ORIGINAL PAPER

Management of reflux esophagitis: does the choice of

proton pump inhibitor matter?
J. Labenz,1 D. Armstrong,2 A. Leodolter,3 I. Baldycheva4

1
Medical Department, Diakonie
SUMMARY Klinikum Jung-Stilling, Siegen,
What’s known
Numerous studies have demonstrated the efficacy of Germany
Background: Proton pump inhibitors (PPIs) are the treatment of choice for reflux 2
Division of Gastroenterology,
esophagitis (RE). The effectiveness of PPIs throughout RE management, from heal- proton pump inhibitors (PPIs) for initial healing of
McMaster University, Hamilton,
reflux esophagitis and maintenance of endoscopic
ing to maintenance, has not been fully studied. Aim: To compare esomeprazole ON, Canada
remission. However, the effect of different PPIs in 3
Medical Department, Ev.
with lansoprazole or pantoprazole for RE management using a management
achieving healing and then maintaining remission has Krankenhaus, Herne, Germany
model. Methods: Data from six studies comparing esomeprazole with lansopraz- not been fully studied. 4
AstraZeneca Pharmaceuticals
ole or pantoprazole for healing (4–8 weeks) or maintenance of healing (6 months) LP, Biometrics and Information
of RE were incorporated into hypothetical management models to determine the What’s new Sciences, Wilmington, DE, USA
proportion of patients in endoscopic remission after sequential healing and mainte- In this management model, esomeprazole offers
improved clinical efficacy compared with lansoprazole Correspondence to:
nance therapy, assuming that patients received the same PPI throughout. The
Professor Joachim Labenz,
number needed to treat (NNT) to achieve one more patient in remission with or pantoprazole throughout the course of
Medical Department, Diakonie
management (i.e. initial healing of reflux esophagitis
esomeprazole vs. other PPIs was estimated. The hypothetical model was validated Klinikum Jung-Stilling,
followed by maintenance of remission) Wichernstr. 40 D-57074,
using results from the EXPO study, which compared esomeprazole with pantopraz-
Siegen, Germany
ole for RE healing and maintenance. Results: Overall, esomeprazole 40 mg pro-
Tel.: + 49 271 333 42 43
duced higher rates of healing (life-table estimates) than lansoprazole 30 mg Fax: + 49 271 333 42 42
(82.4–92.6% vs. 77.5–88.8%; p < 0.01) or pantoprazole 40 mg (95.5% vs. Email: j.labenz@t-online.de
92.0%; p < 0.001) and higher rates of endoscopic and symptomatic remission at
Disclosures
6 months than lansoprazole (83.0–84.8% vs. 74.0–75.9%; p < 0.001; life-table
JL has received consultation
estimates) or pantoprazole (70.9% vs. 59.6%; p < 0.0001; observed rates). In the fees, speakers’ honoraria and
hypothetical management model, the NNT for esomeprazole was 9 vs. lansopraz- grant support from
ole and 8 vs. pantoprazole. The actual NNT for esomeprazole vs. pantoprazole in AstraZeneca. DA has received
speakers’ fees, consulting fees,
the EXPO study was 9 (95% confidence interval: 6; 16). Conclusions: In this
research funding or unrestricted
management model, esomeprazole was more effective than either lansoprazole or support for educational events
pantoprazole for maintaining remission after sequential healing and 6 months’ from Abbvie, Aptalis,
maintenance therapy for RE. AstraZeneca, Cook, Ferring,
Forest, Janssen, Nycomed,
Olympus, Pendopharm, Pentax,
Shire, Takeda and Warner-
Chilcott. AL does not have any
RE (8–10). Numerous studies have demonstrated the
Introduction conflicts of interest to declare.
efficacy of PPIs for initial healing of RE (11–18) and IB is an employee of
AstraZeneca.
Gastroesophageal reflux disease (GERD) is a chronic numerous separate studies have demonstrated the effi-
condition (1,2) associated with troublesome symp- cacy of PPIs for maintaining endoscopic remission
toms that significantly reduce quality of life (3,4). Pos- (8,10). The EXPO study (14,15), which compared
sible complications include reflux esophagitis (RE), esomeprazole with pantoprazole, is one of the few
which may affect up to 50% of GERD patients (5). clinical trials to follow patients with RE through the
For patients with RE, short-term management goals entire course of management, i.e. initial healing of RE
include prompt resolution of symptoms and healing and subsequent maintenance of remission of healing.
of erosions (6). However, following initial healing of However, comparative data for other PPIs are lacking.
RE, few patients remain in endoscopic and symptom- The aim of this analysis was to compare the out-
atic remission unless provided with maintenance ther- come of RE treatment (i.e. initial healing for
apy (7). Therefore, long-term maintenance therapy is 4–8 weeks followed by maintenance for 6 months)
necessary for the prevention of recurrent RE and with esomeprazole, lansoprazole or pantoprazole,
GERD symptoms in a high proportion of patients. using a hypothetical management model. This hypo-
Proton pump inhibitors (PPIs) are the treatment of thetical model was then validated using data from the
choice for both healing and maintenance therapy of EXPO study (an ‘actual’ management model) (14,15).

ª 2015 John Wiley & Sons Ltd

Int J Clin Pract doi: 10.1111/ijcp.12623 1
2 Management of reflux esophagitis

Maintenance therapy studies

Methods
Three studies evaluated the efficacy of 6 months’
Selection of studies maintenance therapy with esomeprazole 20 mg
To generate a hypothetical management model, Pub- (esomeprazole magnesium trihydrate 22.3 mg) vs.
Med literature searches were conducted to identify lansoprazole 15 mg (capsules containing 15 mg of
relevant studies. The terms ‘proton pump inhibitor’ active ingredient) (16,20) or pantoprazole 20 mg
AND ‘reflux esophagitis’ were used in the first search (pantoprazole sodium 22.56 mg) (14). All three
and the terms ‘proton pump inhibitor’ AND ‘reflux maintenance studies were extensions of initial healing
oesophagitis’ were used in the second search. Results phases, in which patients received once-daily
were limited to the last 10 years. Studies in children esomeprazole 40 mg (15,16,20), pantoprazole 40 mg
were excluded. The former search yielded 73 results (15) or lansoprazole 30 mg (20).
and the latter search yielded 14 results. For inclusion in the maintenance phases, patients
To be eligible for inclusion in the model, studies were required to have endoscopically-confirmed heal-
were required to: be of multicentre, randomised, ing of RE and mild or no symptoms during the last
double-blind, parallel-group design; include patients 7 days of healing therapy. In the studies by DeVault
with endoscopically-confirmed RE; and investigate et al. (20) and Lauritsen et al. (16), patients who
the efficacy of standard RE healing (for up to were healed and asymptomatic (symptoms assessed
8 weeks) and maintenance doses (for up to by the investigator as ‘none’) after esomeprazole
6 months) of esomeprazole vs. an active comparator. 40 mg healing treatment were randomised to mainte-
During the initial selection process, 14 healing and nance therapy with esomeprazole 20 mg or lansop-
eight maintenance studies appeared relevant. Upon razole 15 mg. The DeVault study (20) comprised
in-depth examination of the abstracts, 11 healing patients with healed severe RE (LA grade C or D)
studies and five maintenance studies were excluded. from the Fennerty healing study (12) plus patients
Reasons for exclusion included: non-English lan- with healed mild RE (LA grade A or B) who were
guage; non-comparative study; absence of endoscopy not eligible for inclusion in the Fennerty study (12).
data; absence of standardised RE grading system; and The Lauritsen study (16) included patients with
on-demand rather than continuous treatment. Three healed RE of all severities (LA grade A–D). In the
healing studies (11,12,15,19) and three maintenance EXPO study (14), patients with healed RE and at
studies (14,16,20) were therefore included in the most mild symptoms (symptoms assessed by the
hypothetical management model. investigator as ‘none’ or ‘mild’) after 8 weeks’ treat-
ment with esomeprazole 40 mg or pantoprazole
Healing studies 40 mg received maintenance treatment with esomep-
Three studies evaluating healing of RE after 4–8 weeks razole 20 mg or pantoprazole 20 mg.
of once-daily treatment with esomeprazole 40 mg Endoscopy and symptom assessments were per-
(esomeprazole magnesium trihydrate 44.5 mg) or a formed at 3 and 6 months, or in the event of symp-
comparator PPI were included (11,12,15,19). In all tom relapse. The primary efficacy end-point in all
studies, the primary efficacy end-point was endoscopi- three maintenance studies was symptomatic and
cally-confirmed RE healing at week 8. Endoscopy was endoscopic remission during the 6-month treatment
performed at week 4 and those with healed RE were period (14,16,20). In all three studies, relapse was
discharged from the studies. Data from these patients defined as esophagitis (LA grade A–D) or discontin-
were carried over to week 8, based on the assumption uation from the study because of GERD symptoms.
that patients would have remained healed if they had
stayed in the study. Management models
Two of the three studies compared the healing effi- For esomeprazole vs. pantoprazole, a hypothetical
cacy of esomeprazole 40 mg with lansoprazole 30 mg management model was constructed by combining
(capsules containing 30 mg of active ingredient) PPI healing rates from a healing study with preven-
(11,12,19). Of these two studies, one included patients tion of relapse (i.e. remission) rates from a separate
with RE of Los Angeles (LA) classification grade A–D maintenance study in a similar population treated
(11,19), while the other included only patients with with the same PPI. The same approach was taken for
more severe RE, i.e. LA grade C–D (12). The third esomeprazole vs. lansoprazole. The hypothetical
study, EXPO, compared esomeprazole 40 mg with management model was therefore based on patients
pantoprazole 40 mg (pantoprazole sodium 45.1 mg) receiving the same PPI throughout the healing and
(15). For the healing phase of this study, patients with maintenance periods, while taking into consideration
RE of LA grades A–D were enrolled (15). baseline severity of RE.

ª 2015 John Wiley & Sons Ltd

Int J Clin Pract
 Management of reflux esophagitis 3

For the hypothetical management model, the final with esomeprazole than with lansoprazole or pantop-
remission rate was calculated as the product of the razole across all grades of RE (Table 1). Healing rates
estimated RE healing and remission rates from the dif- were significantly higher (p < 0.05) with esomepraz-
ferent studies (i.e. symptom relief was not considered ole than with pantoprazole for patients with LA
in the healing phase). Remission rates during the grade B, C or D at baseline (Table 1).
maintenance period were assumed to be unaffected by
the treatment received during the healing phase. Relapse rates during maintenance therapy
The number needed to treat (NNT) to achieve one Among all patients, life-table estimates of the pro-
more patient in remission with esomeprazole vs. other portions of patients maintaining healing and symp-
PPIs was estimated using the hypothetical manage- tomatic remission at 6 months were significantly
ment models. The NNT was calculated as the recipro- higher with esomeprazole than with either lansopraz-
cal of the absolute risk reduction [based on life-table ole [83.0% vs. 74.0% in the Lauritsen study;
estimates (i.e. the probability of survival) for hypo- p < 0.0001 (16) and 84.8% vs. 75.9% in the DeVault
thetical and actual management models] and was study; p < 0.001 (20)] or pantoprazole [87.0% vs.
related to healing plus 6 months of maintenance ther- 74.9% in the EXPO study; p < 0.0001 (14)].
apy. In order to determine whether the hypothetical Esomeprazole was associated with higher endo-
management models provided an accurate assessment scopic and symptomatic remission rates than lansop-
of the complete management of patients with RE, the razole and pantoprazole, regardless of the severity of
NNT generated for EXPO using the hypothetical RE prior to healing therapy (Table 2). With the
model was compared with the actual remission rates exception of LA grade A, observed remission rates
reported in the EXPO study (the latter being an were significantly greater (p < 0.05) with esomepraz-
‘actual’ management model). Data from the EXPO ole than with lansoprazole across all grades of RE
study were used to validate the hypothetical manage- (Table 2). Esomeprazole was also significantly more
ment model because it combined healing and mainte- effective than pantoprazole for LA grades A, B and C
nance phases in one study. (Table 2).

Management models
Results
Management model results are shown in Table 3 and
Healing rates Figure 1. For lansoprazole, the hypothetical manage-
When all patients were considered together, the pro- ment model yielded an NNT of 9, indicating that
portion of patients achieving healing of RE was sig- esomeprazole therapy would avoid one treatment
nificantly higher for esomeprazole than for either failure for every 9 patients with RE of LA grade A–D
lansoprazole or pantoprazole [life-table estimates, treated with lansoprazole. As data were also avail-
p < 0.01 (Table 1)]. able for studies including patients with more severe
While healing rates tended to decrease as the base- disease (LA grade C–D), it was possible to generate
line severity of RE increased, they remained higher an NNT for this population. The hypothetical man-

Table 1 Estimated proportions of reflux esophagitis patients healed after 4–8 weeks’ treatment with esomeprazole 40 mg, lansoprazole 30 mg, or
pantoprazole 40 mg by baseline severity of reflux esophagitis (Kaplan–Meier analysis)†

Patients healed (%)†

Baseline LA grade

Comparator/study Treatment arm A B C D All

Lansoprazole 30 mg
Castell et al. (11) and Vakil (19) Esomeprazole 97.2 (n = 962) 92.0 (n = 1022) 88.3 (n = 482) 81.4 (n = 158) 92.6 (n = 2624)***
Lansoprazole 97.0 (n = 916) 91.0 (n = 1054) 77.3 (n = 477) 64.4 (n = 169) 88.8 (n = 2617)
Fennerty et al. (12) Esomeprazole Not applicable 80.3 (n = 390)‡ 67.6 (n = 108)‡ 82.4 (n = 498)**
Lansoprazole 74.9 (n = 403)‡ 66.3 (n = 98)‡ 77.5 (n = 501)
Pantoprazole 40 mg
Labenz et al. (EXPO study) (15) Esomeprazole 97.3 (n = 523) 96.9 (n = 665)* 91.3 (n = 304)** 88.1 (n = 70)* 95.5 (n = 1562)***
Pantoprazole 97.1 (n = 478) 93.1 (n = 716) 87.6 (n = 303) 73.6 (n = 92) 92.0 (n = 1589)

†
Life-table estimates, except where stated. ‡Observed. *p < 0.05, **p < 0.01, ***p < 0.001 vs. comparator (log-rank test).

ª 2015 John Wiley & Sons Ltd

Int J Clin Pract
4 Management of reflux esophagitis

Table 2 Estimated proportions of reflux esophagitis patients in remission at 6 months, following treatment with esomeprazole 20 mg,
lansoprazole 15 mg, or pantoprazole 20 mg, by baseline severity of reflux esophagitis (Kaplan–Meier analysis)

Patients in remission (%)

Baseline LA grade

Comparator/study Treatment arm A B C D All

Lansoprazole 15 mg
Lauritsen et al. (16) Esomeprazole 87.0 (n = 232) 83.0 (n = 269)** 75.0 (n = 95)* 77.0 (n = 19)* 83.0 (n = 615)****
Lansoprazole 84.0 (n = 229) 72.0 (n = 278) 61.0 (n = 82) 50.0 (n = 20) 74.0 (n = 609)
DeVault et al.† (20) Esomeprazole 87.2 (n = 380)‡ 77.6 (n = 121)‡ 84.8 (n = 501)***
Lansoprazole 78.7 (n = 369)‡ 68.4 (n = 131)‡ 75.9 (n = 500)
Pantoprazole 20 mg
Labenz et al. (EXPO study) (14) Esomeprazole 89.8 (n = 447)*** 88.0 (n = 607)**** 84.1 (n = 263)**** 69.4 (n = 60) 87.0 (n = 1377)****
Pantoprazole 81.0 (n = 451) 75.2 (n = 621) 67.3 (n = 251) 58.8 (n = 66) 74.9 (n = 1389)

†
Patients with LA grade A–D disease were included in the study but only data from patients with LA grade C or D disease were extracted for the hypothetical
management model in Table 3. ‡p-values were not calculated for LA grade A/B and C/D. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 vs. comparator
(log-rank test).

Table 3 Management models: estimated proportions of patients who had healed reflux esophagitis (after 4–8 weeks’ treatment) and remained in
remission (endoscopic and symptomatic) after 6 months’ maintenance therapy with esomeprazole or comparator proton pump inhibitors

Patients (%)

Baseline LA grade

Model/study Treatment arm A B C D All NNT*

Hypothetical management models†

Castell et al. (11) and Lauritsen et al. (16) Esomeprazole 40 mg/20 mg 84.6 76.4 66.2 62.7 76.9 9
Lansoprazole 30 mg/15 mg 81.5 65.5 47.2 32.2 65.7
Fennerty et al.‡ (12) and Lauritsen et al.§ (16) Esomeprazole 40 mg/20 mg 62.6 6
Lansoprazole 30 mg/15 mg 45.7
Fennerty et al.‡ (12) and DeVault et al.§ (20) Esomeprazole 40 mg/20 mg 63.9 9
Lansoprazole 30 mg/15 mg 53.2
Labenz et al. (15) and Labenz et al. (14) (EXPO study) Esomeprazole 40 mg/20 mg 87.4 85.3 76.8 61.2 83.1 8
Pantoprazole 40 mg/20 mg 78.7 70.0 59.0 43.3 68.9
Actual management model¶
Labenz et al. (15) and Labenz et al. (14) (EXPO study) Esomeprazole 40 mg/20 mg 76.4 72.8 61.6 52.6 70.9 9 (95% CI: 6; 16)
Pantoprazole 40 mg/20 mg 68.1 58.2 53.7 44.0 59.6

*Number needed to treat (NNT) with esomeprazole to avoid one treatment failure with the comparator agent. Calculation of the corresponding 95% confidence
interval (CI) was not appropriate for the hypothetical management models, given that the NNT was based on the difference between two products of estimates
(each of which was based on more than one study). †Life-table estimates (generated by multiplication of separate healing and remission rates from different studies
or from different phases of the same study). ‡Patients with Los Angeles (LA) grade C or D disease were included in the study. §Patients with LA grade A–D disease
were included in the study but only data from patients with LA grade C or D disease were extracted for the maintenance model. ¶Observed rates.

agement model yielded an NNT of 6 for these

Discussion
patients.
For pantoprazole (the EXPO study), the hypothet- Based on hypothetical management models with
ical management model NNT was 8 for esomeprazole esomeprazole vs. lansoprazole or pantoprazole, and
vs. pantoprazole. The EXPO trial results (the ‘actual’ verified by an actual management model based on
management model) yielded a similar NNT of 9 the results of the EXPO study, our findings indicate
(95% confidence interval: 6; 16) for esomeprazole vs. that esomeprazole is superior to lansoprazole and
pantoprazole. pantoprazole throughout the entire course of RE

ª 2015 John Wiley & Sons Ltd

Int J Clin Pract
 Management of reflux esophagitis 5

100 Esomeprazole Lansoprazole Pantoprazole

Patients with healed reflux esophagitis

and who remained in remission (%)
90 83.1
80 76.9
68.9 70.9
70 65.7 63.9
62.6
59.6
60 53.2
50 45.7

40
30
20
10
0
Castell et al. (11) Fennerty et al. Fennerty et al. Labenz et al. (15) Labenz et al. (15)
and Lauritsen (12) and Lauritsen (12) and DeVault and Labenz and Labenz
et al. (16) et al. (16) et al. (20) et al. (14) et al. (14)

Hypothetical Actual
management models* management model†

Figure 1 Management models: overall proportion of patients who had healed reflux esophagitis (after 4–8 weeks’
treatment) and remained in remission (endoscopic and symptomatic) after 6 months’ maintenance therapy with
esomeprazole or comparator proton pump inhibitors. *Life-table estimates; †Observed rates

management (i.e. initial healing followed by mainte- the large comparative clinical trials in the present
nance of clinical remission). The NNT values from analysis. Indeed, as many as a quarter of patients
the hypothetical management models demonstrate receiving either pantoprazole or lansoprazole had
that one treatment failure would be avoided with experienced a relapse by the end of the maintenance
esomeprazole for approximately 8–9 patients treated phase, compared with only 13–17% of those treated
with lansoprazole or pantoprazole. Similarly, in the with esomeprazole (14,16). This highlights the need
actual management model (based on the EXPO study for effective acid suppression throughout the course
results) the NNT was 9 for esomeprazole vs. pantop- of healing and maintenance therapy for RE. Patients
razole. who do relapse may benefit from a higher degree of
The superiority of esomeprazole over lansoprazole acid suppression, either by dose escalation or by drug
and pantoprazole was also evident for the manage- switching.
ment models that accounted for RE severity. This analysis was subject to some limitations.
Esomeprazole generally produced consistently greater Firstly, the primary end-point in the healing studies
healing and remission rates than other PPIs after ini- was based on endoscopic healing only (i.e. symptom
tial and maintenance therapy, irrespective of baseline relief was not considered) whereas the primary end-
LA grade. These findings are of relevance to primary points in the maintenance studies dictated that, in
care physicians, who typically manage GERD patients order to be in remission, patients had to have healed
without endoscopic assessment of mucosal damage RE and be asymptomatic. Similarly, in the mainte-
severity and therefore need to use a PPI that pro- nance studies, relapse was defined not only by endo-
duces consistently successful outcomes across all scopically-confirmed RE but also by discontinuation
grades of RE severity. from the study because of GERD symptoms. Hence,
These findings reiterate the importance of ade- healing and maintenance data may not be directly
quate acid suppression in the management of RE. comparable. However, Kahrilas et al. showed that
Healing rates in patients with RE receiving acid-sup- there is a good correlation between healing and
pressive therapy are directly related to the duration symptom relief; patients with RE who have symptom
of time that intragastric pH > 4 can be maintained relief after 4 weeks of PPI treatment seldom have
during treatment (21–24). At the standard oral dose persistent esophagitis (13,31). Thus, the differences
of 40 mg, esomeprazole has been shown to provide in definitions between the healing and maintenance
more effective acid control (intragastric pH > 4) phases may not have affected study results.
than standard doses of lansoprazole (25–28) or pan- Secondly, in order to be eligible for inclusion in
toprazole (25–27,29). Furthermore, at a maintenance the maintenance phase, patients were required to
dose of 20 mg, esomeprazole has also been shown to have endoscopically-confirmed healing of RE and
provide a significantly greater amount of time with mild or no symptoms during the last 7 days of heal-
pH > 4 than maintenance-dose lansoprazole (28,30) ing therapy. This definition therefore assumed that
or pantoprazole (29,30). This effect is mirrored by those who were not healed at 8 weeks would not be
higher rates of healing and lower rates of relapse in healed with a longer duration of therapy.

ª 2015 John Wiley & Sons Ltd

Int J Clin Pract
6 Management of reflux esophagitis

In conclusion, these data from both hypothetical

Acknowledgements
and actual models indicate that esomeprazole offers
improved clinical efficacy compared with lansopraz- This analysis was funded by AstraZeneca. We thank
ole and pantoprazole when evaluated for the over- Claire Byrne and Katharine Williams, of inScience
all management of RE including both initial and Communications, Springer Healthcare, who provided
subsequent maintenance of remission over medical writing support funded by AstraZeneca. This
6 months. Hypothetical models of RE management manuscript is dedicated to the memory of our col-
may yield valuable information representative of league, Ola Junghard.
the real-life setting such as the likelihood of remis-
sion on standard dose healing therapy and half-
Author contributions
dose maintenance therapy and the development of
appropriate management strategies, although these All authors were involved in data analysis/interpreta-
strategies will then need to be validated in clinical tion, drafting the article, critical revision of the arti-
practice. cle and approval of the final article. IB conducted
the statistical analysis and approved the final article.

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