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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.
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
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
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
Exact test
for 2 x 2
contingency
tables
p>0.05
Na
Na
///
83
I/ ///
I/
//
//
//
PP
(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).
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.
REFERENCES
I . Tytgat GNJ, Hameeteman W, van Olffen GH. Sucralfate, bismuth compounds, substituted benzimidazoles, trimipramine and
pirenzepine in the short- and long-term treatment of duodenal
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
ulcers. S Afr Med J 1980, 57, 567-573
Received 15 May 1991
Accepted 9 September 1991