Maintenance Therapy for Duodenal Ulcer: A Randomized Controlled Comparison of Seven Forms of Treatment WAI MO HUI, M.D., SHIU KUM LAM, M.D., ANNASUK FONGLOK, M.D., MATTHEWMATAING, M.B.B.s., CHING LUNG LAI, M.B.B.s., HongKong
PURPOSE: We performed a randomized controlled trial to compare the efficacy of seven forms of maintenance treatment of duodenal ulcer, including a mealtime regimen of antacids. PATIENTSANDMETHODS: Werandomized patients with healed duodenal ulcer to receive: (1) no treatment; (2) mealtime antacids with an acid-neutralizing capacity of 80 mmol/day; (3) an antidepressant, trimipramiue 25 mg; (4) an anticholinergic, pirenzepine 50 mg; (5) cimetidine 200 mg; (6) cimetidine 400 mg; (7) ranitidine 150 mg; or (8) sucralfate 1 g twice a day. Symptomatology and side effects were assessed every 2 months and endoscopy was performed every 4 months up to 1 year. RESULTS: The patients were comparable in the majority of clinical characteristics before entry. The cumulative percentages of patients with relapse of ulcers at 12 months by life-table analysis were 61% with no treatment, 38% with mealtime antacids, 60% with trimipramine, 52% with pirenzepine, 46% with cimetidiue 200 mg, 44% with cimetidine 400 mg, 30% with ranitidine 150 mg, and 40% with sucralfate. Cimetidine 400 mg, antacids, ranitidine 150 mg, and sucralfate were significantly better than no treatment and the other forms of treatment. Ranitidine was significantly better than antacids, cimetidine, and sucralfate in preventing endoscopically documented duodenal ulcer relapse by multiple comparison at 12 months, but not by life-table analysis nor when symptomatic relapses were compared. No significant difference was detected among antacids, cimetidine, and sucralfate. No major side effects occurred with the seven forms of treatment, but those receiving antacids
From the Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong. This study was supported by the Peptic Ulcer Research Fund (311/041/6372) of the University of Hong.Kong. Requests for reprints should be addressed to Wai MO Hui. M.D., Department of Medicine, University of Hong Kong, Queen Mary Hospital. Pokfulam Road, Hong Kong. Manuscript submitted May 10, 1991, and accepted in revised form October 15, 1991.
had the highest incidence of minor adverse events (26%). CONCLUSION: This study suggests that mealtime antacids are as effective as Hz-receptor antagonists and sucralfate in the maintenance treatment of duodenal ulcer disease, but have to be taken three times a day and had the highest incidence of reported minor adverse events. The relapse rate was lower with ranitidine than with cimetidine, sucralfate, and antacids, but the difference was small and may not be clinically important.
lthough the available antiulcer therapies including antimuscarinics, Hz-blockers, prostaglandin analogues, and proton pump inhibitors heal ulcers effectively, 60% to 80% of ulcers relapse within 1 year [1,2]. Maintenance therapy has been recommended for patients with frequent relapses. Antiulcer agents that have been demonstrated in placebo-controlled trials to be of value in maintenance treatment include Hz-receptor antagonists [3,4] and mucosal-protective agents like sucralfate [5]. Other agents including pirenzepine [6,7], a selective antimuscarinic agent, and trimipramine 181, a tricyclic antidepressant, have also been claimed to be of use, but data are either scanty or controversial. Recently, antacids given at a dose with a neutralizing capacity of 162 mmol have been demonstrated to be as effective as cimetidine 400 mg at night in reducing duodenal ulcer relapse [9]. We have shown that antacids given at a dose with a neutralizing capacity of 175 mmol/day can heal ulcers effectively [lo]. Furthermore, a mealtime regimen of cimetidine has been shown to achieve a similar healing rate as the nighttime regimen [ll]. Therefore, the first aim of the study was to investigate whether a mealtime regimen of antacid is effective in preventing ulcer relapse and to compare its efficacy with that of other antiulcer agents. Although the antiulcer agents have been compared with one or two other agents as maintenance therapy to prevent duodenal ulcer recurrence [12], no study has been performed to compare the agents in
A
March
1992
The American
Journal
of Medicine
Volume
92
265
MAINTENANCE
THERAPY
FOR DUODENAL
ULCER
/ HUI ET AL
than 50 g/day = 1; estimated at more than 50 g/day = 2. Analgesic consumption for at least 1 year was scored as none = 0; one dose per month = 1; at least one dose per week = 2. Analgesics include aspirin, nonsteroidal anti-inflammatory agents, and the many forms of patent Chinese herbal medicine, the nature of which is mostly undefined. The patients were not told to stop smoking, consuming alcohol, or taking analgesics, but they were told that these habits might be harmful to ulcer healing. At subsequent visits, these habits were assessed by direct questioning, and consumption per day was recorded. The level of consumption during treatment was scored at the end of the trial as none to begin with = 0; discontinued completely = 1; reduced by more than 50% = 2; unchanged = 3. In addition, before and at each subsequent visit, the following nonulcer symptoms were recorded: loose bowel movements, constipation, skin rash, dizziness, headache, palpitation, blurring of vision, dryness of mouth, gynecomastia or galactorrhea, impotence, and changes in libido.
a single center. This forms the second aim of the study. This is an important consideration because duodenal ulcer disease is believed to be a heterogeneous group of disorders and multifactorial in origin [13,14], which therefore makes the validity of the comparison between the groups limited unless they are compared simultaneously. On that basis, we performed an adequately sized, randomized controlled trial to compare the efficacy of these agents in the maintenance treatment of duodenal ulcer.
PATIENTS AND METHODS Patients were recruited from the outpatients and inpatients of the Department of Medicine, Queen Mary Hospital, Hong Kong. Patients were excluded from consideration if they had a concomitant medical problem, particularly renal disease, cardiovascular disease, diabetes mellitus, chronic obstructive airways disease, pyloric stenosis, previous gastric operations for ulcer, or an associated gastric ulcer. They were ambulatory, and had an ulcer size of at least 5 mm.
Physiologic Characteristics Before the commencement of treatment, blood was obtained from the patients in the fasting state and 2 hours after a standard meal to determine serum gastrin levels, as described previously [15]. On another day, basal acid output, maximal acid output, and dose of pentagastrin required for halfmaximal acid output (D50) and corrected for basal acid output (D50C) were measured from a pentagastrin dose-response test, as described previously [16,17]. D50C was taken to represent the sensitivity of the parietal cells. Hypersecretion was defined as a maximal acid output per kilogram of total body weight more than 2 SD above the mean value established previously in 100 normal Chinese subjects [18]. A low D50C was defined as a value of less than 50 rig/kg/hour as established previously in 38 normal control subjects 1191. This was performed during the active phase of treatment. Antisecretory drugs were withheld within 48 hours before gastric analysis.
Clinical and Persoqal Characteristics After being accepted into the study, the patients were interviewed in detail, and their clinical and personal characteristics (Table I) were carefully recorded. Early onset was defined as age at onset of symptoms before age 30. Pain severity, which was also assessed at subsequent visits, was scored as follows: none = 0; mild = 1; serious enough to interfere with work or result in sick leave = 2; severe enough to require immediate medical attention = 3. Period of remission referred to the time interval between the last relapse of ulcer symptoms and the present attack. Duration of symptoms referred to the number of years that the patient had ulcer symptoms. Familial dyspepsia was considered present when the patient indicated that ulcer, dyspepsia, gastrointestinal bleeding, perforation, and/or gastric surgery had occurred in a first-degree relative: this was scored as none = 0; one first-degree relative = 1; two = 2; three or more or both parents = 3. Stress at work was scored subjectively by the patient as 0 to 3 and included work pressure and/or labor intensity of the job. Neurosis was scored according to the number of neurotic traits present, with a maximum of three (insomnia, tension headache, palpitation, hand tremors, nonpostural dizzy spells). Cigarette smoking was scored as none = 0; fewer than 10 per day = 1; more than 10 per day = 2. The majority of smokers had smoked continuously for more than 10 years, and all smokers had smoked for at least 5 years. Alcohol consumption for at least 5 years was scored as none = 0; estimated at less 266
March
1992
The American
Journal
of Medicine
Volume
Endoscopic Characteristics Endoscopy was performed with a forward-viewing panendoscope (Olympus GIF-Q and &lo, Olympus Co. Ltd., Tokyo, Japan) within 72 hours before commencement of treatment after healing of the duodenal ulcer, and at the end of 4, 8, and 12 months of treatment or when the ulcer relapsed. If it was feasible, throughout the study each patient underwent endoscopy by the same investigator, who was unaware of the patient’s treatment and clinical progress. The size of the ulcer was estimated 92
-
Characteristics
49.5
Neurosis present (%)
(%I
40
28.5 s_ 1.49
MAO (mmolih)
Hypersecretor
3.0 + 0.29
56.2 15.7 22.5 5.6
BAO immolih)
,FB
i
Blood group (%)
57.3
0.70 2 0.08
Work stress score (O-3)
Positive family history (%)
49.5
Work stress present (%)
20.4
10.7
Hematemesis present (%)
Analgesic user (%)
64.0
Melena present (%I
41.7
62.1
Nocturnal pain 1%)
14.6
28.1
Back pain (%)
Alcohol user (%)
1.4 ? 0.35
Pain duration (h)
Smokers (%)
6.2 + 1.2
Remission period (mo)
No Rx (n = 103)
Before Treatment
30.1 i 13.5
Obtained
Age of onset(y)
different
Prospectively
Characteristics not significantly between groups
Patients’
TABLE I
32
24.4 i 0.95
2.8 t 0.23
52.8 21.3 22.5 2.2
49.1
21.4
13.0
37.9
51.9
0.74 i 0.09
45.4
19.4
67.6
55.6
13.0
1.6 f 0.34
7.0 A 1.4
33.5 A 15.8
Triact (n = 1081
in the Eight Groups
30 Con timed
25.0 I 1.2
2.9 IO.31
50.7 21.9 20.5 6.8
66.7
13.6
7.4
30.9
on next page
38
26.6 2 1.4
3.3 + 0.31
55.4 18.1 20.5 6.0
58.3
17.7
6.25
34.4
49.0
45.7
55.2 0.83 f 0.09
46
28.0 + 1.1
3.5 A 0.30
12.9 12.9 23.5 3.5
60.2
15.3
11.2
44.9
51.0
0.97 2 0.10
60.4
19.8
68.4
20.8
56.1
58.3
21.4
1.3 i 0.35
4.6 i 0.64
30.4 t 14.7
Cimet 200 mg (n = 98)
68.7
25.0
1.2 i 0.33
7.0 c 1.6
28.7 ” 13.5
0.78 + 0.10
50.6
3.7
32.4
50.6
19.8
1.5 -c 0.43
6.3 i- 1.6
31.5 2 15.4
Trimipramine (n = 86)
33
27.0 f 1.2
3.4 + 0.35
57.5 22.5 16.3 3.8
58.5
9.8
12.9
44.1
53.3
0.71 rL 0.10
46.8
13.8
58.0
70.6
18.2
1.4 i 0.48
8.1 I!Z 1.2
31.9 ? 14.5
Cimet 400 mg (n = 94)
45
27.7 c 1.3
3.1 + 0.32
53.5 24.4 20.9 1.2
66.0
12.0
6.0
42.0
42.0
0.79 2 0.09
53.0
23.2
67.7
55.5
23.2
1.0 2 0.16
7.7 A 1.5
33.7 i 16.1
Ranitidine (n = 100)
47
29.0 + 1.4
2.9 r 0.30
39.4 27.7 27.7 5.3
56.0
7.0
11.0
39.0
49.0
0.64 t 0.07
49.5
20.0
68.0
62.2
20.4
1.3 + 0.28
6.8 t 0.94
28.6 f 14.1
Sucralfate (n = 100)
0.07
0.11
0.72
0.55
0.34
0.20
0.61
0.08
0.81
0.27
0.62
0.60
0.37
0.46
0.27
0.97
0.73
0.09
p Value*
-
different
33.7 f 1.9
0.6 t 0.1
24.8 ? 1.6
2-hour postprandial gastrin (nmol/h/L)
5.2
No. of ulcers (> 1) (%)
8.2
44.3 12.4 82.5 17.5 8.5
4.2 i 0.3
8.8 2.9 20.6
46.2 12.9 4.3 23.7 3.2 9.6
39.7 7.7 11.5 29.5 3.8 6.4
28.1 + 1.8
0.7 k 0.05
1.0 t 0.1 26.8 2 2.0
3.8 + 0.3
3.4 79.3 17.2
5.3 f 0.58
24.2 i. 5.3
66.6
75
1.1 f 0.13
7.3 2 0.73
32
108.8 t 13.1
134.2 2 14.4
Pirenzepine (n = 96)
4.6 r 0.3
4.5 90.9 4.5
5.5 t 0.48
16.3 2 3.4
54.3
70.3
1.3 _+ 0.16
6.1 f 0.46
30
134.6 + 17.7
148.1 ? 18.6
Trzir8;ne
Cimet
0
33.3 11.5 17.2 24.1 3.4
32.6 + 1.7
0.8 + 0.05
3.7 2 0.3
11.1 75.0 13.9
4.8 k 0.22
49.4 f 15.5
60.2
80.6
1.4 i 0.16
6.5 zt 0.68
34
112.7 k 12.8
130.4 + 13.3
200 mg (n = 98)
3.5
44.8 10.4 7.4 26.8 3.0
30.1 2 2.0
1.0 t 0.1
4.6 2 0.5
57.7 42.3 -
7.9 + 0.84
22.9 ? 40.8
59.6
70.2
1.6 _+ 0.15
6.9 2 0.79
35
125.9 f 16.6
153.4 + 18.4
Cimet 400 mg (n = 94)
0.68 k 0.07 0.69 f 0.08 0.69 + 0.08 0.57 f 0.07 0.90 2 0.10 0.87 2 0.09 Degree of inflammation (O-3) Rx = therapy; Cimet = cimetidine; BAO = basalacid output;,MAO = maximal acid output; D50 = dose of pentagastrin that gives 50% MAO; D50C = dose of pentagastrin that gives 50% MAO corrected for BAO. *Level of significanceof statistical comparison betweenthe erghtgroups; p < 0.05 was taken as significant.
51.1 5.4 4.3 15.2
Site of ulcer (%) Anterior Posterior Roof Floor Apex
.
3.2 i 0.2
(nmol/L)
Fastinggastrin
Duration of treatment(d)
1.0 * 0.1
12.5 71.9 15.6
Smoking habit during treatment (%) Reduced Same Greater
7.1 2 0.98
8.5 i 1.2
Duration of symptoms(y)
39.8 f 13.4
50.9
23.6 f 5.4
62.1
Early onset (%)
70.4
1.4 + 0.14
Symptom period before treatment (d)
74.6
Sex (% male)
Characteristics significantly between groups
1.1 ? 0.12
Depth of ulcer (mm)
5.8 + 0.54
38
35
Low D50C (%I 5.9 f 0.44
158.9 + 20
145.6 + 14.7
D50C (nglkgih)
Size of ulcer (mm)
182.6 ? 20
174.2 + 17.0
Triact (n = 108)
050 (rig/kg/h)
NoRx (n = 103)
TABLE I Patients’ CharacteristicsProspectivelyObtained Before Treatment in the Eight Groups (Cont’d)
0.97 t 0.09
12.4
46.8 11.7 8.5 11.7 10.6
41.3 It 1.5
0.98 k 0.08
12.6
52.2 10.9 5.4 23.9 4.3
32.7 k 2.1
0.6 + 0.1
2.6 + 0.3
3.5 k 0.3 0.8 + 0.1
79.5 20.5
4.2 + 0.14
48.7 + 28.6
70.0
79.0
1.2 ? 0.12
6.3 + 0.63
32
134.9 f 14.8
171.2 + 20.3
Sucralfate (n = 100)
5.4 89.2 5.6
6.2 + 0.73
55.9 ? 17.6
50.0
69.0
1.2 _+ 0.18
6.9 + 0.65
38
155.3 f 19.3
184.9 ?I 20.9
Ranitidine (n = 100)
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.05
0.04
0.03
0.21
0.59
0.1
0.25
0.21
p Value*
MAINTENANCE
with the open tips of the biopsy forceps. The longest diameter was taken as the index of the size of the ulcer and included the exudative areas only and not the surrounding inflammation. The endoscopic characteristics (Table I) were recorded. Ulcer site was described as anterior, posterior, floor, roof, and apex (near the exit) of the duodenal bulb. The degree of surrounding inflammation was scored as gross hyperemia, granularity, or edema, or any combination thereof = 3; moderate = 2; mild = 1; absent = 0. The degree of deformity of the duodenal bulb was scored as follows: actual narrowing of entrance or exit of the duodenal bulb by scar but still admitting the endoscope (external diameter = 9 mm) = 3; bilateral deformity = 2; unilateral deformity of bulb = 1; absent = 0. A duodenal ulcer was defined as having relapsed when a fresh ulcer was detected endoscopically in the duodenum. Symptomatic relapse included those with relapse of symptoms of pain and bleeding, with and without endoscopy. A scar and symptomatic relapse without endoscopically proven ulcer were not counted as a symptomatic recurrence. Study Design INITIAL TREATMENT OF ULCER: After being recruited into the study, the patients were treated with Hz-receptor antagonists, either cimetidine (Smith Kline & French Laboratories, Philadelphia, PA) 400 mg or ranitidine (Glaxo Co. Ltd., Greenford, UK) 150 mg twice a day. Healing was defined as complete disappearance of ulcer with or without residual inflammation usually in the form of hyperemia and granularity. Patients underwent endoscopy every 4 weeks until the ulcer healed or up to a total treatment of 12 weeks. MAINTENANCETREATMENT: Thisisasingle-blind randomized trial. The patients were randomized to receive one of the following regimens: (1) no treatment; (2) Triact Tab 2, 1 hour after meals three times a day (each tablet containing 200 mg aluminiurn hydroxide, 150 mg magnesium trisilicate, and 25 mg simethicone [Regent Lab., London, UK] with a neutralizing capacity of 80 mmol/day); (3) trimipramine maleate, 25 mg at night (May & Baker, Bournemouth, UK); (4) pirenzepine 50 mg at night (Boehringer Ingelheim, Mannheim, West Germany); (5) cimetidine (Smith Kline & French Laboratories, Philadelphia, PA) 200 mg at night; (6) cimetidine 400 mg at night; (7) ranitidine 150 mg at night (Glaxo Co. Ltd., Greenford, UK); (8) sucralfate 1 g (Chugai Pharmaceutical Co., Tokyo, Japan) between breakfast and lunch, and at night. No antacid was allowed. Patients were instructed to eat no more than three regular meals per day, and not to take any other medication without notifying the
THERAPY
FOR DUODENAL
ULCER / HUI ET AL
trial clinic nurse. They were told to bring to each visit any remaining medications, which would then be counted. Patients were followed up at 2-month intervals and had endoscopy at 4-month intervals irrespective of whether the patient was symptomatic or not, up to a total of 12 months. Endoscopy was performed whenever patients were symptomatic (pain, bleeding, or dyspepsia). The detection of an active ulcer on endoscopy marked the endpoint of the study. Statistical Analysis Chi-square test with Yates’ correction and oneway analysis of variance were used to compare characteristics among the eight groups [20]. Two methods of analyses were performed on the relapse rates: (1) life-table analysis with multiple pairwise comparison using Lee-Desu statistics over 12 months [20,21]; (2) Tukey procedure of multiple comparison of the relapse rates at 12 months among the eight groups [22]. Analyses were performed on endoscopic relapse (including symptomatic and asymptomatic and amenable to endoscopy) and symptomatic relapses (those with and without endoscopy). Values were expressed as mean f SE. Probability values of less than 0.05 were considered significant. The potential factors, including clinical, physiologic, and endoscopic (Table I), that might affect the relapse of duodenal ulcer were examined. Those factors that demonstrated a significant difference were examined by stepwise logistic regression analysis using the BMDP statistical software package [23] to examine the simultaneous effects of these factors on endoscopic relapse. Relapse within 12 months was the dependent variable. The other clinical, physiologic, and endoscopic variables were the independent variables. Before being entered into the logistic regression analysis, they were first separated by univariate analysis to reach a significant level of p = 0.1. To avoid overoptimistic bias in the final discriminant function, a conditional rule was used in the stepwise selection of variables, so that their maximum F-to-enter and their minimum Fto-remove carried a p value of at least 0.05 and 0.1, respectively.
RESULTS Patients A total of 785 patients were randomized to receive one of the eight forms of treatment, and the breakdown of the number of patients who were recruited and who left the study is given in Table II. There was no significant difference in the number that dropped out among the eight groups (x2 = 4.21, df = 7, p
PURPOSE: We performed a randomized controlled trial to compare the efficacy of seven forms of maintenance treatment of duodenal ulcer, including a mealtime regimen of antacids. PATIENTSANDMETHODS: Werandomized patients with healed duodenal ulcer to receive: (1) no treatment; (2) mealtime antacids with an acid-neutralizing capacity of 80 mmol/day; (3) an antidepressant, trimipramiue 25 mg; (4) an anticholinergic, pirenzepine 50 mg; (5) cimetidine 200 mg; (6) cimetidine 400 mg; (7) ranitidine 150 mg; or (8) sucralfate 1 g twice a day. Symptomatology and side effects were assessed every 2 months and endoscopy was performed every 4 months up to 1 year. RESULTS: The patients were comparable in the majority of clinical characteristics before entry. The cumulative percentages of patients with relapse of ulcers at 12 months by life-table analysis were 61% with no treatment, 38% with mealtime antacids, 60% with trimipramine, 52% with pirenzepine, 46% with cimetidiue 200 mg, 44% with cimetidine 400 mg, 30% with ranitidine 150 mg, and 40% with sucralfate. Cimetidine 400 mg, antacids, ranitidine 150 mg, and sucralfate were significantly better than no treatment and the other forms of treatment. Ranitidine was significantly better than antacids, cimetidine, and sucralfate in preventing endoscopically documented duodenal ulcer relapse by multiple comparison at 12 months, but not by life-table analysis nor when symptomatic relapses were compared. No significant difference was detected among antacids, cimetidine, and sucralfate. No major side effects occurred with the seven forms of treatment, but those receiving antacids
From the Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong. This study was supported by the Peptic Ulcer Research Fund (311/041/6372) of the University of Hong.Kong. Requests for reprints should be addressed to Wai MO Hui. M.D., Department of Medicine, University of Hong Kong, Queen Mary Hospital. Pokfulam Road, Hong Kong. Manuscript submitted May 10, 1991, and accepted in revised form October 15, 1991.
had the highest incidence of minor adverse events (26%). CONCLUSION: This study suggests that mealtime antacids are as effective as Hz-receptor antagonists and sucralfate in the maintenance treatment of duodenal ulcer disease, but have to be taken three times a day and had the highest incidence of reported minor adverse events. The relapse rate was lower with ranitidine than with cimetidine, sucralfate, and antacids, but the difference was small and may not be clinically important.
lthough the available antiulcer therapies including antimuscarinics, Hz-blockers, prostaglandin analogues, and proton pump inhibitors heal ulcers effectively, 60% to 80% of ulcers relapse within 1 year [1,2]. Maintenance therapy has been recommended for patients with frequent relapses. Antiulcer agents that have been demonstrated in placebo-controlled trials to be of value in maintenance treatment include Hz-receptor antagonists [3,4] and mucosal-protective agents like sucralfate [5]. Other agents including pirenzepine [6,7], a selective antimuscarinic agent, and trimipramine 181, a tricyclic antidepressant, have also been claimed to be of use, but data are either scanty or controversial. Recently, antacids given at a dose with a neutralizing capacity of 162 mmol have been demonstrated to be as effective as cimetidine 400 mg at night in reducing duodenal ulcer relapse [9]. We have shown that antacids given at a dose with a neutralizing capacity of 175 mmol/day can heal ulcers effectively [lo]. Furthermore, a mealtime regimen of cimetidine has been shown to achieve a similar healing rate as the nighttime regimen [ll]. Therefore, the first aim of the study was to investigate whether a mealtime regimen of antacid is effective in preventing ulcer relapse and to compare its efficacy with that of other antiulcer agents. Although the antiulcer agents have been compared with one or two other agents as maintenance therapy to prevent duodenal ulcer recurrence [12], no study has been performed to compare the agents in
A
March
1992
The American
Journal
of Medicine
Volume
92
265
MAINTENANCE
THERAPY
FOR DUODENAL
ULCER
/ HUI ET AL
than 50 g/day = 1; estimated at more than 50 g/day = 2. Analgesic consumption for at least 1 year was scored as none = 0; one dose per month = 1; at least one dose per week = 2. Analgesics include aspirin, nonsteroidal anti-inflammatory agents, and the many forms of patent Chinese herbal medicine, the nature of which is mostly undefined. The patients were not told to stop smoking, consuming alcohol, or taking analgesics, but they were told that these habits might be harmful to ulcer healing. At subsequent visits, these habits were assessed by direct questioning, and consumption per day was recorded. The level of consumption during treatment was scored at the end of the trial as none to begin with = 0; discontinued completely = 1; reduced by more than 50% = 2; unchanged = 3. In addition, before and at each subsequent visit, the following nonulcer symptoms were recorded: loose bowel movements, constipation, skin rash, dizziness, headache, palpitation, blurring of vision, dryness of mouth, gynecomastia or galactorrhea, impotence, and changes in libido.
a single center. This forms the second aim of the study. This is an important consideration because duodenal ulcer disease is believed to be a heterogeneous group of disorders and multifactorial in origin [13,14], which therefore makes the validity of the comparison between the groups limited unless they are compared simultaneously. On that basis, we performed an adequately sized, randomized controlled trial to compare the efficacy of these agents in the maintenance treatment of duodenal ulcer.
PATIENTS AND METHODS Patients were recruited from the outpatients and inpatients of the Department of Medicine, Queen Mary Hospital, Hong Kong. Patients were excluded from consideration if they had a concomitant medical problem, particularly renal disease, cardiovascular disease, diabetes mellitus, chronic obstructive airways disease, pyloric stenosis, previous gastric operations for ulcer, or an associated gastric ulcer. They were ambulatory, and had an ulcer size of at least 5 mm.
Physiologic Characteristics Before the commencement of treatment, blood was obtained from the patients in the fasting state and 2 hours after a standard meal to determine serum gastrin levels, as described previously [15]. On another day, basal acid output, maximal acid output, and dose of pentagastrin required for halfmaximal acid output (D50) and corrected for basal acid output (D50C) were measured from a pentagastrin dose-response test, as described previously [16,17]. D50C was taken to represent the sensitivity of the parietal cells. Hypersecretion was defined as a maximal acid output per kilogram of total body weight more than 2 SD above the mean value established previously in 100 normal Chinese subjects [18]. A low D50C was defined as a value of less than 50 rig/kg/hour as established previously in 38 normal control subjects 1191. This was performed during the active phase of treatment. Antisecretory drugs were withheld within 48 hours before gastric analysis.
Clinical and Persoqal Characteristics After being accepted into the study, the patients were interviewed in detail, and their clinical and personal characteristics (Table I) were carefully recorded. Early onset was defined as age at onset of symptoms before age 30. Pain severity, which was also assessed at subsequent visits, was scored as follows: none = 0; mild = 1; serious enough to interfere with work or result in sick leave = 2; severe enough to require immediate medical attention = 3. Period of remission referred to the time interval between the last relapse of ulcer symptoms and the present attack. Duration of symptoms referred to the number of years that the patient had ulcer symptoms. Familial dyspepsia was considered present when the patient indicated that ulcer, dyspepsia, gastrointestinal bleeding, perforation, and/or gastric surgery had occurred in a first-degree relative: this was scored as none = 0; one first-degree relative = 1; two = 2; three or more or both parents = 3. Stress at work was scored subjectively by the patient as 0 to 3 and included work pressure and/or labor intensity of the job. Neurosis was scored according to the number of neurotic traits present, with a maximum of three (insomnia, tension headache, palpitation, hand tremors, nonpostural dizzy spells). Cigarette smoking was scored as none = 0; fewer than 10 per day = 1; more than 10 per day = 2. The majority of smokers had smoked continuously for more than 10 years, and all smokers had smoked for at least 5 years. Alcohol consumption for at least 5 years was scored as none = 0; estimated at less 266
March
1992
The American
Journal
of Medicine
Volume
Endoscopic Characteristics Endoscopy was performed with a forward-viewing panendoscope (Olympus GIF-Q and &lo, Olympus Co. Ltd., Tokyo, Japan) within 72 hours before commencement of treatment after healing of the duodenal ulcer, and at the end of 4, 8, and 12 months of treatment or when the ulcer relapsed. If it was feasible, throughout the study each patient underwent endoscopy by the same investigator, who was unaware of the patient’s treatment and clinical progress. The size of the ulcer was estimated 92
-
Characteristics
49.5
Neurosis present (%)
(%I
40
28.5 s_ 1.49
MAO (mmolih)
Hypersecretor
3.0 + 0.29
56.2 15.7 22.5 5.6
BAO immolih)
,FB
i
Blood group (%)
57.3
0.70 2 0.08
Work stress score (O-3)
Positive family history (%)
49.5
Work stress present (%)
20.4
10.7
Hematemesis present (%)
Analgesic user (%)
64.0
Melena present (%I
41.7
62.1
Nocturnal pain 1%)
14.6
28.1
Back pain (%)
Alcohol user (%)
1.4 ? 0.35
Pain duration (h)
Smokers (%)
6.2 + 1.2
Remission period (mo)
No Rx (n = 103)
Before Treatment
30.1 i 13.5
Obtained
Age of onset(y)
different
Prospectively
Characteristics not significantly between groups
Patients’
TABLE I
32
24.4 i 0.95
2.8 t 0.23
52.8 21.3 22.5 2.2
49.1
21.4
13.0
37.9
51.9
0.74 i 0.09
45.4
19.4
67.6
55.6
13.0
1.6 f 0.34
7.0 A 1.4
33.5 A 15.8
Triact (n = 1081
in the Eight Groups
30 Con timed
25.0 I 1.2
2.9 IO.31
50.7 21.9 20.5 6.8
66.7
13.6
7.4
30.9
on next page
38
26.6 2 1.4
3.3 + 0.31
55.4 18.1 20.5 6.0
58.3
17.7
6.25
34.4
49.0
45.7
55.2 0.83 f 0.09
46
28.0 + 1.1
3.5 A 0.30
12.9 12.9 23.5 3.5
60.2
15.3
11.2
44.9
51.0
0.97 2 0.10
60.4
19.8
68.4
20.8
56.1
58.3
21.4
1.3 i 0.35
4.6 i 0.64
30.4 t 14.7
Cimet 200 mg (n = 98)
68.7
25.0
1.2 i 0.33
7.0 c 1.6
28.7 ” 13.5
0.78 + 0.10
50.6
3.7
32.4
50.6
19.8
1.5 -c 0.43
6.3 i- 1.6
31.5 2 15.4
Trimipramine (n = 86)
33
27.0 f 1.2
3.4 + 0.35
57.5 22.5 16.3 3.8
58.5
9.8
12.9
44.1
53.3
0.71 rL 0.10
46.8
13.8
58.0
70.6
18.2
1.4 i 0.48
8.1 I!Z 1.2
31.9 ? 14.5
Cimet 400 mg (n = 94)
45
27.7 c 1.3
3.1 + 0.32
53.5 24.4 20.9 1.2
66.0
12.0
6.0
42.0
42.0
0.79 2 0.09
53.0
23.2
67.7
55.5
23.2
1.0 2 0.16
7.7 A 1.5
33.7 i 16.1
Ranitidine (n = 100)
47
29.0 + 1.4
2.9 r 0.30
39.4 27.7 27.7 5.3
56.0
7.0
11.0
39.0
49.0
0.64 t 0.07
49.5
20.0
68.0
62.2
20.4
1.3 + 0.28
6.8 t 0.94
28.6 f 14.1
Sucralfate (n = 100)
0.07
0.11
0.72
0.55
0.34
0.20
0.61
0.08
0.81
0.27
0.62
0.60
0.37
0.46
0.27
0.97
0.73
0.09
p Value*
-
different
33.7 f 1.9
0.6 t 0.1
24.8 ? 1.6
2-hour postprandial gastrin (nmol/h/L)
5.2
No. of ulcers (> 1) (%)
8.2
44.3 12.4 82.5 17.5 8.5
4.2 i 0.3
8.8 2.9 20.6
46.2 12.9 4.3 23.7 3.2 9.6
39.7 7.7 11.5 29.5 3.8 6.4
28.1 + 1.8
0.7 k 0.05
1.0 t 0.1 26.8 2 2.0
3.8 + 0.3
3.4 79.3 17.2
5.3 f 0.58
24.2 i. 5.3
66.6
75
1.1 f 0.13
7.3 2 0.73
32
108.8 t 13.1
134.2 2 14.4
Pirenzepine (n = 96)
4.6 r 0.3
4.5 90.9 4.5
5.5 t 0.48
16.3 2 3.4
54.3
70.3
1.3 _+ 0.16
6.1 f 0.46
30
134.6 + 17.7
148.1 ? 18.6
Trzir8;ne
Cimet
0
33.3 11.5 17.2 24.1 3.4
32.6 + 1.7
0.8 + 0.05
3.7 2 0.3
11.1 75.0 13.9
4.8 k 0.22
49.4 f 15.5
60.2
80.6
1.4 i 0.16
6.5 zt 0.68
34
112.7 k 12.8
130.4 + 13.3
200 mg (n = 98)
3.5
44.8 10.4 7.4 26.8 3.0
30.1 2 2.0
1.0 t 0.1
4.6 2 0.5
57.7 42.3 -
7.9 + 0.84
22.9 ? 40.8
59.6
70.2
1.6 _+ 0.15
6.9 2 0.79
35
125.9 f 16.6
153.4 + 18.4
Cimet 400 mg (n = 94)
0.68 k 0.07 0.69 f 0.08 0.69 + 0.08 0.57 f 0.07 0.90 2 0.10 0.87 2 0.09 Degree of inflammation (O-3) Rx = therapy; Cimet = cimetidine; BAO = basalacid output;,MAO = maximal acid output; D50 = dose of pentagastrin that gives 50% MAO; D50C = dose of pentagastrin that gives 50% MAO corrected for BAO. *Level of significanceof statistical comparison betweenthe erghtgroups; p < 0.05 was taken as significant.
51.1 5.4 4.3 15.2
Site of ulcer (%) Anterior Posterior Roof Floor Apex
.
3.2 i 0.2
(nmol/L)
Fastinggastrin
Duration of treatment(d)
1.0 * 0.1
12.5 71.9 15.6
Smoking habit during treatment (%) Reduced Same Greater
7.1 2 0.98
8.5 i 1.2
Duration of symptoms(y)
39.8 f 13.4
50.9
23.6 f 5.4
62.1
Early onset (%)
70.4
1.4 + 0.14
Symptom period before treatment (d)
74.6
Sex (% male)
Characteristics significantly between groups
1.1 ? 0.12
Depth of ulcer (mm)
5.8 + 0.54
38
35
Low D50C (%I 5.9 f 0.44
158.9 + 20
145.6 + 14.7
D50C (nglkgih)
Size of ulcer (mm)
182.6 ? 20
174.2 + 17.0
Triact (n = 108)
050 (rig/kg/h)
NoRx (n = 103)
TABLE I Patients’ CharacteristicsProspectivelyObtained Before Treatment in the Eight Groups (Cont’d)
0.97 t 0.09
12.4
46.8 11.7 8.5 11.7 10.6
41.3 It 1.5
0.98 k 0.08
12.6
52.2 10.9 5.4 23.9 4.3
32.7 k 2.1
0.6 + 0.1
2.6 + 0.3
3.5 k 0.3 0.8 + 0.1
79.5 20.5
4.2 + 0.14
48.7 + 28.6
70.0
79.0
1.2 ? 0.12
6.3 + 0.63
32
134.9 f 14.8
171.2 + 20.3
Sucralfate (n = 100)
5.4 89.2 5.6
6.2 + 0.73
55.9 ? 17.6
50.0
69.0
1.2 _+ 0.18
6.9 + 0.65
38
155.3 f 19.3
184.9 ?I 20.9
Ranitidine (n = 100)
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.05
0.04
0.03
0.21
0.59
0.1
0.25
0.21
p Value*
MAINTENANCE
with the open tips of the biopsy forceps. The longest diameter was taken as the index of the size of the ulcer and included the exudative areas only and not the surrounding inflammation. The endoscopic characteristics (Table I) were recorded. Ulcer site was described as anterior, posterior, floor, roof, and apex (near the exit) of the duodenal bulb. The degree of surrounding inflammation was scored as gross hyperemia, granularity, or edema, or any combination thereof = 3; moderate = 2; mild = 1; absent = 0. The degree of deformity of the duodenal bulb was scored as follows: actual narrowing of entrance or exit of the duodenal bulb by scar but still admitting the endoscope (external diameter = 9 mm) = 3; bilateral deformity = 2; unilateral deformity of bulb = 1; absent = 0. A duodenal ulcer was defined as having relapsed when a fresh ulcer was detected endoscopically in the duodenum. Symptomatic relapse included those with relapse of symptoms of pain and bleeding, with and without endoscopy. A scar and symptomatic relapse without endoscopically proven ulcer were not counted as a symptomatic recurrence. Study Design INITIAL TREATMENT OF ULCER: After being recruited into the study, the patients were treated with Hz-receptor antagonists, either cimetidine (Smith Kline & French Laboratories, Philadelphia, PA) 400 mg or ranitidine (Glaxo Co. Ltd., Greenford, UK) 150 mg twice a day. Healing was defined as complete disappearance of ulcer with or without residual inflammation usually in the form of hyperemia and granularity. Patients underwent endoscopy every 4 weeks until the ulcer healed or up to a total treatment of 12 weeks. MAINTENANCETREATMENT: Thisisasingle-blind randomized trial. The patients were randomized to receive one of the following regimens: (1) no treatment; (2) Triact Tab 2, 1 hour after meals three times a day (each tablet containing 200 mg aluminiurn hydroxide, 150 mg magnesium trisilicate, and 25 mg simethicone [Regent Lab., London, UK] with a neutralizing capacity of 80 mmol/day); (3) trimipramine maleate, 25 mg at night (May & Baker, Bournemouth, UK); (4) pirenzepine 50 mg at night (Boehringer Ingelheim, Mannheim, West Germany); (5) cimetidine (Smith Kline & French Laboratories, Philadelphia, PA) 200 mg at night; (6) cimetidine 400 mg at night; (7) ranitidine 150 mg at night (Glaxo Co. Ltd., Greenford, UK); (8) sucralfate 1 g (Chugai Pharmaceutical Co., Tokyo, Japan) between breakfast and lunch, and at night. No antacid was allowed. Patients were instructed to eat no more than three regular meals per day, and not to take any other medication without notifying the
THERAPY
FOR DUODENAL
ULCER / HUI ET AL
trial clinic nurse. They were told to bring to each visit any remaining medications, which would then be counted. Patients were followed up at 2-month intervals and had endoscopy at 4-month intervals irrespective of whether the patient was symptomatic or not, up to a total of 12 months. Endoscopy was performed whenever patients were symptomatic (pain, bleeding, or dyspepsia). The detection of an active ulcer on endoscopy marked the endpoint of the study. Statistical Analysis Chi-square test with Yates’ correction and oneway analysis of variance were used to compare characteristics among the eight groups [20]. Two methods of analyses were performed on the relapse rates: (1) life-table analysis with multiple pairwise comparison using Lee-Desu statistics over 12 months [20,21]; (2) Tukey procedure of multiple comparison of the relapse rates at 12 months among the eight groups [22]. Analyses were performed on endoscopic relapse (including symptomatic and asymptomatic and amenable to endoscopy) and symptomatic relapses (those with and without endoscopy). Values were expressed as mean f SE. Probability values of less than 0.05 were considered significant. The potential factors, including clinical, physiologic, and endoscopic (Table I), that might affect the relapse of duodenal ulcer were examined. Those factors that demonstrated a significant difference were examined by stepwise logistic regression analysis using the BMDP statistical software package [23] to examine the simultaneous effects of these factors on endoscopic relapse. Relapse within 12 months was the dependent variable. The other clinical, physiologic, and endoscopic variables were the independent variables. Before being entered into the logistic regression analysis, they were first separated by univariate analysis to reach a significant level of p = 0.1. To avoid overoptimistic bias in the final discriminant function, a conditional rule was used in the stepwise selection of variables, so that their maximum F-to-enter and their minimum Fto-remove carried a p value of at least 0.05 and 0.1, respectively.
RESULTS Patients A total of 785 patients were randomized to receive one of the eight forms of treatment, and the breakdown of the number of patients who were recruited and who left the study is given in Table II. There was no significant difference in the number that dropped out among the eight groups (x2 = 4.21, df = 7, p
