Association of age with the efficacy and safety of ranitidine and cimetidine in acute duodenal ulcer disease

Age and Ageing, Nov, 1993 by J.S. Dixon, J.G. Mills, R.S.B. Ehsanullah, J.R. Wood

Summary

This multinational double-blind trial compared the efficacy and safety of ranitidine 300 mg nocte, 300 mg post-evening meal (pem) and cimetidine 800 mg nocte in patients with endoscopically verified duodenal ulcer disease aged < 60 years (n = 1318) and [greater than or equal to] 60 years (n = 354). The relative efficacy of the treatments was not dependent upon age after either 2 or 4 weeks of therapy. However, ulcer healing after 2 weeks of therapy was significantly higher in patients receiving ranitidine 300 mg pem than in those receiving cimetidine (p = 0.003) in the < 60-year group, but the difference was not significant in the [greater than or equal to] 60-year group. Fewer patients aged [greater than or equal to] 60 years on cimetidine (62%) became pain free compared with those on ranitidine (72% in both groups). Relief of epigastric pain and heartburn was related to pre-trial severity in both age groups. The incidence and type of adverse events were similar in the two age groups. It is concluded that ranitidine and cimetidine are as effective at healing duodenal ulcer and relieving ulcer symptoms in elderly as in younger patients.

Introduction

The proportion of people considered |elderly' in the population of most countries is increasing, and is predicted to continue to increase into the next century [1]. The mortality and morbidity associated with peptic ulcer disease is also increasing in elderly people [2-7].

The efficacy and safety of [H.sub.2]-receptor antagonists is of considerable importance in the management of peptic ulcer disease in elderly people. A study comparing ranitidine (hydrochloride) 150 mg bd and placebo showed no difference in the healing of duodenal ulcer for patients < 60 years and those [greater than or equal to] 60 years (74% and 71%, respectively, for ranitidine) [8]. Ulcer symptom relief was also similar in the two age groups. Four-week ulcer healing frequencies in an open study of 695 patients aged [greater than or equal to] 65 years who received ranitidine 150 mg bd or ranitidine 300 mg nocte were 81% and 78%, respectively [9].

A large multinational clinical trial to compare ranitidine 300 mg post-evening meal (pem), 300 mg nocte and cimetidine 800 mg nocte in the treatment of acute duodenal ulcer [10], has provided an opportunity to compare the efficacy and safety of ranitidine and cimetidine in patients < 60 years and those [greater than or equal to] 60 years old.

Patients and Methods

A double-blind, randomized comparison of ranitidine 300 mg pem, ranitidine 300 mg nocte and cimetidine 800 mg nocte in the healing of acute duodenal ulceration during 4 weeks of therapy was carried out. The study was conducted in 130 study centres in 13 countries. The protocol was approved by the local Hospital Ethics Committee or equivalent in all participating centres. All patients gave their consent after details of the study had been discussed with them. The study was conducted in accordance with the Declaration of Helsinki, Venice amendment 1983.

Patients aged 18-75 years with an endoscopically confirmed duodenal ulcer measuring [greater than or equal to] 5 mm and [less than or equal to] 25 mm in the longest diameter were eligible for entry into the study. Patients were excluded if they had other concomitant upper gastro-intestinal disease, severe renal impairment, clinically relevant abnormal liver function, or mental impairment. Patients who were taking potentially ulcerogenic drugs were also excluded, as were pregnant women, nursing mothers, and night workers.

Routine laboratory screens were carried out and demographic details noted for eligible patients. Patients were allocated to treatment with ranitidine (Zantac[R]) 300 mg pem with matching placebo nocte, ranitidine 300 mg nocte with matching placebo pem, or cimetidine 800 mg nocte (tablets matching ranitidine and bio-equivalence with UK commercially available Tagamet[R] verified) with matching placebo pem in accordance with the predetermined randomization list. All patients therefore took two tablets each day - one immediately after the evening meal (18 h 30-19 h 00) and one at bedtime (22 h 45-23 h 15). Patients were also provided with a diary card to record the daily evening meal times, tablet consumption and ulcer-related pain.

After 2 weeks of treatment, patients returned for endoscopic and symptomatic assessment, which included the presence or absence of epigastric pain, heartburn (reflux), nausea and vomiting each graded as none, mild, moderate or severe. If the ulcer had healed at this time the patient was withdrawn from the study. If the ulcer was unhealed, treatment was continued for a further 2 weeks with repeat assessment.

Adverse events and intercurrent illnesses were monitored throughout the study. At each follow-up visit patients were questioned about any adverse events that had occurred.

Statistical analyses: The sample size was chosen to be able to detect a difference between ranitidine 300 mg nocte and cimetidine 800 mg nocte of 10% at 2 weeks with 80% power at the 5% level of significance. Three patient populations were considered: