence for causality between a risk factor and outcome

Dependent* / Independent** T Test ; P ( 0,01, 0,05, atau 0,1)

Note : Controlled Positive = drug of choice

2. What is the study type?

Chi Square Test, P = ( 0,01, 0,05, atau 0,1)

2.What is the study type?

2. What is the study type?

3. WHAT IS SAMPLING METHOD

3. WHAT IS SAMPLING METHOD

Referance Population : Pelajar SD di Indonesia

4. How were subjects assigned to group and

4. How were subjects assigned to group and were

Aspirin 325 Mg (36) 34

Clopidogrel (36) 18 Terminated

4.How were subjects assigned to group and were

Aspirin Users Cardiovascular

Non Users Cancer

4.How were subjects assigned to group and were

4. How were subjects assigned to group and were

4. How were subjects assigned to

Medical(260) 258 (96,1%)

No randomization 131 (99,2%)

4. How were subject assigned to

5. What are the study factors and

5. What are the study factors and

6. What are the outcome factors

6. What are the outcome factors

6. What are the outcome factors

7. What important potential

7. What important potential

7. What important confounders are

8.Are statistical tests considered?

8. Are statistical test considered?

9. Are the results clinically/socially

9. Are the results clinically/socially

9. Are the results clinically/socially

10. What conclusion did the authors reach about the

10. What conclusion did the authors reach about the

5. What conclusion did authors reach about the research

Published: 22 May 2006 Received: 27 November 2005

Background expressed as percentage of baseline, using 1.1 g/ml colla-gen

Sample size 36 36 Primary outcome

Baseline (SD) Final (SD) Difference (95% CI) P value

Percentage aggregation (using 1.1 g/ml collagen)

Publish with BioMed Central and every

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Clinical comparison of selective and non-selective a1A-

smooth muscles of the bladder neck and prostate, decrease

606 1997 British Journal of Urology

1997 British Journal of Urology 80, 606611

1997 British Journal of Urology 80, 606611

Table 3 The mean (sd) change in total,

1997 British Journal of Urology 80, 606611

1997 British Journal of Urology 80, 606611

1997 British Journal of Urology 80, 6066