Digestive Diseases and Sciences, Vol. 36, No. 6 (June 1991), pp. 761-768
U.S. Experience with Omeprazole in Duodenal Ulcer Multicenter Double-Blind Comparative Study with Ranitidine J.E. VALENZUELA, MD, R.G. BERLIN, MD, W.J. SNAPE, MD, T.L. JOHNSON, MD, B.I. HIRSCHOWITZ, MD, J. COLON-PAGAN, MD, R.S. MORSE, MD, J. PETROZZA, MD, G.M. VAN DEVENTER, MD, A. CAGLIOLA, BS, J. WHIPPLE, MS, R. BERMAN, MS, T.J. HUMPHRIES, MD, and THE OMEPRAZOLE DU COMPARATIVE STUDY GROUP
To assess the comparative efficacy o f omeprazole 20 mg, a proton pump inhibitor, versus ranitidine 150 mg twice a day, an H2-receptor antagonist, in healing duodenal ulcers we performed a randomized, double-blind, multicenter trial in 309 patients with endoscopically diagnosed ulcers. Patients were treated for up to four weeks and were seen at week 2 and at week 4, if unhealed at week 2, for determination o f ulcer status by endoscopy, review of daily self-assessment symptom diaries, and clinical laboratory including fasting serum gastrin. Gastrin levels were repeated two weeks after cessation of study medication. Evaluation o f baseline demographic and laboratory parameters demonstrated no significant differences between the two groups at entry. At week 2, 42% o f the omeprazole and 34% o f the ranitidine-treated patients were healed (P = NS). At week 4, there was a 19% advantage in ulcer healing for the omeprazole-treated patients in comparison to those treated with ranitidine (82% vs 63%, respectively, P < 0.05). Healing o f ulcers >- 1.0 cm occurred in 83% of those treated with omeprazole versus 37% treated with ranitidine (P < 0.01). There were no significant differences in rate o f pain relief or incidence o f clinical laboratory abnormalities. Mean fasting serum gastrin value during treatment increased over the baseline in both groups, (P < 0.05). The percent change was significantly greater with omeprazole but f e w patients had elevations above the upper limit o f normal for the assay. Both drugs were well tolerated. Omeprazote 20 mg demonstrated superiority in healing duodenal ulcers at four weeks in comparison to ranitidine 150 mg twice daily and was more effective in healing ulcers >-1.0 cm. KEY WORDS: duodenal ulcer; acute therapy; substituted benzimidazole; omeprazole; Hz-antagonist; raniti-
dine; gastrin.
Manuscript received June 30, 1990; revised manuscript received December 26, 1990; accepted January 3, 1991. From the USC School of Medicine, Los Angeles, California; Torrance, California; West Point, Pennsylvania; Amarillo, Texas; Birmingham, Alabama; Hato Rey, Puerto Rico; Sarasota, Florida; Statesville, North Carolina; CURE-VAH Wadsworth, Los Angeles, California; and 12 additional U.S. study sites. This work was supported by the National Institutes of Arthritis and Metabolism and Digestive Diseases grant AM34840, Veterans AdministrationResearch Funds, and Merck, Sharp and Dohme Research Laboratories. Address for reprint requests: Dr. J.E. Valenzuela, USC School of Medicine, Department of Medicine, Gastrointestinal and Liver Diseases Division, 2025 Zonal Avenue, Los Angeles, California 90033.
Peptic ulcer is believed to result from an interplay of multiple factors with the presence of acid considered essential. Treatment of duodenal ulcer has historically been designed to reduce the secretion of acid or neutralize acid once it is produced. This approach has been successful in accelerating ulcer healing and in proyiding pain relief (1). A fundamental question remaining with regard to this approach has been one of dose response. While it is clear that acid neutralization or moderate reduction in secreted acid is beneficial in terms of ulcer outcome,
Digestive Diseases and Sciences, Vol. 36, No. 6 (June 1991)
0163-2116/91/0600-0761506.50/0~!~1991PlenumPublishingCorporation
761
VALENZUELA ET AL it has been less certain whether healing might be enhanced as a result of greater acid secretory inhibition (2). A more recent evaluation of this question has shown that ulcer healing can be accurately predicted on the basis of pH control achieved over a 24-hr period (3). These data suggest that 24-hr acid suppression as produced by omeprazole should translate into a therapeutic advantage in treating duodenal ulcer. Omeprazole, a substituted benzimidazole, potently inhibits gastric acid secretion in animals and humans (4). In contrast to the currently available gastric antisecretory agents that inhibit acid secretion by antagonizing receptor-mediated binding of histamine on the basolateral surface of the parietal cell, omeprazole irreversibly blocks the metabolic activity of a luminal surface proton pump, resulting in a dose-dependent, potent, and long-lasting inhibition of acid secretion (5). The drug acts by noncompetitive inhibition of H § K+-adenosine triphosphatase activity in the secretory membrane of the parietal cell, blocking H § production (6). Doses of 20 mg daily effectively inhibit 58-80% of intragastric acidity in healthy volunteers and duodenal ulcer patients for a 24-hr period (7, 8). Efficacy trials in European duodenal ulcer patients have demonstrated rates exceeding 92% at four weeks (9-11). These studies suggest that antisecretory potency correlates directly with rate of ulcer healing and that 24-hr reductions in secretion offer an advantage over nocturnal reduction in secretion alone. Clinical use of potent antisecretory agents may cause hypergastrinemia, and this has been raised as a potential concern. Elevations in serum gastrin result from a decrease in intragastric acidity since acid is the physiologic negative inhibitory influence on the release of gastrin from the antral ~ cell. During omeprazole treatment, moderate hypergastrinemia develops, which usually resolves within two weeks following cessation of therapy (11-13). Although rat carcinogenicity studies involving lifelong drug exposure (two years) have demonstrated enterochromaffin-like (ECL) cell carcinoids in the setting of hypergastrinemia (14), no change in the E C L cell population has been identified in man (15-17). The recent finding that rats exposed to ranitidine 2 g/kg/day in the diet for 106 weeks also developed E C L cell carcinoids (18) demonstrates the unique sensitivity of the rat and provides further evidence that the "gastrin hypothesis" of the causation of these lesions is correct. Gastric E C L cell carcinoids in humans are rare but may occasionally
762
be seen in clinical states associated with chronic, marked hypergastrinemia, such as pernicious anemia (19) and Zollinger-Ellison syndrome (20). This study was undertaken to determine the comparative efficacy of omeprazole and ranitidine in healing ulcers and to generate further information regarding the effects of these therapies on fasting serum gastrin during and two weeks after cessation of therapy. MATERIALS AND METHODS Patients. Three-hundred seventeen patients with duodenal or pyloric channel ulcers entered into the study after giving written informed consent. The protocol was approved by the Human Subjects Protection Committees at each study site. These 20 sites and the corresponding principal investigator are listed in Table 1. Patients age 18 or older were eligible to enter the study if an acute duodenal or pyloric channel ulcer, 0.5-2.5 cm in the largest diameter was endoscopically verified within three days of randomization. Patients with multiple ulcers also were enrolled; the largest ulcer was considered the index ulcer for stratification. Hospitalized patients were discharged within three days of start of study drug. Exclusion criteria were: history of ulcer surgery other than simple closure of a perforation; presence of pyloric channel obstruction; refractory ulcer disease defined as failure to heal after standard dose/duration of an approved agent; hypersecretory states; patients who had taken therapeutic doses of antiulcer medication for more than five consecutive days within the two weeks immediately preceding start of study drug; or any unstable medical condition. Study Design. Patients were randomly assigned to one of two treatment groups stratified for ulcer size (-< 1 cm and > 1 cm). Patients received two bottles of medication one containing omeprazole 20-mg capsules or identical placebo and the other either ranitidine 150-mg tablets or identical placebo. All patients received one active drug. One capsule of omeprazole was taken each morning before breakfast and one tablet of ranitidine was taken each morning at breakfast and each evening at bedtime. Gelusil antacid tablets were taken as needed for pain. Ulcer-related symptoms were recorded on a scale of 0-3 (0 = none, 1 = mild, 2 = moderate, 3 = severe) for day and night pain in a daily diary. Patients returned at weeks 1, 2, and if unhealed at week 2, week 4 for interim progress visits and laboratory evaluation, and at weeks 2 and 4 for endoscopic assessment. Relative day numbers for endoscopies were as follows: baseline to day 3; week 2, day 2-18; and week 4, day 29-32. When endoscopy demonstrated complete ulcer healing, study medication was discontinued. Healing was defined as complete reepithelialization of the ulcer crater. Fasting Serum Gastrin. Fasting serum gastrin determinations were obtained at baseline, during treatment at week 2, week 4, if unhealed at week 2, and two weeks posttreatment. These samples were taken 24-hr after the last omeprazole dose and 12 hr after the last ranitidine Digestive Diseases and Sciences, Vol. 36, No. 6 (June 1991)
DUODENAL ULCER THERAPY TABLE 1. OMEPRAZOLEDUODENALULCERSTUDYGROUP Investigator
Nabeel Adham, MD Martin J. Collen, MD Juan Colon-Pagan, MD Stephen S. Frost, MD Basil I. Hirschowitz, MD Jon I. Isenberg, MD James H. Johnson, MD Thomas L. Johnson, MD Thomas Kovacs, MD David T. Lyon, MD Jay W. Marks, MD Richard W. McCallum, MD Richard S. Morse, MD Walter L. Peterson, MD Joseph Petrozza, MD William J. Snape, MD E. Clinton Texter, Jr, MD Jorge E. Valenzuela, MD Gary Van Deventer, MD Z. Reno Vlahcevic, MD
Facility
Location
VA Medical Center Georgetown University Center Institute of Gastroenterology Presbyterian/UPMC University of Alabama University Hospital Watson Clinic Amarillo Diagnostic Clinic UCLA Medical Center Long Island College Hospital Cedars Sinai Medical Center University of Virginia 1219 Southwest Avenue VA Medical Center Iredell Digestive Disease Clinic Harbor-UCLA Medical Center University of Arkansas Medical Center USC School of Medicine CURE-VAH Wadsworth Medical College of Virginia
Sepulveda, California Washington, District of Columbia Hato Rey, Puerto Rico Philadelphia, Pennsylvania Birmingham, Alabama San Diego, California Lakeland, Florida Amarillo, Texas Los Angeles, California Brooklyn, New York Los Angeles, California Charlottesville, Virginia Sarasota, Florida Dallas, Texas Statesville, North Carolina Torrance, California Little Rock, Arkansas Los Angeles, California Los Angeles, California Richmond, Virginia
dose. Samples were obtained in glass, centrifuged, and frozen promptly. The frozen serum was stored at -40 ~ C until analysis. All samples were analyzed in a single run radioimmunoassay procedure (21) with the upper limit or normal being 150 pg/ml. Statistical Analysis. The allocation schedule for this study was double-blinded. The data base was not unblinded until all the data were screened and protocol violators were identified. The analysis of efficacy at each time point was done as an end-point analysis (22). Two approaches to the analysis of the data were used. These approaches differed only in the manner in which exclusions were handled. The "per-protocol" approach used data from all evaluable patients not excluded as protocol violators. The "all-patients-treated" approach used data from all patients with baseline and treatment data. The proportions of patients healed cumulatively at each time point were compared among treatment groups. The crude healing rate was assessed using Fisher's exact test (22). The time to healing and the effect of various concomitant factors on ulcer healing were assessed using the MantelHaenszel method and other survival analysis methods (18). The time points used were weeks 2, 4, and after week 4. Dropouts were considered to be not healed. Day and night pain were assessed by analyzing the time until complete relief of pain using the Mantel-Haenszel life table method, stratifying on the baseline pain score. Within-group tests were performed using Wilcoxon's signed-rank test (22). For dichotomous demographic or concomitant variables, pairwise differences between treatment groups and clinical adverse experiences were assessed using Fisher's exact test. The analysis of distribution by predefined limits of change for laboratory measurements was done using the chi-square test (22). All tests were two-tailed with an a = 0.05 level of significance. The study was designed to detect a 15% difference in ulcer healing between the two treatment groups with 95% power. Digestive Diseases and Sciences, Vol. 36, No. 6 (Jane 1991)
RESULTS Demographics. By the completion of the study 317 patients had entered. Eight patients were randomized but failed to return and/or take study medication, leaving 309 patients evaluable by the all-patients-treated approach. The baseline characteristics of these 309 patients studied is shown in Table 2. Overall, both groups were comparable at baseline. The mean age was 46.3 years for the omeprazole group and 50.5 years for the ranitidine groups. The sex ratio, M/F, was similar in both groups, approximately 3: I. There were some differences in incidence of secondary conditions unrelated to ulcer; in the omeprazole group there was a higher reported incidence of anemia; in the ranitidine group there was a higher incidence of hypertension. Patients in the omeprazole group tended to have slightly larger ulcers and a slightly longer TABLE2. COMPARABILITYOF TREATMENTGROUPSAT BASELINE Characteristic
Mean age (years) Males (%) Smokers (%) Alcohol Use (%) Duration of ulcer history (%) ~1 year 1.1-9.9 years -10 years Mean initial ulcer size (cm)
Omeprazole ( N = 151)
Ranitidine (N = 158)
46.3 77 42 11
50.5 69 46 11
38 26 36 0.94
48 22 30 0.90
763
VALENZUELA
ET AL
TABLE 3. NUMBER OF PATIENTS OMt~ED FROM ANALYSIS OF EFFICACY Omeprazole Week 2
Failed to return/take study medicine Baseline visit out of range Concomitant ranitidine/cimetidine Concomitant aspirin Lost study medication Total Number evaluable "all patients treated" Number evaluable " p e r protocol"
history of duodenal ulcer; these differences were not statistically significant. An additional 16 patients were determined to be "protocol violators," leaving a total of 293 patients evaluable by the "per protocol approach." Reasons for exclusion from the analysis are shown in Table 3. One-hundred forty-five (145) patients who received omeprazole, and 148 who received ranitidine were included in the per protocol analysis. Of the 20 participating centers, each contributed a mean of 15 patients (range of 1-28). Compliance. Compliance was measured by counts of returned pills. Ninety-nine percent of patients randomized to receive omeprazole and 97% of patients randomized to receive ranitidine took at least 80% of the medication. When compliance was analyzed by ulcer size no differences in compliance were noted for either treatment group. Ulcer Healing Efficacy. The healing rates, by per-protocol analysis, for the omeprazole group were numerically greater than for the ranitidine group at week 2 and week 4 and significantly greater at week 4, (P < 0.01, see Figure 1). At week 2, 42% (34.5-50%, 95% CI) of patients in the omeprazoletreated group had healed versus 34% (26-41%, 95% CI) in the ranitidine-treated group. At week 4 the percentage of patients healed for omeprazole and ranitidine were 82% (76-88% 95% CI) and 63% (56-71%, 95% CI), respectively. The advantage of omeprazole over ranitidine in healing duodenal ulcer was 8% ( - 3 to + 19%, 95% CI) at week 2 and 19% (9-29%, 95% CI) at week 4. At week 2 three patients in the omeprazole group and nine in the ranitidine group had dropped out and at week 4 an additional three and four patients, respectively, had dropped out. When the data from all investigators with 15 or f e w e r patients was combined, analysis showed no treatment by investigator interaction. Using an all-patients-treated ap-
764
Ranitidine
Week 4
Week 2
Week 4
6 1 3 1 1
6 1 3 1
1
1
1
0
0
12 151 145
12 151 145
12 158 148
12 158 148
2 6 3
2 6 3
proach, 42% (34-50%, 95% CI) of omeprazole patients had completely healed ulcers by week 2, and 82% (76-88%, 95% CI) by week 4. The corresponding result for ranitidine patients was 34% (27-42%, 95% CI) by week 2 and 63% (56-71%, 95% CI) by week 4. Utilizing a survival analysis omeprazole was also superior to ranitidine with respect to time to healing (P < 0.01). There was no effect of a variety of baseline variables on outcome, except for ulcer size (Table 4). Patients in the omeprazole group responded well regardless of initial ulcer size. Specifically, smoking, caffeine, and alcohol use; age; sex; or duration of ulcer disease did not alter the healing rates observed with omeprazole. In contrast, the percentage of patients healed on ranitidine was 72% for nonsmokers versus 55% for smokers. Omeprazole was also markedly more effective than ranitidine in healing larger ulcers 1.1-2.5 cm in diameter; 83% healed on omeprazole versus 37% on ranitidine (P < 0.01). Relief of Pain. Symptoms of daytime pain were rated as severe at baseline by 28% of patients in both the omeprazole and ranitidine groups (Figure 2). Pain data were stratified for baseline severity and analyzed for time to complete pain relief, defined as complete absence of pain without recurrence. There were significant (P < 0.01) reductions in day pain for both treatment groups, but no significant differences between the two treatment groups. Median time to complete relief of day pain was nine days for the omeprazole patients and 15 days for the ranitidine patients. Total relief of day pain was reported by 67% of the omeprazole patients and 61% of those on ranitidine. A failure to obtain pain relief was reported by 27% and 32% of the omeprazole and ranitidine patients, respectively. The relationship of pain relief to the status of ulcer healing is shown in Table 5. Pain relief was Digestive Diseases and Sciences, Vol. 36, No. 6 (June 1991)
DUODENAL ULCER THERAPY TABLE 4. BACKGROUND VARIABLE OUTCOME PER PROTOCOL ANALYSIS
Treatment* Omeprazole Factor
Ulcer Size (cm) Smoking Alcohol Caffeine Antacids Use Age Sex Duration of Disease: (years)
.50-1.0 1.1-2.5 No Yes No Yes No Yes No Yes 60 Male Female >1 1.1-9.9 >10
Ranitidine
T
H
%
T
H
%
115 30 84 61 128 88 57 88 46 99 54 55 36 112 33 55 37 53
94 25 72 50 108 76 46 76 38 84 44 46 32 95 27 47 30 45
82? 83~ 86 82 84 86 81 86 83 85 82 84 89 85 82 86 81 85
121 27 81 67 130 84 64 84 40 108 43 49 56 100 48 70 33 45
83 10 58 37 84 52 43 52 24 71 26 33 36 64 31 43 23 29
69 37 72 55 65 62 67 62 60 66 61 67 64 64 65 61 70 64
*T = total number; H = number healed; % = percent healed. t P < .05, Sp < 0.01 per protocol analysis.
achieved in 90% of omeprazole-treated patients with a healed duodenal ulcer versus 71% in the ranitidine group. For those who did not experience pain relief, 62% of those in the omeprazole group and 49% of those in the ranitidine group had a healed duodenal ulcer. Symptoms of night pain were rated as severe by 30% of omeprazole patients and 25% of ranitidine patients. The night pain relief results were similar to those described above for day pain, requiring a median of eight days for omeprazole patients and 12 days for ranitidine patients to achieve complete 100
lOO
Legend
90--
[]
Orneprazole N = 145
80--
9
Ranitidine N = 148
70--
9o
82%"
8o
* p < 0.01
50-40--
7o
63% Percent of Patients with Day Pain
60-Percent Healed
relief. Although there was a numerical advantage shown for omeprazole versus ranitidine, this difference was not statistically significant. Complete nighttime pain relief was obtained in 68% of the omeprazole patients and 64% of the ranitidine patients by the end of the study. Fasting Serum Gastrin. The serum gastrin results are reported as median, interquartile range, and spectral range for each treatment group at baseline, week 2, week 4, and two weeks posttreatment (Figure 3). All patients completing four weeks of treatment with serum gastrin assays for each of the
42% - - ]
34%
60 50 40 3O
30--
2O
20--
10
10~
0 0
0 Wk 2
Wk 4
Fig 1. Duodenal ulcer healing rates by per-protocol analysis for the two treatment groups, omeprazole and ranitidine, 2 and 4 weeks following entry, demonstrate an advantage for omeprazole. Ulcer healing was defined endoscopicaily and required reepithelialization of all ulcers without any residual erosion at the index ulcer site. Digestive Diseases and Sciences, Vol. 36, No. 6 (June 1991)
2
4
Week
Fig 2. Most patients (>83%) presented with symptoms of pain. Both treatment groups experienced significant reductions from baseline in diurnal pain during the course of the study. The percentages of patients with any day pain at each time point are displayed. There were no significant differences in day pain relief for either treatment group.
765
VALENZUELA ET AL TABLE 5. RELATIONSHIP OF PAIN RELIEF AND HEALING STATUS PER PROTOCOL ANALYSIS
Omeprazole
Ranitidine
Pain relief
status
Healed
Total
%
Healed
Total
%
Unknown
96 23 0
107 37 1
90** 62 0
68 25 0
96 51 1
71 49 0
Total
119
145
82"*
93
148
63
Pain relieved Pain unrelieved
*P < 0.01 with respect to healing.
four intervals specified were included in the analysis. A change from baseline analysis was observed in all patients in the study. End-point analysis compared baseline to off study, and baseline to two-week posttreatment gastrins in all patients (Table 6). Those in the study for only two weeks were analyzed separately from those in the study for four weeks. Patients treated for only two weeks demonstrated similar elevations in serum gastrin and returned to their mean baseline serum gastrin levels by the end of the 2-week posttreatment period, independent of study agent. Patients who continued in the study for four weeks, on the other hand, demonstrated a significantly greater increase from baseline gastrin with omeprazole, than with ranitidine (P < 0.01). In the omeprazole group mean serum gastrin continued to rise after week 2, whereas it remained unchanged in the 400350 300 -
o > o =
t~
250 -
TABLE 6. SERUM GASTRIN*
200-
150 - -
I--'10meprazole FFZl Ranitidine
so-Pre
Wk 2
Wk 4
Wks Post
2
Fig 3. Fasting serum gastrin results are reported for all patients with serum obtained at each of the four scheduled intervals (treated four weeks and returned for posttreatment lab). At each time point, the range (minimum and maximum), 25%, 50%, and 75% values are given. A significant change from baseline (median) was seen in both treatment groups at the two- and four-week intervals; however, the omeprazole group had a significantly greater mean increase than the ranitidine group at both weeks 2 and 4 (P < 0.01). At two weeks posttreatment, the omeprazole treatment group remained significantly changed from baseline, although decreased from on-treatment levels; the ranitidine treatment group had returned to baseline levels. A significant difference between groups was observed (P < 0.05).
766
ranitidine group. The range in absolute serum gastrin values noted among the patients at baseline was considerable. For most patients all measured serum gastrin values were within the normal range. The omeprazole patient with the highest measured gastrin was treated for only two weeks and had a baseline value of 441 pg/ml and a two-week value of 596 pg/ml. In the ranitidine group the highest reported on-treatment values was 395 pg/ml. Sixteen omeprazole patients (11.5%) had on-treatment gastrin values above the upper limits of normal for the assay, as compared to six patients (4.1%) in the ranitidine group. The ratio of treatment to baseline gastrin was 1:9 for the omeprazole group and 1:4 for the ranitidine group. By the end of the two-week posttreatment period, the median serum gastrin for the ranitidine group returned to baseline; the median for the omeprazole group remained elevated approximately 20% above baseline, although well within the normal range for the assay. A significant difference (P < 0.05) existed between the two groups at the posttreatment interval, although there were three patients in both
End of treatment Baseline Last value Change from baseline 9 % change from baseline Two Week Post-treatment Baseline Two-week posttreatment Change from baseline % change from baseline
Omeprazole
Ranitidine
N = 137 30 58 24tr
N = 145 32 44 1I t
94.5tr
36.3t
N = 109 27
N = 119 28
33 7tw 25.3t
34 1 2.1
tDifferent from baseline, P
U.S. Experience with Omeprazole in Duodenal Ulcer Multicenter Double-Blind Comparative Study with Ranitidine J.E. VALENZUELA, MD, R.G. BERLIN, MD, W.J. SNAPE, MD, T.L. JOHNSON, MD, B.I. HIRSCHOWITZ, MD, J. COLON-PAGAN, MD, R.S. MORSE, MD, J. PETROZZA, MD, G.M. VAN DEVENTER, MD, A. CAGLIOLA, BS, J. WHIPPLE, MS, R. BERMAN, MS, T.J. HUMPHRIES, MD, and THE OMEPRAZOLE DU COMPARATIVE STUDY GROUP
To assess the comparative efficacy o f omeprazole 20 mg, a proton pump inhibitor, versus ranitidine 150 mg twice a day, an H2-receptor antagonist, in healing duodenal ulcers we performed a randomized, double-blind, multicenter trial in 309 patients with endoscopically diagnosed ulcers. Patients were treated for up to four weeks and were seen at week 2 and at week 4, if unhealed at week 2, for determination o f ulcer status by endoscopy, review of daily self-assessment symptom diaries, and clinical laboratory including fasting serum gastrin. Gastrin levels were repeated two weeks after cessation of study medication. Evaluation o f baseline demographic and laboratory parameters demonstrated no significant differences between the two groups at entry. At week 2, 42% o f the omeprazole and 34% o f the ranitidine-treated patients were healed (P = NS). At week 4, there was a 19% advantage in ulcer healing for the omeprazole-treated patients in comparison to those treated with ranitidine (82% vs 63%, respectively, P < 0.05). Healing o f ulcers >- 1.0 cm occurred in 83% of those treated with omeprazole versus 37% treated with ranitidine (P < 0.01). There were no significant differences in rate o f pain relief or incidence o f clinical laboratory abnormalities. Mean fasting serum gastrin value during treatment increased over the baseline in both groups, (P < 0.05). The percent change was significantly greater with omeprazole but f e w patients had elevations above the upper limit o f normal for the assay. Both drugs were well tolerated. Omeprazote 20 mg demonstrated superiority in healing duodenal ulcers at four weeks in comparison to ranitidine 150 mg twice daily and was more effective in healing ulcers >-1.0 cm. KEY WORDS: duodenal ulcer; acute therapy; substituted benzimidazole; omeprazole; Hz-antagonist; raniti-
dine; gastrin.
Manuscript received June 30, 1990; revised manuscript received December 26, 1990; accepted January 3, 1991. From the USC School of Medicine, Los Angeles, California; Torrance, California; West Point, Pennsylvania; Amarillo, Texas; Birmingham, Alabama; Hato Rey, Puerto Rico; Sarasota, Florida; Statesville, North Carolina; CURE-VAH Wadsworth, Los Angeles, California; and 12 additional U.S. study sites. This work was supported by the National Institutes of Arthritis and Metabolism and Digestive Diseases grant AM34840, Veterans AdministrationResearch Funds, and Merck, Sharp and Dohme Research Laboratories. Address for reprint requests: Dr. J.E. Valenzuela, USC School of Medicine, Department of Medicine, Gastrointestinal and Liver Diseases Division, 2025 Zonal Avenue, Los Angeles, California 90033.
Peptic ulcer is believed to result from an interplay of multiple factors with the presence of acid considered essential. Treatment of duodenal ulcer has historically been designed to reduce the secretion of acid or neutralize acid once it is produced. This approach has been successful in accelerating ulcer healing and in proyiding pain relief (1). A fundamental question remaining with regard to this approach has been one of dose response. While it is clear that acid neutralization or moderate reduction in secreted acid is beneficial in terms of ulcer outcome,
Digestive Diseases and Sciences, Vol. 36, No. 6 (June 1991)
0163-2116/91/0600-0761506.50/0~!~1991PlenumPublishingCorporation
761
VALENZUELA ET AL it has been less certain whether healing might be enhanced as a result of greater acid secretory inhibition (2). A more recent evaluation of this question has shown that ulcer healing can be accurately predicted on the basis of pH control achieved over a 24-hr period (3). These data suggest that 24-hr acid suppression as produced by omeprazole should translate into a therapeutic advantage in treating duodenal ulcer. Omeprazole, a substituted benzimidazole, potently inhibits gastric acid secretion in animals and humans (4). In contrast to the currently available gastric antisecretory agents that inhibit acid secretion by antagonizing receptor-mediated binding of histamine on the basolateral surface of the parietal cell, omeprazole irreversibly blocks the metabolic activity of a luminal surface proton pump, resulting in a dose-dependent, potent, and long-lasting inhibition of acid secretion (5). The drug acts by noncompetitive inhibition of H § K+-adenosine triphosphatase activity in the secretory membrane of the parietal cell, blocking H § production (6). Doses of 20 mg daily effectively inhibit 58-80% of intragastric acidity in healthy volunteers and duodenal ulcer patients for a 24-hr period (7, 8). Efficacy trials in European duodenal ulcer patients have demonstrated rates exceeding 92% at four weeks (9-11). These studies suggest that antisecretory potency correlates directly with rate of ulcer healing and that 24-hr reductions in secretion offer an advantage over nocturnal reduction in secretion alone. Clinical use of potent antisecretory agents may cause hypergastrinemia, and this has been raised as a potential concern. Elevations in serum gastrin result from a decrease in intragastric acidity since acid is the physiologic negative inhibitory influence on the release of gastrin from the antral ~ cell. During omeprazole treatment, moderate hypergastrinemia develops, which usually resolves within two weeks following cessation of therapy (11-13). Although rat carcinogenicity studies involving lifelong drug exposure (two years) have demonstrated enterochromaffin-like (ECL) cell carcinoids in the setting of hypergastrinemia (14), no change in the E C L cell population has been identified in man (15-17). The recent finding that rats exposed to ranitidine 2 g/kg/day in the diet for 106 weeks also developed E C L cell carcinoids (18) demonstrates the unique sensitivity of the rat and provides further evidence that the "gastrin hypothesis" of the causation of these lesions is correct. Gastric E C L cell carcinoids in humans are rare but may occasionally
762
be seen in clinical states associated with chronic, marked hypergastrinemia, such as pernicious anemia (19) and Zollinger-Ellison syndrome (20). This study was undertaken to determine the comparative efficacy of omeprazole and ranitidine in healing ulcers and to generate further information regarding the effects of these therapies on fasting serum gastrin during and two weeks after cessation of therapy. MATERIALS AND METHODS Patients. Three-hundred seventeen patients with duodenal or pyloric channel ulcers entered into the study after giving written informed consent. The protocol was approved by the Human Subjects Protection Committees at each study site. These 20 sites and the corresponding principal investigator are listed in Table 1. Patients age 18 or older were eligible to enter the study if an acute duodenal or pyloric channel ulcer, 0.5-2.5 cm in the largest diameter was endoscopically verified within three days of randomization. Patients with multiple ulcers also were enrolled; the largest ulcer was considered the index ulcer for stratification. Hospitalized patients were discharged within three days of start of study drug. Exclusion criteria were: history of ulcer surgery other than simple closure of a perforation; presence of pyloric channel obstruction; refractory ulcer disease defined as failure to heal after standard dose/duration of an approved agent; hypersecretory states; patients who had taken therapeutic doses of antiulcer medication for more than five consecutive days within the two weeks immediately preceding start of study drug; or any unstable medical condition. Study Design. Patients were randomly assigned to one of two treatment groups stratified for ulcer size (-< 1 cm and > 1 cm). Patients received two bottles of medication one containing omeprazole 20-mg capsules or identical placebo and the other either ranitidine 150-mg tablets or identical placebo. All patients received one active drug. One capsule of omeprazole was taken each morning before breakfast and one tablet of ranitidine was taken each morning at breakfast and each evening at bedtime. Gelusil antacid tablets were taken as needed for pain. Ulcer-related symptoms were recorded on a scale of 0-3 (0 = none, 1 = mild, 2 = moderate, 3 = severe) for day and night pain in a daily diary. Patients returned at weeks 1, 2, and if unhealed at week 2, week 4 for interim progress visits and laboratory evaluation, and at weeks 2 and 4 for endoscopic assessment. Relative day numbers for endoscopies were as follows: baseline to day 3; week 2, day 2-18; and week 4, day 29-32. When endoscopy demonstrated complete ulcer healing, study medication was discontinued. Healing was defined as complete reepithelialization of the ulcer crater. Fasting Serum Gastrin. Fasting serum gastrin determinations were obtained at baseline, during treatment at week 2, week 4, if unhealed at week 2, and two weeks posttreatment. These samples were taken 24-hr after the last omeprazole dose and 12 hr after the last ranitidine Digestive Diseases and Sciences, Vol. 36, No. 6 (June 1991)
DUODENAL ULCER THERAPY TABLE 1. OMEPRAZOLEDUODENALULCERSTUDYGROUP Investigator
Nabeel Adham, MD Martin J. Collen, MD Juan Colon-Pagan, MD Stephen S. Frost, MD Basil I. Hirschowitz, MD Jon I. Isenberg, MD James H. Johnson, MD Thomas L. Johnson, MD Thomas Kovacs, MD David T. Lyon, MD Jay W. Marks, MD Richard W. McCallum, MD Richard S. Morse, MD Walter L. Peterson, MD Joseph Petrozza, MD William J. Snape, MD E. Clinton Texter, Jr, MD Jorge E. Valenzuela, MD Gary Van Deventer, MD Z. Reno Vlahcevic, MD
Facility
Location
VA Medical Center Georgetown University Center Institute of Gastroenterology Presbyterian/UPMC University of Alabama University Hospital Watson Clinic Amarillo Diagnostic Clinic UCLA Medical Center Long Island College Hospital Cedars Sinai Medical Center University of Virginia 1219 Southwest Avenue VA Medical Center Iredell Digestive Disease Clinic Harbor-UCLA Medical Center University of Arkansas Medical Center USC School of Medicine CURE-VAH Wadsworth Medical College of Virginia
Sepulveda, California Washington, District of Columbia Hato Rey, Puerto Rico Philadelphia, Pennsylvania Birmingham, Alabama San Diego, California Lakeland, Florida Amarillo, Texas Los Angeles, California Brooklyn, New York Los Angeles, California Charlottesville, Virginia Sarasota, Florida Dallas, Texas Statesville, North Carolina Torrance, California Little Rock, Arkansas Los Angeles, California Los Angeles, California Richmond, Virginia
dose. Samples were obtained in glass, centrifuged, and frozen promptly. The frozen serum was stored at -40 ~ C until analysis. All samples were analyzed in a single run radioimmunoassay procedure (21) with the upper limit or normal being 150 pg/ml. Statistical Analysis. The allocation schedule for this study was double-blinded. The data base was not unblinded until all the data were screened and protocol violators were identified. The analysis of efficacy at each time point was done as an end-point analysis (22). Two approaches to the analysis of the data were used. These approaches differed only in the manner in which exclusions were handled. The "per-protocol" approach used data from all evaluable patients not excluded as protocol violators. The "all-patients-treated" approach used data from all patients with baseline and treatment data. The proportions of patients healed cumulatively at each time point were compared among treatment groups. The crude healing rate was assessed using Fisher's exact test (22). The time to healing and the effect of various concomitant factors on ulcer healing were assessed using the MantelHaenszel method and other survival analysis methods (18). The time points used were weeks 2, 4, and after week 4. Dropouts were considered to be not healed. Day and night pain were assessed by analyzing the time until complete relief of pain using the Mantel-Haenszel life table method, stratifying on the baseline pain score. Within-group tests were performed using Wilcoxon's signed-rank test (22). For dichotomous demographic or concomitant variables, pairwise differences between treatment groups and clinical adverse experiences were assessed using Fisher's exact test. The analysis of distribution by predefined limits of change for laboratory measurements was done using the chi-square test (22). All tests were two-tailed with an a = 0.05 level of significance. The study was designed to detect a 15% difference in ulcer healing between the two treatment groups with 95% power. Digestive Diseases and Sciences, Vol. 36, No. 6 (Jane 1991)
RESULTS Demographics. By the completion of the study 317 patients had entered. Eight patients were randomized but failed to return and/or take study medication, leaving 309 patients evaluable by the all-patients-treated approach. The baseline characteristics of these 309 patients studied is shown in Table 2. Overall, both groups were comparable at baseline. The mean age was 46.3 years for the omeprazole group and 50.5 years for the ranitidine groups. The sex ratio, M/F, was similar in both groups, approximately 3: I. There were some differences in incidence of secondary conditions unrelated to ulcer; in the omeprazole group there was a higher reported incidence of anemia; in the ranitidine group there was a higher incidence of hypertension. Patients in the omeprazole group tended to have slightly larger ulcers and a slightly longer TABLE2. COMPARABILITYOF TREATMENTGROUPSAT BASELINE Characteristic
Mean age (years) Males (%) Smokers (%) Alcohol Use (%) Duration of ulcer history (%) ~1 year 1.1-9.9 years -10 years Mean initial ulcer size (cm)
Omeprazole ( N = 151)
Ranitidine (N = 158)
46.3 77 42 11
50.5 69 46 11
38 26 36 0.94
48 22 30 0.90
763
VALENZUELA
ET AL
TABLE 3. NUMBER OF PATIENTS OMt~ED FROM ANALYSIS OF EFFICACY Omeprazole Week 2
Failed to return/take study medicine Baseline visit out of range Concomitant ranitidine/cimetidine Concomitant aspirin Lost study medication Total Number evaluable "all patients treated" Number evaluable " p e r protocol"
history of duodenal ulcer; these differences were not statistically significant. An additional 16 patients were determined to be "protocol violators," leaving a total of 293 patients evaluable by the "per protocol approach." Reasons for exclusion from the analysis are shown in Table 3. One-hundred forty-five (145) patients who received omeprazole, and 148 who received ranitidine were included in the per protocol analysis. Of the 20 participating centers, each contributed a mean of 15 patients (range of 1-28). Compliance. Compliance was measured by counts of returned pills. Ninety-nine percent of patients randomized to receive omeprazole and 97% of patients randomized to receive ranitidine took at least 80% of the medication. When compliance was analyzed by ulcer size no differences in compliance were noted for either treatment group. Ulcer Healing Efficacy. The healing rates, by per-protocol analysis, for the omeprazole group were numerically greater than for the ranitidine group at week 2 and week 4 and significantly greater at week 4, (P < 0.01, see Figure 1). At week 2, 42% (34.5-50%, 95% CI) of patients in the omeprazoletreated group had healed versus 34% (26-41%, 95% CI) in the ranitidine-treated group. At week 4 the percentage of patients healed for omeprazole and ranitidine were 82% (76-88% 95% CI) and 63% (56-71%, 95% CI), respectively. The advantage of omeprazole over ranitidine in healing duodenal ulcer was 8% ( - 3 to + 19%, 95% CI) at week 2 and 19% (9-29%, 95% CI) at week 4. At week 2 three patients in the omeprazole group and nine in the ranitidine group had dropped out and at week 4 an additional three and four patients, respectively, had dropped out. When the data from all investigators with 15 or f e w e r patients was combined, analysis showed no treatment by investigator interaction. Using an all-patients-treated ap-
764
Ranitidine
Week 4
Week 2
Week 4
6 1 3 1 1
6 1 3 1
1
1
1
0
0
12 151 145
12 151 145
12 158 148
12 158 148
2 6 3
2 6 3
proach, 42% (34-50%, 95% CI) of omeprazole patients had completely healed ulcers by week 2, and 82% (76-88%, 95% CI) by week 4. The corresponding result for ranitidine patients was 34% (27-42%, 95% CI) by week 2 and 63% (56-71%, 95% CI) by week 4. Utilizing a survival analysis omeprazole was also superior to ranitidine with respect to time to healing (P < 0.01). There was no effect of a variety of baseline variables on outcome, except for ulcer size (Table 4). Patients in the omeprazole group responded well regardless of initial ulcer size. Specifically, smoking, caffeine, and alcohol use; age; sex; or duration of ulcer disease did not alter the healing rates observed with omeprazole. In contrast, the percentage of patients healed on ranitidine was 72% for nonsmokers versus 55% for smokers. Omeprazole was also markedly more effective than ranitidine in healing larger ulcers 1.1-2.5 cm in diameter; 83% healed on omeprazole versus 37% on ranitidine (P < 0.01). Relief of Pain. Symptoms of daytime pain were rated as severe at baseline by 28% of patients in both the omeprazole and ranitidine groups (Figure 2). Pain data were stratified for baseline severity and analyzed for time to complete pain relief, defined as complete absence of pain without recurrence. There were significant (P < 0.01) reductions in day pain for both treatment groups, but no significant differences between the two treatment groups. Median time to complete relief of day pain was nine days for the omeprazole patients and 15 days for the ranitidine patients. Total relief of day pain was reported by 67% of the omeprazole patients and 61% of those on ranitidine. A failure to obtain pain relief was reported by 27% and 32% of the omeprazole and ranitidine patients, respectively. The relationship of pain relief to the status of ulcer healing is shown in Table 5. Pain relief was Digestive Diseases and Sciences, Vol. 36, No. 6 (June 1991)
DUODENAL ULCER THERAPY TABLE 4. BACKGROUND VARIABLE OUTCOME PER PROTOCOL ANALYSIS
Treatment* Omeprazole Factor
Ulcer Size (cm) Smoking Alcohol Caffeine Antacids Use Age Sex Duration of Disease: (years)
.50-1.0 1.1-2.5 No Yes No Yes No Yes No Yes 60 Male Female >1 1.1-9.9 >10
Ranitidine
T
H
%
T
H
%
115 30 84 61 128 88 57 88 46 99 54 55 36 112 33 55 37 53
94 25 72 50 108 76 46 76 38 84 44 46 32 95 27 47 30 45
82? 83~ 86 82 84 86 81 86 83 85 82 84 89 85 82 86 81 85
121 27 81 67 130 84 64 84 40 108 43 49 56 100 48 70 33 45
83 10 58 37 84 52 43 52 24 71 26 33 36 64 31 43 23 29
69 37 72 55 65 62 67 62 60 66 61 67 64 64 65 61 70 64
*T = total number; H = number healed; % = percent healed. t P < .05, Sp < 0.01 per protocol analysis.
achieved in 90% of omeprazole-treated patients with a healed duodenal ulcer versus 71% in the ranitidine group. For those who did not experience pain relief, 62% of those in the omeprazole group and 49% of those in the ranitidine group had a healed duodenal ulcer. Symptoms of night pain were rated as severe by 30% of omeprazole patients and 25% of ranitidine patients. The night pain relief results were similar to those described above for day pain, requiring a median of eight days for omeprazole patients and 12 days for ranitidine patients to achieve complete 100
lOO
Legend
90--
[]
Orneprazole N = 145
80--
9
Ranitidine N = 148
70--
9o
82%"
8o
* p < 0.01
50-40--
7o
63% Percent of Patients with Day Pain
60-Percent Healed
relief. Although there was a numerical advantage shown for omeprazole versus ranitidine, this difference was not statistically significant. Complete nighttime pain relief was obtained in 68% of the omeprazole patients and 64% of the ranitidine patients by the end of the study. Fasting Serum Gastrin. The serum gastrin results are reported as median, interquartile range, and spectral range for each treatment group at baseline, week 2, week 4, and two weeks posttreatment (Figure 3). All patients completing four weeks of treatment with serum gastrin assays for each of the
42% - - ]
34%
60 50 40 3O
30--
2O
20--
10
10~
0 0
0 Wk 2
Wk 4
Fig 1. Duodenal ulcer healing rates by per-protocol analysis for the two treatment groups, omeprazole and ranitidine, 2 and 4 weeks following entry, demonstrate an advantage for omeprazole. Ulcer healing was defined endoscopicaily and required reepithelialization of all ulcers without any residual erosion at the index ulcer site. Digestive Diseases and Sciences, Vol. 36, No. 6 (June 1991)
2
4
Week
Fig 2. Most patients (>83%) presented with symptoms of pain. Both treatment groups experienced significant reductions from baseline in diurnal pain during the course of the study. The percentages of patients with any day pain at each time point are displayed. There were no significant differences in day pain relief for either treatment group.
765
VALENZUELA ET AL TABLE 5. RELATIONSHIP OF PAIN RELIEF AND HEALING STATUS PER PROTOCOL ANALYSIS
Omeprazole
Ranitidine
Pain relief
status
Healed
Total
%
Healed
Total
%
Unknown
96 23 0
107 37 1
90** 62 0
68 25 0
96 51 1
71 49 0
Total
119
145
82"*
93
148
63
Pain relieved Pain unrelieved
*P < 0.01 with respect to healing.
four intervals specified were included in the analysis. A change from baseline analysis was observed in all patients in the study. End-point analysis compared baseline to off study, and baseline to two-week posttreatment gastrins in all patients (Table 6). Those in the study for only two weeks were analyzed separately from those in the study for four weeks. Patients treated for only two weeks demonstrated similar elevations in serum gastrin and returned to their mean baseline serum gastrin levels by the end of the 2-week posttreatment period, independent of study agent. Patients who continued in the study for four weeks, on the other hand, demonstrated a significantly greater increase from baseline gastrin with omeprazole, than with ranitidine (P < 0.01). In the omeprazole group mean serum gastrin continued to rise after week 2, whereas it remained unchanged in the 400350 300 -
o > o =
t~
250 -
TABLE 6. SERUM GASTRIN*
200-
150 - -
I--'10meprazole FFZl Ranitidine
so-Pre
Wk 2
Wk 4
Wks Post
2
Fig 3. Fasting serum gastrin results are reported for all patients with serum obtained at each of the four scheduled intervals (treated four weeks and returned for posttreatment lab). At each time point, the range (minimum and maximum), 25%, 50%, and 75% values are given. A significant change from baseline (median) was seen in both treatment groups at the two- and four-week intervals; however, the omeprazole group had a significantly greater mean increase than the ranitidine group at both weeks 2 and 4 (P < 0.01). At two weeks posttreatment, the omeprazole treatment group remained significantly changed from baseline, although decreased from on-treatment levels; the ranitidine treatment group had returned to baseline levels. A significant difference between groups was observed (P < 0.05).
766
ranitidine group. The range in absolute serum gastrin values noted among the patients at baseline was considerable. For most patients all measured serum gastrin values were within the normal range. The omeprazole patient with the highest measured gastrin was treated for only two weeks and had a baseline value of 441 pg/ml and a two-week value of 596 pg/ml. In the ranitidine group the highest reported on-treatment values was 395 pg/ml. Sixteen omeprazole patients (11.5%) had on-treatment gastrin values above the upper limits of normal for the assay, as compared to six patients (4.1%) in the ranitidine group. The ratio of treatment to baseline gastrin was 1:9 for the omeprazole group and 1:4 for the ranitidine group. By the end of the two-week posttreatment period, the median serum gastrin for the ranitidine group returned to baseline; the median for the omeprazole group remained elevated approximately 20% above baseline, although well within the normal range for the assay. A significant difference (P < 0.05) existed between the two groups at the posttreatment interval, although there were three patients in both
End of treatment Baseline Last value Change from baseline 9 % change from baseline Two Week Post-treatment Baseline Two-week posttreatment Change from baseline % change from baseline
Omeprazole
Ranitidine
N = 137 30 58 24tr
N = 145 32 44 1I t
94.5tr
36.3t
N = 109 27
N = 119 28
33 7tw 25.3t
34 1 2.1
tDifferent from baseline, P
