Original Article
A Controlled Study of Ranitidine for the Prevention of Recurrent Hemorrhage from Duodenal Ulcer
N Engl J Med 1994; 330:382-386February 10, 1994
- Abstract
Background
Hemorrhage is the most common complication of duodenal ulcer disease, but there is little information about the effectiveness and safety of long-term maintenance therapy with histamine H2-receptor blockers.
Methods
We conducted a double-blind study in patients with endoscopically documented hemorrhage from duodenal ulcers. Patients were randomly assigned to maintenance therapy with ranitidine (150 mg at night) or placebo and were followed for up to three years. Endoscopy was performed at base line (to document that the ulcers had healed), at exit from the study, and when a patient had persistent ulcer symptoms unrelieved by antacids or had gastrointestinal bleeding. Symptomatic relapses without bleeding were treated with ranitidine; if the ulcer healed within eight weeks, the patient resumed taking the assigned study medication.
Results
The two groups were similar at entry, which usually occurred about three months after the index hemorrhage. After a mean follow-up of 61 weeks, 3 of the 32 patients treated with ranitidine had recurrent hemorrhage, as compared with 12 of the 33 given placebo (P<0.05). Half the episodes of recurrent bleeding were asymptomatic. One patient in the ranitidine group withdrew from the study because of asymptomatic thrombocytopenia during the first month.
Conclusions
For patients whose duodenal ulcers heal after severe hemorrhage, long-term maintenance therapy with ranitidine is safe and reduces the risk of recurrent bleeding.
Media in This Article
Figure 1
Time to the Recurrence of Bleeding from Ulcer.Table 1
Characteristics of the Patients at Study Entry.Article Activity
- Article
Although hemorrhage is the most common complication of duodenal ulcer disease, there are few controlled trials of maintenance therapy in patients with documented hemorrhage1,2. We and others have found no previous randomized, controlled, double-blind study reporting a statistically significant reduction in complications of duodenal ulcer disease with medical treatment1-3. Several uncontrolled studies suggest that medical maintenance therapy can reduce the risk of recurrent hemorrhage4-7. One recent randomized, controlled trial in patients with a history of hemorrhage from duodenal ulcers found no difference in rates of recurrent hemorrhage between ranitidine and placebo8. The rate of hospital admissions for this complication has not significantly changed in the United States for at least 20 years, despite the fact that histamine H2-receptor antagonists have been widely used for 15 years9,10 and the incidence of uncomplicated duodenal ulcer disease has been declining for more than 30 years. Nevertheless, H2-receptor antagonists heal active duodenal ulcers within six to eight weeks in 75 to 85 percent of patients with symptoms and significantly reduce symptomatic recurrences of ulcer for up to two years in patients receiving maintenance therapy in randomized, controlled studies2,11. Patients with chronic symptomatic peptic ulcer disease have high rates of recurrence when they stop maintenance treatment2,11.
We compared the efficacy and safety of maintenance treatment with ranitidine with the effects of placebo for the prevention of recurrent bleeding from duodenal ulcers. We studied patients with a recent severe hemorrhage, the group most likely to benefit from maintenance treatment9,12,13.
Methods
In this multicenter, double-blind study, 65 patients with endoscopically documented hemorrhage from an ulcer and subsequent healing were studied as outpatients from May 1986 through December 1989. The study centers were the UCLA Center for the Health Sciences, the Center for Ulcer Research and Education, and Sunset Kaiser Permanente in Los Angeles; Valley Medical Center in Van Nuys, California; Highland Hospital in Oakland, California; and the Ochsner Medical Institutions in New Orleans. All the patients gave written informed consent before they entered the study. The study was approved by the research and human-studies committees at each center, all of which agreed that the study was ethically and scientifically justified and had substantial clinical relevance.
Study Population
The criteria for entry were an age of at least 18 years, a life expectancy of at least 3 years, upper gastrointestinal hemorrhage severe enough to lead to hospitalization, and a decline in the hematocrit of at least 5 percentage points (or the transfusion of red cells). The hemorrhage, from a duodenal or pyloric-channel ulcer, had to have been documented by endoscopy within one year before randomization. In addition, the healing of all ulcers was confirmed endoscopically within five days before randomization, and the use of ulcer medications (except antacids) was suspended for five days before randomization.
We excluded patients who had ingested ulcerogenic drugs (aspirin or other nonsteroidal antiinflammatory drugs) before the hemorrhage or who had pyloric obstruction, previous ulcer surgery except simple oversewing of a perforation, uncompensated or unstable medical conditions, hepatic disease, cancer (except of the skin), Zollinger-Ellison syndrome, hypersensitivity to any H2-receptor antagonist, or a history of drug or alcohol abuse that would interfere with participation in the study. Women of reproductive age who were pregnant, lactating, or not using birth control were excluded.
Protocol
Within five days before randomization, the patients underwent outpatient endoscopy to document healing (re-epithelialization) of the ulcer that had bled and the absence of other ulcers or major abnormalities of the upper gastrointestinal tract. All the patients underwent medical examination, medical history taking, and testing for fecal occult blood. Blood and urine samples were obtained. The patients received tablets to be taken nightly as maintenance therapy that were prepared, coded, and randomly distributed by Glaxo. The tablets, which were identical in appearance, contained 150 mg of ranitidine (Zantac) or placebo. Antacid tablets (Maalox) were also given to the patients for the relief of ulcer pain. Each patient kept a diary recording the occurrence of ulcer symptoms, evidence of gastrointestinal bleeding, the ingestion of medications, and the occurrence of non-ulcer illness.
Follow-up visits were scheduled for 1, 2, and 3 months after randomization and every 3 months thereafter for as long as 36 months. At each visit, the patient's diary was reviewed and a history was taken, with emphasis on symptoms of ulcer or evidence of gastrointestinal bleeding; laboratory tests were performed; and tests for fecal occult blood were evaluated. The study tablets and antacid tablets taken were counted, and a new supply of medications was issued.
There were unscheduled follow-up visits in the event of persistent symptoms of ulcer unrelieved by study medication and antacids, evidence of gastrointestinal bleeding, major non-ulcer illness, or hospitalization for any reason. The patients underwent endoscopy only if they reported persistent symptoms for at least seven days that suggested recurrent ulceration, if they had an upper gastrointestinal hemorrhage (hematemesis, melena, or hematochezia), or if they completed or withdrew from the study.
Recurrence, Retreatment, and Treatment Failure
In cases of recurrent symptomatic ulcers without bleeding, coded treatment was discontinued and the patient entered a relapse phase of the protocol, receiving open-label ranitidine (300 mg twice a day) and antacid pills as needed for the relief of pain. If there was endoscopic healing within eight weeks, the patient returned to the maintenance study and received the same coded treatment as before the symptomatic relapse. The relapse phase was counted as part of the three years of the study. If the ulcer did not heal within eight weeks, the coded treatment was considered a failure and the patient was withdrawn from the study.
Study treatment was considered to have failed in patients who had clinical evidence of upper gastrointestinal bleeding and endoscopic evidence of a bleeding ulcer or the stigmata of recent hemorrhage from ulcer,14-16 and these patients were withdrawn from the study. Patients were also withdrawn from the study if they had a third symptomatic recurrence of ulcer (without recurrent bleeding), a marked adverse reaction to a study medication that required its discontinuation, or a life-threatening illness that required hospitalization or the discontinuation of the coded treatment.
Data Collection and Statistical Analysis
Data were collected on standard forms by a research study nurse, checked for accuracy, and sent to the study data center, where they were prospectively entered into computer files and checked. An interim analysis was planned according to the methods of O'Brien and Fleming17 and was performed during the fourth year of study. Because chi-square analysis found a significant difference between the treatment groups in the incidence of recurrent hemorrhage from ulcer, the study was terminated. A comprehensive biostatistical analysis was then performed. All the patients who entered the study were included in the final analysis, whether they dropped out, had a failure of treatment, or had recurrent bleeding during the study.
The base-line characteristics of the study groups were compared by t-test and chi-square analysis. The primary outcome was the recurrence of hemorrhage from ulcer. This was analyzed in two ways, according to treatment group: by chi-square analysis and survival analysis. The chi-square test was used for comparisons of dichotomous outcomes, such as the presence or absence of recurrent bleeding. The time to recurrence was analyzed by product-limit survival analysis with the BMDP software program18. The equality of event curves between study groups was analyzed with the log-rank test (Mantel-Cox generalized Savage test) and the Breslow generalized Wilcoxon test18. For all analyses, a two-sided P value of less than 0.05 was considered to indicate statistical significance.
Results
The study groups were comparable at the time of randomization (Table 1Table 1
Characteristics of the Patients at Study Entry.). There were no significant differences in base-line characteristics. Most patients were men, and their mean age was 49 years. Two risk factors, cigarette smoking and alcohol consumption, were more frequent in the ranitidine group, but the difference from the placebo group was not significant. Although smoking may influence the recurrence of ulcer,11 no patient stopped smoking during the study.Recurrence of Ulcers and Dropout Rates
Table 2Table 2
Outcome According to Treatment Group. shows the outcomes in each study group. The mean follow-up time was 61 weeks. Twelve patients in the placebo group and three in the ranitidine group had the primary outcome, recurrent bleeding ulcers (P<0.05 by chi-square test). Because bleeding ulcers were significantly less frequent in the ranitidine group, the study was stopped before all patients had completed 36 months of follow-up.Symptomatic ulcers recurred in seven patients in the placebo group and four in the ranitidine group. Four other patients in the placebo group had asymptomatic ulcers on endoscopy at the end of the study, as compared with two in the ranitidine group. Although not all patients underwent endoscopy when they left the study, the proportion who did was similar in the placebo group (88 percent) and the ranitidine group (91 percent). During the study, 11 patients in the placebo group (33 percent) had endoscopically documented ulcers (symptomatic or asymptomatic) without recurrent bleeding, as compared with 6 patients in the ranitidine group (19 percent).
There was a higher dropout rate in the placebo group (27 percent) than in the ranitidine group (19 percent) (Table 2). In the first three months 15 percent of the placebo group (five patients) and 16 percent of the ranitidine group (five patients) dropped out of the study. An additional 12 percent (four patients) and 3 percent (one patient), respectively, dropped out during the remainder of the study. We considered all patients who discontinued follow-up because of medical reasons, adverse events, noncompliance or a refusal to return to the study center, or a move to have dropped out (Table 2).
Details of Ulcer and Bleeding Recurrences
Table 3Table 3
Outcomes of Symptomatic Recurrences of Ulcer and Recurrent Bleeding. gives details of recurrent painful ulcers and bleeding ulcers. The median time to recurrences of bleeding was similar in the two groups -- 8.5 months in the placebo group and 6.2 months in the ranitidine group. In the placebo group, 50 percent of the recurrent bleeding ulcers (6 of 12 patients) were “silent” -- i.e., not associated with antecedent or concurrent pain or other symptoms of ulcer. Of the three patients in the ranitidine group with recurrent bleeding, two also had dyspepsia. In both groups bleeding ulcers frequently recurred in the same location, as indicated by endoscopy and their occurrence at the site of previously documented scars.Time to Recurrent Bleeding
Figure 1Figure 1
Time to the Recurrence of Bleeding from Ulcer. shows the time to recurrent bleeding from ulcer. In the survival analysis, the fraction of patients without recurrent bleeding was significantly greater in the ranitidine group than in the placebo group. After the first year there was no recurrent bleeding in the ranitidine group. In contrast, recurrences continued in the placebo group throughout the study. Patients in the placebo group appeared to remain at comparable levels of risk during the entire study. According to survival analysis, approximately 50 percent of the patients in the placebo group had recurrent hemorrhage within two years, as compared with 10 percent of the patients given ranitidine (P<0.02) (Figure 1).Complications and Adverse Events
Of the 65 patients who entered the study with a recent upper gastrointestinal hemorrhage from a duodenal ulcer, 15 had a recurrent hemorrhage during the study period. One other patient in whom a nonbleeding visible vessel was found on endoscopy was withdrawn for symptoms of ulcer recurrence without bleeding. No other complications of ulcer disease were found.
One patient receiving ranitidine and none receiving placebo had adverse events leading to withdrawal from the study. The episode of reversible thrombocytopenia in the patient who withdrew appeared to be related to ranitidine, although the patient refused rechallenge with it. There were no significant differences between the two groups on other laboratory tests. There were no deaths during the study.
Discussion
Our study was designed to test the hypothesis that the high risk of recurrent hemorrhage from ulcer in patients with chronic duodenal ulcer disease could be significantly reduced by the long-term administration of an H2-receptor antagonist. We chose to study patients with prior documented duodenal hemorrhage because there were no data from randomized, controlled trials indicating that medical treatment prevents this complication and because there is a high risk of recurrent hemorrhage in this group13.
Several risk factors significantly increase the likelihood of symptomatic recurrence of ulcer in studies of patients with uncomplicated disease (i.e., without hemorrhage) who are given placebo1,5,6,8,20-22. In a recent two-year maintenance study of patients with symptomatic ulcers, these risk factors were alcohol consumption, smoking, early onset of ulcers or repeated ulcers, and evidence of duodenal scarring or erosion on index endoscopy11. The incidence of these risk factors was similar in the two treatment groups in our study. Long-term maintenance therapy with an H2-receptor blocker has often been recommended in such patients and, by extrapolation, in patients with previous complications such as hemorrhage4,5,12,22,23. The rationale is that patients with recurrent, symptomatic duodenal ulceration are at increased risk for recurrence and future complications such as hemorrhage4,5,12,22,23. The problems with continuous maintenance therapy are the cost, patient compliance, and uncertainty about the safety of very-long-term acid suppression24,25. Unfortunately, patients with previous complications of ulcers have not been the primary focus of most maintenance studies, and they have been excluded from most randomized, controlled trials of maintenance therapy3,6,8.
Murray et al. recently reported on a randomized, double-blind, controlled trial of medical maintenance therapy for patients with hemorrhage from duodenal ulcers8. Their study did not find any difference in the incidence of recurrent hemorrhage between the placebo and the ranitidine groups. During that two-year trial, ulcerations or severe erosions (symptomatic or asymptomatic) recurred in 24 of the 40 patients studied, but hemorrhage recurred in only 2. In the light of our data, this was a surprisingly low frequency of recurrent bleeding in the patients who received placebo. A few other studies have examined the natural history of peptic ulcer disease and the possible efficacy of maintenance therapy with H2-receptor blockers in preventing complications4-7,12. However, these either focused on patients with uncomplicated disease4,12 or were nonrandomized or retrospective studies5-7.
Ulcer surgery is the only treatment besides maintenance medical therapy that has significantly reduced the risk of recurrent hemorrhage13,24,26. Ulcer surgery has risks, however, particularly in older patients. Our controlled study demonstrates that patients with a documented history of hemorrhage from duodenal ulcers have a high risk of recurrence that can be significantly reduced by continuous medical therapy. Conversely, according to survival analysis, with placebo the risk of bleeding was high over the 36 months of follow-up and did not decrease during the study. Intermittent medical treatment for symptomatic recurrences of ulcer in the placebo group apparently did not reduce the risk of subsequent hemorrhage. This may be because about 50 percent of the episodes of recurrent bleeding in both study groups were silent, unaccompanied by pain or other symptoms of ulcer.
These data have enormous public health implications. Patients with ulcer and prior hemorrhage have frequent recurrences when they are not receiving maintenance therapy, and they present with recurrent hemorrhage3,13. These patients account for a substantial portion of the hospital admissions for hemorrhage from ulcer each year. The subgroup of patients with documented hemorrhage is the most likely to benefit from maintenance medical therapy or elective surgery2,3,13. If these patients do receive long-term medical treatment, it could markedly reduce hospital admissions for hemorrhage from duodenal ulcer and reduce the cost of care24,25,27.
Supported in part by grants (AM 33273 and 41301 -- Human Studies CORE) from the National Institute of Diabetes and Digestive and Kidney Diseases and by Glaxo, Inc.
We are indebted to Assumpta Oturu for assistance in the preparation of the manuscript and to our colleagues who referred their patients for inclusion in this study.
Source Information
From the Center for Ulcer Research and Education, UCLA, and the West Los Angeles Veterans Affairs Medical Center, Los Angeles (D.M.J., S.C., T.O.G.K., G.R., M.E.J., T.R., G.V.D.); Kaiser Permanente, Los Angeles (H.F.); Valley Medical Center, Van Nuys, Calif. (G.M.); Ochsner Medical Institutions, New Orleans (J.S.); and Highland Hospital, Oakland, Calif. (M.S.).
Address reprint requests to Dr. Jensen at 44-133 CHS, GI Division, UCLA Center for the Health Sciences, Los Angeles, CA 90024-1684.
- References
References
1
Feldman M ,Burton ME . Histamine2-receptor antagonists: standard therapy for acid-peptic diseases. N Engl J Med 1990;323:1672-1680
Full Text | Web of Science | Medline2
Feldman M ,Burton ME . Histamine2-receptor antagonists: standard therapy for acid-peptic diseases. N Engl J Med 1990;323:1749-1755
Full Text | Web of Science | Medline3
Jensen DM ,You S ,Jensen ME , et al. Randomized controlled study of ranitidine maintenance for patients with a recent severe duodenal ulcer hemorrhage. Gastroenterology 1990;98:Suppl:A65-A65 abstract.4
Boyd EJ ,Wilson JA ,Wormsley KG . Safety of ranitidine maintenance treatment of duodenal ulcer. Scand J Gastroenterol 1984;19:394-400
Web of Science | Medline5
Elashoff JD ,Van Deventer G ,Reedy TJ , et al. Long-term follow-up of duodenal ulcer patients. J Clin Gastroenterol 1983;5:509-515
CrossRef | Web of Science | Medline6
Wade AG ,Rowley-Jones D . Long term management of duodenal ulcer in general practice: how best to use cimetidine? BMJ 1988;296:971-974
CrossRef | Web of Science | Medline7
Capria A ,Geloni M ,Federici G ,Palumbo A ,Corsini G . The long-term treatment of peptic ulcer after a bleeding episode. Int J Tissue React 1987;9:439-442
Web of Science | Medline8
Murray WR ,Cooper G ,Laferla G ,Rogers P ,Archibald M . Maintenance ranitidine treatment after haemorrhage from a duodenal ulcer: a 3-year study. Scand J Gastroenterol 1988;23:183-187
CrossRef | Web of Science | Medline9
Kurata JH ,Honda GD ,Frankl H . Hospitalization and mortality rates for peptic ulcers: a comparison of a large health maintenance organization and United States data. Gastroenterology 1982;83:1008-1016
Web of Science | Medline10
Kurata JH ,Corboy ED . Current peptic ulcer time trends: an epidemiological profile. J Clin Gastroenterol 1988;10:259-268
CrossRef | Web of Science | Medline11
Van Deventer GM ,Elashoff JD ,Reedy TJ ,Schneidman D ,Walsh JH . A randomized study of maintenance therapy with ranitidine to prevent the recurrence of duodenal ulcer. N Engl J Med 1989;320:1113-1119
Full Text | Web of Science | Medline12
Walan A ,Bianchi-Porro G ,Hentschel E ,Bardhan KD ,Delattre M . Maintenance treatment with cimetidine in peptic ulcer disease for up to 4 years. Scand J Gastroenterol 1987;22:397-405
CrossRef | Web of Science | Medline13
Jensen DM, Machicado GA, Kovacs TOG, Randall GM, Reedy T, CURE Hemostasis Research Group 14
Jensen DM. Endoscopic control of nonvariceal upper gastrointestinal hemorrhage. In: Yamada T, Alpers D, Owyang C, Powell D, Silverstein F, eds. Textbook of gastroenterology. Vol. 2. Philadelphia: J.B. Lippincott, 1991:2618-34.
15
Swain CP ,Bown SG ,Storey DW ,Kirkham JS ,Northfield TC ,Salmon PR . Controlled trial of argon laser photocoagulation in bleeding peptic ulcers. Lancet 1981;2:1313-1316
CrossRef | Web of Science | Medline16
Swain CP ,Kirkham JS ,Salmon PR ,Bown SG ,Northfield TC . Controlled trial of Nd-YAG laser photocoagulation in bleeding peptic ulcers. Lancet 1986;1:1113-1117
CrossRef | Web of Science | Medline17
O'Brien PC ,Fleming TR . A multiple testing procedure for clinical trials. Biometrics 1979;35:549-556
CrossRef | Web of Science | Medline18
Dixon WJ, ed. BMDP statistical software. Berkeley: University of California Press, 1985.
19
Samloff IM . Pepsinogens I and II: purification from gastric mucosa and radioimmunoassay in serum. Gastroenterology 1982;82:26-33
Web of Science | Medline20
Alstead EM ,Ryan FP ,Holdsworth CD ,Ashton MG ,Moore M . Ranitidine in the prevention of gastric and duodenal ulcer relapse. Gut 1983;24:418-420
CrossRef | Web of Science | Medline21
Silvis SE . Final report on the United States Multicenter Trial comparing ranitidine to cimetidine as maintenance therapy following healing of duodenal ulcer. J Clin Gastroenterol 1985;7:482-487
CrossRef | Web of Science | Medline22
Gough KR ,Korman MG ,Bardhan KD , et al. Ranitidine and cimetidine in prevention of duodenal ulcer relapse: a double-blind, randomised, multicentre, comparative trial. Lancet 1984;2:659-662
CrossRef | Web of Science | Medline23
Strum WB . Prevention of duodenal ulcer recurrence. Ann Intern Med 1986;105:757-761
Web of Science | Medline24
Sonnenberg A . Comparison of different strategies for treatment of duodenal ulcer. BMJ 1985;290:1185-1187
CrossRef | Web of Science | Medline25
Jensen DM . Economic assessment of peptic ulcer disease treatments. Scand J Gastroenterol Suppl 1988;146:214-224
CrossRef | Medline26
Debas HT, Orloff SL. Surgery for peptic ulcer disease. In: Yamada T, Alpers D, Owyang C, Powell D, Silverstein F, eds. Textbook of gastroenterology. Vol. 1. Philadelphia: J.B. Lippincott, 1991:1379-98.
27
Jensen DM ,Osterhaus J ,You S , et al. Health and economic impact of ranitidine in a randomized controlled study for patients with a recent severe duodenal ulcer hemorrhage. Gastroenterology 1990;98:Suppl:A5-A5 abstract.
- Citing Articles (43)
Citing Articles
1
Loren Laine, Dennis M Jensen. (2012) Management of Patients With Ulcer Bleeding. The American Journal of Gastroenterology
CrossRef2
Naoki Chiba. 2010. Ulcer Disease and Helicobacter pylori Infection: Etiology and Treatment. , 102-138.
CrossRef3
Kassem Barada, Heitham Abdul-Baki, Ihab I. El Hajj, Jana G. Hashash, Peter H. Green. (2009) Gastrointestinal Bleeding in the Setting of Anticoagulation and Antiplatelet Therapy. Journal of Clinical Gastroenterology 43:1, 5-12
CrossRef4
E. L. MASSÓ GONZÁLEZ, L. A. GARCÍA RODRÍGUEZ. (2008) Proton pump inhibitors reduce the long-term risk of recurrent upper gastrointestinal bleeding: an observational study. Alimentary Pharmacology & Therapeutics 28:5, 629-637
CrossRef5
Javier P. Gisbert, Xavier Calvet, Faust Feu, Felipe Bory, Angel Cosme, Pedro Almela, Santos Santolaria, Rosario Aznárez, Manuel Castro, Nuria Fernández, Rafael García-Grávalos, Nuria Cañete, Adolfo Benages, Miguel Montoro, Fernando Borda, Angeles Pérez-Aisa, Jose María Piqué. (2007) Eradication of Helicobacter pylori for the Prevention of Peptic Ulcer Rebleeding. Helicobacter 12:4, 279-286
CrossRef6
J.P. Gisbert. (2005) Prevención de la recidiva hemorrágica por úlcera péptica mediante la erradicación de Helicobacter pylori. Gastroenterología y Hepatología 28:9, 567-575
CrossRef7
Javier P Gisbert, Sam Khorrami, Fernando Carballo, Xavier Calvet, Emili Gené, Enrique Dominguez-Muñoz, Javier P Gisbert. 2004. Helicobacter pylori eradication therapy vs. antisecretory non-eradication therapy (with or without long-term maintenance antisecretory therapy) for the prevention of recurrent bleeding from peptic ulcer. .
CrossRef8
J. P. Gisbert, S. Khorrami, F. Carballo, X. Calvet, E. Gene, E. Dominguez-Munoz. (2004) Helicobacter pylori eradication therapy vs. antisecretory non-eradication therapy for the prevention of recurrent bleeding from peptic ulcer. Alimentary Pharmacology and Therapeutics 19:6, 617-629
CrossRef9
Uday Chand Ghoshal, Rakesh Aggarwal, Chalamalasetty Sreenivasa Baba. (2003) Recurrent duodenal ulcer haemorrhage: a pharmacoeconomic comparison of various management strategies. Expert Opinion on Pharmacotherapy 4:9, 1593-1603
CrossRef10
JP Gisbert, S Khorrami, F Carballo, X Calvet, E Gené, JE Dominguez-Muñoz. 2003. H. pylori eradication therapy vs. antisecretory non-eradication therapy (with or without long-term maintenance antisecretory therapy) for the prevention of recurrent bleeding from peptic ulcer. .
CrossRef11
Yasushi Fukushima, Takayuki Shindo, Motonobu Anai, Toshihito Saitoh, Yuhui Wang, Midori Fujishiro, Yoshio Ohashi, Takehide Ogihara, Kouichi Inukai, Hiraku Ono, Hideyuki Sakoda, Yukiko Kurihara, Miho Honda, Nobuhiro Shojima, Harumi Fukushima, Yukiko Haraikawa-Onishi, Hideki Katagiri, Yasuhito Shimizu, Masao Ichinose, Takashi Ishikawa, Masao Omata, Ryozo Nagai, Hiroki Kurihara, Tomoichiro Asano. (2003) Structural and functional characterization of gastric mucosa and central nervous system in histamine H2 receptor-null mice. European Journal of Pharmacology 468:1, 47-58
CrossRef12
V. K. Sharma, A. V. Sahai, F. A. Corder, C. W. Howden. (2001) Helicobacter pylori eradication is superior to ulcer healing with or without maintenance therapy to prevent further ulcer haemorrhage. Alimentary Pharmacology and Therapeutics 15:12, 1939-1947
CrossRef13
Claus Aalykke, Karsten Lauritsen. (2001) Epidemiology of NSAID-related gastroduodenal mucosal injury. Best Practice & Research Clinical Gastroenterology 15:5, 705-722
CrossRef14
R.H. Hunt, K. Sumanac, J.-Q. Huang. (2001) Review article: should we kill or should we save Helicobacter pylori?. Alimentary Pharmacology and Therapeutics 15:s1, 51-59
CrossRef15
Robert M. Rodriguez, Howard L. Corwin, Andrew Gettinger, Michael J. Corwin, Dean Gubler, Ronald G. Pearl. (2001) Nutritional deficiencies and blunted erythropoietin response as causes of the Amemia of critical illness. Journal of Critical Care 16:1, 36-41
CrossRef16
Rinaldo Pellicano, Sergio Peyre, Nicola Leone, Alessandro Repici, Claudio De Angelis, Roberto Rizzi, Mario Rizzetto, Antonio Ponzetto. (2001) The Effect of the Eradication of Helicobacter pylori Infection on Hemorrhage Because of Duodenal Ulcer. Journal of Clinical Gastroenterology 32:3, 222-224
CrossRef17
Kam-Chuen Lai, Wai-Mo Hui, Wai-Man Wong, Benjamin Chun-Yu Wong, Wayne Hsing Cheng Hu, Chi-Kong Ching, Shiu-Kum Lam. (2000) Treatment of Helicobacter pylori in patients with duodenal ulcer hemorrhage- a long-term randomized, controlled study. The American Journal of Gastroenterology 95:9, 2225-2232
CrossRef18
Thomas J. Savides, Dennis M. Jensen. (2000) THERAPEUTIC ENDOSCOPY FOR NONVARICEAL GASTROINTESTINAL BLEEDING. Gastroenterology Clinics of North America 29:2, 465-487
CrossRef19
C.J. Hawkey. (2000) Management of gastroduodenal ulcers caused by non-steroidal anti-inflammatory drugs. Best Practice & Research Clinical Gastroenterology 14:1, 173-192
CrossRef20
Joachim Labenz. (2000) Consequences of Helicobacter pylori cure in ulcer patients. Best Practice & Research Clinical Gastroenterology 14:1, 133-145
CrossRef21
Ulrich Halm, Farahnaz Halm, Daniela Thein, Friedrich W. Mohr, Joachim M??ssner. (2000) Helicobacter pylori infection: A risk factor for upper gastrointestinal bleeding after cardiac surgery?. Critical Care Medicine 28:1, 110-113
CrossRef22
Loren Laine, Sean Harper, Thomas Simon, Richard Bath, John Johanson, Howard Schwartz, Steven Stern, Hui Quan, James Bolognese. (1999) A randomized trial comparing the effect of rofecoxib, a cyclooxygenase 2–specific inhibitor, with that of ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis. Gastroenterology 117:4, 776-783
CrossRef23
Kovacs, Campbell, Richter, Haber, Jennings, Rose. (1999) Double-blind comparison of lansoprazole 15 mg, lansoprazole 30 mg and placebo as maintenance therapy in patients with healed duodenal ulcers resistant to H2-receptor antagonists. Alimentary Pharmacology and Therapeutics 13:7, 959-967
CrossRef24
C. J. Hawkey. (1999) Helicobacter pylori, NSAIDs and cognitive dissonance. Alimentary Pharmacology and Therapeutics 13:6, 695-702
CrossRef25
Paul E Marik. (1999) Stress Ulcer Prophylaxis: A Practical Approach. Journal of Intensive Care Medicine 14:1, 1-8
CrossRef26
CJ Hawkey, Z Tulassay, L Szczepanski, CJ van Rensburg, A Filipowicz-Sosnowska, A Lanas, CM Wason, RA Peacock, KRW Gillon. (1998) Randomised controlled trial of Helicobacter pylori eradication in patients on non-steroidal anti-inflammatory drugs: HELP NSAIDs study. The Lancet 352:9133, 1016-1021
CrossRef27
Giuseppe Macri, Stefano Milani, Elisabetta Surrenti, Maria Teresa Passaleva, Giuseppe Salvadori, Calogero Surrenti. (1998) Eradication of helicobacter pylori reduces the rate of duodenal ulcer rebleeding: a long-term follow-up study. The American Journal of Gastroenterology 93:6, 925-927
CrossRef28
Hawkey, Christopher J., Karrasch, Jeffrey A., Szczepañski, Leszek, Walker, Donald G., Barkun, Alan, Swannell, Anthony J., Yeomans, Neville D., . (1998) Omeprazole Compared with Misoprostol for Ulcers Associated with Nonsteroidal Antiinflammatory Drugs. New England Journal of Medicine 338:11, 727-734
Full Text29
Cullen, Bardhan, Eisner, Kogut, Peacock, Thomson, Hawkey. (1998) Primary gastroduodenal prophylaxis with omeprazole for non-steroidal anti-inflammatory drug users. Alimentary Pharmacology and Therapeutics 12:2, 135-140
CrossRef30
K. MARAZOVA, E. KLOUCHEK, A. POPOV, CH. IVANOV, I. KRUSHKOV. (1997) Gastroprotective Effect of MX1 (a Novel Salt of the Active Metabolite of Roxatidine with a Complex of Bismuth and Citric Acid) Against Stress Ulcers in Rats. Journal of Pharmacy and Pharmacology 49:8, 791-795
CrossRef31
Shinichi OTA. (1997) Current Regimen for Peptic Ulcer Treatment. Digestive Endoscopy 9:3, 163-166
CrossRef32
O. M. P. Jolobe. (1997) Reduced long-term survival following major peptic ulcer haemorrhage. British Journal of Surgery 84:6, 889-889
CrossRef33
(1996) Famotidine to Prevent Peptic Ulcer Caused by NSAIDs. New England Journal of Medicine 335:17, 1322-1323
Full Text34
J. H. L. M. Groenendael, H. M. Markusse, B. A. C. Dijkmans, F. C. Breedveld. (1996) The effect of ranitidine on NSAID related dyspeptic symptoms with and without peptic ulcer disease of patients with rheumatoid arthritis and osteoarthritis. Clinical Rheumatology 15:5, 450-456
CrossRef35
E. K. W. Ng, S. C. S. Chung, J. T. F. Lau, J. J. Y. Sung, J. W. C. Leung, S. A. Raimes, A. C. W. Chan, A. K. C. Li. (1996) Risk of further ulcer complications after an episode of peptic ulcer bleeding. British Journal of Surgery 83:6, 840-844
CrossRef36
Geoffrey C. Jiranek, Richard A. Kozarek. (1996) A COST-EFFECTIVE APPROACH TO THE PATIENT WITH PEPTIC ULCER BLEEDING. Surgical Clinics of North America 76:1, 83-103
CrossRef37
Wood, Alastair J.J., , Walsh, John H., Peterson, Walter L., . (1995) The Treatment of Helicobacter pylori Infection in the Management of Peptic Ulcer Disease. New England Journal of Medicine 333:15, 984-991
Full Text38
J. H. WALSH. (1995) Unanswered questions about Helicobacter pylori. Alimentary Pharmacology & Therapeutics 9, 31-37
CrossRef39
W. L. PETERSON. (1995) The role of acid in upper gastrointestinal haemorrhage due to ulcer and stress-related mucosal damage. Alimentary Pharmacology & Therapeutics 9, 43-46
CrossRef40
R.P. Walt. (1995) Preventing admissions for gastrointestinal bleeding. The Lancet 345:8942, 77-78
CrossRef41
Laine, LorenPeterson, Walter L.. (1994) Bleeding Peptic Ulcer. New England Journal of Medicine 331:11, 717-727
Full Text42
(1994) Ranitidine and Recurrent Hemorrhage from Duodenal Ulcer. New England Journal of Medicine 331:1, 53-54
Full Text43
Peterson, Walter L., . (1994) Prevention of Upper Gastrointestinal Bleeding. New England Journal of Medicine 330:6, 428-429
Full Text
- Letters
