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Intravenous Esomeprazole for Prevention of Recurrent Peptic Ulcer Bleeding
A Randomized Trial
- Joseph J.Y. Sung, MD;
- Alan Barkun, MD;
- Ernst J. Kuipers, MD;
- Joachim Mössner, MD;
- Dennis M. Jensen, MD;
- Robert Stuart, MD;
- James Y. Lau, MD;
- Henrik Ahlbom, BSc;
- Jan Kilhamn, MD;
- Tore Lind, MD; and
- for the Peptic Ulcer Bleed Study Group*
- From the Institute of Digestive Diseases, Chinese University of Hong Kong, Hong Kong, China; McGill University Health Center, Montreal, Quebec, Canada; Erasmus MC University Medical Center, Rotterdam, the Netherlands; Medizinische Klinik und Poliklinik II, University of Leipzig, Leipzig, Germany; David Geffen School of Medicine at the University of California, Los Angeles, and Center for Ulcer Research and Education (CURE), Digestive Diseases Research Center, Los Angeles, California; Glasgow Royal Infirmary, Glasgow, United Kingdom; and AstraZeneca Research and Development, Mölndal, Sweden.
Abstract
Background: Use of proton-pump inhibitors in the management of peptic ulcer bleeding is controversial because discrepant results have been reported in different ethnic groups.
Objective: To determine whether intravenous esomeprazole prevents recurrent peptic ulcer bleeding better than placebo in a multiethnic patient sample.
Design: Randomized trial conducted between October 2005 and December 2007; patients, providers, and researchers were blinded to group assignment.
Setting: 91 hospital emergency departments in 16 countries.
Patients: Patients 18 years or older with peptic ulcer bleeding from a single gastric or duodenal ulcer showing high-risk stigmata.
Intervention: Intravenous esomeprazole bolus, 80 mg, followed by 8-mg/h infusion, over 72 hours or matching placebo, each given after successful endoscopic hemostasis. Intervention was allocated by computer-generated randomization. After infusion, both groups received oral esomeprazole, 40 mg/d, for 27 days.
Measurements: The primary end point was rate of clinically significant recurrent bleeding within 72 hours. Recurrent bleeding within 7 and 30 days, death, surgery, endoscopic re-treatment, blood transfusions, hospitalization, and safety were also assessed.
Results: Of 767 patients randomly assigned, 764 provided data for an intention-to-treat analysis (375 esomeprazole recipients and 389 placebo recipients). Fewer patients receiving intravenous esomeprazole (22 of 375) had recurrent bleeding within 72 hours than those receiving placebo (40 of 389) (5.9% vs. 10.3%; difference, 4.4 percentage points [95% CI, 0.6% to 8.3%]; P = 0.026). The difference in bleeding recurrence remained significant at 7 days and 30 days (P = 0.010). Esomeprazole also reduced endoscopic re-treatment (6.4% vs. 11.6%; difference, 5.2 percentage points [95% CI of difference, 1.1 percentage points to 9.2 percentage points]; P = 0.012), surgery (2.7% vs. 5.4%), and all-cause mortality rates (0.8% vs. 2.1%) more than placebo, although differences for the latter 2 comparisons were not significant. About 10% and 40% of patients in both groups reported serious and nonserious adverse events, respectively.
Limitation: Endoscopic therapy was not completely standardized; some patients received epinephrine injection, thermal coagulation, or hemoclips alone, whereas others received combination therapy, but there were similar proportions with single therapy in each group.
Conclusion: High-dose intravenous esomeprazole given after successful endoscopic therapy to patients with high-risk peptic ulcer bleeding reduced recurrent bleeding at 72 hours and had sustained clinical benefits for up to 30 days.
Primary Funding Source: AstraZeneca Research and Development.
Article and Author Information
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Acknowledgment: The authors acknowledge the contribution of all investigators who participated in this study (see the Appendix Table) and thank Dr. Madeline Frame for medical writing assistance sponsored by AstraZeneca. They also thank Dr. Grigoris Leontiadis and Dr. Colin Howden for providing data from the second update to their Cochrane meta-analysis on PPI and bleeding ulcers.
View this table:Appendix Table. Investigators and Study Centers -
Grant Support: AstraZeneca Research and Development.
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Potential Financial Conflicts of Interest: Employment: H. Ahlbom (AstraZeneca), J. Kilhamn (AstraZeneca), T. Lind (AstraZeneca). Consultancies: A. Barkun (AstraZeneca, Olympus), E.J. Kuipers (AstraZeneca), J. Mössner (AstraZeneca), J.Y. Lau (AstraZeneca). Honoraria: J.J.Y. Sung (AstraZeneca, Nycomed), A. Barkun (Olympus, AstraZeneca), J. Mössner (AstraZeneca), J.Y. Lau (AstraZeneca, Nycomed). Stock ownership or options (other than mutual funds): J. Kilhamn (AstraZeneca). Grants received: E.J. Kuipers (AstraZeneca). Other: AstraZeneca manufactures esomeprazole, the drug under study in this article.
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Reproducible Research Statement: Study protocol: Further information is available from Dr. Lind (e-mail, tore.lind{at}astrazeneca.com). Statistical code: Further information is available from Mr. Ahlbom (e-mail, henrik.ahlbom{at}astrazeneca.com). Data set: Further information is available from Mr. Ahlbom (e-mail, henrik.ahlbom{at}astrazeneca.com).
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Requests for Single Reprints: Joseph J.Y. Sung MD, PhD, Institute of Digestive Diseases, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, China; e-mail, e-mail, joesung{at}cuhk.edu.hk.
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Current Author Addresses: Dr. Sung: Institute of Digestive Diseases, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, China.
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Dr. Barkun: Division of Gastroenterology, McGill University Health Centre, Room D16.257B, 1650 Cedar Avenue, Montreal, Quebec H3G 1A4, Canada.
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Dr. Kuipers: Erasmus MC University Medical Center, Departments of Internal Medicine and Gastroenterology & Hepatology, Dr Molewaterplein 40, 3015 GD Rotterdam, Netherlands.
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Dr. Mössner: Universitätsklinikum der Universität Leipzig, Medizinische Klinik II, Philipp-Rosenthal Strasse 27, 04103 Leipzig, Germany.
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Dr. Jensen: David Geffen School of Medicine at UCLA and CURE Digestive Diseases Research Center, Suite 365A, Los Angeles, CA 90095.
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Dr. Stuart: Department of Surgery, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 OSF, United Kingdom.
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Dr. Lau: Gastroenterology Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong, China.
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Mr. Ahlbom and Drs. Kilhamn and Lind: AstraZeneca Research and Development, Pepparedsleden 1, 431 83 Mölndal, Sweden.
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Author Contributions: Conception and design: J.J.Y. Sung, A. Barkun, E.J. Kuipers, J. Mössner, D.M. Jensen, R. Stuart, J.Y. Lau, T. Lind.
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Analysis and interpretation of the data: J.J.Y. Sung, A. Barkun, E.J. Kuipers, J. Mössner, D.M. Jensen, R. Stuart, J.Y. Lau, H. Ahlbom, J. Kilhamn, T. Lind.
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Drafting of the article: J.J.Y. Sung, A. Barkun, E.J. Kuipers, R. Stuart, J.Y. Lau, T. Lind.
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Critical revision of the article for important intellectual content: J.J.Y. Sung, A. Barkun, E.J. Kuipers, J. Mössner, D.M. Jensen, R. Stuart, J.Y. Lau, J. Kilhamn.
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Final approval of the article: J.J.Y. Sung, A. Barkun, E.J. Kuipers, J. Mössner, D.M. Jensen, R. Stuart, J.Y. Lau, T. Lind.
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Provision of study materials or patients: J.J.Y. Sung, E.J. Kuipers, J. Mössner, J.Y. Lau.
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Statistical expertise: J.J.Y. Sung, A. Barkun, H. Ahlbom.
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Administrative, technical, or logistic support: J.J.Y. Sung, J. Kilhamn, T. Lind.
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Collection and assembly of data: J.J.Y. Sung, E.J. Kuipers, R. Stuart, J.Y. Lau, J. Kilhamn, T. Lind.
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Other: D.M. Jensen, R. Stuart (end point committee members).
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ClinicalTrials.gov registration number: NCT00251979.
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↵* For a list of study centers and principal investigators in the Peptic Ulcer Bleed Study Group, see the Appendix Table.
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