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Long-Term Treatment with Omeprazole for Refractory Reflux Esophagitis: Efficacy and Safety

Elly C. Klinkenberg-Knol, MD, PhD; Henk P. M. Festen, MD, PhD; Jan B. M. J. Jansen, MD, PhD; Cornelis B. H. W. Lamers, MD, PhD; Frits Nelis, MD, PhD; Pleun Snel, MD, PhD; Anton Luckers, MD; Cornelius P. M. Dekkers, MD; Niilo Havu, MD, PhD; and Stephan G. M. Meuwissen, MD, PhD
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From the Free University Hospital, Amsterdam; Groot Ziekengasthuis Hertogenbosch; State University, Leiden; Sophia Hospital, Zwolle; Slotervaart Hospital, Amsterdam; Jacobus Hospital, Zwijndrecht; St. Ignatius Hospital, Breda; Catholic University, Nijmegen, the Netherlands; AB Astra, Sodertalje, Sweden. Requests for Reprints: E. C. Klinkenberg-Knol, MD, PhD, Free University Hospital, Department of Gastroenterology, P.O. Box 7057, 1007 MB Amsterdam, the Netherlands. Acknowledgments: The authors thank L. Frison, AB Hassle, Goteborg, Sweden, and J. Nauta, Department of Theory of Medicine, Epidemiology and Biostatistics, Free University, Amsterdam, the Netherlands, for performing the statistical analyses. Grant Support: By AB Hassle, a subsidiary of AB Astra, Sodertalje, Sweden.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1994;121(3):161-167. doi:10.7326/0003-4819-121-3-199408010-00001
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Objective: To evaluate the long-term efficacy and safety of omeprazole in patients with gastroesophageal reflux disease resistant to treatment with histamine-2 (H2)-receptor antagonists.

Design: Cohort analytic study with a mean follow-up of 48 months (range, 36 to 64 months).

Setting: Patients receiving ambulatory care from referral centers.

Patients: 91 patients with gastroesophageal reflux disease resistant to treatment with an H2-receptor antagonist but subsequently responsive to 40 mg of omeprazole daily.

Intervention: Open maintenance therapy consisting of 20 mg of omeprazole daily in 86 patients and 40 mg daily in 5 patients.

Outcome Measures: Endoscopy to assess healing; side effects, laboratory values, fasting serum gastrin level, and gastric corpus biopsies to assess safety.

Results: Esophagitis recurred in 47% of the patients receiving 20 mg of omeprazole daily, but all rehealed after the dose was doubled. Seven of 40 patients (18%) had a second relapse after a mean follow-up time of 24 months (range, 9 to 36 months) that was successfully treated with a further 20-mg dose increment for a mean period of 36 months (range, 6 to 39 months). Median gastrin levels increased initially from 60 ng/L before study entry to 162 ng/L (P < 0.01) with treatment and reached a plateau during maintenance treatment. Very high gastrin levels (>500 ng/L) were observed in a subgroup (11%) of patients. The incidence of micronodular hyperplasia increased from 2.5% of the patients at first biopsy to 20% at the last biopsy (P = 0.001), with a corresponding progression of gastritis to subatrophic or atrophic gastritis from less than 1% to 25% (P < 0.001), which was more pronounced in patients with very high serum gastrin levels.

Conclusions: Maintenance therapy with omeprazole was effective for at least 5 years in patients with gastroesophageal reflux disease resistant to treatment with H2-receptor antagonists. Treatment was accompanied by a persistent increase in serum gastrin levels and an increase of micronodular argyrophil cell hyperplasia and subatrophic or atrophic gastritis.


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Figure 1.
Remission rates (%) in 86 patients with reflux esophagitis during maintenance treatment with 20 mg of omeprazole once daily during 60 months of follow-up (life-table method.

* = number of persons at risk.

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Figure 2.
Cumulative remission rates with dose adjustments required to maintain remission in 91 patients with reflux esophagitis during maintenance treatment with omeprazole.

Cumulative remission rate in 91 patients after 36 months: 100% (95% CI, 96% to 100%); in 67 patients after 48 months: 100% (CI, 95% to 100%); and in 27 patients after 60 months: 100% (CI, 87% to 100%). The 5 patients receiving 40 mg of omeprazole at 0 months follow-up were not healed after the acute treatment period of 12 weeks and continued to receive this dose. The other patients receiving 40 mg of omeprazole represent a first relapse, whereas the patients receiving 60 mg of omeprazole represent a second relapse.

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Figure 3.
Distribution of fasting serum gastrin levels (all measured individual values) during maintenance treatment with omeprazole.

Horizontal line indicates normal values (< 100 ng/L). 40 mg = acute treatment period.

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Figure 4.
Argyrophil cell hyperplasia during maintenance treatment with omeprazole: distribution in normal, diffuse hyperplasia, linear hyperplasia, and micronodular hyperplasia according to the classification of Solcia and colleagues[26].
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Figure 5.
Degree of corpus gastritis during maintenance treatment with omeprazole.

Distribution in normal, superficial gastritis, and subatrophic or atrophic gastritis.

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