032901 preventing recurrent upper gastrointestinal bleeding

P R EV E N T I N G U P P E R GAST R O I N T E ST I N A L B L E E D I N G I N PAT I E N T S W I T H H E L I C O B AC T E R PY LO R I I N F EC T I O N
PREVENTING RECURRENT UPPER GASTROINTESTINAL BLEEDING
IN PATIENTS WITH HELICOBACTER PYLORI INFECTION WHO ARE TAKING
LOW-DOSE ASPIRIN OR NAPROXEN
FRANCIS K.L. CHAN, M.D., S.C. SYDNEY CHUNG, M.D., BING YEE SUEN, R.N., YUK TONG LEE, M.D., WAI KEUNG LEUNG, M.D., VINCENT K.S. LEUNG, M.D., JUSTIN C.Y. WU, M.D., JAMES Y.W. LAU, M.D., YUI HUI, M.D., MOON SING LAI, M.D., HENRY L.Y. CHAN, M.D., AND JOSEPH J.Y. SUNG, M.D., PH.D.
ABSTRACT
Background
gastrointestinal bleeding continue to take low-dose aspirin for cardiovascular prophylaxis or other non- steroidal antiinflammatory drugs (NSAIDs) for mus- increasingly used for cardiovascular prophylaxis, but culoskeletal pain. It is uncertain whether infection with it doubles the risk of bleeding ulcers, even at doses Helicobacter pylori is a risk factor for bleeding in such as low as 75 mg daily.1 Other NSAIDs are commonly taken for musculoskeletal pain. Epidemiologic stud- Methods
We studied patients with a history of up- ies have shown that the use of NSAIDs increases the per gastrointestinal bleeding who were infected with risk of ulcer complications by a factor of 4.2 A his- H. pylori and who were taking low-dose aspirin or tory of upper gastrointestinal bleeding is a signifi- other NSAIDs. We evaluated whether eradication ofthe infection or omeprazole treatment was more ef- cant risk factor for recurrent bleeding in those taking fective in preventing recurrent bleeding. We recruited low-dose aspirin3 or other NSAIDs.3,4 To date, there patients who presented with upper gastrointestinal are few strategies that effectively prevent ulcers from bleeding that was confirmed by endoscopy. Their ul- bleeding in people who take aspirin or other NSAIDs cers were healed by daily treatment with 20 mg of omeprazole for eight weeks or longer. Then, those One approach is concurrent therapy with proton- who had been taking aspirin were given 80 mg of pump inhibitors. Recent epidemiologic data suggest aspirin daily, and those who had been taking other that this treatment reduces the risk of bleeding in pa- NSAIDs were given 500 mg of naproxen twice daily tients taking low-dose aspirin3 or other NSAIDs.3,5 for six months. The patients in each group were then However, the long-term cost of this therapy would be randomly assigned separately to receive 20 mg ofomeprazole daily for six months or one week of erad- ication therapy, consisting of 120 mg of bismuth sub- Another approach is the eradication of Helicobacter citrate, 500 mg of tetracycline, and 400 mg of metroni- pylori infection.6,7 It is uncertain whether H. pylori dazole, all given four times daily, followed by placebo infection is a risk factor for bleeding ulcers in people who are taking aspirin or other NSAIDs. There are Results
data to suggest that H. pylori increases,8 has no effect were taking aspirin and 150 of whom were taking other on,9,10 or even decreases11 the risk of bleeding among NSAIDs). Among those taking aspirin, the probability users of aspirin or other NSAIDs. It is not known of recurrent bleeding during the six-month period was whether eradicating the infection would substantial- 1.9 percent for patients who received eradication ly reduce the risk of bleeding ulcers in those taking therapy and 0.9 percent for patients who receivedomeprazole (absolute difference, 1.0 percent; 95 per- low-dose aspirin or other NSAIDs and would thus cent confidence interval for the difference, ¡1.9 to obviate the need for acid-suppressive therapy.
3.9 percent). Among users of other NSAIDs, the prob- We hypothesized that eradicating H. pylori infection ability of recurrent bleeding was 18.8 percent for pa- was equivalent to maintenance therapy with omep- tients receiving eradication therapy and 4.4 percent razole in terms of preventing recurrent upper gastro- for those treated with omeprazole (absolute differ- intestinal bleeding in people with H. pylori infection ence, 14.4 percent; 95 percent confidence interval for who were taking low-dose aspirin or other NSAIDs.
the difference, 4.4 to 24.4 percent; P=0.005).
Conclusions
Among patients with H. pylori infec- tion and a history of upper gastrointestinal bleeding Patients
who are taking low-dose aspirin, the eradication of This study was a randomized comparison of the eradication of H. pylori is equivalent to treatment with omeprazole H. pylori and treatment with omeprazole for the prevention of re- in preventing recurrent bleeding. Omeprazole is su-perior to the eradication of H. pylori in preventing From the Departments of Medicine and Therapeutics (F.K.L.C., Y.T.L., recurrent bleeding in patients who are taking other W.K.L., J.C.Y.W., Y.H., H.L.Y.C., J.J.Y.S.) and Surgery (S.C.S.C., B.Y.S., NSAIDs, such as naproxen. (N Engl J Med 2001;344: J.Y.W.L.), Prince of Wales Hospital, Chinese University of Hong Kong; and the Medical Unit, Alice Ho Miu Ling Nethersole Hospital (V.K.S.L.,M.S.L.) — all in Hong Kong. Address reprint requests to Dr. Francis K.L.
Copyright 2001 Massachusetts Medical Society.
Chan at the Department of Medicine and Therapeutics, Prince of WalesHospital, 30–32 Ngan Shing St., Shatin, Hong Kong, China, or at [email protected].
N Engl J Med, Vol. 344, No. 13 · March 29, 2001 · www.nejm.org · 967
Downloaded from www.nejm.org at UNIVERSITEIT MAASTRICHT on September 2, 2009 . Copyright 2001 Massachusetts Medical Society. All rights reserved. The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne current upper gastrointestinal bleeding in patients with H. pylori Statistical Analysis
infection who were taking low-dose aspirin for coronary heart dis- We considered that the effect of the eradication of H. pylori ease or stroke and patients who were infected with H. pylori who would be equivalent to the effect of treatment with omeprazole were taking NSAIDs other than aspirin for arthritis. The protocol if the upper limit of the 95 percent confidence interval of the dif- was approved by the ethics committee at the Chinese University ference in the probability of recurrent bleeding at six months did of Hong Kong, and all participants provided written informed not exceed 5 percentage points. The power calculations were applied separately for the aspirin and the naproxen groups. On the assump- From May 1995 to January 2000, we screened users of low-dose tion that omeprazole would reduce the six-month probability of aspirin («325 mg per day) or other NSAIDs who presented with recurrent bleeding to 1.5 percent, we calculated that 125 patients upper gastrointestinal bleeding at the Prince of Wales Hospital.
would be required in the eradication-therapy group and 125 pa- The patients underwent endoscopy within 24 hours after presen- tients in the omeprazole group to give the study a power of 80 tation to identify the site of bleeding and determine their H. pylori percent at a 5 percent significance level with the use of a one-sided status. The inclusion criteria were endoscopically confirmed ul- equivalence test of proportions (PASS software, version 2000, cers or bleeding erosions, histologically documented H. pylori in- fection, and long-term use or anticipated long-term use (i.e., use for Because recurrent bleeding is a serious complication, two planned at least six months) of low-dose aspirin or other NSAIDs. The ex- interim analyses were performed in July 1997 and July 1999 to clusion criteria were concomitant use of nonaspirin NSAIDs and compare the safety of the two treatments. To terminate the trial if low-dose aspirin, corticosteroids, or anticoagulants; a history of gas- one treatment was markedly inferior to the other, we used a pre- tric surgery; or the presence of erosive esophagitis, gastroesoph- defined early stopping rule that specified a level of significance of ageal varices, gastric-outlet obstruction, renal failure (defined by 0.0005 for the first analysis and 0.01 for the second analysis.12 a serum creatinine level of more than 2.26 mg per deciliter [200 The first interim results did not justify early termination.13 The sec- µmol per liter]), terminal illness, or cancer.
ond interim analysis included data for 150 patients in the naproxen All patients were given 20 mg of omeprazole daily for eight group (median follow-up, 6 months; range, 10 days to 6 months) weeks to promote ulcer healing. Aspirin and other NSAIDs were and 180 in the aspirin group (median follow-up, 6 months; range, withheld during this period. Follow-up endoscopy was performed 2 to 6 months). The results showed that in the aspirin group, the by one investigator to determine whether the ulcer had healed. Un- probability of recurrent bleeding was similar for patients receiving healed ulcers were treated with additional courses of omeprazole either treatment (P=1.00). In the naproxen group, however, there until complete healing occurred, as determined endoscopically.
was a marked difference in the probability of recurrent bleeding:it was 18.8 percent among patients treated with eradication therapy Randomization
and 4.4 percent among patients treated with omeprazole (P= Eligible patients underwent randomization once the healing of 0.005). Because this difference reached the criterion for early stop- ulcers was confirmed. Patients with coronary heart disease or stroke ping, the assignment of patients to the naproxen group was ter- were given 80 mg of aspirin daily for six months and patients with minated after the second interim analysis. The final analysis was arthritis were given 500 mg of naproxen twice daily for six months.
performed in July 2000, after 250 patients in the aspirin group had Randomization was carried out separately in these two groups. In completed the study. Data analyses were carried out exclusively each group, the patients were randomly assigned to receive 20 mg by a data-review committee at these specified dates.
of omeprazole daily for six months or a one-week course of eradi- The Kaplan–Meier method was used to estimate the likelihood cation therapy (consisting of 120 mg of bismuth subcitrate, 500 mg of reaching the end point of recurrent upper gastrointestinal bleed- of tetracycline, and 400 mg of metronidazole, all of which were giv- ing within six months according to the intention-to-treat princi- en four times daily), followed by an identical-appearing omeprazole ple. The log-rank test was used for comparisons between treat- placebo. Randomization was carried out through the use of com- ment groups. The intention-to-treat analysis included all patients puter-generated lists of random numbers in blocks of 10. Consecu- who had taken at least one dose of a study medication. Failure to tively numbered, sealed packages of drugs were dispensed by a re- take at least 70 percent of the study drugs or use of nonstudy drugs, including antiulcer agents, corticosteroids, anticoagulants,NSAIDs other than aspirin or naproxen, or antiplatelet agents, was Monitoring
considered a protocol violation. In the naproxen group, a Cox One investigator monitored the patients’ hemoglobin levels, se- proportional-hazards model was used to adjust for possibly con- rum biochemical values, and symptoms of recurrent bleeding every founding covariates, including age, the presence or absence of oth- eight weeks for six months. A research nurse evaluated drug compli- er illnesses, location of the ulcers (stomach, duodenum, or both), ance and adverse events. A direct telephone line was provided so that diameter of the ulcers (greater than 2 cm, or 2 cm or less), and the patients could report any serious adverse events. The final H. py- the presence or absence of previous ulcer disease (symptomatic lori status was determined by a carbon-13 urea breath test four ulcer or bleeding ulcers).14 The patients’ base-line characteristics weeks after the study medications were stopped. Patients who with- were compared with use of Student’s t-test for parametric data, drew early were reassessed at six months for recurrent bleeding.
the Mann–Whitney U test for nonparametric data, and Pearson’schi-square test for proportions (SPSS software, version 10.0, SPSS, End Point
Chicago). All P values are two-tailed.
The end point was recurrent upper gastrointestinal bleeding with- in six months, which was defined as hematemesis or melena with ul-cers or bleeding erosions confirmed by endoscopy or a decrease in Study Groups
the hemoglobin level of at least 2 g per deciliter in the presence of We screened 896 users of low-dose aspirin (from endoscopically proved ulcers or erosions. An ulcer was defined as a May 1995 through January 2000) or other NSAIDs circumscribed mucosal break that was at least 0.5 cm in diameterand had a perceptible depth, and a bleeding erosion was defined as (from May 1995 through July 1999) who presented a flat mucosal break of any size in the presence of blood in the stom- with upper gastrointestinal bleeding. A total of 58 ach. Endoscopy was performed if hematemesis or melena was con- percent of aspirin users and 49 percent of users of firmed by the admitting medical officer. Undocumented hematem- other NSAIDs were positive for H. pylori infection.
esis or melena or the presence of heme-positive stool was not an We enrolled 400 patients with H. pylori infection: indication for endoscopy. Members of an independent adjudicationcommittee who were not aware of the patients’ treatment assign- 250 in the aspirin group and 150 in the naproxen ments performed endoscopy and determined the source of bleeding.
group (Fig. 1). The study groups were similar with re- 968 · N Engl J Med, Vol. 344, No. 13 · March 29, 2001 · www.nejm.org
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2 Died1 Was taking warfarin1 Had gastric cancer1 Had an unhealed ulcer Figure 1. Design of and Outcome of the Study.
NSAID denotes nonsteroidal antiinflammatory drug. Early withdrawal refers to the discontinuation of the randomized treatment,but with continued follow-up for recurrent bleeding.
*Patients in this group received naproxen.
†Patients in this group received low-dose aspirin.
N Engl J Med, Vol. 344, No. 13 · March 29, 2001 · www.nejm.org · 969
Downloaded from www.nejm.org at UNIVERSITEIT MAASTRICHT on September 2, 2009 . Copyright 2001 Massachusetts Medical Society. All rights reserved. The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne spect to demographic characteristics, the prevalence ofcoexisting conditions, the location and size of the ul- TABLE 1. BASE-LINE CHARACTERISTICS OF THE PATIENTS
cers, the severity of bleeding at presentation, and the prevalence of previous ulcer disease (Tables 1 and 2).
OMEPRAZOLE ERADICATION
Aspirin Group
CHARACTERISTIC
We enrolled 250 patients in the aspirin group (me- dian follow-up, 6 months; range, 2 to 6 months). A predefined level of drug compliance was achieved in 98 percent of the patients who received eradication therapy or omeprazole. Eradication therapy was ef- fective in 93 percent of the patients who received it.
Seven percent of the patients in the omeprazole group Five patients met the criteria for repeated endos- copy: three had hematemesis or melena, and two had Ulcers with active bleeding or nonbleeding only a drop in the hemoglobin level of at least 2 g per deciliter. All five patients underwent endoscopy.
Units of blood transfused before randomization Three of them were confirmed to have recurrent bleeding: two had been assigned to eradication ther- apy, and one to omeprazole (Table 3). Of the two patients who had recurrent bleeding after the eradi- Dose of aspirin used before the index event cation of H. pylori, one took a concomitant nonaspi- rin NSAID for musculoskeletal pain. The two pa- tients with a drop in hemoglobin of at least 2 g per deciliter had normal findings on endoscopy (one re- ceived eradication therapy, and one received omep- Previous upper gastrointestinal bleeding razole). The estimated probability of recurrent bleed- ing during the six-month study was 1.9 percent for *Plus–minus values are means ±SD. There were no significant differenc- patients who received eradication therapy and 0.9 per- cent for patients who received omeprazole (absolutedifference, 1.0 percent; 95 percent confidence inter-val for the difference, ¡1.9 to 3.9 percent) (Table 4).
The number of early withdrawals was similar in the two subgroups (Fig. 1). Four patients who receivederadication therapy died (one from myocardial in- razole) (Table 3). The two patients with a drop in farction, one from heart failure, one from acute renal hemoglobin of at least 2 g per deciliter had normal failure, and one from aspiration pneumonia), and four findings on endoscopy (one had received eradication patients who received omeprazole died (two from therapy and one had received omeprazole). The es- heart failure, one from aspiration pneumonia, and timated probability of recurrent bleeding during the six-month study was 18.8 percent for patients whoreceived eradication therapy and 4.4 percent for pa- Naproxen Group
tients who received omeprazole (absolute difference, We enrolled 150 patients in the naproxen group 14.4 percent; 95 percent confidence interval for the (median follow-up, 6 months; range, 10 days to difference, 4.4 to 24.4 percent; P=0.005) (Table 4 6 months). Predefined drug compliance was achieved and Fig. 2). In the Cox proportional-hazards model, in 88 percent of the patients who received eradica- only a history of ulcer disease was significantly asso- tion therapy and 87 percent of those who received ciated with an increased risk of recurrent bleeding omeprazole. Eradication therapy was effective in 91 (hazard ratio, 5.4; 95 percent confidence interval, 1.9 percent of the patients who received it. Ten percent to 15.5). After adjustment for the covariates of age, of the patients in the omeprazole group had a neg- the presence or absence of other illnesses, the size and location of the ulcers, and the presence or absence Eighteen patients met the criteria for repeated en- of a history of ulcer disease, the adjusted hazard ratio doscopy: 16 had hematemesis or melena, and 2 had was 7.1 (95 percent confidence interval, 1.9 to 27.6).
only a drop in hemoglobin of at least 2 g per deci- The number of early withdrawals was similar in the liter. All 18 patients underwent endoscopy, and 16 two subgroups (Fig. 1). Patients who withdrew early were confirmed to have recurrent bleeding (13 had did not have recurrent bleeding six months after the received eradication therapy and 3 had received omep- beginning of treatment. One patient in the omepra- 970 · N Engl J Med, Vol. 344, No. 13 · March 29, 2001 · www.nejm.org
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P R EV E N T I N G U P P E R GAST R O I N T E ST I N A L B L E E D I N G I N PAT I E N T S W I T H H E L I C O B AC T E R PY LO R I I N F EC T I O N
TABLE 2. BASE-LINE CHARACTERISTICS OF THE PATIENTS
TABLE 3. CHARACTERISTICS OF PATIENTS WITH
RECURRENT UPPER GASTROINTESTINAL BLEEDING.
OMEPRAZOLE ERADICATION
ASPIRIN NAPROXEN
CHARACTERISTIC
CHARACTERISTIC
Ulcers with active bleeding or nonbleeding Units of blood transfused before randomization *The ulcers were complicated by duodenal stenosis in two †One patient in the aspirin group and two in the naproxen group were in shock when they were admitted. None under- went a surgical intervention or died.
Previous upper gastrointestinal bleeding *Plus–minus values are means ±SD. There were no significant differenc- TABLE 4. KAPLAN–MEIER ESTIMATES OF THE LIKELIHOOD
OF RECURRENT UPPER GASTROINTESTINAL BLEEDING AT SIX †Coexisting conditions included congestive heart failure, hypertensive MONTHS IN THE ASPIRIN GROUP AND THE NAPROXEN GROUP.* heart disease, cerebrovascular disease, chronic obstructive airway disease,and cirrhosis.
ABSOLUTE DIFFERENCE
IN THE PROBABILITY OF
PROBABILITY OF RECURRENT BLEEDING
RECURRENT BLEEDING
(95% CI)†
zole group died of nasopharyngeal carcinoma three months after the beginning of treatment.
DISCUSSION
We set out to test the hypothesis that eradication of H. pylori is equivalent to maintenance treatment with omeprazole for the secondary prevention of †The two treatments were considered equivalent if the upper limit of the upper gastrointestinal bleeding in patients who are 95 percent confidence interval for the difference in the probability of recur- taking low-dose aspirin or other NSAIDs. The pa- rent bleeding at six months did not exceed 5 percent.
tients enrolled in this study were at risk for recurrentbleeding because they had a recent history of uppergastrointestinal bleeding.3,4 Our results show that inpatients infected with H. pylori who are taking low-dose aspirin, the eradication of H. pylori alone is as and who take aspirin, bleeding ulcers could be at- effective as maintenance treatment with omeprazole tributed to H. pylori, aspirin, or both. It is impossi- in preventing recurrent upper gastrointestinal bleed- ble to distinguish ulcers related to H. pylori from ul- ing. The equivalence was demonstrated by the ab- cers related to aspirin.15 One might argue that the sence of a clinically important difference between the eradication of H. pylori may not prevent ulcers relat- results of the two treatments. In contrast, we found ed to aspirin use. However, our findings suggest that that omeprazole is superior to the eradication of the eradication of H. pylori prevents recurrent bleed- H. pylori in preventing recurrent bleeding in patients ing in patients who are taking low-dose aspirin irre- with H. pylori infection who are taking naproxen.
spective of the location or cause of the ulcers. Thus, Among persons who are infected with H. pylori H. pylori and low-dose aspirin may have a synergistic N Engl J Med, Vol. 344, No. 13 · March 29, 2001 · www.nejm.org · 971
Downloaded from www.nejm.org at UNIVERSITEIT MAASTRICHT on September 2, 2009 . Copyright 2001 Massachusetts Medical Society. All rights reserved. The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne Figure 2. Cumulative Probability of Recurrent Bleeding in Users of Nonaspirin NSAIDs Who Received
Eradication Therapy for Helicobacter pylori plus Naproxen or Maintenance Omeprazole plus Naproxen.
The difference between groups was significant (P=0.005 by the log-rank test).
effect that increases the risk of bleeding from ulcers, aspirin.18 Alternatively, low-dose aspirin may provoke so that curing the infection would substantially low- bleeding from preexisting H. pylori–induced ulcers through its antiplatelet effect. Eradication of H. py- In contrast to the case with recurrent bleeding as- lori restores the mucosal barrier and thus the ability sociated with low-dose aspirin use, our results indi- to withstand the damaging effects of aspirin. In con- cate that the eradication of H. pylori is inferior to trast, other NSAIDs can induce peptic ulcers in the omeprazole in preventing recurrent bleeding associ- absence of H. pylori.19 It is possible that in H. pylori– ated with nonaspirin NSAIDs. Whether the eradica- infected long-term users of nonaspirin NSAIDs, tion of H. pylori can reduce the risk of ulcers appears many ulcers are induced by NSAIDs rather than by to vary according to the group of patients using non- aspirin NSAIDs. For people who have never been Previous endoscopic studies found that among us- treated with nonaspirin NSAIDs, we showed in an ear- ers of nonaspirin NSAIDs who were receiving omep- lier study that eradicating H. pylori before NSAID razole, those infected with H. pylori had less severe treatment was initiated reduces the risk of ulcers.16 mucosal injury than those who were not infected with For long-term users of nonaspirin NSAIDs, however, H. pylori.20,21 H. pylori augments the acid-suppress- the eradication of H. pylori has not been shown to ing effect of proton-pump inhibitors.22,23 It is unclear prevent gastroduodenal injury.17 Our current find- whether omeprazole can effectively prevent bleeding ings indicate that the eradication of H. pylori alone ulcers in users of nonaspirin NSAIDs who are not in- is not sufficient to prevent recurrent bleeding in sus- fected with H. pylori. Even so, augmentation of the ceptible long-term users of nonaspirin NSAIDs.
acid-suppressing effect of proton-pump inhibitors by The divergent outcomes in patients taking aspirin H. pylori cannot be used to justify the failure to treat and those taking other NSAIDs suggest that H. py- H. pylori infection in users of nonaspirin NSAIDs who lori may have a more important role in ulcer bleed- are receiving acid-suppressive therapy, since H. pylori ing associated with low-dose aspirin than in bleed- is a risk factor both for peptic ulcer and for cancer ing associated with other NSAIDs. One explanation is that low-dose aspirin may not be as ulcerogenic as Our study had several limitations. First, the abso- other NSAIDs. Other factors, such as H. pylori in- lute reduction in the risk of recurrent bleeding that fection, may need to be present for aspirin to induce was attributable to the eradication of H. pylori can- substantial gastroduodenal bleeding. Infection with not be determined, because a placebo group was not H. pylori has been shown to impair gastric adapta- included. However, our objective was to investigate tion to aspirin. The eradication of H. pylori restores whether the eradication of H. pylori could substitute this ability and increases the mucosal resistance to for omeprazole therapy in persons at high risk for 972 · N Engl J Med, Vol. 344, No. 13 · March 29, 2001 · www.nejm.org
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upper gastrointestinal bleeding. It would be unethi- rin, other nonsteroidal antiinflammatory drugs, and the risk of upper gas- cal to withhold treatment to prevent recurrence of trointestinal bleeding. N Engl J Med 2000;343:834-9.
4. Garcia Rodriguez LA, Jick H. Risk of upper gastrointestinal bleeding
ulcer bleeding from such patients. Second, therapy and perforation associated with individual non-steroidal anti-inflammatory with bismuth may have a slight protective effect on drugs. Lancet 1994;343:769-72. [Erratum, Lancet 1994;343:1048.]
5. Garcia Rodriguez LA, Ruigomez A. Secondary prevention of upper
mucosa, although it is very unlikely that one week of gastrointestinal bleeding associated with maintenance acid-suppressing bismuth could prevent complications of ulcers, such treatment in patients with peptic ulcer bleed. Epidemiology 1999;10:228- as bleeding. Third, we studied only naproxen and thus 32.
6. Russell RI. Helicobacter pylori and non-steroidal anti-inflammatory
did not address the differences in the ulcerogenicity drugs: ulcers and bleeding ulcers. Ital J Gastroenterol Hepatol 1999;31: of other NSAIDs. Since epidemiologic studies do not suggest that naproxen is associated with a higher risk 7. McCarthy DM. Helicobacter pylori and non-steroidal anti-inflammatory
drugs: does infection affect the outcome of NSAID therapy? Yale J Biol
of ulcer bleeding than are other commonly used non- aspirin NSAIDs,24 we believe it is reasonable to ex- 8. Aalykke C, Lauritsen JM, Hallas J, Reinholdt S, Krogfelt K, Lauritsen
K. Helicobacter pylori and risk of ulcer bleeding among users of nonsteroi-
tend our findings to other nonaspirin NSAIDs.
dal anti-inflammatory drugs: a case-control study. Gastroenterology 1999; In summary, we found that in patients who were infected with H. pylori and who were receiving low- 9. Labenz J, Peitz U, Kohl H, et al. Helicobacter pylori increases the risk
of peptic ulcer bleeding: a case-control study. Ital J Gastroenterol Hepatol
dose aspirin, the eradication of H. pylori is as effec- tive as maintenance therapy with omeprazole in pre- 10. Cullen DJ, Hawkey GM, Greenwood DC, et al. Peptic ulcer bleeding
venting recurrent upper gastrointestinal bleeding. In in the elderly: relative roles of Helicobacter pylori and non-steroidal anti-inflammatory drugs. Gut 1997;41:459-62.
the light of the increasing use of aspirin for cardio- 11. Santolaria S, Lanas A, Benito R , Perez-Aisa MP, Montoro M, Sainz R.
vascular prophylaxis, our findings suggest that patients Helicobacter pylori infection is a protective factor for bleeding gastric ulcers but not for bleeding duodenal ulcers in NSAID users. Aliment Pharmacol who are at risk for bleeding from ulcers should be tested for H. pylori infection and treated for it if the 12. O’Brien PC, Fleming TR. A multiple testing procedure for clinical tri-
infection is found. In contrast, we found that thera- als. Biometrics 1979;35:549-56.
13. Chan FKL, Sung JY, Suen R , et al. Eradication of H. pylori versus
py with omeprazole is superior to the eradication of maintenance acid suppression to prevent recurrent ulcer hemorrhage in H. pylori for the secondary prevention of upper gas- high risk NSAID users: a prospective randomized study. Gastroenterology trointestinal bleeding in H. pylori–infected users of 1998;114:A87. abstract.
14. Cox DR. Regression models and life-tables. J R Stat Soc [B] 1972;34:
naproxen, and presumably other nonaspirin NSAIDs.
187-220.
15. Graham DY. Nonsteroidal anti-inflammatory drugs, Helicobacter py-
lori, and ulcers: where we stand. Am J Gastroenterol 1996;91:2080-6.
Supported by research grants from the Research Grant Council (CUHK 16. Chan FK, Sung JJ, Chung SC, et al. Randomised trial of eradication
277/96M) and the Health Services Research Committee of Hong Kong of Helicobacter pylori before non-steroidal anti-inflammatory drug therapy to prevent peptic ulcers. Lancet 1997;350:975-9.
The interim results were presented at the plenary session of the annual 17. Hawkey CJ, Tulassay Z, Szczepanski L, et al. Randomised controlled
meeting of the American Gastroenterology Association, San Diego, Calif., trial of Helicobacter pylori eradication in patients on non-steroidal anti- inflammatory drugs: HELP NSAIDs study. Lancet 1998;352:1016-21. [Erratum, Lancet 1998;352:1634.] We are indebted to Drs. Michael K.K. Li, Gabriel Yip, K.S. Wong, 18. Konturek JW, Dembinski A, Konturek SJ, Stachura J, Domschke W.
Raymond Wong, Michael Fu, K.M. Chow, and Thomas S.T. Li for Infection of Helicobacter pylori in gastric adaptation to continued adminis-tration of aspirin in humans. Gastroenterology 1998;114:245-55.
their referrals; to Dr. K.F. To of the Department of Anatomical and 19. Laine L, Marin-Sorensen M, Weinstein WM. Nonsteroidal antiinflam-
Cellular Pathology at the Chinese University of Hong Kong for his- matory drug-associated gastric ulcers do not require Helicobacter pylori for tologic assessment; to Mr. Albert Cheung of the Center of Clinical their development. Am J Gastroenterol 1992;87:1398-402.
Trials and Epidemiological Research at the Chinese University of 20. Yeomans ND, Tulassay Z, Juhász L, et al. A comparison of omeprazole
Hong Kong and Professor S.K. Lo at the Polytechnic University for with ranitidine for ulcers associated with nonsteroidal antiinflammatory statistical advice; to Dr. C.C. Szeto of the Department of Medicine drugs. N Engl J Med 1998;338:719-26.
and Therapeutics at the Chinese University of Hong Kong for his 21. Hawkey CJ, Karrasch JA, Szczepañski L, et al. Omeprazole compared
valuable comments; and to Ms. Jessica Ching, Ms. M.Y. Yung, Ms. with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. N Engl J Med 1998;338:727-34.
Agnes Yu, Ms. Roxanna Liu, our surgical colleagues, and the nurs- 22. Labenz J, Tillenburg B, Peitz U, et al. Helicobacter pylori augments the
ing staff of the endoscopy center at the Prince of Wales Hospital for pH-increasing effect of omeprazole in patients with duodenal ulcer. Gas- troenterology 1996;110:725-32.
23. Gillen D, Wirz AA, Neithercut WD, Ardill JES, McColl KEL. Helico-
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