Ranitidine and Sucralfate As Maintenance Therapy for Gastric Ulcer Disease: Endoscopic Control and Assessment of Scarring

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Gut, 1989, 30, 1692-1697

Ranitidine and sucralfate as maintenance therapy for gastric ulcer disease: endoscopic control and assessment of scarring

T TAKEMOTO, M NAMIKI, M ISHIKAWA, K TSUNEOKA, S OSHIBA, K KAWAI, AND N OGAWA From the Yamaguchi University School ofMedicine, Asahikawa Medical College, Yamagata University School of Medicine, Nippon Medical School, Osaka Medical College, Kyoto Prefectural University of Medicine, Ehime University School of Medicine, Japan

SUMMARY The efficacy of ranitidine (150 mg nocte), and sulcralfate (1 g tds) as maintenance therapy to prevent gastric ulcer relapse was evaluated in a 12 month trial in 363 patients. The relapse rates were 8.8% at three months, 14.7% at six months, 18/1% at nine months, and 21V0% at 12 months for the ranitidine group and 1477%, 21/3%, 29.9%, and 30.2% respectively for the sucralfate group. At nine and 12 months the cumulative relapse rates for the ranitidine group were significantly lower than those for the sucralfate group (p<005). In both groups ulcers recurred mainly from red scars observed at the endoscopic scarring stage. This indicated the necessity of drug treatment up to the white scar stage. The results suggest that ranitidine is effective in preventing gastric ulcer relapse.

Gastric acid is generally considered to be a key factor Methods http://gut.bmj.com/ in peptic ulcer development and the histamine H receptor blockers which inhibit its formation have PATIENTS become standard therapy for treatment of both Patients whose gastric ulcers had healed after any duodenal and gastric ulcer. active treatment were recruited if endoscopy had On average duodenal ulcer patients secrete more confirmed the ulcer and its healing and if they were gastric acid than healthy control subjects. Many suitable for outpatient management. clinical trials have therefore been conducted with H, on September 27, 2021 by guest. Protected copyright. blockers to evaluate their use as to prevent duodenal DOSAGE AND ADMINISTRAIION ulcer relapse.` The effects of ranitidine (Glaxo, UK), 150 mg/day at In contrast gastric ulcer patients as a group secrete bedtime, and sucralfate (Chugai Pharmaceutical Co, less acid than normal and are usually considered to Japan), 1 g tds, on the rate of gastric ulcer relapse have an imbalance between agressive and defensive were compared in a one year maintenlance trial factors resulting from impaired gastric defence. conducted by investigators in 72 centres. This imbalance may, in theory, be rectified by Each patient received either four 250 mg tablets of therapeutic intervention which acts to increase sucralfate three times a day (before breakfast and mucosal defence or to inhibit gastric acid and pepsin. lunch and at bedtime) or four placebo tablets before As there is no definitive information on the relative breakfast and lunch and one 150 mg ranitidine tablet merits of these two approaches to treatment we have with three placebo tablets at bedtime. In order to conducted a large clinical trial to compare the effects maintain blindness, all the drugs and placebo tablets of ranitidine, an agent which inhibits gastric acid were prepared in packages which were indistinguish- secretion and sucralfate, a mucosal protective agent able in their appearance. in the prevention of gastric ulcer relapse. I RIAI DE SIGN Address for correspondence: Professor T Tikernoto. lirst )ep.rtmnenit of Medicine. Yarnagunchi Unisersity School of Medlicinl. 114 (Ocushi. Ufe-shi Endoscopic examination of the stomach was per- Y.iniiguchi-ken. Japai. formed on five occasions, - that is, when healing was Accepted for public.itio n April l1989. confirmed and at three, six, nine, and 12 months 1692 Gut: first published as 10.1136/gut.30.12.1692 on 1 December 1989. Downloaded from

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Table 1 Esxcliusion criteria ing to the criteria, a red scar or white scar was judged as non-relapse and the A 1, A2, H 1, or H2 stages were Reason Druig Ratnitielit Sucraljate judged as a relapse. Protocol v iolation The patients were enrolled irrespective of their Scar of DU I previous ulcer treatment, but patients with con- Scar of linear ulcer I current duodenal ulceration or those with a linear Combined use of anti-ulcer drug - Concurrent DU 1 ulcer were excluded. Also excluded were patients Gastric cancer ' who were or might be pregnant or lactating. Pyloric tumour embolus by HCC+hepatic - I Use of all other anti-ulcer drugs was prohibited as cirrhosis were known ulcerogenic agents such as oral steroids Patients w ho failed to visit hospital after start 4 5 of trial and non-steroidal anti-inflammatory drugs. Total 9 8 To evaluate drug safety the patients were questioned concerning adverse effects. In addition clinical laboratory tests including hepatic and renal function tests and urinalysis, were performed on Table 2 Background ofpatients three occasions: at the time of confirmation of healing, and at six and 12 months after the start of Ranuluud'n Sui('rall'att y' test maintenance therapy. Patients (n) 171 175 ns 1211 116 ns Male STAIISTICAI ANAI YSIS Femalle > I 59 Age Mean age (SEM) 532 (119) 52:8 (()n9)is Ulcer relapse rates were calculated by Cutler-Ederer Sniioking Yes 98 1(14 ns life-table analysis. The X' test by the Mantel Haenzel No 73 71 method was used for comparison of cumulative (offee Yes 57 61 [is The rate of transition of the endoscopic No 113 11(0 relapse rates. Alcohol No 911( (X) ns scarring stage was also calculated by the Cutier- Occasionalls 41 3 Ederer life table analysis. Eversvdav 4)0 41 The background factors of the patients were History of First occurrence 78 76 ns compared by the x)' test. g.astric Recurrence 81 86 ulcer For all of these statistical methods, p<0.005 was

D)escription Location Angulus 53 47 ns regarded as indicative of a significant difference. http://gut.bmj.com/ of sentriculi atid pres ious lesser curse Results gastric Others 1 22 134 ulcer Number Single 49 1 5I ns Multiple 22 24 C OMPARISON OF SUBJICTS Shape Circle 1(02 105 ns Three hundred and sixty three patients with a healed Oval 63 *X gastric ulcer were randomised into two groups; 180 Irregular 7 14 ranitidine and 183 patients sucralfate. Size Sniall ('9 nim) 47 4n ns received on September 27, 2021 by guest. Protected copyright. Mediuinm ( 11) 19 9" 96 Seventeen subjects were excluded for the reasons mm) presented in Table 1. Table 2 shows the demographic Large (20ninm ) 23 25 346 received Depth Shallos ( 5 mm) 69 %6 ns data for the remaining subjects (171 Medium (6 mimi- 7(0 79 ranitidine and 175 sucralfate) who were eligible for 1(0 mm) Deep (ll mnl) 11 7 Fndloscopic scarring Red scar 141 145 ns Table 3 Prt'iou{ioCsulcer terapl)Y stage White scar 3(1 30( Paletits randloiisnxed1(: X (SE). ns: No signilficant differeice. Previous ulcer tiherapy Rtailuidliut S rul/jl l2 blocker alone (FERA) t1 44 Sucralfate alone (S) () thereafter. Administration of the drugs was started H2RA+sucralfate 9 soon after confirmation of ulcer healing by endo- ILRA+S+others* 32 30( scopy. Furthermore, whenever recurrence was VERA+others 56 7(0 S+others 7 1() suspected from the patient's symptoms, an additional Others 16 14 endoscopic examination was performed to confirm or Unknowsn () deny ulcer relapse using the endoscopic scarring stages classification reported by Sakita et al.' Accord- Others (eftarnate. Cetraxate, etc. Gut: first published as 10.1136/gut.30.12.1692 on 1 December 1989. Downloaded from

1694 Takemoto, Namiki, Ishikawa, Tsuineoka, Oshiba, Kawai, and Ogaw,a

analysis, and no significant differences were noted for 50- any of those factors. Previous ulcer treatment for the L Ranitidine group (150 mg/day) healing phase is shown in Table 3. In both drug E Sucralfate group (3g/day) groups many subjects had been treated with HW- * p<0-05 receptor blockers but there was no difference in the distribution of any of the treatments. Also, in most X test by Mantel-Haenzel r*i cases in both groups, a red scar stage was detected at analysis method 29.9 30.2 4-1 the initial endoscopic examination (Table 2). X 25- CD 21.3 21*O CL0. CUMUIATIVE RELAPSE RAFES 10 18.1 Table 4 shows the relapse status for the two treatment 14.7 1 groups for each three month period of the study. The

number of patients who had relapsed was 29 for O- ranitidine and 44 for sucralfate. In both treatment groups, ulcer relapse occurred most frequently during the first three cases month period: 14 for (171)(175) (134)(127) (106) (97) (89) (76) ranitidine and 24 cases for sucralfate. Figure 1 shows No of patients the cumulative relapse rates with both drugs calcu- 3 6 9 12 lated by Cutler-Ederer life table analysis. The Months cumulative relapse rates for ranitidine at three, six, nine, and 12 months were 8.8%, 14-7%, 18X 1%, and Fig. 1 Ulcer recurrence rate ini each1 treatment group at 21-0%, while those for the sucralfate group were thiree, six, nine, and 12 montilis calculated by tile Cutler- 14-7%, 21-3%, 29-9%, and 30(2% respectively. The Ederer life-table analysisimethiod. cumulative relapse rates at nine and 12 months in the ranitidine group were significantly lower than those ranitidine groups and 71-4% of the non-relapse cases in the sucralfate group (p<005). The symptomatic in the sucralfate group were in the white scar stage. relapse rates at three and six months were 6.9% and 10.9% for the ranitidine group and 9-2% and 10-7% ADVERSE EFFECIS AND LABORA IORY for sucralfate group. The differences between the ABNORMALITIES

groups were not statistically significant. The sympto- Adverse effects developed in three of 171 patients http://gut.bmj.com/ matic relapse rates at nine and 12 months were 11-7% (1.8*%) in the ranitidine group and in six of 175 and 12-7% for ranitidine and 18.5% and 19.6% for patients (3.4%) in the sucralfate group. The three sucralfate, however, suggesting more symptomatic patients in the ranitidine group suffered from allergic relapse with sucralfate but this was not statistically symptoms including skin rash, aggravation of chronic significant. eczema and skin itchiness, while the six cases in the sucralfate group complained of gastrointestinal ENDOSCOPIC SCARRING STAGE symptoms comprising gastric distension (two cases), Figure 2 shows the breakdown of the endoscopic diarrhoea, heartburn, belching, abdominal pain, and on September 27, 2021 by guest. Protected copyright. scarring stages for the patients who had remained in nausea. remission during the trial and for those who had All the adverse effects developed during the first relapsed immediately before confirmation of the six weeks of the trial. Those symptoms resolved or ulcer recurrence. Approximately 79% each of the were alleviated in all cases as the drug treatment was relapse cases in each group developed from a red continued or stopped. scar, whilst 83-5% of the non-relapse cases in the No clinically significant changes were detected in

Table 4 Patients outcome

Patienit Period I dav-3 ntiotitli 4-6 months 7-90iotiotlis 10 12r' o/iis D)rug category (1-104 davs) (105-194 (havs) (1952-48 d1a(J!) (285-365 days) Ranitidine Non-relapsed 134 106 89 79 Relapsed 14 8 (22) 4 (26) 3 (29) Dropouts 23 2( (43) 13 (56) 7 (63) Sucralfate Non-relapsed 127 97 76 7(0 Relapsed 24 9 (33) 1( (43) 1 (44) Dropouts 24 21 (45) ll (56) 5(61)

():Number of cumulatise patients. Gut: first published as 10.1136/gut.30.12.1692 on 1 December 1989. Downloaded from

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0 50 101o (Ranitidine group) 16-5% (13) 83.5% (66) Non-relapse patinets Red White scar (one year after administration) scar p< 0*001 79.3% (23) 20.7% (6) (X2 = 33.044) Relapsed patients (before confirmation of relapse) Red scar White scar -

(Sucralfate group) 28-6% (20) 71.4% (50) Non-relapsed patients (one year after administration) Red scar White scar [ A h p<0001 79.5% (35) 20.5% (9) (x2 = 231 Relapsed patients (before confirmation of relapse)I- Red scar White scar ( )= No of patients

Fig. 2 Scarring stages for non-relapsed patients at tile end ofthe study andfor relapsed patients at the previous endoscopy before relapse.

routine biochemical tests (electrolytes, liver, and dine's effects on ulcer relapse by recruiting a large http://gut.bmj.com/ renal function tests) with the exception of a small number of patients, and they reported cumulative increase in total serum bilirubin in one patient relapse rates for one year of 22-6% and 17.1% treated with ranitidine (0.7 mg/dl pre-trial, 1-3 mgldl respectively. at six months, 1-5 mg/dl at 12 months) and a slight Sucralfate, the control drug for this trial, is widely increase in LDH in one patient receiving sucralfate prescribed in Japan for gastric ulcer treatment, and (357 IU/l pretrial, 384 IU/l at six months, 431 IU/I at several papers'" have dealt with its use as mainten-

12 months). ance therapy. In one of those reports, Marks et al'3 on September 27, 2021 by guest. Protected copyright. commented that the recommended therapeutic Discussion dosage for satisfactory prevention of gastric ulcer relapse is 3 g/day, given as 1 g between breakfast and A number of clinical trials have been conducted with lunch and 2 g before bedtime. histamine H2-receptor blockers, especially ranitidine In our study, ranitidine 150 mg/day and sucralfate and cimetidine to evaluate their efficacy in the 1 g tds (method of administration differed from that prevention of peptic ulcer relapse. For both of these reported by Marks et al), were compared for their compounds the majority of trials have been con- effects on gastric ulcer relapse. As a result, ranitidine ducted in duodenal ulcer patients. Gough et alP and showed a cumulative relapse rate for one year of Silvis et a17 reported that ranitidine 150 mg/day, 21-0%, and its effect on ulcer relapse was signific- which has a stronger inhibitory effect on nocturnal antly superior to sucralfate (p<0-05) after nine and acid secretion than cimetidine 400 mg (Santana et 12 months treatment. In the studies by Boyd et al" al),' showed significant superiority in terms of the and Cockel et al," the cumulative relapse rates for cumulative relapse rate over 12 months. Reports on one year were also about 20% . For sucralfate, Marks the prevention of gastric ulcer relapse are few. Barr et et all4 reported a relapse rate of 16-0% for six months. al" and Morgan et al." reported studies with cimeti- Our relapse rate of 21-3% for six months was similar dine, but the number of enrolled patients were small to their result. and their data analysis techniques were not standard- In our study, endoscopic examination was con- ised. Boyd et al' and Cockel et al' studied raniti- ducted at three monthly intervals and at unscheduled Gut: first published as 10.1136/gut.30.12.1692 on 1 December 1989. Downloaded from

1696 Takemoto, Namiki, Ishikawa, Tsluneoka, Oshiba, Kawai, and Ogawa times whenever the symptoms warranted; this per- establish the safety of longterm administration of mitted accurate monitoring of asymptomatic recur- histamine H2-receptor blockers. rence. The total cumulative relapse rate and the Based on the results of our study, administration of cumulative symptomatic relapse rate for the open ranitidine, in a dose of 150 mg/day nocte for 12 study of Boyd et al were 22-6% and 14-0%, respect- months is more effective in preventing gastric ulcer ively. Similar relapse rates of 21 -0% and 12-7% were relapse than sucralfate, in a dose of I g tds (before observed in our study, thus elucidating the ratio of breakfast, lunch, and bed-time). symptomatic relapse to asymptomatic relapse of gastric ulcer in ranitidine maintenance therapy. In any case, in our comparative study enrolling a large We are grateful to Dr John R Wood for his critical number of patients, ranitidine, a histamine H2- comments on this paper. receptor blockers, showed satisfactory prevention of gastric ulcer relapse, in which a decrease in defensive factors is said to have a strong causal relation, in References comparison with sucralfate, which has a mucosal I Bardhan KD, Saul DM, Edwards JL, et al. Double-blind protective action. This finding suggests that comparison of cimctidine and placebo in the mainten- ranitidine is an effective drug for gastric ulcer ance of healing of chronic duodenal ulceration. Gti maintenance therapy. 1979; 20: 158-62. The gastric ulcer relapse rate peaked during the 2 Fitzpatrick WJF, Blackwood WS, Northfield TC. Bed- first three months of maintenance therapy, and this time cimetidine maintenance treatment: optimum dose may be attributable to many factors, including and effect on subsequent natural history of duodenal previous ulcer treatment. Furthermore, there is a ulcer. Gut 1982: 23: 239-42. question as to whether the relapse observed in the 3 Kozarek R, Berenson M, Berkowitz J, et al. Mainten- first three months is a genuine relapse of merely ance therapy with ranitidine following healing of acute duodenal ulcer. C'turr Tlier Res 1985: 38: 341-5 1. incomplete prior healing. 4 Texter EC, Navab F, Mantell G, Berman R. Mainten- Peptic ulcers are judged as healed by endoscopic ance therapy of duodenal ulcer with famotidine. A confirmation of a scar. Generally, in Japan scars are multicenter United States Study. Am J Med 1986; 81 classified as red scars and white scars. In a study on [suppl 4B1: 25-32. sucralfate in the prevention of gastric ulcer relapse, 5 Sakita T. Principles ofgastroenterological en(doscopy (in Miyake et al' reported that relapse rates are higher Japanese). Tokyo: Chugai-Igaku C, 1970: 32. from red scars, suggesting that endoscopic character- 6 Gough KR, Korman MG, Bardhan KD. et al. http://gut.bmj.com/ isation of the scar is useful for predicting ulcer Ranitidine and cimetidinc in prevention of duodenal relapse. ulcer relapse. A doubie-blind. randomised. multicenter. comparative trial. Lancet 1984; ii: 659-62. During our study relapse in both treatment groups 7 Silvis SE. Final report on the United States multicenter was greater in patients with a red scar than those trial comparing ranitidine to cimetidine as maintenance having a white scar. These observations suggest that therapy following healing of duodenal ulcer. J Clini it may be necessary to continue therapy at the Gaistoe(nterol 1985: 7: 482-7. therapeutic dosage until confirmation of a white scar, 8 Santana IA. Pounder RE. Orchard K. Wood EC. on September 27, 2021 by guest. Protected copyright. in contrast with concluding that a red scar is proof of Chronos N. Neame R. Intragastric acidity during duo- healing. denal ulcer maintenance treatment with H, blockers. There is considerable discussion regarding the J C/lin Nuti Gastiroenterol 1986; 1: 122-6. of main- 9 Barr GD, Kang JY. Canalese J, Piper DW. A two-year safety longterm administration, including prospective controlled study of maintenance cimetidine tenance therapy, of histamine H2-receptor blockers, and gastric ulcer. Gastiroenterology 1983; 85: 100-4. but because they have been clinically available for 1t) Morgan AG, Pacsoo G, McAdam WAF. Maintenance only 10 years, lifetime safety data are not available. therapy: a two year comparison between Caved-S and On the other hand, sucralfate has been used for 20 cimetidine treatment in the prevention of symptomatic years in Japan without serious side effects; it is a non- gastric ulcer recurrence. Gut 1985: 26: 5996012. systemic drug and therefore it is a good choice in 11 Boyd EJS, Wilson JA, Wormsley KG. Maintenance terms of safety of longterm administration. treatment of duodenal and gastric ulcer with ranitidine. All the areas of adverse effects in both drug groups Ranitidine Proceedings of an International Symposium in this study developed during the first three months, held in the context of the seventh world congress of gastroenterology, Stockholm, 17 June 1982, and no severe cases were observed throughout the Amsterdam. 1982: 102. year. For sucralfate, no untoward effects were noted 12 Cockel R, Dawson J, Jain S. Ranitidine in the long-term which could have been ascribed to aluminium treatment of gastric ulcers. The clinical use of ranitidine. toxicity. Further studies over a longer period and Oxford: The Medicine Publishing Foundation including a larger number of patients are needed to Symposium Series 5, 1982: 232. 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13 Miyake T, Ariyoshi J Suzukaki T, Oishi M, Sakai M, rate of gastric ulccr recurrcncc. Am J Med 1985; 79 Ucda S. Endoscopic evaluation of the effect of sucral- Isuppl 2C1: 32-5. fate therapy and other clinical parameters on the recur- 15 Takemoto T, Kimura K, Okita K. et al. Efficacy of rcnce rate of gastric ulccrs. Dig INs Sci 1980; 25: 1-7. sucralfate in the prevention of peptic ulcer - double 14 Marks IN, Wright JP, Girdwood AH. Gilinsky NH, blind multicenter study with cimetidine. Scand J Gastro- Lucke W. Maintenancc therapy with sucralfate reduces enterol 1987; 22 [Suppl 140]: 49-60. http://gut.bmj.com/ on September 27, 2021 by guest. Protected copyright.