In Patients with Gastroesophageal Reflux Disease
is Esomeprazole the most Effective Proton Pump Inhibitor
to Induce and to Maintenance of Mucosal Healing? A Systematic Review and
Meta-Analysis
Ana Lopes (ana_cplopes@hotmail.com); Andreia Pinto (muifilipa@hotmail.com); Catarina
Melo (clmelo@sapo.pt); Diogo Dias (diogo.diaz@hotmail.com); Isabel Saavedra
(ixabeu_xaavedinhah@hotmail.com); João Matias (joaomatias1@gmail.com); Mariana Ferreira
(yellowg_2@hotmail.com); Mariana Mangas (mariana_mangas@hotmail.com); Paula Neves
(paula_lotrfan@hotmail.com); Rita Sapage (rita.sapage@hotmail.com); Rui Coelho
(rui_pc_coelho@hotmail.com); Teresa Caridade (teresacaridade@msn.com); Teresa Tavares
(teresa_tavares5@hotmail.com)
Doctor Mário Dinis Ribeiro, Class 16
ABSTRACT
Introduction and Aim: Gastroesophageal reflux disease (GERD) is a chronic disease, which
impairs quality of life and has a high tendency to relapse, requiring a long term treatment strategy.
The pharmacological management of patients with GERD aims both to provide oesophageal healing
and induce symptom relief. Proton pump inhibitors (PPIs) are the current mainstay therapy, with
Esomeprazole being the most recent. Several studies focus potential discrepancies in efficacy among
the different PPIs used for treatment of GERD. The aim of this work is to compare efficacy of
esomeprazole in inducing and maintenance of mucosal healing in GERD patients, relatively to other
PPIs (omeprazole, lansoprazole, rabeprazole and pantoprazole). Methodology: A systematic review
and a metanalysis of RCT studies are performed. MEDLINE, SCOPUS and ISI Web of Knowledge
controlled trials register were searched up to December 2007. Clinical trials focused on Human adults
treated with PPIs were selected.The primary outcome of interest was inducing mucosal healing to a
specific PPI. Information on study design, participant characteristics, interventions, and results were
also extracted. Results: 12 trials were eligible in this study. 6 studies compared esomeprazole 20 mg
with omeprazole 20mg, lanzoprazole 15mg, rabeprazole 10mg and pantoprazole 20mg; while other 6
compared esomeprazole 40mg versus omeprazole 20mg, lanzoprazole 30mg and pantoprazole 40
mg. A meta-analysis of mucosal healing of esomeprazole 40mg compared with standard dose PPIs,
at 8 weeks, gave a relative risk (RR) of 1.57 and a 95% Confidence Interval (CI): 1.41 - 1.76. To
esomeprazole 20mg, at 24 weeks, the results were the following: RR 1.75; 95% CI 1.49 – 2.04.
Conclusions: As compared with other PPIs, esomeprazole appears to be the most effective Proton
Pump Inhibitor in inducing and maintenance of mucosal healing.
KEY-WORDS: Gastroesophageal Reflux Disease, Bile Reflux, Esophageal Motility Disorders,
esomeprazole, systematic review, esophagitis, Proton Pump Inhibitor.
INTRODUCTION
Gastroesophageal reflux disease (GERD) is a prevalent and chronic condition in which reflux
of the stomach contents into the oesophagus causes a range of troublesome symptoms (including
heartburn and acid regurgitation) and complications 1. Such symptoms can cause marked disruption
of physical, social and emotional well-being
2, 3
with possible long-term complications of GERD
including reflux oesophagitis, haemorrhage, stricture, Barrett’s oesophagus and adenocarcinoma of
the distal oesophagus 1, 4.
Heartburn, the most characteristic symptom of GERD, affects an estimated 20–40% of
Western populations, with approximately 7% experiencing daily symptoms 5. In Portugal 35% of
Portuguese adults refer GERD symptoms6. The prevalence of the disease tends to be
underestimated, with unrecognised GERD occurring in >50% of patients seen in general practice for
unrelated conditions 5. In fact, GERD is the most common condition encountered by pediatric and
adult gastroenterologists.
The pharmacological management of patients with GERD aims to provide symptom relief,
improved quality of life and protection from long-term complications 7. A number of drugs are
registered for GERD treatment, mainly: antacids, alginic acid, Histamine H2-receptor antagonists,
prokinetics, sucralfate and proton pump inhibitors.
Proton pump inhibitors (PPIs) are the mainstay of medical therapy in gastroesophageal reflux
disease. The site of action of the PPIs is the gastric acid pump (H+/K+ ATPase), which is the final
common pathway for acid secretion in the stomach. PPIs are a highly effective therapy for GERD and
its complications, and are the agents of choice for the suppression of gastric acid production 5. They
produce significantly faster and more complete relief of heartburn symptoms than H2RAs, as well as
healing erosive GERD significantly faster and with higher rates after 4 and 8 weeks of treatment 5.
PPIs also have more convenient dosing than most H2RAs; the approved standard dose of PPIs for
GERD treatment being once-daily.
In addition to symptomatic relief of heartburn, PPIs heal esophageal mucosal injury and
reduce the need for frequent dilatation in patients with peptic stricture. PPIs are highly selective and
effective in their action and have few short- or long-term adverse effects 7.
Currently, five PPIs are available on the market: omeprazole, lansoprazole, rabeprazole,
pantoprazole, and esomeprazole. Although all PPIs have the same general mechanism of action, the
nature of the pyridine and benzimidazole substituents may confer physical and chemical differences
and differ in their clinical pharmacology.
Esomeprazole, the S-isomer of omeprazole, is the new-generation PPIs and it has been
suggested it has superior pharmacologic and clinical effects compared with its racemic parent
compound. Moreover, some authors suggested that its administration offers several pharmacokinetic
advantages relatively to first generation PPIs. In subgroups, such as severe esophagitis,
esomeprazole may be more efficient than others PPIs 8. Quite the opposite, others authors demand
advantages in the use of old PPIs. Glatzel and colleagues demonstrate that pantoprazole 40 mg was
at least as effective as esomeprazole 40 mg for relieving GERD symptoms and during the post
treatment phase, patients on pantoprazole had a significantly lower risk to relapse and experienced
significantly fewer symptom episodes 9. In fact, despite PPI increasing use, up to 40% of patients are
not fully satisfied with their antireflux therapy 8.
Recent data on efficacy and safety are reviewed and causes of failure are discussed. Several
randomized studies dated until December 2007, have shown marginal differences in efficacy
between various proton pump inhibitor regimens.
While reports of treatment efficacy from clinical trials and qualitative reviews can guide clinical
decision-making, metanalysis reviews allow for an objective assessment of the overall magnitude of
treatment effects across a number of tests of treatment efficacy
10.
Currently, there are only eighteen
metanalyses about GERD, and only a few guide PPI treatment recommendations.
Although all PPIs have the same general mechanism of action, they have physical and
chemical differences; differences between them should be considered when choosing a treatment
regimen.
RESEARCH QUESTION
In patients with Gastroesophageal Reflux disease is Esomeprazole the most efficient Proton
Pump Inhibitor to induce and maintain mucosal healing?
AIM
The aim of this work is to use a systematic review to compare the efficacy of esomeprazole in
inducing and maintenance of mucosal healing in GERD patients, relatively to oldest PPIs,
omeprazole, lansoprazole, rabeprazole and pantoprazole.
PARTICIPANTS AND METHODS
The systematic review is a gliding revision to answer to a specific question and it uses explicit
and systematic methods critically to identify, select and to evaluate the studies. It also collect and
analyze the data of these enclosed studies in the revision. This method involves some different
stages:
1- Literature Search Strategy
An extensive literature search was conducted in PubMed, ISI Web of Knowledge and
SCOPUS from the first available year to December 2007. Searches were made using the following
queries, respectively to databases PubMed, ISI Web of Knowledge and SCOPUS:

(gastroesophageal "Gastroesophageal reflux OR Reflux"[Mesh non-esophagitis ] OR
GERD OR NERD OR reflux esophagitis disease OR) AND (regurgitation OR heartburn) AND
(randomized
controlled
trial[Publication
Type
]
OR
(randomized[Title/Abstract
]
AND
controlled[Title/Abstract ] AND trial[Title/Abstract ])) AND (omeprazole OR "Omeprazole"[Mesh ] OR
pantoprazole OR "pantoprazole"[Substance Name ] OR rabeprazole OR "rabeprazole"[Substance
Name ] OR lansoprazole OR "lansoprazole"[Substance Name ]) AND (esomeprazole OR
"Omeprazole"[Mesh ]) NOT ("Barrett esophagus" [ Mesh ])
 ((gastroesophageal reflux OR GERD OR NERD OR non-esophagitis reflux disease OR
esophagitis) AND (regurgitation OR heartbun) AND (omeprazole OR pantoprazole OR rabeprazole
OR lansoprazole) AND (esomeprazole) NOT (Barrett Syndrome))
 ((gastroesophageal reflux OR gerd OR nerd OR non-esophagitis reflux disease OR
esophagitis) AND (regurgitation OR heartbun) AND (omeprazole OR pantoprazole OR rabeprazole
OR lansoprazole) AND (esomeprazole) AND NOT (barrett syndrome)) AND (EXCLUDE(DOCTYPE,
"re") OR EXCLUDE(DOCTYPE, "cp"))
2 - Study Inclusion and exclusion Criteria
Each study selected for inclusion was original articles and clinical trials, focused on Human
adults (18 – 75 years) that were treated only with PPIs. Additionally, exclusion criteria were: previous
articles to the launching of esomeprazole, articles published from December of 2007, studies in
pregnant, studies in people with other illnesses beyond GERD.
3- Extraction and Data Processing
When analyzing each article, the type of study, methodology adopted, it aims and results, and
the type of PPI used were data considered. The number of initial participants of the study and the
amount of people who had abandoned it (as well as the reasons that had taken them to live) was
listed. The characteristics of the participants, as the ethnia, age, sex and physiological state
(example, gestation, menopause), their daily habits, their symptoms and the other medication taken
(beyond PPI) were also data analyzed.
Two reviewers code all studies for intervention and statistical information; all of the intervention
and outcome data was compared for consistency.
4 - Quality assessment
A quality evaluation was done to explain the difference of results between the studies and the
reason why they are excluded (quality scales). To do this CONSORT statement was used, which is
an evidence-based, minimum set of recommendations for reporting RCTs.
CONSORT statement comprises a 22-item checklist and a flow diagram, along with some brief
descriptive text. The checklist items focus on reporting how the trial was designed, analyzed, and
interpreted; the flow diagram displays the progress of all participants through the trial.
5 - Statistical Analysis
Data collected was analyzed and submitted to Statistical Package for Social Sciences (SPSS).
SPSS is a modular, tightly integrated, full-featured product line for the analytical process-planning,
data collecting, data access, data management and preparation, data analysis, reporting, and
deployment. In addition to statistical analysis, SPSS allow data management (case selection, file
reshaping, creating derived data) and data documentation.
In addition Review Manager (RevMan), a specific software for metanalysis, was used. RevMan
allows to enter protocols, as well as complete reviews, including text, characteristics of studies,
comparison table, and study data. It can perform meta-analysis of the data entered, and present the
results graphically. This software allows to calculate the relative risk (RR) with 95% confidence
intervals (95% CI), where a confidence interval that crosses the value 1.00 indicates no statistically
significant difference in treatment effects. A value >1.00 shows a benefit to Esomeprazole while a
value <1.00 shows a benefit for the comparator PPI.
5.1 - Analysis of data, heterogeneity and setbacks of publication
Concluding on measures of effect (average, relative risk...), applying a quantitative synthesis
of evidence through the goal-analysis, identifying heterogeneities causes that cannot be explained by
the variability of the sample.
RESULTS

Study selection
Figure 1. Results of a search on Pubmed, ISI Web of Knowledge and SCOPUS for RCT comparing Esomeprazole with
other PPIs.
Figure 1 shows the process of study selection. Using the queries defined previously to
databases Pubmed, ISI Web of Knowledge and SCOPUS, 158, 35 and 57 articles were available,
respectively, becoming a total of 250 articles. Of these, initially 28 articles had been excluded as
duplicates and after a pre-selection 115 articles were excluded because did not fulfill the explicit
requirements of inclusion criteria, mainly because clinical trials didn’t compare Esomeprazole with
other PPI. From the 99 included, 33 articles were not found published in full. After this pre-selection,
the abstract of each one of the 66 articles was read and selected, in accordance with the exclusion
and inclusion criteria, by two elements of the group (reviewers). This process resulted in the
reduction of the included article number to 12.
Study characteristics
The 12 articles selected were considered to be of sufficient quality to have data extracted for
inclusion in the analyses. Six studies compared esomeprazole 20 mg with different doses of
omesoprazole, lanzoprazole, rabeprazole and pantoprazole. Other six studies comparing
esomeprazole 40 mg with distinct doses of omeprazole, lanzoprazole and pantoprazole were eligible
for this systematic review (Table 1).
Eighteen different outcomes were measured across the domains of interest. Remission rate was the
domain from which mucosal healing was most frequently determined.
Table 1. Characteristics of RCTs reporting on the use of PPIs for prevention of mucosal healing.
Comparation
group
Number of
participants
Age of
participants
(min-max)
Duration of
treatment
(weeks)
Dose of
other PPI
(mg/day)
Results
(Esomeprazole/PPI)
(%)
1960
-
8
20
90/87
1391
>18*
24
15
85/75
774
[18,80]
24
15
93/88
134
[25,65]
4
10
88/96
236
[39;57]
24
20
79/68
1452
>19*
24
20
Esomeprazole 20mg
vs. omeprazole
vs. lansoprazole
vs. rabeprazole
vs.pantoprazole
Kahrilas PJ et al
200011
Lauritsen K et al
2003 12
Tsai HH et al
2004 13
Fock KM et al
2005 14
Scholten T et al
2003 15
Goh KL et al
2007 16
85/84
Esomeprazole 40mg
vs omeprazole
Chen CY et al
48
[36,72]
8
2005 17
Richter JE et al
2425
[18,75]
8
2001 18
Schmitt C et al
1946
[18,75]
8
2006 19
vs lansoprazole
Fennerty MB et
4015
[18,75]
8
al 2005 20
Castell DO et al
5241
[18,75]
8
2002 21
vs pantoprazole
Labenz J et al
3170
50,6**
8
2005 22
* in these studies, the maximum value was not fixed.
** in this study, the mean of the ages of the participants was the variable considerate.
20
72/50
20
94/84
20
87/86
30
78/73
30
93/89
40
92/89
Data analysis
Data for standard dose PPIs were combined and compared with esomeprazole. To analyze
the feature “healing”, studies with treatment duration of 8 weeks were considered. The feature
“maintenance” was examined in the studies of 24 weeks.
Because the reduced number of articles that compare esomeprazole 20 mg vs. old PPIs
during 8 weeks (only one), and the inexistence of studies that compare esomeprazole 40 mg vs. old
PPIs in a treatment of 24 weeks, theses analyzes were not done.
Relative efficacy of Esomeprazole 40 mg in Healing
To discuss healing, Esomeprazole 40 mg was compared with Lanzoprazole, Omeprazole and
Pantoprazole in treatment duration of 8 weeks (Fig. 2). Six studies were considered and RR ranged
between 1.10 and 2.36. 95% CIs for most studies are extensive, reflecting to some extent the small
sample sizes. Analyses show that Esomeprazole is more efficient in mucosal healing although there
is only a significant difference when compared with pantoprazole (Fig. 3).
Test for heterogeneity is statistical significative (p<0.00002) which may be for the reason of the
reduced number of articles analyzed (Fig. 2).
Figure 2. Relative risk (RR with 95% confidence intervals) of mucosal healing of Esomeprazole 40 mg vs. standard
doses of old PPIs.
Relative efficacy of Esomeprazole 20 mg in Maintenance
Esomeprazole 20 mg was compared with Lanzoprazole and Pantoprazole (Fig. 3).
Four studies were compared and RR ranged between 1.21 and 3.06. 95% CIs for most
studies are extensive, reflecting to some extent the small sample sizes. In this analyze test of
heterogeneity is statistical significative, p=0.00001 (Fig. 3). This result may result of the limited
number of articles evaluated.
Results obtained with RevMan show that Esomeprazole is more efficient in maintenance of
mucosal healing. Results, when compared with Lanzoprazole, are that Esomeprazole is statistically
significative more effective in the maintenance of mucosal healing. There are no statistical
significative differences between esomeprazole and pantoprazole, however the new generation PPI
tends to be better.
Figure 3. Relative risk (RR with 95% confidence intervals) of mucosal maintenance of Esomeprazole 20 mg vs. standard
doses of old PPIs.
.
DISCUSSION
GERD is a major healthcare problem in the adult population and has a significant negative
impact on patient quality of life and long- term complications. A number of PPIs have been approved
for the treatment of these conditions. Esomeprazole is the most recent PPI and its efficacy has been
object of many discussions. Some authors support it superiority relatively to older PPIs whereas
others demand advantages in the use of older PPIs. These discrepancies lead us to analyse and
compare the efficacy of esomeprazole in inducing and maintenance of mucosal healing in GERD
patients relatively to omeprazole, lansoprazole, rabeprazole and pantoprazole.
This meta-analysis showed a significant benefit in favour of esomeprazole at 8 and 24 weeks
relatively to pantoprazole and lansoprazole, respectively. Comparatively to omeprazole, results are
not statistical significative but apparently there is a tendency to esomeprazole be more effective in
healing of mucosal healing.
Unfortunately there are no articles comparing rabeprazole and esomeprazole in the healing
and maintenance of mucosal healing. However, it should be noted that a previous review
demonstrated no significant difference with rabeprazole 20 mg compared with omeprazole 20 mg at 4
weeks (RR 1.00; 95% CI: 0.87, 1.14; P ¼ 0.95) or at 8 weeks (RR 0.98; 95% CI: 0.91, 1.05; P ¼
0.55) 23.
A few systematic reviews about PPIs have been published, being the last one available in
2006 24. This research only analyzed six articles; therefore this review includes more information.
A potential limitation of this research is that it doesn´t analyze 33 articles that have been
selected because they were not found published in full. However, this review demonstrates the same
results that last ones. This fact and the results obtained lead us to consider that these articles will not
change the results obtained. Esomeprazole seems to be the most efficient Proton Pump Inhibitor to
induce and maintain mucosal healing.
Another restriction of this review is that it doesn’t analyse esomeprazole 40mg at 24 weeks of
treatment and either 20 mg at 8 weeks, due to the inexistence and reduced number of articles
describing it, respectively.
This systematic review should be viewed as promising evidence of Esomeprazole superiority,
and suggests that it is perhaps reasonable to use this PPI in routine care because of its efficiency in
healing and maintenance of mucosal injury.
CONCLUSION
Esomeprazole appears to be the most efficient Proton Pump Inhibitor to induce and
maintenance of mucosal healing. Once GERD is a chronic and prevalent disease that induces so
many long-term complications this result will be of extreme importance because it will allow to provide
symptom relief, improved quality of life and protection from long-term complications for GERD
patients.
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