Healing and relapse of severe peptic esophagitis after treatment with omeprazole

GASTROENTEROLOGY

ALIMENTARY

1988;95:903-12

TRACT

Healing and Relapse of Severe Peptic Esophagitis After Treatment With Omeprazole DAVID FIROZE

J, HETZEL,

JOHN DENT,

M. NARIELVALA,

JUSTIN H. MCCARTHY, BERNARD ALAN

D. REED,

M. MACKINNON, BRENT

H. LAURENCE,

KERR GRANT,

WILLIAM MITCHELL,

GEOFFREY

DAVID

BRUCE R. BEVERIDGE,

G. GIBSON.

J. C. SHEARMAN,

KICHARD WHITEHEAD, and PETER J. BUCKLE lkp;rrtrnellts of Medicine, Gastroenterology. and Histopathology. Blinders t2t:pCrtriation General Hospital. and Koyal Adelaide Hospital. Adelaide, (;ast~ot:nterolclRy and Liver Unit, Sir Charles Gairdner Hospital. Perth, I’h,l~lnac:~:utic.;lls Pty. l,td.. Sydney. Australia

We have studied the response of erosive or ulcerative esophagitis to treatment with omeprazole and its subsequent relapse on cessation of therapy in 196 patients. In the first phase of the study omeprazole (20 or 40 mg daily) was compared with placebo in 64 patients. After 4 wk there was endoscopic healpatients ing in 81% (25 of 31) of omeprazole-treated and in only 6% (2 of 32) of placebo-treated patients. Endoscopic healing of esophagitis was accompanied by symptom relief and histologic healing of ulceration. In the second (dose finding) phase a further 132 patients were randomized to omeprazole (20 or 40 mg daily) and endoscopic healing was assessed. In patients with the mildest grade of ulcerative esophagitis (grade 2), healing occurred at 4 wk in 87% receiving 20 mg and in 97% receiving 40 mg. In patients with grade 3 esophagi&, 67% (20 mg) and 88% (40 mg) were healed. Less than half the patients with grade 4 esophagitis (Barrett’s ulcers or confluent ulceration) healed with either 20 mg (48%) or 40 mg (44%). Regression analysis in the 164 omeprazole-treated patients showed no evidence that healing was influenced by factors other than severity of esophagitis at entry and omeprazole dose. In phase 3 of the study the rate of endoscopic relapse was determined in 107 endoscopically healed patients after stopping omeprazole. Erosive or ulcerative esophagitis recurred in 88 of 107 (82%) by 6 mo. Neither initial dose, grade of esophagi& nor smoking was shown to influence relapse rate. Omeprazole is a highly effective treatment for peptic esophagitis. The 40-mglday dosage produces

Medical Centrr. Australia: Australia: and Astra

endoscopic healing slightly more quickly than the 20-mglday dosage, and the initial endoscopic gradings are of prognostic value. Relapse occurs rapidly when treatment is stopped.

C

linical trials of many widely advocated nonsurgical therapies for peptic esophagitis have failed (l-5).Notably, the efto show substantial benefit ficacy of histamine HZ-receptor antagonist therapy has been disappointing (6-19) compared with its uniform success in the treatment of chronic duodenal ulcer. Omeprazole, a substituted benzimidazole, is a member of a new class of gastric antisecretory agents that specifically inhibit the enzyme hydrogenpotassium adenosine triphosphatase in the parietal cell, the final step in the formation of hydrochloric acid. It is a highly effective inhibitor of gastric acid secretion (20,21)and produces more complete and long-lasting suppression of basal and stimulated gastric acid secretion than currently available HZreceptor antagonists (22). Omeprazole reduces the acidity of gastric juice, even in the fed state, to levels shown to be ineffective for the production of peptic esophagitis in animal models (23).Its effectiveness in reducing the damaging effect of severe reflux on the esophageal mucosa has been supported by our physiologic and endoscopic studies in a small group of patients with severe peptic esophagitis (24)and by the finding that high-dose omeprazole (60 mg daily) 0 1988 by the American

Gastroenterological 0016.5085/88/$3.50

Association

904

HETZEL ET AL.

was superior to ranitidine (150 mg twice daily) in relieving symptoms and producing endoscopic healing in 51 patients with erosive esophagitis (25). The present study was designed to evaluate several questions about the efficacy of omeprazole as a treatment for erosive or ulcerative esophagitis. We planned to test omeprazole in the most severe categories of peptic esophagitis, and so included patients with peptic stricture or esophageal columnar metaplasia. These patients were excluded from the ranitidine study (25). Our trial was conducted in three phases: (a] to determine whether omeprazole was an effective therapy when compared with placebo: (b) when the efficacy of omeprazole was cstablished, to evaluate the optimal dose (20 or 40 mg daily) and duration of therapy (4 or 8 wk) in a large group of patients so that clinical or endoscopic factors of prognostic importance might also be identified; and (c) as peptic esophagitis is a chronic problem, to determine the longer-term benefits of an effective treatment. Therefore, in the third phase we studied the pattern and rate of recurrence of csophagitis and reflux symptoms over a 6-mo period after stopping omeprazole in patients whose esophagitis had healed.

Materials and Methods This multicenter study was conducted doubleblind on outpatients with erosive or ulcerative esophagitis at four Australian university hospitals: Royal Adelaide Hospital, Flinders Medical Centre, and Repatriation General Hospital, Adelaide, and Sir Charles Gairdner Hospital, Perth. The design of the study for phase 1 (placebo controlled) and phase z (dose comparative) is summarized in Figure 1. In phase 3, patients whose esophagitis had healed were followed up for 6 mo after stopping omeprazole to determine the relapse rate of symptoms and ulceration. Patients were excluded if aged under 18 yr or over 80 yr. Other reasons for exclusion were previous esophagogastric surgery (other than failed antireflux surgery); esophagitis associated with systemic disease (e.g., scleroderma); esophagitis due to viral or fungal infection or caustic, radiation, or other physicochemical trauma; concurrent gastric ulcer, duodenal ulcer, pyloric stenosis, or malignancy; ongoing gastrointestinal hemorrhage: other serious illness (cardiac, renal, or hepatic disease); other investigational drug use within 4 wk of the initial endoscopy or use of any other antisecretory or prokinetic medication after the initial endoscopy; or alcoholism, drug abuse, or other disorders considered to prevent compliance with treatment. Use of analgesics or nonsteroidal antiinflammatory drugs was noted but patients using them were not excluded. Benign peptic strictures were dilated before entry at the discretion of the endoscopist. No pregnant or lactating women were included in the study. Approval for the study was obtained from the Human Research Review Committee at each of the participating hospitals. Each patient was given full verbal and written

CASTROENTEROLOGY

information about draw. Each patient

Endoscopic

Vol. 95, No. 4

the study and their freedom provided signed consent.

to with-

Procedures

In phases 1 and 2, upper gastrointestinal endoscopy (Olympus GIF XQlO or Pentax FG34JH) was carried out by an experienced observer not more than 7 days before commencing the test treatment. The severity and extent of macroscopic esophageal ulceration or erosion was scored as follows: grade 0, no mucosal abnormalities: grade 1, no macroscopic erosions but erythema, hyperemia. or mucosal friability; grade 2, superficial erosions involving 50% of the mucosal surface of the last 5 cm of esophageal squamous mucosa. Only patients with unequivocal erosive peptic esophagitis of grade 2 or greater entered the study. Patients with chronic reflux disease characterized by columnar metaplasia or benign stricture without macroscopic mucosal erosion were not entered. The presence of an esophageal stricture was recorded and dilatation was performed after endoscopic grading. In phase 1 (placebo controlled) multiple endoscopic pinch biopsy specimens were obtained in all patients. Three samples were taken at evenly spaced radial intervals, every 2-4 cm along the length of the esophagus (according to the extent of metaplasia or erosion, or both] starting from the endoscopically identified gastroesophageal junction to a level above the squamocolumnar junction. In phase 2 of the study, specimens were taken before treatment when clinically indicated to exclude malignancy and viral or fungal infection. Endoscopic grading (and biopsy in phase 1) was re-

October

1988

peated after 4 wk on day 29 of treatment, and if esophagitis was not healed, again after 8 wk on day 57. In 89’1/0 of patients the same endoscopist performed all assessments on individual patients. Patients were categorized as healed if all macroscopic erosion or ulceration had resolved (i.e., treatment was stopped. In grade (1 or 1) and omeprazole unhealed patients in whom grading was unchanged or improved, medication was continued for 8 wk. Deterioration by at least one grade at 4 wk required withdrawal and patients were treated subsequently according to standard practice in each hospital. In phase 3, asymptomatic patients with healed esophagitis were assessed monthly for 6 mo for recurrent symptoms after withdrawal of omeprazole. Between these appointments patients who developed symptoms made contact and were reassessed individually. Patients were questioned in a standardized manner about their symptoms (see below) and endoscopy was performed on recurrence of typical moderate or severe symptoms on at least 3 days out of 7. Patients who remained asymptomatic were examined endoscopically after 6 mo. Relapse was defined as grade z erosive esophagitis or worse.

Biopsy specimens were examined within each illstitution to exclude malignancy and viral or fungal infection. Microscopic: ulceration or healing was assessed histologically only during phase 1 in 64 patients. Samples were assessed by a single observer (R. W.), who was blind to treatment allocation and endoscopic and clinical findings, for epithelial type (squamous or columnar) and for the presence of ulceration and acute inflammation in the form of neutrophil polymorphonuclear leukocytes. Epithelial necrosis or neutrophil polymorphonuclear leukocyte infiltration was scored as present if it was seen in any one of the biopsy specimens from a patient.

Trecltment Phuse 1. Patients were randomized to treatment with either omeprazole (20 or 40 mg) daily or placebo (Figure 1).Randomization was carried out separately for each center in balanced blocks of 4. Two capsules that contained either omeprazole as enteric-coated granules or placebo were taken each morning before breakfast. Mylanta tablets or liquid (12.5 mmol acid binding capacity per tablet or per 5 ml of liquid; Stuart Pharmaceuticals. Wilmington, Del.) were supplied for control of dyspeptic symptoms. Specific advice on diet, smoking, alcohol intake, posture, or other measures was not given. Anticholinergic and other antisecretory or prokinetic drugs were forbidden. Details of all other medications required before and during the study were recorded. Phase 2. Patients were randomized to receive either 20 or 40 mg of omeprazole daily, given as two capsules daily to maintain double-blind conditions. Those allocated to the 20-mg daily, dosage received one active capsule and one identical placebo capsule. All other aspects of treatment were identical to phase 1. Phclse J. In patients who had healed during phase

OME:PKA%OI,E TKEAThlEKT

1 or phase 2, test treatment were permitted to control Clinical

and

FOK E:SOPHAXGITIS

905

was discontinued but antacids dyspeptic: symptoms.

Laborator!

Assessment

Clinical and laboratory assessments are summarized in Figure 1. On the day of entry, and at 2-wk intervals thereafter, heartburn. regurgitation, dysphagia, and nausea were graded as none, mild (easily tolerated], moderate (interfering with usual activity). or severe (incapacitating, preventing usual activity). Patients recorded antacid consumption and any other symptoms on diary Lards. At each visit. patients rated their symptoms as completely gone, or improved, unchanged. or worsened compared with the day of entry. Alcohol and tobacco use were recorded at each visit. Patients were specificall). questioned about the occurrence of adverse symptoms. Compliance, assessed at each visit by capsule counts, was judged adequate only if ~73% of the prescribed capsules were consumed. Patients experiencing unacceptable reflux symptoms, adverse effects. or interc.urrent illness requiring other therapy were withdra\vn from the study. as were those who failed to attend or comply adequately Lvith medication. Blood and urine samples were taken for hematologic and biochemical evaluation and gastrin assay us shown in Figure 1 and 1 mo after completing initial treatment. Fasting serum gastrin was measured by duplicate batch analysis at the completion of the trial. A Becton-Dickinson kit was used with a high-affinity antibody (gastrin 17 sensitivity, 12 pg/ml) with minimal cross-reactivity (c,holecystokinin1 .!Y%, of gastrin 17 1. pancreozymin. Datu

Annlysis

Healing rates for each treatment group were compared using the Mantel-Haenszel test stratified by baseline endoscopic grade. A weighted Wilcoxon rank test stratified by baseline severity grades was used to evaluate changes in severity of symptoms and differences in the final endoscopic grades. In phase 1. patients withdrawn without endoscopy were regarded as unhealed and allocated to grade 4. Demographic and clinical variables in the treatment groups xvere compared with Student’s unpaired t-test or the Wilcoxon Mann-Whitney rank test. In phase 2, a study design allowing “group sequential analysis” Was adopted in an effort to avoid unnecessary prolongation of the trial. This allowed interim analysis of efficacy (healed/not healed) to be undertaken legitimately according to the O’Brien-Fleming procedure after 50 and 100 patients had completed 4 wk of treatment (26,27). The predefined level of statistical significance was not reached and entry continued until 150 valid patients had entered the study and the current randomization block was completed at each center. Statistical analysis on the endoscopic healing data was performed using the most rigorous “intention to treat” principle, inclucling all patients who entered the study. In phase 2. withdrawn patients were assigned their last endoscopic grade in each analysis. An alternative “per protocol” analysis was also performed and included all patients who completed the study according to the protocol requirements at a particular visit. A logistic regression analysis was performed on the 4-wk and

906

HETZEL

ET AL.

GASTROENTEROLOGY

a-wk healing data and included the possible prognostic factors (chosen before the study) of dose (20 or 40 mg), sex (smoker/ (male/female), age (<65 yr, 265 yr), smoking nonsmoker), deep ulcer (yes/no), Barrett’s columnar metaplasia (yes/no), and grade at preentry. Symptoms were analyzed per protocol at 2 and 4 wk using a ridit analysis for global assessment of symptoms. Laboratory variables were analyzed whenever possible in terms of the mean change from preentry to the last day in the study. Comparisons between treatment groups of mean change from baseline were based on the unpaired t-test. Changes from baseline for variables that showed a skewed distribution were expressed as medians and tested using the sign test with 2 analysis of changes between treatment groups. In phase 3 life-table analysis was used for the calculation of cumulative relapse rates using BMDP statistical software. Cox regression analysis was conducted considering the prognostic variables of initial treatment dose (20 or 40 mg), smoking habits (smoker/nonsmoker), and initial grade of esophagitis (2, 3, or 4).

PLACEBO Day 0

I. Clinical

and Endoscopic

Data From

4 weeks

1

1 2

3

1

:

4 1

* Withdrawn

Study

Euch

Day 0

3

Sixty-four patients entered the study between June and August 1985. One patient entry was found to be nonvalid because of previous vagotomy and the Demoresults from 63 patients were evaluated. graphic, clinical, and endoscopic data were similar for the two treatment groups on entry into the trial (Table 1). The omeprazole-treated group had a highly significant (p < 0.0001) improvement of endoscopic grading compared with placebo (Figure 2). The incidence 25 of 31, 81%; of healing at 4 wk (omeprazole, placebo, 2 of 32, 6%) and 8 wk (omeprazole, 25 of 31, 81%; placebo, 3 of 32, 9%) was also significantly greater with omeprazole (p < 0.0001). Endoscopy at 8 wk in patients unhealed at 4 wk showed that 16 of Table

weeks

J

Results Healing

OYEPRAZOLE 4

0

Figure

Phase z : Placebo-Controlled

Vol. 95, No. 4

2. Endoscopic grading of severity of esophagitis in omeprazole and placebo groups in phase 1 before and after 4 wk of treatment. Each fine represents 1 patient. For details of grading see text.

20 placebo-treated patients were unchanged in grade, 2 had healed, and 2 had deteriorated. The endoscopic grading of the 3 unhealed omeprazoletreated patients remained unchanged: two grade 4, one grade 3. Alternative statistical analyses (e.g., excluding withdrawn patients) were also performed but none of these altered the clear-cut difference in outcome between the treatments. The response to omeprazole treatment was similar in each of the four hospital centers. Before treatment histologic evidence of peptic esophagitis was present in 55 of the 63 patients. Necrotic tissue was present in biopsy specimens

Treatment

nt Entry

Group

to the Study Phase 2”

Phase

Number entered Male:female Mean age (range) (yr) Median symptom duration (mo) Cigarette smokers Recent UNSAID therapy Recent HA-receptor antagonists Esophagitis at entry Grade 2 Grade 3 Grade 4 Columnar esophageal mucosa Peptic esophageal stricture NSAID.

nonsteroidal

antiinflammatory

Placebo

Omeprazole (20 mg)

Omeprazole

Omeprazole 32 24:7 5Y [28-78) 66 .I 8 16

32 18:14 64 (18-80) 66 2 8 17

82 51:31 60 (24-78) GO 15 15 33

82 49:33 63 (19-84) 60 7 18 41

11 14 G 6 6 drug.

1

” Includes

11 11 10 7 7 32 patients

from phase

31 30 21 17 13

1 and 132 additional

patients.

(40 mgl

30 34 1N 13 26

%

100

0

None

Q

Mild

q n

80

Moderate severe

60

40

relief and the median number of doses taken was significantly less in the omeprazole-treated group group in each 2-wk treatthan the placebo-treated ment period. Median consumption in each 2-wk treatment period was 42, 41, 50. and 45 doses in the placebo group and 2, 0, 0. and 0 doses in the omeprazole group.

20

0

Placebo Omeprazole Day 0 Figure

Placebo Omeprazole 4 weeks

3. Proportion

of patients with mild, moderate. or severe heartburn. or none. before and after 4 wk of treatment with omeprazole or placebo in phase 1.

from 45 patients (22 of 31 omeprazole. 23 of 32 placebo) and neutrophil polymorphonuclear infiltration was present in 54 (26 of 31 omeprazole, 28 of 32 placebo]. After 4 wk of treatment ulceration was present in 5 of 29 omeprazole-treated patients and 22 of 29 patients who received placebo (p < O.OOl), with neutrophil polymorphonuclear infiltration in 6 of 29 (omeprazole) and 23 of 29 (placebo), respectively (p < 0.001). Macroscopic healing of esophagitis, judged at endoscopy, occurred in 25 omeprazoleHistologic evidence of necrotic treated patients. tissue was absent in 24 of these patients, with supporting the endoulceration in only 1 patient, scopic findings. In contrast, biopsy specimens taken from 26 unhealed placebo-treated patients at the completion of the study demonstrated necrotic ulcer tissue in 19 patients. Ulceration was confirmed histologically in all 4 omeprazole-treated patients who were not healed macroscopically at 4 wk. Heartburn, regurgitation, or dysphagia were present in 62 patients before treatment. Patients randomized to omeprazole showed much more rapid and complete relief of heartburn than those receiving placebo (Figure 3). In addition, a significantly greater number of omeprazole-treated patients experienced relief from regurgitation and dysphagia. If only patients with these symptoms at entry are considered, then by 4 wk regurgitation was abolished in 16 of 21 receiving omeprazole and 5 of 22 receiving placebo (p < 0.006). Similarly, dysphagia disappeared in 9 of 12 omeprazole-treated patients and only 1 of 14 placebo-treated patients (p < 0.01) by 4 wk. The rapidity and completeness of symptom relief in many patients receiving omeprazole was striking. In a global assessment of symptoms a significant advantage was apparent for omeprazole within the first 2 wk, with 12 of 31 (39%) patients reporting complete relief of all symptoms at 2 wk compared with 1 of 32 (3%) patients in the placebo group (p < 0.001). The number of patients taking antacids for symptom

Phase 2: Comparison Omeprnzole

of 20 clnd 40 mgiduy

of

One hundred thirty-two patients were enrolled in this phase in addition to the 32 patients randomized to 20 or 40 mg of omeprazole in phase 1, making a study group of 164 patients. The demographic, clinical, and endoscopic: data on the 20- and 40-mg treatment groups were similar (Table 1). After 4 wk, 67 of 82 (82%) patients treated with 40 mg of omeprazole daily had healed compared with 57 of 82 (70%) in the 20-mg group. This difference is just statistically significant (,$ = 2.61. p == 0.05, onesided). Continued treatment to 8 wk in patients who had not healed at 4 wk increased the cumulative healing rate to 70 of 82 (85%)) in the 40-mg group and 65 of 82 (79%) in the 20-mg group, (2 = 0.48, p =; 0.10. one-sided). Healing of esophagitis was strikingly influenced by the severity of esophagitis at entry to the study (Figure 4). Fewer than half of the patients with grade 4 esophagitis healed with either 20 (48%) or 40 mg (44%) of omeprazole. Treatment for a further 4 wk produced small increases in cumulative healing rates in grade 4 patients: 62% (20 mg) and 560/o (40 mg), respectiI:ely. There was no evidence from a logistic regression analvsis that sex, age, smoking habits, or the presence of deep ulcer, Barrett’s mucosa, or stricture could improve the model. Therefore, the final model chosen included only dose and pretreatment grade. This analysis confirms that the major factor in determining healing at both 4 and 8 wk is the preentry grade of esophagitis, with a small effect in favor of 40 mg of omeprazole that is statistically significant at 4 wk but not at 8 wk. Symptoms of heartburn, regurgitation, or dysphagia were present in 94% of patients at entry to this phase of the study. The remaining patients had presented with anemia or gastrointestinal hemorrhage. Relief of heartburn was rapid and profound with both the 20- and 40-mg doses, with a small advantage for the 40-mg dose at 2 wk (Wilcoxon test, Z = 1.61, p = 0.05, one-sided], but not at 4 wk (Figure 5). The number of episodes of heartburn each week was also reduced more rapidly by 40 than 20 mg. Regurgitation. dysphagia. and nausea improved in both the 20- and 40-mg treatment groups, with resolution of these symptoms in 82’5,. 80%,, and 81(%,

HETZEL

ET AL.

GASTROENTEROLOGY

20mg

OMEPRAZOLE

OMEPRAZOLE

Vol. 95, No. 4

40mg

100

Figure

4.

50

Cumulative endoscopic healing rates of esophagitis after 4 and 8 wk of treatment with 20 The or 40 mg of omeprazole. solid line indicates the healing rate of all patients (n = 82 in each group). Open triangles represent patients initially with grade 2 erosive esophagitis (mild), closed triangles those with grade 3 esophagitis (moderate), and open squares those with grade 4 esophagitis (severe). Results were calculated on “intention to treat,” including withdrawals as unhealed.

0 4 WEEKS

8 WEEKS

4 WEEKS

of omeprazole-treated patients who had noted them at entry. The number of patients taking antacids and the amount used decreased more rapidly in the 40-mg group. From day 1 to 2 wk, 48 of 70 (69%) patients in the 20-mg group and 34 of 39 (49%) patients in the 40-mg group used antacids. From 2 to 4 wk the proportion fell to 25 of 66 (38%) and 18 of 66 (27%), respectively. During weeks 7 and 8 only 7 of 19 and 2 of 5 of the 20- and 40-mg groups, respectively, used any antacid.

Phase

3: Relapse

After

Stopping

8 WEEKS

suffered myocardial infarction, 2 recommenced HZantagonists, 3 were lost to follow-up); 4 patients with recurrent symptoms had only grade 1 erythema without ulceration at endoscopy and were also withdrawn (2 from each treatment group). Figure 6 shows the cumulative rate of recurrence of esophageal ulceration. There was no difference in outcome between the ZO- and 40-mg groups (p = 0.923, generalized Wilcoxon test). At the 6-mo follow-up endoscopy only 9 patients had not relapsed (20-mg group,

Treatment

Of 125 healed eligible patients, 107 entered phase 3 (5 refused, 11 started other therapy. 1 had persistent heartburn, and 1 was considered noncompliant). Fifty of these 107 patients had received 20 mg of omeprazole and 57 had received 40 mg. Seven patients withdrew without an exit cndoscopy (2 -

0

None

q q n

Mild

“““. Omeprazole 20mg (n = 50) Omeprazole 40mg (n = 57)

Moderate Severe

.h_

20mg Day

40mg 0

20mg 2 weeks

40mg

20mg

40mg

4 weeks

5

Severity of heartburn before treatment and at 2 and 4 wk in patients treated with 20 or 40 mg of omeprazole. The length of each bar represents the proportion of patients with mild, moderate, or severe heartburn or none. Per protocol analysis.

I

I

20

Figure

i

40

I

60

I

I

I

L

80

100

120

140

I

160

I

180

I

200

Days Figure

6. Cumulative relapse ods after stopping omeprazole.

rate calculated by life-table treatment with 2.0 or 40

methmg of

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1988

Twelve patients were excluded from the per protocol analysis due to violation of inclusion/exclusion criteria or time limits. In phase 1, 4 patients withdrew before 4 wk because of nonattendance (1 omeprazole), hypcrcalcemia due to bronchial carcinoma (1 placebo), and symptom deterioration (2 placebo). Eight patients were withdrawn in weeks 5-8, 6 because of worsening endoscopic: grading (1 omeprazole, 5 placebo] and 2 because of noncompliance (both placebo). In phase 2, 3 patients were withdrawn from the study because of dysphagia (1) and vomiting (2); they were included in the per protocol analysis as treatment faillires.

5; 40-mg group, 4). Cox regression analysis on the relapse data showed no evidence that omeprazole dose, smoking, or esophagitis grade at entry influenced the rate of relapse.

Adverse

Events

and

Withdrawals

Three patients suffered serious adverse events in phase 1 but all recovered fully. One developed pulmonary embolus after 2 doses of omeprazole. 1 vomited during placebo treatment, and 1 developed asthma during placebo treatment. Minor adverse events that resolved were recorded in each group: 23 events in the omeprazole-treated patients and 21 events in the patients receiving placebo. In phase 2. 5 additional patients were withdrawn because of 1;vomiting, 2; gallstone adverse events (dysphagia, pancreatitis, 1;and diarrhea, 1). None of these effects were thought to be specifically related to omeprazolc treatment and, overall, omeprazole appeared to be well tolerated.

:t

500

1000

l

$- 640

Minor abnormalities in laboratory variables occurred with similar frequencv in the 2@mg omeprazole, 40-mg omeprazole. and placebo trcatment groups. Most abnormalities (c:.g., low hcmoglobin because of recent hematemr:sis. minor elf:vations

Taken 4 weeks after treatment stopped.

.

450

. 400

. 350

.

300

250

.

.

200

.

.

150

100

50

0

u-uDay 0

---4 weeks

8 weeks

OMEPRAZOLE Figure

20mg

7. Serum gastrin concentrations in patients treated stopping treatment. Each dot represents 1 patient. 100 pgiml.

Post s

Day 0

4 weeks

8 weeks

OMEPRAZOLE

Post s

40mg

with 20 or 40 mg of omoprazole at day 0. 4 lvk. ant1 8 wk. and 1 mo after The bar indicates the median xralue. The upper limit of the normal range is

910

HETZEL ET AL.

of alanine transaminase, or serum y-glutamyl transpeptidase) were present before treatment. A small but statistically significant (p = 0.005)rise in mean aspartate transaminase values from 20.0 IUiL at day 0 to 22.5 IU/L occurred in the 40-mg omeprazole group during the study. Most aspartate transaminase values remained within the normal range and none of the abnormal values were considered clinically significant. Serum gastrin concentrations at entry were skewed by abnormally high values in each treatment group, usually associated with prior HZ-receptor antagonist treatment (Figure 7).There was a significant increase in serum gastrin after treatment with both omeprazole doses. One month after treatment was stopped serum gastrin had returned to the normal range in all but 5 patients (Figure 7). The highest concentrations at day 0 (450 pg/ml) and at 4 wk (1000 pgiml) occurred in the incorrectly entered patient who had undergone previous vagotomy.

Discussion Our results indicate that when compared with placebo, omeprazole is a highly effective healing agent for ulcerative peptic esophagitis and provides rapid and complete symptom relief for the majority of patients. The results are particularly striking in view of the fact that all of the patients recruited had erosive or ulcerative esophagitis, which was endoscopically extensive or severe (grades 3 or 4) in 64%. Histopathology confirmed the highly significant advantage of omeprazole in the healing of ulceration and reduction of polymorphonuclear inflammatory infiltration by 4 wk. The 81% healing rate with omeprazole at 4 wk in phase 1 is unprecedented for any other medical therapy for peptic esophagitis. In contrast, previous placebo-controlled studies of H,receptor antagonists found endoscopic healing in of patients with erosive esophagitis only 20%46% treated for 6-8 wk (6,7,11,12,15). The healing rate with placebo therapy found in the present study (6% at 4 wk, 9% at 8 wk) provides a firm basis for comparison of our results with placebocontrolled studies with HZ-receptor antagonists (6,7,11,12,15). In these studies placebo healing rates ranged from 0% to 27%, results comparable with the present figures, which suggests that our study group is not atypical. The knowledge by the blinded observer that the study is placebo controlled also removes the possibility of bias in favor of therapeutic intervention. Finally, the persistent esophageal ulceration found in most placebo-treated patients, despite symptom improvement in many, emphasizes the importance of not relying on symptoms as a guide to treatment response in these patients.

GASTROENTEROLOGY

Vol. Y5. No. 4

What factors influence the outcome of omeprazole treatment? Our results in the entire group of omeprazole-treated patients show that most patients heal except for those with the most extensive or severe ulceration. The frequency of healing at 4 wk in patients with grade 4 esophagitis (deep ulcers in Barrett’s mucosa or confluent ulceration) with either 20 (48%) or 40 mg (41%) was only half that found in patients with grade 2 (isolated spots or streaks of erosion) receiving 20 (87%) or 40 mg (97%). The larger omeprazole dose produced little additional benefit in the whole group of grade 4 patients, although deep Barrett’s ulcers healed in 12 of 12 patients treated with 40 mg and in only 7 of IO patients treated with 20 mg. Treatment of grade 4 patients for 8 wk produced small increases in cumulative healing rate to 62% (20 mg) and 56% (40 mg), and some of the unhealed deep Barrett’s ulcers diminished in size during treatment, although they were still scored as grade 4. The prognostic importance of extent of macroscopic ulceration has also been demonstrated in a study with ranitidine (28). That study found that cigarette smoking negatively influenced the healing of esophagitis. The present study found no reduction in healing rate in smokers, and this is in keeping with studies of omeprazole in duodenal ulcer (29,30). This study provides new information on the optimal dose and duration of omeprazole treatment. The small advantage for 40 mg of omeprazole at day 29 may be clinically advantageous in maximizing the rate of healing for all patients, but continuation of 20 mg of omeprazole for 8 wk allows similar results to be achieved. Further increase in omeprazole dose to 60 mg daily, in the ranitidine comparative study (25), was not associated with a greater healing rate than that found with 40 mg of omeprazole in this study. These observations are in accord with data on the reduction in 24-h intragastric acidity by omeprazole in patients with duodenal ulcer, which show that either 40 or 60 mg daily produces 96(/o-98’% reduction in intragastric acidity, whereas 20 mg produces 90% reduction (31.32). A lo-mg daily dose of omeprazole shows wide interindividual variation in acid inhibition (32,33), making 20 mg likely to be the lowest dose for routine clinical use. The duration of the present study is too short to allow conclusions to be drawn on the impact of omeprazole treatment on the complications of severe reflux esophagitis. In phase 1 dysphagia was present at entry in 26 patients and resolved in most who received omeprazole but not in those on placebo. Strictures were present and dilated at entry in only 6 omeprazole-treated and 7 placebo-treated patients. These data suggest that much of the initial dysphagia was not due to fibrous stricture and that resolution of

October

1988

dysphagia is associated with healing of ulceration and inflammation. Possibly, dysphagia lessened because of improved motor function or esophageal wall compliance, or by alteration of esophageal sensory perception due to mucosal healing. However, our study was not designed to investigate these factors. In phase z strictures present at entry were dilated initially in 20 of 26 patients (40 mg) and 11 of 13 patients (20 mg). At 4 wk stricture was still evident in 8 (40 mg) and 7 (20 mg] patients. These results are encouraging, and if strictures arise from scarring at the site of mucosal ulceration, we can speculate that effective longer-term prevention of ulceration will be beneficial in reducing stricture formation. Our own anecdotal information in a patient receiving long-term omeprazole on a compassionate basis supports this optimistic view (34). The healing of deep Barrett’s ulcers (discussed above] was not accompanied by any convincing change in the endoscopic extent of esophageal columnar mucosa, which was noted in 30 patients at entry and 25 patients at 4 wk. Further studies will be required to assess whether longer-term use of omeprazole can influence the extent of columnar metaplasia. Within 6 mo of stopping omeprazole, recurrence of symptoms and ulceration was evident in >80% of patients. The tendency to relapse is therefore similar to gastroduodenal ulcer disease and suggests that the short-term endoscopic and histologic mucosal healing produced by omeprazole does not alter the natural history of reflux disease. The high rates of healing and subsequent relapse we have found in this study are in keeping with the results of our earlier pilot study (24). A 30-mg daily dose of omeprazole abolished postprandial acid exposure with prolonged elevation of gastric pH above 5, a much greater effect than previously reported with 1200 mg of cimetidine daily (35), but simultaneous manometric recordings showed that reflux continued and that the frequency of reflux episodes was not altered significantly by omeprazole. There was no significant difference in the number of postprandial transient lower esophageal sphincter relaxations, nor in the magnitude of basal lower esophageal sphincter pressure. Radionuclide studies have also shown that omeprazole has no significant effect on gastric emptying in humans (36). These findings and our present results indicate that it is the profound and persistent increase in pH of the gastric refluxate that results in healing of peptic esophagitis. However, on cessation of therapy intragastric pH returns to pretreatment values within a week and the pathophysiologic setting for recurrence of ulceration is reestablished. Omeprazole treatment was well tolerated. No side

OMEPRAZOLE

TREATMENT

FOR ESOPHAGITIS

911

effects were observed that were specifically attributed to omeprazole and the frequency of adverse events was similar to that found with placebo. In in reflux symptoms causing phase 1, deterioration patient withdrawal and nonattendance was more common with placebo than omeprazole treatment, and any underreporting of adverse events was therefore more likely to have occurred in the placebo group. Hematologic and biochemical testing also confirmed the safety of omeprazole treatment. The elevation of serum gastrin found in this short-term study appeared clinically unimportant but indicates the need for careful monitoring of serum gastrin and gastric mucosal biopsies in longer-term studies. Animal toxicologic studies with omeprazole have reported localized enterochromaffinlike cell proliferation, and in some cases carcinoid tumors, in the stomach of rats treated for 2 yr with very large doses of omeprazole (37). Reversible enterochromaffinlike cell proliferation can also be induced by high-dose ranitidine treatment and appears to be the result of sustained hypergastrinemia produced by prolonged inhibition of acid secretion (38), although no enterochromaffinlike tumors have been reported after this treatment. Changes in serum gastrin and enterochromaffinlike cells show substantial species differences and appear unlikely to be clinically important in short-term studies in humans. Concerns about longer-term elevation of serum gastri;. in humans apply not only to omeprazole, for as seen in patients at entry to the study, hypergastrinemia also occurs with HZ-receptor antagonist therapy and after vagotomy. In conclusion, this study shows that omeprazole is a highly effective agent for healing of severe peptic esophagitis and that the effect is dose-related. The initial endoscopic findings are of important prognostic value in indicating the chance of healing. Cessation of omeprazole treatment is followed by a high rate of relapse. The substantial clinical benefits found in this study and the high rate of relapse off therapy indicate the need for longer-term studies of omeprazole (and other agents) as prophylactic treatment for the prevention of esophageal mucosal ulceration and its attendant complications.

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Received January 6, 1988. Accepted May 18, 1988. Address requests for reprints to: Dr. John Dent, Gastroenterology Unit, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000. Omeprazole and placebo capsules and financial support were provided by Astra Pharmaceuticals Pty. Ltd., Australia. The authors thank their colleagues Dylan Bartholomeusz, Ian Churchward, Robert Hecker, Neil McIntosh, Dora Rao, Robert Rowland, Keith Shilkin, Peter Wilson, Jim Watts, Derwyn Williams, and Richard Willing for their invaluable support: and Wendy Ferguson, Joylene McKay, Liz Nordstrom, Julie Shirley, David Cosh, and Janet Bickley for help in enrolling and caring for the patients. They also thank Susan Devenish-Meares and Sandra Webb of Astra Pharmaceuticals Pty. Ltd. for their constant logistic support.