Correspondence
Famotidine to Prevent Peptic Ulcer Caused by NSAIDs
N Engl J Med 1996; 335:1322-1323October 24, 1996
- Article
To the Editor:
With regard to the report by Taha et al. (May 30 issue)1 on the effect of famotidine in preventing endoscopically diagnosed gastric and duodenal ulcers, it is important to distinguish between endoscopic lesions induced by nonsteroidal antiinflammatory drugs (NSAIDs) and NSAID-induced serious gastrointestinal complications such as bleeding and perforation. The former are common, and depending on how they are defined, can be seen in up to 80 percent of patients treated with NSAIDs.2 Among the 389 patients screened by Taha et al., 104 (27 percent) had an endoscopic ulcer and were therefore excluded from the trial. Over the next 24 weeks, ulcers developed in 28 percent of the patients in the placebo group, an annual incidence rate of close to 60 percent. On the other hand, clinically important NSAID-related gastrointestinal complications are many times less common, with annual incidence rates of about 1 percent.3
It is impossible to predict what effect famotidine will have on the incidence of clinical complications. We found that prophylactic antacid and histamine H2–antagonist therapy in patients with rheumatoid arthritis who were receiving long-term NSAID therapy was associated with a nearly threefold increase in the risk of a serious gastrointestinal complication.3 Although these drugs may suppress gastrointestinal symptoms, they may actually increase the probability of a serious complication because absence of symptoms may encourage the use of higher doses of NSAIDs for longer periods, ultimately resulting in more severe gastrointestinal complications.
3 ReferencesGurkirpal Singh, M.D.
James F. Fries, M.D.
Stanford University School of Medicine, Palo Alto, CA 943041
Taha AS ,Hudson N ,Hawkey CJ , et al. Famotidine for the prevention of gastric and duodenal ulcers caused by nonsteroidal antiinflammatory drugs. N Engl J Med 1996;334:1435-1439
Full Text | Web of Science | Medline2
Ehsanullah RS ,Page MC ,Tildesley G ,Wood JR . Prevention of gastroduodenal damage induced by non-steroidal anti-inflammatory drugs: controlled trial of ranitidine. BMJ 1988;297:1017-1021
CrossRef | Web of Science | Medline3
Singh G ,Ramey DR ,Morfeld D ,Shi H ,Hatoum HT ,Fries JF . Gastrointestinal tract complications of nonsteroidal anti-inflammatory drug treatment in rheumatoid arthritis: a prospective observational cohort study. Arch Intern Med 1996;156:1530-1536
CrossRef | Web of Science | Medline
To the Editor:
In reference to the study by Taha et al., previous studies with ranitidine, cimetidine, and nizatidine, as well as the U.S. multicenter famotidine trial, all failed to show benefit in preventing gastric ulcer in patients receiving NSAIDs.1-3 Why then should famotidine be effective — or is it? Unfortunately, information needed to put this new study into perspective is lacking. An ulcer was defined as a mucosal break 3 mm or greater in diameter. Many investigators now define an ulcer as being 5 mm or greater in diameter, because the definition of an ulcer as a lesion 3 mm in diameter increases the proportion of trivial lesions. Would famotidine be effective if an ulcer had been defined as a lesion of 5 mm or more in diameter (and possibly 1 cm or more in diameter)?
This study is very similar to the initial study comparing misoprostol and placebo.4 In later misoprostol studies, the frequency of gastric ulcer in the placebo group was approximately the same as in this study, but the frequency of gastric ulcer with misoprostol was much lower than that with even the higher dose of famotidine (i.e., about 1 percent vs. 8 percent at 12 weeks).2-4 I suspect that when the results of the famotidine study are reanalyzed using the same criterion for ulcer size used in previous studies, the reported advantage will disappear.
4 ReferencesDavid Y. Graham, M.D.
Veterans Affairs Medical Center, Houston, TX 770301
Agrawal NM . Epidemiology and prevention of non-steroidal anti-inflammatory drug effects in gastrointestinal tract. Br J Rheumatol 1995;34:Suppl 1:5-10
CrossRef | Medline2
Koch M ,Capurso L ,Dezi A , et al. Prevention of NSAID-induced gastroduodenal mucosal injury: meta-analysis of clinical trials with misoprostol and H2-receptor antagonists. Dig Dis 1995;13:Suppl 1:62-74
CrossRef | Web of Science | Medline3
Simon TJ ,Berger ML ,Hoover ME ,Stauffer LA ,Berline RG . A dose-ranging study of famotidine in prevention of gastroduodenal lesions associated with non-steroidal anti-inflammatory drugs (NSAIDs): results of a U.S. multicenter trial. Am J Gastroenterol 1994;89:1644-1644 abstract.4
Graham DY ,Agrawal NM ,Roth SH . Prevention of NSAID-induced gastric ulcer with misoprostol: multicentre, double-blind, placebo-controlled trial. Lancet 1988;2:1277-1280
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Although the incidence of complications of peptic ulcers was not the end point of our study, it is difficult, given the ability of famotidine to prevent ulcers,1 to understand how complications can develop from an ulcer that does not exist. We think that preventing ulcers does prevent complications,2 and there is evidence that acid suppression with ranitidine reduces ulcer complications to a greater extent than it reduces endoscopically evident ulceration.3,4
The possibility of an increase in NSAID therapy in patients taking an antacid and a histamine H2 antagonist is unlikely to apply to our study, because our patients were required to take standard-dose NSAID therapy for at least one month before the study and to continue it throughout the study. We agree, however, that the use of antacids or other drugs of unproved efficacy to suppress gastrointestinal symptoms in patients who require long-term NSAID therapy is potentially dangerous. This is different from taking therapeutic doses of an effective prophylactic drug regularly in the presence or absence of symptoms.
With reference to Dr. Graham's letter, the failure of previous studies to demonstrate benefit in preventing gastric ulcers with other H2-receptor antagonists can be explained by both the efficacy of famotidine and the methodology used by the various studies. Famotidine is the most potent H2-receptor antagonist currently available, especially at the doses we investigated. The protection achieved by that level of acid suppression is further evidenced by recently reported studies showing that omeprazole is also effective in preventing and healing NSAID-related gastric ulcers.5 Our study was longer than those cited by Dr. Graham, and our patients, the majority of whom had rheumatoid arthritis, were taking large doses of potent NSAIDs, which also explains the higher incidence of ulcers in our study. More important, we believe that in our study, unlike previous multicenter studies of the prevention of NSAID-related ulcers, the end points were more reliably reported because the endoscopic assessments were carried out by only two gastroenterologists. We used the definition of an ulcer that was orthodox when our study was initiated, and this remains the favored definition of the U.S. Food and Drug Administration.
5 ReferencesAli S. Taha, M.D., Ph.D.
Royal Infirmary, Glasgow G31 2ER, United KingdomChristopher J. Hawkey, M.D., D.M.
University Hospital, Nottingham NG7 2UH, United KingdomRobin I. Russell, M.D., Ph.D.
Royal Infirmary, Glasgow G31 2ER, United Kingdom1
Taha AS ,Hudson N ,Hawkey CJ , et al. Famotidine for the prevention of gastric and duodenal ulcers caused by nonsteroidal antiinflammatory drugs. N Engl J Med 1996;334:1435-1439
Full Text | Web of Science | Medline2
Silverstein FE ,Graham DY ,Senior JR , et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995;123:241-249
Web of Science | Medline3
Penston JG ,Wormsley KG . Nine years of maintenance treatment with ranitidine for patients with duodenal ulcer disease. Aliment Pharmacol Ther 1992;6:629-645
CrossRef | Web of Science | Medline4
Jensen DM ,Cheng S ,Kovacs TOG , et al. A controlled study of ranitidine for the prevention of recurrent hemorrhage from duodenal ulcer. N Engl J Med 1994;330:382-386
Full Text | Web of Science | Medline5
Cullen D ,Bardhan KD ,Eisner M , et al. Primary gastroduodenal prophylaxis with omeprazole for NSAID users. Gastroenterology 1996;110:Suppl:A86-A86 abstract.
Web of Science
- Citing Articles (1)
Citing Articles
1
Francis K.L. Chan, Joseph J.Y. Sung. (2001) Role of acid suppressants in prophylaxis of NSAID damage. Best Practice & Research Clinical Gastroenterology 15:3, 433-445
CrossRef
