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Sucralfate maintenance therapy in duodenal ulcer disease
Sucralfate Maintenance Therapy in Duodenal Ulcer Disease A Review TERRY
D. BOLIN, M.D. (N.S.W.),B.S.(SYD.), F.R.C.P.(LoND.), F.R.C.P.(EDIN.),
F.R.A.C.P.
D.C.H.(LoND.)
Sydney, Austraiia
There are a large number of patients with chronic duodenal ulcer disease who.warrant long-term maintenance therapy to diminish the risk of recurrence and thereby the risk.of further complications such as gastrointestinal bleeding. The efficacy of sucralfate has been compared with both placebo and histamine (H.&receptor antagonists and sucralfate in a dose of 1 g twice a day or 2 g taken at night. It is a safe and effective medication in preventing duodenal ulcer recurrence. However, duodenal ulcer relapse rates always exceed 20 percent and frequently approach 50 percent, whether the therapy be HZreceptor antagonists or sucralfate, and the use of dosages that are half the healing dose seems irrational. It would therefore seem reasonable to continue maintenance therapy at the healing dose, whatever medication is used. Any increased costs for drugs should be outweighed by savings in indirect costs.
From the Gastrointestinal Unit, The Prince of Wales Hospital, Randwick 2031, Sydney, Australia. Requests for reprints should be addressed to Associate Professor Terry D. Bolin, Gastrointestinal Unit, The Prince of Wales Hospital, Randwlck 2031, Sydney, Australia.
148
June 9, 1989
The American Journal of Medicine
Volume 86 (suppl 6A)
lthough there may be some controversy over the A indications for maintenance therapy in chronic duodenal ulcer disease, there is little doubt that there are a substantial number of patients who require continuous therapy in an attempt to prevent recurrence. The major body of information on maintenance therapy relates to histamine (H&receptor antagonists [l91 and the observation that neither cimetidine nor ranitidine achieves perfect control in maintenance therapy in their recommended doses has led to the search for more optimal therapy. The development of sucralfate. as a non-systemic therapy in treating duodenal ulceration has generated new information on its role in the prevention of duodenal ulcer recurrence [lo]. It has the additional potential advantage of not interfering with the hepatic metabolism of some drugs being used concurrently and might therefore be better suited for maintenance therapy. This review addresses the role of sucralfate versus placebo and its evaluation against HZ-receptor antagonists. SUCRALFATE VERSUS PLACEBO Figure 1 compares the data of five studies investigating sucralfate versus placebo. The earliest maintenance study by Classen et al [ll] compared sucralfate with placebo over a six-month period in a dose of 2 g per day. The relapse rate at six months was 21.2 percent with sucralfate as compared with 50 percent with placebo. Moshal et al [12] in a 1Zmonth study utilizing a four times per day dosage of 2.5 g achieved a remission rate with sucralfate of 64 percent versus 27 percent with placebo at six months and 54 percent versus 18 percent at 12 months. The study by Bolin et a2 [lo] using 1 g of sucralfate twice per day versus placebo over 12 months achieved a remission rate with sucralfate of 58 percent versus 19 percent with placebo, these findings being comparable with those of Moshal and co-workers [12] from South Africa. It seemed likely, therefore, that the optimal remission rate with 2 g of sucralfate per day was in the order of 60 percent. However, Marks and Girdwood 1131 obtained a remission rate at 12 months of 68 percent versus 19 percent for placebo in another South African study, and Behar et al [14] in a multicenter study in the United States reported a remission rate of 73 percent for sucralfate as opposed to 20 percent for placebo at 12 months. This latter result, however, raises the question of what should be regarded as recurrence. Behar and, his colleagues [14] did not classify erosions and superficial ulceration as recurrence and that definition no doubt accounts for the excellent remission rate.
SYMPOSIUM
ON SUCRALFATE I BOLIN
Placebo
Figure 1. Remission rates at 12 months: sucralfate versus placebo.
12 MOSHAL
13 MARKS
14 BEHAR
10 BOLIN
20 MARKS
!+l Cm SC
S&r
Figure 2. Remission rates at 12 months: ranitidine versus cimetidine versus sucralfate.
MASOERO
This definition of recurrence, however, is at variance with almost all other maintenance studies and until a valid end-point is agreed it does provide some difficulty in making comparisons. The total absence of erosive disease and superficial ulceration should be the criteria upon which the success of healing is judged lm. The frequency of asymptomatic ulcer recurrence [lo] re-emphasizes the need for routine endoscopic surveillance in any maintenance evaluation program. This important point has recently been addressed by Bynum et al [16], who examined the issue of point prevalence versus traditional ulcer prevalence. The former identifies ulcers found only at scheduled visits, and in this study monthly endoscopies were carried out over a four-month period. It therefore excludes interim ulcer diagnoses identified by symptoms, these being included in the traditional ulcer prevalence information. Traditional ulcer prevalence was margin-
i7
MARKS
*’
RODRIGO
i8 TAKEMOTO
ally more effective in identifying ulcer recurrence with there being a 42 percent recurrence rate at Month 4 versus 36 percent with point prevalence alone in the sucralfate-treated group and 63 versus 55 percent, respectively, in the placebo group. At least with this duration of study and monthly endoscopies there is no advantage for point prevalence studies alone, and it would be impractical to continue monthly endoscopies in a large number of subjects over a protracted period of time. It therefore seems reasonable to continue! as most studies do, with four to six monthly endoscoples and recognize the fact that some ulcers may have recurred and healed within that time span. SUCRALFATE VERSUS Hz-RECEPTOR ANTAGONISTS The data of four studies concerning sucralfate versus Hz-receptor antagonists are compared in Figure 2. The published studies of cimetidine and ranitidine June 9, 1989
The American Journal of Medicine
Volume 86 (suppl 6A)
149
SYMPOSIUM
ON SUCRALFATE/
BOLIN
as maintenance therapy give remission rates of 57 to 7’7 percent at 12 months for cimetidine and 77 to 87.5 percent for ranitidine [lo]. The question of whether sucralfate was as effective as either of those drugs in preventing ulcer recurrence therefore needed comparative studies. Masoero et al [17] compared ranitidine 150 mg taken at night with sucralfate 1 g twice per day in 59 patients endoscopically evaluated at four, eight, and 12 months. Remission rates were comparable in both groups, being 90, 85, and 53 percent with ranitidine and 62, 62, and 53 percent with sucralfate, respectively. Ulcer relapse was independent of sex, smoking habits, and alcohol and coffee consumption of patients, whereas a history longer than five years was significantly related to a higher probability of recurrence. Rodrigo et al [181 compared sucralfate 2 g per day with cimetidine 400 mg taken at night over a sixmonth period in 71 patients and again there was no significant difference in relapse rates at the end of six months. Takemoto et al [19] compared sucralfate 1 g twice per day with a combination of sucralfate 2 g per day plus cimetidine 400 mg taken at night and a further group receiving cimetidine 400 mg at night. At 12 months, there was no significant difference between the three groups with remission rates being 41.91, 47.7, and 40.5 percent, respectively. More recently, Marks and his colleagues [20] have compared sucralfate 2 g taken at night with cimetidine 400 mg at night and placebo and found similar remission rates at 12 months in the sucralfate group (42 percent) and cimetidine group (41 percent). It! therefore, is apparent that there is no significant difference in duodenal ulcer remission whether patients are treated with sucralfate or a He-receptor antagonist. POTENTIAL PROBLEMS WITH MAINTENANCE THERAPY Adverse reactions and withdrawals from the studies because of non-compliance have been similar with all medications, and the incidence of side effects remains exceptionally low whatever the therapy. The fact that sucralfate is a basic aluminum salt of sulphated sucrose raises the possibility that long-term therapy might produce alterations in serum aluminum or inorganic phosphate levels [21]. Bolin and colleagues [lo] found that such was not the case. The failure to demonstrate a reduction in serum inorganic phosphate levels suggested that phosphate binding in the gastrointestional tract during long-term maintenance therapy did not present a problem in patients with normal renal function. Neither was there any significant elevation of serum aluminum levels or alteration of other hematologic or biochemical values. Similar safety data have been presented by Marks et al [20] and more recently by Tovey and colleagues [221. Whether or not tissue levels of aluminum remain normal with long-term therapy remains to be evaluated. WHY IS THE MAINTENANCE DOSE HALF THE HEALING DOSE? A traditional conclusion from the maintenance data would be that sucralfate in a dose of 1 g twice per day or 2 g taken at night is a safe and effective medication in preventing duodenal ulcer recurrence. The incontrovertible fact, however, that duodenal ulcer relapse 150
June 9, 1989
The American Journal of Medicine
Volume 86 (suppl 6A)
rates are always in excess of 20 percent and frequently approach 50 percent, whether the therapy be Ha-receptor antagonist or sucralfate, indicates that maintenance therapy is less than ideal. A maintenance dose of half the healing dose was initially chosen for the Ha-receptor antagonists because of the concept that acid reduction would permit the proliferation of bacteria in the stomach with the possibility that some of these bacterial species would be capable of reducing dietary and salivary nitrate to nitrite, and the latter might subsequently react with nitrogen-containing groups such as amines to produce nitrogen-nitroso derivatives, which were potentially carcinogenic. Wormsley [231 has persuasively argued that this hypothesis has no basis in fact. It would therefore seem reasonable to continue maintenance therapy at the healing dose, whatever medication is used, thereby achieving potential remission rates of 90 to 100 percent. The increased costs for drugs should therefore be outweighed by the theoretical savings in indirect costs, which are measured by loss of economic productivity in absenteeism, disability, and mortality, together with an improvement in economic productivity consequent on a diminution in pain and suffering [24]. Bodemar et al [25] demonstrated a dramatic reduction in absenteeism at work during a one-year maintenance study with cimetidine and those authors have also estimated that indirect costs always exceed direct costs and have shown that indirect costs range from 54 percent in the United States to 79 percent in the Netherlands. Newly granted disability pensions for peptic ulcer disease in Sweden are currently reported to be about 25 percent of what they were 10 years ago [26], and Alexander Williams [26], in comparing the direct cost estimates of surgery versus Hz-receptor maintenance, estimated that patients could be treated for approximately 20 years with maintenance therapy before the total cost equalled that of surgery. There is no reason to believe that the cost advantages would be any less with sucralfate. Perhaps the time has come, therefore, to modify our philosophy regarding maintenance therapy. If the studies of Tovey and colleagues [22] can be validated to confirm that sucralfate produces a better quality of ulcer healing and if this is matched with longer remission, then E-month maintenance therapy periods might be appropriate, particularly in non-smokers in contrast to the likely requirement for continuous maintenance therapy in smokers and those patients with other risk factors allied to early recurrence. REFERENCES 1. Hunt RH, Walt RP, Trotman IF, et al: Comparison of ranitidine, 150 mg nocte, with cimetidine, 400 mg nocte, in the maintenance treatment of duodenal ulcer. In: Misiewicz JJ, Wormsley KG, eds. The clinical use of ranitidrne. Oxford: Medicine Publishing, 1982; 192-195. 2. Van Dommelen CKV, Stadler FH, Bockhorst JC Comparrson of ranitidlne and cimetidine in the treatment of duodenal ulcer. In: Westdorp ICE, ed. The clinical use of ranrtidine. Amsterdam: Excerpta Medica, 1982; 10-12. 3. Bresci G, Capria A, Rindi G, Gelonr M, Fedena G, Corsrni G: Ranitidrne, cimehdine and antacids in the prevention of recurrence after healed duodenal ulcer: one year experience. Int J Tissue React 1983; 5: 545-548. 4. Guslandi M, Masci E, Testoni PA, Basdarin E: Comparison of cimetidrne and ranrtidine in long-term treatment of duodenal ulcer. Clin Trials J 1982: 20: 67-70. 5. Gough KR: Interim analysis of a comparative trral of ranihdine and cimetidine rn the prevention of duodenal ulcer. Am J Med 1984; 77 (suppl 58): 39-42. 6. Gough KR, Bardhan KD, Crowe JP, et al: Ranihdine and cimetidine in prevention of
SYMPOSIUM duodenal ulcer relapse. A double-blrnd randomrsed, multicentre, comparahve trial. Lancet 1984: II: 659-662. 7. Walt RP, Hunt RH, Misiewicz JJ. et ai: Comparison of ranitidine and cimetidme maintenance treatment of duodenal ulcer. Stand J Gastroenterol 1984; 19: 1045-1047. 8. Silvis SE: Final report on the United States multicenter trial comparing ranitidrne to cimetidine as maintenance therapy following healing of duodenal ulcer. J Clan Gastroenterol 1985; 7: 482-487. 9. Bolin TD, Davis AE, Billington B: Prevention of duodenal ulcer occurrence. Double-blrnd comparrson of ramtidine and cimetidine. J Clin Gastoenterol 9 (3): 1987; 310-313. 10. Bolin TD, Davis AE, Duncombe VM, Billington B: Role of maintenance sucralfate in preventron of duodenal ulcer recurrence. Am J Med 1987; 83 (suppl 3B): 91-94. 11. Classen M, Bethge H, Brunner G, etal: Effect of sucralfate on peptic ulcer recurrence: a controlled double-blind multicenter study. Stand J Gastroenterol 1982; 18 (suppl 83): 61-68. 12. Moshal MG, Spitaels JM, Kahn F: Sucralfate in the treatment of duodenal ulcers. A double-blind endoscopically controlled trial. S Air Med J 1980; 57: 742-744. 13. Marks IN, Girdwood AH: Recurrence of duodenal ulceration in patients on maintenance sucralfate-a 12 month follow-uo studv. S Afr Med J 1985: 67: 626-628. 14. Behar J, Roufaii W, Thomas E, Keller’F, Dernbach W, Tesler M: Efficacy of sucralfate in the prevention of recurrence of duodenal ulcers. J Ciin Gastroenterol 9 (suppl 1): 1987; 23-30. 15. Martin F: Sucralfate suspension 1 g four times per day rn the shod-term treatment of active duodenal ulcer. Am J Med 1989; 86 (suppl 6A): 1044107. 16. Bynum TE, Multicenter Study Group: Sucralfate 1 gm twrce a day prevents duodenal ulcer recurrence (abstr). Gastroenterology, 1988; 94 (5): A% 17. Masoero G, Rocchia F, Rossanino A, Marchetto M, Benitb V, De la Pierre M: Compari-
ON SUCRALFATE / BOLIN
son of ranitidine and sucralfate in the long-term treatment of duodenal ulcer. J ClanGastroenterol 1986; 8 (6): 624-627. 18. Rodrigo M, Berenguer J, Hinojosa J, Balanzo JM, Segu JL: Sucralfate and cimetidrne as maintenance treatment in the preventron of duodenal ulcer recurrence. Am J Med 1987; 83 (suppl 3B): 99-104. 19. Takemoto T, Kimura K, Okita K, et al: Efficacy of sucralfate in the prevention of recurrence of peptic ulcer-double blind multicenter study with cimetrdine. Stand J Gastroenterol 1987; 22 (suppl 140): 49-60 20. Marks IN, Girdwood AH, Newton KA, O’Keefe SJ, Marotta F, Lucke W: Maintenance sucralfate 2 g at night reduces the relapse rate in duodenal ulcer disease: a one-year follow-up study. Am J Med 1989; 86 (suppl 6A): 145-147. 21. Leung ACT, Henderson IS, Halls DJ, Dobbie JW Aluminium hydroxide versus sucralfate as a phosphate binder in uremia. Br Med J 1983; 286: 1379-1381. 22. Tovev FL Husband EM, Yui YC. ef ai: Three-vear duodenal ulcer relaose rates followrng one-year maintenance treatment with sucralfate or crmetidine with histological and ultra structural evaluation. Am J Med 1989; 86 (suppl 6A): 141-144 23. Wormsley KG: Is chronic long-term inhibition of gastric secretion really dangerous? Stand J Gastroenterol 1988; 23 (suppl 146): 166-174. 24. Jensen DM: Economic assessment of oeotic ulcer disease treatments. Stand J Gastroenterol 1988; 23 (suppl 146): 214-224.’ 25. Bodemar G, Gottard R, Strom M, Walan A, Jonsson B, Bjurulf B: Further experience with HP receptor antagonists in peptrc ulcer drsease and progress in hrstamine research. In: Trosoli A, Luchelii PR, Bnmblecomb RW, eds. Progress in histamine research. Excerpta Medica, Amsterdam, 1980; 59-69. 26. Walan A: Case 2: the chronically recurring ulcer. Stand J Gastroenterol 1987; 22 (suppl 132): 14-20.
June 9, 1989
The American Journal of Medicine
Volume 86 (suppl 6A)
151
D. BOLIN, M.D. (N.S.W.),B.S.(SYD.), F.R.C.P.(LoND.), F.R.C.P.(EDIN.),
F.R.A.C.P.
D.C.H.(LoND.)
Sydney, Austraiia
There are a large number of patients with chronic duodenal ulcer disease who.warrant long-term maintenance therapy to diminish the risk of recurrence and thereby the risk.of further complications such as gastrointestinal bleeding. The efficacy of sucralfate has been compared with both placebo and histamine (H.&receptor antagonists and sucralfate in a dose of 1 g twice a day or 2 g taken at night. It is a safe and effective medication in preventing duodenal ulcer recurrence. However, duodenal ulcer relapse rates always exceed 20 percent and frequently approach 50 percent, whether the therapy be HZreceptor antagonists or sucralfate, and the use of dosages that are half the healing dose seems irrational. It would therefore seem reasonable to continue maintenance therapy at the healing dose, whatever medication is used. Any increased costs for drugs should be outweighed by savings in indirect costs.
From the Gastrointestinal Unit, The Prince of Wales Hospital, Randwick 2031, Sydney, Australia. Requests for reprints should be addressed to Associate Professor Terry D. Bolin, Gastrointestinal Unit, The Prince of Wales Hospital, Randwlck 2031, Sydney, Australia.
148
June 9, 1989
The American Journal of Medicine
Volume 86 (suppl 6A)
lthough there may be some controversy over the A indications for maintenance therapy in chronic duodenal ulcer disease, there is little doubt that there are a substantial number of patients who require continuous therapy in an attempt to prevent recurrence. The major body of information on maintenance therapy relates to histamine (H&receptor antagonists [l91 and the observation that neither cimetidine nor ranitidine achieves perfect control in maintenance therapy in their recommended doses has led to the search for more optimal therapy. The development of sucralfate. as a non-systemic therapy in treating duodenal ulceration has generated new information on its role in the prevention of duodenal ulcer recurrence [lo]. It has the additional potential advantage of not interfering with the hepatic metabolism of some drugs being used concurrently and might therefore be better suited for maintenance therapy. This review addresses the role of sucralfate versus placebo and its evaluation against HZ-receptor antagonists. SUCRALFATE VERSUS PLACEBO Figure 1 compares the data of five studies investigating sucralfate versus placebo. The earliest maintenance study by Classen et al [ll] compared sucralfate with placebo over a six-month period in a dose of 2 g per day. The relapse rate at six months was 21.2 percent with sucralfate as compared with 50 percent with placebo. Moshal et al [12] in a 1Zmonth study utilizing a four times per day dosage of 2.5 g achieved a remission rate with sucralfate of 64 percent versus 27 percent with placebo at six months and 54 percent versus 18 percent at 12 months. The study by Bolin et a2 [lo] using 1 g of sucralfate twice per day versus placebo over 12 months achieved a remission rate with sucralfate of 58 percent versus 19 percent with placebo, these findings being comparable with those of Moshal and co-workers [12] from South Africa. It seemed likely, therefore, that the optimal remission rate with 2 g of sucralfate per day was in the order of 60 percent. However, Marks and Girdwood 1131 obtained a remission rate at 12 months of 68 percent versus 19 percent for placebo in another South African study, and Behar et al [14] in a multicenter study in the United States reported a remission rate of 73 percent for sucralfate as opposed to 20 percent for placebo at 12 months. This latter result, however, raises the question of what should be regarded as recurrence. Behar and, his colleagues [14] did not classify erosions and superficial ulceration as recurrence and that definition no doubt accounts for the excellent remission rate.
SYMPOSIUM
ON SUCRALFATE I BOLIN
Placebo
Figure 1. Remission rates at 12 months: sucralfate versus placebo.
12 MOSHAL
13 MARKS
14 BEHAR
10 BOLIN
20 MARKS
!+l Cm SC
S&r
Figure 2. Remission rates at 12 months: ranitidine versus cimetidine versus sucralfate.
MASOERO
This definition of recurrence, however, is at variance with almost all other maintenance studies and until a valid end-point is agreed it does provide some difficulty in making comparisons. The total absence of erosive disease and superficial ulceration should be the criteria upon which the success of healing is judged lm. The frequency of asymptomatic ulcer recurrence [lo] re-emphasizes the need for routine endoscopic surveillance in any maintenance evaluation program. This important point has recently been addressed by Bynum et al [16], who examined the issue of point prevalence versus traditional ulcer prevalence. The former identifies ulcers found only at scheduled visits, and in this study monthly endoscopies were carried out over a four-month period. It therefore excludes interim ulcer diagnoses identified by symptoms, these being included in the traditional ulcer prevalence information. Traditional ulcer prevalence was margin-
i7
MARKS
*’
RODRIGO
i8 TAKEMOTO
ally more effective in identifying ulcer recurrence with there being a 42 percent recurrence rate at Month 4 versus 36 percent with point prevalence alone in the sucralfate-treated group and 63 versus 55 percent, respectively, in the placebo group. At least with this duration of study and monthly endoscopies there is no advantage for point prevalence studies alone, and it would be impractical to continue monthly endoscopies in a large number of subjects over a protracted period of time. It therefore seems reasonable to continue! as most studies do, with four to six monthly endoscoples and recognize the fact that some ulcers may have recurred and healed within that time span. SUCRALFATE VERSUS Hz-RECEPTOR ANTAGONISTS The data of four studies concerning sucralfate versus Hz-receptor antagonists are compared in Figure 2. The published studies of cimetidine and ranitidine June 9, 1989
The American Journal of Medicine
Volume 86 (suppl 6A)
149
SYMPOSIUM
ON SUCRALFATE/
BOLIN
as maintenance therapy give remission rates of 57 to 7’7 percent at 12 months for cimetidine and 77 to 87.5 percent for ranitidine [lo]. The question of whether sucralfate was as effective as either of those drugs in preventing ulcer recurrence therefore needed comparative studies. Masoero et al [17] compared ranitidine 150 mg taken at night with sucralfate 1 g twice per day in 59 patients endoscopically evaluated at four, eight, and 12 months. Remission rates were comparable in both groups, being 90, 85, and 53 percent with ranitidine and 62, 62, and 53 percent with sucralfate, respectively. Ulcer relapse was independent of sex, smoking habits, and alcohol and coffee consumption of patients, whereas a history longer than five years was significantly related to a higher probability of recurrence. Rodrigo et al [181 compared sucralfate 2 g per day with cimetidine 400 mg taken at night over a sixmonth period in 71 patients and again there was no significant difference in relapse rates at the end of six months. Takemoto et al [19] compared sucralfate 1 g twice per day with a combination of sucralfate 2 g per day plus cimetidine 400 mg taken at night and a further group receiving cimetidine 400 mg at night. At 12 months, there was no significant difference between the three groups with remission rates being 41.91, 47.7, and 40.5 percent, respectively. More recently, Marks and his colleagues [20] have compared sucralfate 2 g taken at night with cimetidine 400 mg at night and placebo and found similar remission rates at 12 months in the sucralfate group (42 percent) and cimetidine group (41 percent). It! therefore, is apparent that there is no significant difference in duodenal ulcer remission whether patients are treated with sucralfate or a He-receptor antagonist. POTENTIAL PROBLEMS WITH MAINTENANCE THERAPY Adverse reactions and withdrawals from the studies because of non-compliance have been similar with all medications, and the incidence of side effects remains exceptionally low whatever the therapy. The fact that sucralfate is a basic aluminum salt of sulphated sucrose raises the possibility that long-term therapy might produce alterations in serum aluminum or inorganic phosphate levels [21]. Bolin and colleagues [lo] found that such was not the case. The failure to demonstrate a reduction in serum inorganic phosphate levels suggested that phosphate binding in the gastrointestional tract during long-term maintenance therapy did not present a problem in patients with normal renal function. Neither was there any significant elevation of serum aluminum levels or alteration of other hematologic or biochemical values. Similar safety data have been presented by Marks et al [20] and more recently by Tovey and colleagues [221. Whether or not tissue levels of aluminum remain normal with long-term therapy remains to be evaluated. WHY IS THE MAINTENANCE DOSE HALF THE HEALING DOSE? A traditional conclusion from the maintenance data would be that sucralfate in a dose of 1 g twice per day or 2 g taken at night is a safe and effective medication in preventing duodenal ulcer recurrence. The incontrovertible fact, however, that duodenal ulcer relapse 150
June 9, 1989
The American Journal of Medicine
Volume 86 (suppl 6A)
rates are always in excess of 20 percent and frequently approach 50 percent, whether the therapy be Ha-receptor antagonist or sucralfate, indicates that maintenance therapy is less than ideal. A maintenance dose of half the healing dose was initially chosen for the Ha-receptor antagonists because of the concept that acid reduction would permit the proliferation of bacteria in the stomach with the possibility that some of these bacterial species would be capable of reducing dietary and salivary nitrate to nitrite, and the latter might subsequently react with nitrogen-containing groups such as amines to produce nitrogen-nitroso derivatives, which were potentially carcinogenic. Wormsley [231 has persuasively argued that this hypothesis has no basis in fact. It would therefore seem reasonable to continue maintenance therapy at the healing dose, whatever medication is used, thereby achieving potential remission rates of 90 to 100 percent. The increased costs for drugs should therefore be outweighed by the theoretical savings in indirect costs, which are measured by loss of economic productivity in absenteeism, disability, and mortality, together with an improvement in economic productivity consequent on a diminution in pain and suffering [24]. Bodemar et al [25] demonstrated a dramatic reduction in absenteeism at work during a one-year maintenance study with cimetidine and those authors have also estimated that indirect costs always exceed direct costs and have shown that indirect costs range from 54 percent in the United States to 79 percent in the Netherlands. Newly granted disability pensions for peptic ulcer disease in Sweden are currently reported to be about 25 percent of what they were 10 years ago [26], and Alexander Williams [26], in comparing the direct cost estimates of surgery versus Hz-receptor maintenance, estimated that patients could be treated for approximately 20 years with maintenance therapy before the total cost equalled that of surgery. There is no reason to believe that the cost advantages would be any less with sucralfate. Perhaps the time has come, therefore, to modify our philosophy regarding maintenance therapy. If the studies of Tovey and colleagues [22] can be validated to confirm that sucralfate produces a better quality of ulcer healing and if this is matched with longer remission, then E-month maintenance therapy periods might be appropriate, particularly in non-smokers in contrast to the likely requirement for continuous maintenance therapy in smokers and those patients with other risk factors allied to early recurrence. REFERENCES 1. Hunt RH, Walt RP, Trotman IF, et al: Comparison of ranitidine, 150 mg nocte, with cimetidine, 400 mg nocte, in the maintenance treatment of duodenal ulcer. In: Misiewicz JJ, Wormsley KG, eds. The clinical use of ranitidrne. Oxford: Medicine Publishing, 1982; 192-195. 2. Van Dommelen CKV, Stadler FH, Bockhorst JC Comparrson of ranitidlne and cimetidine in the treatment of duodenal ulcer. In: Westdorp ICE, ed. The clinical use of ranrtidine. Amsterdam: Excerpta Medica, 1982; 10-12. 3. Bresci G, Capria A, Rindi G, Gelonr M, Fedena G, Corsrni G: Ranitidrne, cimehdine and antacids in the prevention of recurrence after healed duodenal ulcer: one year experience. Int J Tissue React 1983; 5: 545-548. 4. Guslandi M, Masci E, Testoni PA, Basdarin E: Comparison of cimetidrne and ranrtidine in long-term treatment of duodenal ulcer. Clin Trials J 1982: 20: 67-70. 5. Gough KR: Interim analysis of a comparative trral of ranihdine and cimetidine rn the prevention of duodenal ulcer. Am J Med 1984; 77 (suppl 58): 39-42. 6. Gough KR, Bardhan KD, Crowe JP, et al: Ranihdine and cimetidine in prevention of
SYMPOSIUM duodenal ulcer relapse. A double-blrnd randomrsed, multicentre, comparahve trial. Lancet 1984: II: 659-662. 7. Walt RP, Hunt RH, Misiewicz JJ. et ai: Comparison of ranitidine and cimetidme maintenance treatment of duodenal ulcer. Stand J Gastroenterol 1984; 19: 1045-1047. 8. Silvis SE: Final report on the United States multicenter trial comparing ranitidrne to cimetidine as maintenance therapy following healing of duodenal ulcer. J Clan Gastroenterol 1985; 7: 482-487. 9. Bolin TD, Davis AE, Billington B: Prevention of duodenal ulcer occurrence. Double-blrnd comparrson of ramtidine and cimetidine. J Clin Gastoenterol 9 (3): 1987; 310-313. 10. Bolin TD, Davis AE, Duncombe VM, Billington B: Role of maintenance sucralfate in preventron of duodenal ulcer recurrence. Am J Med 1987; 83 (suppl 3B): 91-94. 11. Classen M, Bethge H, Brunner G, etal: Effect of sucralfate on peptic ulcer recurrence: a controlled double-blind multicenter study. Stand J Gastroenterol 1982; 18 (suppl 83): 61-68. 12. Moshal MG, Spitaels JM, Kahn F: Sucralfate in the treatment of duodenal ulcers. A double-blind endoscopically controlled trial. S Air Med J 1980; 57: 742-744. 13. Marks IN, Girdwood AH: Recurrence of duodenal ulceration in patients on maintenance sucralfate-a 12 month follow-uo studv. S Afr Med J 1985: 67: 626-628. 14. Behar J, Roufaii W, Thomas E, Keller’F, Dernbach W, Tesler M: Efficacy of sucralfate in the prevention of recurrence of duodenal ulcers. J Ciin Gastroenterol 9 (suppl 1): 1987; 23-30. 15. Martin F: Sucralfate suspension 1 g four times per day rn the shod-term treatment of active duodenal ulcer. Am J Med 1989; 86 (suppl 6A): 1044107. 16. Bynum TE, Multicenter Study Group: Sucralfate 1 gm twrce a day prevents duodenal ulcer recurrence (abstr). Gastroenterology, 1988; 94 (5): A% 17. Masoero G, Rocchia F, Rossanino A, Marchetto M, Benitb V, De la Pierre M: Compari-
ON SUCRALFATE / BOLIN
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June 9, 1989
The American Journal of Medicine
Volume 86 (suppl 6A)
151