Omeprazole versus high-dose ranitidine in mild gastroesophageal reflux disease: short- and long-term treatment

THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 1999 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.

Vol. 94, No. 4, 1999 ISSN 0002-9270/99/$20.00 PII S0002-9270(99)00044-1

Omeprazole Versus High-Dose Ranitidine in Mild Gastroesophageal Reflux Disease: Short- and Long-Term Treatment Henk P. M. Festen, M.D., Ph.D., Ed Schenk, M.D., Gie Tan, M.D., Pleun Snel, M.D., Ph.D., Frits Nelis, M.D., Ph.D., and The Dutch Reflux Study Group Departments of Internal Medicine, Groot Ziekengasthuis, ’s-Hertogenbosch; Department of Gastroenterology, Free University Hospital, Amsterdam; Department of Internal Medicine, Streekziekenhuis Midden-Twente, Hengelo; Department of Gastroenterology, Slotervaart Ziekenhuis, Amsterdam; Department of Gastroenterology, Sophia Ziekenhuis, Zwolle, The Netherlands

OBJECTIVE: Patients with reflux esophagitis suffer from a chronic condition that may cause considerable discomfort because of recurrent symptoms and diminished quality of life. This study was designed to evaluate acute and longterm treatment comparing standard doses of omeprazole and high-dose ranitidine. METHODS: Patients with endoscopically verified symptomatic esophagitis grade I or II were initially treated with omeprazole 20 mg daily or ranitidine 300 mg twice daily for 4 – 8 wk. Patients who were symptom free were randomized to maintenance treatment with omeprazole 10 mg daily or ranitidine 150 mg twice daily. Patients were seen every 3 months or at symptomatic relapse. RESULTS: The percentage of asymptomatic patients after 4 and 8 wk treatment were 61% and 74%, respectively, for omeprazole and 31% and 50%, respectively, for ranitidine. Of 446 patients treated initially, 277 were asymptomatic, of whom 263 entered the maintenance study. The estimated proportion of patients in remission after 12 months of maintenance treatment with omeprazole 10 mg daily (n 5 134) and ranitidine 150 mg twice daily (n 5 129) were 68% and 39%, respectively (p , 0.0001). CONCLUSIONS: Omeprazole 20 mg daily is superior to highdose ranitidine in the symptomatic treatment of reflux esophagitis grade I and II. Furthermore, omeprazole at half the standard dose is more effective than ranitidine in a standard dose in keeping patients in remission for a period of 12 months. (Am J Gastroenterol 1999;94:931–936. © 1999 by Am. Coll. of Gastroenterology)

INTRODUCTION Reflux esophagitis is a common disorder, with symptoms of heartburn, regurgitation, or dysphagia. The reflux of gastric acid is considered to have a central pathogenetic role in this disorder. There are primarily two types of treatment: life-

style modifications, such as changes in diet, posture, weight control, and cessation of smoking, and drug therapy, such as prokinetics, antacids, H2 receptor antagonists, and proton pump inhibitors (PPI). Several studies have shown omeprazole to be more efficacious than ranitidine in healing and symptom relief in patients with moderate and severe reflux esophagitis (1–7). Few studies, however, have compared omeprazole and ranitidine in patients with mild reflux esophagitis (SavaryMiller grades I and II). Reflux disease is often a chronic condition that may cause considerable discomfort because of recurrent symptoms and diminished quality of life. After cessation of therapy, relapse is usually rapid. A simple, safe, and effective maintenance treatment is therefore desirable. The efficacy of such maintenance treatment is well established for H2 receptor antagonists in peptic ulcer disease, but not in reflux esophagitis, where results have been disappointing. Omeprazole 20 mg o.m. as maintenance treatment in GERD has been studied thoroughly, showing superior clinical efficacy to H2 receptor blockade (8 –10). Omeprazole 10 mg also showed promising results in maintenance therapy, with higher remission rates when compared to ranitidine (11–13). All the studies mentioned evaluated the efficacy of the treatments on the basis of endoscopic healing. In daily practice however, physicians treat their patients on the basis of symptom relief, and endoscopy is performed only in complicated disease or when symptoms persist. In almost all available studies omeprazole 20 mg was compared with a regular-dose H2 receptor antagonist (ranitidine 300 mg nocte or 150 mg b.i.d.). However, in day-today practice, quite often double doses of H2 receptor antagonists are used to treat patients with reflux esophagitis. This study was designed to evaluate acute and long-term treatment comparing standard doses of a PPI with high-dose H2 receptor antagonist in reflux esophagitis grade I and II in a setting and under conditions imitating, as much as possible, standard daily practice. We therefore focused only on

932

Festen et al.

subjective symptom scores, as this reflects the way physicians treat their patients.

MATERIALS AND METHODS The study was divided into two phases: an acute healing phase and a relapse prevention phase. Patients were recruited from among subjects referred for upper gastrointestinal endoscopy because of symptoms suggestive of gastroesophageal reflux disease. Patients aged 18 – 80 yr with esophagitis grade I or II (Savary-Miller) were eligible to participate in the study. Exclusion criteria were evidence of other uncontrolled, clinically significant disease; use of PPIs in the month before the study; and use of H2 receptor antagonists in doses higher than the recommended healing dose 1 month before the study. The study was performed as a prospective, randomized, double-blind multicenter study. Twenty-eight centers participated in the study. Patients with reflux esophagitis as defined here were randomized to treatment with omeprazole 20 mg o.d. or ranitidine 300 mg b.i.d. for 4 wk (6 3 days). The same treatment was given for another 4 wk (6 3 days) in case of persisting symptoms. If symptoms still persisted after 8 wk, the patient left the study and was treated at the discretion of the physician. Patients who were symptom free after 4 or 8 wk were eligible to be rerandomized to treatment with omeprazole 10 mg o.d. or ranitidine 150 mg b.i.d. for up to 12 months. Patients visited the outpatient clinic every 3 months (6 7 days) or in the case of recurrence of symptoms. Randomization was performed by a computer-generated list, in the healing phase, in blocks of two with a 1:1 ratio, and in the maintenance phase, in blocks of four with a 1:1 ratio. The study was rendered double-blind with the double-dummy technique. In both the healing and relapse prevention phases, the patients were instructed to take one capsule and one tablet in the morning before breakfast and one tablet in the evening at bedtime. Compliance was assessed by counting the returned study medication. Intake # 75% or $ 125% of the total number of scheduled doses of the study drug was considered inadequate compliance. In both phases of the study the patients were allowed to take antacids on a pro re nate basis. Assessments Before entry into the acute healing phase of the study, a general medical history was obtained and a physical examination performed. The severity of reflux symptoms was assessed during each visit by standardized questioning on the symptoms of heartburn, regurgitation, and dysphagia, and by an overall evaluation using a 4-point Likert scale with the scorings 0 5 none, 1 5 mild, 2 5 moderate, and 3 5 severe. During the first 4 wk of treatment the patients noted on a diary card the presence or absence of reflux symptoms and the number of antacid tablets used. At study entry and after 4 wk, patients were asked to complete the Gastrointestinal Symptom Rating Scale

AJG – Vol. 94, No. 4, 1999

(GSRS), a disease-specific quality-of-life questionnaire (14). This validated questionnaire was developed for the assessment of symptoms associated with upper gastrointestinal disorders. The questionnaire, which includes 15 items, uses a 7-point graded Likert scale. In its present form it consists of five dimensions: indigestion syndrome, diarrhea syndrome, obstipation syndrome, abdominal pain syndrome, and reflux syndrome. Symptom free was defined as no episodes of reflux symptoms during the past week. Only slight or moderate regurgitation was accepted. Relapse was defined as recurrence of episodes of moderate or severe overall reflux symptoms occurring on at least 2 days during the past 7 days. Any adverse event occurring during the study was recorded at each visit. Statistical Methods The sample size calculation was based on the assumption that the permanent disease remission in the relapse prevention phase would be 65% and 40% during treatment with omeprazole 10 mg o.d. and ranitidine 150 mg b.i.d., respectively, with an a of 0.05 and b of 0.80. A total of $300 asymptomatic patients should be included in the relapse prevention phase of the study. Assuming that 30% of the patients would not become symptom free (based on the response in the ranitidine group) and an additional 15% would dropout during the study, a total of 450 patients had to be included in the healing phase of the study. Two approaches were used to analyze the data: all-patientstreated and per-protocol; the latter included all patients who completed the study with no major violations of the protocol. In this article we present only the all-patients-treated analysis, the reason being the lack of any difference between the two analyses with respect to the main efficacy variables. The proportions of patients without symptoms in the acute phase were compared by means of a x2 test. From the diaries, the mean time until the patient was symptom free was computed. From the GSRS questionnaire, the sum of scores for the five predetermined dimensions and the total score were computed. If .40% of the questions constituting a dimension were missing, the dimension was considered missing. For the dimensions from the GSRS questionnaire, the change from baseline to wk 4 was analyzed by two-way lay-out analysis of variance, in which center and treatment were factors. Treatment effects are presented together with their 95% confidence intervals. Time to recurrence of symptoms was analyzed in survival analysis and compared by using the log-rank test. The study was performed in accordance with the Declaration of Helsinki and approved by the ethical committees of all participating centers. Patients were given written and verbal information about the study, and written or witnessed verbal informed consent was obtained from each patient before inclusion.

AJG – April, 1999

Omeprazole in GERD

Table 1. Clinical Characteristics of the 446 Patients at the Start of the Study (Mean [SD]) Variable

Omeprazole (n 5 222)

Ranitidine (n 5 224)

Age, yr 51.1 (14.5) 49.8 (13.9) Gender (male/female), N 118/104 115/109 Weight, kg 80.0 (14.0) 81.5 (13.7) Grade of esophagitis, 0/1/2 1/160/61 0/167/57 Concurrent medication, no/yes 132/90 131/93 Heartburn, none/mild/moderate/ 12/24/128/58 10/31/125/58 severe Regurgitation, none/mild/moderate/ 51/51/99/21 62/58/82/22 severe Dysphagia, none/mild/moderate/ 139/47/31/5 153/45/21/5 severe

RESULTS Acute Healing Phase and Enrollment for Relapse Prevention Phase Four hundred forty-eight patients were enrolled in the healing phase of the study. One patient received the wrong medication, and another patient never received medication, resulting in 446 patients randomized to either omeprazole 20 mg o.m. (n 5 222) or ranitidine 300 mg b.i.d. (n 5 224). At baseline, the treatment groups were well matched for selected characteristics (Table 1). In the omeprazole 20 mg group, 28 patients were withdrawn for the following reasons: adverse events in eight cases; noncompliance in four cases; deterioration of symptoms in seven cases; refusal to cooperate in four cases; and other reasons in five cases. Twenty-nine patients were withdrawn from the ranitidine

933

group: adverse events in nine cases; noncompliance in three cases; deterioration of symptoms in eight cases; refusal to cooperate in six cases; and other reasons in three cases. After 4 wk of treatment 135 patients (60.8%) in the omeprazole group and 70 patients (31.3%) in the ranitidine group were asymptomatic (p , 0.0001). After another 4 wk of treatment, an additional 30 patients taking omeprazole and 42 patients taking ranitidine became asymptomatic. After 8 wk, the cumulative percentages of asymptomatic patients were (165/222) 74.3% for omeprazole and (112/ 224) 50% for ranitidine (p , 0.001). Analysis of the patients’ diary cards substantiated that more patients treated with omeprazole were symptom free than patients treated with ranitidine. Also, the onset of symptom relief occurred earlier in the omeprazole-treated patients than in the ranitidine-treated patients (Fig. 1). The use of antacid tablets did not differ between treatment groups. The median value of the number of ingested antacids was 0 for both treatment. At baseline, the mean (SD) for the total GSRS scores were 19.8 (10.4) and 20.8 (12.1), respectively, for the omeprazole and ranitidine group (p 5 ns). After 4 wk of treatment, the reduction in total score was statistically significant for both treatments. Within the treatment groups, statistically significant improvements between baseline and 4 wk were found for the five dimensions of the GSRS. After 4 wk of treatment, the reflux dimension showed a significantly greater improvement in the omeprazole than in the ranitidine group (4.06 vs 2.84, p , 0.013). The reduction in the total GSRS score was also significantly greater with omeprazole than with ranitidine (12.28 vs 9.95, p 5 0.001). Other symptom clusters did not differ significantly (Fig. 2).

Figure 1. Percentage of patients symptom free by day: omeprazole n 5 214, ranitidine n 5 222.

934

Festen et al.

Figure 2. Change in gastrointestinal symptoms (GSRS): 95% CI.

Adverse events were recorded for 45 patients treated with omeprazole and 63 patients treated with ranitidine. Most of these were abdominal complaints. In 17 cases, adverse events caused withdrawal from the study, and two of these were considered serious, without differences between the treatment groups: One patient treated with omeprazole was hospitalized because of severe epigastric pain and another patient treated with ranitidine was hospitalized because of angina pectoris. Relapse Prevention Phase Of the 277 asymptomatic patients, 13 were excluded from entry into the relapse prevention phase of the study: unwillingness to continue in nine cases, residual symptoms in two cases, and severe headache and (nonspecified) complaints in two individual cases. Altogether, 264 patients entered the maintenance study. One patient received the wrong study medication and was never randomized. One hundred thirtyfour patients were allocated to treatment with omeprazole 10 mg o.d., and 129 patients to treatment with ranitidine 150 mg b.i.d. For three of the 263 patients randomized in to the study, it was unknown whether or when they experienced a relapse. Therefore, these patients were considered failures in the analysis. During the study there were 22 and 11 postrandomization discontinuations in the omeprazole and ranitidine groups, respectively. The different reasons were: adverse events (omeprazole, eight; ranitidine, one); unwillingness to continue (omeprazole, nine; ranitidine, five); unacceptable study disease-related symptoms (omeprazole, one); noncompliance (ranitidine, two); and other reasons (omeprazole, four; ranitidine, three). The estimated number of patients in remission within 12 months of maintenance treatment were 68% and 39% in the omeprazole 10 mg o.m. and ranitidine 150 mg b.i.d. groups, respectively (p , 0.0001). Time to recurrence was influenced by the treatment given in the acute healing phase of the study. The estimated proportion of patients in symptomatic remission after 12 months of maintenance treatment, when stratified for treatment given in the acute phase of the study, were:

AJG – Vol. 94, No. 4, 1999

ranitidine (acute phase)/omeprazole (maintenance phase) 74%; omeprazole (acute phase)/omeprazole (maintenance phase) 65%; ranitidine (acute phase)/ranitidine (maintenance phase) 45%; and omeprazole (acute phase)/ranitidine (maintenance phase) 35%, respectively (p , 0.0001) (Fig. 3). Adverse events were recorded for 61 patients treated with omeprazole and 42 patients treated with ranitidine. Most of these were abdominal complaints. In nine cases (omeprazole, eight; ranitidine, one) adverse events caused withdrawal from the study, and one of these was considered serious. One patient treated with omeprazole was hospitalized because of acute myeloid leukemia. This numerical difference in adverse events did not reflect a real difference. When corrected for the number of treatment days by group—ranitidine, 24.993 days; omeprazole, 34.453 days— this difference disappeared.

DISCUSSION Of patients with various forms of acid peptic disease, those with gastroesophageal reflux disease require the most acid inhibition to relieve symptoms and allow mucosal healing (15). Several double-blind studies have shown that omeprazole therapy (20 mg/day) produces significantly higher healing rates for erosive and ulcerative reflux esophagitis than ranitidine (150 mg b.i.d.) in short-term studies (1–7). Most of these patients are currently treated with PPIs, but H2 receptor antagonists are still widely used in the treatment of mild reflux disease. Nowadays, H2 receptor antagonists for GERD are often given in high doses (i.e., 300 mg b.i.d.). To date, no studies have compared treatment with omeprazole and ranitidine in patients with lower grades of reflux esophagitis (Savary-Miller grades I–II). It seems that increasing the dose of ranitidine to 300 mg b.i.d. does not improve the efficacy in the treatment of GERD patients (16, 17). Only when ranitidine is given four times a day does the efficacy improve (18, 19). The present study confirms that omeprazole 20 mg once daily in the morning is also more effective than ranitidine 300 mg twice daily in the symptomatic treatment of mild reflux esophagitis. Furthermore, this study confirms the superiority of omeprazole 10 mg once daily in keeping patients with reflux esophagitis in remission, compared with maintenance treatment with ranitidine 150 mg twice daily. Omeprazole 10 mg o.m. was associated with a 1-yr symptomatic remission rate of 68%, which is similar to previously published figures for this regimen (11–13). The finding of 39% of patients in symptomatic remission in the group treated with ranitidine 150 mg b.i.d. after 12 months is also in accordance with an earlier study (11). Other than assessing the therapeutic effect on symptoms, the present study also evaluated the patients’ quality of life. The GSRS, a disease-specific questionnaire, showed significant improvement after 4 wk of treatment with either drug. Statistically significant differences between omeprazole 20

AJG – April, 1999

Omeprazole in GERD

935

Figure 3. Survival analyses (APT): 263 patients included (worst case scenario for patients with missing primary variables). RAN(itidine)/ OME(prazole): treatment acute phase/treatment maintenance phase.

mg o.m. and ranitidine 300 mg b.i.d. were identified for the reflux dimension and for the total score, both favoring omeprazole 20 mg o.m. These results endorse the data derived from the evaluation of patients’ reflux symptoms. The efficacy of maintenance therapy is clearly influenced by the treatment applied in the acute phase. Omeprazole is more effective than ranitidine in the acute treatment of GERD. Because of this greater efficacy, not only a larger number of patients but also patients with more severe forms of reflux disease are healed with omeprazole treatment. Therefore, patients first treated with omeprazole and rerandomized to ranitidine are more prone to relapse. Conversely, patients treated with ranitidine do much better during maintenance treatment with omeprazole, reflecting the selection of a milder form of the disease. In most patients treated with omeprazole, in contrast to patients treated with ranitidine, symptom improvement correlates with endoscopic healing (20, 21). Hence, patients receiving omeprazole are considered unlikely to require endoscopy to detect their relapse. This is an important consideration, given the present high demands being placed upon endoscopy services, and one that is financially attractive for health care providers/purchasers. In conclusion, omeprazole 20 mg once daily is superior to high-dose ranitidine in the symptomatic treatment of reflux esophagitis grade I–II. Furthermore, omeprazole at half the

standard dose is more effective than ranitidine in a standard dose in long-term management of the disease, because of prolonged remission. Omeprazole 10 mg once daily may be used when starting maintenance treatment. Some patients, including those slow to attain remission, prone to troublesome symptoms, or with a history of complication, may need a higher dose.

ACKNOWLEDGMENTS This study was made possible by a grant from Astra Pharmaceutica BV, The Netherlands. The following investigators participated in this study: W. F. J. M. Bartelsman (Academisch Medisch Centrum, Amsterdam), J. H. W. Bergmann (Martini Ziekenhuis, loc.v.Swieten, Groningen), Dr. W. A. Bode (IJsselland Ziekenhuis, Capelle a/d IJssel), P. J. Boekema (Academisch Ziekenhuis Utrecht, Utrecht), Dr. G. H. de Groot (Rode Kruis Ziekenhuis, Beverwijk), A. C. T. M. Depla (Andreas Ziekenhuis, Amsterdam), P. Fockens (Academisch Medisch Centrum, Amsterdam), Dr. H. Geldof (IJsselland Ziekenhuis, Capelle a/d IJssel), Dr. A. A. M. Geraedts (Onze Lieve Vrouwe Gasthuis, Amsterdam), W. P. Haanstra (Scheperziekenhuis, Emmen), P. W. E. Haeck (Christelijk Refaja Ziekenhuis, Stadskanaal), B. P. Hazenberg, Drechtsteden Ziekenhuis, loc. Refaja, Dordrecht), Dr. E. J. Kuipers (Academisch Ziekenhuis

936

Festen et al.

VU, Amsterdam), H. G. T. Lam (Diakonessenhuis, Utrecht), A. E. G. Luckers (Maasziekenhuis Boxmeer, Boxmeer), Dr. J. J. Nicolai (Leijenburg Ziekenhuis, Den Haag), Dr. L. A. Noach (Ziekenhuis Amstelveen, Amstelveen), Dr. S. H. A. Peters (Zuiderzee Ziekenhuis, Lelystad), J. A. J. Staal (St. Streekziekenhuis Midden Twente, Hengelo), Dr. K. te Velde (St. Deventer Ziekenhuizen, Deventer), Dr. A. Teunen (Bovenij Ziekenhuis, Amsterdam), R. J. Timmerman (Gemini Ziekenhuis, Den Helder), P. C. van de Meeberg (Ziekenhuis Eemland, Amersfoort), D. M. van den Boomgaard (Leijenburg Ziekenhuis, Den Haag), H. van der Heide (Martini Ziekenhuis, Groningen), Dr. G. H. M. van der Linden (Drechtsteden Ziekenhuis, Dordrecht), C. T. B. M. van Deursen (St. Gregorius Ziekenhuis, Brunssum), M. van Haastert (Martini Ziekenhuis, loc.v. Swieten, Groningen), W. van Kleef (Streekziekenhuis Gooi-Noord, Blaricum), R. J. M. van Leendert (Drechtsteden Ziekenhuis, loc. Jacobus, Zwijndrecht), J. H. van Maanen (Reinier de Graaf Gasthuis, Delft), Dr. R. A. A. van Zanten (Twenteborg Ziekenhuis, Almelo), W. J. R. R. Venekamp (St. Gregorius Ziekenhuis, Brunssum), P. P. Viergever (Gemini Ziekenhuis, Den Helder), Dr. H. J. Voerman (Ziekenhuis Amstelveen, Amstelveen), G. D. C. Vosmaer (Scheperziekenhuis, Emmen), Dr. H. Walinga (Diaconessenhuis, Voorburg), J. Wals (St. Gregorius Ziekenhuis, Brunssum), Dr. I. C. E. Wesdorp (Andreas Ziekenhuis, Amsterdam), A. M. H. Wetzels (Christelijk Refaja Ziekenhuis, Stadskanaal). Reprint requests and correspondence: H. P. M. Festen, M.D., Ph.D., Groot Ziekengasthuis, Department of Internal Medicine, 5211 NL Den Bosch, The Netherlands. Received May 14, 1998; accepted Dec. 29, 1998.

REFERENCES 1. Zeitoun P, Desjars, De Keranroue N, et al. Omeprazole versus ranitidine in erosive oesophagitis. Lancet 1987;12:621–2. 2. Klinkenberg-Knol EC, Jansen JMBJ, Festen HPM, et al. Double-blind multicentre comparison of omeprazole and ranitidine in the treatment of reflux oesophagitis. Lancet 1987;1:349 –51. 3. Sandmark S, Carlsson R, Fauso O, et al. Omeprazole or ranitidine in the treatment of reflux oesophagitis. Scand J Gastroenterol 1988;23:625–32. 4. Vantrappen G, Coenegrachts JL, Rutgeerts L, et al. Omeprazole (40 mg) is superior to ranitidine in the short-term treatment of ulcerative reflux oesophagitis. Dig Dis Sci 1988;33:523–9. 5. Zeitoun P, Rambal P, Barbier P, et al. Omeprazole (20 mg o.m.) versus ranitidine (150 mg b.i.d.) in reflux esophagitis. Results of a double-blind randomized trial. Gastroenterol Clin Biol 1989;13:457– 62.

AJG – Vol. 94, No. 4, 1999

6. Bate CM, Crowe JP, Dickinson RJ, et al. Reflux oesophagitis resolves more rapidly with omeprazole 20 mg once daily than with ranitidine 150 mg twice daily: Omeprazole 40 mg once daily provides further benefit in unresponsive patients. Br J Clin Res 1991;2:133– 48. 7. Havelund T, Laursen LS, Skoubo-Kristensen E, et al. Omeprazole and ranitidine in the treatment of reflux oesophagitis: Double-blind comparative trial. Br Med J 1988;296:89 –92. 8. Lundel L, Backman L, Ekstro¨m P, et al. Prevention of relapse of reflux esophagitis after endoscopic healing: The efficacy and safety of omeprazole compared with ranitidine. Scand J Gastroenterol 1991;26:248 –56. 9. Dent J, Yeomans ND, Mackinnon M, et al. Omeprazole versus ranitidine for prevention of relapse in reflux oesophagitis. A controlled double blind trial of their efficacy and safety. Gut 1994;35:590 – 8. 10. Vigneri S, Termini R, Leandro G, et al. A comparison of five maintenance therapies for reflux esophagitis. N Engl J Med 1995;333:1106 –10. 11. Hallerba¨ck B, Unge P, Carling L, et al, and The Scandinavian Clinics, for United Research Group. Omeprazole or ranitidine in long-term treatment of reflux esophagitis. Gastroenterology 1994;107:1305–11. 12. Bate CM, Booth SN, Crowe JP, et al. Omeprazole 10 mg or 20 mg once daily in the prevention of recurrence of reflux oesophagitis. Gut 1995;36:492– 8. 13. Stærk Laursen L, Havelung T, Bondesen S, et al. Omeprazole in the long-term treatment of gastro-oesophageal reflux disease. A double-blind randomized dose-finding study. Scand J Gastroenterol 1995;30:839 – 46. 14. Dimena¨s E, Glise H, Hallerba¨ck H, et al. Quality of life in patients with upper gastrointestinal symptoms. An improved evaluation of treatment regimens? Scand J Gastroenterol 1993; 28:681–7. 15. Robertson DAF, Alderly MA, Shephard H, et al. H2 antagonists in the treatment of reflux oesophagitis: Can physiological studies predict the response? Gut 1987;28:946 –9. 16. Schaub N, Thomas JM, Misiewicz JJ, et al. Investigation of ranitidine 150 mg bd or 300 mg bd in the treatment of reflux disease. Hepato-Gastroenterol 1986;33:208 –13. 17. Bianchi Porro G, Pace F, Lazzaroni M. Esophagitis healing with ranitidine. Gastroenterology 1987;92:2051–2. 18. Johnson NJ, Boyd EJS, Milss JG, et al. Acute treatment of reflux oesophagitis: A multicentre trial to compare 150 mg ranitidine bd with 300 mg ranitidine q.d.s. Aliment Pharmacol Ther 1989;3:259 – 66. 19. Roufail W, Belsito A, Robinson M, et al. Ranitidine for erosive oesophagitis: A double-blind, placebo-controlled study. Aliment Pharmacol Ther 1992;6:597– 607. 20. Green JRB. Is there such an entity as mild oesophagitis? Eur J Clin Res 1993;4:29 –34. 21. Bate CM, Keeling PWN, O’Morain CO, et al. Comparison of omeprazole and cimetidine in reflux oesophagitis: Symptomatic, endoscopic, and histological evaluations. Gut 1990;31: 968 –72.