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SUMMARY
Correspondence to:
S. C. Tan, Double Helix Consulting,
Asia Pacic, 40A Orchard Road, The
MacDonald House, #09-01,
Singapore 238838.
E-mail: tsengchuen@gmail.com
Aim
Publication data
Submitted 3 April 2013
First decision 16 April 2013
Resubmitted 7 May 2013
Accepted 7 May 2013
Ev Pub Online 29 May 2013
Background
Dexlansoprazole is a new proton pump inhibitor (PPI) with a dual delayed-release
system. Both dexlansoprazole and esomeprazole are an enantiomer of lansoprazole
and omeprazole respectively. However, there is no head-to-head trial data or indirect comparison analyses between dexlansoprazole and esomeprazole.
Methods
Randomised Controlled Trials (RCTs) comparing dexlansoprazole or esomeprazole
with either placebo or another PPI were systematically reviewed. Random-effect
meta-analyses and adjusted indirect comparisons were conducted to compare the
treatment effect of dexlansoprazole and esomeprazole using a common comparator. The relative risk (RR) and 95% condence interval (CI) were calculated.
Results
The indirect comparisons revealed signicant differences in symptom control of
heartburn in patients with NERD at 4 weeks. Dexlansoprazole 30 mg was more
effective than esomeprazole 20 mg or 40 mg (RR: 2.01, 95% CI: 1.153.51; RR:
2.17, 95% CI: 1.393.38). However, there were no statistically signicant differences
between the two drugs in EO healing and maintenance of healed EO. Comparison
of symptom control in healed EO was not able to be made due to different denitions used in the RCTs.
Conclusions
Adjusted indirect comparisons based on currently available RCT data suggested signicantly better treatment effect in symptom control of heartburn in patients with
NERD for dexlansoprazole against esomeprazole. No statistically signicant differences were found in other EO outcomes. However, these study ndings need to be
interpreted with caution due to small number of studies and other limitations.
Aliment Pharmacol Ther 2013; 38: 190201
190
METHODS
Identication of studies
We sought completed randomised controlled trials
reporting outcomes on the comparative efcacy and/or
safety of different PPI drugs for GERD. We searched for
randomised trials comparing dexlansoprazole or esomeprazole with placebo or any of the following drugs (as primary treatment): omeprazole, pantoprazole, lansoprazole
and rabeprazole. Eligible studies must be randomised
controlled trials that have compared dexlansoprazole or
esomeprazole with a common comparator, which could
be placebo or another PPI drug. In addition, the eligible
trials should have included patients with GERD (including EO or NERD) and reported the outcomes related to
healing data. Studies comparing treatment combinations
or only comparing different doses of a single drug were
excluded.
We identied studies by searching Medline, Embase
and Cochrane Library, scanning reference list of papers.
We found no other systematic reviews focusing on comparison of dexlansoprazole and esomeprazole for treatment of GERD. We included all the fully published
study in peer-reviewed journals written in English. See
Appendix S1, for full search strategies.
Data extraction
Two reviewers independently screened all the titles and
abstracts of the retrieved studies from the searches, and
then independently assessed the full articles of selected
trials, which were possibly eligible, to conrm whether
the studies met the inclusion criteria. The results were
checked and discussed by two reviewers, to agree upon a
nal list of included studies. Using a structured data collection form, all relevant data in each included paper
were extracted by two reviewers independently, and all
the data extracted were cross-checked.
For each included study, we extracted study identiers, characteristics of participants and interventions, outcomes reported and collected, sample size in each arm,
191
M. S. Wu et al.
numerical results and losses to follow-up. The Jadad
scale was employed for assessment of methodological
quality of included RCTs.15 The aspects that were independently assessed by two reviewers included study
design, method and appropriateness of randomisation,
status and method of double-blinding, and loss of follow-up. The range of Jadad score is from 0 to 5, the
study quality is high if the Jadad score is higher than 3;
otherwise, the study quality is low.
Outcomes
To assess the comparative efcacy of dexlansoprazole
and esomeprazole in healing EO, we analysed the complete healing rate of patients with baseline EO at Los
Angeles (LA) grade A, B, C and D at 8 weeks, as well as
that of subgroup patients with baseline EO at LA grade
C and D. Complete healing was dened as endoscopically conrmed healing with no mucosal breaks according to the LA classication.16
We evaluated the comparative efcacy in maintaining
healed EO over 6 months, which was dened as the
absence of EO conrmed by endoscopy at 6 months
after the patients received treatment. We intended to
analyse the comparative effect in symptom control (i.e.,
heartburn absence) at 6 months; however, we found that
the statistics from the RCTs were differently dened
between the trials that compared dexlansoprazole with
placebo and the trials that compared esomeprazole with
placebo; therefore, we were not able to perform the indirect comparisons for this outcome.
To compare the effect of dexlansoprazole and esomeprazole in relieving symptoms of NERD, we analysed the
number of patients with complete resolution of heartburn (symptom control) for short-term treatment
(4 weeks) of NERD. The complete resolution of heartburn was dened as no episodes of heartburn during the
last seven consecutive days of treatment, which was documented by the patients.
The choice of these outcomes for analyses was pragmatic, as they were the consistently dened and frequently reported common outcomes among the different
RCTs, making indirect comparisons possible and reliable
between dexlansoprazole and esomeprazole.
Statistical analyses
We assessed the homogeneity of the included RCTs by
their characteristics of PICOS participants, interventions, comparators, outcomes and study methods,17
RCTs with similar characteristics were included for
meta-analyses and indirect comparisons.18 We used the
192
RESULTS
Included studies and interventions
Our searches retrieved 438 studies and identied 17 relevant reports that described related randomised trials that
compared dexlansoprazole or esomeprazole with placebo
or another PPI drug as a common comparator (Figure 1).8, 10, 11, 2538 We excluded three studies from the
analyses for assessment of NERD healing because these
studies included the patients with and without EO, that
is to say, the study population included patients with
either
symptomatic
(non-erosive)
or
erosive
11, 29, 30
GERD.
We only included the studies that had
recruited the patients with endoscopically conrmed EO,
healed EO or NERD for analysing the treatment effect
on EO healing, maintenance of EO healing and symptom
relief of NERD separately. Furthermore, we excluded two
studies from the analyses for assessment of treatment
effect in NERD, because these studies only recruited
patients with well-treated NERD and therefore investigated the efcacy of esomeprazole in maintaining symptom relief of NERD (long-term management of patients
with NERD).34, 35 For NERD, only the studies that
assessed the treatment effect of dexlansoprazole or
Aliment Pharmacol Ther 2013; 38: 190-201
2013 John Wiley & Sons Ltd
Figure 1 | Flow chart of the inclusion process of the RCTs. From: Moher D, Liberati A, Tetzlaff J, Altman DG, The
PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement.
PLoS Med 6(6): e1000097. doi: 10.1371/journal.pmed1000097. For more information, visit www.prisma-statement.org.
esomeprazole for active NERD were included. Two studies had also been excluded from the analysis for treatment efcacy of NERD as one study only reported the
symptom control of nocturnal heartburn,27 and another
study only reported the symptom control at week 8,36 as
all other identied NERD studies assessed the treatment
effect for symptom control of complete resolution of
heartburn at week 4.
In addition, we also screened the RCTs that were
included in other systematic review publications of PPIs
for the same indications to rule out any missing relevant
RCTs in our systematic review. We identied 19 relevant
systematic review studies.13, 3956 We scrutinised the reference lists of all these studies and found one more relevant randomised trial (Figure 1).57
In total, 11 studies of randomised trials had been
included in our meta-analyses. Five studies assessed the
treatment effect for EO healing, of which, one study
compared dexlansoprazole with lansoprazole33 and four
studies compared esomeprazole with lansoprazole.9, 25, 38, 57 There were four studies that assessed the
Aliment Pharmacol Ther 2013; 38: 190-201
2013 John Wiley & Sons Ltd
M. S. Wu et al.
Table 1 | Comparisons for effect of complete EO healing at 8 weeks baseline LA grades A, B, C and D
Dexlansoprazole
60 mg
Study
Sharma P, 2009, 1
Sharma P, 2009, 2
Total
Pooled results
Heterogeneity
Events
Total
Events
Total
621
638
1259
673
685
1358
589
615
1204
684
672
1356
Study
Sharma P, 2009, 1
Sharma P, 2009, 2
Total
Pooled results
Heterogeneity
Lansoprazole
30 mg
Events
Total
Events
Total
613
645
1258
665
680
1345
589
615
1204
684
672
1356
Study
Lansoprazole
30 mg
Lansoprazole
30 mg
Events
Total
Events
Total
2430
123
62
2615
2624
138
65
2827
2324
127
60
2511
2617
139
67
2823
Indirect comparison
Dexlansoprazole 60 mg vs. Esomeprazole 40 mg
Dexlansoprazole 90 mg vs. Esomeprazole 40 mg
Events
Total
Events
Total
170
174
344
191
199
390
155
170
325
208
194
402
Study
Sharma P, 2009, 1
Shaima P, 2009, 2
Total
Pooled results
Heterogeneity
Lansoprazole
30 mg
Events
Total
Events
Total
160
178
338
191
191
382
155
170
325
208
194
402
Study
Lansoprazole
30 mg
Lansoprazole
30 mg
Events
Total
Events
Total
410
47
457
498
51
555
388
48
436
501
52
553
Indirect comparison
Dexlansoprazole 60 mg vs. Esomeprazole 40 mg
Dexlansoprazole 90 mg vs. Esomeprazole 40 mg
with placebo, while another trial compared dexlansoprazole 60 mg and 90 mg with placebo. Two trials compared
esomeprazole 40 mg and 20 mg with placebo. Meta-analyses showed that all the included PPI drugs with different
doses (including dexlansoprazole 30 mg, 60 mg and
90 mg, esomeprazole 20 mg and 40 mg) were superior to
placebo with signicant differences in maintaining healed
EO (Table 3). The calculations of indirect comparisons
found that there were no signicant differences between
any doses of dexlansoprazole and any doses of esomeprazole in maintenance of healed EO (Table 3).
Heterogeneity
Signicant heterogeneity appeared in the comparisons of
dexlansoprazole 60 mg with lansoprazole 30 mg
(I = 78% and 89%, respectively, in Tables 1 and 2) and
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M. S. Wu et al.
Table 3 | Comparisons of efcacy for healed EO over 6 months maintenance
Dexlansoprazole
30 mg
Study
Metz DC, 2009
Total
Pooled results
Heterogeneity
Placebo
Events
Total
Events
Total
103
103
137
137
39
39
145
145
Not applicable
Dexlansoprazole
60 mg
Study
Howden CW, 2009
Metz DC, 2009
Total
Pooled results
Heterogeneity
Placebo
Events
Total
Events
Total
138
126
264
159
153
312
36
39
75
140
145
285
Study
Howden CW, 2009
Total
Pooled results
Heterogeneity
Placebo
Events
Total
Events
Total
125
125
152
152
36
36
140
140
Not applicable
Esomeprazole
40 mg
Study
Johnson DA, 2001
Vakil NB, 2001
Total
Pooled results
Heterogeneity
Placebo
Events
Total
Events
Total
77
81
158
82
92
174
22
27
49
77
94
171
Study
Johnson DA, 2001
Vakil NB, 2001
Total
Pooled results
Heterogeneity
Events
Total
Events
Total
76
77
153
82
98
180
22
27
49
77
94
171
Indirect comparison
Dexlansoprazole
Dexlansoprazole
Dexlansoprazole
Dexlansoprazole
Dexlansoprazole
Dexlansoprazole
196
30
30
60
60
90
90
Placebo
mg vs. Esomeprazole 40 mg
mg vs. Esomeprazole 20 mg
mg vs. Esomeprazole 40 mg
mg vs. Esomeprazole 20 mg
mg vs. Esomeprazole 40 mg
mg vs. Esomeprazole 20 mg
Placebo
Events
Total
Events
Total
184
184
312
312
43
43
310
310
Not applicable
Dexlansoprazole
60 mg
Study
Fass R, 2009
Total
Pooled results
Heterogeneity
Placebo
Events
Total
Events
Total
129
129
307
307
43
43
310
310
3.03 (2.23,4.12)
3.03 (2.23,4.12)
Not applicable
Esomeprazole
40 mg
Study
Katz PO, 2003, 1
Katz PO, 2003, 2
Total
Pooled results
Heterogeneity
Placebo
Events
Total
Events
Total
62
57
119
123
118
241
37
24
61
124
118
242
Study
Katz PO, 2003, 1
Katz PO, 2003, 2
Total
Pooled results
Heterogeneity
Placebo
Events
Total
Events
Total
61
63
125
121
113
234
37
24
61
124
118
242
Indirect comparison
Dexlansoprazole
Dexlansoprazole
Dexlansoprazole
Dexlansoprazole
30
30
60
60
mg vs. Esomeprazole 40 mg
mg vs. Esomeprazole 20 mg
mg vs. Esomeprazole 40 mg
mg vs. Esomeprazole 20 mg
in the results of esomeprazole 20 mg compared with placebo (I = 72%, Table 4) between the results of trials
came from the same study with identical design and
similar patients characteristics, no explanation of the
heterogeneity observed. Signicant heterogeneity was also
found between the trials that compared esomeprazole
40 mg and lansoprazole 30 mg (I = 79%), but there was
no possible explanation as well (Table 2). There was no
statistically signicant heterogeneity in the other comparisons for the treatment effect of different PPI drugs.
Aliment Pharmacol Ther 2013; 38: 190-201
2013 John Wiley & Sons Ltd
DISCUSSION
In the context of health technology assessment, comparative evidence is usually required to assist in the formulary listing decision making. However, head-to-head
direct comparisons for evaluation of the treatment effect
are always not available; the method of adjusted indirect
comparison has then been developed and increasingly
used across different therapy areas.22, 58 Although there
remain methodological controversies of indirect comparison,24, 59, 60 and sometimes the data were limited,58 the
197
M. S. Wu et al.
Bucher method has been widely recognised and accepted
for indirect comparison as it maintains the power of randomisation in the original trials when calculating the
magnitude of the treatment efcacy.22 Nevertheless, it is
always worthy to note that the comparative efcacy generated through indirect comparisons needs to be interpreted with caution due to the factors such as the
number of studies included in the analysis often tends to
be small, study population heterogeneity, variation in
study design, etc.60
The quality of included studies in our systematic
review was mostly high, with a Jadad score 45 (Appendix S2), although the data available for the analyses were
limited only 11 RCTs were eligible to be included in
the meta-analyses and indirect comparisons partly due
to the discrepancy in denitions of participants, interventions, comparators and outcomes in different RCTs,
our systematic review and data syntheses have still
strictly evaluated the evidence currently available for the
comparative effect of dexlansoprazole vs. esomeprazole
in the treatment of GERD.
In the included RCTs in this presented systematic
review, all direct comparisons of the newly developed PPI
drug dexlansoprazole with placebo or lansoprazole
showed greater effectiveness of dexlansoprazole in treatment of NERD or EO. The method of adjusted indirect
comparison was further employed to compare dexlansoprazole with esomeprazole in the treatment efcacy for
NERD or EO; the indirect comparisons demonstrated
higher rate with signicant difference of symptom control
in favour of dexlansoprazole 30 mg vs. esomeprazole
20 mg or 40 mg in treating active NERD at 4 weeks,
although there were not statistically signicant differences
between dexlansoprazole and esomeprazole in other outcomes for treatment of EO. However, these ndings could
not be interpreted without considering the common limitations of an indirect comparison study as highlighted
above. Besides, compared with the study endpoint of EO
studies, which is always based on endoscopy examination,
patient-reported outcome endpoint for NERD studies
tends to be less objective introducing an additional degree
of uncertainty in study results.61 This probably explains
the observation of higher symptom control rate for dexlansoprazole 30 mg than dexlansoprazole 60 mg vs. placebo among the NERD patients reported in Fass R,
et al.26 The same was observed between esomeprazole
20 mg and 40 mg in another clinical study on NERD.31
Both of these studies were included in our analyses.
On a separate note, in a switching study, after stepping down from a twice-daily therapy with different PPIs
198
CONCLUSIONS
Adjusted indirect comparisons based on currently available randomised controlled trials suggested that patients
treated with dexlansoprazole 30 mg would have higher
rate with signicant difference of symptom control than
esomeprazole 20 mg or 40 mg in the management of
NERD at 4 weeks, although there were no statistically
AUTHORSHIP
Guarantor of the article: S.C. Tan.
Author contributions: M.S. Wu and S.C. Tan developed
the study objective and scope, search strategy and conducted selection of included studies and outcomes
measures and data extraction. S.C. Tan and T. Xiong
did preliminary literature search and statistical analyses. The manuscript was reviewed and agreed by all
co-authors. All authors approved the nal version of
the manuscript.
ACKNOWLEDGEMENT
Declaration of personal interests: M.S. Wu has served as
a speaker for Astra Zeneca and Takeda as well as a consultant for ALDEA Pharmaceuticals. S.C. Tan has served
as a consultant for Bayer, GlaxoSmithKline, Leo Pharma,
Merck Sharp Dohme, Millennium, Novo Nordisk, Pzer
and Takeda.
Declaration of funding interests: This study was funded
in part by Takeda Pharmaceutical Company Limited.
Funding was not contingent upon publication of the
manuscript. None of the authors holds stocks or shares
in Takeda. No patents have been applied for relating to
the content of the manuscript. None of the authors has
any other nancial or nonnancial competing interests.
SUPPORTING INFORMATION
Additional Supporting Information may be found in the
online version of this article:
Appendix S1. Search strategy.
Appendix S2. Study characteristics of included RCTs.
Appendix S3. Study design of included RCTs.
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