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Alimentary Pharmacology and Therapeutics

Indirect comparison of randomised controlled trials:


comparative efcacy of dexlansoprazole vs. esomeprazole in
the treatment of gastro-oesophageal reux disease
M. S. Wu*, S. C. Tan & T. Xiong

*Department of Internal Medicine,


Taiwan National University, Taipei,
Taiwan.

Double Helix Consulting, Asia Pacic,


Singapore.

School of Clinical Medicine,


University of Cambridge, Cambridge,
UK.

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.

To compare the efcacy of dexlansoprazole with esomeprazole in healing erosive


oesophagitis (EO), the maintenance of healed EO and the treatment of non-erosive
reux disease (NERD).

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

2013 John Wiley & Sons Ltd


doi:10.1111/apt.12349

Indirect comparison: dexlansoprazole with esomeprazole in GERD


INTRODUCTION
Gastro-oesophageal reux disease (GERD) is a common
medical condition with abnormal reux of gastric contents into the oesophagus.1, 2 The most common symptoms of GERD include heartburn and regurgitation,
which affects about 1020% of the population in western
countries3, 4; especially, 1520% of the population in the
US are suffering GERD symptoms at least weekly.5, 6
According to the manifestations of mucosal damage of
the oesophagus conrmed by upper endoscopy, GERD is
further categorised as erosive oesophagitis (EO) and
non-erosive reux disease (NERD) the EO patients are
diagnosed with a positive endoscopy, whereas the NERD
patients only have the condition symptoms without the
presence of oesophageal abnormalities by endoscopy.7
Among the patients with GERD, EO accounts for about
30% and NERD accounts for about 70%.8
Esomeprazole is a proton pump inhibitor (PPI) that
has been widely used for the treatment of GERD.
Numerous randomised controlled trials (RCT) had demonstrated that it is effective and well tolerated in healing
EO and relieving symptoms of NERD, as well as maintenance of healed EO.911
Dexlansoprazole is the most recently developed PPI
drug, which had been approved by the US Food and
Drug Administration (FDA) on 30 January 2009.12 Dexlansoprazole has a novel dual delayed-release system for
the treatment of heartburn associated with NERD, healing of all grades of EO, and maintenance of the healed
EO.12, 13
A recent pH comparator study in healthy subjects
showed that for the entire 24-h postdose period following a single dose of dexlansoprazole 60 mg, the average
intragastric pH = 4.3, which was higher than the result
observed following a single dose of esomeprazole 40 mg
(average pH = 3.7), and the difference was statistically
signicant
(P < 0.0001).
Statistical
signicance
(P = 0.003) was also found in the difference in the mean
percentage of time with intragastric pH >4 with 58% for
dexlansoprazole and 48% for esomeprazole.14 It is not
clear, however, how these would mean in terms of clinical outcomes differences between the two treatments
among the GERD patients.
There is no RCT, to date, directly compared dexlansoprazole with esomeprazole for efcacy in treatment of
GERD. We therefore performed a systematic review and
indirect comparison of RCTs to assess the relative effectiveness between dexlansoprazole and esomeprazole in
the management of GERD.

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2013 John Wiley & Sons Ltd

In the situation of indirect comparison, we rst need


to identify studies of RCTs that directly compared dexlansoprazole with placebo and esomeprazole with placebo. By applying statistical methods, we then could use
the placebo as a common comparator to perform an
indirect comparison of dexlansoprazole and esomeprazole. The common comparator could also be another PPI
drug.

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
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statistic I to measure the heterogeneities between the


studies; a rough guide to interpretation of I takes 50%
and more as substantial heterogeneity.19
To conduct the adjusted indirect comparison for each
of the outcomes of interest, a traditional pair-wise MantelHaenszel random-effects meta-analysis was performed for dexlansoprazole or esomeprazole vs. placebo
or another PPI drug as a common comparator.20 Given
that the outcomes to be compared were all binary events,
relative risks (RRs) with 95% condence intervals (CI)
were calculated, and the meta-analyses were carried out
using RevMan v5.2.21 All analyses were based on the
intention-to-treat (ITT) data reported in the manuscripts
published for the included RCTs.
Bucher-adjusted method with the indirect treatment
comparison calculator developed by Canadian Agency
for Drugs and Technologies in Health (CADTH) was
employed to convert the summary estimates from the
meta-analyses of direct comparisons into relative risks
and 95% condence intervals representing the comparative efcacy between dexlansoprazole and esomeprazole
for treatment of GERD.22, 23 The Bucher method has
been a central consideration for performing indirect
treatment comparisons in meta-analyses of RCTs; the
method has been commonly used and well validated.24

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
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Indirect comparison: dexlansoprazole with esomeprazole in GERD


438 abstracts were retrieved from the
searches of electronic database

421 studies were excluded due to:


duplicates; non randomized trials;
comparators were combination of
treatments; other conditions

17 papers of randomized trials were


identified

7 studies were further excluded due to


different settings of patients, conditions
and outcome measured

1 study was identified from 19 relevant


systemtic reviews

11 randomized trials were included

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

treatment efcacy in maintaining healed EO. Among


them, two studies compared dexlansoprazole with placebo28, 32 and two studies compared esomeprazole with
placebo.10, 37 There were two studies that assessed the
effectiveness of short-term treatment for NERD; one
study compared dexlansoprazole with placebo26 and the
other one compared esomeprazole with placebo.31
Most of the included studies have high quality of evidence; the small number of studies precluded the investigation of potential reporting biases across studies (for
example, using funnel plots). The possibility of publication bias cannot be excluded. It remains unclear, however, whether reporting biases would tend to favour any
particular treatment. See Appendix S2 and S3, for study
characteristics including Jadad score.

Treatment efcacy for EO healing


The complete healing rate at 8 weeks of EO patients
with baseline LA grade A, B, C and D was reported in
four studies.25, 33, 38, 57 One study conducted two identical double-blind RCTs that compared dexlansoprazole 60
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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

M-H, random-effect: Relative risk (95% CI)

621
638
1259

673
685
1358

589
615
1204

684
672
1356

1.07 (1.03, 1.11)


1.02 (0.99, 1.05)
1.04 (0.99, 1.10)

Tau2 = (0.00); Chi2 = 4.52, df = l (P = 0.03); I2 = 78%


Dexlansoprazole
90 mg

Study
Sharma P, 2009, 1
Sharma P, 2009, 2
Total
Pooled results
Heterogeneity

Castell DO, 2002


Howden CW, 2002
Zheng EN, 2009
Total
Pooled results
Heterogeneity

Lansoprazole
30 mg

Events

Total

Events

Total

M-H, random-effect: Relative risk (95% CI)

613
645
1258

665
680
1345

589
615
1204

684
672
1356

1.07 (1.03, 1.11)


1.04 (1.01, 1.07)
1.05 (1.02, 1.09)

Tau2 = 0.00; Chi2 = 1.90, df = l (P = 0.17); I2 = 47%


Esomeprazole
40 mg

Study

Lansoprazole
30 mg

Lansoprazole
30 mg

Events

Total

Events

Total

M-H, random-effect: Relative risk (95% CI)

2430
123
62
2615

2624
138
65
2827

2324
127
60
2511

2617
139
67
2823

1.04 (1.02, 1.06)


0.98 (0.90, 1.05)
1.07 (0.99, 1.17)
1.03 (0.99, 1.07)

Tau2 = 0.00; Chi2 = 2.94, df = l (P = 0.23); I2 = 32%

Indirect comparison
Dexlansoprazole 60 mg vs. Esomeprazole 40 mg
Dexlansoprazole 90 mg vs. Esomeprazole 40 mg

or 90 mg with lansoprazole 30 mg once daily, three


other trials compared esomeprazole 40 mg with lansoprazole 30 mg. Meta-analyses showed that only dexlansoprazole 90 mg was more effective than lansoprazole
30 mg (RR: 1.05, 95% CI: 1.02, 1.09), and there were no
signicant differences between dexlansoprazole 60 mg or
esomeprazole 40 mg, and lansoprazole 30 mg (Table 1).
The calculations of indirect comparisons based on the
common comparator lansoprazole showed no signicant
difference between dexlansoprazole 60 or 90 mg and
esomeprazole 40 mg on treatment effect of complete EO
healing at 8 weeks (RR: 1.01, 95% CI: 0.95, 1.08; and
RR: 1.02, 95% CI: 0.97, 1.07, respectively, in Table 1).
The treatment efcacy of complete EO healing at
8 weeks for baseline LA grade C and D patients was
reported in three studies.9, 33, 57 One study compared
dexlansoprazole 60 or 90 mg with lansoprazole 30 mg,
and the other two studies compared esomeprazole 40 mg
194

Relative risk (95% CI)


1.01 (0.95, 1.08)
1.02 (0.97, 1.07)

with lansoprazole 30 mg. The individual meta-analyses


demonstrated again that only the dexlansoprazole 90 mg
was more effective than lansoprazole 30 mg (RR: 1.08,
95% CI: 1.02, 1.14), and there were no signicant differences between dexlansoprazole 60 mg or esomeprazole
40 mg, and lansoprazole 30 mg (Table 2). Using lansoprazole as the common comparator, the indirect comparisons were conducted, but did not reveal any signicant
difference between dexlansoprazole 60 or 90 mg and
esomeprazole 40 mg for treatment effect on complete
EO healing at 8 weeks for LA grade C and D patients
(RR: 1.10, 95% CI: 0.86, 1.41; and RR: 1.09, 95% CI:
0.91, 1.31, respectively, in Table 2).

Treatment efcacy for healed EO maintenance


Four RCTs reported the outcome of treatment efcacy
for maintenance of healed EO over 6 months.10, 28, 32, 37
One trial compared dexlansoprazole 30 mg and 60 mg
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Indirect comparison: dexlansoprazole with esomeprazole in GERD


Table 2 | Comparisons for effect of complete BE healing at 8 weeks baseline LA grades C and D
Dexlansoprazole
60 mg
Study
Sharma P, 2009, 1
Shaima P, 2009, 2
Total
Pooled results
Heterogeneity

Events

Total

Events

Total

M-H, random-effect: Relative risk (95% CI)

170
174
344

191
199
390

155
170
325

208
194
402

1.19 (1.09, 1.31)


1.00 (0.93, 1.08)
1.09 (091, 1.30)

Tau2 = 0.01.; Chi2 = 8.99, df = 1 (P = 0.003); I2 = 89%


Dexlansoprazole
90 mg

Study
Sharma P, 2009, 1
Shaima P, 2009, 2
Total
Pooled results
Heterogeneity

Fennerty MB, 2005


Howden CW, 2002
Total
Pooled results
Heterogeneity

Lansoprazole
30 mg

Events

Total

Events

Total

M-H, random-effect: Relative risk (95% CI)

160
178
338

191
191
382

155
170
325

208
194
402

1.12 (1.02, 1.24)


1.06 (1.00, 1.14)
1.08 (1.02, 1.14)

Tau2 = 0.00; Chi2 = 094, df = 1 (P = 0.33); I2 = 0%


Esomeprazole
40 mg

Study

Lansoprazole
30 mg

Lansoprazole
30 mg

Events

Total

Events

Total

M-H, random-effect: Relative risk (95% CI)

410
47
457

498
51
555

388
48
436

501
52
553

1.06 (1.00, 1.13)


0.89 (0.77, 1.03)
099 (0.83, 1.17)

Tau2 = 0.01; Chi2 = 4.87, df = 1 (P = 0.03;) I2 = 79%

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).

Treatment efcacy for symptom relief of NERD


Only the outcome of symptom control (i.e. complete resolution of heartburn) in treatment of NERD was commonly reported in two studies.26, 31 One study compared
dexlansoprazole 30 mg or 60 mg with placebo, while
another study included two identical RCTs that comAliment Pharmacol Ther 2013; 38: 190-201
2013 John Wiley & Sons Ltd

Relative risk (95% CI)


1.10 (0.86, 1.41)
1.09 (0.91, 1.31)

pared both esomeprazole 40 mg and 20 mg with placebo.


The meta-analyses showed that both dexlansoprazole and
esomeprazole with different doses were signicantly superior to placebo in symptom control of NERD (Table 4).
The calculations of indirect comparison found statistically
signicant differences in favour of dexlansoprazole 30 mg
vs. esomeprazole 20 or 40 mg for symptom control in
treatment of NERD (RR: 2.01, 95% CI: 1.15, 3.51; and
RR: 2.17, 95% CI: 1.39, 3.38 respectively). There were no
statistically signicant differences, however, between dexlansoprazole 60 mg and esomeprazole 20 or 40 mg (RR:
1.43, 95% CI: 0.81, 2.52; and RR: 1.55, 95% CI: 0.98, 2.43,
respectively, in Table 4).

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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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

M-H, random-effect: Relative risk (95% CI)

103
103

137
137

39
39

145
145

2.80 (2.10, 3.72)


2.80 (2.10, 3.72)

Not applicable
Dexlansoprazole
60 mg

Study
Howden CW, 2009
Metz DC, 2009
Total
Pooled results
Heterogeneity

Placebo

Events

Total

Events

Total

M-H, random-effect: Relative risk (95% CI)

138
126
264

159
153
312

36
39
75

140
145
285

3.38 (2.53, 4.50)


3.06 (2.32, 4.04)
3.21 (2.63, 3.92)

Tau2 = 0.00; Chi2 = 0.23, df = l (P = 0.63); I2 = 0%


Dexlansoprazole
90 mg

Study
Howden CW, 2009
Total
Pooled results
Heterogeneity

Placebo

Events

Total

Events

Total

M-H, random-effect: Relative risk (95% CI)

125
125

152
152

36
36

140
140

3.20 (2.39, 4.28)


3.20 (2.39, 4.28)

Not applicable
Esomeprazole
40 mg

Study
Johnson DA, 2001
Vakil NB, 2001
Total
Pooled results
Heterogeneity

Placebo

Events

Total

Events

Total

M-H, random-effect: Relative risk (95% CI)

77
81
158

82
92
174

22
27
49

77
94
171

3.29 (2.30, 4.70)


3.07 (2.21, 4.25)
3.16 (2.49, 4.03)

Tau2 = 0.00; Chi2 = 0.08, df = l (P = 0.78); I2 = 0%


Esomeprazole
20 mg

Study
Johnson DA, 2001
Vakil NB, 2001
Total
Pooled results
Heterogeneity

Events

Total

Events

Total

Relative risk (95% CI) M-H, random effect

76
77
153

82
98
180

22
27
49

77
94
171

3.24 (2.27, 4.64)


2.74 (1.96, 3.82)
2.96 (2.32, 3.78)

Tau2 = 0.00; Chi2 = 0.46, df = l (P = 0.50); I2 = 0%

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

Relative risk (95% CI)


0.89 (0.61, 1.29)
0.95 (0.65, 1.38)
1.02 (0.74, 1.39)
1.08 (0.79, 1.49)
1.01 (0.69, 1.48)
1.08 (0.74, 1.58)

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Indirect comparison: dexlansoprazole with esomeprazole in GERD


Table 4 | Comparisons of efcacy for NERD symptom control (complete resolution of heartburn) at week 4
Dexlansoprazole
30 mg
Study
Fass R, 2009
Total
Pooled results
Heterogeneity

Placebo

Events

Total

Events

Total

M-H, random-effect: Relative risk (95% CI)

184
184

312
312

43
43

310
310

4.25 (3.17, 5.70)


4.25 (3.17, 5.70)

Not applicable
Dexlansoprazole
60 mg

Study
Fass R, 2009
Total
Pooled results
Heterogeneity

Placebo

Events

Total

Events

Total

M-H, random-effect: Relative risk (95% CI)

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

M-H, random-effect: Relative risk (95% CI)

62
57
119

123
118
241

37
24
61

124
118
242

1.69 (1.22, 2.33)


2.38 (1.59, 3.55)
1.96 (1.40, 2.73)

Tau2 = 0.02; Chi2 = l.69, df = 1 (P = 0.19); I2 = 41%


Esomeprazole
20 mg

Study
Katz PO, 2003, 1
Katz PO, 2003, 2
Total
Pooled results
Heterogeneity

Placebo

Events

Total

Events

Total

M-H, random-effect: Relative risk (95% CI)

61
63
125

121
113
234

37
24
61

124
118
242

1.69 (1.22, 2.33)


2.74 (1.85, 4.06)
2.12 (1.32, 3.42)

Tau2 = 0.08; Chi2 = 3.51, df = 1 (P = 0.06); I2 = 72%

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

Relative risk (95% CI)


2.17 (1.39, 3.38)
2.01 (1.15, 3.51)
1.55 (0.98, 2.43)
1.43 (0.81, 2.52)

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

to once-daily dexlansoprazole 30 mg, heartburn


remained well controlled in 88% of patients (125 of
142). These patients were able to maintain their GERDrelated symptom severity and QOL, indicated by marginal changes in the PAGISYM and PAGI-QOL total
and subscale scores respectively. Eighty-four per cent of
the patients who were previously on twice-daily esomeprazole were well controlled with once-daily dexlansoprazole.62
In clinical practice, reux-related symptoms are always
the principal reason for patients to seek treatment.
Patients with heartburn are frequently treated without
endoscopic assessment of the presence of mucosal disease. Empirical treatment with a PPI in clinical practice
is common. In addition, symptom relief and control contribute substantially to the improvement in the patients
quality of life.63 As symptom control, e.g. the absence of
heartburn, is a justiable practical treatment goal, the
superiority of dexlansoprazole against esomeprazole in
symptom control in treating NERD should be considered
along other factors, e.g. treatment cost, interaction with
food, etc. when choosing a PPI.
There were signicant heterogeneities that appeared
according to the I estimates in the comparisons of direct
evidence; some of them existed between the two RCTs
that came from the same study with identical trial design
and patients characteristics, and some of the heterogeneity might have come from the different setting of the trials. We investigated possible sources and performed
subgroup analyses if necessary, but that still failed to
explain this heterogeneity. The recent research of heterogeneity suggested that I estimates need to be interpreted
with caution when the meta-analysis only includes a limited number of events or trials.64 Furthermore, observations in clinical practice tend to suggest the intrinsic
heterogeneity nature of the overall GERD population.
For instance, it is known that Helicobacter pylori infection has been reported to inuence the healing of EO by
PPI.65 Also, the impact of the availability of over-thecounter of PPIs on the recent study population remains
unclear. Theoretically, patients who failed to obtain relief
from self-treatment with over-the-counter PPIs might be
more likely to seek medical consultation and hence participate in the recent clinical trials.
Study discontinuation because of loss of treatment
efcacy or relapse of EO from the trials of most placebotreated patients made meaningful safety comparisons difcult within each trial. In addition, pooling of adverse
event rates tends to include RCTs of the same molecule
regardless of study populations. Therefore, no indirect
Aliment Pharmacol Ther 2013; 38: 190-201
2013 John Wiley & Sons Ltd

Indirect comparison: dexlansoprazole with esomeprazole in GERD


comparisons were attempted on the safety endpoints in
this review, which is limited to the only 11 eligible RCTs
for indirect treatment effectiveness comparisons on different study populations. However, in general, both dexlansoprazole and esomeprazole were well tolerated in the
reviewed RCTs with majority of the reported adverse
events being mild or moderate, similar to that of lansoprazole and omeprazole, respectively, which have a longestablished history of use in patients with GERD and
other acid-related disorders.25, 33
Fixed-effect models have not been run as sensitivity
analyses in this study, as simulations studies suggested
that xed-effect model tended to underestimate standard
errors of pooled estimates in indirect comparison.24 We
therefore only used the random-effects model, which has
been validated in Bucher method,24 for the quantitative
pooling in both the direct and the adjusted indirect comparisons.
Dexlansoprazole is different from any other PPI drugs;
it is formulated with an improved technology dual
delayed-release system, which has been conrmed in
studies that dexlansoprazole was well tolerated, effective
in the healing and maintenance of EO, and in the treatment of NERD,13 that is consistent with the ndings in
our systematic review and meta-analyses. Our study further made it possible to compare dexlansoprazole with
another widely used PPI drug esomeprazole to evaluate
the comparative treatment effect in the absence of the
head-to-head RCTs between dexlansoprazole and
esomeprazole.

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

signicant differences between dexlansoprazole and


esomeprazole in other outcomes for the treatment and
maintenance of healed EO. However, these study ndings need to be interpreted with caution due to small
number of studies and other limitations.

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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