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Background and Aim: This prospective cohort observational study, set in a district hospital, presents our experience (1976-1993) of duodenal ulcer refractory to histamine H2 receptor antagonists (defined as not healed after 3 months' treatment) and comments on onset, outcome and spontaneous decline., Methods: Patients were treated mainly with cimetidine, the dose being titrated (up to 3.2 g daily) according to response, and followed by serial check endoscopy and clinical assessment., Results: A total of 782 of the 4032 duodenal ulcer patients seen (19%) were refractory; the incidence declined over time: 1976-1978: 124/379 (33%); 1979-1983: 390/1240 (31%); 1984-1988: 190/1295 (15%); 1989-1993: 78/1118 (7%). A total of 344 were refractory for the first time on their first healing course and 174 on their second. Healing was achieved in two-thirds after a mean of 7 months' treatment with cimetidine 1 g; treatment for 12-18 months with higher doses was needed in the remainder. Relapse occurred in up to three-quarters of patients despite maintenance cimetidine up to 3 g daily. Eventually 47 patients were operated upon but good results (i.e., no ulcer, no symptoms) were achieved in only 11., Conclusion: Refractoriness was common until recently. Its incidence has declined dramatically, the fall preceding the newer more powerful treatment with proton pump inhibitors and with Helicobacter pylori eradication. We suggest this phenomenon is a modern example of a spontaneous change in the natural history of the disease.

Objective: The aim of this paper is to study the natural history and outcome of medical treatment of giant gastric ulcer in the histamine H2-receptor antagonist era., Methods: All patients with gastric ulcer were prospectively followed. We assessed the special features (in particular, demography and treatment outcome) in patients with giant gastric ulcer, defined as ulcers large enough to occupy at least one wall., Results: Between 1976 and 1991, 537 patients with gastric ulcer were seen, of whom 129 (24%) had giant gastric ulcer. Giant gastric ulcer patients were significantly older (p < 0.05) than patients with smaller ulcers and had more aggressive disease, reflected by a higher incidence of bleeding, anorexia, weight loss, and emergency admission. More giant gastric ulcers were located in the body of the stomach and a higher proportion looked malignant. Four of 129 patients died immediately (bleed n = 3, unrelated cause n = 1), 15 had urgent surgery (bleed n = 11, perforation n = 2, suspected cancer n = 2) and 110 were treated medically, mainly with cimetidine 1 g daily. Healing occurred in 97 of 110 (88%), including 14 of 15 with refractory disease, i.e., healing took >3 months and/or needed cimetidine 2-3 g daily. Of the remaining 13 patients, six died (from unrelated causes), three had surgery for failed medical treatment, two defaulted, and two were still on treatment (one with refractory ulcer). Refractoriness was more common in patients with associated major medical illness (42% vs 12%, p < 0.01) or with giant gastric ulcers that looked malignant although they were benign (53% vs 21%, p < 0.01). Relapse off treatment was higher (13 of 26) than on maintenance treatment with cimetidine 0.4-2 g daily (14 of 70). Complications occurred in six patients: four off treatment and two on maintenance treatment. Only two giant gastric ulcers finally proved to be malignant. Of the 129 patients, 47 (36%) died, 14 within 3 months (two from bleeding, three postoperatively, nine from unrelated causes) and 33 later (two with gastric cancer and 31 from unrelated causes)., Conclusions: Giant gastric ulcer is uncommon. Patients are more seriously ill than those with smaller ulcers. Most giant gastric ulcers heal with histamine H2-receptor antagonist treatment. The condition is a marker of poor general health, reflected by the high long term mortality.

We studied 2119 patients presenting with duodenal ulcer as sole lesion, in the period 1976-1993, the era of H2 receptor antagonist (H2RA) therapy, prior to the introduction of Helicobacter pylori eradication. We used clinical assessment and serial check endoscopy to investigate the incidence of bleeding at presentation (group I, n = 286, 13.5%), the long-term outcome in this group and in that presenting with pain alone (group II, n = 1833, 87%) with respect to ulcer recurrence and bleeding, and the effect of H2RA maintenance therapy. Most patients were treated with H2RA, principally cimetidine. In group I, seven patients died early on; 38 had urgent surgery, of whom six died post-operatively. The remainder were treated; five immediately re-bled, of whom three were operated on. On follow-up, 98/227 group I patients relapsed, 21 (21%) of whom rebled. Relapse in group II was 1017/1668, with only 42 (4%) bleeding (p < 0.001). In patients without maintenance treatment, relapse was markedly higher (50/78 group I, 529/742 group II), but group II still bled significantly less (20% group I vs. 3% group II). Relapse on maintenance was: 48/149 with five (10%) rebleeding in group I, and 488/926 with five (1%) bleeding in group II (p < 0.001). Despite the introduction of H2RA therapy, patients presenting with haemorrhage still have a risk of bleeding at ulcer relapse about 7-fold higher than that for those presenting with pain alone.

Background: Erosive oesophagitis refractory to high dose histamine H2 receptor antagonists (definition: failure to heal fully after > or = 3 months' treatment with cimetidine 3.2 g or ranitidine 0.9 g) responds well to omeprazole 40 mg daily but frequently relapses when the patients are put back on maintenance H2 receptor antagonists at medium or even high dose (e.g. cimetidine 1.6 g and 3.2 g, respectively)., Aim: To investigate the efficacy of maintenance omeprazole 20 mg daily in refractory erosive oesophagitis., Patients & Methods: In this open, sequential study, patients with H2 receptor antagonist-refractory oesophagitis were healed on omeprazole 40 mg daily and then put on maintenance H2 receptor antagonists (cimetidine 1.6 g or 3.2 g). Relapses were re-treated with omeprazole 40 mg; upon rehealing, patients were put on maintenance omeprazole 20 mg daily for up to 4.5 years., Results: Healing on omeprazole occurred in 38 out of 39 patients (97%) at 12 weeks. Only six of the 38 patients (16%) relapsed (asymptomatic in half) during subsequent maintenance treatment, whereas all had relapsed earlier on high dose H2 receptor antagonists., Conclusion: Within the limits of interpretation of an open study, omeprazole 20 mg daily seems effective in maintaining prolonged remission in this group of patients with H2 receptor antagonist-refractory oesophagitis.

Studies of gastric secretion were carried out on 14 subjects, some of whom had taken acid secretion inhibitors. In vitro studies were performed in an attempt to ascertain the effect of H+ and Na+ ions on conductivity. There is a strong correlation between intragastric pH and conductivity for pH < 2, but none of the gastric samples were isotonic. The measured conductivity of the samples was therefore considerably lower than predicted for isotonic gastric juice.

Ulcer relapse rates during up to 2 years of prophylactic low-dose maintenance therapy (LDMT) with cimetidine 400 mg at bedtime was examined in 261 patients. Endoscopy was repeated every 6 months if asymptomatic, or whenever symptoms recurred. Relapse was defined as the recurrence of an ulcer crater or erosions or both. In patients with non-refractory duodenal ulcer (those healed within 3 months) who comprise the majority, their likelihood of relapse at 6, 12, 18 and 24 months was: symptomatic 8%, 13%, 18%, 20%; silent 14%, 28%, 38%, 43%, respectively. In contrast, in patients with refractory ulcer, their symptomatic relapse rates were 36%, 45%, 46%, 48%, and silent 28%, 38%, 46%, 48% respectively. The outcome of a second course of LDMT was similar to the first. Narrowing the definition of relapse to exclude recurrence of erosions alone but without an ulcer decreased asymptomatic relapse in non-refractory ulcer patients by about half. No patient had any major side effects. Thus, LDMT is a safe and effective way of keeping most patients with duodenal ulcer symptom free over 2 years.

A refractory duodenal ulcer was arbitrarily defined as one that had failed to heal completely after treatment with cimetidine 1 g daily for three months. Of 66 patients with refractory duodenal ulcer, healing eventually occurred in 37 patients, after treatment for an average of 7.4 months. But 28 patients did not heal despite treatment for an average of 9.4 months; and one patient defaulted. In 41 patients the daily dose of cimetidine was increased to 2 g: the ulcers in 31 patients healed. In eight patients the daily dose was increased to 3 g and healing occurred in four patients. Eighteen patients required admission on 22 occasions because of severe symptoms despite treatment. Nine patients underwent surgery but in five the results were poor. Differences in clinical and endoscopic features between refractory and non-refractory ulcer patients were small. Acid and pepsin secretion were similar and gastrin concentrations normal. Blood levels of the drug and suppression of acid secretion were both satisfactory. Identification of refractory ulcer patients at the start of treatment was therefore not possible. Refractoriness could occur at any time during the course of the disease, previous treatment with cimetidine often having resulted in rapid healing, but subsequent relapses were also usually refractory. The cause of refractoriness remains unknown and the rather poor results of surgery in this series suggests that optimal management of these patients remains to be determined. Refractoriness probably indicates a changed natural history of the disease and in some patients a more poor prognosis.

Cimetidine 1 g daily is often continued for a fixed period beyond the time of healing of duodenal ulcer on the assumption that it might reduce the subsequent relapse rate. To test this, 194 patients whose ulcers had healed after one month of cimetidine 1 g daily were allocated at random to three groups for further treatment with cimetidine 1 g daily for two months (n = 63) or five months (n = 66) or placebo (n = 65). Thereafter all patients received placebo. Endoscopy was done routinely every three months, or earlier if symptoms recurred. During follow-up in the placebo phase, which lasted for up to 25 months, the estimated total proportions of patients in the three groups with symptomatic recurrences of ulcer were 80%, 90%, and 77%, respectively; the corresponding proportions with silent plus symptomatic relapses were 92%, 90%, and 100%. The relapse rates were also similar in all three groups. Statistical analysis showed a significant variation in relapse rate but the differences were regarded as clinically unimportant. These findings show that full-dose cimetidine continued for several months beyond the time of healing of duodenal ulcer dose not decrease the risk of subsequent relapse.

A multinational maintenance trial was conducted in 1842 peptic ulcer patients to investigate the efficacy and safety of continuous cimetidine maintenance therapy for up to 4 years. Patients with healed ulcers entered maintenance treatment with a 400-mg bedtime dose of cimetidine. Symptomatic ulcer relapse occurred in 17.2% of patients during the 1st year of treatment, in 9.6% during the 2nd year, and in 8.8% during the 3rd year. In addition to life-table analysis, the monthly prevalence of active ulceration over the 3-year period was examined. The average monthly prevalence rates were 2.1%, 1.8%, and 1.5% for the three successive yearly periods of continued cimetidine treatment. The adverse reactions observed in this study were not different from those previously reported with cimetidine. Moreover, there was a progressive decrease in the incidence of adverse events over the 4 years, thus establishing the long-term safety of continuous cimetidine treatment. It is concluded from this study that cimetidine maintenance treatment not only continues to be effective and safe beyond 1 year but also may reduce the risk of relapse over time.

In a comparative trial of preventive medication for duodenal ulceration with 51 participating centres, 484 patients were recruited for a year's maintenance treatment with the recommended bedtime dose of ranitidine (150 mg; n = 243) or cimetidine (400 mg; n = 241). These outpatients had recently healed duodenal ulcers, confirmed by endoscopy before and after healing, and ulcer relapse was monitored by endoscopy every 4 months. The distribution of factors likely to influence ulcer recurrence was similar in the two treatment groups. A life-table method of analysis showed that the ulcer relapse rate was consistently and significantly lower on ranitidine that on cimetidine (8% v 21%, p = 0.0018 at 4 months; 14% v 34%, p less than 0.0001 at 8 months; and 23% v 37%, p = 0.004 at 12 months). Crude relapse rate calculations, which underestimate the probability of ulcer recurrence, also confirmed the significant superiority of ranitidine 150 mg over cimetidine 400 mg nightly in preventing ulcer recurrence throughout the year.

The management of peptic ulcer disease with up to 6 years of continuous cimetidine treatment has been studied at four centres in the UK and Ireland. Cimetidine, 1 g daily for up to 12 weeks, was used to heal duodenal or gastric ulceration, alternating with 400 mg each night to maintain remission. After an initial healing phase, 402 patients started maintenance therapy. Classical life-table analyses showed that after 5 years one-quarter of the patients had suffered a symptomatic relapse, about half during the first year of maintenance treatment. Prevalence analyses (reflecting the cyclical nature of H2-antagonist use in peptic ulcer disease) over 6 years show that, on average, over 97% remain free of symptomatic ulceration at any one time. Patients 'lost' to the study due to withdrawal or default may, however, bias the results. A model designed to account for these estimates that during the long-term management of peptic ulcer with cimetidine, on average around 95% of patients remain free of symptomatic ulceration at any one time. Safety studies, including haematological and biochemical testing over the whole period, revealed no previously unknown adverse reaction. Seven patients were withdrawn for events considered to be related to the drug. Eleven patients died; none of the deaths appears to be connected with the treatment. It is concluded that long-term use of cimetidine is effective in the management of peptic ulcer disease, and continuous treatment for up to 6 years has not revealed any previously unknown hazard.

Patients suffering from chronic duodenal ulceration were allocated at random to treatment with either cimetidine (400 mg twice daily) or matching placebo for six months. Before entry to the trial all patients were shown to have healed ulcers on endoscopy. Most of the patients had participated in a one-month trial of cimetidine during which their ulcers healed. The trial showed that four of 29 patients relapsed on maintenance treatment with cimetidine, which therefore did not confer complete immunity from relapse. However, cimetidine treatment was very much better than placebo treatment, on which 18 of 31 patients relapsed. Of the 22 patients who relapsed clinically, 20 were submitted to endoscopy and 19 of these were shown to have ulcerated again. Endoscopy at the end of the trial showed that ulcers had also redeveloped in five of 28 asymptomatic patients. Length of previous dyspeptic history had no bearing on the results of the trial but there was evidence that relapse on placebo was less likely if the ulcer had originally healed on a high dose of cimetidine. Clinical relapse was associated with worsening duodenitis. Symptoms, clinical observation, and laboratory tests showed no important abnormalities in the patients.

The purpose of this study was to determine if pirenzepine and cimetidine given together was superior to cimetidine alone in inducing healing of refractory duodenal ulcers which remained unhealed after treatment with cimetidine or ranitidine for at least eight weeks. One hundred and thirty one patients from six centres were randomised to receive either cimetidine (C) 800 mg daily or cimetidine 800 mg plus pirenzepine (C + P) 100 mg daily under double blind conditions for six weeks. The healing rate was similar in both groups, irrespective of the method of calculation. On an intent-to-treat analysis, healing was: C 66%, C + P 57%, and amongst the patients who completed treatment, healing was 70% in both groups. Patients on C and on C + P experienced a similar decrease in daytime and in night time pain. Side effects of treatment, notably dry mouth and blurred vision, were reported more often by patients on combination therapy. Combined treatment with cimetidine plus pirenzepine in patients with refractory duodenal ulcer is unlikely to be beneficial.

Intermittent treatment with short courses of cimetidine given only when symptoms recurred was assessed in patients with duodenal ulcer as an alternative to maintenance treatment. Their progress was followed up for up to 22 months. Gastroscopy was carried out in most attacks to confirm recurrence of the ulcer and subsequent healing. Out of 125 patients treated, 83 relapsed, of whom 21 defaulted. After retreatment 36 patients relapsed again. The pattern of relapse and remission for the group as a whole was similar after both courses of treatment, indicating an unchanged natural history. Nevertheless, wide variation occurred in individual patients, so that the pattern of relapse could not be predicted by the duration of the initial remission. Most patients had one or two or rarely three symptomatic relapses a year, which were rapidly treated successfully with cimetidine. Therefore, unless the necessity for long-term maintenance treatment is established, intermittent treatment provides an adequate alternative in most patients with duodenal ulcer.