Sucralfate and cimetidine as maintenance treatment in the prevention of duodenal ulcer recurrence

Sucralfate and Cimetidine as Maintenance Treatment in the Prevention of Duodenal Ulcer Recurrence

MIGUEL RODRIGO, Ph.D.

Granada, Spain

JOAQUIN BERENGUER, Ph.D. JOAQUIN HINOJOSA, M.D. Valencia, Spain

JOSE M. BALANZO, Ph.D. JOSE L. SEGU, Ph.D. Barcelona, Spain

From the Gastroenterology Service Section, Hospi- tal Virgen de las Nieves, Granada; the Gastroen- terology Service Section, Hospital La Fe and the Gastroenterology Section, Residencia Sagunto, Valencia; and the Gastroenterology Service Sec- tion, Hospital San Pablo and the Clinical Research Department, Merck, Barcelona, Spain, This work was supported by a grant from Merck Igoda, S.A. Requests for reprints should be addressed to Dr. Jose L. Segu Juan, Clinical Research Department, Merck-lgoda, S.A., P.O. Box 47, Mallet del Valles, Barcelona, Spain.

This multicenter trial investigated the ability of the cytoprotective agent sucralfate and the antisecretory agent cimetidine to prevent ulcer relapses. Seventy-one patients with recently healed duodenal ulcer were Included, randomly assigned to one of the two treatment groups, and administered sucralfate 2 g per day or cimetidlne 400 mg per day for six months; the treatment period was followed by another six months of follow-up without treatment. The response to therapy was evaluated by systematic single-blind endoscopy con- trols during the sixth and the 12th months. Quantitative (42 percent relapse rate with sucralfate and 52 percent with cimetldine) as well as qualitative (20 percent silent relapses with sucralfate and 47 percent wlth cimetidine) differences were observed, although these could not be demonstrated to be statistically slgnlflcant.

The purpose of all pharmacologic treatment of peptic, duodenal, and gastric ulcer disease should be not only the healing of acute episodes, but also the prevention of relapses [1,2]. The capacity of several antiulcer drugs, such as cimetidine [3,4] and sucralfate [5,6], to heal peptic ulcer is well documented, and these two drugs were also compared in this study. The problem of preventing relapses, thus changing the natural chronic- recurrent history of ulcer disease, remains still to be solved. For this reason, many clinical studies are currently being conducted toward this end, with encouraging results so far [7-91.

The main reason for choosing cimetidine and sucralfate is to investi- gate whether two different therapeutic approaches, although comple- mentary, namely the antisecretory agent [lo] (cimetidine), and the cytoprotective agent [l l-131 (sucralfate), behave in a significantly different way regarding their capacity to prevent relapse.

PATIENTS AND METHODS

This single-blind, randomized clinical trial of two groups was carried out at four sites. Seventy-one patients, aged 18 to 65, with a history of active duodenal ulcer endoscopically confirmed on at least one occasion, were randomly assigned to one of two groups after giving informed consent. A basic inclusion criterion was that the latest ulcer episode should have healed one day to a maximum of seven days before the start of treatment; endoscopic confirma- tion of the absence of the ulcer had to have taken place during the week before treatment.

Exclusion criteria included active gastric ulcer, any type of gastric surgery during the previous year, hypersecretory situation, multiple ulcers, regular intake of ulcerogenic drugs during the past three months and during the study period, pregnancy, and serious concomitant diseases. Patients smoking more than nine cigarettes daily [14], as well as patients regularly drinking more than 80 g of alcohol per day [15,16], were excluded.

September 28, 1987 The American Journal ol Medlclne Volume 83 (suppl 38) 99

SYMPOSIUM ON SUCRALFATE-RODRIGO ET AL

PREeTuw 1 PHASE I I PHASE it

I Malntonance I I Follow-up

I I (no troatmont) I I

I I I I I I s”c,al,ofe tg BID I

4-7 dOys ; 0 1 2 3 4 5 6 ’ t monnl I , t ;

Baseline 1 I Scheduled I Scheduled

Endoscow I Monthly Clinical Exam Endoscofzrj I Optional Endaco~ Endoscopy

F/gun, 1. Clinical trial design and examination times.

The classic definitions of Karch and Lasagna [I 7] (relation gency table (chi-square test) with an eventual Yates’ correc- stated in terms from “doubtful” to “definite”) were used as tion for small samples, assessing possible intergroup differ- assessment criteria of the cause-effect relationship for possi- ences in connection with the number of relapses and their ble undesired effects of the treatment. clinical type (silent or symptomatic).

Two parallel groups were established for comparison, one group that was treated with sucralfate 2 g per day divided into two doses (1 g in the morning before a meal and 1 g at bedtime), and another group that was treated with 400 mg of cimetidine as a single dose at night (two 200-mg tablets). The trial was structured so that the endoscopist was unaware of the drug administered to each patient. When possible, the same endoscopist carried out all examinations for a particular patient.

Figure 1 shows the trial design, with its two phases, as well as the times of clinical revisions and endoscopic examinations. Two systematic controlled endoscopies were carried out: one at the end of maintenance treatment (sixth month) and the other at the end of the follow-up phase without treatment (12th month). The patient atso underwent endoscopy whenever a relapse was suspected.

Patient compliance was assessed by monthly tablet counts and patient diaries of daily medication intake. Use of antacids was allowed when needed for pain. Concomitant use of other anti-ulcerative drugs was not permitted.

Statistical significance was determined using the ccntin-

RESULTS

The randomized assignment of the patients to either treatment group led to hOtTIOgWWOU8 distribution of their characteristics for factors having a potential’influence on the response to the drug [ 181 (Table I), such as use of alcohol and tobacco, duration of ulcer history, number of previous episodes, family history, and latest anti-ulcer therapy (cimetidine in 70 percent of the cases and ranitidine in 30 percent). The cigarette use in the sucralfate group was twice as high as in the cimetidine group. Of the 71 patients included, 15 (21 percent) withdrew from the study because they failed to appear at the monthly examinations (two or more absences) and/or because they were not compliant (ingestion of less than 70 percent or more than 130 percent of total dose prescribed monthly). Fifty-six patients were included in the evaluation: 28 from the sucralfate group and 30 from the cimetidine group. Of the 56 patients, 28 (50 percent) finished the 12 months of the trial-l 4 from the sucralfate group and 14 from the cimetidine group-without relapses or any other relevant inci- dences occurring. Of the remaining 28 patients, 25 presented with relapses, as well as three with adverse reactions-one receiving cimetidine and two receiving sucralfate-which led to discontinuation of treatment because of presumed drug intolerance. Thus, 29 patients in the cimetidine group and 24 in the sucralfate group were included in the evaluation to calculate the relapse rates.

TABLE I Demographic Characteristics of Patients

6eeretfets (n = 26)

Clmatldlne (n = 30)

Sex Male Female

Age (mean st SEM) Cigarettes per day

21 23 5 7

45.07 k 2.4 45.9 + 2.1 10.92 + 3.0 5.85 + 1.5

As described in Table II, the total number of relapses during the year of study was 25 (corresponding to a rate of 47 percent), of which 15 (52 percent) occurred in the ci-

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TABLE II Relapses Classified as to Presence or Absence of Symptoms for Both Treatment Groups during the Year of Study

Phase I + II (n = 53) Sucrnllate (n = 24)

Cimetldine (n = 29)

Significance (chi-square)

Total (percent) 25 (47)’ 10 (42) 15 (52) NS Symptomatic (percent) 16 (64)+ 8 w) 8 (53) NS Silent (percent) 9 (36)+ 2 (20) 7 (47) NS

NS = no significant differences between both treatment groups. *Percentages of total relapses (relapse rates) correspond to the quotient between the absolute number of relapses and the number of assessable patients (n) in each group. +Classified relapse percentages represent the quotient between the number of relapses of one or the other type and the total number of relapses in each group.

TABLE III Relapses Classified as to Presence or Absence of Symptoms for Both Groups and by Study Phases

Sucrnlfnte Cimstidlne Slgniflcance (n = 53) (n = 24) (n = 29) @hi-square)

Phase I Total (percent) 21 (39.6)’ a (33.3) 13 (44.8) NS Symptomatic (percent) 12 (57)+ 6 (75) 6 W NS Silent (percent) 9 bw+ 2 (25) 7 (54) NS

Phase II Total (percent) 4 (7.5) 2 (8.3) 2 (6.9) NS Symptomatic (percent) 4 uw 2 (100) 2 VW NS Silent (percent) 0 0 0 NS

NS = no significant differences between both treatment groups. *Percentages of total relapses (relapse rates) correspond to the quotient between the absolute number of relapses and the number of assessable patients (n) in each group. +Classified relapse percentages represent the quotient between the number of relapses of one or the other type and the total number of relapses in each group.

metidine group and 10 (42 percent) in the sucralfate group. This quantitative difference was not statistically significant at a 95 percent confidence level. The qualitative behavior of both drugs was also shown to differ. Only two of 10 sucralfate group recurrences were asymptomatic (20 percent), compared with seven of the 15 cases in the cimetidine group (47 percent), six being discovered during the systematic endoscopy in the sixth month and the seventh identified in a patient hospitalized because of severe digestive hemorrhage as a complication of silent relapse. Nevertheless, comparison of the two drugs did not show a statistically significant difference either.

By dividing the 12-month study period into its two phases, the total number of relapses in phase I was 21 (corresponding to a rate of 39.6 percent), of which eight (33.3 percent) occurred with sucralfate and 13 (44.8 percent) with cimetidine. During phase II, the total number of relapses was four (rate of 7.5 percent), of which two (8.3 percent) occurred in the sucralfate group and two (6.9 percent) occurred in the cimetidine group. Table Ill shows the results for both treatment groups in each of the two phases, taking into consideration the total number of re-

currences as well as their classification regarding the presence or absence of symptoms.

The three presumable side effects observed included a painful and reversible gynecomastia in a patient treated with cimetidine, as well as one case of persistent dyspep- sia and another of amenorrhea in the sucralfate group. Furthermore, as an anecdote, we might mention one case of iatrogenic ulcer relapse that was observed in a rheu- matic patient treated with sucralfate, who took 4 g of acetylsalicylic acid 15 days after starting prophylaxis and who presented with melena.

COMMENTS

From an effectiveness point of view, the justification of antisecretory preventive treatment is based on minimizing the re-exposure of the ulcer wound to damaging acid. The prophylactic use of sucralfate is based on the fact that the drug generally strengthens the mucosa barrier, because of its greater affinity for the newly healed ulcer scar than for the healthy mucosa [19,20].

Although no statistically significant difference was found in this trial, which may be due to the small size of the

September 28, 1987 The American Journal of Medicine Volume 83 (suppl 38) 101


sample after withdrawal of some participants and the fact that tobacco consumption was higher in the sucralfate group, there was a tendency toward fewer relapses in the sucralfate group than in the cimetidine group (42 percent versus 52 percent, respectively) and toward more symptomatic relapses (80 percent versus 53 percent). The relapse indexes shown here correspond to those found in other studies [9], the current study placing particular em- phasis upon a polemic and less known aspect, which is that of possible qualitative differences (symptomatic relapses) between the two types of drugs. Our results show a high percentage (47 percent) of asymptomatic relapses with cimetidine, which is lower than that described by Boyd et al [21], up to 58 percent for ranitidine. Cargill et al [22], on their part, observed that, when introducing control groups with placebo or without treatment, the percentage of silent recurrences amounted to up to 29 percent, which is higher than the 20 percent obtained with sucralfate.

The incidence and prevalence of asymptomatic ulcers in the general population are not well known, although Boyd et al [23] found that one third of the patients with duodenal ulcer perforation and one sixth of those with hemorrhagic complication had not previously shown dyspeptic symptoms. The reason why some episodes do not produce symptoms is not known either. On the other hand, these silent ulcers do not seem to have a greater tendency than the symptomatic ones towards causing complications, for which reason the authors conclude that it seems unnecessary to carry out routine endDSCOpieS during maintenance treatment.

Regarding the subject of the prevention of ulcer relapses, two well-differentiated aspects should be distin- guished: the influence of a certain anti-ulcer agent used in the treatment of an acute episode on the spontaneous relapse rate after healing, and the influence of post-healing maintenance treatment on said rate. With regard to the first aspect, this seems to be influenced by the anti-ulcer drug administered during the acute episode; there is the opinion that a drug that strengthens defensive mechanisms of the gastroduodenal mucosa offers greater bene- fits than one that reduces acid secretion. In support of this opinion, Marks et al [24] have shown that, compared with cimetidine, sucralfate delays the incidence of relapses to a statistically significant extent, since the mean duration of remission was 7.3 and 4.6 months, respectively. Other authors [25-271 have also confirmed that ulcers cured with cimetidine tend toward earlier relapses.

As to the second aspect, i.e., whether it is possible to significantly reduce relapse rates by carrying out prevent- ative treatment, Blackwood et al [28] have demonstrated that long-term cimetidine maintenance doses can significantly reduce recurrence rates in comparison with placebo, as long as treatment is continued. Nevertheless, once cimetidine treatment is discontinued, the percentage

of relapses is exactly the same for patients with short-term treatment as for those with 12 months [29] of treatment, which leads to the question of whether the medication should continue to be administered without interruption or whether intermittent treatment with cimetidine at full dos- age [30] WDUld be sufficient.

For sucralfate, several authors [31,32] have shown that dDSeS of 2 g per day, administered for six or 12 months, are significantly more effective than placebo in reducing the number of relapses. Moreover, Libeskind [33] found in a double-blind placebo-controlled trial that sucralfate 3 g per day administered for six months led to a relapse rate of only 11 percent, whereas the rate was 33 percent with 600 mg of cimetidine and 59 percent with placebo. This evidence suggests that the minimum effective dose would be 2 g per day [34] to provide significant protection from duodenal ulcer relapse.

From the clinical safety point of view, the justification for using one or another type of drug would be in favor of sucralfate [35], considering its local mechanism of action [36] and absence of the systemic side effects occurring with cimetidine [371 and ranitidine [38].

In connection with the safety of handling antisecretory agents in long-term treatment, it has been speculated that cimetidine might increase the risk of gastric cancer [39,40]. The proposed mechanism involved is that by reducing gastric secretion, cimetidine would allow intragas- tric proliferation of bacteria (which is pH-dependent [41,42]), some of which are able to reduce diet and saliva nitrates [43]. At the same time, they would promote quicker nitrosation of amines, amides, and urea of the diet [44], leading to the formation of nitrous-N compounds, in- cluding stable nitrosamines-N and relatively unstable [45] nitrosoureas-N and nitrosamides-N. The latter two compounds are carcinogenic in animals.

Regarding comparative studies between sucralfate and cimetidine, Morris et al [46] found an increase in the con- centration of nitrosamines and in the mutagenicity rate only in the group treated with cimetidine, and concluded that sucralfate should be used preferably because of its greater safety, especially in cases where long-term treatment is indicated.

The hemorrhagic relapse shown in a patient who took 4 g of acetylsalicylic acid, after 15 days of taking sucralfate 2 g per day, should imply a case of resistance to the protective action shown of 4 g per day against antirheu- matic-induced erosions. Thus, Tesler and Lim [47] found in a placebo-controlled trial complete protection in eight persons and partial protection in three of 12 healthy volun- teers treated with 3 to 8 g of acetylsalicylic acid for five days. However, since patients with duodenal ulcer have less tolerance of analgesics than do healthy subjects [48], the authors conclude that studies should be promoted to show whether sucralfate has a similar protective effect in

102 September 28,1987 The American Journal of Medicine Volume 63 (euppl38)


patients with ulcers who take nonsteroidal anti-inflamma- ACKNOWLEDGMENT tory drugs. We wish to thank Dr. J. Pleguezuelo, Dr. J. Martinez, Dr.

There is no doubt that cimetidine [49-521 and ranitidine J. Esteban (Hospital Virgen de las Nieves, Granada, [9,53-551 have been investigated more extensively than Spain), Dr. V. Garrigues, Dr. M. Sarrachina (Hospital la sucralfate regarding the ability to prevent relapses; there- Fe, Valencia, Spain), Dr. J. Primo, and Dr. C. Sanchis fore, further comparative clinical trials with said antisecre- (Residencia de Sagunto, Valencia, Spain) for their sub- tory agents are required to confirm the better quantitative stantial collaboration in undertaking this clinical trial, in the as well as qualitative results obtained with sucralfate in capacity of collaborators of the main investigator of each this study compared with cimetidine. center.

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Documents

Sucralfate and cimetidine as maintenance treatment in the prevention of duodenal ulcer recurrence