Is intermittent therapy advisable in long-term medical management of gastroesophageal reflux patients?
S. Bank, M. Blumstein, R. Greenberg,
L. Austin-Brigante (New York)
Reflux esophagitis is generally a nonfatal, uncomfortable disease which most patients treat intermittently for symptoms with Phase l life-style changes, antacids or OTC or conventional H2-RAs . With the advent of the proton pump inhibitors (PPIs) it soon became apparent that symptoms resistant to conventional H2-receptor therapy (H2-RAs) were being ameliorated by omeprazole to the point where patients were continuing their therapy for long periods despite regulatory constraints allowing only 2-month treatment . To overcome the latter, we embarked on a program of allowing patients with grade II to IV esophagitis who had healed endoscopically to space their omeprazole dose to prevent recurrence and to investigate the PPI requirements in relation to endoscopic findings, serum gastrin, ECL cells and mucosal changes [3-5].
Material and methods
Seventy-three patients with healed reflux esophagitis have been on maintenance omeprazole for 1-8 years. Of these, 16 have grade I esophagitis and 57 had at least grade II disease and have been on a program of spacing their dose of omeprazole according to symptoms and endoscopic findings for a period of 2-8 years. Previously, all had continuing symptoms on conventional doses of H2-RAs with inadequate endoscopic healing.
The patients were contacted every 3-6 months, gastrins were done 6 monthly and endoscopy every year to evaluate esophagitis, presence of Barrett's, fundic polyps and fundal biopsies taken. To date, 1 patient has been on omeprazole for 8 years, 5 for 7, 8 for 6, 3 for 5, 10 for 4, 15 for 3 and 15 for 2 years. The remaining 16 have been on for 1 year and will not be considered in this paper.
Table I shows the omeprazole requirements in the 57 patients with grade II to IV esophagitis and Figure 1 compares these 8 year results to our previous 1-5 year findings in the same patients . By the 2-8 year period, the number of patients requiring daily dosing rather than alternate day dosing had increased from 13% to 28%. However, 78% at 5 years and 61% at 8 years could be maintained in remission on 20mg on alternate days. Eleven percent could space their therapy to the third day or longer, at 5 and 8 years.
Figure 1. Change in omeprazole requirements in 57 patients comparing maintenance therapy at 1-5 years  and present study (2-8 years).
Endoscopic findings and Barrett's mucosa
No patients on daily or alternate day therapy showed an increase in esophagitis grade on endoscopy. Two patients who attempted to space their therapy for more than 3 days relapsed to their original grade III esophagitis. The incidence of Barrett's was 50% in these H2-RA resistant/omeprazole maintenance requiring patients. The Barrett's neither increased or decreased in length in any patient. Two patients, 1 at 4 years and 1 at 5 years showed squamous islets in the Barrett's epithelium.
Relation of initial esophagitis grading to omeprazole requirements
Table II shows that daily or alternate day therapy was required in all patients with initial grade IV esophagitis. In grade III or II esophagitis more than 50% of the patients could be maintained on alternate day therapy and about one quarter on every third day or intermittent treatment.
Fasting gastrin levels taken 6 monthly showed fluctuations ranging from normal to moderately elevated values (greater than 150 pg/ml) in 7 of the 57 patients. Two showed more marked elevation on daily or bi-daily dosing. In case 1 (on 20-40 mg per day) the levels were 153, 229, 385, 248, 1040, 377, 286. In case 2 (on 20 mg daily) the levels were 93, 385, 416, 275, 371, 266. Only 2 patients on alternate day or longer spacing had fasting levels at one time during the course that was greater than 250 pg/ml.
Gastric polyps, ECL cells and histology
Seven (12%) developed new fundic hyperplastic polyps during therapy - most occurring after 1-2 years, a few occurring after a few months. Six of the 7 were on daily omeprazole and 1 was on spaced therapy.
None of the patients developed nodular ECL hyperplasia, only 5 developed simple ECL hyperplasia.
The gastrointestinal pathologist at our hospital was unable to discern any evidence of atrophic (or for that matter any other gastritis) at any of the 8 year time periods.
This 8-year extension of our previous 3- and 5-year follow-up studies on alternate day or spaced/intermittent omeprazole therapy for the prevention of recurrence of severe reflux esophagitis showed that although an increase number of patients eventually required daily dosing, (i.e. from 13% to 28%) the majority could still maintain their symptom and endoscopic improvement on alternate day therapy and about a steady 11% could space their dosages even further, i.e. to every third day or even intermittently [3-5]. This study differed from that of Klinkenberg-Knol et al., in that patients with initial grade III or IV esophagitis who remained asymptomatic and showing a reduction to grade I esophagitis were not required to increase their dose to 40-60 mg to realize complete healing . However, patients who had increased esophagitis at a yearly endoscopy were advised to increase their dosage to the next step upward, i.e. alternate day to daily or intermittent to alternate days. It is of interest that 50% of patients in this series with H2-RA resistant/PPI maintenance requiring reflux disease, had Barrett's epithelium suggesting that Barrett's may be anticipated in one half of all patients with resistant reflux.
This study was carried out in patients with marked esophagitis (at least grade II and mostly III and IV) and does not address the vast majority of our patients with lesser symptoms or grade 0 to I esophagitis, many of whom are taking intermittent antacids,
H2-RAs or PPIs for symptoms without recourse to repeat endoscopy. This study does however suggest that omeprazole requirements for global remission is dependent on initial endoscopic grading, e.g. no patient with grade IV esophagitis could be maintained in complete remission with an omeprazole dose of 20 mg at least on alternate days and 72% required daily maintenance [7, 8]. However, patients with grade III and II esophagitis could often remain in remission on alternate day or intermittent therapy (occasionally with 1 or 2 weeks of upgrading of their dose to contain symptoms).
Apart from the decreased cost are there any pros and cons to alternate day or spaced therapy?
This study suggests that the vast majority of patients who remain in symptomatic remission also have endoscopic healing or at least considerable downgrading of their esophagitis decreasing the necessity for repeated endoscopy. On the other hand, the high incidence of Barrett's would probably mandate 2 yearly endoscopies for surveillance in many cases.
Excessively high serum gastrin levels and ECL hyperplasia were extremely rare in this study suggesting that allowing some acid to return on a spaced regime might minimize these changes [2, 3, 5, 9]. Only one of the gastrins approximated the high values reported on daily therapy in the Holland study and similar results to ours were obtained in a study from Israel [6, 10]. In addition, none of the patients in this series developed atrophic gastritis which was found relatively commonly in Klinkenberg-Knol's study .
The development of hyperplastic polyps was a definite but insignificant finding occurring at about double the incidence in a control age matched population (i.e. 12% vs 6% in the general population) . There are no comparisons between 20 mg spaced dosing and 10 mg daily therapy on the above effects and we are currently undertaking this study [12,13].
Are there then any downsides to allowing patients to space their therapy to maintain symptomatic remission or to treat individual episodes on demand in less severe disease? There was no extension in Barrett's length at any period of this study and no dysplastic changes were observed. Neither did any of the patients progress to irreversible stricture formation, (a few had to be dilated on presentation) or any other serious complication. Although some authors maintain that Barrett's patients should receive high dose PPI therapy on a continuous basis, there is currently no scientific evidence for this hypothetical treatment.
5. Bank S, Greenberg R, Blumstein M, et al. "Spaced" omeprazole dosing in maintenance therapy of H2RA resistant reflux esophagitis - results from 1-5 years. Abstracts of 4th International Congress of OESO, Paris l993 l2:80.
7. Bank S, Blumstein M, Greenberg R, et al. Long-term maintenance omeprazole dosing regimens in relation to esophagitis grading in H2RA resistant esophagitis 2-6 years of continuous therapy. Gastroenterology 1995;108:52.
8. Festen HPM, Wesdorp ICE, Dekker W. Factors accelerating relapse during maintenance treatment of reflux esophagitis: significance of initial severity of esophagitis and strength and duration of acute treatment. Gastroenterology 1992;102:67.
12. Laursen LS, Bondesen S, Hansen J, et al. Omeprazole l0 mg of 20 mg daily for the prevention of relapse in gastroesophageal reflux disease? A double blind comparative study. Gastroenterology 1992;102:109.