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Recurrent ulcer after successful treatment with cimetidine or antacid
Recurrent Ulcer After Successful Treatment With Cimetidine or Antacid A. IPPOLITI, J. ELASHOFF, J. VALENZUELA, R. CANO, H. FRANKL, M. SAMLOFF, and R. KORETZ (knter for lllcer Research and Education. CJC1.A: Los Angeles (:ount~-lJni~rrsit~ California Medical Center: Valley Medical Harbor-I!CL:\. Los Angeles. California
Center:
This study was designed to compare the rates of duodenal ulcer healing and recurrence after treatment with cimetidine or antacid. Patients with endoscopically documented duodenal ulcer received cimetidine, 1200 mg daily, or Mylanta II, 7 oz daily, in a randomized, double-blind trial. For the 69 patients in each group who completed the healing phase of the trial, endoscopic ulcer healing was almost idenpercent tical. At 2, 4, and 6 wk, the cumulative healed on antacid was 33%, 64%, and 80°f, and on cimetidine it was 25%, 62%, and 86%. The 114 patients with healed ulcer were observed on no therapy and underwent additional endoscopy to detect recurrences when symptomatic or at 3, 6, and 12 mo. There was no difference in the frequency of recurrences between treatments. At 3 and 6 mo, the cumulative percentages of patients with recurrence were 29% and 56% after antacid therapy and 36% and 55% after cimetidine therapy. Some patient variables were associated with delayed ulcer healing or ulcer recurrence. These included sex, pain frequency, smoking, disease duration, and acid secretion. Controlled clinical trials have shown that medical therapy with the HZ-receptor antagonist, cimetidine, or with an intensive regimen of antacids produces relief of pain and duodenal ulcer healing within 4-6 wk in most patients (1-3). However, after cessation of therapy, many patients develop a recurrent ulcer within E-12 mo. These recurrences have been obKec.eivcxl July 19, 1982. A(.cc:pted April 15. 1983. Atltlrr:ss requests for reprints to: Janet D. Elashoff, Ph.D.. Building 115. Room 22:~. i%‘adsworth Veterans Administration, Los Angeles. (California 90(17:<. This work was supported in part by National Institute of Arthritis. hletabolism dnd t)igestive Diseases. grant #AM17328. Medical Research Ser1,ic.t: of the Veterans Administration and CURE ((Zenter for IJl(.r:r Research and Education). ( 1983 1)~ the Amerir.ao Gastroenterological Association 001R-5085’H3’$3.00
Kaiser-Sunset:
Sepulveda
ot Southc~rn VA Hospit,il: ,III~
served in patients whose treatment had produced complete ulcer healing confirmed by endoscopy. Recurrence rates as high as 80% in 1 yr were reported for patients who healed on cimetidine and were randomized to placebo maintenance (4). It was considered possible that cimetidine withdrawal enhanced the likelihood of an ulcer recurrence. While there are many studies of duodenal ulcer healing, much less is known about recurrence after healing or the factors that predispose to early recurrence. The purpose of this study was to compare the frequency of ulcer healing and recurrence after treatment with cimetidine versus intensive antacid regimen. [n addition, the influence of variables other than treatment on ulcer healing, relapse, or both was examined.
Methods Patient
Selection
Patients were drawn from six institutions*: two veteran’s hospitals, two county hospitala, a prepaid medical plan, and the practice of one private gastroenterologist. The study was approved by the Human Subject Protection Committees of the participating institutions in August and September 1977. Signed informed consent was obtained from each subject. Patients with duodenal, pyloric channel, or prepyloric ulcer (within 2 cm of the pylorus) were considered for the study. The latter were included since the acid secretory rate for this group is comparable to that for duodenal ulcer disease (5). Patient exclusions included age cl8 yr, concomitant proximal gastric ulcer, gastric surgery other than closure of a perforation, ZollingerEllison syndrome, concomitant disease or therapy that might affect evaluation of outcome, pregnancy, and significant ulcer complications. Patients with gastrointestinal bleeding not requiring transfusion were acceptable. After documentation of ulcer disease. patients were * Wadsworth Harbor-IJCLA.
VA, Sepulveda VA. County-IJSC Medical Kaiser-Sunset. and Dr. Cane‘s practice.
Center.
876
IPPOLITI
ET AL.
randomly assigned in double-blind fashion to cimetidine, 1200 mg daily in divided doses before meals and at bedtime, plus placebo liquid antacid, or to Mylanta II (Stuart Pharmaceuticals, Wilmington, Del.), 7 oz daily with 1 oz 1 and 3 h after meals and at bedtime, plus placebo cimetidine. The in vitro buffering capacity of a loz dose of Mylanta is 144 mmol of 0.1 N HCI. Symptom assessment and endoscopy were carried out at 2-wk intervals (endoscopist was unaware of symptoms). Patients discontinued therapy whenever ulcer healing occurred, i.e., after 2, 4, or 6 wk of therapy. Patients unhealed at 6 wk were withdrawn from the study. Ulcer healing was defined as a bulb free of ulcers and erosions. Patients with healed ulcers were contacted monthly for symptom recurrence. Endoscopy was carried out at the time of symptom recurrence or at 3,6,and 12 mo in those who remained asymptomatic. The presence of an ulcer or erosive duodenitis constituted a recurrence whether or not symptoms were present. The following variables were recorded for each patient: age, sex, smoking history (packs per day at the time of study), duration of ulcer disease, previous ulcer complications, family history of ulcer, bleeding at entry to the study, frequency of pain (the average number of episodes of pain per 24 h in the week before entry into the study), and pain at night. Basal acid output (BAO) and peak acid output (PAO, the two highest consecutive 15-min periods after stimulation with pentagastrin 6 @g/kg) were determined in 78% of the patients. Statistical
Analyses
The statistical procedures used for each reported analysis are indicated either in the text or as footnotes in the tables; two-sided p < 0.05 was used as the significance level throughout.
Results Ulcer Healing Eighty-three patients were entered into the Mylanta II treatment group and 78 into the cimetidine treatment group. Patient characteristics in each group are shown in Table 1 (there were no significant differences between groups). Fourteen patients in the Mylanta group (17%) and 9 patients in the cimetidine group (12%) did not complete the healing phase of the study. Sixteen patients (8 in each group) failed to return; 3 patients were withdrawn for reasons unrelated to ulcer disease or treatment; 2 patients who were treated with Mylanta were withdrawn for severe diarrhea; and 1 patient in each group had worsening ulcer symptoms. The endoscopic healing data are in Table 2 and Figure 1. Results for the two treatments are similar; of those patients completing the study, the cumulative percent healed at 2, 4, and 6 wk was 33%, 64%, and 80% for antacid, and 25%, 62%, and 86% for
GASTROENTEROLOGY
Table 1. Patient Characteristics
Sample
size
Vol.85, No. 4
at Entrv Mylanta 83
Age (X 5 SE, yr) Sex (Oh females)
47 t 2 12
Duration (median mo [range])” Complications (OJL)~ Bleeding at entry (Oh) Family history of ulcer (oh) Pain frequency (#/day)” Smokers (%] BAO (mmolih) PA0 (mmolih)
48 60 38 28 4 58 5 34
(l-480)
? 0.4 -’ 0.5 t 2
Cimetidine 78 47 21 66 66 36 20 5 60 5 34
-+ 2 (l-372)
+ 0.5 ? 0.6 -’ 2
a Time from onset of ulcer disease to entry into the trial. ’ Patients with complications prior to entry into the trial. ’Average number of episodes of pain per 24 h in the week before entry into the trial. More than 14iday coded as 14.
cimetidine. The 95% confidence interval for the difference in percent healed at 6 wk (of those completing the study) is from 8% in favor of Mylanta to 19% in favor of cimetidine.+ Of the 138 patients completing the healing phase of the study, 68% were asymptomatic at 2 wk. At the end of 6 wk, 82% were asymptomatic (antacid 77%, cimetidine 87%). Figure 2 depicts the relationship between healing and symptoms; for unhealed patients, this is the presence or absence of symptoms at 6 wk. For one-fourth of the patients the healing and symptom status were inconsistent, i.e., 13% were healed but symptoms were still present, and 12% were asymptomatic but had not healed. Ulcer Recurrence There were no differences in the frequencies of ulcer recurrence at 3, 6, and 12 mo for patients originally treated with antacid or with cimetidine (see Figure 3 and Table 3). Of patients whose status was known at each interval, i.e., recurrence or no recurrence, the cumulative percent recurrence after antacid at 3, 6, and 12 mo was 29%, 56%, and 70% and after cimetidine was 36%, 55%, and 75%. Of the 58 patients with recurrences, 47 were symptomatic (40 ulcer, 7 duodenitis), and 11 were asymptomatic (8 ulcer, 3 duodenitis). Patient
Variables
Patient variables were examined to assess their relationship to ulcer healing and relapse (Table 4). The results are presented for the combined group of antacid- and cimetidine-treated patients, since there were no differences in healing or relapse be+ Confidence limits at 2 (and 4 wk) were 24% (19%) in favor of Mylanta to 8% (16%) in favor of cimetidine.
CIMETIUINE
Table
2.
Healed
at week 4
6
83
23
21
11
4
10
78
17
26
16
4
6
tween the groups and preliminary analyses did not indicate any differences between groups in the relationship of the variables to healing or relapse. There was a significant effect of patient sex, frequency of pain, smoking, and acid secretion on the speed of healing (2 vs. 4 vs. 6 wk vs. not healed).* Healing occurred earlier in women, in patients with fewer episodes of pain before the onset of treatment, in nonsmokers, and in those with lower rates of basal and stimulated acid secretion. The duration of ulcer disease significantly influenced both the incidence of ulcer healing and of relapse, but not the speed of healing. The duration was less for healed patients (median 8 mo) versus nonhealed patients (median 162 mo) and was less in those without recurrence at 6 mo (median 12 mo) versus those with recurrence (median 66 mo) (p < 0.05).The only other variable significant for relapse was the PA0 (at 6 mo). Time to healing of the original ulcer was not related to time of recurrence.
Discussion The results ulcer healing
of this study was similar
indicate that duodein the antacidand
* Correlation with time to healing by test for linear trend after an analysis of variance or xz method; Table 4 calculations are all xL using dichotomized data and 6-wk healing.
,
Unhealed Erosion Ulcer
2
Total entered
Mylanta Cimetidine
100
TREATMENT
877
Results
Healing
Treatment
nal
OK ANTACID
r-l
Total completing 651 69
Dropped 14 9
cimetidine-treated patients and that the frequency of ulcer recurrence after cessation of treatment was not different for the two treatments. Patients who healed and did not relapse tended to be of a younger age, to be women, to have a more recent onset of ulcer disease but fewer episodes of pain at entry into the trial, to be lighter smokers, and to have lower BAO and PAO. None of the three previous trials of duodenal ulcer healing comparing cimetidine (800-1200 mg daily) to 7 oz of antacid daily [Mylanta or Maalox (William H. Rorer, Inc., Fort Washington, Pa.)] showed a (l-3). significant difference between treatments Combining the results of this study and the three previous ones, 4- and 6-wk healing rates for cimetiand for antacdine were 65% and 84%, respectively, id were 63% and 72%, respectively. Ulcer recurrence rates after cessation of therapy in healed patients have not been extensively studied. In a recent paper, Berstad et al. (6) found that ulcer relapse was similar after treatment with trimipramine plus antacid or cimetidine with antacid. As in our study, Strom et al. (7)and Hansky et al. (8)found no difference in ulcer recurrence after cimetidine or antacid. Although no difference in ulcer recurrence has been found after treatment with different antisecretory drugs and antacid, Martin et al. (9) reported that relapse rates were significantly less for up to 1 yr
CIMETIDINE
I k
WEEK 2
Figure
WEEK 4
WEEK 6
1. The cumulative percent healed at 2, 4, and 6 wk of the 69 patients in each group completing the healing phase of the study was 33%, 64%, and 80% for antacid and 25%,, 62%, and 86% for cimetidine.
(AS) syMpToMAM: (s)
ASYMPTOMATK:
Figure
LrgYyTEy
2. Status of healing and symptoms at 6 wk in 138 patients completing the trial. H = healed, NH = not healed, S = symptomatic, AS = asymptomatic.
878
IPPOLITI
ET AL.
GASTROENTEROLOGY
CIMETIDINE
ANTACID
12MO
Figure
3. Of patients whose status was known, the cumulative percent recurrence of ulcer at 3,6, and 12 mo was 29%, 56%, and 70% for antacid and 36%, 55%, and 75% for cimetidine.
after treatment with bismuth subcitrate (De-Nol), as compared with cimetidine. Most controlled trials of duodenal ulcer healing report that ZO%-30% of patients fail to heal and the likelihood of recurrence, off treatment, is as high as it seems probable that some 80% at 1 yr. Thus, variables may impair the efficacy of ulcer therapies and enhance the frequency of relapse. However, while most randomized trials report the characteristics of their groups, e.g., age, and sex, the influence of these variables on the outcome is rarely determined. In over 60 trials with endoscopic assessment of ulceration published since 1976, less than onehalf reported the effect of any variables other than treatment on healing or recurrence. Eighteen trials, including this one, have reported the effect of smoking versus nonsmoking on duodenal ulcer healing (2,6,10-24). In this study, there was a significant difference in ulcer healing at 4 wk between nonsmokers (77% healed) and smokers (52% healed). Figure 4 shows reported healing rates for nonsmokers plotted against those for smokers in all 18 trials (it should be noted that some of these figures are based on very small numbers). Significantly greater ulcer healing in nonsmokers than in smokers was reported in six trials (2,10-14). In all of the 11 trials with a placebo group, nonsmokers had higher healing rates than smokers. Considering all 35 treated groups, nonsmokers healed more frequently than smokers in 29 (83%); the median difference in ulcer healing between nonsmokers and smokers was 20%. Comparing patients with a history of 54 yr to those with ulcer for >4 yr, healing at 6 wk was 90% vs. 75% and relapse at 6 mo was 43% vs. 72%. Few
Vol.
85, No. 4
studies have reported the relationship of duration of disease to healing or relapse. Of 11 studies that addressed healing and disease duration, six reported greater healing in patients with shorter history of ulcer (three were significant differences) (912,15,17,18,23,25-27). In eight studies of ulcer relapse, three reported fewer relapses in the patients with a short disease duration (7,9,17,28-32). Ulcer healing was significantly higher in women (80% vs. 59% at 4 wk) and recurrences were lower (35% vs.60% at 6 mo). However only 2 of 11 studies indicated a significantly greater healing rate in women than in men (911,15,20,21,23-25,27,33). Since the proportion of women in ulcer trials is only about 20%-25%, the numbers were usually too small to draw any conclusions. In this study, higher rates of acid secretion were associated with failure to heal or with early relapse. In three of five studies acid secretion, either basal or peak, was higher in those patients not healing (10,12,16,20,26), and in one of four studies a high found in hypersecretors recurrence rate was (7,28,29,34). Maybury and Carr-Locke (35) found that a high response to insulin predicted both failure to heal and recurrence. Severity of ulcer symptoms as judged by patient reports of frequency of pain was highly variable in this study, ranging from painless bleeding to nearly continuous pain. The frequency of pain varied directly with length of time to healing, while it appeared to have no relationship to ulcer relapse. Massarrat and Eisenmann (10) also found that severity of pain, as judged by the duration of the symptomatic relapse, significantly affected initial ulcer healing. The rapid developments in peptic ulcer therapeutics and the ease and accuracy of endoscopy have produced a great deal of interest in randomized trials of ulcer healing and prevention. However, most studies have failed to consider the influence of any variables other than treatment on outcome. Since the typical trial often numbers no more than 30 patients per treatment group, the likelihood of a type II error as regards predictors is substantial. However, if the characteristics of the healed versus unhealed paTable 3. Recurrence Initial treatment Antacid (55) Cimetidine (591
After
Month
Healing
Recurrence
No recurrence
Lost
3 6 12 3 6
14 10 4 19 7
34 19 12 34
7 5 3 6
21
6
12
4
11
6
Table
4.
Relationship
of Patient
Variables
to Healing
and Relapse Recurrence at 6 mo [%I
Healing at 6 wk (“41 Healed Age
c50
\r
,50
vr
87 77 80 96 90 75 74 87 81 85 84 79 87 78 88 73 91 79 94 77
hl
Sex
F IIuration
(48
Camp
248 ma none 2-1
Bleed
none yes
Fam Hx
neg pas r3 z-3
Pain trequency
i0.5 20.5 14 -24
Smoking HA0
,no
pack/day pack/day
-c3rl
PA0
” Significant
ul
13
23 20 4 10”
25 26 13
19 15 16 21 13 22 12” 27 9 21 6”
23
No recurrence
Recurrenc:e 54 58 fN 35 43” 72 62 53 60 49 51 70 56 55 49 70 49 59 41” 65
at p c 0.05 h!; x2.
tients were reported (for example, age, sex, smoking habits) whether or not significant in the individual trial, the effect of these variables could be assessed by combining information from several trials (36). This would provide an opportunity to define the influence of these factors on the course of ulcer disease. It might identify variation in response to a treatment within certain subgroups and could also explain differences in results between studies. In this trial there was no obvious interdependence among unrelated variables predictive of healing or relapse. However, the data from a single study are
n
Not healed
100
r
??
oo-
/ /
not adequate for a rigorous exploration of either the possible interrelationships of variables, such as sex and smoking, or the relative importance of individual variables with respect to healing or relapse. This study as well as others have suggested that a number of factors other than treatment may influence healing. It is hoped that future ulcer trials will include these factors in the analysis and reporting of results. The best test of the importance of a factor in the outcome of ulcer disease is reproducibility. If one considers this study and three previous reports in which the influence of variables other than treatment were systematically studied, smoking has an important relation to ulcer healing. In each report healing was delayed in smokers, with an average difference in healing between smokers and nonsmokers of about 20%. Other variables that are found in some of these studies to delay healing are male sex, long disease duration, high frequency of pain, and high rates of acid secretion.
References
20
40
60
80
100
SMOKERS - PERCENT HEALED
Figure
4. Percent of nonsmokers healed versus percent of smokers healed in the same treatment group in 18 trials of duodenal ulcer healing. A = placebo, 0 = cimetidine, ., = other drugs including antacid.
Ippoliti AF, Sturdevant RAL. lsenherg 11. et al. Cimetidine versus intensive antacid therapy for duodenal ulcer. Gastroenterology 1978;74:393-5. Korman MG, Shaw RG, Hansky J, Schmidt GT, Stern Al. Influence of smoking on healing rate of duodenal ulcer in response to cimetidine or high dose antacid. Gastroenterology 198~1;80:1451-3. Fedeli G, Auti M, Rapaccini GL, De Vitris 1, Butti A, Civello IM. A controlled study comparing cimetidine treatment to an
880
4. 5.
6.
7.
8.
9.
10.
11.
12.
13. 14.
15.
16.
17.
18. 19. 20.
IPPOLITI
ET AL.
intensive antacid regimen in the therapy of uncomplicated duodenal ulcer. Dig Dis Sci 1979;24:758-62. Bodemar G, Walan A. Maintenance treatment of recurrent peptic ulcer by cimetidine. Lancet 1978;i:403-7. Isenberg I, Richardson CT, Fordtran JS. Pathogenesis of peptic ulcer in gastrointestinal disease. In: Sleisenger M, Fordtran J, eds. Gastrointestinal disease; pathophysiology, diagnosis, management. 2nd ed. Philadelphia: WB Saunders, 1978:796. Berstad A, Aadland E, Bjerke K, et al. Relapse of duodenal ulcer after treatment with trimipramineiantacid or cimetidine/antacid. Stand J Gastroenterol 1981;16:933-6. Strom M, Gotthard R, Bodemar G, et al. Antacidianticholinergic, cimetidine, and placebo in treatment of active peptic ulcers. Stand J Gastroenterol 1981;16:593-602. Hansky J, Korman MG, Schmidt GT, Stern AI, Shaw RC. Relapse of duodenal ulcer after healing with cimetidine or Mylanta II. Gastroenterology 1980;78:1179. Martin DF, Hollanders D, May SJ, et al. Difference in relapse rates of duodenal ulcer after healing with cimetidine or tripotassium dicitrato bismuthate. Lancet 1981;i:7-10. Massarrat S, Eisenmann A. Factors affecting the healing rate of duodenal and pyloric ulcers with low-dose antacid treatment. Gut 1981;22:97-102. Sonnenberg A, Muller-Lissner SA, Vogel E, et al. Predictors of duodenal ulcer healing and relapse. Gastroenterology 1981; 81:1061-7. Lam SK, Lam KC, Lai CL, Yeung CK, Yam LYC, Wong WS. Treatment of duodenal ulcer with antacid and sulpiride. Gastroenterology 1979:76:315-22. Porro GB. Petri110 M, Grossi E, Lazzaroni M. Smoking and duodenal ulcer. Gastroenterology 1980;79:180-81. Korman MG, Hansky J, Merrett A, Schmidt GT. Ranitidine in duodenal ulcer: healing rate and effect of smoking. Gastroenterology 1981;80:1197. Bardham KD, Saul DM, Edwards JL, et al. Comparison of two doses of cimetidine and placebo in the treatment of duodenal ulcer: a multicentre trial. Gut 1979;20:68-74. Hetzel DJ, Hansky J, Shearman DJC, et al. Cimetidine treatment of duodenal ulceration: clinical trial and a maintenance study. Gastroenterology 1978;74:389-92. Manousos ON, Zografos A, Nicolaou A, Scandaus N, Kalogerakou-Ioannidi E. A double-blind study of cimetidine in patients with duodenal or gastric ulcer in Greece. J Intern Med Res 1978;6:381-3. Nagy GS. An evaluation of carbenoxolone sodium in the treatment of duodenal ulcer. Gastroenterology 1978;74:7-10. Young GP, St. John DJB, Coventry DA. Treatment of duodenal ulcer with carbenoxolone sodium. Med J Aust 1979;1:2-5. Peterson WL, Sturdevant RA, Frank1 HD, et al. Healing of
GASTROENTEROLOGY
21.
22.
23.
24.
25. 26.
27.
28.
Vol.
85. No. 4
duodenal ulcer with an antacid regimen. N Engl J Med 1977:297:341-5. Walt RP, Trotman IF, Frost R, et al. Comparison of twice-daily ranitidine with standard cimetidine treatment of duodenal ulcer. Gut 1981;22:319-22. Marks IN, Wright JP, Denyer M. Garisch JAM, Lucke W. Comparison of sucralfate with cimetidine in short-term treatment of chronic peptic ulcer. S Afr Med J 1980:57:567-73. Marks IN. Healing of peptic ulcers on conventional antacid therapy with or without butriptyline. S Afr Med J 1979;55: 331-7. Barbara L, Belasso E, Porro GB, et al. Pirenzepine in duodenal ulcer: a multicentre double-blind controlled clinical trial. Stand J Gastroenterol 1979;14(Suppl 57):11-5. Moshal MG, Spitael JM, Bhoola R. Treatment of duodenal ulcer with cimetidine. S Afr Med J 1977:52:760-3. Binder HJ, Cocco A, Crossley RJ, et al. Cimetidine in the treatment of duodenal ulcer. Gastroenterology 1978;74:3808. Moshal MG. The treatment of duodenal ulcers with TDB: a duodenoscopic double-blind crossover investigation. Postgraduate Med J 1975;51(Suppl 5):36-40. Rune SJ, Mollman KM, Rahbek I. Frequency of relapses in duodenal ulcer patients treated with cimetidine during symptomatic periods. Stand J Gastroenterol 1980;15(Suppl 58): 85-92.
29. Rune SJ, Greibe J, Mollman KM, et al. Recurrence of duodenal ulcer pain after treatment with cimetidine for four and eight weeks. Gut 1980;21:151-3. 30. Dronfield MW, Batchelor AJ, Larkworth W. Langman MJS. Controlled trial of maintenance cimetidine treatment in healed duodenal ulcer: short and long-term effects. Gut 1979;20:526-30. 31. Bardham KD, Saul DM. Edwards JL, et al. Double-blind comparison of cimetidine and placebo in the maintenance of healing of chronic duodenal ulceration. Gut 1979;20:158-62. 32. Gudmand-Hoyer E, Jensen KB, Krag E. et al. Prophylactic effect of cimetidine in duodenal ulcer disease. Br Med J 1978;1:1095-7. 33. Peden N, Boyd EJS, Wormsley KG. Women and duodenal ulcer. Br Med J 1981;282:866. 34. Cargill JM, Peden N. Saunders JHB, Wormsley KG. Very longterm treatment of peptic ulcer with cimetidine. Lancet 1978;ii:1113-5. 35. Maybury NK, Carr-Locke DL. The value of the new interpretation of the insulin test in predicting duodenal ulcer relapse after treatment with cimetidine. Br J Surg 1980;67:315-7. 36. Elashoff JD. Combining results of clinical trials. Gastroenterology 1978;75:1170-4.
Center:
This study was designed to compare the rates of duodenal ulcer healing and recurrence after treatment with cimetidine or antacid. Patients with endoscopically documented duodenal ulcer received cimetidine, 1200 mg daily, or Mylanta II, 7 oz daily, in a randomized, double-blind trial. For the 69 patients in each group who completed the healing phase of the trial, endoscopic ulcer healing was almost idenpercent tical. At 2, 4, and 6 wk, the cumulative healed on antacid was 33%, 64%, and 80°f, and on cimetidine it was 25%, 62%, and 86%. The 114 patients with healed ulcer were observed on no therapy and underwent additional endoscopy to detect recurrences when symptomatic or at 3, 6, and 12 mo. There was no difference in the frequency of recurrences between treatments. At 3 and 6 mo, the cumulative percentages of patients with recurrence were 29% and 56% after antacid therapy and 36% and 55% after cimetidine therapy. Some patient variables were associated with delayed ulcer healing or ulcer recurrence. These included sex, pain frequency, smoking, disease duration, and acid secretion. Controlled clinical trials have shown that medical therapy with the HZ-receptor antagonist, cimetidine, or with an intensive regimen of antacids produces relief of pain and duodenal ulcer healing within 4-6 wk in most patients (1-3). However, after cessation of therapy, many patients develop a recurrent ulcer within E-12 mo. These recurrences have been obKec.eivcxl July 19, 1982. A(.cc:pted April 15. 1983. Atltlrr:ss requests for reprints to: Janet D. Elashoff, Ph.D.. Building 115. Room 22:~. i%‘adsworth Veterans Administration, Los Angeles. (California 90(17:<. This work was supported in part by National Institute of Arthritis. hletabolism dnd t)igestive Diseases. grant #AM17328. Medical Research Ser1,ic.t: of the Veterans Administration and CURE ((Zenter for IJl(.r:r Research and Education). ( 1983 1)~ the Amerir.ao Gastroenterological Association 001R-5085’H3’$3.00
Kaiser-Sunset:
Sepulveda
ot Southc~rn VA Hospit,il: ,III~
served in patients whose treatment had produced complete ulcer healing confirmed by endoscopy. Recurrence rates as high as 80% in 1 yr were reported for patients who healed on cimetidine and were randomized to placebo maintenance (4). It was considered possible that cimetidine withdrawal enhanced the likelihood of an ulcer recurrence. While there are many studies of duodenal ulcer healing, much less is known about recurrence after healing or the factors that predispose to early recurrence. The purpose of this study was to compare the frequency of ulcer healing and recurrence after treatment with cimetidine versus intensive antacid regimen. [n addition, the influence of variables other than treatment on ulcer healing, relapse, or both was examined.
Methods Patient
Selection
Patients were drawn from six institutions*: two veteran’s hospitals, two county hospitala, a prepaid medical plan, and the practice of one private gastroenterologist. The study was approved by the Human Subject Protection Committees of the participating institutions in August and September 1977. Signed informed consent was obtained from each subject. Patients with duodenal, pyloric channel, or prepyloric ulcer (within 2 cm of the pylorus) were considered for the study. The latter were included since the acid secretory rate for this group is comparable to that for duodenal ulcer disease (5). Patient exclusions included age cl8 yr, concomitant proximal gastric ulcer, gastric surgery other than closure of a perforation, ZollingerEllison syndrome, concomitant disease or therapy that might affect evaluation of outcome, pregnancy, and significant ulcer complications. Patients with gastrointestinal bleeding not requiring transfusion were acceptable. After documentation of ulcer disease. patients were * Wadsworth Harbor-IJCLA.
VA, Sepulveda VA. County-IJSC Medical Kaiser-Sunset. and Dr. Cane‘s practice.
Center.
876
IPPOLITI
ET AL.
randomly assigned in double-blind fashion to cimetidine, 1200 mg daily in divided doses before meals and at bedtime, plus placebo liquid antacid, or to Mylanta II (Stuart Pharmaceuticals, Wilmington, Del.), 7 oz daily with 1 oz 1 and 3 h after meals and at bedtime, plus placebo cimetidine. The in vitro buffering capacity of a loz dose of Mylanta is 144 mmol of 0.1 N HCI. Symptom assessment and endoscopy were carried out at 2-wk intervals (endoscopist was unaware of symptoms). Patients discontinued therapy whenever ulcer healing occurred, i.e., after 2, 4, or 6 wk of therapy. Patients unhealed at 6 wk were withdrawn from the study. Ulcer healing was defined as a bulb free of ulcers and erosions. Patients with healed ulcers were contacted monthly for symptom recurrence. Endoscopy was carried out at the time of symptom recurrence or at 3,6,and 12 mo in those who remained asymptomatic. The presence of an ulcer or erosive duodenitis constituted a recurrence whether or not symptoms were present. The following variables were recorded for each patient: age, sex, smoking history (packs per day at the time of study), duration of ulcer disease, previous ulcer complications, family history of ulcer, bleeding at entry to the study, frequency of pain (the average number of episodes of pain per 24 h in the week before entry into the study), and pain at night. Basal acid output (BAO) and peak acid output (PAO, the two highest consecutive 15-min periods after stimulation with pentagastrin 6 @g/kg) were determined in 78% of the patients. Statistical
Analyses
The statistical procedures used for each reported analysis are indicated either in the text or as footnotes in the tables; two-sided p < 0.05 was used as the significance level throughout.
Results Ulcer Healing Eighty-three patients were entered into the Mylanta II treatment group and 78 into the cimetidine treatment group. Patient characteristics in each group are shown in Table 1 (there were no significant differences between groups). Fourteen patients in the Mylanta group (17%) and 9 patients in the cimetidine group (12%) did not complete the healing phase of the study. Sixteen patients (8 in each group) failed to return; 3 patients were withdrawn for reasons unrelated to ulcer disease or treatment; 2 patients who were treated with Mylanta were withdrawn for severe diarrhea; and 1 patient in each group had worsening ulcer symptoms. The endoscopic healing data are in Table 2 and Figure 1. Results for the two treatments are similar; of those patients completing the study, the cumulative percent healed at 2, 4, and 6 wk was 33%, 64%, and 80% for antacid, and 25%, 62%, and 86% for
GASTROENTEROLOGY
Table 1. Patient Characteristics
Sample
size
Vol.85, No. 4
at Entrv Mylanta 83
Age (X 5 SE, yr) Sex (Oh females)
47 t 2 12
Duration (median mo [range])” Complications (OJL)~ Bleeding at entry (Oh) Family history of ulcer (oh) Pain frequency (#/day)” Smokers (%] BAO (mmolih) PA0 (mmolih)
48 60 38 28 4 58 5 34
(l-480)
? 0.4 -’ 0.5 t 2
Cimetidine 78 47 21 66 66 36 20 5 60 5 34
-+ 2 (l-372)
+ 0.5 ? 0.6 -’ 2
a Time from onset of ulcer disease to entry into the trial. ’ Patients with complications prior to entry into the trial. ’Average number of episodes of pain per 24 h in the week before entry into the trial. More than 14iday coded as 14.
cimetidine. The 95% confidence interval for the difference in percent healed at 6 wk (of those completing the study) is from 8% in favor of Mylanta to 19% in favor of cimetidine.+ Of the 138 patients completing the healing phase of the study, 68% were asymptomatic at 2 wk. At the end of 6 wk, 82% were asymptomatic (antacid 77%, cimetidine 87%). Figure 2 depicts the relationship between healing and symptoms; for unhealed patients, this is the presence or absence of symptoms at 6 wk. For one-fourth of the patients the healing and symptom status were inconsistent, i.e., 13% were healed but symptoms were still present, and 12% were asymptomatic but had not healed. Ulcer Recurrence There were no differences in the frequencies of ulcer recurrence at 3, 6, and 12 mo for patients originally treated with antacid or with cimetidine (see Figure 3 and Table 3). Of patients whose status was known at each interval, i.e., recurrence or no recurrence, the cumulative percent recurrence after antacid at 3, 6, and 12 mo was 29%, 56%, and 70% and after cimetidine was 36%, 55%, and 75%. Of the 58 patients with recurrences, 47 were symptomatic (40 ulcer, 7 duodenitis), and 11 were asymptomatic (8 ulcer, 3 duodenitis). Patient
Variables
Patient variables were examined to assess their relationship to ulcer healing and relapse (Table 4). The results are presented for the combined group of antacid- and cimetidine-treated patients, since there were no differences in healing or relapse be+ Confidence limits at 2 (and 4 wk) were 24% (19%) in favor of Mylanta to 8% (16%) in favor of cimetidine.
CIMETIUINE
Table
2.
Healed
at week 4
6
83
23
21
11
4
10
78
17
26
16
4
6
tween the groups and preliminary analyses did not indicate any differences between groups in the relationship of the variables to healing or relapse. There was a significant effect of patient sex, frequency of pain, smoking, and acid secretion on the speed of healing (2 vs. 4 vs. 6 wk vs. not healed).* Healing occurred earlier in women, in patients with fewer episodes of pain before the onset of treatment, in nonsmokers, and in those with lower rates of basal and stimulated acid secretion. The duration of ulcer disease significantly influenced both the incidence of ulcer healing and of relapse, but not the speed of healing. The duration was less for healed patients (median 8 mo) versus nonhealed patients (median 162 mo) and was less in those without recurrence at 6 mo (median 12 mo) versus those with recurrence (median 66 mo) (p < 0.05).The only other variable significant for relapse was the PA0 (at 6 mo). Time to healing of the original ulcer was not related to time of recurrence.
Discussion The results ulcer healing
of this study was similar
indicate that duodein the antacidand
* Correlation with time to healing by test for linear trend after an analysis of variance or xz method; Table 4 calculations are all xL using dichotomized data and 6-wk healing.
,
Unhealed Erosion Ulcer
2
Total entered
Mylanta Cimetidine
100
TREATMENT
877
Results
Healing
Treatment
nal
OK ANTACID
r-l
Total completing 651 69
Dropped 14 9
cimetidine-treated patients and that the frequency of ulcer recurrence after cessation of treatment was not different for the two treatments. Patients who healed and did not relapse tended to be of a younger age, to be women, to have a more recent onset of ulcer disease but fewer episodes of pain at entry into the trial, to be lighter smokers, and to have lower BAO and PAO. None of the three previous trials of duodenal ulcer healing comparing cimetidine (800-1200 mg daily) to 7 oz of antacid daily [Mylanta or Maalox (William H. Rorer, Inc., Fort Washington, Pa.)] showed a (l-3). significant difference between treatments Combining the results of this study and the three previous ones, 4- and 6-wk healing rates for cimetiand for antacdine were 65% and 84%, respectively, id were 63% and 72%, respectively. Ulcer recurrence rates after cessation of therapy in healed patients have not been extensively studied. In a recent paper, Berstad et al. (6) found that ulcer relapse was similar after treatment with trimipramine plus antacid or cimetidine with antacid. As in our study, Strom et al. (7)and Hansky et al. (8)found no difference in ulcer recurrence after cimetidine or antacid. Although no difference in ulcer recurrence has been found after treatment with different antisecretory drugs and antacid, Martin et al. (9) reported that relapse rates were significantly less for up to 1 yr
CIMETIDINE
I k
WEEK 2
Figure
WEEK 4
WEEK 6
1. The cumulative percent healed at 2, 4, and 6 wk of the 69 patients in each group completing the healing phase of the study was 33%, 64%, and 80% for antacid and 25%,, 62%, and 86% for cimetidine.
(AS) syMpToMAM: (s)
ASYMPTOMATK:
Figure
LrgYyTEy
2. Status of healing and symptoms at 6 wk in 138 patients completing the trial. H = healed, NH = not healed, S = symptomatic, AS = asymptomatic.
878
IPPOLITI
ET AL.
GASTROENTEROLOGY
CIMETIDINE
ANTACID
12MO
Figure
3. Of patients whose status was known, the cumulative percent recurrence of ulcer at 3,6, and 12 mo was 29%, 56%, and 70% for antacid and 36%, 55%, and 75% for cimetidine.
after treatment with bismuth subcitrate (De-Nol), as compared with cimetidine. Most controlled trials of duodenal ulcer healing report that ZO%-30% of patients fail to heal and the likelihood of recurrence, off treatment, is as high as it seems probable that some 80% at 1 yr. Thus, variables may impair the efficacy of ulcer therapies and enhance the frequency of relapse. However, while most randomized trials report the characteristics of their groups, e.g., age, and sex, the influence of these variables on the outcome is rarely determined. In over 60 trials with endoscopic assessment of ulceration published since 1976, less than onehalf reported the effect of any variables other than treatment on healing or recurrence. Eighteen trials, including this one, have reported the effect of smoking versus nonsmoking on duodenal ulcer healing (2,6,10-24). In this study, there was a significant difference in ulcer healing at 4 wk between nonsmokers (77% healed) and smokers (52% healed). Figure 4 shows reported healing rates for nonsmokers plotted against those for smokers in all 18 trials (it should be noted that some of these figures are based on very small numbers). Significantly greater ulcer healing in nonsmokers than in smokers was reported in six trials (2,10-14). In all of the 11 trials with a placebo group, nonsmokers had higher healing rates than smokers. Considering all 35 treated groups, nonsmokers healed more frequently than smokers in 29 (83%); the median difference in ulcer healing between nonsmokers and smokers was 20%. Comparing patients with a history of 54 yr to those with ulcer for >4 yr, healing at 6 wk was 90% vs. 75% and relapse at 6 mo was 43% vs. 72%. Few
Vol.
85, No. 4
studies have reported the relationship of duration of disease to healing or relapse. Of 11 studies that addressed healing and disease duration, six reported greater healing in patients with shorter history of ulcer (three were significant differences) (912,15,17,18,23,25-27). In eight studies of ulcer relapse, three reported fewer relapses in the patients with a short disease duration (7,9,17,28-32). Ulcer healing was significantly higher in women (80% vs. 59% at 4 wk) and recurrences were lower (35% vs.60% at 6 mo). However only 2 of 11 studies indicated a significantly greater healing rate in women than in men (911,15,20,21,23-25,27,33). Since the proportion of women in ulcer trials is only about 20%-25%, the numbers were usually too small to draw any conclusions. In this study, higher rates of acid secretion were associated with failure to heal or with early relapse. In three of five studies acid secretion, either basal or peak, was higher in those patients not healing (10,12,16,20,26), and in one of four studies a high found in hypersecretors recurrence rate was (7,28,29,34). Maybury and Carr-Locke (35) found that a high response to insulin predicted both failure to heal and recurrence. Severity of ulcer symptoms as judged by patient reports of frequency of pain was highly variable in this study, ranging from painless bleeding to nearly continuous pain. The frequency of pain varied directly with length of time to healing, while it appeared to have no relationship to ulcer relapse. Massarrat and Eisenmann (10) also found that severity of pain, as judged by the duration of the symptomatic relapse, significantly affected initial ulcer healing. The rapid developments in peptic ulcer therapeutics and the ease and accuracy of endoscopy have produced a great deal of interest in randomized trials of ulcer healing and prevention. However, most studies have failed to consider the influence of any variables other than treatment on outcome. Since the typical trial often numbers no more than 30 patients per treatment group, the likelihood of a type II error as regards predictors is substantial. However, if the characteristics of the healed versus unhealed paTable 3. Recurrence Initial treatment Antacid (55) Cimetidine (591
After
Month
Healing
Recurrence
No recurrence
Lost
3 6 12 3 6
14 10 4 19 7
34 19 12 34
7 5 3 6
21
6
12
4
11
6
Table
4.
Relationship
of Patient
Variables
to Healing
and Relapse Recurrence at 6 mo [%I
Healing at 6 wk (“41 Healed Age
c50
\r
,50
vr
87 77 80 96 90 75 74 87 81 85 84 79 87 78 88 73 91 79 94 77
hl
Sex
F IIuration
(48
Camp
248 ma none 2-1
Bleed
none yes
Fam Hx
neg pas r3 z-3
Pain trequency
i0.5 20.5 14 -24
Smoking HA0
,no
pack/day pack/day
-c3rl
PA0
” Significant
ul
13
23 20 4 10”
25 26 13
19 15 16 21 13 22 12” 27 9 21 6”
23
No recurrence
Recurrenc:e 54 58 fN 35 43” 72 62 53 60 49 51 70 56 55 49 70 49 59 41” 65
at p c 0.05 h!; x2.
tients were reported (for example, age, sex, smoking habits) whether or not significant in the individual trial, the effect of these variables could be assessed by combining information from several trials (36). This would provide an opportunity to define the influence of these factors on the course of ulcer disease. It might identify variation in response to a treatment within certain subgroups and could also explain differences in results between studies. In this trial there was no obvious interdependence among unrelated variables predictive of healing or relapse. However, the data from a single study are
n
Not healed
100
r
??
oo-
/ /
not adequate for a rigorous exploration of either the possible interrelationships of variables, such as sex and smoking, or the relative importance of individual variables with respect to healing or relapse. This study as well as others have suggested that a number of factors other than treatment may influence healing. It is hoped that future ulcer trials will include these factors in the analysis and reporting of results. The best test of the importance of a factor in the outcome of ulcer disease is reproducibility. If one considers this study and three previous reports in which the influence of variables other than treatment were systematically studied, smoking has an important relation to ulcer healing. In each report healing was delayed in smokers, with an average difference in healing between smokers and nonsmokers of about 20%. Other variables that are found in some of these studies to delay healing are male sex, long disease duration, high frequency of pain, and high rates of acid secretion.
References
20
40
60
80
100
SMOKERS - PERCENT HEALED
Figure
4. Percent of nonsmokers healed versus percent of smokers healed in the same treatment group in 18 trials of duodenal ulcer healing. A = placebo, 0 = cimetidine, ., = other drugs including antacid.
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IPPOLITI
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