Scandinavian Journal of Gastroenterology
ISSN: 0036-5521 (Print) 1502-7708 (Online) Journal homepage: http://www.tandfonline.com/loi/igas20
Maintenance of Duodenal Ulcer Healing by Antacids J. P. Miller To cite this article: J. P. Miller (1990) Maintenance of Duodenal Ulcer Healing by Antacids, Scandinavian Journal of Gastroenterology, 25:sup174, 54-59, DOI: 10.3109/00365529009091931 To link to this article: http://dx.doi.org/10.3109/00365529009091931
Published online: 08 Jul 2009.
Submit your article to this journal
Article views: 1
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=igas20 Download by: [RMIT University Library]
Date: 20 April 2016, At: 03:01
Maintenance of Duodenal Ulcer Healing by Antacids J. P. MILLER Dept. of Medicine, University Hospital of South Manchester, Manchester, U.K.
Scandinavian Journal of Gastroenterology 1990.25:54-59.
Miller JP. Maintenance of duodenal ulcer healing by antacids. Scand J Gastroenterol 1990, 25(~uppl174), 54-59 Three studies have investigated the ability of long-term antacid treatment to prevent duodenal ulcer relapse. The first of these, more than 30 years ago. showed that antacids could reduce recurrence or persistence of symptoms when compared with placebo. There are two studies from the ‘modem era’ of fibreoptic endoscopy and H,-reception antagonists. The Milan study found antacid (one tablet four times daily), cimetidine (400 mg at night), or a combination of the two,to be approximately equally effective in the prevention of relapse. The international study found antacid (three tablets three times daily) to be as effective as cimetidine (400 mg at night) and to be better than placebo for maintenance purposes. Antacid, three tablets at night had intermediate efficacy. Key words: Aluminium hydroxide; antacids; cimetidine; duodenal ulcer; Maalox; magnesium hydroxide; maintenance; H2-receptor antagonists; relapse
J. Paul Miller, M. D., Dept. of Medicine, University Hospital of South Manchester, Manchester M20 8LR, U.K.
Antacids have had a long-standing role in the management of dyspepsia and peptic ulceration. They were generally prescribed for the relief of symptoms, although not all controlled studies have been able to show that single doses are better at this than placebo (1). Just over a decade ago it was shown that large doses of antacid could promote the healing of duodenal ulceration (2), and since then several studies have suggested that much lower doses are effective in this regard (3). The role of antacids in the short-term healing of duodenal ulceration is reviewed elsewhere in this volume by Bianchi Porro and Parente. Although healing of duodenal ulceration is readily achievable with various agents, relapse is generally rapid once the treatment is withdrawn (4). The problem of relapse can be approached by using repeated courses of ulcer-healing drugs, or, in those who relapse rapidly and predictably, long-term maintenance treatment may be adopted. This has usually involved reduced dosage of an H2-receptor antagonist given in the evening (5,6), although other agents have also been investigated (7). Surgery remains an option, but this
has been invoked less often since the advent of the H2-antagonists. In view of the efficacy of antacids in healing duodenal ulcers it became relevant to know whether they too could be used for the long-term maintenance of healing. MAINTENANCE TRIALS USING ANTACIDS The first study on this topic was published by Cayer et al. (8) from North Carolina more than 30 years ago, long before the advent of fibreoptic endoscopy and the H2-receptor antagonists. They randomized 144 patients with particularly severe duodenal ulcer disease to treatment with dihydroxyaliiminium aminoacetate or placebo. The trial lasted just over 8 months, and the results were judged on the basis of symptoms, assessed double-blind. The incidence of complications was also recorded. Of the antacid group 74% had no ulcer symptoms or an improvement, compared with only 24% in the placebo group. Haemorrhage was equally common in the two groups,
Antacidr Prevent DV Relapse
Scandinavian Journal of Gastroenterology 1990.25:54-59.
at about 5%. Perforation and pyloric stenosis occurred in 4.5% of the placebo group but were not seen in the active treatment group. Constipation, as might be expected, was commoner in those taking the aluminium antacid.
55
Patients were stratified into smokers and nonsmokers and then randomized into four treatment groups: 1) placebo; 2) Maalox therapeutic concentrate (Maalox TC, Rorer), three tablets at night; 3) MaaloxTC, three tablets twice daily (1 h after breakfast and at bedtime); and 4) cimetidine (Smith, Kline and French), 400 mg at night. Each The Milan study In 1986 Bianchi Porro et al. (9) published the Maalox TC tablet contained 600 mg aluminium results of a maintenance study in which they ran- hydroxide gel and 300 mg magnesium hydroxide, domized 75 patients with healed duodenal ulcers to give a hydrogen ion neutralizing capacity of to treatment with cimetidine (Smith, Kline and about 27 mmol. The study was double-blind, French), 400 mg at night; aluminium hydroxide- double-dummy in design. As in the Milan study, containing antacid (Maaloxm, Rorer), one tablet patients were endoscoped on recurrence of sympafter each meal and at night; or a combination of toms or routinely at 6 and 12 months if they the two medications. Each Maalox tablet con- remained asymptomatic. Seventy-five patients were excluded from effitained 400 mg of both aluminium and magnesium cacy analysis, most often for protocol violations. hydroxides and had a neutralizing capacity of about 25 mmol of hydrogen ion. The protocol was strictly enforced, and a patient Patients were followed up for 1 year and endo- was excluded if, for example, a scheduled endosscoped whenever symptoms recurred or at 6 and copy was performed even 24 h outside the pro12 months if they remained asymptomatic. Sixty- tocol limits. These 75 patients were drawn roughly nine patients completed the study. Relapse rates equally from the four treatment groups and were are shown in Table I, and all three treatment similar to the rest of the subjects with regard to regimens seemed to be similarly effective, with no base-line demographic characteristics. It is unsignificant differences emerging. The treatments likely, therefore, that the withdrawal of these patients from efficacy analysis has led to bias in were well tolerated. the interpretation of the results. They are included in the trial analysis from the point of International multi-centre study In 1986 preliminary reports appeared (10,ll) view of safety and adverse events. One hundred and seventy-six patients remained of a multi-centre study conducted in the USA (six centres), the U.K. (four centres), Canada, and who were evaluable for efficacy. The cumulative France (one centre each). The full report is in relapse data for the four treatments are shown in press (12). Fig. 1. Patients taking Maalox TC at night had Two hundred and fifty-one patients were numerically but not statistically fewer relapses recruited. Each had had an endoscopically proven than those taking placebo. Patients taking Maalox duodenal ulcer within the previous year which TC twice daily or cimetidine at night had the had been shown to be healed at endoscopy 7 least relapses, and the two groups were virtually days or less before beginning the trial medication. indistinguishable. Their experience was significantly better than that of the Maalox at night (p = 0.04) and the placebo groups (p = 0.01). Table I . Relapse rates: the Milan study The proportion of asymptomatic relapses in the Maalox + four groups varied from 21% to 44%, but this did Maalox, Cimetidine, cimetidine, not attain statistical significance (Table 11). When n = 22 n = 24 n = 23 Relapse (%) the relapse experience of smokers and non-smo6 months 41 25 26 kers was examined separately, the effect of the 54 42 43 12 months maintenance treatments was most apparent in Difference in relapse rates not significant at either 6 cigarette smokers (Table 11). Smokers in the Maaor 12 months. lox TC twice daily group had the least relapses
56
J . P. Miller PLACEBO
601
ap E
Scandinavian Journal of Gastroenterology 1990.25:54-59.
--i
I
3
I
6 TIME (MONTHS)
I
9
1
12
Fig. 1. Cumulative relapse rates in the international study. (Reproduced with the permission of Cur).
this group. Overall, patients taking Maalox T C twice daily had 10-11bowel movements per week, compared with about 8 per week in the other groups. No significant changes were detected in serum magnesium or aluminium levels in any of the groups.
(20%), followed by the cimetidine group (29%). This difference is not significant, but both groups had significantly fewer relapses than the smokers taking placebo (p < 0.01). In general, non-smokers had fewer relapses than smokers. Non-smokers receiving active treatment fared better than those taking placebo. The effect of treatment in the non-smokers, however, did not attain statistical significance (Table 11). The overall incidence of adverse events was similar in the four treatment groups. Dyspepsia was commonest in the placebo group and diarrhoea in the Maalox twice daily group. Seven of these patients withdrew because of diarrhoea, but this was not a problem for most patients in
DISCUSSION The three trials discussed here appear to establish a definite role for antacids in the prevention of duodenal ulcer relapse. In the Milan study four Maalox tablets daily (100 mmol hydrogen ion neutralizing capacity) was apparently as effective as 400 mg cimetidine at night, and no advantage was
Table 11. Asymptomatic relapse and the effects of cigarette smoking on relapse (international study)
Total relapses at 1 year (%) Proportion of relapses asymptomatic (%) Relapse at 1 year (%) Smokers (n = 100) Non-smokers ( n = 76) * p = 0.01 compared with placebo. ** p < 0.01 compared with placebo.
Placebo, n = 43
Maalox TC at night, n = 42
Maalox TC twice daily, n = 43
57 21
39 44
23* 33
25' 36
67 41
49 29
20** 29
29; * 21
Cimetidine, n = 48
Scandinavian Journal of Gastroenterology 1990.25:54-59.
Antacids Prevent
observed by combining the two regimens. The relapse rate was numerically slightly higher in the antacid group than the H2-antagonist group, but not significantly so. As the authors themselves point out, there is scope for a type-2 error in single-centre studies of limited size, and one cannot therefore assume that the antacid and cimetidine regimens are of equal efficacy. Nevertheless, the data from the international multicentre study support the idea that an antacid regimen (81 mmol hydrogen ion neutralizing capacity twice daily) can be essentially as effective as a well-established H2-receptor antagonist in maintaining duodenal ulcer healing. It might be argued that the Milan study has not established that antacid maintenance treatment is more effective than placebo, since no placebo group was studied. A control group taking cimetidine was studied, however, and it has been established repeatedly that cimetidine is more effective than placebo in preventing duodenal ulcer relapse (13). Moreover, the data from both the North Carolina and the international multicentre study show the efficacy of antacids compared with placebo in this respect. It is notable that the benefit of maintenance treatment in the international study was most apparent in smokers. Although a similar trend was seen in non-smokers, it did not reach significance. Once again, there is scope for type2 error, and it cannot safely be assumed that maintenance treatment with antacid orcimetidine is without benefit in non-smokers. There were fewer non-smokers than smokers in this study, and further studies are required to examine the question in non-smokers. Sontag et al. (14) also found that cimetidine was especially effective in preventing relapse in smokers. An important feature of the design of the international study was the stratification of the patients in accordance with smoking habit. This is a superior approach to that adopted in many studies of the effects of smoking on peptic ulcer healing and relapse, in which the data are examined retrospectively in the smokers and non-smokers without initial stratification. The antacid regimens were generally well tolerated in the studies described here, although a
DU Relapse
57
small number of patients in the international study treated with antacid twice daily withdrew because of diarrhoea. Most of the patients in this group, however, experienced only a minor non-troublesome increase in stool frequency. No significant increases in serum magnesium or aluminium levels were encountered in this study. Some technical problems and considerable variability were encountered in the aluminium measurements, however, which were all performed in a single specialist laboratory in the USA. The safety of antacids in general has recently been reviewed by Holtermiiller & Konig (15). The reduction of intragastric hydrogen ion concentration and the postprandial delivery of titrable acid into the duodenum produced by a single dose of antacid is relatively short-lived compared with that which follows a dose of cimetidine (16, 17). This may explain why the Maalox at night regimen was less effective than cimetidine at night in the International study. When antacid was administered twice daily (international study) or four times daily (Milan study), it then appeared to be as effective as the cimetidine regimen. In the international study it may be that increasing the frequency of administration was the crucial factor in improving efficacy and that the amount of antacid given at each dose could have been reduced, thus lessening the potential for diarrhoea in the small number of subjects who found this troublesome. It has been customary to assume that antacids exert their effects in upper gastrointestinal disorders by raising intragastric and duodenal pH. As already observed, however, this effect is shortlived after a single dose, and several other mechanisms of action have been investigated. Raising the pH has the potential to reduce mucosal damage caused not only by acid but also by pepsin, since the enzyme is irreversibly inactivated at elevated pH. This effect is, however, likely to be short-lived after a single dose of antacid and of uncertain significance. There is also evidence that aluminium-containing antacids can stimulate local mucosal prostaglandin production (18,19). In the last few years there has been considerable interest in the possibility that the organism Cam-
Scandinavian Journal of Gastroenterology 1990.25:54-59.
58
1. P. Miller
pylobacter pylori may be involved in the genesis 6. Silvis SE. Final report on the United States multicenter trial comparing ranitidine to cimetidine as and relapse of peptic ulcers (20,21), particularly maintenance therapy following healing of duodenal since duodenal ulcers treated with colloidal bisulcer. J Clin Gastroenterol 1985, 7, 482487 muth subcitrate, which is toxic to the organism, 7. Takemoto T, Kimura K, Okita K, et al. Efficacy of sucralfate in the prevention of recurrence of peptic relapse more slowly than those treated with an ulcer-double blind multicenter study with cimeH2-antagonist (22). There has recently been a tidine. Scand J Gastroenterol 1987, 22(suppl 140), 49-60 report (23) that antacids too can reduce the frequency of C. pylori infection, although this was 8. Cayer D, Sohmer MF, Ruffin JM. The effect of prolonged continuous therapy on the course of apparently not associated with a reduction in chronic recurring peptic ulcer. NC Med J 1957, 18, 315-317 mucosal inflammation, and it has not been established that antacid-treated duodenal ulcers 9. Bianchi Porro G, Lauaroni M, Pace F, Petrillo M. Long-term low-dose antacid versus cimetidine relapse more slowly. therapy in the treatment of duodenal ulcer recurrence. Scand J Gastroenterol 1986,21, 1144-1146 Ulcer maintenance trials, as usually conducted, may miss a significant number of asymptomatic 10. Bardhan KD. Are antacids as effective as cimetidine in preventing duodenal ulcer relapse? Gastrorelapses because of the relative infrequency with enterology 1986, 90,1336 which asymptomatic patients are endoscoped 11. Miller JP. Antacids can prevent duodenal ulcer relapse. Proceedings of the World Congresses of (24,25). These relapses are by definition silent Gastroenterology, Silo Paulo, Brazil, 1986 and therefore perhaps not clinically of great 12. Bardhan KD,Hunter JO, Miller JP, et al. Antacid maintenance therapy in the prevention of duodenal importance. There is no reason to suppose that ulcer relapse. Gut (in press) these missed relapses are more likely to occur 13. Bianchi Porro G, Petrillo M, Lazzaroni M, Sanwith antacid than with an H2-antagonist.Indeed, galetti 0. The longer-term treatment of duodenal ulceration with cimetidine. In: Bianchi Porro G , it might be argued that the less prolonged elevBardhan KD, eds. Peptic ulcer disease, advances in ation of pH obtained with antacid might be more pathogenesis and treatment. Cortina International, likely to allow symptoms to emerge in the presVerona, 1982, 107-113 ence of an ulcer. In practice, the proportion of 14. Sontag S, Graham DY.Belsito A, et al. Cimetidine, cigarette smoking and recurrence of duodenal ulcer. detected asymptomaticrelapse in the international N Engl J Med 1984,311,689-693 study was not significantly different in the dif- 15. Holtermiiller K-H, Konig U. Safety of antacids. In: Bianchi Porro G, Richardson CT, eds. Antacids ferent treatment groups. in peptic ulcer disease: state of the art. Cortina Whatever the mechanisms, antacids are effecInternational, Verona, 1988, 41-52 tive both for short-term healing and for the pre- 16. Rune SJ, Bendtsen F. Effect of antacids on gastric and duodenal bulb acidity. In: Bianchi Porro G , vention of relapse in duodenal ulcer disease and Richardson CT, eds. Antacids in peptic ulcer are a valid alternative to the other established disease: state of the art. Cortina International, agents. Verona, 1988, 17-29 17. Deering TB, Malagelada J-R. Comparison of an
REFERENCES 1. Heading RC. Antacids and duodenal ulcer. Gut 1984,25, 1195-1198
2. Peterson WL, Sturdevant RAL, Frank1 HD, et al. Healing of duodenal ulcer with an antacid regimen. N Engl J Med 1977,297, 341-345 3. Berstad A, Weberg R. Antacids in the treatment of gastroduodenal ulcer. Scand J Gastroenterol 1986, 21.385-391 4. Miller JP, Faragher EB. Relapse of duodenal ulcer:
does it matter which drug is used in initial treatment? Br Med J 1986,293, 1117-1118 5. Gough KR, Korman MG, Bardhan KD, Crowe JP, Reed PI, Smith RN. Ranitidine and cimetidine in prevention of duodenal ulcer relapse. Lancet 1984, 2,659-662
H2-receptor antagonist and a neutralising antacid on postprandial acid delivery into the duodenum in patients with duodenal ulcer. Gastroenterology 1977, 73, 11-14 18. Domschke W, Hagel J, Ruppin H, Kaduk B. Ant-
acids and gastric mucosal protection. Scand J Gastroenterol 1986, Zl(supp1 125), 144-149 19. Ruppin H. Antacids in peptic ulcer diseas-ffect on prostaglandin synthesis and gastric rnucosal barrier. In: Bianchi Porro G, Richardson CT, eds. Antacids in peptic ulcer disease: state of the art. Cortina International, Verona, 1988, 25-29 20. Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1984, 1, 1311-1314 21. Dooley CP, Cohen H. The clinical significance of Campylobacter pylori. Ann Intern Med 1988, 108, 70-79
Antacids Prevent DU Relapse
Scandinavian Journal of Gastroenterology 1990.25:54-59.
22. Miller JP, Faragher EB. The potential impact of Campylobacterpylori on the treatment of duodenal ulcer disease. Scand J Gastroenterol 1989,24(suppl 160). 39-45 23. Berstad A, Alexander B, Weberg R, Serck-Hanssen A, Holland S, Hirschowitz BI. Antacids reduce Campylobacter pylori colonization without healing the gastritis in patients with nonulcer dyspepsia and
59
erosive prepyloric changes. Gastroenterology 1988, 95, 619-624 24. Boyd EJS, Penston JG, Johnston DA, Wormsley KG. Does maintenance therapy keep duodenal ulcers healed? Lancet 1988, 1, 1324-1327 25. Elashoff JD, Koch GG, Chi GYH. Designing a clinical trial to demonstrate prevention of ulcer recurrence: modelling simulation approaches. Statist Med 1988, 7, 877-888
ISSN: 0036-5521 (Print) 1502-7708 (Online) Journal homepage: http://www.tandfonline.com/loi/igas20
Maintenance of Duodenal Ulcer Healing by Antacids J. P. Miller To cite this article: J. P. Miller (1990) Maintenance of Duodenal Ulcer Healing by Antacids, Scandinavian Journal of Gastroenterology, 25:sup174, 54-59, DOI: 10.3109/00365529009091931 To link to this article: http://dx.doi.org/10.3109/00365529009091931
Published online: 08 Jul 2009.
Submit your article to this journal
Article views: 1
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=igas20 Download by: [RMIT University Library]
Date: 20 April 2016, At: 03:01
Maintenance of Duodenal Ulcer Healing by Antacids J. P. MILLER Dept. of Medicine, University Hospital of South Manchester, Manchester, U.K.
Scandinavian Journal of Gastroenterology 1990.25:54-59.
Miller JP. Maintenance of duodenal ulcer healing by antacids. Scand J Gastroenterol 1990, 25(~uppl174), 54-59 Three studies have investigated the ability of long-term antacid treatment to prevent duodenal ulcer relapse. The first of these, more than 30 years ago. showed that antacids could reduce recurrence or persistence of symptoms when compared with placebo. There are two studies from the ‘modem era’ of fibreoptic endoscopy and H,-reception antagonists. The Milan study found antacid (one tablet four times daily), cimetidine (400 mg at night), or a combination of the two,to be approximately equally effective in the prevention of relapse. The international study found antacid (three tablets three times daily) to be as effective as cimetidine (400 mg at night) and to be better than placebo for maintenance purposes. Antacid, three tablets at night had intermediate efficacy. Key words: Aluminium hydroxide; antacids; cimetidine; duodenal ulcer; Maalox; magnesium hydroxide; maintenance; H2-receptor antagonists; relapse
J. Paul Miller, M. D., Dept. of Medicine, University Hospital of South Manchester, Manchester M20 8LR, U.K.
Antacids have had a long-standing role in the management of dyspepsia and peptic ulceration. They were generally prescribed for the relief of symptoms, although not all controlled studies have been able to show that single doses are better at this than placebo (1). Just over a decade ago it was shown that large doses of antacid could promote the healing of duodenal ulceration (2), and since then several studies have suggested that much lower doses are effective in this regard (3). The role of antacids in the short-term healing of duodenal ulceration is reviewed elsewhere in this volume by Bianchi Porro and Parente. Although healing of duodenal ulceration is readily achievable with various agents, relapse is generally rapid once the treatment is withdrawn (4). The problem of relapse can be approached by using repeated courses of ulcer-healing drugs, or, in those who relapse rapidly and predictably, long-term maintenance treatment may be adopted. This has usually involved reduced dosage of an H2-receptor antagonist given in the evening (5,6), although other agents have also been investigated (7). Surgery remains an option, but this
has been invoked less often since the advent of the H2-antagonists. In view of the efficacy of antacids in healing duodenal ulcers it became relevant to know whether they too could be used for the long-term maintenance of healing. MAINTENANCE TRIALS USING ANTACIDS The first study on this topic was published by Cayer et al. (8) from North Carolina more than 30 years ago, long before the advent of fibreoptic endoscopy and the H2-receptor antagonists. They randomized 144 patients with particularly severe duodenal ulcer disease to treatment with dihydroxyaliiminium aminoacetate or placebo. The trial lasted just over 8 months, and the results were judged on the basis of symptoms, assessed double-blind. The incidence of complications was also recorded. Of the antacid group 74% had no ulcer symptoms or an improvement, compared with only 24% in the placebo group. Haemorrhage was equally common in the two groups,
Antacidr Prevent DV Relapse
Scandinavian Journal of Gastroenterology 1990.25:54-59.
at about 5%. Perforation and pyloric stenosis occurred in 4.5% of the placebo group but were not seen in the active treatment group. Constipation, as might be expected, was commoner in those taking the aluminium antacid.
55
Patients were stratified into smokers and nonsmokers and then randomized into four treatment groups: 1) placebo; 2) Maalox therapeutic concentrate (Maalox TC, Rorer), three tablets at night; 3) MaaloxTC, three tablets twice daily (1 h after breakfast and at bedtime); and 4) cimetidine (Smith, Kline and French), 400 mg at night. Each The Milan study In 1986 Bianchi Porro et al. (9) published the Maalox TC tablet contained 600 mg aluminium results of a maintenance study in which they ran- hydroxide gel and 300 mg magnesium hydroxide, domized 75 patients with healed duodenal ulcers to give a hydrogen ion neutralizing capacity of to treatment with cimetidine (Smith, Kline and about 27 mmol. The study was double-blind, French), 400 mg at night; aluminium hydroxide- double-dummy in design. As in the Milan study, containing antacid (Maaloxm, Rorer), one tablet patients were endoscoped on recurrence of sympafter each meal and at night; or a combination of toms or routinely at 6 and 12 months if they the two medications. Each Maalox tablet con- remained asymptomatic. Seventy-five patients were excluded from effitained 400 mg of both aluminium and magnesium cacy analysis, most often for protocol violations. hydroxides and had a neutralizing capacity of about 25 mmol of hydrogen ion. The protocol was strictly enforced, and a patient Patients were followed up for 1 year and endo- was excluded if, for example, a scheduled endosscoped whenever symptoms recurred or at 6 and copy was performed even 24 h outside the pro12 months if they remained asymptomatic. Sixty- tocol limits. These 75 patients were drawn roughly nine patients completed the study. Relapse rates equally from the four treatment groups and were are shown in Table I, and all three treatment similar to the rest of the subjects with regard to regimens seemed to be similarly effective, with no base-line demographic characteristics. It is unsignificant differences emerging. The treatments likely, therefore, that the withdrawal of these patients from efficacy analysis has led to bias in were well tolerated. the interpretation of the results. They are included in the trial analysis from the point of International multi-centre study In 1986 preliminary reports appeared (10,ll) view of safety and adverse events. One hundred and seventy-six patients remained of a multi-centre study conducted in the USA (six centres), the U.K. (four centres), Canada, and who were evaluable for efficacy. The cumulative France (one centre each). The full report is in relapse data for the four treatments are shown in press (12). Fig. 1. Patients taking Maalox TC at night had Two hundred and fifty-one patients were numerically but not statistically fewer relapses recruited. Each had had an endoscopically proven than those taking placebo. Patients taking Maalox duodenal ulcer within the previous year which TC twice daily or cimetidine at night had the had been shown to be healed at endoscopy 7 least relapses, and the two groups were virtually days or less before beginning the trial medication. indistinguishable. Their experience was significantly better than that of the Maalox at night (p = 0.04) and the placebo groups (p = 0.01). Table I . Relapse rates: the Milan study The proportion of asymptomatic relapses in the Maalox + four groups varied from 21% to 44%, but this did Maalox, Cimetidine, cimetidine, not attain statistical significance (Table 11). When n = 22 n = 24 n = 23 Relapse (%) the relapse experience of smokers and non-smo6 months 41 25 26 kers was examined separately, the effect of the 54 42 43 12 months maintenance treatments was most apparent in Difference in relapse rates not significant at either 6 cigarette smokers (Table 11). Smokers in the Maaor 12 months. lox TC twice daily group had the least relapses
56
J . P. Miller PLACEBO
601
ap E
Scandinavian Journal of Gastroenterology 1990.25:54-59.
--i
I
3
I
6 TIME (MONTHS)
I
9
1
12
Fig. 1. Cumulative relapse rates in the international study. (Reproduced with the permission of Cur).
this group. Overall, patients taking Maalox T C twice daily had 10-11bowel movements per week, compared with about 8 per week in the other groups. No significant changes were detected in serum magnesium or aluminium levels in any of the groups.
(20%), followed by the cimetidine group (29%). This difference is not significant, but both groups had significantly fewer relapses than the smokers taking placebo (p < 0.01). In general, non-smokers had fewer relapses than smokers. Non-smokers receiving active treatment fared better than those taking placebo. The effect of treatment in the non-smokers, however, did not attain statistical significance (Table 11). The overall incidence of adverse events was similar in the four treatment groups. Dyspepsia was commonest in the placebo group and diarrhoea in the Maalox twice daily group. Seven of these patients withdrew because of diarrhoea, but this was not a problem for most patients in
DISCUSSION The three trials discussed here appear to establish a definite role for antacids in the prevention of duodenal ulcer relapse. In the Milan study four Maalox tablets daily (100 mmol hydrogen ion neutralizing capacity) was apparently as effective as 400 mg cimetidine at night, and no advantage was
Table 11. Asymptomatic relapse and the effects of cigarette smoking on relapse (international study)
Total relapses at 1 year (%) Proportion of relapses asymptomatic (%) Relapse at 1 year (%) Smokers (n = 100) Non-smokers ( n = 76) * p = 0.01 compared with placebo. ** p < 0.01 compared with placebo.
Placebo, n = 43
Maalox TC at night, n = 42
Maalox TC twice daily, n = 43
57 21
39 44
23* 33
25' 36
67 41
49 29
20** 29
29; * 21
Cimetidine, n = 48
Scandinavian Journal of Gastroenterology 1990.25:54-59.
Antacids Prevent
observed by combining the two regimens. The relapse rate was numerically slightly higher in the antacid group than the H2-antagonist group, but not significantly so. As the authors themselves point out, there is scope for a type-2 error in single-centre studies of limited size, and one cannot therefore assume that the antacid and cimetidine regimens are of equal efficacy. Nevertheless, the data from the international multicentre study support the idea that an antacid regimen (81 mmol hydrogen ion neutralizing capacity twice daily) can be essentially as effective as a well-established H2-receptor antagonist in maintaining duodenal ulcer healing. It might be argued that the Milan study has not established that antacid maintenance treatment is more effective than placebo, since no placebo group was studied. A control group taking cimetidine was studied, however, and it has been established repeatedly that cimetidine is more effective than placebo in preventing duodenal ulcer relapse (13). Moreover, the data from both the North Carolina and the international multicentre study show the efficacy of antacids compared with placebo in this respect. It is notable that the benefit of maintenance treatment in the international study was most apparent in smokers. Although a similar trend was seen in non-smokers, it did not reach significance. Once again, there is scope for type2 error, and it cannot safely be assumed that maintenance treatment with antacid orcimetidine is without benefit in non-smokers. There were fewer non-smokers than smokers in this study, and further studies are required to examine the question in non-smokers. Sontag et al. (14) also found that cimetidine was especially effective in preventing relapse in smokers. An important feature of the design of the international study was the stratification of the patients in accordance with smoking habit. This is a superior approach to that adopted in many studies of the effects of smoking on peptic ulcer healing and relapse, in which the data are examined retrospectively in the smokers and non-smokers without initial stratification. The antacid regimens were generally well tolerated in the studies described here, although a
DU Relapse
57
small number of patients in the international study treated with antacid twice daily withdrew because of diarrhoea. Most of the patients in this group, however, experienced only a minor non-troublesome increase in stool frequency. No significant increases in serum magnesium or aluminium levels were encountered in this study. Some technical problems and considerable variability were encountered in the aluminium measurements, however, which were all performed in a single specialist laboratory in the USA. The safety of antacids in general has recently been reviewed by Holtermiiller & Konig (15). The reduction of intragastric hydrogen ion concentration and the postprandial delivery of titrable acid into the duodenum produced by a single dose of antacid is relatively short-lived compared with that which follows a dose of cimetidine (16, 17). This may explain why the Maalox at night regimen was less effective than cimetidine at night in the International study. When antacid was administered twice daily (international study) or four times daily (Milan study), it then appeared to be as effective as the cimetidine regimen. In the international study it may be that increasing the frequency of administration was the crucial factor in improving efficacy and that the amount of antacid given at each dose could have been reduced, thus lessening the potential for diarrhoea in the small number of subjects who found this troublesome. It has been customary to assume that antacids exert their effects in upper gastrointestinal disorders by raising intragastric and duodenal pH. As already observed, however, this effect is shortlived after a single dose, and several other mechanisms of action have been investigated. Raising the pH has the potential to reduce mucosal damage caused not only by acid but also by pepsin, since the enzyme is irreversibly inactivated at elevated pH. This effect is, however, likely to be short-lived after a single dose of antacid and of uncertain significance. There is also evidence that aluminium-containing antacids can stimulate local mucosal prostaglandin production (18,19). In the last few years there has been considerable interest in the possibility that the organism Cam-
Scandinavian Journal of Gastroenterology 1990.25:54-59.
58
1. P. Miller
pylobacter pylori may be involved in the genesis 6. Silvis SE. Final report on the United States multicenter trial comparing ranitidine to cimetidine as and relapse of peptic ulcers (20,21), particularly maintenance therapy following healing of duodenal since duodenal ulcers treated with colloidal bisulcer. J Clin Gastroenterol 1985, 7, 482487 muth subcitrate, which is toxic to the organism, 7. Takemoto T, Kimura K, Okita K, et al. Efficacy of sucralfate in the prevention of recurrence of peptic relapse more slowly than those treated with an ulcer-double blind multicenter study with cimeH2-antagonist (22). There has recently been a tidine. Scand J Gastroenterol 1987, 22(suppl 140), 49-60 report (23) that antacids too can reduce the frequency of C. pylori infection, although this was 8. Cayer D, Sohmer MF, Ruffin JM. The effect of prolonged continuous therapy on the course of apparently not associated with a reduction in chronic recurring peptic ulcer. NC Med J 1957, 18, 315-317 mucosal inflammation, and it has not been established that antacid-treated duodenal ulcers 9. Bianchi Porro G, Lauaroni M, Pace F, Petrillo M. Long-term low-dose antacid versus cimetidine relapse more slowly. therapy in the treatment of duodenal ulcer recurrence. Scand J Gastroenterol 1986,21, 1144-1146 Ulcer maintenance trials, as usually conducted, may miss a significant number of asymptomatic 10. Bardhan KD. Are antacids as effective as cimetidine in preventing duodenal ulcer relapse? Gastrorelapses because of the relative infrequency with enterology 1986, 90,1336 which asymptomatic patients are endoscoped 11. Miller JP. Antacids can prevent duodenal ulcer relapse. Proceedings of the World Congresses of (24,25). These relapses are by definition silent Gastroenterology, Silo Paulo, Brazil, 1986 and therefore perhaps not clinically of great 12. Bardhan KD,Hunter JO, Miller JP, et al. Antacid maintenance therapy in the prevention of duodenal importance. There is no reason to suppose that ulcer relapse. Gut (in press) these missed relapses are more likely to occur 13. Bianchi Porro G, Petrillo M, Lazzaroni M, Sanwith antacid than with an H2-antagonist.Indeed, galetti 0. The longer-term treatment of duodenal ulceration with cimetidine. In: Bianchi Porro G , it might be argued that the less prolonged elevBardhan KD, eds. Peptic ulcer disease, advances in ation of pH obtained with antacid might be more pathogenesis and treatment. Cortina International, likely to allow symptoms to emerge in the presVerona, 1982, 107-113 ence of an ulcer. In practice, the proportion of 14. Sontag S, Graham DY.Belsito A, et al. Cimetidine, cigarette smoking and recurrence of duodenal ulcer. detected asymptomaticrelapse in the international N Engl J Med 1984,311,689-693 study was not significantly different in the dif- 15. Holtermiiller K-H, Konig U. Safety of antacids. In: Bianchi Porro G, Richardson CT, eds. Antacids ferent treatment groups. in peptic ulcer disease: state of the art. Cortina Whatever the mechanisms, antacids are effecInternational, Verona, 1988, 41-52 tive both for short-term healing and for the pre- 16. Rune SJ, Bendtsen F. Effect of antacids on gastric and duodenal bulb acidity. In: Bianchi Porro G , vention of relapse in duodenal ulcer disease and Richardson CT, eds. Antacids in peptic ulcer are a valid alternative to the other established disease: state of the art. Cortina International, agents. Verona, 1988, 17-29 17. Deering TB, Malagelada J-R. Comparison of an
REFERENCES 1. Heading RC. Antacids and duodenal ulcer. Gut 1984,25, 1195-1198
2. Peterson WL, Sturdevant RAL, Frank1 HD, et al. Healing of duodenal ulcer with an antacid regimen. N Engl J Med 1977,297, 341-345 3. Berstad A, Weberg R. Antacids in the treatment of gastroduodenal ulcer. Scand J Gastroenterol 1986, 21.385-391 4. Miller JP, Faragher EB. Relapse of duodenal ulcer:
does it matter which drug is used in initial treatment? Br Med J 1986,293, 1117-1118 5. Gough KR, Korman MG, Bardhan KD, Crowe JP, Reed PI, Smith RN. Ranitidine and cimetidine in prevention of duodenal ulcer relapse. Lancet 1984, 2,659-662
H2-receptor antagonist and a neutralising antacid on postprandial acid delivery into the duodenum in patients with duodenal ulcer. Gastroenterology 1977, 73, 11-14 18. Domschke W, Hagel J, Ruppin H, Kaduk B. Ant-
acids and gastric mucosal protection. Scand J Gastroenterol 1986, Zl(supp1 125), 144-149 19. Ruppin H. Antacids in peptic ulcer diseas-ffect on prostaglandin synthesis and gastric rnucosal barrier. In: Bianchi Porro G, Richardson CT, eds. Antacids in peptic ulcer disease: state of the art. Cortina International, Verona, 1988, 25-29 20. Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1984, 1, 1311-1314 21. Dooley CP, Cohen H. The clinical significance of Campylobacter pylori. Ann Intern Med 1988, 108, 70-79
Antacids Prevent DU Relapse
Scandinavian Journal of Gastroenterology 1990.25:54-59.
22. Miller JP, Faragher EB. The potential impact of Campylobacterpylori on the treatment of duodenal ulcer disease. Scand J Gastroenterol 1989,24(suppl 160). 39-45 23. Berstad A, Alexander B, Weberg R, Serck-Hanssen A, Holland S, Hirschowitz BI. Antacids reduce Campylobacter pylori colonization without healing the gastritis in patients with nonulcer dyspepsia and
59
erosive prepyloric changes. Gastroenterology 1988, 95, 619-624 24. Boyd EJS, Penston JG, Johnston DA, Wormsley KG. Does maintenance therapy keep duodenal ulcers healed? Lancet 1988, 1, 1324-1327 25. Elashoff JD, Koch GG, Chi GYH. Designing a clinical trial to demonstrate prevention of ulcer recurrence: modelling simulation approaches. Statist Med 1988, 7, 877-888
