Correspondence
Therapies for Ulcers Associated with Nonsteroidal Antiinflammatory Drugs
N Engl J Med 1998; 339:349-351July 30, 1998
- Article
To the Editor:
The articles by Yeomans et al. and Hawkey et al. (March 12 issue) demonstrate the efficacy of omeprazole as compared with either ranitidine1 or misoprostol2 for ulcers associated with nonsteroidal antiinflammatory drugs (NSAIDs). Thus, all patients who are receiving NSAID therapy may be advised to take omeprazole as well. This possibility raises an important issue regarding coexisting gastric infection with Helicobacter pylori. In both studies, H. pylori–positive patients were not treated for this infection and as a consequence had better short-term healing and remission rates than H. pylori–negative patients. Patients with H. pylori infection who are receiving long-term omeprazole therapy have a 6.1 percent annual incidence of atrophic gastritis,3 a premalignant condition. The World Health Organization has classified H. pylori as a class 1 carcinogen.4 Thus, there is real potential for gastric carcinoma among H. pylori–positive patients who are receiving long-term omeprazole therapy.
Elliott and Yeomans have recommended the eradication of H. pylori in patients with NSAID-induced ulceration.5 We favor the eradication of H. pylori in patients for whom long-term omeprazole therapy is prescribed even if, as in the case of NSAID-induced ulceration, the therapy is slightly less effective in the short term.
5 ReferencesFrank Weilert, M.B., B.Ch.
Anthony C. Smith, M.B., Ch.B.
Peter L. Stokes, M.D.
Waikato Hospital, Hamilton, New Zealand1
Yeomans ND ,Tulassay Z ,Juhasz L , et al. A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs. N Engl J Med 1998;338:719-726
Full Text | Web of Science | Medline2
Hawkey CJ ,Karrasch JA ,Szczepanski L , et al. Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. N Engl J Med 1998;338:727-734
Full Text | Web of Science | Medline3
Kuipers EJ ,Lundell L ,Klinkenberg-Knol EC , et al. Atrophic gastri-tis and Helicobacter pylori infection in patients with reflux esophagitis treated with omeprazole or fundoplication. N Engl J Med 1996;334:1018-1022
Full Text | Web of Science | Medline4
IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. IARC monographs on the evaluation of carcinogenic risks to humans. Vol. 61. Schistosomes, liver flukes and Helicobacter pylori. Lyon, France: International Agency for Research on Cancer, 1994.
5
Elliott SL, Yeomans ND. Eradication of Helicobacter pylori. Royal Australasian College of Physicians, February 1998.
To the Editor:
Although the studies by Yeomans et al. and Hawkey et al. were both very well designed, the clinical impact of the findings remains uncertain. Many investigators have emphasized the importance of distinguishing between endoscopic lesions and serious gastrointestinal complications such as bleeding and perforation induced by NSAIDs.1 What is the relevance of preventing minor lesions (i.e., erosions or tiny ulcers) if they do not cause complications? One might argue that ulcer complications will not develop if these endoscopic lesions do not exist. Nevertheless, only a very small percentage of the lesions detected by endoscopy would actually progress to clinically important ulcers.1 In fact, in these two large-scale studies, only two patients who were receiving placebo had ulcer complications. Interestingly, during the maintenance phase a bleeding ulcer developed in one patient who was receiving omeprazole but in none of those who were receiving ranitidine or misoprostol. Would the improvement in endoscopic appearance be translated into clinical benefit?
The finding that omeprazole is more effective than ranitidine was based on the use of a standard dose of ranitidine. A previous study showed that high doses of a histamine H2-receptor antagonist (famotidine) can effectively prevent NSAID-induced gastric and duodenal ulcers.2 The reported cumulative six-month incidence of gastric ulcer was only 8 percent. It would be interesting to compare the efficacy of omeprazole with that of a high-dose H2-receptor antagonist.
Silverstein et al. showed that misoprostol could reduce serious NSAID-induced gastrointestinal complications.3 However, the estimated cost is enormous: $119,000 to prevent a single episode of gastrointestinal bleeding.4 Contrary to the finding of Yeomans et al. that H. pylori infection is associated with protection against NSAID-induced ulcers, we recently showed that eradicating H. pylori infection before commencing NSAID therapy significantly reduced the occurrence of ulcers by a factor of almost four.5 The degree of protection conferred by a single week of antimicrobial agents was similar to that provided by maintenance therapy with acid-suppressive drugs. Before proton-pump inhibitors can be generally recommended to NSAID users for the prevention of peptic diseases, the cost of various treatment strategies has to be considered.
5 ReferencesFrancis K.L. Chan, M.D., M.R.C.P.
Joseph J.Y. Sung, M.D., F.R.C.P., Ph.D.
Chinese University of Hong Kong, Shatin, Hong Kong, China1
McCarthy DM . NSAID-induced gastrointestinal damage: a critical review of prophylaxis and therapy. J Clin Gastroenterol 1990;12:Suppl 2:S13-S20
CrossRef | Web of Science | Medline2
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 | Medline3
Silverstein FE ,Graham DY ,Senior JR , et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal antiinflammatory drugs: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995;123:241-249
Web of Science | Medline4
Levine JS . Misoprostol and nonsteroidal anti-inflammatory drugs: a tale of effects, outcomes, and costs. Ann Intern Med 1995;123:309-310
Web of Science | Medline5
Chan FK ,Sung JJ ,Chung SC , et al. Randomised trial of eradication of Helicobacter pylori before non-steroidal anti-inflammatory drug therapy to prevent peptic ulcers. Lancet 1997;350:975-979
CrossRef | Web of Science | Medline
To the Editor:
In the study by Hawkey et al. assessing the effectiveness of omeprazole and misoprostol, treatment failure during the maintenance phase was defined not only as recurrence of an ulcer or the development of more than 10 erosions, but also as the appearance of moderate symptoms of dyspepsia. This is surprising, since most NSAID-related lesions are asymptomatic and the correlation between symptoms and mucosal damage is poor.1 The use of this definition introduces an evident bias in favor of omeprazole, a powerful gastric acid inhibitor that, predictably, is particularly effective in controlling symptoms such as epigastric pain and heartburn.
The difference in the relapse rates between the misoprostol group and the omeprazole group is mainly due to differences in the recurrence of dyspeptic symptoms (19 percent and 7 percent, respectively); the rates of recurrence of ulcers, erosions, or both were the same in the two groups (28 percent). On the other hand, misoprostol was superior to omeprazole in terms of both healing and preventing relapses of mucosal erosions. To a certain extent, these findings were also predictable, since local ischemia has a key role in the development of gastroduodenal erosions.2,3 Gastric acid inhibitors are scarcely effective in the treatment of erosions2,3; better results are obtained with the use of agents that increase mucosal blood flow.2 Prostaglandin derivatives such as misoprostol, among their other gastroprotective properties, reportedly improve the gastric microcirculation.4
4 ReferencesMario Guslandi, M.D.
S. Raffaele Hospital, 20132 Milan, Italy1
Shallcross TM ,Heatley RV . Effect of non-steroidal anti-inflammatory drugs on dyspeptic symptoms. BMJ 1990;300:368-369
CrossRef | Web of Science | Medline2
Guslandi M ,Daniotti S ,Ballarin E ,Basilico M ,Tittobello A . Pirenzepine in erosive duodenitis: a controlled clinical trial versus ranitidine. Scand J Gastroenterol 1985;20:751-755
CrossRef | Web of Science | Medline3
Guslandi M ,Sorghi M ,Foppa A ,Tittobello A . Mucosal blood flow in erosive duodenitis. J Clin Gastroenterol 1993;17:201-203
CrossRef | Web of Science | Medline4
Hui WM ,Chen BW ,Cho CH ,Lam SK ,Luk CT . The effect of misoprostol, omeprazole and sucralfate on nicotine- and ethanol-induced gastric injury and gastric mucosal blood flow: a comparative study. J Gastroenterol Hepatol 1990;5:653-658
CrossRef | Web of Science | Medline
To the Editor:
In their comparison of the efficacy of omeprazole with that of ranitidine, Yeomans et al. did not discuss the effects of the specific types of NSAIDs used by the patients. NSAIDs differ in their ability to cause serious gastrointestinal side effects. Among the NSAIDs taken by the study patients, diclofenac and naproxen have a similar adjusted relative risk of causing upper gastrointestinal bleeding and perforation. However, the risk of complications with indomethacin is more than three times as high as the risks associated with diclofenac and naproxen.1 How did omeprazole and ranitidine compare when the results were analyzed according to the type of NSAID used?
1 ReferencesPaul J. DeMarco, M.D.
Stacey Schulman, M.D.
Alexander R. Shikhman, M.D., Ph.D.
Scripps Clinic and Research Foundation, La Jolla, CA 920371
Garcia Rodriguez LA ,Jick H . Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs. Lancet 1994;343:769-772
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: When our trials were planned, there was no consensus on the need for the eradication of H. pylori, even for patients who were not using NSAIDs. Direct but conflicting evidence regarding the need for eradication in NSAID users only emerged after our studies were finished. Chan and colleagues reported benefit over a period of two months in patients without a history of ulcer disease who were starting NSAID therapy for the first time.1 Conversely, we found that patients who were already taking NSAIDs who had a documented ulcer or who had had one in the past derived no benefit over a six-month period.2 Although H. pylori has been declared a carcinogen, eradication of this agent to prevent gastric cancer is not widely practiced for lack of evidence. Such a strategy would seem to be particularly unjustified in patients using NSAIDs, since these patients have a substantially reduced incidence of gastric cancer, which has been ascribed to the use of NSAIDs.3
At present, eradication of H. pylori is not an evidence-based approach to the care of patients who are already taking NSAIDs, particularly if they require acid-suppressive prophylaxis, since our studies showed that this type of prophylaxis is less effective in patients who are H. pylori–negative than in those who are H. pylori–positive.
Chan and Sung argue that our six-month endoscopic study might not predict clinically important end points such as complications. They advocated the eradication of H. pylori on the basis of a two-month endoscopic study.1 Until recently, endoscopy has been the standard method for assessing ulcer healing and prevention. Since the publication of the study by Silverstein et al.,4 it has become commonplace to suggest that ulcer complications should become the favored trial end point.
The results of prevention of ulcer complications with the use of both misoprostol4 and omeprazole5 so closely reflect endoscopic data as to validate endoscopy as a surrogate predictor of complications. Given this and the organizational problems of mounting trials targeted at ulcer complications, it becomes hard to justify the use of such studies to replace rather than supplement the endoscopic approach.
In all trials of treatments to prevent ulcers, patients in whom unacceptable dyspepsia develops but who are found not to have an ulcer are withdrawn, often on an ad hoc basis. We believe that having explicit rules for handling such patients was a strength rather than a weakness of our studies. Guslandi correctly points out that omeprazole is better tolerated as prophylaxis than misoprostol, controls symptoms better, and is overall of similar effectiveness for endoscopically detected lesions. These advantages seem to make its use worthwhile.
5 ReferencesChristopher J. Hawkey, D.M.
University Hospital, Nottingham NG7 2UH, United KingdomNeville D. Yeomans, M.D.
Western Hospital, Footscray, Victoria 3011, Australia1
Chan FK ,Sung JJ ,Chung SC , et al. Randomised trial of eradication of Helicobacter pylori before non-steroidal anti-inflammatory drug therapy to prevent peptic ulcers. Lancet 1997;350:975-979
CrossRef | Web of Science | Medline2
Hawkey CJ . Large six month trial of Helicobacter pylori eradication for lesion prevention in NSAID users. Gut 1997;41:Suppl:A197-A197 abstract.
Web of Science3
Thun MJ ,Namboodiri MM ,Calle EE ,Flanders WD ,Heath CW Jr . Aspirin use and risk of fatal cancer. Cancer Res 1993;53:1322-1327
Web of Science | Medline4
Silverstein FE ,Graham DY ,Senior JR , et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal antiinflammatory drugs: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995;123:241-249
Web of Science | Medline5
Chan FKL ,Sung JY ,Suen R , et al. Eradication of H. pylori versus maintenance acid suppression to prevent recurrent ulcer hemorrhage in high risk NSAID users: a prospective randomized study. Gastroenterology 1998;114:A87-A87 abstract.
CrossRef | Web of Science
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Denis M. McCarthy. (2001) Prevention and treatment of gastrointestinal symptoms and complications due to NSAIDs. Best Practice & Research Clinical Gastroenterology 15:5, 755-773
CrossRef4
Maarten Boers. (2001) NSAIDS and selective COX-2 inhibitors: competition between gastroprotection and cardioprotection. The Lancet 357:9264, 1222-1223
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