Triple Therapy with Sucralfate Is as Effective as Triple Therapy Containing Bismuth in Eradicating Helicobacter pylori and Reducing Duodenal Ulcer Relapse Rates

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J. A. LOUW, J. ZAK, W. LUCKE, E. LE ROUX, K. JASKIEWICZ, T. WINTER, A. LASTOVICA & I. N. MARKS Gastrointestinal Unit and Dept. of Medicine, Tygerberg Hospital and University of Stellenbosch, Parow; Gastrointestinal Clinic, Dept. of Medicine, and Dept. of Anatomical Pathology, Groote Schuur Hospital and University of Cape Town, Observatory; and Dept. of Microbiology, Red Cross Children’s Hospital, Rondebosch; South Africa Louw JA, Zak J, Lucke W, le Roux E, Jaskiewicz K, Winter T, Lastovica A, Marks IN. Triple therapy with sucralfate is as effective as triple therapy containing bismuth in eradicating Helicobacter pylori and reducing duodenal ulcer relapse rates. Scand J Gastroenterol 1992;27 Suppl 191:28-31. Duodenal ulcer relapse rates after therapy with sucralfate or bismuth are lower than those after H2receptor antagonist therapy. This may be mediated by an antibacterial effect of these drugs on Helicobacter pylori. Bismuth has become an integral part of ‘triple therapy’ because of its documented anti-H. pylori effect. In vitro and clinical data suggest that sucralfate may also have an anti-H. pylori effect. The aim of this randomized, prospective therapeutic trial was to compare the efficacy of triple therapy containing bismuth with that containing sucralfate and to determine the effect of therapy with these combinations on duodenal ulcer relapse. Forty H. pylori-positive duodenal ulcer patients were healed with omeprazole and randomized to receive either 1 g sucralfate four times daily or 120mg bismuth compound four times daily. All patients received 400 mg metronidazole three times daily and either 250 or 500 mg tetracycline four times daily for 7-14 days. Thirty-five patients could be analysed. Overall eradication rates did not differ in the treatment groups (10 of 17 eradicated with sucralfate and 11 of 18 with bismuth). Relapse rates were significantly lower in the eradicated group (1 of 21 compared with 8 of 14 in the non-eradicated group) and did not differ between treatment groups in those patients not eradicated. A triple therapy regimen utilizing sucralfate appears to be as effective as the bismuthcontaining regimen. Key words: Bismuth; duodenal ulcer relapses; Helicobacter pylori; sucralfate; triple therapy Professor I. N. Marks, Gastrointestinal Clinic, Groote Schuur Hospital, Observatory, South Africa 7925

Duodenal ulcer relapse rates after therapy with bismuthcontaining compounds and sucralfate are lower than those after therapy with the H2-receptor antagonists. This finding may be due to the tendency to acid rebound or increased parietal cell sensitivity after healing with an H2-blocker, on the one hand (1,2), or to the antibacterial effect o n Helicobacter pylori of the mucosal protective agents, on the other. Bismuth has been shown to have an antibacterial activity and to interfere with the mucosal attachment of this organism and rids patients of the organism in up to 20% of cases treated (3,4). This observed anti-H. pylori effect has led to the entrenchment of bismuth in the therapeutic regimen currently advocated for eradication of H. pylori, the so-called triple therapy (5). Sucralfate has also been shown to affect H. pylori status. In vitro studies indicate that sucralfate inhibits H.pylori haemagglutinin, a fibrillar component thought to be an important colonization factor of the organism (6), and clinical studies have shown that therapy with sucralfate may clear the antrum of the organism in up to 47% of cases (7-9). This suggests that sucralfate may

be an effective component of anti-H. pylori combination therapy. This randomized, prospective therapeutic trial compares the efficacy of a sucralfate-containing triple therapy regimen with that of the ‘conventional’ bismuth-containing regimen, with regard to both H . pylori eradication and subsequent early relapse. PATIENTS A N D METHODS Patients Forty patients with aggressive H. pylori-positive duodenal ulcer disease, whose ulcers had been healed by a 4-week course of 20mg omeprazole per day, were studied. For purposes of this study, aggressive duodenal ulcer disease was defined as the failure t o heal after 2 months’ conventional treatment or duodenal ulcer recurrence within 1 year of previously documented active ulceration. Omeprazole was used as healing therapy in an attempt t o achieve uniformity of healing in this group with ‘aggressive’ duodenal ulcer

Triple Therapy Table I . Eradication data

Sucralfate Bismuth

Entered

Completed

Eradicated

20 ( I 1 * / 9 ) 20 (l3*/7)

17 (9*/8) I8 (13*/5)

11 (8*/3)

(3/7)

(Tetracycline, 250 mg/tetracycline, 500 mg). * One patient treated with arnoxicillin instead of tetracycline.

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disease. Each patient gave informed consent, and the study was approved by the Ethics and Research Committee of the University of Cape Town. Therapy Ulcer healing was confirmed endoscopically. and the patients were then randomized to receive either a colloidal bismuth preparation, 120 mg. or sucralfate, 1 g four times daily; all patients received metronidazole, 400 mg three times daily. In an attempt to reduce the incidence of sideeffects of eradication therapy, the recommended tetracycline dosage of 500 mg four times daily was used only in patients weighing 75 kg or more. Those weighing less than 75 kg received 250 mg four times daily. Eighteen patients were treated for 7 days and 22 patients for 14 days. Two patients in the 1-week treatment group received amoxicillin instead of tetracycline because of suspected photosensitivity (bismuth regimen, one; sucralfate regimen, one). Triple therapy was started within 1 month of documented healing. Patients were encouraged to report all suspected adverse effects immediately to one of the investigators (J. A. Louw or W. Lucke). Therapy was discontinued if symptoms were intolerable or led to work loss. Those with minor adverse effects such as nausea and dysgeusia were encouraged to complete therapy. Patients were endoscoped at entry to the healing phase, after healing (and before commencement of triple therapy), a minimum of 4 weeks after completion of triple therapy, and 6 and 12 months after healing, or whenever symptoms suggested a relapse. H . pylori status was determined at all endoscopy sessions by means of four antral biopsies, taken within 5 cm of the pylorus, which were assessed for urease status by means of the Rapid Urease Test (lo), histologic evaluation of multiple sections of Giemsa-stained biopsy specimens (two), and by biopsy culture (one). The specimen taken for culture was transported in a jar under microaerophylic conditions (Anaerocult C, 13682; Merck) and cultured on tryptose blood agar (CM 233; Oxoid Ltd) containing lysed horse blood (5% vol/vol) at 37°C under microaerophylic conditions (12% COz, 88% air, 95% humidity) for a minimum of 7 days. H. pylori was positively identified by colony morphology and urease reaction (Christensen’s urea slope). Patients were considered H. pylori-positive if the organism was found on histology and/or culture, with or without a positive urease reaction.

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Only patients who took a minimum of 60% of the antibiotic components of the 2-week therapy or 90% of the 1week therapy were analysed for eradication efficacy. Compliance was assessed by post-therapy interview and/or tablet counts. Statistical analysis of the categorical data was done by of Fisher’s exact test, and a value of less than 0.05 was taken to indicate significance. RESULTS The results are summarized in Table I. Thirty-five of the 40 patients were available for analysis and follow-up. One patient did not return for follow-up, and the other four did not satisfy the minimum compliance criteria.

H. pylori status All but seven patients remained H . pylori-positive immediately after healing. Five of these seven were H . pylori-positive 1 month later, at which stage triple therapy was commenced. Triple therapy in the remaining two was commenced at the time of ulcer healing, once it became clear that omeprazole clears, but does not eradicate, the organism (1 1, 12). Both these patients were randomized to the bismuth treatment group. Medication distribution Nine patients were entered into each of the sucralfate and bismuth 1-week treatment groups, and 11 into each of the sucralfate and bismuth 2-week treatment groups. In the 1week treatment groups six of the nine patients in the bismuth group received 500 mg tetracycline, compared to three of nine in the sucralfate group (NS). The antibiotic distribution in the 2-week treatment groups differed significantly, however, with only one patient in the bismuth group receiving 500 mg of tetracycline, compared with six in the sucralfate group. Eradication efjicacy Overall eradication efficacy did not differ between the sucralfate and bismuth treatment groups, 10 of 17 (59%) of the sucralfate-treated group and 11 of 18 (61%) of the bismuth group being eradicated. Although not significantly different, eradication efficacy tended to be superior in the 2-week treatment group; 6 of 14 (43%) patients were eradicated in the 1-week group, and 15 of 21 (71%) in the 2-week treatment group (p > 0.05). In the 1-week treatment group eradication was achieved in only one of seven patients on the sucralfate regimen, with five of seven patients in the bismuth treatment group being eradicated. In the 2-week treatment group 9 of 10 sucralfatetreated patients were eradicated, compared with 6 of 11 bismuth-treated subjects. Neither of these differences was significant. Eradication rates tended to be higher, albeit not sig-

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J . A . Louw et al.

Table 11. 3- to 12-month relapse rates after triple therapy Not eradicated Therapy

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Sucralfate Bismuth Total

n

7 7 14

Eradicated

Relapse

n

Relapse

4 4 8 (57%)

10 11

0

21

1(5%)

1

nificantly so, in those patients treated with 500 mg of tetracycline, occurring in 10 of 20 (50%) treated with 250 mg (7 days, 1 of 6; 14 days, 9 of 14), a n d i n 10 of 13 (77%) patients treated with 500 mg (7 days, 4 of 6; 14 days, 6 of 7). Eradication was achieved in 21 of 35 patients satisfying the minimum compliance criteria, compared with none of four patients withdrawn from the study because of inadequate compliance. In the 1-week treatment group, however, 8 of 14 (57%) who took more than 90% of therapy were not eradicated (250 mg, 6 of 8; 500 mg, 2 of 6 ) , and in the 2-week treatment group 5 of 20 (25%) patients who took more than 90% of therapy were not eradicated (250 mg, 4 of 13; 500mg. 1 of 7). Side effects Eleven of the 40 patients (28%) who entered into the study reported significant adverse effects. These were nausea (9,dizziness (3), vomiting (3), diarrhoea ( 5 ) , including one patient with C. difficile-positive diarrhoea, and a single case with paresthesiae. These symptoms occurred in six patients receiving 500 mg and in five receiving 250 mg of antibiotic and were considered serious enough to stop therapy in six patients (500 mg, 4; 250 mg, 2). Five of these patients did not meet the minimum compliance criteria (500mg, 3; 250 mg, 2). Duodenal ulcer relapses (Table 11) Eight of 14 patients with persistent H. pylori infection after triple therapy relapsed during the follow-up period of 3 to 12 months (3 within 3 months, 3 within 3-6 months, and 2 within 6-12 months), 4 each in the sucralfate and bismuth treatment groups. Only 1 of the 21 patients in whom eradication was achieved developed a recurrence-an asymptomatic ulcer at the 1-year follow-up (p < 0.005).

DISCUSSION This study suggests that triple therapy with sucralfate is at least as effective as the conventional triple therapy with bismuth in eradicating H . pylori. It also supports the view that H . pylori is an important risk factor for the development of duodenal ulcer relapse. The study does not answer the question as to the strategic role of sucralfate or bismuth in such combination therapy. Although H. pylori clearance is documented after mon-

otherapy with sucralfate or bismuth, eradication has not been documented after sucralfate, and the eradication rate after bismuth is of the order of 20%. Despite this low eradication rate, bismuth has become entrenched as an integral part of anti-Hi. pylori combination therapy, as it is thought to prevent the development of antibiotic resistance by H. pylori. It would seem, on the basis of our results, that sucralfate can successfully replace bismuth as an adjunct in triple therapy. The use of the mucosal protective agents in this setting is analogous to the use of omeprazole, another agent that suppresses rather than eradicates the organism. The combination of omeprazole with amoxicillin has recently been shown to eradicate the organism in almost 60% of patients, with minimal side-effects (13). The antibiotic components of combination therapy would appear to be of primary importance in determining successful eradication. The trend for greater efficacy with the higher antibiotic dosage and the lack of eradication in a significant number of patients with more than 90% compliance suggests that organism susceptibility may differ. Antibiotic resistance to metronidazole may be as high as 32% (14), and the same may well pertain, albeit to a lesser extent, to other antibiotics. This, coupled with the unacceptably high incidence of side-effects with the currently employed antibiotic regimes, will ensure the search for more appropriate H. pylori eradication therapy. This may take the form of a more effective antibiotic or the use of H. pyfori-suppressive ulcer healing agents combined with a suitable antibiotic.

REFERENCES 1. Marks IN, Young GO. Changes in acid secretory response and parietal cell sensitivityon healing predict early relapse in patients with duodenal ulcer [abstract]. Am J Gastroenterol1988;3: 1075. 2. Marks IN, Young GO, Tigler-WybrandiNA, Bridger S, Newton

KA. Acid secretory response and parietal cell sensitivity in patients with duodenal ulcer before and after treatment with sucralfate or ranitidine. Am J Med 1989;86 Suppl 6A:145-7. 3. Tytgat GJN. Helicobacrerpylori and duodenal ulcer disease. In: Halter F, Garner A, Tytgat GNJ, editors. Mechanisms of peptic ulcer healing. Dordrecht: Kluwer Academic Publishers, 1991:283-94. 4. Marshall BJ, Armstrong JA, Francis GJ, Nokes NT, Wee SH. Antibacterial action of bismuth in relation to Campylobacter pyloridis colonization and gastritis. Digestion 1987;37 Suppl 2:16-30. 5. Tytgat GNJ, Axon ATR, Dixon MF, Graham DY, Lee A, Marshall BJ. Helicobacter pylori: causal agent in peptic ulcer disease? Working Party Reports, World Con resses of Gastroenterology; Sydney, Australia, 26-31/8j990. Oxford: Blackwell Scientific Publications, 1990:36-45. 6. Slomiany BL, Piotrowsky J , Samantha A, van Horn K, Murty VLN, Slomiany A. Campylobacter pylori colonization factor shows specificity for lactosylceramide sulfate and GM3 ganglioside. Biochem Int 1989;19:929-36. 7. Hui WM, Lam SK, Ho J , et al. Effect of sucralfate and cimetidine on duodenal ulcer associated antral gastritis and Campylobacter pylori. Am J Med 1989;86 Suppl 6A:60-5. 8. Kjoller M, Nielsen I, Kristensen E, Pronge A A , Rasmussen NR. De No1 versus Antepsin in the treatment of gastric ulcer. World Congresses of Gastroenterology, Sydney, Australia 2631/8/1990; Abstr 11: PD 307.

Triple Therapy

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9. De Korwin JD, Vicari F, Foliquet B, Chambre V, Laurent J, Schmitt J. Follow up of Campylobacter pylori gastric infection after treatment of gastroduodenal ulcers with sucralfate or H2blockers. In: Megraud F, Lamouliatte H, editors. Gastroduodenal pathology and Carnpylobacter pylori. Amsterdam: Elsevier Science Publishers, 1989:619-23. 10. Arvind AS, Cook RS, Tabaqchali S , Tarthing MJG. One minute endoscopy room test for Campylobacter pylori [letter]. Lancet 1988; 1:704. 11. Weil J, Bell GD, Powell K , et al. Omeprazole and Helicobacter

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pylori: temporary suppression rather than true eradication. Aliment Pharmacol Ther 1991;5:309-13. 12. Louw JA, Zak J , Lastovica A , Jaskiewicz K , Lucke W, Marks IN. Omeprazole may clear, but does not eradicate, Helicobacter pylori [abstract]. S Afr Med J 1991;80:48. 13. Unge P, Eriksson K, Bergman B, et al. Omeprazole and amoxicillin in patients with duodenal ulcer: effect on Helicobacter pylori eradication and ulcer relapse during a 6 month follow up. Microb Ecol Health Dis 1991;4:S186. 14. Dawes PD, Taylor JP, Mtetwa T. A survey of Helicobacter pylori at Hillbrow Hospital [abstract]. S Afr Med J 1991;80:42.

Triple therapy with sucralfate is as effective as triple therapy containing bismuth in eradicating Helicobacter pylori and reducing duodenal ulcer relapse rates.

Duodenal ulcer relapse rates after therapy with sucralfate or bismuth are lower than those after H2-receptor antagonist therapy. This may be mediated ...
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