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


Therapeutics

Omeprazole was better than H2-antagonists in esophagitis and stricture

ACP J Club. 1994 Nov-Dec;121:64. doi:10.7326/ACPJC-1994-121-3-064


Source Citation

Marks RD, Richter JE, Rizzo J, et al. Omeprazole versus H2-receptor antagonists in treating patients with peptic stricture and esophagitis. Gastroenterology. 1994 Apr;106:907-15.


Abstract

Objective

To determine whether healing of esophagitis improves dysphagia and decreases the need for dilatation in patients with stricture and to compare the effectiveness of omeprazole with that of histamine-2-receptor antagonists (H2RAs).

Design

Randomized controlled trial with 6-month follow-up.

Setting

A university and a Veterans Affairs gastroenterology service.

Patients

37 patients (mean age 60 y, 89% men) with solid-food dysphagia occurring ≥ 1 time/wk, endoscopic esophagitis ≥ grade 2, and benign peptic stricture (luminal diameter ≤ 12.5 mm). Exclusion criteria were esophageal malignancy, history of scleroderma, or previous esophageal or gastric resection. 32 patients (86%) completed the study.

Intervention

Patients were stratified by severity of endoscopic esophagitis and were allocated to omeprazole, 20 mg/d (n = 18), or H2RA (ranitidine, 150 mg twice daily or famotidine, 20 mg twice daily; n = 16). The choice of H2RA was made by the attending physician. The dose of the study medication was doubled at 3 months if esophagitis remained ≥ grade 2. Patients were dilated at baseline and received further dilatation during follow-up if dysphagia frequency was ≥ 1 time per week.

Main outcome measures

Esophagitis healing, dysphagia relief, subsequent bougienage requirements, and cost-effectiveness of the study medications.

Main results

Regardless of drug treatment, patients with esophagitis healing had greater dysphagia relief at 3 and 6 months than did those without healing (61% vs 19%, { P = 0.01}* and 88% vs 0%, { P < 0.001}*). Dilatation was required in 44% of patients with esophagitis healing compared with 100% of those without healing { P = 0.008}*. At 6 months, patients receiving omeprazole, compared with those receiving H2RA, had a higher rate of esophagitis healing { P = 0.001}*, a higher rate of dysphagia relief { P = 0.001}*, and a trend toward a lower rate of need for dilatation { P = 0.07}* (Table). Omeprazole was also 40% to 50% more cost-effective.

Conclusions

Healing of esophagitis in patients with stricture improved dysphagia and decreased the need for dilatation. Omeprazole was more effective than histamine-2 receptor antagonists in healing esophagitis and relieving dysphagia and was more cost-effective.

Source of funding: In part, Merck and Company.

For article reprint: Dr. J.E. Richter, Chairman, Department of Gastroenterology/S40, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195-5164, USA. FAX 216-444-9047.

* P values calculated from article.


Table. Omeprazole vs H2-receptor antagonists for peptic stricture and esophagitis†

Outcomes at 6 months Omprazole H2-receptor antagonists RBI (95% CI) NNT (CI)
Esophagitis healing 100% 53% 88% (25 to 224) 3 (2 to 5)
Dysphagia relief 94% 40% 135% (41 to 378) 2 (2 to 5)
RRR (CI) NNT
Dilatation requirement 41% 73% 44% (-4 to 72) Not significant

†Abbreviations defined in Glossary; RBI, RRR, NNT, and CI calculated from data in article.


Commentary

Omeprazole was better than H2-antagonists in reflux esophagitisandDaily omeprazole prevented relapse of 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 H2RAfor 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.