Helicobacter ISSN 1523-5378

Rabeprazole- versus Esomeprazole-Based Eradication Regimens

for H. pylori Infection

Wu
O
PPI
r i gand
eti nal.
aUK
H.
l Publishing
Apylori
r t i c lTreatment
e s Ltd,
Oxford,
Blackwell
1083-4389
Helicobacter
HEL
XXX
Ltd 2007

I-Chen Wu,* Deng-Chyang Wu,* Ping-I. Hsu, Chien-Yu Lu,* Fang-Jung Yu,* Tsang-En Wang, Wen-Hsiung
Chang, Jyh-Jon Chen, Fu-Chen Kuo, Jeng-Yih Wu,* Wen-Ming Wang* and Ming-Jong Bair**
*

Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, Graduate Institute of Medicine
and Department of Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, Division of Gastroenterology,
Department of Internal Medicine, Kaohsiung Veterans General Hospital and National Yang-Ming University, Kaohsiung, Taiwan, Division of
Gastroenterology, Department of Internal Medicine, and **Department of Gastroenterology, Mackay Memorial Hospital, Taipei, Taiwan, Department of
Internal Medicine, Chi-Mei Medical Center, Tainan, Taiwan, Department of Gynecology and Obstetrics, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan

Keywords
Proton pump inhibitor, Helicobacter pylori,
triple therapy, esomeprazole, rabeprazole.
Reprint requests to: Ming-Jong Bair, Division of
Gastroenterology, Department of Internal
Medicine, Mackay Memorial Hospital, Taitung
Branch, 1, Lane 303, Changsha Street, Taitung,
Taiwan. Tel.: +886-89-310150; Fax: +886-89321240; E-mail: a5963@ttms.mmh.org.tw

Abstract
Background: Different kinds of proton pump inhibitor-based triple therapies
could result in different Helicobacter pylori eradication rates.
Aim: The aims of this study were to compare the efficacy and safety of
rabeprazole- and esomeprazole-based triple therapy in primary treatment of
H. pylori infection in Taiwan.
Patients and Methods: From June 2005 to March 2007, 420 H. pylori-infected
patients were randomly assigned to receive a 7-day eradication therapy with
either esomeprazole 40 mg daily (EAC group, n = 209) or rabeprazole 20 mg
b.i.d. (RAC group, n = 211) in combination with amoxicillin 1 g b.i.d. and
clarithromycin 500 mg b.i.d.. Follow-up endoscopy with biopsy was done
1216 weeks after completion of eradication therapy. Those who refused
endoscopic exams underwent 13C-urea breath test to assess the treatment
response.
Results: Intention-to-treat analysis revealed that the eradication rate was
89.4% in the EAC group and 90.5% in RAC groups (p-value = .72). All of the
subjects returned for assessment of compliance (100% in EAC group vs. 99.5%
in RAC group, p-value = .32) and adverse events (3.83% in EAC group vs.
6.16% in RAC group, p-value = .27). Sixty (28.7%) and 37 (17.6%) patients in
EAC and RAC group, respectively, refused endoscopy and underwent a 13C-urea
breath test to determine the treatment effect.
Conclusion: In conclusion, rabeprazole- and esomeprazole-based primary
therapies for H. pylori infection are comparable in efficacy and safety.

Helicobacter pylori infection is known to be associated

with the development of gastritis, peptic ulcer, and gastric
cancer [1]. The worldwide prevalence rate of H. pylori
infection is approximately 50%, with the highest in
developing countries. In Taiwan, the overall prevalence
rate is 54% and this rises with age [2]. More than 70%
of subjects older than 40 years are seropositive for
anti-H. pylori antibody [2]. Eradication of the bacteria is
suggested in patients with atrophic gastritis, post-gastric
cancer resection, peptic ulcers, non-ulcer dyspepsia and
mucosa-associated lymphoid tissue (MALT) lymphoma, as
well as first-degree relation to patients with gastric cancer
[3]. Therefore, it is important to develop and evaluate different treatment regimens. Seven-day triple therapy (proton
pump inhibitor [PPI], amoxicillin, and clarithromycin)

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Journal compilation 2007 Blackwell Publishing Ltd, Helicobacter 12: 633 637

has been the main first-line therapy for H. pylori infection in Taiwan, Europe, and many other countries [4]. If
primary therapy fails, bismuth-based quadruple therapy is
the second-line regimen of choice [4,5]. With the increase
in antibiotic resistance, initial triple therapy has become
less efficacious. Recent studies have shown that the
average cure rate is about 7089% [6]. Many studies have
compared the efficacy and safety of combination regimens
using different kinds, doses, and duration of antibiotics
and/or PPIs. However, there is still no conclusion as to
which PPI is the most efficacious in triple therapy for
H. pylori eradication.
PPIs not only increase the activity of some antibiotics by
reducing gastric acid secretion but also possess direct antiH. pylori activity [7,8]. They are metabolized by hepatic

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PPI and H. pylori Treatment

cytochrome P450 system, especially S-mephenytoin 4hydroxylase (CYP 2C19) and CYP 3A4 [9]. There are
genetically determined differences in the activity of
these enzymes, leading to variable plasma PPI levels and
intragastric pH during PPI treatment. Compared with
omeprazole and lansoprazole, the acid suppressive
effects of rabeprazole and esomeprazole, the S-isomer of
omeprazole, were less affected by CYP 2C19 polymorphism
[10,11]. Esomeprazole-based triple therapy has been shown
to provide a higher eradication rate than pantoprazolebased regimens [12]. Compared with omeprazole and
lansoprazole, rabeprazole is a more potent inhibitor of
gastric acid secretion and has a higher degree of activity
against H. pylori [13,14]. It was shown that rabeprazolebased triple therapy achieves similar H. pylori eradication
rates compared to omeprazole and lansoprazole-based
regimens [15]. However, there is still no randomized trial
to compare the efficacy of rabeprazole and esomeprazole in
first-line triple therapy. The aims of this study are to compare
the efficacy and safety of these two PPIs-based regimens in
primary treatment of H. pylori infection in Taiwan.

Materials and Methods

Patients and Study Design
Patients were those who visited the gastroenterological
clinic of Kaohsiung Medical University Hospital between
June 2005 and March 2007 with the complaint of dyspepsia.
Exclusion criteria included 1, ingestion of antibiotics,
bismuth, or PPI within the prior 4 weeks; 2, patients with
allergic history to the medications used; 3, patients with
previous gastric surgery; 4, the coexistence of serious
concomitant illness (e.g. decompensated liver cirrhosis,
uremia), and 5, pregnant women. All of the participants
underwent a 13C-urea breath test (UBT) and endoscopic
examination with biopsy of the gastric mucosa to establish
H. pylori infection status. We included 420 cases (184 men,
236 women; mean age = 52.6 13.1 years, range: 1683
years) who were diagnosed as gastritis or peptic ulcer with
H. pylori infection. They were interviewed by a trained
interviewer who used a standardized questionnaire to obtain
demographic data and medical history. The participants
were randomly assigned to the EAC group (esomeprazole
40 mg q.d., amoxicillin 1 g b.i.d., and clarithromycin 500 mg
b.i.d. for 7 days) or the RAC group (rabeprazole 20 mg
b.i.d., amoxicillin 1 g b.i.d., and clarithromycin 500 mg
b.i.d. for 7 days). Patients were asked to return during the
second week to assess drug compliance and adverse
effects. Endoscopy with biopsy for rapid urease test,
histology, and culture were repeated 1216 weeks later to
confirm H. pylori infection status. For patients who refused
follow-up endoscopy, UBT was used to confirm H. pylori

Wu et al.

status. The technicians who performed the H. pylori tests

(culture, rapid urease test, and UBT) or filled in the
questionnaires as well as the pathologists were blinded
to the eradication regimens the patients received. All
participants gave written informed consent. This study was
approved by the Institutional Review Board of Kaohsiung
Medical University.

Questionnaire
The questionnaire contained questions regarding personal
history of smoking and alcohol drinking. Smokers were
those who consumed more than one pack of cigarettes a
week and drinkers were those who drank more than one
cup of alcoholic beverage a day. Compliance was defined
as good (taken more 70% of the total medication) or poor
by counting unused medication after the treatment was
completed. The adverse events included abdominal pain,
diarrhea, constipation, dizziness, taste perversion, headache,
anorexia, nausea, vomiting, and skin rash. Those who
considered those symptoms disturbed their daily life were
defined to have positive adverse effects. Those who did not
experience these symptoms or did experience them but
did not consider them a disturbance to their daily life were
defined as negative adverse effects.

Diagnosis of H. pylori infection

Culture and Pathologic Examination
Biopsy specimens were rubbed on the surface of a
Columbia blood agar plate and then incubated at 35 C
under microaerobic conditions for 45 days. The result
for the Grams stain was considered positive when a curvy,
gram-negative bacterium on the smear was found. Culture
of H. pylori was considered positive if one or more colonies
showed gram negativity, oxidase (+), catalase (+), urease (+),
and spiral or curved rods in morphology. The biopsy
specimens were fixed with formalin, embedded in paraffin,
and stained with hematoxylin and eosin. They were interpreted and reported on by the same pathologist.
Rapid Urease Test
The results of CLO test (Delta West Bentley, WA,
Australia) were interpreted as positive if the color of the
gel turned pink or red 6 hours after examination at
room temperature.
13

C-UBT

The 13C-urea was manufactured by the Institute of Nuclear

Energy Research, Taiwan. One hundred millilitres of

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Wu et al.

fresh whole milk was used as the test meal. This detailed
procedure was reported in our previous study [16].
For patients who received follow-up endoscopy, H. pylori
infection was established if the culture was positive, or
both CLO test and histology were positive.

Statistical analysis
The distribution of sex and the initial endoscopic diagnosis
between subjects in EAC and RAC groups were compared
using 2 statistics. The same method was applied to
compare the efficacy and the frequency of side-effects of
the two regimens. The analyzed efficacy outcome was cure
of H. pylori infection. The difference of patients age in the
two groups was examined using Students t-test. A twosided p-value of less than 0.05 was considered statistically
significant. The data were analyzed using the SAS statistical
package (SAS Institute, Cary, NC, USA); all p-values were
two-sided. Assuming that the conventional eradication
rate (EAC group) was 85%, and that the RAC group
achieved to have 95% eradication rate, a 10% difference
of increase, our statistical power in this study will have
91% under the samples size of about 210 subjects in each
group and two-sided p-value of 0.05 if 95% of patients
completed the follow up [17].

PPI and H. pylori Treatment

Table 1 Demographic distribution of the subjects receiving different

eradication regimens

Age (years)
45
4553
5361
> 61
Sex
Male
Female
Diagnosis
Gastritis
Gastric ulcer
Duodenal ulcer
Peptic ulcera

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Journal compilation 2007 Blackwell Publishing Ltd, Helicobacter 12: 633 637

RAC group
(n = 211)

64 (30.6%)
54 (25.9)
46 (22.0%)
45 (21.5%)

46 (21.8%)
49 (23.2%)
61 (28.9%)
55 (26.1%)

88 (42.1%)
121 (57.9%)

96 (45.5%)
115 (54.5%)

0.48

71 (34.0%)
24 (11.5%)
104 (49.7%)
10 (4.8%)

69 (32.7%)
32 (15.2%)
98 (46.4%)
12 (5.7%)

0.43

p-value
0.10

Peptic ulcer: concurrent gastric ulcer and duodenal ulcer.

EAC: esomeprazole, amoxicillin, and clarithromycin; RAC: rabeprazole,
amoxicillin, and clarithromycin.

Table 2 The outcomes of esomeprazole- and rabeprazole-based triple

therapies

Results
All of the 420 study subjects have returned at the second
week and had compliance and adverse effects assessed. As
shown in Table 1, the distribution of age, sex, and initial
endoscopic diagnoses in the EAC and RAC groups were
similar. Most of them were diagnosed with ulcer diseases
(66.0% in EAC group; 67.3% in RAC group). Sixty (28.7%)
and 37 (17.6%) subjects who received EAC and RAC regimens,
respectively, refused follow-up endoscopic examination and
received UBT to confirm the status of H. pylori infection.
The efficacy and safety profiles of the two regimens were
shown in Table 2. In intention-to-treat analysis, 89.4%
(187/208) and 90.5% (191/211) of the patients in EAC
and RAC groups, respectively, were free of H. pylori infection after eradication therapy. All study patients, except
one in RAC group, took at least 70% of the prescribed pills;
the compliance was 100% in EAC group and 99.5% in
RAC group. Eight (3.83%) patients in the EAC group
reported adverse events. Five of them complained of taste
perversion, two had dizziness and the other one had
abdominal pain. Among the 13 (6.16%) cases in the RAC
group who reported adverse events, eight experienced
taste perversion and five had dizziness. There were no
statistically significant differences between the two groups
in eradication rates, compliance rates, or the presence of
adverse events between the two groups.

EAC group
(n = 209)

Eradication rate
Intention-to-treat
Per-protocol
Compliance
Adverse events

EAC group
(n = 209)

RAC group
(n = 211)

p-value

89.4% (187/209)
92.1% (187/203)
100% (209/209)
3.83% (8/209)

90.5% (191/211)
92.7% (191/206)
99.5% (210/211)
6.16% (13/211)

0.72
0.82
0.32
0.27

EAC: esomeprazole, amoxicillin and clarithromycin; RAC: rabeprazole,

amoxicillin and clarithromycin.

Discussion
Our data showed an equivalent compliance and frequency
of side-effects between the two groups. The common sideeffects of PPI-based therapy include abdominal symptoms
(e.g. abdominal pain, diarrhea, constipation, and nausea)
skin rash, headache, and dizziness. In our study, taste
perversion was the most common adverse effect complained.
One study in Japan showed a higher frequency of adverse
effects in patients receiving higher dose of rabeprazolebased triple therapy (4.8% in 40 mg group vs. 0% in
20 mg group). However, the compliance was similar in
both groups [18]. In order to avoid bias, we used the same
dose of esomeprazole (40 mg daily) and rabeprazole (20 mg
twice daily) in the eradication regimens. The patients
tolerated both regimens well and showed good compliance.

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High-dose esomeprazole (40 mg twice daily) has been

suggested during H. pylori eradication in Western
countries. However, the prevalence of CagA+ strains of
H. pylori is much higher among East Asians (> 80%),
including the Taiwanese [19] than that in of Caucasians
(~50%) [20,21]. Despite of difference in races and H. pylori
strains, we found compatible eradication rates using the
two regimens and this finding was similar to that Dupas
et al. had reported in France [6]. PPIs are affected by
CYP2C19 polymorphism to varied degrees. Esomeprazole
has minimal first pass metabolism, undergoes less hydroxylation via CYP2C19, and was shown to have greater
gastric acid suppression effect than omeprazole [22,23].
A recent meta-analysis study also indicated rabeprazole
was least affected by CYP2C19 polymorphism followed
by lansoprazole and omeprazole [11]. Although the
metabolism of rabeprazole and esomeprazole in human
could be different, we could not demonstrate a difference
in eradication efficacy in Taiwanese at a sample size of 420
and statistical power of at least 91%.
Based on our results, a 7-day triple therapy using either
rabeprazole 20 mg b.i.d. or esomeprazole 40 mg daily is
recommended as the first-line therapy for H. pylori
infection. It is well tolerated and the eradication rate is quiet
high (> 85% in both groups). For esomeprazole, splitting
doses is not necessary. A meta-analysis of rabeprazolebased therapies showed the eradication rate for the
regimen using rabeprazole 20 mg, amoxicillin 1 g, and
clarithromycin 500 mg b.i.d. for 7 days was 75 98%. No
difference was observed when extending the treatment
duration to more than 7 days (78% for 7 days vs. 75% for
10 days) or using a higher rabeprazole does (81% for
20 mg/day vs. 75% for 40 mg/day) [15]. However, our
study showed a much higher eradication rate (90.5%) using
high-dose (20 mg b.i.d.) rabeprazole-based therapy.
In conclusion, our study found no differences in eradication rates, compliance, and the incidence of adverse
events between rabeprazole- and esomeprazole-based
primary therapies for H. pylori infection in Taiwan.

Wu et al.

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This work was supported by grants from Kaohsiung Medical

University Hospital (93-ND-006) and Mackay Memorial Hospital
(MMH-KMU-05 and MMH-KMU-09).

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