|
Chih-Yen Chen,
Ching-Liang lu, Jiing-Chyuan
Luo, Full-Young Chang,
Shou-Dong Lee, Division of Gastroenterology, Department
of Medicine, Taipei Veterans General Hospital and School of
Medicine, National Yang-Ming University, Taipei, Taiwan, China
Yung-Ling Lai, AstraZeneca Taiwan Limited, Taipei, Taiwan,
China
Supported by the Research Foundation of Digestive Medicine,
Taiwan, China
Correspondence to: Full-Young Chang, MD, Chief, Division of
Gastroenterology, Taipei Veterans General Hospital, No. 201, Sec. 2,
Shih-Pai Road, Taipei 112, Taiwan, China.
changfy@vghtpe.gov.tw
Telephone: +886-2-28757308
Fax: +886-2-28739318
Received: 2004-05-12
Accepted: 2004-06-29
Abstract
Aim: Esomeprazole,
an oral S-form of omeprazole, has been a greater acid inhibitor over
omeprazole in treating acid-related diseases. Only less published
data is available to confirm its efficacy for Asian people.
Therefore, a perspective, double-blind, randomized comparison of
esomeprazole tablets 40 mg (Nexiumâ)
vs omeprazole capsules 20 mg (Losecâ)
in treating Chinese subjects with erosive/ulcerative reflux
esophagitis (EE) was conducted.
Methods: A
total of 48 EE patients were enrolled and randomized into two
treatment groups under 8-wk therapy: 25 receiving esomeprazole,
while another 23 receiving omeprazole treatment. Finally, 44
completed the whole 8-wk therapy.
Results: The
difference in healing EE between two groups was 22.7% (72.7% vs
50.0%), not reaching significant value (P = 0.204). The
median of the first time needed in relieving heartburn sensation was
1 d for both groups and the remission rates for heartburn on the 1st
d after treatment were 77.3% and 65%, respectively (NS). The scores
of various reflux relieving symptoms evaluated either by patients or
by investigators were not different. Regarding drug safety, 28% of
esomeprazole group and 26.1% of omeprazole group reported at least
one episode of adverse effects, while constipation and skin dryness
were the common side effects in both groups (NS).
Conclusion:
Esomeprazole 40 mg is an effective and safe drug at least comparable
to omeprazole in treating Chinese EE patients.
© 2005 The WJG Press and Elsevier Inc. All rights reserved.
Key words: Esomeprazole; Someprazole; Esophagitis
Chen CY, lu
CL, Luo JC,
Chang FY, Lee SD,
Lai YL. Esomeprazole tablet vs omeprazole capsule in
treating erosive esophagitis. World J Gastroenterol
2005; 11(20): 3112-3117
http://www.wjgnet.com/1007-9327/11/3112.asp
INTRODUCTION
The reflux of gastric acid and duodenal contents into esophagus
is a normal physiological phenomenon. However, the sustained
esophageal mucosal damage, e.g. erosive/reflux esophagitis induced
by this kind of reflux, may happen when the normal esophageal
clearance and mucosal protection ability are impaired[1].
Gastroesophageal reflux disease (GERD) refers to individuals who are
exposed to the physical complications from this reflux, or who
experience clinically significant impairment of healthy well-being
and quality of life due to reflux-related symptoms[2].
Today, prompt and effective relief of GERD symptoms is the primary
goal for these patients. Since acid has been the major pathogen
leading to reflux-associated symptoms, current GERD treatment is
mainly aimed to reduce the acid exposure to esophagus[3,4].
For example, omeprazole (Losecâ),
the first proton pump inhibitor (PPI) showing an effective acid
inhibitory ability, provides the satisfactory therapy either in GERD
symptom relief or in healing of erosive esophagitis[5-7].
The modified formulation of omeprazole, multiple unit pellet system,
remains effective in healing and relieving symptoms in GERD patients[8].
Up to date, omeprazole efficacy and safety are well established in
many trials because more than 600 million patients have used
omeprazole capsules worldwide including Taiwan[9,10].
Esomeprazole (Nexiumâ),
the new S-isomer of omep-razole, is introduced to reduce gastric
acid secretion more efficiently[9].
Unlike omeprazole, pharmacodynamic data suggest that the metabolism
of esomeprazole in human liver microsomes is less dependent on
CYP2C19 but mainly via CYP3A4[11].
Based on this observation, perhaps the inter-individual variation of
esomeprazole metabolism is less compared to omeprazole[12].
In addition, studies have pointed out that esomeprazole exhibits
significantly higher bioavailability, leading to the greater
inhibition of gastric acid secretion compared to omeprazole[11,13].
Accordingly, many studies conducted in Western countries have
confirmed the superior efficacy of esomeprazole over omeprazole in
treating GERD patients[9,14].
GERD appears less common in East Asian
countries compared to Western ones[15,16].
It is of interest to know the reason for the efficacy of
esomeprazole in Asian GERD patients. Kao et al.[17],
indicated that esomeprazole achieved 68-73.9% sustained symptomatic
response rate for GERD patients in an on-demand therapy trial. Based
on the study design of a double-blind, randomized and controlled
trial, the purpose of our study was to compare the efficacy and
safety of esomeprazole tablet 40 mg and omeprazole capsule 20 mg in
treating patients with endoscopically confirmed reflux esophagitis
(EE) enrolled in a single center. Our primary objective was to
assess the EE healing rate using both agents by an 8-wk treatment
period. While the secondary objectives were to compare the response
of reflux symptoms and general well-being by both agents at wk 4 and
8, respectively, to compare the time needed to relieve heartburn by
both agents, and to evaluate the tolerability and safety of both
agents.
MATERIALS AND METHODS
Design and study population
This was an active-controlled, double-blinded, double-dummy,
randomized, single-center study with a parallel group designed to
enroll 48 EE patients. Forty-eight outpatients (M/F: 38/10,
age: 54.1±17.8 years), who sought medical care because of typical
GERD symptoms for at least 1 mo, were consecutively enrolled in the
study. They all received an endoscopy to confirm the EE diagnosis
according to Los Angeles (LA) grading system[18],
and met an inclusion criterion for an 8-wk treatment period with
either esomeprazole tablet 40 mg or omeprazole capsule 20 mg (AstraZeneca,
Gothenburg, Sweden). While endoscopy specimens were simultaneously
obtained from stomach antrum and body for a rapid urease test to
determine Helicobacter pylori infection. Those subjects with
the following conditions were excluded: coexistence of healed or
active peptic ulcer, gastrointestinal malignancy, esophago-gastric
surgical history, esophagitis obviously resulted from systemic
diseases, infections, drugs, burn, radiotherapy or physical
deformity, severe esophageal stricture requiring dilatation at first
endoscopy or expectation of requiring dilatation during the study,
recent PPI treatment within 8 d prior to endoscopy, or using PPIs
for more than 5 d in the last 28 d prior to endoscopy, with H
pylori eradication therapy within the last 28 d prior to
randomization or at any time during the study, using other
antisecretory or prokinetic agents between endoscopy and
randomization or at any time during the study, or with any
investigational (non-approved) drug during the last 30 d prior to
randomization. In addition, those with severe concurrent diseases
judged by the investigators to complicate the evaluation of the
trial, pregnancy, lactation or child-bearing potential without
adequate contraception (contraceptive pill or intrauterine device),
chronic alcoholism, drug abuse or any other conditions associated
with poor patient compliance including expected non-co-operation,
previous randomization in the study, and patients who needed
continuously concomitant therapy with anticholinergics, cisapride,
prostaglandin analogs, non-steroidal anti-inflammatory drugs
(including COX-II) and aspirin (excluding low-dose aspirin e.g. 100
mg, as anti-platelet) were also excluded from this study. This study
was approved by the Ethical Committee of Taipei Veterans General
Hospital and carried out in accordance with the World Medical
Association Helsinki Declaration. Written informed consent was
obtained before any study-related procedures were performed.
The GERD symptoms such as heartburn, acid
regurgitation, epigastric/chest pain, belching, nausea, vomiting and
global well-being were assessed based on a standard visual analog
scaled (VAS) questionnaire. Study medication was administered only
to those subjects included in this study, following the procedures
set out in the clinical study protocol. A sequence of patient
numbers was assigned to the study center. All subjects entering the
study received a patient number. This patient number was printed on
the case report form and was used to identify the subject throughout
the study. A randomization schedule was generated by the AstraZeneca
using a validated system that automated the random assignment of
treatment groups according to the randomization numbers. This
schedule linked sequential numbers to treatment codes allocated at
random. The schedule was prepared with a 1:1 randomization ratio in
block size of 4. The study medication was labeled with the
randomization numbers (medication numbers). At the end of baseline
visit, eligible patients were randomized to the study medication in
accordance with the randomization schedule. The next eligible
subject received the study medication with the lowest available
randomization number. Each subject was given only the study
medication carrying his/her randomization number. The investigator
documented the randomization number by sticking the label provided
on the appropriate case report form. Subjects who permanently
discontinued from the study were to retain their subject number and
their randomization number, if already given. New subjects were
always allotted a new subject number and, if applicable, a new
randomization number.
Patients were asked to come back to the study
office on three occasions (baseline, wk 4 and 8, respectively)
during the trial. All doses were taken by mouth once daily in the
morning before breakfast. During the study period, the patients were
instructed to take one tablet of esomeprazole or matching placebo
and one capsule of omeprazole or matching placebo in the morning
with a glass of water. The first dose of study medication was taken
on the morning after randomization. This was considered as d 1 of
treatment. After the whole course of treatment, they were asked to
come back on the last day of medication. At that time, they received
the 2nd endoscopy
to assess the EE status again. Meanwhile GERD symptoms based on VAS
after treatment were scored again. All the endoscopic EE diagnoses
and their follow-up according to LA grading were initially performed
by an experienced endoscopist (Chang), while all the endoscopic
findings including EE were recorded by Polaroid films. When all the
studies were completed, the recorded films assigned to their study
codes were reviewed independently by another two endoscopists (Lu
and Chen) who were blind to the order and code of endoscopy for each
patient. If three readings in each film were dissimilar, this film
was discussed by the above three investigators together to obtain
the final endoscopic assessment. Healing was defined as no EE
evidence.
Efficacy data
The primary endpoint of this trial was the percentage of enrolled
patients whose EE was healed by wk-8 visit. The secondary efficacy
variables included for the first time the relief of heartburn
symptoms, changes of reflux symptom scores (based on VAS score) and
overall therapeutic effects judged via either subjective (patient)
or objective (investigator) assessment.
Safety data
The safety assessments included observed and reported adverse events
(AE) and clinical laboratory evaluations (hematology and serum
chemistry).
Study duration and dates
The study took place between 28 March, 2001 and 26 October, 2001.
Statistical procedures
For the primary efficacy parameter, the healing rate for each group
was calculated with 95%CI. The difference between the two treatment
groups and the corresponding 95%CI were also provided and compared
by using Fisher’s exact test. The cumulative percentage of
patients who exhibited the first relief of their diary-recorded
symptom of heartburn was compared using Fisher’s exact test on d
1, 7, and 28, respectively. The median first time to relieve
heartburn symptom between the two groups were compared using
log-rank test. For reflux symptoms, Wilcoxon rank sum test was used
to assess patient VAS score, and Fisher’s exact test was used to
assess investigator scores as well as the overall therapeutic
effect.
AE were summarized according to coding symbols
for thesaurus of adverse reaction terms. The number of patients who
reported a particular event and the number of events were
summarized. Comparative incidence of AE was evaluated using
Fisher’s exact test. Each laboratory parameter was listed with
values outside the reference range identified. For each laboratory
parameter, changes in abnormality/normality status from pre- to
post-treatment were summarized in shift tables and assessed using
McNemar test.
Interim analysis
No interim analysis was performed in this study.
RESULTS
Study subjects and conduct
Finally, 48 eligible EE patients were enrolled and randomized
according to the protocol. Their demographics and baseline
characteristics are summarized in Table 1. Of them, 25 patients were
distributed into esomeprazole group whereas 23 patients were on
omeprazole treatment. Table 1 illustrates that both groups were
comparable in their demographic characteristics and basal clinical
manifestations except the subjects of esomeprazole group had a
higher chance of belching (P<0.05). Among the 48
randomized patients, only 44 (esomeprazole: 24; omeprazole: 20)
completed the whole study course. The reasons why four of them did
not finish the trial were as follows: two lost their follow-up and
another two discontinued the study medication. In addition, 2 (all
were esomeprazole) of 44 who finished the study refused endoscopy
follow-up at wk-8 visit were excluded from per protocol analysis.
Table 1 Demographics
and baseline characteristics of erosive esophagitis patients treated
with esomeprazole or omeprazole (mean±SE)
| |
Esomeprazole
40 mg n = 25 |
Omeprazole
20 mg n = 23 |
P |
| Age
(yr) |
49.2±3.7 |
59.0±3.4 |
0.0596 |
| Sex
(male%) |
20
(80) |
18
(78.3) |
1.0000 |
| Body
weight (kg) |
68.4±2.4 |
70.9±2.5 |
0.4779 |
| Height
(cm) |
166.7±1.3 |
169.0±1.4 |
0.2096 |
| Basal
reflux symptoms (VAS) |
|
|
|
| Heartburn |
29.4±5.7 |
23.6±5.9 |
0.2683 |
| Nausea |
18.7±5.5 |
13.8±5.8 |
0.8520 |
| Regurgitation |
29.8±6.1 |
24.5±6.4 |
0.3365 |
| Vomiting |
14.0±4.7 |
8.8±4.9 |
0.5702 |
| Belching |
47.0±6.0 |
25.2±6.3 |
0.0121 |
| Dysphagia |
7.5±5.0 |
14.7±5.2 |
0.7421 |
| Epigastric
pain |
15.8±5.5 |
16.7±5.8 |
0.9223 |
| LA
grade of erosive esophagitis [n (%)] |
|
|
0.6617 |
| A |
15
(60) |
11
(47.8) |
|
| B |
7
(28) |
7
(30.4) |
|
| C |
2
(8) |
2
(8.7) |
|
| D |
1
(4) |
3
(13.0) |
|
| Hp
infection status |
10
(40) |
11
(47.8) |
0.5643 |
VAS: visual
analog scale, scored from 0 (none) to 100 (most severe); Hp: Helicobacter
pylori; LA: Los Angeles.
Efficacy
The EE healing rates of esomeprazole and omeprazole treatment judged
at the end of 8-wk trial [per-protocol (PP)] were 72.7% (16/22,
95%CI: 49.8-89.3%) and 50.0% (10/20, 27.2-72.8%) respectively
[intent-to-treat (ITT): 64% (16/25, 95%CI: 44.3-83.8%) vs
45.5% (10/22, 95%CI: 22.7-68.3%), P = 0.2481], while the odds
ratio was 2.667 (PP: 95%CI: 0.739-9.63, P = 0.2040) for
esomeprazole over omeprazole.
In order to understand whether esomeprazole was
effective in reducing LA-based EE grading, we further analyzed their
extent of changed grading for both groups, e.g. 0 (no change), -1 (A
to healed, B to A, C to B and D to C), -2 (B to healed, C to A and D
to B) and -3 (C to healed, D to A), respectively (Figure 1).
Although esomeprazole showed a better healing ability, however, no
significant difference was found.
The median time to the first relief of heartburn
between esomeprazole and omeprazole groups was similar on d 1 after
treatment. On d 1, 77.3% and 65% of EE patients recorded the first
relief of heartburn, respectively (Figure 2). Table 2 denotes that
esomeprazole treatment was not significantly different from
omeprazole in any of improved GERD symptom scores evaluated by
patients themselves based on VAS except belching improvement was
marked in patients undergoing esomeprazole treatment (P<0.05).
Table 3 illustrates that the therapeutic symptomatic response scores
of both treatments were similar (NS).
Figure 1
(PDF) Histogram
showing endoscopic assessment for the improved LA grading in erosive
esophagitis patients after esomeprazole or omeprazole treatment.
Grade of improvement: -3 means D to A or C to healed, -2 means D to
B, C to A, or B to healed, -1 means D to C, C to B, B to A, or A to
healed.
Figure 2
(PDF) No cumulative percentage difference in relieving
heartburn between erosive esophagitis patients after esomeprazole or
omeprazole treatment illustrated by scattering plot.
esomeprazole,
omeprazole.
Table 2 Changes of
reflux symptoms assessed on visual analog scale of studied patients
8 wk after esomeprazole or omeprazole treatment (mean±SE)
| Reflux
symptoms |
Esomeprazole
n = 22 |
Omeprazole
n = 22 |
P |
| Heartburn |
-22.3±2.1 |
-21.4±2.2 |
0.5453 |
| Nausea |
-11.9±2.2 |
-12.7±2.4 |
0.8867 |
| Regurgitation |
-22.4±2.2 |
-20.4±2.3 |
0.8598 |
| Vomiting |
-9.1±1.61 |
-8.8±1.7 |
0.4438 |
| Belching |
-24.1±4.3 |
-17.9±4.6 |
0.0113 |
| Dysphagia |
-8.4±1.4 |
-6.5±1.5 |
0.8044 |
| Epigastric
pain |
-10.6±2.0 |
-11.1±2.1 |
0.1747 |
VAS was scored
from 0 (none) to 100 (most severe).
Table 3 Changed
reflux symptoms of studied patients 8 wk after esomeprazole or
omeprazole treatment (%)
| |
|
Esomeprazole (n = 22) |
Omeprazole
(n = 20) |
P |
| Heartburn |
Improved |
50.0 |
65.0 |
0.0993 |
| |
No
change |
50.0 |
25.0 |
|
| |
Worse |
0.0 |
10.0 |
|
| Regurgitation |
Improved |
77.3 |
85.0 |
1.0000 |
| |
No
change |
18.2 |
15.0 |
|
| |
Worse |
4.5 |
0.0 |
|
| Dysphagia |
Improved |
36.4 |
35.0 |
0.8697 |
| |
No change |
63.6 |
60.0 |
|
| |
Worse |
0.0 |
5.0 |
|
| Epigastric
pain |
Improved |
27.3 |
50.0 |
0.1895 |
| |
No
change |
63.6 |
50.0 |
|
| |
Worse |
9.1 |
0.0 |
|
| Nausea |
Improved |
22.7 |
35.0 |
0.5036 |
| |
No
change |
68.2 |
65.0 |
|
| |
Worse |
9.1 |
0.0 |
|
| Vomiting |
Improved |
22.7 |
40.0 |
0.3200 |
| |
No
change |
77.3 |
60.0 |
|
| |
Worse |
0.0 |
0.0 |
|
| Belching |
Improved |
54.5 |
45.0 |
0.8999 |
| |
No
change |
36.4 |
45.0 |
|
| |
Worse |
9.1 |
10.0 |
|
Safety
In general, EE patients receiving esomeprazole (28.0%) and
omeprazole (26.1%) treatment reported AE at least once during the
trial (NS). Among them, constipation, dry skin sensation, diarrhea,
headache, somnolence, etc., were the recorded AE in both
groups (Table 4). Their distributions were also not different. Only
one patient in omeprazole group reported a serious adverse event of
cellulites during the treatment period, this causal relationship to
treatment was judged to be unrelated. In addition, there were no
clinically meaningful differences between treatment groups in terms
of changed laboratory values or physical examinations.
Table 4 AE in
studied patients 8 wk after esomeprazole or omeprazole treatment
(ITT)
| |
Esomeprazole
(n = 25) n
(%) |
Omeprazole
(n = 23) n
(%) |
P |
| Patient
with at least one AE |
7
(28.0) |
6
(26.1) |
1.0000 |
| Constipation |
2
(8.0) |
1
(4.4) |
1.0000 |
| Dry
skin |
1
(4.0) |
3
(13.0) |
0.3381 |
| Diarrhea |
1
(4.0) |
1
(4.4) |
1.0000 |
| Headache |
1
(4.0) |
1
(4.4) |
1.0000 |
| Somnolence |
1
(4.0) |
1
(4.4) |
1.0000 |
| Cellulites |
0
(0.0) |
1
(4.4) |
0.4792 |
| Bronchitis |
0
(0.0) |
1
(4.4) |
0.4792 |
DISCUSSION
Our study mainly indicated that both esomeprazole and omeprazole
were similarly effective in healing EE, relieving reflux symptoms
for the Chinese EE patients in Taiwan. Gastro-esophageal
reflux-induced EE is one of the GERDs, which ranges from endoscopy
negative reflux to severe complications of Barrett’s esophagus as
either high-grade dysplasia or adenocarcinoma[19,20].
Unlike endoscopy negative reflux, EE is very easily identified in
GERD subjects based on experienced endoscopy. Until now, EE
treatment is similar to any kind of GERD, e.g. reducing acid reflux,
healing erosive lesions and preventing future relapse[2].
The EE severity is usually related to the extent
and time of esophageal acid exposure[22].
It means the greater the acid exposure the severe the mucosal
damage. Among the refluxed contents, acid is the most important
pathogen leading to GERD, while effective acid reduction remains the
only available method to treat GERD at this moment[2,22,23].
Accordingly, effective acid control for GERD subjects likely results
in faster resolution of reflux symptoms, healing of reflux lesions
quickly, better response of those with severe lesions and less
frequent relapse. Symptom relief is indeed very important to all
GERD patients because these symptoms usually bother their daily
quality of life. Now step down treatment for GERD patients beginning
with an effective PPI was recommended by the Genval consensus[2].
Although many of our studied GERD patients had mild EE, however,
they still complained of cardinal reflux symptoms and other
reflux-related symptoms. After 1 d of active esomeprazole and
omeprazole treatment, 77.3% and 65% of patients recorded their first
relief of heartburn. After 8-wk treatment, the VAS scores of many
reflux symptoms were improved in both groups. In addition, the
objective ranking of overall therapeutic effect showed a favorable
and comparable result in both groups. We thus confirmed that 40 mg
esomeprazole and 20 mg omeprazole daily for 8 wk could offer a
sufficient acid suppression leading to the effective symptomatic
relief for Asian EE patients without serious AE.
Benefits have been demonstrated in studies of
esomeprazole vs omeprazole and lansoprazole[15,25-27].
Our study was to compare the therapeutic efficacy of a single isomer
PPI, esomeprazole and omeprazole in treating EE patients in Taiwan.
In fact, we found that EE was finally healed in more than half of
our enrolled patients after 8-wk treatment. This EE healing rate was
obviously lower than that in previous reports (67-85%) using PPI for
a similar duration[5-7,28-33].
It has been pointed out that EE is usually less commonly presented
and milder in nature among the Orientals in comparison with
Occidentals[28-35].
In our study, the EE severity scored via LA grading system among the
48 consecutively enrolled patients was mainly classified as LA grade
A, whereas previous reports from Western studies often included EE
patients with an advanced grade[5-7,15-18,22-24].
Theoretically, our study should provide a better efficacy since many
of the enrolled subjects had mild EE in nature. Surprisingly, we
obtained a lower EE healing efficacy based on the similar PPI for a
similar therapeutic duration. It is unknown whether the ethnic
factor compromises the therapeutic efficacy. For example, PPI
treatment for GERD patients only achieved 57.7% and 77% healing
rates in two Japanese group studies, respectively[36,37].
Because our study was a single center trial and only enrolled a
limited number of eligible EE patients, we believe that the lower
and indistinguishable efficacy of esomeprazole vs omeprazole
treatment was most likely originated from a type II error of
inadequate study power, which was common in many drug trial studies[38,39].
In addition, long-term management of EE patients with PPI maybe more
meaningful since initial management of EE patients to achieve
healing has been overemphasized[40].
In summary, esomeprazole is at least similar to
omeprazole in healing EE and removing reflux-related symptoms. Both
esomeprazole and omeprazole are safe and well tolerated by Asian EE
patients.
ACKNOWLEDGMENTS
The authors thank Jack Chai, MS, for his secretarial assistance.
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