J. G. Penston

Review article : maintenance treatment with H2-receptor antagonists for peptic ulcer disease

In recent years a number of different strategies for managing patients with peptic ulcer disease have become available. The present review discusses the relative merits of each form of treatment. Intermittent treatment (whether given in response to symptoms or as a prophylactic regimen prescribed seasonally or at weekends) fails to prevent ulcer recurrence and leaves patients at risk of haemorrhage and perforation. Anti‐Helicobacter pylori therapy, although useful in certain circumstances, cannot be recommended for all patients with ulcer disease because of side effects and, in any case, requires further assessment of efficacy. Gastric surgery reduces ulcer recurrence and complications, but operations which have a low incidence of side effects are associated with higher rates of ulcer recurrence, particularly when patients are followed up for more than 10 years. Long‐term continuous maintenance treatment with H2‐receptor antagonists for 5 or more years effectively prevents ulcer recurrence in the majority of patients and significantly reduces the risk of ulcer complications. In addition, maintenance treatment has proved to be safe and is well tolerated by patients.

Efficacy and Safety of Long-Term Maintenance Therapy of Duodenal Ulcers

The efficacy and safety of continuous (maintenance) treatment with ranitidine has been studied retrospectively in 388 patients with duodenal ulcer. The cumulative rate of symptomatic relapse was 16% after 5 years. Very few of the patients developed ulcer complications during maintenance treatment, with a cumulative risk of haemorrhage of 1.8% during 5 years. The patients developed no drug-related disease. We conclude that long-term, continuous treatment with ranitidine is effective in maintaining remission of duodenal ulcers, protects the patients against the risk of complications, and is safe.

Nine years of maintenance treatment with ranitidine for patients with duodenal ulcer disease

Four hundred and sixty‐four patients with duodenal ulcer disease received continuous maintenance treatment with ranitidine for up to 9 years. Treatment failure was defined as either the first symptomatic recurrence of ulcer or the first ulcer recurrence accompanied by haemorrhage. Life tables were constructed using the Kaplan‐Meier product‐limit method; comparisons of survival curves were performed using the log‐rank test; and multivariate analysis was carried out using the Cox proportional hazards model.

9. Clinical Assessment, Gastrin Concentrations, and Gastric Histology after 5 Years of Maintenance Treatment with Ranitidine for Duodenal Ulcers

This study was designed to assess the safety of long-term maintenance treatment with ranitidine in 50 patients with duodenal ulcer disease. All patients had received continuous treatment with ranitidine for 5 years or more and were asymptomatic. No abnormalities were found on physical examination, and results of routine biochemical and haematologic screening were normal. No clinically significant abnormalities of fasting or post-prandial gastrin concentrations were observed. Endoscopic examination detected four duodenal ulcers and two benign gastric ulcers. Histology of gastric biopsy specimens showed mild superficial inflammatory cell infiltrate of the fundic mucosa but more extensive infiltration with atrophy of mucosal glands in the antral mucosa. Patchy type-I intestinal metaplasia was observed in 18 patients; one patient showed type-HI intestinal metaplasia but without dysplasia. Therefore, after 5 years maintenance treatment with ranitidine, patients remain healthy and have no evidence of pre-malig...

6. The Effect of Maintenance Treatment with Ranitidine on the Complications of Duodenal Ulcer Disease

A population of 392 patients with duodenal ulcers were studied to determine the rate of development of the complications of ulcer disease during long-term maintenance treatment with ranitidine. By the product limit method of survival analysis, the proportions of patients who remained free from haemorrhage associated with ulcer recurrence during maintenance treatment were 98-99% at 1 year, 97-98% at 3 years, and 97-98% at 6 years. During periods of time when 124 of 392 patients were not receiving active anti-ulcer therapy, the proportion of patients who developed haemorrhage (15.2% at 3 years) was significantly greater than that observed in the remaining 268 patients (1.3% at 3 years), who continued to take ranitidine throughout the follow-up period (P< 0.0001, logrank test). No cases of perforation were observed, and only one patient developed pyloric stenosis. Maintenance treatment with ranitidine for up to 6 years successfully reduced the risk of haemorrhage in patients with duodenal ulcer disease.

5. Maintenance Treatment versus No Treatment in Patients with Duodenal Ulcer Disease

population of 388 patients with duodenal ulcers, 265 patients received continuous maintenance treatment with ranitidine (RNT MT group) and 123 patients had periods of time without active anti-ulcer therapy (RNT NOMT group). The proportions of patients remaining free from symptomatic recurrence of ulcer during maintenance treatment (RNT MT) were 93% at 1 year, 87% at 3 years, and 85% at 5 years, compared with 51% at 1 year, 25% at 3 years, and 14% at 5 years in patients who were not receiving treatment (RNT NOMT). This result was highly significant (P = 0.0001, logrank test). Incidence density analysis of all patients showed that the average number of symptomatic recurrences per month was 0.0057 during maintenance treatment and 0.0629 during periods without active treatment (P = 0.0001). This study showed that maintenance treatment with ranitidine for 5 years significantly reduced the rate of symptomatic recurrence of ulcer in patient with duodenal ulcer disease.

A placebo-controlled investigation of duodenal ulcer recurrence after withdrawal of long-term treatment with ranitidine.

Ninety‐two patients with duodenal ulcer disease, who had received long‐term continuous treatment with ranitidine for an average of 7.5 years, participated in a double‐blind, placebo‐controlled study to determine whether stopping ranitidine resulted in ulcer recurrence. Patients were randomized to continue with ranitidine (n= 46) or to receive placebo (n= 46) and were followed up for six months. Treatment failure was defined as the first symptomatic recurrence of ulcer. The occurrence of epigastric pain during the follow‐up period was significantly less frequent in the ranitidine group (13%) than in the placebo group (43%) (P= 0.001). At six months, 9% of the ranitidine group had developed ulcer recurrence, compared with 48 % in the placebo group (P < 0.001, logrank test). Multivariate analysis using the Cox proportional hazards model showed that younger age (P= 0.041) and a long history of ulcer disease (P= 0.025) were risk factors for ulcer recurrence but gender, smoking and duration or dose of previous ranitidine treatment were not predictive of relapse during treatment with placebo. In conclusion, withdrawal of ranitidine after more than five years of continuous treatment results in almost half of the patients developing symptomatic ulcer recurrence within six months. Thus, long‐term continuous therapy does not alter the natural history of duodenal ulcer disease. Younger patients and those with a long history of ulcer disease appear to be at increased risk of developing ulcer recurrence if long‐term treatment is withdrawn.

Review article: asymptomatic duodenal ulcers—implications of heterogeneity

The present review examines the evidence for the existence of an asymptomatic variant of duodenal ulcer disease, as well as its clinical significance and therapeutic implications. Asymptomatic duodenal ulcers have definitely been shown to occur only in patients treated with nonsteroidal anti‐inflammatory drugs (NSAIDs) and in patients who have previously suffered from ulcer disease, especially if the latter have been subjected to gastric surgery or are receiving long‐term continuous (maintenance) treatment with drugs. It seems likely (although conclusive evidence is not yet available) that NSAID‐associated asymptomatic duodenal ulcers are predisposed to haemorrhage or perforation and should therefore be healed and kept in remission. Asymptomatic duodenal ulcers discovered during maintenance treatment appear to be clinically innocuous and do not therefore indicate therapeutic failure, nor require modification of therapy.

Ranitidine maintenance treatment of non‐steroidal anti‐inflammatory drug‐induced duodenal ulceration

Fifty‐six patients who presented with non‐steroidal anti‐inflammatory drug‐associated duodenal ulcers received maintenance treatment with ranitidine. Forty‐eight of these patients stopped treatment with nonsteroidal anti‐inflammatory drugs. The cumulative symptomatic remission at the end of 5 years of maintenance treatment was 97.7%. While half the patients had presented with haemorrhage from the ulcer, only one patient bled during maintenance treatment, giving a cumulative risk of 2.3% in 5 years of maintenance treatment.

3. Duodenal Ulcer Recurrence during Maintenance Treatment with Ranitidine

Three hundred and eighty-eight patients with duodenal ulcer disease received maintenance treatment with ranitidine for periods of time ranging from less than 1 year to more than 7 years. The product limit method was used to calculate the proportion of patients remaining free from symptomatic recurrence of ulcer. Intention-to-treat and efficacy analyses showed that for patients receiving ranitidine, 150mg/day, the cumulative remission rates were 95% at 1 year, 86-89% at 2 years, and 84-87% at 5 years, and for patients receiving ranitidine, 300 mg/day, the rates were 92-93% at 1 year, 88-90% at 3 years, and 82-90% at 5 years. An alternative method designed to analyse all patients, regardless of dose of ranitidine, showed that the remission rates were 94% at 1 year, 86% at 3 years, and 84% at 5 years. It is concluded that more than 80% of patients with duodenal ulcer disease remain free from symptomatic recurrence of ulcer during 5 years maintenance treatment with ranitidine.