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

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Date: 09 February 2016, At: 21:27

Combination Therapy of Sucralfate and Ranitidine, Compared with Sucralfate Monotherapy , in Patients with Peptic Reflux Esophagitis

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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-

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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/

1

//

//

//

/

/

/

/

P

PP

0

0

7

m

k

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);

P

0

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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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

3. Weiss W, Brunner H, Buettner GR, et al. Therapy of reflux esophagitis with sucralfate [German]. Dtsch Med Wochenschr 1983, 108, 1706-1711 4. Hameeteman WVD, Boomgaard DM, Dekker W, Schrijver M, Wesdorp ICE, Tytgat GNJ. Sucralfate versus cimetidine in reflux esophagitis, a single-blind multicentre study. J Clin Gastroenterol 1987, 9, 390-394 5. Schotborgh RH, Hameeteman W, Dekker W, et al. Combination therapy of sucralfate and cimetidine. compared with sucralfate monotherapy, in patients with peptic reflux esophagitis. Am J Med 1987, 86 Suppl 6A, 77-80 6. Savary M, Miller G. Das Oesophagus-Lehrbuch und endoskopischer Atlas. Verlag Grassmann, Solothurn, 1977, 135 7. Nagashima R. Mechanisms of action of sucralfate. J Clin Gastroenterology 1981, 3 Suppl 2, 117-127 8. Orlando RC, Turjman NA, Powell DW. Mechanism of mucosal protection of sucralfate and its components in acid-exposed esophagus [abstract]. Gastroenterology 1985, 88, 1524 9. Schweitzer EJ, Geisinger K, Wu WC, Hassan M, Castell DO. Acid-induced esophagitis in cats: cytoprotection by sucralfate [abstract] Gastroenterology 1985, 88, 1438 10. Evreux M. Sucralfate versus alginate/antacid in the treatment of peptic esophagitis. Am J Med 1987, 83 Suppl 3B, 48-50 11. Laitinen S , Staehlberg M, Kairaluoma MI, et al. Sucralfate and alginate/antacid in reflux esophagitis. Scand J Gastroenterol 1985, 20, 229-232 12. Simon 8 , Mueller P. Comparison of the effect of sucralfate and ranitidine in reflux esophagitis. Am J Med 1987. 83 Suppl 3B, 43-47 13. Wesdorp ICE, Dekker W, Klinkenberg-Knol EC. Treatment of reflux esophagitis with ranitidine. Gut 1983, 24, 921-924 14. Brenner CG, Marks IN, Segal I, Simjee A. Reflux esophagitis therapy: sucralfate versus ranitidine in a double blind multicentre trial. Abstract Book, 6th International Sucralfate Symposium, Queensland, Australia, 1990 15. Gudmundson K, Joelson B, Johnsson F. The hourly pattern of gastroesophageal reflux. In: Siewert JR, Holscher SH, editors. Diseases of the esophagus. Springer-Verlag, Berlin, 1987, 10621063 16. Johnsson F, Joelsson B, Isberg PE. Ambulatory 24-hour intraoesophageal pH-monitoring in the diagnosis of gastro-oesophageal reflux disease. Gut 1987, 28, 1145-1150 17. Tytgat GNJ, Nicolai J J , Reman FC. Efficacy of different doses of cimetidine in the treatment of reflux esophagitis. Gastroenterology 1990, 99, 629-634 18. Herrera JL, Shay SS, McCabe M, et al. Sucralfate used as adjunctive therapy in patients with erosive peptic esophagitis resulting from gastroesophageal reflux. Am J Gastroenterol 1990, 85, 1335-1338