comparison of the effect of sucralfate and ranitidine in reflux esophagitis

Comparison of the Effect of Sucralfate and Ranitidine in Reflux Esophagitis

BERND SIMON, M.D. PETER MUELLER, M.D. Heidelberg, Federal Republic of Germany

A total of 49 patients with primary reflux esophagitis were treated in a randomized controlled study at six trial centers. Treatment was given for eight weeks and consisted of daily doses of either 1 g of sucralfate suspension four times daily or one 150-mg ranitidine film-coated tablet twice daily. The evaluation of effect was based on data from 41 patients; 22 of these had received sucralfate, and 19 had received ranitidine. Reflux esophagitis was healed after eight weeks of treatment in 14 sucralfate-treated patients and in 13 ranitidine-treated patients. Alterations in the esophageal mucosa were established by endoscopic examination; the severity of these alterations was expressed in degrees using the Savary-Miller method of classification. The greater the degree of severity as assessed before treatment, the lower were the chances of the condition being com- pletely healed. The endoscopic findings after treatment did not show any difference in the effect of the sucralfate and ranitidine treatments (p >0.05). Both forms of treatment were also found to have a similar positive effect on the subjective symptoms recorded. Overall tolerance of the two forms of treatment was good. One patient treated with ranitidine had to discontinue treatment because of an allergic rash. Based on these results, sucralfate seems to be an effective alternative for the treatment of reflux esophagitis.

In recent years, increasing interest has been focused on the reflux dis- orders of the gastrointestinal tract-reflux gastritis and reflux esophagitis-as well as on the peptic complaints of the stomach and duodenum. The pathogenesis of reflux esophagitis involves the regurgitation of mucosa-damaging gastric juice with hydrochloric acid and pepsin, and secretions from the small intestine with bile acids and lysolecithin.

Therapy for reflux esophagitis using histamine (H&receptor blockers and their effect on the acid secretion of the stomach cannot be considered entirely satisfactory, and the findings from studies using inhibitors of gastric acid secretion would indicate that searching for alternative thera- pies is justified.

From the Department of Gastroenterology, Univer- sity Medical Clinic, Heidelberg, Federal Republic of Germany. Requests for reprints should be ad- dressed to Dr. Bernd Simon, Department of Gas- troenterology, University Medical Clinic, Berg- heimer Strasse 56, 6900 Heidelberg, Federal Re- public of Germany.

Sucralfate, the basic aluminium salt of sucrose octahydrogen sulfate, has the property of binding with proteins in areas of mucosal lesions. In doing so, it provides protection from aggressive substances such as pepsin, bile acids, and hydrochloric acid; furthermore, factors protecting the mucosa are stimulated [1,2]. The effect of sucralfate on peptic diseases of the upper gastrointestinal tract has been demonstrated in numerous studies. The findings from three controlled studies versus placebo, an alginate/antacid combined preparation, and cimetidine have shown that sucralfate has a positive effect in the treatment of reflux esophagitis [3-51.

September 28, 1987 The American Journal of Medicine Volume 83 (suppl 38) 43

SYMPOSIUM ON SUCRALFATE-SIMON and MUELLER

TABLE I Patient Characteristics, Case Histories, and Esophagitis Findings before Therapy

Sucralfate Ranitidine (n = 22) (n = 19)

Male patients 11 14 Female patients 11 5 Age (years)

440 4 4 41-60 10 12 >60 8 3

Smokers 9 11 Alcohol consumers 12 15 Complaint persistent for:

<l year 15 9 l-2 years 3 3 3-12 years 3 5 Not given 1 2

Present symptoms persistent for: ~1 month 6 4 l-l 2 months 15 12 >l year 1 3

Stage of esophagitis before treatment according to Savary Miller:

I 9 10 II 0 8 III 5 1

TABLE II Endoscopic Findings after Eight Weeks of Treatment with Sucralfate and Ranitidine

Finding Sucraifate (n = 22)

Ranitidine (n = 19)

2xc Test

Cured 14 13 Improvement 6 4 No change 2 2

p >0.05

The aim of the current study was to compare the effect of sucralfate with that of ranitidine in patients with reflux esophagitis.

PATIENTS AND METHODS

The study involved outpatients of both sexes with the symptoms of primary reflux esophagitis. Esophagoscopy was performed prior to treatment. The degree of severity of the refiux esophagitis was classified using the criteria described by Savary and Miller [6]: stage I, isolated or several supraves- tibular non-confluent erosive and exudative lesions are present; stage Ii, the erosive and exudative mucosal changes are confluent but do not affect the entire esophagus; stage iii, the erosive and exudative lesions encircle the entire esophageal mucosa but are without stricture; and stage IV, long-term changes in the mucosa develop (ulcer, parietai fibrosis, stricture, brachyesophagus, cylindrical ceil scar).

Patients with rare forms of esophagitis (thrush, herpes, cy- tomegaiia, drug-induced ulcers) and patients with esophagitis

classified as stage IV according to Savary and Miller were excluded from the study. Patients with refiux esophagitis secondary to gastric stenosis or surgery on the stomach and esophagus, and patients with concurrent gastric or duodenal ulcers were not included in the study. Simultaneous treatment with corticosteroids, cytostatic& anti-inflammatories, antichoiinergics, metociopramide, bromopride, domperidone, cimetidine, or carbenoxoione was prohibited.

Detailed case histories were recorded for each patient; the patients were informed of the nature and purpose of the study and gave their informed consent to participate. After these initial procedures, the patients were assigned at random to one of the two following medication groups: (1) sucralfate (UI- cogant) suspension, one 1-g sachet four times daily; three doses to be taken immediately after meals and the fourth dose at bedtime; and (2) ranitidine, one 150-mg film-coated tablet twice daily in the morning and at bedtime. These tablets did not have to be taken in conjunction with meals.

A four-week supply of medication was dispensed to the patients twice during the eight weeks of treatment. Patients were advised to sleep with their heads raised, to eat a fiber-rich diet if constipation developed, and to refrain from smoking. Antacid tablets were permitted to alleviate severe pain. The amounts allowed were stipulated individually by the physician, who supplied the antacid tablets to the patients.

To encourage compliance, patients were instructed to make daily entries on a patient record sheet including subjective esophagitis symptoms, any additional use of antacids, and any undesired side effects. After four and eight weeks of treatment, the physician made an overall assessment of these data for each respective four-week period and entered this on the trial sheet.

The study was an unbiinded, randomized, controlled study with two treatment groups. Six trial centers were involved, each with a minimum of six patients and a maximum of 10 patients. A separate randomization list was compiled for each trial center. The main target variable was the endoscopic findings with classification of the esophagitis according to Savary and Miller. The condition was considered healed when the previously established changes in the esophageal mucosa, in particular epitheiial defects, were no longer detectable. Changes were termed clinically relevant when the intensity of the esophagitis had been reduced by at least one degree. Secondary variables included were subjective symptoms after four and eight weeks, use of antacids, and severity and incidence of undesired side effects.

The 2 x c contingency test was used to compare the effects of therapy on the changes in the esophageal mucosa (healed, improved, unchanged) in the sucraifate and ranitidine groups.

RESULTS

Patients. A total of 49 patients were included in the study. Twenty-five patients were given sucralfate, and 24 were given ranitidine. The data from eight patients could not be used in the evaluation of effect: two sucralfate- treated patients withdrew from the study during treatment; control endoscopic examinations were therefore not pos-

44 September 28, 1987 The American Journal of Medicine Volume 83 (suppl 38)


Figure 1. Reflux esophagitis before and after eight weeks of treatment with 1 g of sucralfate (four times a day) or 150 mg of ranitidine (two times a day); stages of esophagitis (pretreatment and posttreat- ment) were classified by the Savary- Miller method.

SUCRALFATE RANITIDINE

(n=22) in=191

0 8 0 8 WEEKS

sible. After four weeks of therapy, an allergic rash developed in one patient given ranitidine, and treatment was discontinued (endoscopy showed an unchanged stage I reflux esophagitis according to Savary-Miller). Five patients did not meet the inclusion criteria: in one sucralfate- treated patient, Savary-Miller stage IV was established before commencement of treatment, ulcers developed in two ranitidine-treated patients (one gastric, one duodenal), and in two additional ranitidine-treated patients, endoscopic examination was not performed until 12 weeks after the start of treatment.

Of the remaining 41 patients, 22 received sucralfate, and 19 received ranitidine; this number of patients allows a detection of a 30 percent difference with an 80 percent confidence between the two treatment groups. Table I shows the characteristics of these patients and gives in- formation on case history and findings. The ranitidine group contained slightly more men, smokers, and alcohol consumers than did the sucralfate group. The sucralfate group contained more patients with stage III esophagitis than did the ranitidine group. The two groups were other- wise highly comparable. Endoscopic Findings after Eight Weeks of Treatment. In 14 of 22 sucralfate-treated patients (63.6 percent) and in 13 of 19 ranitidine-treated patients (68.4 percent), the esophagitis was healed after eight weeks of treatment. In an additional six sucralfate-treated patients (27.2 percent) and in four ranitidine-treated patients (21 percent), the esophagitis had improved by at least one degree of severity based on the Savary-Miller classification. The findings were unchanged in two patients in each group. A signifi- cant difference between the two groups was not found (p >0.05) (Table II). The results are shown in Figure 1 as a function of the degree of severity according to the

Savary-Miller classification: the changes in the esophageal mucosa classified as stage I changes were healed in all patients with the exception of one ranitidine-treated patient. This result was only obtained in four of eight patients in each group in which stage II had been established. The probability of healing reflux esophagitis within eight weeks of treatment decreased as the degree of severity before treatment increased. Subjective Esophagitis Symptoms and Use of Antac- ids. Table Ill shows subjective symptoms and their de- velopment. Differences between the two groups were not found with respect to these symptoms and their develop- ment. Only about one third of the patients in both groups had taken antacid tablets before the treatment. After eight weeks of treatment, only three patients in each group re- quired antacids (Table IV). Tolerance. All 49 patients were included in the assessment of tolerance. At the end of the treatment, tolerance was assessed as “very good” in 18 of 25 sucralfate- treated patients (72 percent) and in 18 of 24 ranitidine- treated patients (75 percent), and as “good” in an additional five patients in each group. Treatment was discontinued in one patient in the ranitidine group because of side effects (allergic rash after four weeks). An assessment of treatment was not possible in the two sucralfate- treated patients who withdrew from the study. Constipa- tion occurred for the first time during treatment in three sucralfate-treated patients and in one ranitidine-treated patient. Diarrhea developed in one ranitidine-treated patient. An existing tendency towards constipation was increased in one sucralfate-treated patient, two sucralfate- treated patients described a lesser tendency towards constipation, and one ranitidine-treated patient reported dis- appearance of diarrhea.

September 28, 1987 The American Journal of Medicine Volume 83 (suppl 38) 45


TABLE III Subjective Reflux Esophagitis Symptoms before (0) and during Treatment (after four and eight weeks) with Sucralfate and Ranitidine

Number 01 Patients with Symptoms

Symptom

Sucralfate Ranitidine (II = 22), (n = 19),

Week: Week:

0 4 a 0 4 a

Retrosternal burning 21 13 8 18 13 3 Epigastric pain 20 9 5 19 6 2 Difficulty in swallowing 12 3 2 6 1 1 Belching 12 7 4 11 3 1 Regurgitation of food 5 0 0 6 2 0 Vomiting 1 0 0 7 1 0

TABLE IV Use of Antacids before and during Treatment with Sucralfate and Ranitidine

Without Antacids

Number

Sucralfate

With Antacids

Number Percent

Without Antacids

Number

Ranitidlne

With Antacids

Number Percent

Before therapy 18 6 27 13 6 32 After 4 weeks 17 5 23 16 3 16 After 8 weeks 19 3 14 16 3 16

COMMENTS

The current options for treatment of reflux esophagitis are not entirely satisfactory for healing peptic lesions in the esophagus, treating subjective symptoms, or for prevent- ing relapse.

According to animal experiments, sucralfate has a pro- tective action on the mucosa of the esophagus. In vitro experiments on the mucous membrane of the rabbit esophagus [7] have shown that sucralfate prevents the increased transmucous flow of hydrogen ions elicited by reduction in the pH. The intensity of esophagitis induced experimentally by pepsin or hydrochloric acid can be reduced significantly in vivo by sucralfate treatment [8,9].

According to the clinical studies performed to date, after six to 12 weeks of treatment with sucralfate, reflux esophagitis is found to improve or to heal in 31 to 89 percent of patients [3-5,10,11]. These findings correspond to the experience in the therapy of reflux esophagitis using HP- receptor blockers [12-l 41.

In a direct comparison of sucralfate and cimetidine, endoscopic improvement in reflux esophagitis was found in 53 percent of patients after sucralfate therapy, and the condition was healed in 31 percent. The corresponding results after cimetidine therapy were 87 and 14 percent [3], respectively.

The more positive findings in the current study, in which healing rates of 64 percent were found after sucralfate administration and of 68 percent after ranitidine administration, and improvement rates of another 27 and 21 percent, respectively, can be best explained by the larger number of patients in whom classification according to Savary-Miller showed stage I. According to the findings from these two studies, a longer course of treatment would appear to promise greater success when changes in the esophageal mucosa are more pronounced.

The results of the two controlled studies versus HP- receptor blockers permit the conclusion that sucralfate has a comparable good effect. This also applies to the influence on the subjective symptoms of esophagitis and to the use of antacids.

Tolerance of the sucralfate treatment was generally good. The tendency towards constipation, known to be an adverse effect in sucralfate treatment and observed again in some patients in this study, was tolerable; treatment was continued. It was, however, necessary to discontinue treatment prematurely in one ranitidine-treated patient because of an allergic rash.

These results indicate that sucralfate is an effective alternative for the treatment of reflux esophagitis.

46 September 28, 1987 The American Journal of Medicine Volume 83 (suppl 3B)


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6. Savary M, Miller G: Das Osophagus-Lehrbuch und endos- controlled study. Digestion 1984; 29: 119-I 23. kopischer Atlas. Solothurn: Verlag Grassmann AG, 1977; 13. Koelz HR: Cimetidin 2 x 400 mg in der Behandlung der 135. Refluxosophagitis? Z Gastroenterol 1984; 22: 379-381.

7. Orlando RC, Powell DW: Effect of sucralfate on esophageal epi- 14. Temple JG, Bradby GVH, O’Connor FO, et al: Cimetidine and thelial resistance to acid in the rabbit (abstr). Gastroenterol- metoclopramide in oesophageal reflux disease. Br Med J ogy 1984; 86: 1201. 1983; 286: 1863-I 864.

September 28, 1987 The American Journal ot Medicine Volume 83 (suppl 38) 47

comparison of the effect of sucralfate and ranitidine in reflux esophagitis

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