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Prevention of Relapse of Reflux Esophagitis after Endoscopic Healing: The Efficacy and Safety of Omeprazole Compared with Ranitidine L. LUNDELL, L. BACKMAN, P. EKSTROM, L.-K. ENANDER, S. FALKMER, 0. FAUSA, L. GRIMELIUS, N. HAVU, T. LIND, H. L ~ N R O T H , ~ S A N D M A R KB. , SANDZEN, P. UNGE & I. H. WESTIN Dept. of Surgery, Sahlgren’s Hospital, Gothenburg; Dept. of Surgery, Danderyd‘s Hospital, Danderyd; Dept. of Surgery and Medicine, Sandviken’s Hospital, Sandviken; Dept. of Surgery, Central Hospital, Karlstad; Dept. of Tumour Pathology, Karolinska Institute and Hospital, Stockholm; Dept. of Pathology, University Hospital, Uppsala; Dept. of Pathology and Safety Assessments, Astra, Sodertalje; Dept. of Otorhinolaryngology, Medical Centre Hospital, Orebro; Dept. of Surgery, University Hospital, Umei; and Dept. of Clinical Pharmacology and Medicine, Hassle, Molndal; Sweden, and Dept. of Medicine, Rikshospitalet, Oslo, Norway Lundell L, Backman L, Ekstrom P, Enander L-K, Falkmer S, Fausa 0, Grimelius L, Havu N, Lind T, Lonroth H, Sandmark S, SandzCn B, Unge P, Westin IH. Prevention of relapse of reflux esophagitis after endoscopic healing: the efficacy and safety of omeprazole compared with ranitidine. Scand J Gastroenteroll991,26,248256 Ninety-eight patients with erosive and/or ulcerative esophagitis unhealed after at least 3 months’ treatment with standard doses of cimetidine (31200 mg daily) or ranitidine (3300 mg daily) were primarily included in an acute healing phase study, and 51 were allocated to 40 mg omeprazole once daily and 47 to 300 mg ranitidine twice daily. After I2 weeks of treatment, 46 (90%) patients given omeprazole were healed, compared with 22 (47%) allocated to ranitidine. Healed patients were then given maintenance treatment with either 20 mg omeprazole once daily or 150 mg ranitidine twice daily for 12 months. Plasma gastrin was determined and gastric mucosal biopsy specimens were obtained during the entire study to assess the structure of the exocrine and endocrine cell populations of the oxyntic mucosa. Sixty-seven per cent of the total number of patients randomized to omeprazole were maintained in clinical and endoscopic remission throughout the 12-month study period as compared with only 10% among those given ranitidine 0,< 0.0001). After 4 weeks of orneprazole treatment basal gastrin levels were slightly increased, with a 95% confidence interval for the change of from 8.6 to 16.9pmol/l. No further increase in basal gastrin levels was observed during the ensuing study months. No significant histopathologic lesion was found in the oxyntic gland mucosa. In conclusion, omeprazole was far superior to ranitidine in preventing recurrence, a goal achieved without adverse events and significant abnormalities in the oxyntic mucosal exocrine or endocrine cells but with a moderate increase in basal gastrin levels. Key words: Gastric endocrine cells; gastrin; maintenance treatment; omeprazole; ranitidine; reflux esophagitis Lars Lundell, M . D., Ph. D . , Dept. of Surgery, Sahlgren’s Hospital, S-413 45 Gothenburg, Sweden

Until quite recently, pharmacologic acid inhibition induced by histamine Hz-receptor antagonists has constituted the cornerstone in the

medical treatment of reflux esophagitis (1,2). This regimen has, however, left a considerable number of patients with remaining symptoms and

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Prevention of Relapse

incomplete healing of the esophageal lesions. An explanation for the low healing rate after this treatment may be the predominant influence of 24-h intragastric acidity and the importance of the acid component in the subsequently refluxed material. Omeprazole, on the other hand, is known to cause a more sustained and prolonged acid inhibition, although not complete (3). In fact, 24-h pH-monitoring in the distal esophagus of patients before and during treatment with Hzreceptor antagonists compared with omeprazole has demonstrated profound differences in the acid exposure corresponding well with the differences in clinical efficacy (4-7), since recent studies have consistently reported omeprazole to be very effective in promoting healing of esophagitis and in relieving symptoms (8-14). Maintenance treatment with H2-receptor antagonist therapy has, so far, not been successful in preventing relapse in patients with reflux esophagitis and has in fact hitherto not been found superior even to placebo (1,2,15), although administration of higher doses of H2 blockers might be followed by a therapeutic gain (16). The aim of the present study was, therefore, to compare omeprazole with ranitidine with regard to the effect of healing and prevention of recurrence in patients with reflux esophagitis. In addition, as a part of the safety assessment of the studied drugs, the exocrine and endocrine cell populations of the oxyntic gland mucosa of the stomach were also studied histopathologically by means of regular, multiple biopsies. PATIENTS AND METHODS Study design and patient selection

The study was carried out as a randomized, double-blind, multicenter trial with two parallel groups using a double-dummy technique. Ninetyeight patients were randomly allocated to treatment with either 40 mg omeprazole once daily or 300 mg ranitidine twice daily in accordance with a computer-generated, block randomization list, stratified for centers. Patients were treated for 4 to 12 weeks, and if the esophagitis was found to be endoscopically healed. the patients entercd the maintenance phase of the study. Patients with esophagitis of at least grade 2 (11) were included


in the 12-week healing study, and the presence of Barrett’s esophagus and/or esophageal stricture was separately recorded. A prerequisite for inclusion was that the stricture must be easily dilated to enable adequate oral intake during the study period. The main exclusion criteria were age below 18 and above 80 years, pregnancy, lactation, concomitant peptic ulcer in the stomach and/or duodenum, previous esophageal and/or gastric surgery, severe concomitant cardiac, hepatic, or renal disease, the presence of malignant tumors, and significant abnormal laboratory findings at the pre-entry assessment. Patients healed with 40 mg omeprazole were treated with 20 mg omeprazole as maintenance treatment for at most 1 year, and patients healed on 600 mg ranitidine continued with 150 mg ranitidine twice daily for the same period of time. Patients were treated for 3-month periods and continued on this regimen if endoscopic lesions of grade 2 or worse did not appear. If symptoms recurred between two scheduled visits, an endoscopy was carried out, and the treatment was discontinued in case of endoscopic recurrence. All patients were supplied with antacid tablets, as previously described (11). Assessments A general medical history was recorded before entry into the healing phase of the study, including also details on alcohol and tobacco consumption. Endoscopic examination of the esophagus, stomach, and duodenum was performed every 4th week during the acute healing phase and, in patients whose esophagitis had healed, every 3rd month ( 2 2 weeks). The gross appearance of the esophageal mucosa was graded essentially as described by Sandmark et al. (11). Esophageal biopsy specimens were only taken to examine histopathologically whether any cellular atypia occurred in the epithelium and to verify the presence of heterotopic gastric mucosa in the esophagus. Barrett’s esophagus was defined as suggested by Skinner et al. (17). No attempts were made to study specifically the extension of the ectopic gastric mucosa during the study period. All patients were questioned concerning the presence and severity of heartburn, regurgitation, dysphagia, and odynophagia. The severity of


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reflux symptoms was graded, whereas other symptoms were recorded only as present or absent. The physical examination was always performed before the endoscopy. Blood and urine samples were taken for hematologic and biochemical analysis. The patients were asked to return the remaining trial medication at each visit, and the number of returned tablets and capsules was recorded. Histopathologic assessment of the biopsy specimens from the gastric mucosa During each endoscopy, gastric mucosa biopsy specimens were obtained from the corpus-fundus region of the major curvature of the stomach. A standard pair of biopsy forceps (OlympusFB24K) was always used. Five to six biopsy specimens were taken and immediately fixed in 10% neutral formalin. The biopsy specimens were conventionally embedded in paraffin; sections about 4 pm thick were cut and stained with hematoxylin-eosin and with van Gieson’s stain for histopathologic examination. This followed established clinicopathologic routines with some supplementary procedures, aiming to increase the accuracy of the diagnostic assessments and to decrease the extent of individual variations in the criteria used. The examinations were made by three pathologists (S. Falkmer, L. Grimelius. N. Havu) with particular experience and interest in endocrine and gastrointestinal pathology. The histopathologic specimens were evenly allotted by chance (and availability) to the three pathologists. When several biopsy specimens had been taken from one and the same patient, this fact was not paid attention to in allotting the specimens to the three pathologists for these primary assessments. In addition, at this stage of the investigation the pathologist on duty was not informed about previous biopsies (if any) or about the results of the preceding histopathologic assessments, In their reports of these primary histopathologic assessments, the three pathologists followed a standardized investigation scheme. The criteria for an adequate histopathologic assessment of the biopsy specimens were that they should have been oriented and cut in such a

manner as to enable full view of the mucosa. Then, the examination focused particularly on the presence of some kind of cellular atypia, or even genuine neoplasia, in the epithelium of the mucosa and its exocrine and endocrine cells. The occurrence of other lesions was, of course, also carefully registered, such as atrophic gastritis or other non-specific gastritis, either slight or moderate, chronic or acute, patchy or diffuse, and superficial or profound. Erosive gastritis and/or genuine peptic ulcers or focal fibrosis, indicating ulcer scars, were also searched for, as were polyps, either hyperplastic or non-hyperplastic, and foci of heterotopic gut or antral mucosa. Lastly, a note was also made of the occurrence of lymphoid hyperplasia, either diffuse or patchy. For assessment of the endocrine cell population, each biopsy specimen was also stained by the Grimelius silver-staining technique (18). By means of this procedure, a crude semiquantitative estimation of the number of endocrine cells was carried out. In case of an increased number of endocrine cells, the recently described histopathologic classification of non-antral gastric endocrine growths in man was followed (19). With regular intervals (to to three times annually) a second histopathologic assessment was made of all the relevant biopsy specimens; here, all the three pathologists were present together, and all the clinical and histopathologic data about each patient were assembled and arranged, so that full information could be obtained about the results of the primary histopathologic assessments, viewed against the background of the patient’s clinical data and the time intervals between the biopsies. Then the initial histopathologic diagnosis were adjusted for each specimen, considering all the information available. Finally, a conclusive histopathologic diagnosis was made for each patient. The total number of histopathologically examined biopsy specimens amounted to around 2550. Plasma gastrin assay Before each endoscopy a venous blood sample for gastrin analysis was collected in a heparinized tube. After centrifugation the plasma was trans-

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ferred to plastic tubes and stored deep-frozen at -20°C until analysis. All samples were then analyzed at Silab, Malmo, Sweden, using a radioimmunoassay (RIA) technique and antibody K 2604 (Prof. J. F. Rehfeld, Dept. of Clinical Chemistry, Rikshospitalet, Copenhagen, Denmark). Statistical methods and ethics The intention-to-treat approach was used to compare time in remission in patients randomized to the two treatment strategies. These two strategies are treatment with 40 mg omeprazole during the initial acute phase, followed by 20mg omeprazole for prevention of relapse of esophagitis, and treatment with 300 mg ranitidine twice daily during the initial acute phase, followed by 150 mg ranitidine twice daily for prevention of relapse. The end point used in the survival analysis, according to the actuarial life table method (see, for example, Pocock (20)) was recurrence of esophagitis. The LIFETEST program in the SAS package has been used for the estimation of the remission curve. Patients in whom the esophagitis did not heal after a full initial acute treatment course were defined to have time in remission equal to zero. Patients lost to follow-up during the study period or withdrawn for reasons other than relapse of esophagitis have in the survival analysis been considered to have been under risk until the time of the last check-up. In total, 13 patients in the omeprazole group compared with 10 in the ranitidine group had censored follow-up times owing to: 1) withdrawal during the acute healing phase of the study; 2) lost to follow-up during the maintenance phase; 3) withdrawal because of non-compliance or adverse event. The outcome in the study for the two treatment groups was also compared with a Wilcoxon rank sum test. The following ordinal scale was used to classify the clinical outcome: 1 = no recurrence; 2 = lost to follow-up; 3 = recurrence of symptoms only; 4 = recurrence of esophagitis only; 5 = recurrence of esophagitis and symptoms; 6 = withdrawn because of non-compliance or adverse


events; and 7 = unhealed in the acute healing phase of the study. Haematologic and other laboratory variables were analyzed in two ways. Variables with outliers (rare extreme values) or markedly skew distributions were analyzed in the following manner: The number of patients with increased, unchanged, and decreased values between preentry and end of treatment was given, and a sign test was used to test the hypothesis that increased and decreased values were equiprobable. On comparing the pattern of change between treatment groups, a chi-square test was applied. For variables with symmetric and moderately skew distributions, the one-sample t distribution was used to calculate a confidence interval for the mean change from pre-entry to end of treatment. A two-sample t test was used to analyze whether the mean change differed between the treatments. The study protocol was reviewed and approved by the Local Ethics Committees and by the National Health Board of Sweden and Norway, respectively. Informed consent was obtained from each patient before entering the study. RESULTS Ninety-eight patients were included in the healing study, and 51 of these were allocated to 40mg omeprazole once daily. The pre-entry characteristics in the two study groups were quite similar (13).Forty-six patients were healed after 12 weeks of omeprazole treatment as compared with only 22 among the 47 allocated to 600mg ranitidine per day. Four patients treated with omeprazole remained unhealed, and one patient was withdrawn owing to alcohol abuse. In the ranitidine group 21 patients were unhealed, 1 patient was lost to follow-up, and 3 were withdrawn because of diarrhea, hematemesis, or anorexia. Thus considerably more patients in the omeprazole group proceeded to maintenance treatment. Time in remission Twenty-three of the 46 patients receiving omeprazole as maintenance treatment were maintained in remission during the entire 12-month study period compared with only 2 of the 22


L. Lundell et al.

Table I . The fate of patients during maintenance treatment


Ranitidine (n = 22)

( n = 46)

In remission




2 14


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Colonic carcinoma Palpitation Lost to follow-up

1 1*



* This patient was healed but refused to continue with maintenance treatment because of palpitations. t Six omeprazole patients and three given ranitidine had to be withdrawn owing to late permission from the authorities to continue the trial for the last 6 months.

ranitidine-treated patients. Endoscopic relapse was observed in 11 patients in the omeprazole group and in 14 patients in the ranitidine group (2 patients in each group had only minor or no clinical symptoms of recurrence). Eighteen patients were withdrawn during maintenance treatment, 12 in the omeprazole group and 6 in the ranitidine group (Table I). Six patients given omeprazole and three allocated to ranitidine had to be classified as ‘lost to follow-up’ owing to a late permission from the authorities to continue the maintenance trial for more than 6 months. Omeprazole was far superior to ranitidine in

keeping patients in symptomatic and endoscopic remission during the 12-month maintenance study period (Fig. 1).The log rank test for a comparison of the remission curves gave a chi-square value of 31.3 (df = l ) , corresponding to a p value of 0.0001. At the end of the trial, 67% of patients allocated to omeprazole were in remission as compared with only 10% among those given ranitidine. The outcome of the study was also compared by means of a Wilcoxon’s rank sum test. The ordinary scale for comparing the 12 months’ recurrence rate gave a Z value of 5.32, also signifying a substantial difference in clinical efficacy between those given omeprazole and ranitidine ( p < 0.0001).

Histopathologic assessments Since only two patients receiving maintenance treatment with ranitidine were in remission for the whole 12-month study period, the mean treatment period for these patients was much shorter than for those given omeprazole. There were no neoplastic lesions whatsoever in any of the 2550 biopsy specimens investigated histopathologically, not even any kind of cellular atypia, either in the exocrine or in the endocrine parts of the epithelium of the gastric mucosa. Apart from isolated cases of early atrophic gastritis, there were no severe histopathologic lesions in any of the biopsy specimens. The only

Patients in remission % 100 1



> I



Omeprazole 20 mg om

-- Ranitidine 150 mg bid












12 Months

Fig. 1. Cumulative proportion of patients in symptomatic and endoscopic remission when treated with either omeprazole (20 mg once daily) or ranitidine (150 mg twice daily) for 1 year after initial healing of the mucosal lesions.

Preuention of Relapse


Table 11. Survey of the histopathologic diagnosis made on the biopsy specimens from the oxyntic gland mucosa before entry into the trial and at the last visit during the study ~

On completion of treatment

Pre-entry diagnosis

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Normal Lymphoid hyperplasia Slight/moderate gastritis Atrophic gastritis

Treatment group Omeprazole Ranitidine Omeprazole Ranitidine Omeprazole Ranitidine Omeprazole Ranitidine

Normal 25 25

0 0 2 2 0 0

histopathologic lesions found were slight to moderate, non-specific gastritis; this occurred rather inconsistently and could not be ascribed to any kind of treatment. T h e prevalence was the same in the pre-entry specimens as in those after completion of treatment (Table 11). A normal localization of endocrine cells in the lower half of the oxyntic mucosa was observed in all patients throughout the study. The number of argyrophil cells was considered increased on one or more biopsy occasions in five patients; one of them belonged to the ranitidine group and four to the omeprazole group. This hyperplasia was of diffuse type and in n o instance considered to be linear (chain-forming), and no micronodular or adenomatoid hyperplasia of the argyrophil cells was found (19). T h e hyperplasia was patchy and inconsistent and was observed on one or on only a few of the biopsy occasions. In one patient, however, the increase was persistent and stable at 3 , 6 , 9 , and 12 months of the maintenance study period. In another patient, the increase was observed only in specimens obtained at the preentry endoscopy, whereas in one patient a corresponding observation was made in specimens taken 3 months after cessation of drug administration.

Plasma gastrin During the healing part of the study there was a significant increase in fasting gastrin levels only in omeprazole-treated (40 mg once daily) patients, with a 95% confidence interval from 8.6 to 16.9pmol/l for the change and from 8.7

Lymphoid hyperplasia

Slight/moderate gastritis

1 1 1 0 0 0 0 0


Atrophic gastritis

3 0 0 16 14 0 0

to 21.6 pmol/l during the 12-month maintenance study period (normal gastrin range < 50 pmol/l). Of the 43 patients in whom gastrin determinations were carried out during the maintenance study, 37 had an increase in basal gastrin levels already during the healing part of the study, whereas 5 experienced a decreased gastrin concentration, and, finally, in 1 patient no change occurred. This increase in fasting gastrin levels was seen already after 4 weeks of omeprazole treatment (40 mg) and during the 12-month maintenance study period no significant change in basal gastrin levels was observed (Fig. 2).

Adverse events Minor adverse events were recorded with a similar frequency in the two groups. Two patients were withdrawn during maintenance treatment with ranitidine; one patient experienced massive gastrointestinal bleeding, and the other patient had a history of severe vertigo with nausea. In the omeprazole group two patients were withdrawn during maintenance treatment; one patient had a colon carcinoma, and another patient had moderate diarrhea with epigastric pain. N o clinically important changes that could be attributed t o treatment were observed in the laboratory values. DISCUSSION Among several suggested prognostic factors of importance for the healing of esophagitis, essentially two have consistently been reported to be


L. Lundell et al.

m Omeprazole




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I 180

ri 270


20 rng om 0Ranitidine 150 mg bid


Fig. 2. Basalgastrin concentrationsinpatients treated with omeprazole or ranitidine. The mean and SD are given. 0 stands for pre-entry assessment, and A for 40 mg omeprazole and 600 mg ranitidine. Only two patients treated with ranitidine had full series of measurements for 12 months. of importance: the type of drug treatment and the itidine treatment. These results have for the first pre-treatment severity of the esophageal mucosal time demonstrated a medical regimen to be effeclesions (11, 13, 14). Cessation of medical treat- tive in preventing relapse of reflux esophagitis. A low gastric acidity facilitates release of gastrin ment is followed by recurrent symptoms and erosive and/or ulcerative lesions in most cases, from the gastric antrum. A relationship has prealthough the slope of the relapse curve seems to viously been established between the level of differ somewhat between different investigations reduction in gastric acidity achieved by ome(11, 12, 14). Recent observations on unfavorable prazole treatment and the increase in plasma gasprognostic factors for the relapse risk after endo- trin (23,24). Measured continuously over 24 h, scopic healing have indicated very few, if any, to plasma gastrin will be modestly increased during be of importance. In fact, only remaining reflux both short- and long-term treatment with omesymptoms at the time of endoscopic healing was prazole, slightly more after 20 mg daily than after found to be of importance for the relapse risk 150 mg ranitidine given twice daily (25). The fast(21). Such observations further substantiate the ing gastrin elevation during treatment with 20demand for an effective medical maintenance 40 mg omeprazole daily in patients with refractory therapy in patients with reflux esophagitis, at least ulcer disease has been found to stabilize after the in those who are not suitable for surgery. His- first few months of treatment without any further tamine H2-blockers have, so far, not been found progress for 4 years (25). In fact, it has recently superior to placebo in preventing relapse been observed that the increase in plasma con(1,2, 15). Apparently, omeprazole has the poten- centration of gastrin over 24 h after omeprazole tial to be effective as a long-term treatment of is of the same magnitude as after proximal gastric reflux esophagitis and found to be so in uncon- vagotomy (26). The modest increase in fasting trolled trials (22). The schedule, efficacy, and gastrin concentration presently observed during safety of such therapy has, however, not hitherto a 1-year treatment with 20 mg omeprazole further been established in a randomized trial. In the substantiates the notion that well-adjusted, propresent study 67% of the patients randomized found acid inhibition, as obtained by this treatto omeprazole (20 mg once daily) were kept in ment, is not followed by any increase in gastrin symptomatic and endoscopic remission for 1 year, levels that causes concern (23). An important a clinical efficacy that should be compared with observation was that no further increase in basal only 10% kept in remission on 'full-dose' ran- gastrin concentration was seen during the 1-year

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Prevention of Relapse

maintenance study period. The difference in gastrin concentrations noted between patients given omeprazole and those treated with ranitidine is easily reconcilable with the difference in effect on gastric acidity (23,24,28). Evidence has accumulated to show that gastrin exerts a trophic effect on the endocrine cell population of the oxyntic gland mucosa and particularly stimulates the proliferation rate of the enterochromaffin-like (ECL) cells in many species studied, although these cells of the rat gastric mucosa seem to be especially susceptible to gastrin stimulation (29, 30). In patients with antrum-sparing atrophic gastritis and achlorhydria, the massive hypergastrinemia is accompanied by hyperplasia of fundic mucosal endocrine cells, most of which are considered to be ECL cells (31-33). During long-term (2 years) treatment of rats with doses of omeprazole much greater than those used in clinical practice, a hypertrophy of the gastric oxyntic mucosa was seen with diffuse ECL-cell hyperplasia and, in some cases, development of non-metastasizing carcinoids (34). The modest hypergastrinemia caused by long-term omeprazole treatment in man has to be evaluated with regard to the development of hyperplasia of endocrine cells in the oxyntic gland mucosa. However, many problems are related to the classification of endocrine lesions in man (19). In the case of a diffuse parenchyma, such as the endocrine system of the stomach, there is the difficulty of defining changes in this system of disseminated cells in which the structural characteristics may be influenced by a random variation from section to section (19,35). This can be illustrated by the hyperplasia of argyrophil cells observed already at the pre-entry assessment in one patient randomized to ranitidine. Unfortunately, only two patients given ranitidine were available for analyses during a 12month study period. In the considerably larger omeprazole group, some biopsy specimens showed a diffuse hyperplasia of argyrophil cells, although not observed with an increased frequency during the course of the study and without any relationship to the actual gastrin levels. Instead, biopsy specimens showing diffuse hyperplasia of argyrophil cells seem to appear in a


quite irregular pattern, probably representing a variation with no clinicopathologic significance (19,36). Thus, our observations on the endocrine cell population of the human oxyntic mucosa during long-term treatment with omeprazole essentially corroborate those obtained in uncontrolled studies covering a longer time period (37). In conclusion, omeprazole is far more effective than ranitidine in maintaining patients with reflux esophagitis in symptomatic and endoscopic remission when studied over a 12-month period. This goal was achieved without any adverse events attributable to the study medication, without any significant histopathologically detectable effects on the exocrine or endocrine cell gastric population of the gastric mucosa, and with only a modest increase in basal gastrin levels. ACKNOWLEDGEMENTS This study was supported by grants from the Swedish Medical Research Council (projects 12X-102, 12X-718, and 17X-760) and from the Cancer Society of Stockholm, Sweden. REFERENCES 1. Tytgat GNJ, Nio CY. The medical therapy of reflux esophagitis. Clin Gastroenterol 1987, 1, 791-807 2. Koelz HR. Treatment of reflux esophagitis with Hzblockers, antacids and prokinetic drugs. Analysis of randomized clinical trials. Scand J Gastroenterol 1989, 24(suppl 156), 25-36 3. Lind T, Cederberg C, Ekenved G , Haglund U, Olbe L. Effect of omeprazole-gastric proton pump inhibitor on pentagastrin-stimulated acid secretion in man. Gut 1983, 24, 27G276 4. Johansson KE, Tibbling L. Maintenance treatment with ranitidine compared with fundoplication in gastroesophageal reflux disease. Scand J Gastroenterol 1986, 21, 779-788 5. Schaub N, Meurick TJ. Misiewicz J . Love11 D. Troutman IF. Investigation of ranitidine 150 mg b i d . or 300mg b.i.d. in the treatment of reflux disease. Hepatogastroenterology 1986, 33,206-213 Ruth M, Ehnbom H , Lundell L, Lonroth H, Sandberg N, Sandmark S. The effect of omeprazole or ranitidine treatment on 24 hour esophageal acidity in patients with reflux esophagitis. Scand J Gastroenterol 1988, 23, 1141-1146 Pasqual JC, Hemery P, Bruley S, Galmiche JP. Comparison of the effects of two doses omeprazole on 24-hour esophageal pH in gastrocsophageal reflux disease [Abstract]. Gastroenterology 1987, 92, 1567

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8. Klinkenberg-Knol EC, Jansen JMBJ, Festen HPM, Meuwissen SGM, Lamers CBHW. Double blind multicentre comparison of omeprazole and ranitidine in the treatment of reflux esophagitis. Lancet 1987, 1, 349-351 9. Van Trappen G , Rutgeerts L, Shurmans P, Coengrachts JL. Omeprazole (40 mg) is superior to ranitidine in short term treatment of ulcerative reflux esophagitis. Dig Dis Sci 1988, 33, 523-529 10. Havelund T, Laursen LS, Skoubo-Kristensen E, et al. Omeprazole and ranitidine in the treatment of reflux esophagitis: double blind comparative trial. Br Med J 1988, 296, 89-92 11. Sandmark S, Carlsson R, Fausa 0,Lundell L. Omeprazole or ranitidine in the treatment of reflux esophagitis. Results of a double blind, randomized, multicentre study. Scand J Gastroenterol 1988,23, 625-632 12. Hetzel DJ, Dent J, Reed WD, et al. Healing and relapse of severe peptic esophagitis after treatment with omeprazole. Gastroenterology 1988, 95, 903912 13. Lundell L, Backman L, Ekstrom P, et al. Omeprazole or high dose ranitidine in the treatment of patients with reflux esophagitis not responding to standard doses of H2-receptor antagonists. Aliment Pharmacol Ther 1990, 4, 145-155 14. Koelz HR, Birchler R , Bretholz A, et al. Healing and relapse of reflux esophagitis during treatment with ranitidine. Gastroenterology 1986, 91, 119% 1205 15. Armstrong D, Blum L. Full dose H2-receptorantagonist prophylaxis does not prevent relapse of reflux esophagitis. Gut 1989, 30, A1494 16. Johnson NJ, Mills JG, Wood JR. Acute treatment of reflux esophagitis: a multicentre trial comparing ranitidine 150 mg b.i.d. with ranitidine 300 mg q.i.d. Gastroenterology 1989, 96, A242 17. Skinner DB, Walther BC, Ridell RH, Schmidt H, Lascone C, DeMeester TR. Barrett’s esophagus. Comparison of benign and malignant cases. Ann Surg 1983, 198, 554-566 18. Grimelius L. Wilander E. Silver staining in the study of endocrine cells of the gut and pancreas. Invest Cell Pathol 1980, 3, 3-12 19. Solcia E, Bordi C, Creutzfeldt W et al. Histopathological classification of non-antral gastric endocrine growths in man. Digestion 1988,41,145200 20. Pocock S. Clinical trials. Wiley and Sons, Chichester, 1983, 221-227 21. Hetzel DJ, Carlsson R, Dent J, Lundell L. Relapse of esophagitis after endoscopic healing, analyses of unfavourable prognostic factors. Gastroenterol Int 1988, l(suppl l), A846 22. Dent J, Klinkenberg-Knol EC, Elm G, Eriksson K, Rikner L, Solvell L. Omeprazole in the long-term management of patients with reflux esophagitis refractory to histamine H,-receptor antagonist. Gastroenterol Int 1988, l(suppl l ) , A847

Received 27 June 1990 Accepted 20 August 1990

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Prevention of relapse of reflux esophagitis after endoscopic healing: the efficacy and safety of omeprazole compared with ranitidine.

Ninety-eight patients with erosive and/or ulcerative esophagitis unhealed after at least 3 months' treatment with standard doses of cimetidine (greate...
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