Correspondence
Ranitidine and Recurrent Hemorrhage from Duodenal Ulcer
N Engl J Med 1994; 331:53-54July 7, 1994
- Article
To the Editor:
Jensen et al. (Feb. 10 issue)1 showed that recurrent bleeding of duodenal ulcers can be prevented to a large extent by instituting maintenance therapy with histamine H-receptor blockers. Since the authors excluded all patients who were using ulcerogenic drugs, it is likely that almost all the patients had helicobacter-associated duodenal ulcers. Unfortunately, the developments in research on Helicobacter pylori already outdate the results and conclusions of this study.
There is overwhelming scientific evidence that H. pylori is the most important factor in duodenal ulcer disease, especially with respect to relapse2. After successful eradication with triple therapy (the combination of bismuth, metronidazole, and amoxicillin or tetracycline), relapses are rare. Should a relapse occur, it will usually be a reinfection3. Despite maintenance therapy with H-receptor antagonists, relapses do occur. In the study by Jensen et al., almost 10 percent of the patients with duodenal ulcers had a relapse with bleeding. This supports our opinion that all helicobacter-positive duodenal ulcers should be managed with therapy aimed at eradicating H. pylori, thereby preventing recurrences.
In his accompanying editorial, Peterson argues that large, prospective, randomized trials are needed to compare maintenance therapy consisting of antisecretory agents with anti-H. pylori therapy4. The result of such studies is already known, even before they are conducted. If a duodenal ulcer does not recur after successful eradication, how can rebleeding occur? After the cessation of anti-helicobacter treatment, a painstaking search for residual H. pylori should be conducted. If eradication therapy has been successful, maintenance treatment is not necessary. If eradication therapy has failed, maintenance treatment, probably lifelong, with H-receptor blockers or proton-pump inhibitors should be instituted.
Peterson states that triple therapy is complicated and leads to poor compliance because of side effects. Many doctors will confirm that the side effects are usually mild and patients are willing to accept them provided they are encouraged to do so by their doctors5.
5 ReferencesR.J.L.F. Loffeld, M.D., Ph.D.
A.B.M.M. van der Putten, M.D.
Ziekenhuis De Heel, 1500 EE Zaandam, the Netherlands1
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 | Medline2
Rauws EAJ ,Tytgat GNJ . Cure of duodenal ulcer associated with eradication of Helicobacter pylori. Lancet 1990;335:1233-1235
CrossRef | Web of Science | Medline3
Borody T ,Andrews P ,Mancuso N ,Jankiewicz E ,Brandl S . Helicobacter pylori reinfection 4 years post-eradication. Lancet 1992;339:1295-1295
CrossRef | Web of Science | Medline4
Peterson WL . Prevention of upper gastrointestinal bleeding. N Engl J Med 1994;330:428-429
Full Text | Web of Science | Medline5
Loffeld RJLF . Treatment of duodenal ulcer disease. Eur J Gastroenterol Hepatol 1993;5:969-971
CrossRef | Web of Science
Author/Editor Response
The authors reply:
To the Editor: I do not agree with Loffeld and van der Putten that our conclusions and results are outdated as a result of research on H. pylori. In my opinion, the current standard of care for patients with a documented history of a bleeding duodenal or gastric ulcer is a full-dose regimen of an H2-receptor antagonist as maintenance therapy1. This recommendation is based on recent data from the Center for Ulcer Research and Education (CURE), which conducted a large study of patients who complied with such a regimen. The rate of recurrent duodenal-ulcer hemorrhage was 2.4 percent, and the rate of recurrent gastric-ulcer hemorrhage was 3.4 percent, with a mean follow-up of 24 months1. Two small studies of the eradication of H. pylori in patients with hemorrhage from peptic ulcers suggest promising short-term results, with few recurrences2,3. However, there were substantial methodologic problems with these studies (such as lack of blinding, failure to eradicate H. pylori, and failure to control for continued use of nonsteroidal antiinflammatory drugs), which limit their generalizability.
Other problems also temper my enthusiasm for H. pylori eradication alone as a treatment in this group of patients with ulcers. First, ingestion of nonsteroidal antiinflammatory drugs or aspirin preceded ulcer hemorrhage in about 50 percent of patients in the CURE study4. Patients must be educated about these drugs and stop using them regardless of the presence or absence of H. pylori, because their use is an independent risk factor for ulcers and hemorrhage1. Second, careful testing has shown that about 20 to 25 percent of patients with hemorrhage in the CURE study do not have H. pylori infection; they will not benefit from empirical treatment to eradicate H. pylori. Third, triple therapy was often poorly tolerated in the CURE study5. About 25 to 30 percent of my patients have not completed two weeks of this therapy because of side effects1,5. Fourth, even with newer, better-tolerated regimens, eradication of H. pylori is not uniform and must be confirmed1. In the United States, noninvasive tests (such as breath testing) are expensive and not widely available. Finally, hemorrhage from an ulcer is not preceded by symptoms in more than half of elderly patients. Recurrent ulcer hemorrhage is extremely dangerous in such patients and is effectively prevented by full-dose H-receptor-antagonist therapy1.
Although the preliminary data on the efficacy of the eradication of H. pylori in patients with prior ulcer hemorrhage are promising,2,3 I look forward to a large, scientifically rigorous study to document whether this new treatment and full-dose H-receptor blockers are of equivalent benefit in such patients. I agree with the recent recommendation of the National Institutes of Health consensus conference1.
5 ReferencesDennis M. Jensen, M.D.
UCLA School of Medicine, Los Angeles, CA 90024-16841
Helicobacter pylori in peptic ulcer disease. NIH Consensus Development Conference, Bethesda, Md., February 7-9, 1994: program and abstracts. Bethesda, Md.: National Institutes of Health, 1994.
2
Graham DY ,Hepps KS ,Ramirez FC ,Lew GM ,Saeed ZA . Treatment of Helicobacter pylori reduces the rate of rebleeding in peptic ulcer disease. Scand J Gastroenterol 1993;28:939-942
CrossRef | Web of Science | Medline3
Labenz J ,Borsch G . Role of Helicobacter pylori eradication in the prevention of peptic ulcer bleeding relapse. Digestion 1994;55:19-23
CrossRef | Web of Science | Medline4
Egan JV ,Jensen DM . Long-term management of patients with bleeding ulcers: rationale, results, and economic impact. Gastrointest Endosc Clin N Am 1991;1:367-3865
Malfertheiner P . Compliance, adverse effects and antibiotic resistance in Helicobacter pylori treatment. Scand J Gastroenterol 1993;196:34-37
CrossRef | Web of Science
Author/Editor Response
Data from the study of patients with nonbleeding duodenal ulcers indicating that the eradication of H. pylori substantially reduces the rate of recurrent ulcers are persuasive1,2. Loffeld and van der Putten make the plausible extrapolation that an ulcer that does not recur cannot rebleed. On the basis of such logic, they recommend discontinuation of maintenance therapy with H-receptor antagonists if H. pylori has been eradicated in patients who have had bleeding ulcers. I believe this advice is premature.
First, the data are not adequate for us to conclude with confidence the long-term (e.g., three-to-five-year) rate of recurrent duodenal ulcers after the eradication of H. pylori. Ulcers do recur, and the recurrence rate may increase with time. What if these recurrent ulcers present as bleeding ulcers? Second, since suitable noninvasive tests to confirm eradication are not marketed in the United States, patients would need to undergo endoscopy to check for successful eradication. Is this cost effective? Third, false negative results in patients with active H. pylori infection occur even with the best diagnostic tests. Such patients would be left unprotected if treatment with H-receptor antagonists were stopped. Finally, there is a subgroup of patients who, either knowingly or inadvertently, will use nonsteroidal antiinflammatory drugs3. Maintenance therapy with H-receptor antagonists provides protection for such patients4.
One report suggests that bleeding does not recur after the eradication of H. pylori5. However, the size of the sample in this trial was small, and the follow-up short. I stand by my call for long-term, randomized trials to assess the relative roles of the eradication of H. pylori and maintenance therapy with H-receptor antagonists in patients with bleeding duodenal ulcers. Until the results of these trials are available, my advice to clinicians is to eliminate as many risk factors as possible by advising such patients to stop smoking cigarettes and avoid using nonsteroidal antiinflammatory drugs, giving them a course of therapy to eradicate H. pylori, and prescribing full-dose, maintenance therapy with H-receptor antagonists. I do not recommend the use of endoscopy to confirm eradication, and the savings can offset the cost of the H-receptor antagonist.
If long-term trials prove that the eradication of H. pylori is sufficient to prevent rebleeding and if a noninvasive test becomes available to confirm the absence of infection, maintenance therapy with H-receptor antagonists can be stopped. Although my approach may ultimately prove overly cautious, I take bleeding ulcers very seriously and believe it is in our patients' best interest to be cautious until convincing data are forthcoming.
5 ReferencesWalter L. Peterson, M.D.
University of Texas Southwestern Medical School at Dallas, Dallas, TX 752351
Graham DY ,Lew GM ,Klein PD , et al. Effect of treatment of Helicobacter pylori infection on the long-term recurrence of gastric or duodenal ulcer: a randomized, controlled study. Ann Intern Med 1992;116:705-708
Web of Science | Medline2
Hentschel E ,Brandstatter G ,Dragosics B , et al. Effect of ranitidine and amoxicillin plus metronidazole on the eradication of Helicobacter pylori and the recurrence of duodenal ulcer. N Engl J Med 1993;328:308-312
Full Text | Web of Science | Medline3
Lanas A ,Sekar MC ,Hirschowitz BI . Objective evidence of aspirin in both ulcer and nonulcer upper and lower gastrointestinal bleeding. Gastroenterology 1992;103:862-869
Web of Science | Medline4
Robinson MG ,Griffin JW Jr ,Bowers J , et al. Effect of ranitidine on gastroduodenal mucosal damage induced by nonsteroidal antiinflammatory drugs. Dig Dis Sci 1989;34:424-428
CrossRef | Web of Science | Medline5
Graham DY ,Hepps KS ,Ramirez FC ,Lew GM ,Saeed ZA . Treatment of Helicobacter pylori reduces the rate of rebleeding in peptic ulcer disease. Scand J Gastroenterol 1993;28:939-942
CrossRef | Web of Science | Medline
