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Scandinavian Journal of Gastroenterology

ISSN: 0036-5521 (Print) 1502-7708 (Online) Journal homepage: http://www.tandfonline.com/loi/igas20

Combination Therapy of Sucralfate and Ranitidine,


Compared with Sucralfate Monotherapy, in
Patients with Peptic Reflux Esophagitis
J. R. Vermeijden, G. N. J. Tytgat, R. H. Schotborgh, W. Dekker, D. M. Vd
Boomgaard, G. H. Van Olffen, M. Schrijver, G. D. C. Vosmaer & C. P. M.
Dekkers
To cite this article: J. R. Vermeijden, G. N. J. Tytgat, R. H. Schotborgh, W. Dekker, D. M.
Vd Boomgaard, G. H. Van Olffen, M. Schrijver, G. D. C. Vosmaer & C. P. M. Dekkers (1992)
Combination Therapy of Sucralfate and Ranitidine, Compared with Sucralfate Monotherapy, in
Patients with Peptic Reflux Esophagitis, Scandinavian Journal of Gastroenterology, 27:2, 81-84
To link to this article: http://dx.doi.org/10.3109/00365529209165421

Published online: 05 Aug 2009.

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Download by: [University of California, San Diego]

Date: 09 February 2016, At: 21:27

Combination Therapy of Sucralfate and Ranitidine, Compared


with Sucralfate Monotherapy , in Patients with Peptic Reflux
Esophagitis

Downloaded by [University of California, San Diego] at 21:27 09 February 2016

J. R . VERMEIJDEN, G . N. J . TYTGAT, R . H . SCHOTBORGH, W. DEKKER,


D . M. vd B O O M G A A R D , G. H . van OLFFEN, M. SCHRIJVER,
G . D. C. VOSMAER & C . P. M . DEKKERS
Dept. of Gastroenterology, Academic Medical Center, Amsterdam; Elisabeth Hospital and
Mariastichting, Haarlem; Leijenburg Hospital and Bronovo Hospital, The Hague; Scheper Hospital,
Emmen; and St. Ignatius Hospital, Breda; The Netherlands

Vermeijden J R , Tytgat GNJ, Schotborgh R H , Dekker W, vd Boomgaard D M , van Olffen G H , Schrijver


M, Vosmaer G D C , Dekkers CPM. Combination therapy of sucralfate and ranitidine, compared wtih
sucralfate monotherapy, in patients with peptic reflux esophagitis. Scand J Gastroenterol 1992, 27, 8184
A double-blind, multicenter, randomized study was performed in 75 patients with endoscopically
documented reflux esophagitis. Patients were randomly given 1 g sucralfate four times a day or the
combination of sucralfate three times a day and 300 mg ranitidine after dinnertime. Endoscopy was
performed at the beginning of the study, after 8 weeks, and, if the reflux esophagitis was not healed,
after 16 weeks. Four patients had to be excluded from evaluation; 71 patients could therefore be
evaluated. Both groups showed symptomatic improvement to similar extents. Endoscopy showed
symptomatic improvement in 67% of the patients treated with sucralfate and in 74% of the combination
therapy group. Complete healing or Savary-Miller stage 1 was seen in 26.5% and in 31.4%, respectively.
We conclude that sucralfate monotherapy in patients with milder forms of reflux esophagitis is comparable
with a combination of sucralfate during the day and ranitidine after dinnertime. This study does not
support the commonly used combination of sucralfate and H,-receptor antagonists in reflux esophagitis.

Key words: Combination therapy; ranitidine; reflux esophagitis; sucralfate

G. N.J. Tytgat, M . D . , Dept. of Gastroenterology, Academic Medical Center, Meibergdreef 9, I105 A Z


Amsterdam, The Netherlands

Sucralfate, an aluminum hydroxide salt ofsucrose octasulfate,


has been shown to be effective in healing peptic ulcer disease
(1,2). Its mechanism of action is adherence to positively
charged proteins at the ulcer base, protecting the underlying
tissues against pepsin, hydrochloric acid, and bile salts.
Gastroesophageal reflux of acid, pepsin, bile salts, and
lysolecithin has been considered to be the etiologic factor in
the development of esophagitis. Several controlled studies
have shown that sucralfate has a beneficial effect in reflux
esophagitis. A t least for milder forms of esophagitis sucralfate may be considered to have an efficacy comparable to
that of H2-receptor antagonists (3,4). In general, however,
the efficacy of both classes of drugs is suboptimal, especially
for the more severe forms of reflux esophagitis.
As H2-receptor antagonists and sucralfate have different
modes of action, the combination of both regimens seems a
logical step in improving the treatment of gastroesophageal
reflux disease. In our first study, however, the combination
of sucralfate during the day and a low dose of cimetidine at
night showed no benefit compared with sucralfate monotherapy in the treatment of reflux esophagitis ( 5 ) . Lack of
differences in results was thought to be related to insufficient
nocturnal H2-receptor blockade.

Another study was therefore designed combining fulldose sucralfate with more powerful nocturnal H2-receptor
blockade. The purpose of this study was to determine
whether the combination of sucralfate and ranitidine would
improve the results obtained with sucralfate monotherapy.
We performed a randomized, double-blind, multicenter
study in patients with endoscopically proven reflux esophagitis and compared treatment with 1 g sucralfate four times
a day with 1g sucralfate three times a day plus 300 mg
ranitidine after dinnertime.
MATERIALS A N D METHODS
Seventy-five patients with endoscopically documented reflux
esophagitis in accordance with the criteria proposed by
Savary-Miller (6) were treated in a double-blind, multicenter
trial (seven centers) for a period of 8-16 weeks.
Patients were treated with either sucralfate four times a
day in sachets of 1-g suspension after each meal and at
bedtime plus one ranitidine placebo tablet after dinnertime
or sucralfate three times a day after each meal in a I-g
suspension and 300 mg ranitidine after dinnertime with 1 g
sucralfate placebo at bedtime. In addition to medical treat-

82

J . R. Vermeijden el al.

dysphagia, regurgitation, belching, and vomiting were recorded and graded as absent, mild, moderate, or severe.
Symptoms and use of any medication were recorded daily
on a patient record form.
Endoscopy was performed at the beginning of the trial
period, at 8 weeks, and, if the esophagitis was not healed,
at 16 weeks. Endoscopic improvement was measured as a
change of at least one or more stages by the Savary-Miller
criteria. The end point of the trial was complete healing or
Savary-Miller stage 1 without complaints. Asymptomatic
patients with Savary-Miller stage 1 were therefore allowed
to finish the study after 8 weeks.
Results of the treatment after 8 weeks were analyzed by
means of Fisher's exact test and the exact test for 2 x 2
contingency tables.
At p < 0.05 statistical significance was considered.

Table I. Patient characteristics


Sucralfate

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No. of patients
Sex
Men
Women
Mean age/range (years)
Men
Women
Cigarettes (no./day)
Unknown
1-10
Sll

Sucralfate

ranitidine

35

36

22
13
56.3/18-80
53.2/18-80
60.8/37-79

23
13
54.6123-8 1
47.9123-72
66.6136-81

1
6
4

5
3

Table 11. Symptoms as judged by physician at the end of treatment

Sucralfate
(n = 35)

Sucralfate ranitidine
(n = 35')

40%
40%
14.3%
2.9%
2.9%

48.6%
28.6%
20 %
2.9%
-

RESULTS
Essentially improved
Improved
Unchanged
Worsened
Essentially worsened

Seventy-five patients entered the study; 38 received sucralfate and 37 sucralfate and ranitidine. Three patients receiving
sucralfate monotherapy could not be evaluated after 8
weeks. Of these three patients, one had an intercurrent
disease (metastatic renal carcinoma), one showed poor compliance with the test medication, and the third dropped out
because of travel abroad. In the combination therapy group
one patient was withdrawn because of protocol violation, as
he used unauthorized medication (diclofenac).
Side effects were seen in two patients receiving sucralfate
monotherapy. One patient complained of nausea and vomiting, and another complained of abdominal pain (and, in
addition, insufficient efficacy). These complaints required
withdrawal from the study. Three patients per group were
withdrawn because of insufficient efficacy. In total, 71
patients could be evaluated after 8 weeks of treatment.
The two groups were comparable for sex, age, and smoking habits (Table I).
In both treatment groups improvement of symptoms
occurred to similar extents: in the sucralfate group 80% and
in the combination therapy group 77% improved symptomatically (Table 11). Antacid consumption was similar in
both groups. After 8 weeks endoscopy showed improvement
in 68% of the patients treated with sucralfate (Table III),
and complete healing or stage 1 was seen in 26.5%. In the

* Excluding one patient without information.


ment, standard antireflux measures including postural treatment at night were suggested to all patients. They were
also advised to stop smoking. Medication used for other
conditions was noted, but left unchanged. Patients with
secondary esophagitis and patients receiving treatment with
corticosteroids, cytotoxic agents, phenylbutazone, salicylates, anticholinergics, antacids, H2-receptor antagonists,
metoclopramide, domperidone, carbenoxolone, and bismuth subcitrate were excluded from the study. Patients with
renal failure and scleroderma were also excluded. Before
entrance, all medications for reflux esophagitis, except antacids, were withdrawn for at least 7 days.
During the trial patients were allowed to take low-potency
antacid tablets, with one tablet having an acid-neutralizing
capacity of 3 meq H + , to relieve symptoms. The number of
tablets was to be registered.
At the beginning of the treatment and after 4,8, and, if
the esophagitis was not healed, also after 12 and 16 weeks,
the presence and severity of. heartburn, epigastric pain,

Table 111. Change of endoscopic findings (Savary-Miller stage) after 8 weeks


Improvement by

Sucralfate
Sucralfate

+ ranitidine

1
stage

2
stages

3
stages

4
stages

No
change

Deterioration

Total*

16
15

6
8

1
3

0
0

10
9

1
0

34
35

* Excluding one patient without endoscopy in both groups.

Exact test
for 2 x 2
contingency
tables

p>0.05

Sucralfate and Ranitidine in Reflux Esophagitis

Na

Na

///

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83

I/ ///

I/

//

//

//

PP

Fig. 1. Stage of esophagitis in accordance with Savary and Miller,


before and after treatment (post-treatment includes complete healing or Savary-Miller stage 1 without symptoms). Patient having
patient
completed treatment in accordance with study protocol (0);
with premature termination of study owing t o insufficient efficacy
of treatment (0);
patient with premature termination of study owing
to undesired side effects (*); patient without final endoscopy (0);

Fig. 2. Stage of esophagitis in accordance with Savary and Miller,


before and after treatment (post-treatment includes complete healing or Savary-Miller stage 1 without symptoms). Patient having
patient
completed treatment in accordance with study protocol (0);
with premature termination of study owing to insufficient efficacy
of treatment (0);and patient without final endoscopy (0).

(A)= (0)
+ (*I.
combination therapy group these figures were 74% and
31.4%, respectively. These differences between the two
major groups were not significant. After 16 weeks further
improvement of symptoms was obtained in both groups. The
healing rates in patients who did not terminate the study at 8
weeks-that is, symptomatic patients with reflux esophagitis
equally in the two groups.
stage 1 and higher-improved
Because patients were allowed to terminate the trial with
Savary-Miller stage 1 without complaints these results could
not be evaluated further statistically. Figs. 1 and 2 show
the efficacy of treatment in each particular patient. Posttreatment includes all patients healed o r sufficiently
improved (Savary-Miller stage 1, asymptomatic) at 8 weeks
and the remaining patients at 16 weeks.

DISCUSSION
Sucralfate has the property of binding to proteins in areas
of mucosal damage, thus protecting mucosal defects from
aggressive substances such as pepsin, bile acids, and hydrochloric acid (7). In the treatment of peptic ulcer disease the
effect of sucralfate has been well demonstrated (1,2).

Sucralfate prevents hydrogen ion back-diffusion and


injury to the esophageal mucosa in vitro (8). The intensity
of experimentally induced esophagitis can also be reduced
by sucralfate (9). Several controlled studies have shown
sucralfate to be superior to placebo and at least as effective
as antacids in the treatment of reflux esophagitis (3, 10, 11).
The results are also comparable with those obtained after
treatment with cimetidine o r ranitidine, which show improvement of symptoms and endoscopic signs of esophagitis
in up to 70% of the patients (4, 12-14).
Schotborgh et al. (5) showed similar results in the treatment of reflux esophagitis after monotherapy with sucralfate
and after combination therapy with sucralfate during the day
and cimetidine at bedtime. Endoscopy showed complete
healing in 19.4% of the sucralfate group and in 21.9% of
the combination therapy group.
We found a higher percentage of improvement in the
sucralfate monotherapy group. Lack of superiority in the
combination therapy group has been considered t o be due
to insufficient H2-receptor blockade and perhaps the dosing
at bedtime instead of after the evening meal. Indeed, recent
studies show that the bulk of acid reflux occurs during the

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84

J . R. Vermeijden et al.

early evening hours after dinner (15, 16). Tytgat et al. (17)
showed more benefit from 800 mg cimetidine at dinnertime
than the same dosage at bedtime. W e therefore investigated
in our present study whether more potent acid suppression
would improve the results of combination therapy, by using
sucralfate and 300 mg ranitidine at dinnertime versus sucralfate monotherapy. Seventy-one patients, comparable for
sex, age, symptoms and smoking habits, could be evaluated.
No significant differences were found between the two
groups. Improvement of symptoms and endoscopic findings
was equal in the groups.
These results are comparable with those obtained by
Schotborgh et al. ( 5 ) . However, on theoretical grounds we
expected more improvement in the combination therapy
group because of more powerful Hz-receptor blockade and a
more ideal dosage schedule. Thus, our results are somewhat
disappointing. We can only speculate as to why the addition
of ranitidine failed to improve the healing rates: Inappropriate dosage scheme? Insufficient acid secretory
reduction? To some extent our data contrast with those
obtained by Herrera et al. (18), who in a recent study showed
combination therapy with 300 mg cimetidine four times daily
and sucralfate to be superior to cimetidine monotherapy in
stage 2 or more of reflux esophagitis.
Whatever the reason for the failure of H2-receptor antagonists to improve the sucralfate results, it is obvious that
our data provide no support for the common practice of
combining sucralfate with H2-receptor antagonists in reflux
esophagitis.
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ulcer. Clin Gastroenterol 1984, 13, 543-568
2. Marks IN, Wright JP, Denyer M, et al. Comparison of sucralfate
with cimetidine in the short-term treatment of chronic peptic
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Received 15 May 1991
Accepted 9 September 1991

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