- Email: [email protected]
Cimetidine versus intensive antacid therapy for duodenal ulcer
0016-5085/78/7402-0393$02.00/0 GASCROENTEROL~W 74:393-395,1978 Copyright 0 1978by theAmerican Gastroenterological Association
Vol. 74, No. 2, Part 2 Printed in U.S.A.
CIMETIDINE VERSUS INTENSIVE ANTACID THERAPY FOR DUODENALULCER A multicenter trial A. F. IPPOLITI.,R. A. L. STURDEVANT, J. I. ISENBERG, M. BINDER, R. CAMACHO, R. CANO, C. COONEY, M. M. KLINE, R. L. KORETZ, J. H. MEYER, I. M. SAMLOFF, A. D. SCHWABE, E. A. STROM, J. E. VALENZUELA, AND R. H. WINTROUB Departments of Medicine, Wadsworth Veterans Administration Hospital, UCLA Center for the Health Sciences, San Fernando Valley Medical Complex, LAG’-USC Medical Center, Los Angeles; Harbor General Hospital, Torrance; Daniel Freeman Hospital, Inglewood; Valley Medical Center, Fresno, California
In a randomized double blind multicenter trial, patients treated with cimetidine (800 or 1200 mg daily) or an intensive regimen of Al-Mg antacid (210 ml daily) had similar rates of duodenal ulcer healing and pain relief. After 4 weeks of treatment, the proportion of patients with ulcer healing by endoscopy were: cimetidine (1200 mg), 21 of 33 (64%); cimetidine (800 mg), 19 of 32 (59%); and antacids, 15 of 29 (52%). These proportions did not differ significantly. Eighty per cent of cimetidine-treated patients became asymptomatic by week 4, as did 63% of antacid-treated patients (P > 0.1). No untoward effects were observed during cimetidine treatment. Twenty-seven per cent of antacid-treated patients reported diarrhea. In Europe and the United Kingdom cimetidine was more effective than placebo in healing and relieving symptoms of duodenal ulcer. 1-9In those trials antacid was taken irregularly and infrequently by both treatment groups. However, large doses of Al-Mg antacids, taken at fixed intervals after a meal, reduce gastric acidity to a degree comparable to cimetidine.4 Recently, a randomized double blind trial has shown that intensive antacid therapy is superior to placebo in healing duodenal ulcer.” The purpose of this study was to compare ulcer healing and pain relief in patients treated either with cimetidine (800 or 1200 mg daily) or an intensive antacid regimen. Methods Patients with endoscopic demonstration
of a duodenal or pyloric channel ulcer crater were admitted to a randomized, double blind outpatient trial. The study was conducted at seven hospitals under the auspices of the Center for Ulcer Research and Education (CURE), and approval was obtained from the research committee at each hospital. Three treatment groups were compared: 800 mg of cimetidine daily, 1200 mg of cimetidine daily, and 210 ml of an Al-Mg antacid daily. The antacid was similar to Mylanta II (Stuart Pharmaceuticals, Wilmington, Del.) and the in vitro buffering capacity of this antacid was 123 mEq of HCl per 30-ml dose.” The cimetidine tablets (200 or 300 mg) were taken four times a day, with meals and at bedtime. Thirty milliliters of antacid Address requests for reprints to: Andrew Ippoliti, M.D., Gastroenterology Section 691/111C, Wadsworth Veterans Hospital, Wilshire and Sawtelle Boulevards, Los Angeles, California 90073. The authors gratefully acknowledge Smith Kline & French Laboratories, Philadelphia, for supporting these studies and Helen Silket for typing the manuscript.
were taken 1 and 3 hr after meals and at bedtime. Cimetidinetreated patients received a placebo liquid simulating antacid, and antacid-treated patients received placebo tablets simulating cimetidine. Ninety-seven patients with an ulcer crater demonstrated at endoscopy entered the trial. Patients with accompanying gastric ulcer, prior gastric surgery, or Zollinger-Ellison syndrome, or receiving anti-inflammatory drugs were excluded from the study. Patients with ulcer complications such as bleeding or obstruction in whom surgery might be imminent were also excluded. Basal and either betazole-stimulated (1. mg per kg intramuscularly) or pentagastrin-stimulated (6 pg per kg subcutaneously) peak acid outputs were determined on entrance into the study if unavailable within the pervious 6 months. Treatment began within 4 days of endoscopy and acid secretory testing, and lasted 4 weeks. Patients were interviewed at weeks 1, 2, and 4 and at each visit specimens were obtained for complete blood count, liver and renal function tests, and urinalysis. Endoscopy was repeated at weeks 1 and 4. The endoscopic findings were classified as ulcer crater, erosion, i.e., a break in the mucosa without a fibrous base, or normal. The latter category includes hyperemia of the bulb. Endoscopic healing was defined as a bulb free from craters and erosions. Student’s t-test for independent variables and ,$ distribution with Yates’ correction for continuity were used in the statistical analysis of the data.’
Results Sixty-seven patients were randomized to treatment with cimetidine: 33 to 1200 mg daily, and 34 to 800 mg daily. Two patients were withdrawn from the 800-mg cimetidine group. One failed to return after the initial visit and in the other the ulcer was found to be antral rather than duodenal at the time of the week 1 endos393
394
ZPPOLZTZ ET AL.
copy. Thirty patients were randomized to antacid treatment and 1 patient withdrew because of severe diarrhea. The following results pertain only to the patients who completed the study, 33 in the 1200-mg cimetidine group, 32 in the 800-mg cimetidine group, and 29 in the antacid group. Patient profile. There were no significant differences in age, sex, duration of diagnosed duodenal ulcer disease, daily frequency of symptoms upon entrance into the trial, and basal or peak acid output between the cimetidine- and antacid-treated patients (table 1). In approximately 30% of the patients in both treatment groups the diagnosis of duodenal ulcer disease had been documented 1 year or less before the study started. Five of 29 antacid patients and 9 of 65 cimetidine patients were asymptomatic when they entered the trial; these patients presented with bleeding duodenal ulcers requiring transfusion within 10 days before entering the trial. Endoscopic results. The frequency of endoscopic duodenal ulcer healing at 1 or 4 weeks did not differ significantly among the three treatments (fig. 1). Eight of 29 patients receiving 1200 mg of cimetidine, 4 of 27 patients receiving 800 mg of cimetidine, and 2 of 26 patients receiving antacid were healed at 1 week. Nine cimetidine-treated and 3 antacid-treated patients failed to undergo a l-week endoscopy. After 4 weeks of treatment, the proportions of patients healed on cimetidine (1200 and 800 mg) and antacid were 21 of 33 (64%), 19 of 32 (59%), and 15 of 29 (52%), respectively. The endoscopic findings after 4 weeks of treatment TABLE 1. Patient characteristics Age (yr, mean + SE) Male/female Duration of disease (median) Symptom frequency in week prior to entry (mediar$’ Basal acid output (mEq/hr, mean + SE) Peak acid output
(mEq/hr,
mean
?
Cimetidine
Antacid
48.9 2 1.6
46.1 2 2.5
52/13
2514
4 yr G/day
2 Yr 4iday
were compared in the combined cimetidine-treated patients and the antacid-treated patients (table 2). Slightly more cimetidine- than antacid-treated patients had complete healing of the duodenal bulb, 62 versus 52%, but this difference is not statistically significant. Disappearance of the ulcer crater, leading either to reepithelization of the bulb (normal) or to the presence of an erosion, occurred with similar frequency in both treatments, 76% for cimetidine and 86% for antacid. Consequently, persistence of the ulcer crater was found in 24% of the cimetidine-treated and 14% of the antacidtreated patients. Symptom relief. In table 3 the number of patients who were asymptomatic during the 4th week of treatment was compared for cimetidine and antacid. The patients are grouped according to their endoscopic findings at week 4. Only the 80 patients with symptomatic ulcer disease at the onset of the trial are included in this analysis. Over-all, 80% of cimetidine-treated patients became asymptomatic as compared to 63% of antacid-treated patients; this difference is not significant. Forty-two of 44 (95%) patients with a normal duodenal bulb, with either treatment, were asymptomatic compared to 18 of 36 (50%) patients with an ulcer or erosion (P < 0.005). Symptom relief was prompt with both treatments, 55% of cimetidine-treated patients and 58% of antacid-treated patients became asymptomatic by day 7. Side effects. There were no clinically important alterations in blood count or in liver or renal function tests in patients treated with cimetidine or antacid. One antacid-treated patient, as noted, withdrew from the study because of diarrhea and 7 other patients reported diarrhea. Thus diarrhea occurred in 27% of antacidtreated patients. One of the cimetidine-treated patients complained of diarrhea. Acid secretion. The mean peak acid output (PAO) in TABLE 2. Endoscopic findings after 4 weeks of treatment
3.8 * 0.5
5.5 + 1.1
35.7 f 2.2
35.9 2 3.4
SE) a
Vol. 74, No. 2, Part 2
Includes patients with no pain prior to entering the trial.
Cimetidine (n = 65)
Antacid (n = 29)
40 (62)”
15 (52) 10 (34)
Normal Erosion Ulcer
9 (14) 16 (24)
’ Numbers in parentheses
4 (14)
are percentages.
TABLE 3. Proportion ofpatients
asymptomatic in week 4, according to endoscopic finding at week 4
CIYETIDINE CIYETIDINE
I200 nrg 800 mg
ANTACID
Ulcer Erosion Normal Total
Cimetidine
Antacid
B/16 (56)a 517 (71) 32/33 (97) 45/56 (80)
214 (50) 3/9 (33) lO/ll (91) 15/24 (63)
’ Numbers in parentheses TABLE 4. Mean *
SE
are percentages.
basal and peak acid output (milliequivalents per hour) Cimetidine (n = 59)
TREATMENT
PERIOD
(wks)
FIG. 1. Percentage of patients with endoscopic healing of duodenal ulcer after weeks 1 and 4 for 1206 mg of cimetidine (n = 33), 800 mg of cimetidine (n = 32), and antacid (n = 29).
Healed Not healed
Antacid = 28)
(n
Basal
Peak
Basal
Peak
4.2 2 0.6 3.3 * 0.9
39.4 + 2.7 29.4 -r- 3.2
5.6 -t 1.6 6.0 2 1.8
31.6 * 4.0 40.2 f 5.4
February 1978
CIMETIDINE
VERSUS
ANTACID
cimetidine-treated patients with healed ulcers was significantly higher than in those without healing, (P < 0.025) (table 4). Nineteen of 24 (79%) cimetidine-treated patients with a PA0 > 40 n-&q per hr healed as compared to 18 of 35 (51%) patients with a PA0 < 40 mEq per hr (P = 0.02). Among antacid-treated patients healing and PA0 were not correlated. Basal acid output did not correlate with ulcer healing in either group (table 4). Discussion The results of this study indicate that a l-month course of cimetidine and an intensive antacid regimen did not differ significantly in duodenal ulcer healing and pain relief. This is not surprising as both treatments have been shown to be superior to placebo in healing duodenal ulcer,1-3~5 and they have similar effects on intragastric PH.~ Endoscopic healing with cimetidine in this study (40 of 65) is comparable to the study of Bardhan et al. (47 of 65).* In the latter study patients received 1 or 2 g of cimetidine daily. As in a previous report we observed no difference in healing between 800 and 1200 mg of cimetidine daily.’ Although the smaller dose appears as effective as the larger dose of cimetidine, more patients should be studied to clarify this point. Peterson et a1.5 compared ‘an Al-Mg antacid in a similar regimen (30 ml, 1 and 3 hr after meals and at bedtime) to placebo for duodenal ulcer healing. After 4 weeks of treatment 78% of antacid-treated patients were healed as compared to 45% of placebo patients. Their endoscopic criterion for healing was disappearance of the ulcer crater; in the present study, 86% of antacid-treated patients healed by this criterion. Complete relief of symptoms occurred in most patients on both treatments and symptom relief was significantly correlated with ulcer healing. However, ulcer healing was not necessary for symptom relief as 18 of 36 patients (50%) with endoscopic evidence of ulcer or erosion were asymptomatic. There were no side effects associated with cimetidine use, whereas 27% of antacid-treated patients experienced diarrhea. Unfortunately, detailed records of stool frequency and consistency were not kept. In most of
FOR DUODENAL
ULCER
395
these patients diarrhea was controlled by substituting occasional doses of Al(OH), antacid. It is likely that cimetidine will be preferred by patients who are unable to tolerate the change in bowel habits associated with frequent Al-Mg antacid use. We cannot explain the difference in ulcer healing in cimetidine-treated patients with hypersecretion compared to those with normosecretion. Because healing occurred in patients with high peak acid outputs, the data suggest that failure to heal during cimetidine treatment is not caused by the use of an inadequate antisecretory dose. However, study of the effect of cimetidine on acid secretion in these specific (nonhealing) patients would be required to support this suggestion. In summary, 800 and 1200 mg of cimetidine daily produced duodenal ulcer healing and pain relief equivalent to 210 ml of AI-Mg antacid daily. There were no untoward effects of cimetidine, whereas 27% of the antacid-treated patients reported diarrhea. REFERENCES Bodemar G, Walan A: Cimetidine in the treatment of active duodenal and prepyloric ulcers. Lancet 2161-164, 1976 Blackwood WS, Pickard RG, Maudgal DP, et al: Cimetidine in duodenal ulcer-controlled trial. Lancet 2174-176, 1976 Gray GR, Smith IS, McKenzie I, et al: Oral cimetidine in severe duodenal ulceration-a double-blind controlled trial. Lancet 1:4-7, 1977 4. Deering TB, Malagelada JR Comparison of an H,-receptor antagonist and a neutralizing antacid on postprandial acid delivery into the duodenum in patients with duodenal ulcer. Gastroenterology 73:11-14, 1977 5. Peterson WL, Sturdevant RAL, Frank1 HD, et al: The healing of duodenal ulcer with an antacid regimen. N Engl J Med 297:341-345, 1977 Fordtran JS, Morawski SG, Richardson CT: h uiuo and in vitro evaluation of liquid antacids. N Engl J Med 288:923-928, 1973 Snedecor GW, Cochran WG: Statistical Methods. Sixth edition. Ames, Iowa, Iowa State University Press, 1967 Bardhan KD, Saul DM, Balmforth GV, et al: The effect of cimetidine on duodenal ulceration: an interim report of a multicentre double-blind trial. In Cimetidine: Proceedings of the Second International Symposium on Histamine Hz-Receptor Antagonists. Edited by WL Burland, MA Simkins. AmsterdamOxford, Excerpta Medica, 1977, p 260-271
DISCUSSION OF PAPER PRESENTED BY DRS. IPPOLITI ET AL. DR. W. FINKELSTEIN (Boston): Your data suggest a 44% healing rate at the end of 4 weeks on the antacid regimen. The paper presented by Dr. Peterson and others from the CURE (Center for Ulcer Research and Education) group presented a 78% healing rate for those on an antacid regimen that was similar to that used in your study. Can you provide any explanation for the difference? DR. IPPOLITI:Yes. It is a question of definition of duodenal ulcer healing. In the study of Peterson and his associates, disappearance of the ulcer crater constituted ulcer healing. In this study, ulcer healing was defined as disappearance of both craters and erosions. The figure to compare to Dr. Peterson’s 78% healing rate would be our 86% healing
rate in our antacid-treated patients, healing being defined as disappearance of the ulcer crater. DR. J. T. GALAMBOS (Atlanta): Do you have an explanation for why one-third of the placebo-treated patients with erosion were asymptomatic, as compared to almost three-quarters of the patients with erosions who were asymptomatic in the cimetidine ? DR. I?~~:TI: No, I do not have an explanation for that Dr. Galambos. It was not a statistically significant difference. DR. A. R. COOKE(Kansas City): Did you analyze your data with respect to smoking, because of the importance of smoking on the healing rates? DR. IPPOLITI:No, we did not.
Vol. 74, No. 2, Part 2 Printed in U.S.A.
CIMETIDINE VERSUS INTENSIVE ANTACID THERAPY FOR DUODENALULCER A multicenter trial A. F. IPPOLITI.,R. A. L. STURDEVANT, J. I. ISENBERG, M. BINDER, R. CAMACHO, R. CANO, C. COONEY, M. M. KLINE, R. L. KORETZ, J. H. MEYER, I. M. SAMLOFF, A. D. SCHWABE, E. A. STROM, J. E. VALENZUELA, AND R. H. WINTROUB Departments of Medicine, Wadsworth Veterans Administration Hospital, UCLA Center for the Health Sciences, San Fernando Valley Medical Complex, LAG’-USC Medical Center, Los Angeles; Harbor General Hospital, Torrance; Daniel Freeman Hospital, Inglewood; Valley Medical Center, Fresno, California
In a randomized double blind multicenter trial, patients treated with cimetidine (800 or 1200 mg daily) or an intensive regimen of Al-Mg antacid (210 ml daily) had similar rates of duodenal ulcer healing and pain relief. After 4 weeks of treatment, the proportion of patients with ulcer healing by endoscopy were: cimetidine (1200 mg), 21 of 33 (64%); cimetidine (800 mg), 19 of 32 (59%); and antacids, 15 of 29 (52%). These proportions did not differ significantly. Eighty per cent of cimetidine-treated patients became asymptomatic by week 4, as did 63% of antacid-treated patients (P > 0.1). No untoward effects were observed during cimetidine treatment. Twenty-seven per cent of antacid-treated patients reported diarrhea. In Europe and the United Kingdom cimetidine was more effective than placebo in healing and relieving symptoms of duodenal ulcer. 1-9In those trials antacid was taken irregularly and infrequently by both treatment groups. However, large doses of Al-Mg antacids, taken at fixed intervals after a meal, reduce gastric acidity to a degree comparable to cimetidine.4 Recently, a randomized double blind trial has shown that intensive antacid therapy is superior to placebo in healing duodenal ulcer.” The purpose of this study was to compare ulcer healing and pain relief in patients treated either with cimetidine (800 or 1200 mg daily) or an intensive antacid regimen. Methods Patients with endoscopic demonstration
of a duodenal or pyloric channel ulcer crater were admitted to a randomized, double blind outpatient trial. The study was conducted at seven hospitals under the auspices of the Center for Ulcer Research and Education (CURE), and approval was obtained from the research committee at each hospital. Three treatment groups were compared: 800 mg of cimetidine daily, 1200 mg of cimetidine daily, and 210 ml of an Al-Mg antacid daily. The antacid was similar to Mylanta II (Stuart Pharmaceuticals, Wilmington, Del.) and the in vitro buffering capacity of this antacid was 123 mEq of HCl per 30-ml dose.” The cimetidine tablets (200 or 300 mg) were taken four times a day, with meals and at bedtime. Thirty milliliters of antacid Address requests for reprints to: Andrew Ippoliti, M.D., Gastroenterology Section 691/111C, Wadsworth Veterans Hospital, Wilshire and Sawtelle Boulevards, Los Angeles, California 90073. The authors gratefully acknowledge Smith Kline & French Laboratories, Philadelphia, for supporting these studies and Helen Silket for typing the manuscript.
were taken 1 and 3 hr after meals and at bedtime. Cimetidinetreated patients received a placebo liquid simulating antacid, and antacid-treated patients received placebo tablets simulating cimetidine. Ninety-seven patients with an ulcer crater demonstrated at endoscopy entered the trial. Patients with accompanying gastric ulcer, prior gastric surgery, or Zollinger-Ellison syndrome, or receiving anti-inflammatory drugs were excluded from the study. Patients with ulcer complications such as bleeding or obstruction in whom surgery might be imminent were also excluded. Basal and either betazole-stimulated (1. mg per kg intramuscularly) or pentagastrin-stimulated (6 pg per kg subcutaneously) peak acid outputs were determined on entrance into the study if unavailable within the pervious 6 months. Treatment began within 4 days of endoscopy and acid secretory testing, and lasted 4 weeks. Patients were interviewed at weeks 1, 2, and 4 and at each visit specimens were obtained for complete blood count, liver and renal function tests, and urinalysis. Endoscopy was repeated at weeks 1 and 4. The endoscopic findings were classified as ulcer crater, erosion, i.e., a break in the mucosa without a fibrous base, or normal. The latter category includes hyperemia of the bulb. Endoscopic healing was defined as a bulb free from craters and erosions. Student’s t-test for independent variables and ,$ distribution with Yates’ correction for continuity were used in the statistical analysis of the data.’
Results Sixty-seven patients were randomized to treatment with cimetidine: 33 to 1200 mg daily, and 34 to 800 mg daily. Two patients were withdrawn from the 800-mg cimetidine group. One failed to return after the initial visit and in the other the ulcer was found to be antral rather than duodenal at the time of the week 1 endos393
394
ZPPOLZTZ ET AL.
copy. Thirty patients were randomized to antacid treatment and 1 patient withdrew because of severe diarrhea. The following results pertain only to the patients who completed the study, 33 in the 1200-mg cimetidine group, 32 in the 800-mg cimetidine group, and 29 in the antacid group. Patient profile. There were no significant differences in age, sex, duration of diagnosed duodenal ulcer disease, daily frequency of symptoms upon entrance into the trial, and basal or peak acid output between the cimetidine- and antacid-treated patients (table 1). In approximately 30% of the patients in both treatment groups the diagnosis of duodenal ulcer disease had been documented 1 year or less before the study started. Five of 29 antacid patients and 9 of 65 cimetidine patients were asymptomatic when they entered the trial; these patients presented with bleeding duodenal ulcers requiring transfusion within 10 days before entering the trial. Endoscopic results. The frequency of endoscopic duodenal ulcer healing at 1 or 4 weeks did not differ significantly among the three treatments (fig. 1). Eight of 29 patients receiving 1200 mg of cimetidine, 4 of 27 patients receiving 800 mg of cimetidine, and 2 of 26 patients receiving antacid were healed at 1 week. Nine cimetidine-treated and 3 antacid-treated patients failed to undergo a l-week endoscopy. After 4 weeks of treatment, the proportions of patients healed on cimetidine (1200 and 800 mg) and antacid were 21 of 33 (64%), 19 of 32 (59%), and 15 of 29 (52%), respectively. The endoscopic findings after 4 weeks of treatment TABLE 1. Patient characteristics Age (yr, mean + SE) Male/female Duration of disease (median) Symptom frequency in week prior to entry (mediar$’ Basal acid output (mEq/hr, mean + SE) Peak acid output
(mEq/hr,
mean
?
Cimetidine
Antacid
48.9 2 1.6
46.1 2 2.5
52/13
2514
4 yr G/day
2 Yr 4iday
were compared in the combined cimetidine-treated patients and the antacid-treated patients (table 2). Slightly more cimetidine- than antacid-treated patients had complete healing of the duodenal bulb, 62 versus 52%, but this difference is not statistically significant. Disappearance of the ulcer crater, leading either to reepithelization of the bulb (normal) or to the presence of an erosion, occurred with similar frequency in both treatments, 76% for cimetidine and 86% for antacid. Consequently, persistence of the ulcer crater was found in 24% of the cimetidine-treated and 14% of the antacidtreated patients. Symptom relief. In table 3 the number of patients who were asymptomatic during the 4th week of treatment was compared for cimetidine and antacid. The patients are grouped according to their endoscopic findings at week 4. Only the 80 patients with symptomatic ulcer disease at the onset of the trial are included in this analysis. Over-all, 80% of cimetidine-treated patients became asymptomatic as compared to 63% of antacid-treated patients; this difference is not significant. Forty-two of 44 (95%) patients with a normal duodenal bulb, with either treatment, were asymptomatic compared to 18 of 36 (50%) patients with an ulcer or erosion (P < 0.005). Symptom relief was prompt with both treatments, 55% of cimetidine-treated patients and 58% of antacid-treated patients became asymptomatic by day 7. Side effects. There were no clinically important alterations in blood count or in liver or renal function tests in patients treated with cimetidine or antacid. One antacid-treated patient, as noted, withdrew from the study because of diarrhea and 7 other patients reported diarrhea. Thus diarrhea occurred in 27% of antacidtreated patients. One of the cimetidine-treated patients complained of diarrhea. Acid secretion. The mean peak acid output (PAO) in TABLE 2. Endoscopic findings after 4 weeks of treatment
3.8 * 0.5
5.5 + 1.1
35.7 f 2.2
35.9 2 3.4
SE) a
Vol. 74, No. 2, Part 2
Includes patients with no pain prior to entering the trial.
Cimetidine (n = 65)
Antacid (n = 29)
40 (62)”
15 (52) 10 (34)
Normal Erosion Ulcer
9 (14) 16 (24)
’ Numbers in parentheses
4 (14)
are percentages.
TABLE 3. Proportion ofpatients
asymptomatic in week 4, according to endoscopic finding at week 4
CIYETIDINE CIYETIDINE
I200 nrg 800 mg
ANTACID
Ulcer Erosion Normal Total
Cimetidine
Antacid
B/16 (56)a 517 (71) 32/33 (97) 45/56 (80)
214 (50) 3/9 (33) lO/ll (91) 15/24 (63)
’ Numbers in parentheses TABLE 4. Mean *
SE
are percentages.
basal and peak acid output (milliequivalents per hour) Cimetidine (n = 59)
TREATMENT
PERIOD
(wks)
FIG. 1. Percentage of patients with endoscopic healing of duodenal ulcer after weeks 1 and 4 for 1206 mg of cimetidine (n = 33), 800 mg of cimetidine (n = 32), and antacid (n = 29).
Healed Not healed
Antacid = 28)
(n
Basal
Peak
Basal
Peak
4.2 2 0.6 3.3 * 0.9
39.4 + 2.7 29.4 -r- 3.2
5.6 -t 1.6 6.0 2 1.8
31.6 * 4.0 40.2 f 5.4
February 1978
CIMETIDINE
VERSUS
ANTACID
cimetidine-treated patients with healed ulcers was significantly higher than in those without healing, (P < 0.025) (table 4). Nineteen of 24 (79%) cimetidine-treated patients with a PA0 > 40 n-&q per hr healed as compared to 18 of 35 (51%) patients with a PA0 < 40 mEq per hr (P = 0.02). Among antacid-treated patients healing and PA0 were not correlated. Basal acid output did not correlate with ulcer healing in either group (table 4). Discussion The results of this study indicate that a l-month course of cimetidine and an intensive antacid regimen did not differ significantly in duodenal ulcer healing and pain relief. This is not surprising as both treatments have been shown to be superior to placebo in healing duodenal ulcer,1-3~5 and they have similar effects on intragastric PH.~ Endoscopic healing with cimetidine in this study (40 of 65) is comparable to the study of Bardhan et al. (47 of 65).* In the latter study patients received 1 or 2 g of cimetidine daily. As in a previous report we observed no difference in healing between 800 and 1200 mg of cimetidine daily.’ Although the smaller dose appears as effective as the larger dose of cimetidine, more patients should be studied to clarify this point. Peterson et a1.5 compared ‘an Al-Mg antacid in a similar regimen (30 ml, 1 and 3 hr after meals and at bedtime) to placebo for duodenal ulcer healing. After 4 weeks of treatment 78% of antacid-treated patients were healed as compared to 45% of placebo patients. Their endoscopic criterion for healing was disappearance of the ulcer crater; in the present study, 86% of antacid-treated patients healed by this criterion. Complete relief of symptoms occurred in most patients on both treatments and symptom relief was significantly correlated with ulcer healing. However, ulcer healing was not necessary for symptom relief as 18 of 36 patients (50%) with endoscopic evidence of ulcer or erosion were asymptomatic. There were no side effects associated with cimetidine use, whereas 27% of antacid-treated patients experienced diarrhea. Unfortunately, detailed records of stool frequency and consistency were not kept. In most of
FOR DUODENAL
ULCER
395
these patients diarrhea was controlled by substituting occasional doses of Al(OH), antacid. It is likely that cimetidine will be preferred by patients who are unable to tolerate the change in bowel habits associated with frequent Al-Mg antacid use. We cannot explain the difference in ulcer healing in cimetidine-treated patients with hypersecretion compared to those with normosecretion. Because healing occurred in patients with high peak acid outputs, the data suggest that failure to heal during cimetidine treatment is not caused by the use of an inadequate antisecretory dose. However, study of the effect of cimetidine on acid secretion in these specific (nonhealing) patients would be required to support this suggestion. In summary, 800 and 1200 mg of cimetidine daily produced duodenal ulcer healing and pain relief equivalent to 210 ml of AI-Mg antacid daily. There were no untoward effects of cimetidine, whereas 27% of the antacid-treated patients reported diarrhea. REFERENCES Bodemar G, Walan A: Cimetidine in the treatment of active duodenal and prepyloric ulcers. Lancet 2161-164, 1976 Blackwood WS, Pickard RG, Maudgal DP, et al: Cimetidine in duodenal ulcer-controlled trial. Lancet 2174-176, 1976 Gray GR, Smith IS, McKenzie I, et al: Oral cimetidine in severe duodenal ulceration-a double-blind controlled trial. Lancet 1:4-7, 1977 4. Deering TB, Malagelada JR Comparison of an H,-receptor antagonist and a neutralizing antacid on postprandial acid delivery into the duodenum in patients with duodenal ulcer. Gastroenterology 73:11-14, 1977 5. Peterson WL, Sturdevant RAL, Frank1 HD, et al: The healing of duodenal ulcer with an antacid regimen. N Engl J Med 297:341-345, 1977 Fordtran JS, Morawski SG, Richardson CT: h uiuo and in vitro evaluation of liquid antacids. N Engl J Med 288:923-928, 1973 Snedecor GW, Cochran WG: Statistical Methods. Sixth edition. Ames, Iowa, Iowa State University Press, 1967 Bardhan KD, Saul DM, Balmforth GV, et al: The effect of cimetidine on duodenal ulceration: an interim report of a multicentre double-blind trial. In Cimetidine: Proceedings of the Second International Symposium on Histamine Hz-Receptor Antagonists. Edited by WL Burland, MA Simkins. AmsterdamOxford, Excerpta Medica, 1977, p 260-271
DISCUSSION OF PAPER PRESENTED BY DRS. IPPOLITI ET AL. DR. W. FINKELSTEIN (Boston): Your data suggest a 44% healing rate at the end of 4 weeks on the antacid regimen. The paper presented by Dr. Peterson and others from the CURE (Center for Ulcer Research and Education) group presented a 78% healing rate for those on an antacid regimen that was similar to that used in your study. Can you provide any explanation for the difference? DR. IPPOLITI:Yes. It is a question of definition of duodenal ulcer healing. In the study of Peterson and his associates, disappearance of the ulcer crater constituted ulcer healing. In this study, ulcer healing was defined as disappearance of both craters and erosions. The figure to compare to Dr. Peterson’s 78% healing rate would be our 86% healing
rate in our antacid-treated patients, healing being defined as disappearance of the ulcer crater. DR. J. T. GALAMBOS (Atlanta): Do you have an explanation for why one-third of the placebo-treated patients with erosion were asymptomatic, as compared to almost three-quarters of the patients with erosions who were asymptomatic in the cimetidine ? DR. I?~~:TI: No, I do not have an explanation for that Dr. Galambos. It was not a statistically significant difference. DR. A. R. COOKE(Kansas City): Did you analyze your data with respect to smoking, because of the importance of smoking on the healing rates? DR. IPPOLITI:No, we did not.