Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Daily omeprazole prevented relapse of reflux esophagitis

ACP J Club. 1994 Nov-Dec;121:66. doi:10.7326/ACPJC-1994-121-3-066


Source Citation

Dent J, Yeomans ND, Mackinnon M, et al. Omeprazole v ranitidine for prevention of relapse in reflux oesophagitis. A controlled double blind trial of their efficacy and safety. Gut. 1994 May;35:590-8.


Abstract

Objective

To compare omeprazole taken daily or 3 times/wk with ranitidine for preventing recurrences and symptoms of reflux esophagitis.

Design

Randomized, double-blind, controlled trial with 1-year follow-up.

Setting

4 Australian hospital outpatient clinics.

Patients

204 adult outpatients (mean age 61 y, 68% men) with endoscopically proven erosive reflux esophagitis of at least grade 2 severity. Patients with benign esophageal stricture were not excluded if the condition could be dilated effectively. Exclusion criteria were pregnancy or lactation; inadequate contraception; treatment with prokinetic agents or antisecretory therapy; peptic ulcer or complications of ulcer disease; gastrointestinal malignancy; esophagitis caused by systemic disease, infection, intubation or other mechanical trauma, burns, irradiation, or physical deformity; history of esophagogastric surgery; ongoing upper gastrointestinal hemorrhage; other serious disease or abnormalities; or poor compliance or refusal to participate.

Intervention

All patients were treated with omeprazole, 20 mg daily for 4 or 8 weeks. 159 patients (67% men) were healed, 61% at 4 weeks and 81% at 8 weeks, and assigned to maintenance therapy. 53 patients were assigned to omeprazole, 20 mg/d; 55 patients to omeprazole, 20 mg every Friday, Saturday, and Sunday; and 51 patients to ranitidine, 150 mg twice daily. Patients were seen at months 1, 2, 3, 6, and 12. Follow-up was > 99%.

Main outcome measures

Endoscopically proven recurrence and self-reported symptoms of esophagitis and adverse effects.

Main results

At 1 year, and after assessment with endoscopy, 89% of patients taking daily omeprazole were in remission compared with 32% of patients taking weekend omeprazole (95% CI for 57% difference 42% to 71%) and 25% of patients taking ranitidine (CI for 64% difference 50% to 78%). Symptoms of esophagitis showed a similar pattern. The groups did not differ for gastrin concentrations, pathologic findings, or adverse effects.

Conclusions

Daily omeprazole (20 mg/d) was safe and effective for preventing relapse and symptoms of esophagitis. Omeprazole taken 3 times/wk plus ranitidine was not effective.

Source of funding: Not stated.

For article reprint: Professor J. Dent, Gastroenterology Unit, Royal Adelaide Hospital, Adelaide, SA 5000, Australia. FAX 61-8-222-5120.


Commentary

S ee alsoOmeprazole was better than H2-antagonists in esophagitis and strictureandOmeprazole was better than H2-antagonists in reflux esophagitis

Marks and colleagues report a complex study that showed that healing of erosive esophagitis in patients with associated peptic stricture results in significant dysphagia relief and decreased need for dilation. These improvements were observed independent of the rate of stricture resolution. Additionally, the authors address issues of clinical efficacy and cost-effectiveness.

Marks and colleagues compared omeprazole with H2RAs, knowing beforehand that a difference in healing rates would exist. They created an elegant stratification scheme and used the anticipated difference in healing rates to study the relative contributions of erosive esophagitis and stricture to symptoms of dysphagia and dilatation requirements. The research design works well for probing the pathophysiologic mechanisms underlying dysphagia; however, the type of blinding used could affect the appropriateness of this design for a clinical efficacy study.

The cost-effectiveness analysis was carried out within the context of the protocol and, therefore, may not accurately reflect costs in an open clinical situation. For instance, it is unlikely that patients in the asymptomatic peptic stricture group would be given endoscopy after 3 months of successful acid-suppression therapy. Therefore, the cost advantage of omeprazole therapy may be understated. Alternatively, impending patent expirations and price competition among the H2RAs is decreasing their costs. This is particularly true of cimetidine, which was not included among the H2RAs studied. Therefore, the cost disadvantage for H2RAs may be overstated.

The observation that healing erosive esophagitis independently improves dysphagia and dilatation requirements in patients with peptic stricture is extremely important and has immediate clinical applicability. The other goals of the study are more open to varied interpretations and may obscure the important primary finding.

James and Parry-Billings present data confirming that in young and old patients, antisecretory therapy with omeprazole is superior to therapy with H2RAs for healing esophagitis and relieving reflux symptoms. Unfortunately, the study methods used may not detect the subtle difference in age-associated therapy responses sought by the authors.

The study is a retrospective analysis of combined data obtained from 2 multicenter trials done in the United Kingdom and Ireland. True differences may exist between the populations. For example, longevity may differ between the United Kingdom and Ireland. Other differences can easily be postulated. Although the authors state that the 2 protocols used to accrue patients were similar, they do not provide protocol-specific information about demographic characteristics of the patients actually accrued (other than percentage of persons who smoked and percentage of persons who consumed alcohol) or how they were distributed among groups analyzed after combining the 2 populations.

It is unclear how the authors selected the age of 65 years or greater to define "old." In general, an appropriate definition of "old" is lacking in the literature on aging. Application of cluster analysis to the data presented might show age groupings at which significant differences in therapeutic response occur. These groupings could be used to define "young" and "old." An appropriately stratified prospective study might then confirm differences postulated on the basis of cluster analysis.

Should we believe that no age differences exist? Not on the basis of data presented by James and Parry-Billings. If differences exist, are they likely to alter the apparent superiority of omeprazole to H2RAs in all age groups? No.

The study by Dent and colleagues confirms observations made by most clinicians and some investigators (1) shortly after omeprazole became available. Conventional-dose omeprazole is far superior to H2RAs for maintenance therapy of erosive esophagitis. Attempts to cycle patients off omeprazole, ostensibly to avoid argyrophil cell hyperplasia and gastric carcinoid tumors, were notoriously unsuccessful with regard to symptoms and clinical findings (2). More often than not, clinicians were faced with miserable patients begging to be put back on omeprazole and complaining about the costs of double-dose H2RA therapy.

A most useful aspect of this investigation is the valuable histologic data generated that confirm previous work suggesting that long-term omeprazole therapy does not induce neoplastic change in the argyrophilic cell population of the human gastric oxyntic mucosa. Dent and colleagues' statistical treatment of therapy related to argyrophilic cell population and serum gastrin changes is rather obscure but is necessitated by the occurrence of outliers that significantly skew the sample means. Examination of box plots in Figures 5 and 6 of the article shows the outlier phenomenon to be pronounced for serum gastrin levels and minimal for argyrophilic cell population estimates. Indeed, the authors revert to discussing the sample means in their treatment of argyrophilic cell population estimates.

An analysis of the correlation between serum gastrin levels and argyrophilic cell population estimates would have been most enlightening. Are gastrin level outliers associated with outliers for larger values for argyrophilic cell populations? Does a subpopulation of patients receiving long-term omeprazole therapy exist that might warrant further study? Dent and colleagues stopped just short of providing some much-needed insight into this phenomenon. Perhaps we will hear from them later on this topic. They appear to have the data.

This triad of articles substantially improves our knowledge of omeprazole efficacy and safety in the management of gastroesophageal reflux disease and gives scientific legitimacy to many common management practices. Marks and colleagues show that omeprazole is an effective tool in the treatment of dysphagia arising from strictures associated with erosive esophagitis. James and Parry-Billings attempt to assure us that omeprazole is superior to H2RAs in both young and old but leave us wondering what it means to be "old." Dent and colleagues report the first randomized, double-blind, controlled trial comparing the efficacy of omeprazole with that of an H2RA for the prevention of relapse in reflux esophagitis. They have succeeded in scientifically confirming what our patients have long been telling us, but, more importantly, their data suggest that maintenance therapy with omeprazole is safe and does not induce neoplastic change in the argyrophilic cell population of the human gastric oxyntic mucosa.

James S. Barthel, MD
University of MissouriColumbia, Missouri, USA


References

1. Koop H, Arnold R. Long-term maintenance treatment of reflux esophagitis with omeprazole. Prospective study in patients with H2-blocker-resistant esophagitis. Dig Dis Sci. 1991;36:552-7.

2. Larsson H, Carlsson E, Mattsson H, et al. Plasma gastrin and gastric enterochromaffinlike cell activation and proliferation. Studies with omeprazole and ranitidine in intact and antrectomized rats. Gastroenterology. 1986;90:391-9.