There are few therapeutic options for the prevention of gastrointestinal mucosal damage caused by low-dose aspirin. We therefore investigated the efficacy of famotidine, a well-tolerated histamine H2-receptor antagonist, in the prevention of peptic ulcers and erosive oesophagitis in patients receiving low-dose aspirin for vascular protection.

Low-dose aspirin (ie, 75—325 mg), is one of the most widely used drugs in the world. Increasingly, it is being bought over-the-counter or prescribed for its antithrombotic activity in cardiovascular and cerebrovascular diseases, and in diabetes mellitus.

Despite the benefits of antithrombotic strategies, there has been a rise in the incidence of major upper gastrointestinal complications in patients taking aspirin, such as peptic ulcer bleeding, perforation, and sometimes death. The prevention of these side-effects has been hindered by two main factors: the scarcity of studies on gastrointestinal mucosal damage in patients with vascular disorders who require low-dose aspirin, and the few therapeutic options that are currently available. Proton-pump inhibitors are known to be effective in the treatment and prevention of ulcers related to aspirin or non-steroidal anti-inflammatory drugs (NSAIDs), but there have been concerns about their costs, safety, and risk of interaction with clopidogrel, which is frequently prescribed concurrently with aspirin. Also, although studies have focused on peptic ulcers caused by NSAIDs, recent evidence suggests that erosive oesophagitis is frequently seen in patients taking low-dose aspirin for vascular protection. Famotidine is a histamine H2-receptor antagonist that has proved to be well tolerated and able to prevent and heal peptic ulcers in patients receiving conventional NSAIDs. The FAMOUS trial (Famotidine for the Prevention of Peptic Ulcers in Users of Low-dose Aspirin) was designed to assess the efficacy of this drug, at a standard dose of 20 mg twice daily, in the prevention of gastric and duodenal ulcers, and erosive oesophagitis in patients receiving low-dose aspirin for vascular protection.

Adult patients (aged ≥18 years) from the cardiovascular, cerebrovascular, and diabetes clinics at Crosshouse Hospital, Kilmarnock, UK, were eligible for enrolment in this phase III, randomised, double-blind, placebo-controlled trial if they were taking aspirin 75—325 mg per day with or without other cardioprotective drugs. Patients without ulcers or erosive oesophagitis on endoscopy at baseline were randomly assigned by computer-generated randomisation sequence to receive famotidine 20 mg twice daily or placebo twice daily. Patients had a final endoscopic examination at 12 weeks. The primary endpoint was the development of new ulcers in the stomach or duodenum or erosive oesophagitis at 12 weeks after randomisation. Analysis was by intention to treat, including all randomised patients who received at least one dose of study drug (famotidine or placebo).

All 404 randomised patients received at least one dose and were included in the ITT population. 82 patients did not have the final endoscopic examination and were assumed to have had normal findings. 277 (68·6%) patients were men, and the median age was 63 years. Although only a few patients had gastrointestinal symptoms at baseline a substantial proportion had scars or erosions in the gastroduodenal mucosa. Also, most patients had other medical conditions, reflected by their medium and high comorbidity scores.

This study shows that famotidine is effective for the prevention of peptic ulcers and erosive oesophagitis in patients taking low-dose aspirin. The risk of developing these lesions is increased in patients treated concurrently with β blockers and in those with gastrointestinal mucosal scarring or erosions at baseline.

Although our main aim was to investigate the effects of famotidine on the development of peptic ulcers and erosive oesophagitis, it is still important to compare the ulcer rates found in this study with those of previous studies, while being aware that such rates will vary according to the characteristics of the populations studied. The rate of ulcers in our study population (11·4%) is higher than the rates in some recently reported trials, but a clearer view emerges when the individual study populations are considered.

Since most of the patients in our trial had erosions or scars at baseline, our findings can be compared with ulcer rates reported by Laine and colleagues in patients with osteoarthritis (ie, 13% in those with baseline erosions, and 27% in those with previous history of ulcers or their complications). When the clinical indication for the use of aspirin is considered, erosive or ulcerative lesions were found in about 48% of patients taking low-dose aspirin for vascular protection.The important effect of study population on ulcer rates in users of low-dose aspirin has been highlighted in a recent multicentre trial by Yeomans and co-workers: such rates ranged from 0% to 15% among the participating centres, probably reflecting the doses of aspirin used, presence or absence of H pylori, and inter-observer variation in reporting the endoscopic findings. In our trial, we deemed the presence of scars as indicative of healed or previous history of ulcers. In addition to enrolling patients with scars and erosions, which are known to increase the risk of ulcers, we also took into account the possible affect of drugs concurrently prescribed with aspirin. In particular, we found that β blockers act as an independent factor in increasing the risk of erosive or ulcerative lesions in patients on aspirin, which might suggest a role for mucosal ischaemia in patients taking aspirin with already compromised circulation. However, our analysis of concurrently prescribed drugs was exploratory in nature and might represent a chance finding.

Our work differs from other similar studies because it was a single-centre trial, which kept inter-observer variation to a minimum. One cannot exclude the possibility that compliance with aspirin intake improved in the study population because of the emphasis by the research team and the study literature on the importance of taking study drugs as well as other concurrently prescribed agents (including aspirin). Such an improvement might have contributed to more ulcer formation related to aspirin. It is also possible that patients who were at a greater risk of ulceration were more likely to participate in the study. However, these factors do not affect our main findings or conclusions with respect to the efficacy of famotidine.

We have shown that famotidine is capable of preventing oesophagitis in patients taking low-dose aspirin. We previously identified the disorder in 27% of patients taking aspirin who presented with upper gastrointestinal bleeding. The frequency of oesophagitis in the placebo group in this study (19%) is similar to that described by Yeomans and colleagues in non-bleeding patients taking aspirin (ie, 18%). Not unlike peptic ulcers, oesophagitis could be related to interference with mucosal prostaglandins by aspirin, or greater vulnerability to acid, hence the beneficial effect of famotidine.

Gastrointestinal mucosal damage related to low-dose aspirin (similarly to damage associated with NSAIDs) is frequently asymptomatic. Only a small proportion of patients had upper abdominal complaints at enrolment, which reflects their random inclusion. The individual symptoms scores did not change by the end of the study. However, patients assigned to famotidine were less likely to complain of dysphagia and their overall treatment assessment was better than those assigned to placebo. Also, more patients in the placebo group dropped out because of the use of proton-pump inhibitors than did patients assigned to famotidine.

Although this trial was not powered to study serious ulcer complications, it is noteworthy that all patients presenting with upper gastrointestinal bleeding were in the placebo group. Ulcer complications, such as bleeding, generally depend on the size and depth of mucosal damage. Besides its ulcerogenic effect, aspirin brings the added risk of its antiplatelet activity, which might aggravate the bleeding potential of gastrointestinal mucosal damage. We found no evidence of an interaction between famotidine and clopidogrel. This could be because of the fairly small size of our trial, or the fact that the metabolism of famotidine plus clopidogrel differs from that of proton-pump inhibitors plus clopidogrel.

Despite their proven efficacy against NSAID-related and aspirin-related ulcers, concerns continue to be expressed about the overprescribing and long-term use of proton-pump inhibitors, and alternative management strategies have been proposed, including the use of H2-receptor antagonists. Thus, famotidine might be a useful alternative for proton-pump inhibitors in patients taking low-dose aspirin.

(Source:  Lancet, Volume 374, Issue 9684, Pages 119 - 125, 11 July 2009)