Correspondence
Celecoxib versus Diclofenac and Omeprazole to Prevent Recurrent Ulcer Bleeding
N Engl J Med 2003; 348:2464-2466June 12, 2003
- Article
To the Editor:
In their report on the use of celecoxib as compared with diclofenac plus omeprazole to reduce the risk of recurrent ulcer bleeding in patients with arthritis, Chan et al. (Dec. 26 issue)1 state that the probability of recurrent bleeding was 4.9 percent in the celecoxib-treated patients (7 of 144) and 6.4 percent in those receiving the combination of diclofenac and omeprazole (9 of 143). These bleeding complications were considered by the adjudication committee to meet the criteria for recurrent ulcer bleeding, which was the primary end point. However, for the purposes of clinical practice, the eight other gastrointestinal events (two in celecoxib-treated patients and six in patients treated with diclofenac plus omeprazole), which were not adjudicated as meeting the criteria for the primary end point, are also clinically relevant and must be taken into account. From this viewpoint, the percentages of patients with bleeding were actually 6.2 percent and 10.5 percent, respectively (per year, 12.6 percent and 21.0 percent, respectively).
When these rates are considered in combination with the high incidence of other adverse events, particularly unexpectedly high frequencies of renal side effects, it appears that celecoxib and diclofenac plus omeprazole are contraindicated for the category of patients studied — that is, patients with recent ulcer bleeding. It is regrettable that this overall safety profile was underexposed in the article as well as in the accompanying editorial by Graham,2 particularly since a medication such as acetaminophen or tramadol might be an effective and safe option for patients who have contraindications to nonsteroidal antiinflammatory drugs (NSAIDs) or coxibs.3
3 ReferencesMichael T. Nurmohamed, M.D., Ph.D.
Willem F. Lems, M.D., Ph.D.
Vrije Universiteit Medical Center, 1007 MB Amsterdam, the Netherlands
mt.nurmohamed@planet. nl 1
Chan FKL ,Hung LCT ,Suen BY , et al. Celecoxib versus diclofenac plus omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. N Engl J Med 2002;347:2104-2110
Full Text | Web of Science | Medline2
Graham DY . NSAIDs, Helicobacter pylori, and Pandora's box. N Engl J Med 2002;347:2162-2164
Full Text | Web of Science | Medline3
Nurmohamed MT ,van Halm VP ,Dijkmans BAC . Cardiovascular risk profile of antirheumatic agents in patients with osteoarthritis and rheumatoid arthritis. Drugs 2002;62:1599-1609
CrossRef | Web of Science | Medline
To the Editor:
Current evidence indicates that the use of NSAIDs also increases the risk of lower gastrointestinal tract complications and that the magnitude of the increase is similar to that observed with respect to upper gastrointestinal tract complications.1 Randomized, controlled trials have confirmed the results of previous epidemiologic studies. In the Misoprostol Ulcer Complication Outcomes Safety Assessment (MUCOSA) study,2 95 of 242 suspicious complication events were upper gastrointestinal tract events, but 147 were lower gastrointestinal tract events. The Vioxx Gastrointestinal Outcomes Research (VIGOR) study showed that, as compared with naproxen, rofecoxib was associated with more than a 50 percent reduction in the risk of both upper and lower gastrointestinal tract events.3,4
On the basis of their study, Chan and colleagues conclude that among patients with a recent history of ulcer bleeding, treatment with celecoxib was as effective as treatment with diclofenac plus omeprazole. They report that of 24 cases of serious gastrointestinal events, 16 were upper gastrointestinal tract bleeding events, but the rest were lower gastrointestinal tract events. If all serious gastrointestinal events are considered, the proportion of patients with bleeding was 6.2 percent (9 of 144 in the celecoxib group) as compared with 10.5 percent (15 of 143) in the combination-therapy group (relative risk, 0.59; 95 percent confidence interval, 0.26 to 1.31). From this perspective, the data show a trend in favor of the cyclooxygenase-2 (COX-2)–inhibitor group. Since the study by Chan et al. has shown that a significant proportion of patients still have recurrent ulcer bleeding, the combination of a coxib and a proton-pump inhibitor may well reduce the risk of ulcer bleeding by another 50 percent and provide the additional benefit of a 50 to 60 percent reduction in the incidence of lower gastrointestinal tract complications.
4 ReferencesAngel Lanas, M.D., D.Sc.
University Hospital, 50009 Zaragoza, Spain
alanas@posta.unizar. es 1
Lanas A ,Sekar MC ,Hirschowitz BI . Objective evidence of aspirin use in both ulcer and nonulcer upper and lower gastrointestinal bleeding. Gastroenterology 1992;103:862-869
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
Bombadier C ,Laine L ,Reicin A , et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000;343:1520-1528
Full Text | Web of Science | Medline4
Laine L ,Connors LG ,Reicin A , et al. Serious lower gastrointestinal clinical events with nonselective NSAID or coxib use. Gastroenterology 2003;124:288-292
CrossRef | Web of Science | Medline
To the Editor:
In his provocative editorial, Graham exhorts us to test for and eradicate Helicobacter pylori infection “among all those who require long-term . . . aspirin therapy.” Does he include in this group the tens of millions of Americans who should receive aspirin for the prevention of cardiovascular events? The American Diabetes Association advises that all persons with diabetes and any additional risk factor for cardiovascular disease (including an age of more than 30 years) receive daily aspirin.1 Recent American Heart Association guidelines2 cast an even broader net and advocate the prescription of low-dose daily aspirin (75 to 160 mg) for anyone with even a 10 percent 10-year risk of a cardiovascular event. The cost of such intervention, in human terms, seems modest: in its review of trials of aspirin for the primary prevention of cardiovascular events, the U.S. Preventive Services Task Force noted that the excess risk of major gastrointestinal hemorrhage as a result of daily aspirin use was on the order of 1 event per 1000 persons treated per year.3 With this low event rate, an approach that involves testing and treating millions of Americans for H. pylori infection does not appear to be appropriate or cost effective.
3 ReferencesDonogh F. McKeogh, M.B.
Oregon Health and Science University, Portland, OR 97239
mckeoghd@ohsu.edu 1
American Diabetes Association
CrossRef | Web of Science2
Pearson TA ,Blair SN ,Daniels SR , et al. AHA guidelines for primary prevention of cardiovascular disease and stroke: 2002 update: consensus panel guide to comprehensive risk reduction for adult patients without coronary or other atherosclerotic vascular diseases. Circulation 2002;106:388-391
CrossRef | Web of Science | Medline3
Hayden M ,Pignone M ,Phillips C ,Mulrow C . Aspirin for the primary prevention of cardiovascular events: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2002;136:161-172
Web of Science | Medline
Author/Editor Response
Among patients with a recent episode of ulcer bleeding and concomitant risk factors, renal adverse events are common, and neither treatment can completely eliminate the risk of recurrent bleeding. These points were emphasized in the Abstract of our article and in the summary paragraph of the Discussion. Given the substantial risk of gastrointestinal and renal toxicity, we agree that these high-risk patients should avoid using NSAIDs or COX-2–selective NSAIDs if simple analgesics can relieve their symptoms. Lower gastrointestinal tract bleeding is a known but often overlooked complication of traditional NSAIDs.1 Use of NSAIDs with antisecretory drugs prevents upper but not lower gastrointestinal tract complications. Emerging data suggest that COX-2–selective NSAIDs may reduce the risk of lower gastrointestinal tract events.2 Our data showed a trend in favor of celecoxib in terms of lower gastrointestinal tract complications. We did not make any speculation based on post hoc analysis without a predefined end point. Future studies will be needed to determine whether the combination of a COX-2–selective NSAID plus a proton-pump inhibitor will further reduce the risk of both upper and lower tract gastrointestinal complications.
2 ReferencesFrancis K.L. Chan, M.D.
Prince of Wales Hospital, Hong Kong, China
fklchan@cuhk.edu. hk 1
Allison MC ,Howatson AG ,Torrance CJ ,Lee FD ,Russell RI . Gastrointestinal damage associated with the use of nonsteroidal antiinflammatory drugs. N Engl J Med 1992;327:749-754
Full Text | Web of Science | Medline2
Laine L ,Connors LG ,Reicin A , et al. Serious lower gastrointestinal clinical events with nonselective NSAID or coxib use. Gastroenterology 2003;124:288-292
CrossRef | Web of Science | Medline
Author/Editor Response
The risk of a major gastrointestinal event among users of low-dose aspirin ranges from 1.5 to 2.5 percent per year.1 The approximately twofold increase in the risk associated with H. pylori infection is built into those estimates.2 Thus, with a very conservative estimate of risk (about half the actual estimates), if there were 10 million long-term aspirin users in the United States, 1 percent would have a major upper gastrointestinal tract event, with a 5 percent risk of death. Aspirin use thus accounts for more than 100,000 events (mostly bleeding agents) and 5000 deaths per year. This rate would be reduced by half among the subgroup in which H. pylori infection was eradicated. Any savings would accumulate.
Many would add a proton-pump inhibitor for prophylaxis, but this is also associated with a rapid acceleration of the severity of H. pylori corpus gastritis.3 Although the long-term outcome is unknown, corpus gastritis has also been closely linked to the development of gastric cancer.4 The benefits of H. pylori eradication include a halving of the risk of NSAID- or aspirin-related major gastrointestinal events, healing of gastritis, prevention of transmission of the infection, prevention of H. pylori ulcer disease, and a reduced risk of gastric cancer. H. pylori infection is a serious, transmissible infectious disease. Like syphilis and tuberculosis, it is usually latent. H. pylori is always transmissible,5 and the risk of a long-term symptomatic outcome is actually greater than that with latent syphilis or tuberculosis. With so much to gain and nothing to lose, why not provide screening and treatment for H. pylori infection?
5 ReferencesDavid Y. Graham, M.D.
Veterans Affairs Medical Center, Houston, TX 77030
dgraham@bcm.tmc. edu 1
Derry S ,Loke YK . Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. BMJ 2000;321:1183-1187
CrossRef | Web of Science | Medline2
Huang JQ ,Sridhar S ,Hunt RH . Role of Helicobacter pylori infection and non-steroidal anti-inflammatory drugs in peptic-ulcer disease: a meta-analysis. Lancet 2002;359:14-22
CrossRef | Web of Science | Medline3
Graham DY ,Opekun AR ,Yamaoka Y ,Osato MS ,el-Zimaity HM . Early events in proton pump inhibitor-associated exacerbation of corpus gastritis. Aliment Pharmacol Ther 2003;17:193-200
CrossRef | Web of Science | Medline4
Uemura N ,Okamoto S ,Yamamoto S , et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med 2001;345:784-789
Full Text | Web of Science | Medline5
Graham DY . Can therapy even be denied for Helicobacter pylori infection? Gastroenterology 1997;113:Suppl:S113-S117
Web of Science | Medline
- Citing Articles (2)
Citing Articles
1
James M Scheiman. (2005) What are the effects of cyclooxygenase-2-specific inhibitors on the small bowel?. Nature Clinical Practice Gastroenterology & Hepatology 2:5, 212-213
CrossRef2
(2003) Current awareness: Pharmacoepidemiology and drug safety. Pharmacoepidemiology and Drug Safety 12:8, 699-617
CrossRef
